Miriam E. Tucker

GRAPEVINE, TEX.  – In a prospective evaluation of 59 children with venous malformations, the long-pulsed neodymium:YAG laser was more effective in treating mucosal venous malformations than lesions on the limbs.

Venous malformations present in many forms that vary in depth, location, and extent, and treatment is largely symptomatic rather than curative. "It is, therefore, important that treatments given are effective in improving the symptoms medium or long term, with as few side effects as possible," said Dr. Stratos Sofos of Alder Hey Children's Hospital in Liverpool, England.

The long-pulsed Nd:YAG laser has become popular for the treatment of small- to medium-size vessels. Its longer pulse duration provides deeper penetration and weaker melanin absorption, allowing it to heat the vessels slowly and uniformly, thus avoiding the vessel rupture with subsequent purpura and hyperpigmentation that can occur with other lasers.

However, published data do not address whether treatment with a long-pulsed Nd:YAG laser provides long-term symptom relief, nor which types of venous malformations respond better than do others, Dr. Sofos said at the annual meeting of the American Society for Laser Medicine and Surgery.

All children who met criteria such as functional impairment, large facial deformities, and painful or bleeding lesions were treated with Candela Corp.'s GentleYAG 1064-nm laser. They received one to three treatments under general anesthesia, delivered in six to eight weekly intervals. Prior to Nd:YAG laser treatment, 32 of the children had received multiple other treatments, including pulsed dye lasers and sclerotherapy.

The 59 patients were aged 2-18 years (mean, 12.3 years). Venous malformations were present on the head and neck in 23, of which 18 (31% of the total) were mucosal. Malformations were on the upper limbs in 15 and on the lower limbs in 18 (total with limb lesions, 56%). The other three had lesions on the chest wall. Average follow up was 24 months (range, 6 months–9 years).

Based on objective assessment, 18% in the upper- and lower-limb group had excellent results and 27% patients had good results, whereas 55% of patients had no change. For the mucosal group, 28% had excellent results, 56% had good results, and 17% had no improvement, Dr. Sofos reported.

The overall complication rate from the Nd:YAG laser treatment was 20% (12 of 59), including skin blistering in 10%, ulceration in 7%, and hypertrophic scarring in 3%. Overall, 83% of the complications occurred in either upper or lower limbs, he noted.

Recurrence was defined by patients for whom symptoms had improved (with good or excellent results) but subsequently recurred. Of the 15 patients who had good or excellent results in the limbs, 4 had a recurrence (recurrence rate, 27%). Of 15 in the mucosa group who had been treated successfully, one had a recurrence (7%).

Subjective and objective evaluation of efficacy correlated well, and the vast majority of patients found the treatment to be successful and would opt to have it again if necessary, Dr. Sofos said.

"Due to the high risk of complications of treatment, however, we feel that treatment should be offered to a [select] group of patients, and should be carried out with caution. Further study will hopefully help us in establishing the best parameters to achieve better results, with minimal complications," he concluded.

This study was funded by the U.K. National Health Service. Dr. Sofos stated that he had no other disclosures.

GRAPEVINE, TEX.  – In a prospective evaluation of 59 children with venous malformations, the long-pulsed neodymium:YAG laser was more effective in treating mucosal venous malformations than lesions on the limbs.

Venous malformations present in many forms that vary in depth, location, and extent, and treatment is largely symptomatic rather than curative. "It is, therefore, important that treatments given are effective in improving the symptoms medium or long term, with as few side effects as possible," said Dr. Stratos Sofos of Alder Hey Children's Hospital in Liverpool, England.

The long-pulsed Nd:YAG laser has become popular for the treatment of small- to medium-size vessels. Its longer pulse duration provides deeper penetration and weaker melanin absorption, allowing it to heat the vessels slowly and uniformly, thus avoiding the vessel rupture with subsequent purpura and hyperpigmentation that can occur with other lasers.

However, published data do not address whether treatment with a long-pulsed Nd:YAG laser provides long-term symptom relief, nor which types of venous malformations respond better than do others, Dr. Sofos said at the annual meeting of the American Society for Laser Medicine and Surgery.

All children who met criteria such as functional impairment, large facial deformities, and painful or bleeding lesions were treated with Candela Corp.'s GentleYAG 1064-nm laser. They received one to three treatments under general anesthesia, delivered in six to eight weekly intervals. Prior to Nd:YAG laser treatment, 32 of the children had received multiple other treatments, including pulsed dye lasers and sclerotherapy.

The 59 patients were aged 2-18 years (mean, 12.3 years). Venous malformations were present on the head and neck in 23, of which 18 (31% of the total) were mucosal. Malformations were on the upper limbs in 15 and on the lower limbs in 18 (total with limb lesions, 56%). The other three had lesions on the chest wall. Average follow up was 24 months (range, 6 months–9 years).

Based on objective assessment, 18% in the upper- and lower-limb group had excellent results and 27% patients had good results, whereas 55% of patients had no change. For the mucosal group, 28% had excellent results, 56% had good results, and 17% had no improvement, Dr. Sofos reported.

The overall complication rate from the Nd:YAG laser treatment was 20% (12 of 59), including skin blistering in 10%, ulceration in 7%, and hypertrophic scarring in 3%. Overall, 83% of the complications occurred in either upper or lower limbs, he noted.

Recurrence was defined by patients for whom symptoms had improved (with good or excellent results) but subsequently recurred. Of the 15 patients who had good or excellent results in the limbs, 4 had a recurrence (recurrence rate, 27%). Of 15 in the mucosa group who had been treated successfully, one had a recurrence (7%).

Subjective and objective evaluation of efficacy correlated well, and the vast majority of patients found the treatment to be successful and would opt to have it again if necessary, Dr. Sofos said.

"Due to the high risk of complications of treatment, however, we feel that treatment should be offered to a [select] group of patients, and should be carried out with caution. Further study will hopefully help us in establishing the best parameters to achieve better results, with minimal complications," he concluded.

This study was funded by the U.K. National Health Service. Dr. Sofos stated that he had no other disclosures.

GRAPEVINE, TEX.  – In a prospective evaluation of 59 children with venous malformations, the long-pulsed neodymium:YAG laser was more effective in treating mucosal venous malformations than lesions on the limbs.

Venous malformations present in many forms that vary in depth, location, and extent, and treatment is largely symptomatic rather than curative. "It is, therefore, important that treatments given are effective in improving the symptoms medium or long term, with as few side effects as possible," said Dr. Stratos Sofos of Alder Hey Children's Hospital in Liverpool, England.

The long-pulsed Nd:YAG laser has become popular for the treatment of small- to medium-size vessels. Its longer pulse duration provides deeper penetration and weaker melanin absorption, allowing it to heat the vessels slowly and uniformly, thus avoiding the vessel rupture with subsequent purpura and hyperpigmentation that can occur with other lasers.

However, published data do not address whether treatment with a long-pulsed Nd:YAG laser provides long-term symptom relief, nor which types of venous malformations respond better than do others, Dr. Sofos said at the annual meeting of the American Society for Laser Medicine and Surgery.

All children who met criteria such as functional impairment, large facial deformities, and painful or bleeding lesions were treated with Candela Corp.'s GentleYAG 1064-nm laser. They received one to three treatments under general anesthesia, delivered in six to eight weekly intervals. Prior to Nd:YAG laser treatment, 32 of the children had received multiple other treatments, including pulsed dye lasers and sclerotherapy.

The 59 patients were aged 2-18 years (mean, 12.3 years). Venous malformations were present on the head and neck in 23, of which 18 (31% of the total) were mucosal. Malformations were on the upper limbs in 15 and on the lower limbs in 18 (total with limb lesions, 56%). The other three had lesions on the chest wall. Average follow up was 24 months (range, 6 months–9 years).

Based on objective assessment, 18% in the upper- and lower-limb group had excellent results and 27% patients had good results, whereas 55% of patients had no change. For the mucosal group, 28% had excellent results, 56% had good results, and 17% had no improvement, Dr. Sofos reported.

The overall complication rate from the Nd:YAG laser treatment was 20% (12 of 59), including skin blistering in 10%, ulceration in 7%, and hypertrophic scarring in 3%. Overall, 83% of the complications occurred in either upper or lower limbs, he noted.

Recurrence was defined by patients for whom symptoms had improved (with good or excellent results) but subsequently recurred. Of the 15 patients who had good or excellent results in the limbs, 4 had a recurrence (recurrence rate, 27%). Of 15 in the mucosa group who had been treated successfully, one had a recurrence (7%).

Subjective and objective evaluation of efficacy correlated well, and the vast majority of patients found the treatment to be successful and would opt to have it again if necessary, Dr. Sofos said.

"Due to the high risk of complications of treatment, however, we feel that treatment should be offered to a [select] group of patients, and should be carried out with caution. Further study will hopefully help us in establishing the best parameters to achieve better results, with minimal complications," he concluded.

This study was funded by the U.K. National Health Service. Dr. Sofos stated that he had no other disclosures.

Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at both higher and lower risk for fracture, in a post-hoc analysis of data from the FREEDOM trial.

The monoclonal antibody denosumab (Prolia) was approved in June 2010 for treatment of postmenopausal women who have a high risk of osteoporotic fractures. In phase II and III trials, denosumab rapidly decreased bone resorption markers and increased bone mineral density at all skeletal sites, compared with placebo, said Dr. S. Boonen of Leuven (Belgium) University and his associates (J. Clin. Endocrinol. Metab. 2011;96 [doi:10.1210/jc.2010-2784]).

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial enrolled 7,808 postmenopausal women aged 60–80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than −2.5 but not less than −4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

The new analysis compared high-risk and low-risk groups within the FREEDOM population. High-risk groups included women with two or more preexisting vertebral fractures of any degree of deformity, or one or more vertebral fractures of moderate or severe deformity, or both; a femoral neck BMD T score of −2.5 or less; or both multiple and/or moderate or severe vertebral deformities and a femoral neck BMD T score of −2.5 or less.

For hip fractures, the higher-risk subgroups included women who were age 75 years or older; had a femoral neck BMD T score of −2.5 or less; or were 75 years or older with a femoral neck BMD T score of −2.5 or less. Women who did not have those specified risk factors were included in the lower-risk subgroups.

Over 3 years, denosumab treatment was equally effective at reducing the risk of new vertebral fractures in women at both higher and lower risk for those types of fractures, similar to the overall FREEDOM population. Compared with placebo, denosumab reduced the incidence of vertebral fracture in the subgroups at higher risk by prevalent vertebral fracture status by 9.2% (16.6% placebo vs. 7.5% denosumab) in those at risk via baseline femoral neck BMD T score of −2.5 by 6.8% (9.9% vs. 3.1%), and in those with both risk factors by 12.3% (20.1% vs. 8.1%), Dr. Boonen and associates said.

The numbers needed to treat to prevent one vertebral fracture in each of these higher-risk subgroups were 11, 15, and 12, respectively.

Similar results were seen for the lower-risk groups, including a 4.4% absolute risk reduction in those without prevalent vertebral fracture, 3.7% for those with BMD T score greater than −2.5, and 4.5% for those with without one or both risk factors. Subgroup results for hip fractures were also consistent with the findings from the overall FREEDOM population, with the same efficacy of denosumab consistent across patients with different levels of risk. Compared with placebo, denosumab treatment significantly reduced the incidence of hip fracture among those aged 75 years or older by 1.4% (2.3% placebo vs. 0.9% denosumab); those with a baseline femoral neck BMD T score of −2.5 or less by 1.4% (2.8% vs. 1.4%); and by 2.4% among those with both risk factors (4.1% vs. 1.7%).

“It is reassuring to see that the effect is similar across a range of fracture risk. … The FDA-approved indication for denosumab is for 'postmenopausal women at high risk of fracture,' but the FREEDOM trial was not enriched with 'women at high risk,' ” noted Dr. Nelson Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, in an interview. Risk reduction for hip fractures was low in the lower-risk subgroups because the incidence of hip fractures was low, and the difference between the denosumab and placebo groups was therefore not statistically significant. Adverse event incidences were also not statistically different between the treatment groups within any of the higher- and lower-risk subgroups, and were consistent with the adverse event incidences for the overall FREEDOM trial, the investigators said.

Overall mortality was lower – but not significantly so – among all the subgroups with denosumab. However, there was a significantly lower incidence of fatal adverse events with denosumab vs. placebo in the higher-risk group with prevalent vertebral fracture (1.8% vs. 4.9%) and in those with both prevalent vertebral fracture and low femoral neck BMD (1.6% vs. 7.1%). The difference in mortality among the higher-risk subgroups was greater than that of the lower-risk groups, they noted.

The reason for the mortality difference is unclear, Dr. Watts said. “This was not an end point in the main trail and only significant in a small subgroup of high risk patients. It's clear that women who fracture have decreased survival, so it's logical that preventing fracture would reduce mortality.”

The study was funded by Amgen Inc., from which Dr. Boonen has received renumeration for research, consulting, and lecturing. Four of the study's coinvestigators are employees of Amgen, and the others disclosed relationships with Amgen and several other pharmaceutical companies.

Dr. Watts is director, cofounder, and owner OsteoDynamics and holds stock and patents. He has received fees and/or honoraria from numerous drug companies including Amgen, Novartis, Warner Chilcott, Johnson & Johnson, Merck, and Takeda, and Vivus.

Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at both higher and lower risk for fracture, in a post-hoc analysis of data from the FREEDOM trial.

The monoclonal antibody denosumab (Prolia) was approved in June 2010 for treatment of postmenopausal women who have a high risk of osteoporotic fractures. In phase II and III trials, denosumab rapidly decreased bone resorption markers and increased bone mineral density at all skeletal sites, compared with placebo, said Dr. S. Boonen of Leuven (Belgium) University and his associates (J. Clin. Endocrinol. Metab. 2011;96 [doi:10.1210/jc.2010-2784]).

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial enrolled 7,808 postmenopausal women aged 60–80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than −2.5 but not less than −4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

The new analysis compared high-risk and low-risk groups within the FREEDOM population. High-risk groups included women with two or more preexisting vertebral fractures of any degree of deformity, or one or more vertebral fractures of moderate or severe deformity, or both; a femoral neck BMD T score of −2.5 or less; or both multiple and/or moderate or severe vertebral deformities and a femoral neck BMD T score of −2.5 or less.

For hip fractures, the higher-risk subgroups included women who were age 75 years or older; had a femoral neck BMD T score of −2.5 or less; or were 75 years or older with a femoral neck BMD T score of −2.5 or less. Women who did not have those specified risk factors were included in the lower-risk subgroups.

Over 3 years, denosumab treatment was equally effective at reducing the risk of new vertebral fractures in women at both higher and lower risk for those types of fractures, similar to the overall FREEDOM population. Compared with placebo, denosumab reduced the incidence of vertebral fracture in the subgroups at higher risk by prevalent vertebral fracture status by 9.2% (16.6% placebo vs. 7.5% denosumab) in those at risk via baseline femoral neck BMD T score of −2.5 by 6.8% (9.9% vs. 3.1%), and in those with both risk factors by 12.3% (20.1% vs. 8.1%), Dr. Boonen and associates said.

The numbers needed to treat to prevent one vertebral fracture in each of these higher-risk subgroups were 11, 15, and 12, respectively.

Similar results were seen for the lower-risk groups, including a 4.4% absolute risk reduction in those without prevalent vertebral fracture, 3.7% for those with BMD T score greater than −2.5, and 4.5% for those with without one or both risk factors. Subgroup results for hip fractures were also consistent with the findings from the overall FREEDOM population, with the same efficacy of denosumab consistent across patients with different levels of risk. Compared with placebo, denosumab treatment significantly reduced the incidence of hip fracture among those aged 75 years or older by 1.4% (2.3% placebo vs. 0.9% denosumab); those with a baseline femoral neck BMD T score of −2.5 or less by 1.4% (2.8% vs. 1.4%); and by 2.4% among those with both risk factors (4.1% vs. 1.7%).

“It is reassuring to see that the effect is similar across a range of fracture risk. … The FDA-approved indication for denosumab is for 'postmenopausal women at high risk of fracture,' but the FREEDOM trial was not enriched with 'women at high risk,' ” noted Dr. Nelson Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, in an interview. Risk reduction for hip fractures was low in the lower-risk subgroups because the incidence of hip fractures was low, and the difference between the denosumab and placebo groups was therefore not statistically significant. Adverse event incidences were also not statistically different between the treatment groups within any of the higher- and lower-risk subgroups, and were consistent with the adverse event incidences for the overall FREEDOM trial, the investigators said.

Overall mortality was lower – but not significantly so – among all the subgroups with denosumab. However, there was a significantly lower incidence of fatal adverse events with denosumab vs. placebo in the higher-risk group with prevalent vertebral fracture (1.8% vs. 4.9%) and in those with both prevalent vertebral fracture and low femoral neck BMD (1.6% vs. 7.1%). The difference in mortality among the higher-risk subgroups was greater than that of the lower-risk groups, they noted.

The reason for the mortality difference is unclear, Dr. Watts said. “This was not an end point in the main trail and only significant in a small subgroup of high risk patients. It's clear that women who fracture have decreased survival, so it's logical that preventing fracture would reduce mortality.”

The study was funded by Amgen Inc., from which Dr. Boonen has received renumeration for research, consulting, and lecturing. Four of the study's coinvestigators are employees of Amgen, and the others disclosed relationships with Amgen and several other pharmaceutical companies.

Dr. Watts is director, cofounder, and owner OsteoDynamics and holds stock and patents. He has received fees and/or honoraria from numerous drug companies including Amgen, Novartis, Warner Chilcott, Johnson & Johnson, Merck, and Takeda, and Vivus.

Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at both higher and lower risk for fracture, in a post-hoc analysis of data from the FREEDOM trial.

The monoclonal antibody denosumab (Prolia) was approved in June 2010 for treatment of postmenopausal women who have a high risk of osteoporotic fractures. In phase II and III trials, denosumab rapidly decreased bone resorption markers and increased bone mineral density at all skeletal sites, compared with placebo, said Dr. S. Boonen of Leuven (Belgium) University and his associates (J. Clin. Endocrinol. Metab. 2011;96 [doi:10.1210/jc.2010-2784]).

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial enrolled 7,808 postmenopausal women aged 60–80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than −2.5 but not less than −4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

The new analysis compared high-risk and low-risk groups within the FREEDOM population. High-risk groups included women with two or more preexisting vertebral fractures of any degree of deformity, or one or more vertebral fractures of moderate or severe deformity, or both; a femoral neck BMD T score of −2.5 or less; or both multiple and/or moderate or severe vertebral deformities and a femoral neck BMD T score of −2.5 or less.

For hip fractures, the higher-risk subgroups included women who were age 75 years or older; had a femoral neck BMD T score of −2.5 or less; or were 75 years or older with a femoral neck BMD T score of −2.5 or less. Women who did not have those specified risk factors were included in the lower-risk subgroups.

Over 3 years, denosumab treatment was equally effective at reducing the risk of new vertebral fractures in women at both higher and lower risk for those types of fractures, similar to the overall FREEDOM population. Compared with placebo, denosumab reduced the incidence of vertebral fracture in the subgroups at higher risk by prevalent vertebral fracture status by 9.2% (16.6% placebo vs. 7.5% denosumab) in those at risk via baseline femoral neck BMD T score of −2.5 by 6.8% (9.9% vs. 3.1%), and in those with both risk factors by 12.3% (20.1% vs. 8.1%), Dr. Boonen and associates said.

The numbers needed to treat to prevent one vertebral fracture in each of these higher-risk subgroups were 11, 15, and 12, respectively.

Similar results were seen for the lower-risk groups, including a 4.4% absolute risk reduction in those without prevalent vertebral fracture, 3.7% for those with BMD T score greater than −2.5, and 4.5% for those with without one or both risk factors. Subgroup results for hip fractures were also consistent with the findings from the overall FREEDOM population, with the same efficacy of denosumab consistent across patients with different levels of risk. Compared with placebo, denosumab treatment significantly reduced the incidence of hip fracture among those aged 75 years or older by 1.4% (2.3% placebo vs. 0.9% denosumab); those with a baseline femoral neck BMD T score of −2.5 or less by 1.4% (2.8% vs. 1.4%); and by 2.4% among those with both risk factors (4.1% vs. 1.7%).

“It is reassuring to see that the effect is similar across a range of fracture risk. … The FDA-approved indication for denosumab is for 'postmenopausal women at high risk of fracture,' but the FREEDOM trial was not enriched with 'women at high risk,' ” noted Dr. Nelson Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, in an interview. Risk reduction for hip fractures was low in the lower-risk subgroups because the incidence of hip fractures was low, and the difference between the denosumab and placebo groups was therefore not statistically significant. Adverse event incidences were also not statistically different between the treatment groups within any of the higher- and lower-risk subgroups, and were consistent with the adverse event incidences for the overall FREEDOM trial, the investigators said.

Overall mortality was lower – but not significantly so – among all the subgroups with denosumab. However, there was a significantly lower incidence of fatal adverse events with denosumab vs. placebo in the higher-risk group with prevalent vertebral fracture (1.8% vs. 4.9%) and in those with both prevalent vertebral fracture and low femoral neck BMD (1.6% vs. 7.1%). The difference in mortality among the higher-risk subgroups was greater than that of the lower-risk groups, they noted.

The reason for the mortality difference is unclear, Dr. Watts said. “This was not an end point in the main trail and only significant in a small subgroup of high risk patients. It's clear that women who fracture have decreased survival, so it's logical that preventing fracture would reduce mortality.”

The study was funded by Amgen Inc., from which Dr. Boonen has received renumeration for research, consulting, and lecturing. Four of the study's coinvestigators are employees of Amgen, and the others disclosed relationships with Amgen and several other pharmaceutical companies.

Dr. Watts is director, cofounder, and owner OsteoDynamics and holds stock and patents. He has received fees and/or honoraria from numerous drug companies including Amgen, Novartis, Warner Chilcott, Johnson & Johnson, Merck, and Takeda, and Vivus.

Use of the angiotensin II receptor antagonist olmesartan was associated with a delayed onset of microalbuminuria in a randomized, double-blind controlled trial involving more than 4,000 patients with type 2 diabetes.

The time to onset of microalbuminuria was increased by a significant 23% with olmesartan compared with placebo in the Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) trial. But of concern, patients who received olmesartan had a higher rate of fatal cardiovascular events, mostly among patients with preexisting cardiovascular disease, Dr. Hermann Haller and his associates said (N. Engl. J. Med. 2011;364:907-17).

The study randomized 4,449 white patients with type 2 diabetes, aged 18–75 years, to either 40 mg/day of olmesartan or placebo. Additional antihypertensive drugs that do not block the renin-angiotensin system were used as needed to achieve blood pressure of less than 130/80 mm Hg. Nearly 80% of the olmesartan group and about 71% of the placebo group achieved that level of blood pressure control at month 48, said Dr. Haller of Hannover (Germany) Medical School and his ROADMAP trial colleagues.

During a median follow-up of 3.2 years, microalbuminuria developed in 8.2% of the 2,160 patients in the olmesartan group for whom albumin-to-creatinine ratio could be evaluated, compared with 9.8% of the 2,139 evaluable placebo patients. Microalbuminuria was defined as a urinary albumin-to-creatinine ratio of more than 35 in women or more than 25 in men.

The median time to onset of microalbuminuria – the primary study end point – was 576 days in the placebo group and 722 days in the olmesartan group, with a hazard ratio of 0.77. After adjustment for small baseline differences in body mass index, systolic blood pressure, and lipid levels, the hazard ratio remained significant, at 0.75.

The mean estimated glomerular filtration rate – a secondary end point – dropped from 85.0 mL/min per 1.73 m

The proportion of patients who reached the composite secondary end point of cardiovascular complications or cardiovascular-related death was also similar between the two groups, 4.3% of the olmesartan group and 4.2% of the placebo group. The death rate overall was very low, just 1.2% of the olmesartan patients and 0.7% of those taking placebo.

However, the number of deaths from cardiovascular causes was higher in the olmesartan group, 15 vs. 3 on placebo, primarily because of fatal myocardial infarction (5 vs. 0) and sudden cardiac death (7 vs. 1). The majority of deaths from cardiovascular causes, 12 of 18, occurred in the subgroup of 1,104 patients who had preexisting coronary heart disease. Among patients with preexisting heart disease, there were 11 deaths from cardiovascular causes with olmesartan vs. 1 in the placebo group, giving event rates of 6.9 vs. 0.7/1,000 person-years, the investigators said.

Other adverse event rates were similar between the two groups. Serious adverse events occurred in 15.0% with olmesartan vs. 15.2% with placebo, and drug-related adverse events occurred in 11.4% vs. 7.5%. That difference was mostly due to more episodes of hypotension (58 vs. 6 patients) and dizziness (103 vs. 61 patients) with olmesartan.

This study was funded by Daiichi Sankyo. Dr. Haller reported receiving payment for board membership from Novartis. He said he also receives consulting fees, lecture fees, payment for the development of educational presentations, and/or travel support from Bayer Schering Pharma, Daiichi Sankyo, Roche, Menarini, and Amgen.

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FDA Investigates CVD Deaths

Although the analysis is markedly underpowered for cardiovascular end points, given the small number of events in a relatively healthy population of persons with type 2 diabetes, the cardiovascular results of this trial have raised concerns even before publication. While nonfatal cardiovascular events did not differ significantly −3.6% in the olmesartan group and 4.1% in the controls – fatal cardiovascular events were increased in the olmesartan group, 0.7% vs. 0.1%.

The fact that these signals go in opposite directions, together with the feeling that the study was underpowered to determine cardiovascular risk, suggest to some people that the results may well be due to chance. However, the ROADMAP results, combined with those of ORIENT, have led the FDA to investigate. The excess in cardiovascular mortality in ROADMAP occurred mainly among patients in the lowest quartile of blood pressure, so that may have been a factor.

For now, the FDA's Web site still states that olmesartan's benefits continue to outweigh its potential risks. Some nephrologists and cardiologists agree. Others argue that since there are other angiotensin receptor blockers that can be used to prevent the onset of microalbuminuria that have not shown the same signal, why not prescribe one of those?

JULIE INGELFINGER, M.D., is deputy editor of the New England Journal of Medicine. She disclosed having received travel/accommodations/meeting expenses from the National Institutes of Health and the Cystinosis Research Foundation. These comments were excerpted from an editorial that accompanied the study (N. Engl. J. Med.2011;384:970-1).

Use of the angiotensin II receptor antagonist olmesartan was associated with a delayed onset of microalbuminuria in a randomized, double-blind controlled trial involving more than 4,000 patients with type 2 diabetes.

The time to onset of microalbuminuria was increased by a significant 23% with olmesartan compared with placebo in the Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) trial. But of concern, patients who received olmesartan had a higher rate of fatal cardiovascular events, mostly among patients with preexisting cardiovascular disease, Dr. Hermann Haller and his associates said (N. Engl. J. Med. 2011;364:907-17).

The study randomized 4,449 white patients with type 2 diabetes, aged 18–75 years, to either 40 mg/day of olmesartan or placebo. Additional antihypertensive drugs that do not block the renin-angiotensin system were used as needed to achieve blood pressure of less than 130/80 mm Hg. Nearly 80% of the olmesartan group and about 71% of the placebo group achieved that level of blood pressure control at month 48, said Dr. Haller of Hannover (Germany) Medical School and his ROADMAP trial colleagues.

During a median follow-up of 3.2 years, microalbuminuria developed in 8.2% of the 2,160 patients in the olmesartan group for whom albumin-to-creatinine ratio could be evaluated, compared with 9.8% of the 2,139 evaluable placebo patients. Microalbuminuria was defined as a urinary albumin-to-creatinine ratio of more than 35 in women or more than 25 in men.

The median time to onset of microalbuminuria – the primary study end point – was 576 days in the placebo group and 722 days in the olmesartan group, with a hazard ratio of 0.77. After adjustment for small baseline differences in body mass index, systolic blood pressure, and lipid levels, the hazard ratio remained significant, at 0.75.

The mean estimated glomerular filtration rate – a secondary end point – dropped from 85.0 mL/min per 1.73 m

The proportion of patients who reached the composite secondary end point of cardiovascular complications or cardiovascular-related death was also similar between the two groups, 4.3% of the olmesartan group and 4.2% of the placebo group. The death rate overall was very low, just 1.2% of the olmesartan patients and 0.7% of those taking placebo.

However, the number of deaths from cardiovascular causes was higher in the olmesartan group, 15 vs. 3 on placebo, primarily because of fatal myocardial infarction (5 vs. 0) and sudden cardiac death (7 vs. 1). The majority of deaths from cardiovascular causes, 12 of 18, occurred in the subgroup of 1,104 patients who had preexisting coronary heart disease. Among patients with preexisting heart disease, there were 11 deaths from cardiovascular causes with olmesartan vs. 1 in the placebo group, giving event rates of 6.9 vs. 0.7/1,000 person-years, the investigators said.

Other adverse event rates were similar between the two groups. Serious adverse events occurred in 15.0% with olmesartan vs. 15.2% with placebo, and drug-related adverse events occurred in 11.4% vs. 7.5%. That difference was mostly due to more episodes of hypotension (58 vs. 6 patients) and dizziness (103 vs. 61 patients) with olmesartan.

This study was funded by Daiichi Sankyo. Dr. Haller reported receiving payment for board membership from Novartis. He said he also receives consulting fees, lecture fees, payment for the development of educational presentations, and/or travel support from Bayer Schering Pharma, Daiichi Sankyo, Roche, Menarini, and Amgen.

View on the News

FDA Investigates CVD Deaths

Although the analysis is markedly underpowered for cardiovascular end points, given the small number of events in a relatively healthy population of persons with type 2 diabetes, the cardiovascular results of this trial have raised concerns even before publication. While nonfatal cardiovascular events did not differ significantly −3.6% in the olmesartan group and 4.1% in the controls – fatal cardiovascular events were increased in the olmesartan group, 0.7% vs. 0.1%.

The fact that these signals go in opposite directions, together with the feeling that the study was underpowered to determine cardiovascular risk, suggest to some people that the results may well be due to chance. However, the ROADMAP results, combined with those of ORIENT, have led the FDA to investigate. The excess in cardiovascular mortality in ROADMAP occurred mainly among patients in the lowest quartile of blood pressure, so that may have been a factor.

For now, the FDA's Web site still states that olmesartan's benefits continue to outweigh its potential risks. Some nephrologists and cardiologists agree. Others argue that since there are other angiotensin receptor blockers that can be used to prevent the onset of microalbuminuria that have not shown the same signal, why not prescribe one of those?

JULIE INGELFINGER, M.D., is deputy editor of the New England Journal of Medicine. She disclosed having received travel/accommodations/meeting expenses from the National Institutes of Health and the Cystinosis Research Foundation. These comments were excerpted from an editorial that accompanied the study (N. Engl. J. Med.2011;384:970-1).

Use of the angiotensin II receptor antagonist olmesartan was associated with a delayed onset of microalbuminuria in a randomized, double-blind controlled trial involving more than 4,000 patients with type 2 diabetes.

The time to onset of microalbuminuria was increased by a significant 23% with olmesartan compared with placebo in the Randomized Olmesartan and Diabetes Microalbuminuria Prevention (ROADMAP) trial. But of concern, patients who received olmesartan had a higher rate of fatal cardiovascular events, mostly among patients with preexisting cardiovascular disease, Dr. Hermann Haller and his associates said (N. Engl. J. Med. 2011;364:907-17).

The study randomized 4,449 white patients with type 2 diabetes, aged 18–75 years, to either 40 mg/day of olmesartan or placebo. Additional antihypertensive drugs that do not block the renin-angiotensin system were used as needed to achieve blood pressure of less than 130/80 mm Hg. Nearly 80% of the olmesartan group and about 71% of the placebo group achieved that level of blood pressure control at month 48, said Dr. Haller of Hannover (Germany) Medical School and his ROADMAP trial colleagues.

During a median follow-up of 3.2 years, microalbuminuria developed in 8.2% of the 2,160 patients in the olmesartan group for whom albumin-to-creatinine ratio could be evaluated, compared with 9.8% of the 2,139 evaluable placebo patients. Microalbuminuria was defined as a urinary albumin-to-creatinine ratio of more than 35 in women or more than 25 in men.

The median time to onset of microalbuminuria – the primary study end point – was 576 days in the placebo group and 722 days in the olmesartan group, with a hazard ratio of 0.77. After adjustment for small baseline differences in body mass index, systolic blood pressure, and lipid levels, the hazard ratio remained significant, at 0.75.

The mean estimated glomerular filtration rate – a secondary end point – dropped from 85.0 mL/min per 1.73 m

The proportion of patients who reached the composite secondary end point of cardiovascular complications or cardiovascular-related death was also similar between the two groups, 4.3% of the olmesartan group and 4.2% of the placebo group. The death rate overall was very low, just 1.2% of the olmesartan patients and 0.7% of those taking placebo.

However, the number of deaths from cardiovascular causes was higher in the olmesartan group, 15 vs. 3 on placebo, primarily because of fatal myocardial infarction (5 vs. 0) and sudden cardiac death (7 vs. 1). The majority of deaths from cardiovascular causes, 12 of 18, occurred in the subgroup of 1,104 patients who had preexisting coronary heart disease. Among patients with preexisting heart disease, there were 11 deaths from cardiovascular causes with olmesartan vs. 1 in the placebo group, giving event rates of 6.9 vs. 0.7/1,000 person-years, the investigators said.

Other adverse event rates were similar between the two groups. Serious adverse events occurred in 15.0% with olmesartan vs. 15.2% with placebo, and drug-related adverse events occurred in 11.4% vs. 7.5%. That difference was mostly due to more episodes of hypotension (58 vs. 6 patients) and dizziness (103 vs. 61 patients) with olmesartan.

This study was funded by Daiichi Sankyo. Dr. Haller reported receiving payment for board membership from Novartis. He said he also receives consulting fees, lecture fees, payment for the development of educational presentations, and/or travel support from Bayer Schering Pharma, Daiichi Sankyo, Roche, Menarini, and Amgen.

View on the News

FDA Investigates CVD Deaths

Although the analysis is markedly underpowered for cardiovascular end points, given the small number of events in a relatively healthy population of persons with type 2 diabetes, the cardiovascular results of this trial have raised concerns even before publication. While nonfatal cardiovascular events did not differ significantly −3.6% in the olmesartan group and 4.1% in the controls – fatal cardiovascular events were increased in the olmesartan group, 0.7% vs. 0.1%.

The fact that these signals go in opposite directions, together with the feeling that the study was underpowered to determine cardiovascular risk, suggest to some people that the results may well be due to chance. However, the ROADMAP results, combined with those of ORIENT, have led the FDA to investigate. The excess in cardiovascular mortality in ROADMAP occurred mainly among patients in the lowest quartile of blood pressure, so that may have been a factor.

For now, the FDA's Web site still states that olmesartan's benefits continue to outweigh its potential risks. Some nephrologists and cardiologists agree. Others argue that since there are other angiotensin receptor blockers that can be used to prevent the onset of microalbuminuria that have not shown the same signal, why not prescribe one of those?

JULIE INGELFINGER, M.D., is deputy editor of the New England Journal of Medicine. She disclosed having received travel/accommodations/meeting expenses from the National Institutes of Health and the Cystinosis Research Foundation. These comments were excerpted from an editorial that accompanied the study (N. Engl. J. Med.2011;384:970-1).

Using the ultra-long-acting basal insulin degludec three times a week produced glycemic control comparable with that of daily insulin glargine in patients with inadequately controlled type 2 diabetes, in a phase II study.

“A three times a week, weekend-off, dosing regimen might appeal to some people with type 2 diabetes who are inadequately controlled on oral antidiabetic drug treatments, potentially helping with acceptance and early initiation of insulin therapy,” explained Dr. Bernard Zinman of the University of Toronto and his associates (Lancet 2011[doi:10.1016/S0140-6736(10)62305-7]).

Novo Nordisk's insulin degludec is formulated in such a way that dosing could be reduced to just three times a week in previously insulin-naive patients with type 2 diabetes – thereby reducing the risk for hypoglycemia and potentially improving adherence to insulin treatment, the authors wrote.

The trial results were first reported at the annual scientific sessions of the American Diabetes Association (Clinical Endocrinology News, August 2010, p. 19)

The 16-week, randomized, parallel-group trial of 245 patients was done at 28 clinics in four countries. All patients had type 2 diabetes, were insulin naive, and had been treated with one or two oral antidiabetic agents for more than 2 months.

The subjects were randomized to one of four groups: insulin degludec either three times a week (900 nmol/mL formulation, once daily (600 nmol/mL), or once daily (900 nmol/mL); or insulin glargine once daily (600 nmol/mL formulation). All four drug regimens were given in combination with metformin.

Mean hemoglobin A_1c and fasting plasma glucose concentrations were similar between the treatment groups. Reductions in HbA_1c from baseline were between 1.3% and 1.5% (to 7.2%−7.5%) and did not differ significantly between the groups. Fasting plasma glucose concentrations dropped 3.4−4.2 mmol/L from baseline and also did not differ between treatment groups.

The rates of hypoglycemia were low in all of the treatment groups, with 77%–92% reporting no episodes. However, the proportion of patients who had hypoglycemia in the once-daily 600- nmol/mL insulin degludec group was lower than was the proportion in the insulin glargine group and the insulin degludec three times a week group, with odds ratios of 0.26 and 0.31, respectively.

Adverse events were mild or moderate in severity, with no apparent treatment-specific pattern. Dr. Zinman has been a consultant to, an adviser for, and received grant support from Novo Nordisk, GlaxoSmithKline, Merck, Eli Lilly, Amylin, and Boehringer Ingelheim.

Using the ultra-long-acting basal insulin degludec three times a week produced glycemic control comparable with that of daily insulin glargine in patients with inadequately controlled type 2 diabetes, in a phase II study.

“A three times a week, weekend-off, dosing regimen might appeal to some people with type 2 diabetes who are inadequately controlled on oral antidiabetic drug treatments, potentially helping with acceptance and early initiation of insulin therapy,” explained Dr. Bernard Zinman of the University of Toronto and his associates (Lancet 2011[doi:10.1016/S0140-6736(10)62305-7]).

Novo Nordisk's insulin degludec is formulated in such a way that dosing could be reduced to just three times a week in previously insulin-naive patients with type 2 diabetes – thereby reducing the risk for hypoglycemia and potentially improving adherence to insulin treatment, the authors wrote.

The trial results were first reported at the annual scientific sessions of the American Diabetes Association (Clinical Endocrinology News, August 2010, p. 19)

The 16-week, randomized, parallel-group trial of 245 patients was done at 28 clinics in four countries. All patients had type 2 diabetes, were insulin naive, and had been treated with one or two oral antidiabetic agents for more than 2 months.

The subjects were randomized to one of four groups: insulin degludec either three times a week (900 nmol/mL formulation, once daily (600 nmol/mL), or once daily (900 nmol/mL); or insulin glargine once daily (600 nmol/mL formulation). All four drug regimens were given in combination with metformin.

Mean hemoglobin A_1c and fasting plasma glucose concentrations were similar between the treatment groups. Reductions in HbA_1c from baseline were between 1.3% and 1.5% (to 7.2%−7.5%) and did not differ significantly between the groups. Fasting plasma glucose concentrations dropped 3.4−4.2 mmol/L from baseline and also did not differ between treatment groups.

The rates of hypoglycemia were low in all of the treatment groups, with 77%–92% reporting no episodes. However, the proportion of patients who had hypoglycemia in the once-daily 600- nmol/mL insulin degludec group was lower than was the proportion in the insulin glargine group and the insulin degludec three times a week group, with odds ratios of 0.26 and 0.31, respectively.

Adverse events were mild or moderate in severity, with no apparent treatment-specific pattern. Dr. Zinman has been a consultant to, an adviser for, and received grant support from Novo Nordisk, GlaxoSmithKline, Merck, Eli Lilly, Amylin, and Boehringer Ingelheim.

Using the ultra-long-acting basal insulin degludec three times a week produced glycemic control comparable with that of daily insulin glargine in patients with inadequately controlled type 2 diabetes, in a phase II study.

“A three times a week, weekend-off, dosing regimen might appeal to some people with type 2 diabetes who are inadequately controlled on oral antidiabetic drug treatments, potentially helping with acceptance and early initiation of insulin therapy,” explained Dr. Bernard Zinman of the University of Toronto and his associates (Lancet 2011[doi:10.1016/S0140-6736(10)62305-7]).

Novo Nordisk's insulin degludec is formulated in such a way that dosing could be reduced to just three times a week in previously insulin-naive patients with type 2 diabetes – thereby reducing the risk for hypoglycemia and potentially improving adherence to insulin treatment, the authors wrote.

The trial results were first reported at the annual scientific sessions of the American Diabetes Association (Clinical Endocrinology News, August 2010, p. 19)

The 16-week, randomized, parallel-group trial of 245 patients was done at 28 clinics in four countries. All patients had type 2 diabetes, were insulin naive, and had been treated with one or two oral antidiabetic agents for more than 2 months.

The subjects were randomized to one of four groups: insulin degludec either three times a week (900 nmol/mL formulation, once daily (600 nmol/mL), or once daily (900 nmol/mL); or insulin glargine once daily (600 nmol/mL formulation). All four drug regimens were given in combination with metformin.

Mean hemoglobin A_1c and fasting plasma glucose concentrations were similar between the treatment groups. Reductions in HbA_1c from baseline were between 1.3% and 1.5% (to 7.2%−7.5%) and did not differ significantly between the groups. Fasting plasma glucose concentrations dropped 3.4−4.2 mmol/L from baseline and also did not differ between treatment groups.

The rates of hypoglycemia were low in all of the treatment groups, with 77%–92% reporting no episodes. However, the proportion of patients who had hypoglycemia in the once-daily 600- nmol/mL insulin degludec group was lower than was the proportion in the insulin glargine group and the insulin degludec three times a week group, with odds ratios of 0.26 and 0.31, respectively.

Adverse events were mild or moderate in severity, with no apparent treatment-specific pattern. Dr. Zinman has been a consultant to, an adviser for, and received grant support from Novo Nordisk, GlaxoSmithKline, Merck, Eli Lilly, Amylin, and Boehringer Ingelheim.

LAS VEGAS – The overall incidence of malignancy was low among 808 women who underwent laparoscopic supracervical hysterectomy, but those aged 40 years and older with abnormal bleeding were at increased risk.

The findings, which were from a retrospective chart review, suggest that older women who have abnormal bleeding should be considered for total hysterectomy rather than laparoscopic supracervical hysterectomy (LSH) with morcellation. This is especially true for women aged 50 years and older with postmenopausal bleeding, said Dr. Kristal Taylor of the University of Texas, Houston.

LSH with morcellation has been increasing in popularity over the last few decades, given its advantages of less invasiveness, decreased morbidity and mortality, and reduced risk of pelvic floor and sexual dysfunction. However, there is a concern that the morcellation can lead to gross spillage of tumor (if present), resulting in up-staging and possible adverse consequences.

Indeed, in a recent study of 17 patients who were diagnosed with endometrial cancer after supracervical hysterectomy between January 2000 and March 2006, 2 of the 13 who underwent completion surgery were up-staged, both of whom had leiomyosarcoma originally resected with morcellation. No patient who initially underwent supracervical hysterectomy without morcellation was up-staged at the second surgery (Int. J. Gynecol. Cancer 2008;18:1065-70).

There have been no previous reports quantifying the risk of malignancy in LSH in the setting of general practice. Dr. Taylor and her associates reviewed the charts of all consecutive women who underwent planned LSH at the Women's Hospital of Texas, Houston, between Jan. 1, 2002, and Dec. 31, 2008.

The 808 women had a median age of 44 years (range, 23-79 years), body mass index of 27 kg/m

Of the total 808, 96% (777) underwent LSH with or without bilateral salpingo-oophorectomy, whereas the other 31 patients were converted to other types of operations. Adhesions were the most common indication for conversion (17 of the 31).

Endometrial neoplasia was found in 2.5% of the 808 (20 patients), including 13 with endometrial hyperplasia, 3 with hyperplasia confined to a polyp, and 4 with uterine cancer (two endometrial cancers, one leiomyosarcoma, and one stromal carcinoma).

In all, the risk for cancer among the total 808 study population was 0.5%, Dr. Taylor reported.

By age, the incidence of neoplasia (including both hyperplasia and cancer) was 1.9% of the 212 women aged younger than 40 years, and 1.7% of 454 patients aged 40-49 years, compared with 5.6% of the 142 aged 50 years and older. The difference between women aged at least 50 vs. younger than 50 years was statistically significant, with an odds ratio of 3.25 and confidence interval that does not include one, suggesting that the two groups most likely do have different odds of neoplasia.

However, Dr. Taylor noted, “It's a pretty wide confidence interval. … Bottom line, if we had more cases, we might be more confident that the odds are truly greater in the older women.”

Neoplasia was found in 3.1% of the 548 women with abnormal bleeding (either menorrhagia or postmenopausal bleeding), compared with just 1.2% of the 260 without abnormal bleeding. That overall difference was not statistically significant.

But there was a relationship with age. Among the women aged younger than 40 years (none of whom had overt cancer), the risk for neoplasia with abnormal bleeding was 2.2%, compared with 1.4% without abnormal bleeding, an insignificant difference. Similarly, the neoplasia risk among those aged 40-49 (including three with overt cancer) was 2.1% with abnormal bleeding vs. 0.8% without, also not statistically different.

There were 58 patients identified as “menopausal” in a total of 142 who were aged 50 years and older, and there were 77 women aged 50 years and older with abnormal bleeding. In all, 26 women were coded as having postmenopausal bleeding, including 6 who were aged 40-49 years and 20 who were aged 50 and older. No neoplasias were found in the younger group, compared with five (19.2%) in the older group.

Thus, the incidence of neoplasia among women with postmenopausal bleeding was 25% (5 of 20) for those aged 50 and older vs. 0% (0 of 6) for those younger than 50. Among those aged 50 and older, the risk for neoplasia among those with abnormal bleeding was 9.1% (7 of 77), compared with just 1.5% for those without abnormal bleeding (1 of 65). Here, the difference between those aged at least 50 vs. younger than 50 was not statistically significant, but did represent a strong trend, Dr. Taylor said.

Of the total eight women aged 50 and older with neoplasia, six had hyperplasia, one had a polyp with hyperplasia, and one had overt cancer, she reported.

Taken together, she said, the findings suggest that there's a low risk for neoplasia with LSH among women who are younger than 40 even if they have abnormal bleeding, as well as among women aged 49 and younger who do not have abnormal bleeding.

In contrast, there's a high risk among women aged 40 and older with abnormal bleeding, and among those aged 50 and older whether they have bleeding or not. At greatest risk of all are those aged 50 and older with abnormal bleeding.

Dr. Taylor said she had no relevant financial disclosures.

LAS VEGAS – The overall incidence of malignancy was low among 808 women who underwent laparoscopic supracervical hysterectomy, but those aged 40 years and older with abnormal bleeding were at increased risk.

The findings, which were from a retrospective chart review, suggest that older women who have abnormal bleeding should be considered for total hysterectomy rather than laparoscopic supracervical hysterectomy (LSH) with morcellation. This is especially true for women aged 50 years and older with postmenopausal bleeding, said Dr. Kristal Taylor of the University of Texas, Houston.

LSH with morcellation has been increasing in popularity over the last few decades, given its advantages of less invasiveness, decreased morbidity and mortality, and reduced risk of pelvic floor and sexual dysfunction. However, there is a concern that the morcellation can lead to gross spillage of tumor (if present), resulting in up-staging and possible adverse consequences.

Indeed, in a recent study of 17 patients who were diagnosed with endometrial cancer after supracervical hysterectomy between January 2000 and March 2006, 2 of the 13 who underwent completion surgery were up-staged, both of whom had leiomyosarcoma originally resected with morcellation. No patient who initially underwent supracervical hysterectomy without morcellation was up-staged at the second surgery (Int. J. Gynecol. Cancer 2008;18:1065-70).

There have been no previous reports quantifying the risk of malignancy in LSH in the setting of general practice. Dr. Taylor and her associates reviewed the charts of all consecutive women who underwent planned LSH at the Women's Hospital of Texas, Houston, between Jan. 1, 2002, and Dec. 31, 2008.

The 808 women had a median age of 44 years (range, 23-79 years), body mass index of 27 kg/m

Of the total 808, 96% (777) underwent LSH with or without bilateral salpingo-oophorectomy, whereas the other 31 patients were converted to other types of operations. Adhesions were the most common indication for conversion (17 of the 31).

Endometrial neoplasia was found in 2.5% of the 808 (20 patients), including 13 with endometrial hyperplasia, 3 with hyperplasia confined to a polyp, and 4 with uterine cancer (two endometrial cancers, one leiomyosarcoma, and one stromal carcinoma).

In all, the risk for cancer among the total 808 study population was 0.5%, Dr. Taylor reported.

By age, the incidence of neoplasia (including both hyperplasia and cancer) was 1.9% of the 212 women aged younger than 40 years, and 1.7% of 454 patients aged 40-49 years, compared with 5.6% of the 142 aged 50 years and older. The difference between women aged at least 50 vs. younger than 50 years was statistically significant, with an odds ratio of 3.25 and confidence interval that does not include one, suggesting that the two groups most likely do have different odds of neoplasia.

However, Dr. Taylor noted, “It's a pretty wide confidence interval. … Bottom line, if we had more cases, we might be more confident that the odds are truly greater in the older women.”

Neoplasia was found in 3.1% of the 548 women with abnormal bleeding (either menorrhagia or postmenopausal bleeding), compared with just 1.2% of the 260 without abnormal bleeding. That overall difference was not statistically significant.

But there was a relationship with age. Among the women aged younger than 40 years (none of whom had overt cancer), the risk for neoplasia with abnormal bleeding was 2.2%, compared with 1.4% without abnormal bleeding, an insignificant difference. Similarly, the neoplasia risk among those aged 40-49 (including three with overt cancer) was 2.1% with abnormal bleeding vs. 0.8% without, also not statistically different.

There were 58 patients identified as “menopausal” in a total of 142 who were aged 50 years and older, and there were 77 women aged 50 years and older with abnormal bleeding. In all, 26 women were coded as having postmenopausal bleeding, including 6 who were aged 40-49 years and 20 who were aged 50 and older. No neoplasias were found in the younger group, compared with five (19.2%) in the older group.

Thus, the incidence of neoplasia among women with postmenopausal bleeding was 25% (5 of 20) for those aged 50 and older vs. 0% (0 of 6) for those younger than 50. Among those aged 50 and older, the risk for neoplasia among those with abnormal bleeding was 9.1% (7 of 77), compared with just 1.5% for those without abnormal bleeding (1 of 65). Here, the difference between those aged at least 50 vs. younger than 50 was not statistically significant, but did represent a strong trend, Dr. Taylor said.

Of the total eight women aged 50 and older with neoplasia, six had hyperplasia, one had a polyp with hyperplasia, and one had overt cancer, she reported.

Taken together, she said, the findings suggest that there's a low risk for neoplasia with LSH among women who are younger than 40 even if they have abnormal bleeding, as well as among women aged 49 and younger who do not have abnormal bleeding.

In contrast, there's a high risk among women aged 40 and older with abnormal bleeding, and among those aged 50 and older whether they have bleeding or not. At greatest risk of all are those aged 50 and older with abnormal bleeding.

Dr. Taylor said she had no relevant financial disclosures.

LAS VEGAS – The overall incidence of malignancy was low among 808 women who underwent laparoscopic supracervical hysterectomy, but those aged 40 years and older with abnormal bleeding were at increased risk.

The findings, which were from a retrospective chart review, suggest that older women who have abnormal bleeding should be considered for total hysterectomy rather than laparoscopic supracervical hysterectomy (LSH) with morcellation. This is especially true for women aged 50 years and older with postmenopausal bleeding, said Dr. Kristal Taylor of the University of Texas, Houston.

LSH with morcellation has been increasing in popularity over the last few decades, given its advantages of less invasiveness, decreased morbidity and mortality, and reduced risk of pelvic floor and sexual dysfunction. However, there is a concern that the morcellation can lead to gross spillage of tumor (if present), resulting in up-staging and possible adverse consequences.

Indeed, in a recent study of 17 patients who were diagnosed with endometrial cancer after supracervical hysterectomy between January 2000 and March 2006, 2 of the 13 who underwent completion surgery were up-staged, both of whom had leiomyosarcoma originally resected with morcellation. No patient who initially underwent supracervical hysterectomy without morcellation was up-staged at the second surgery (Int. J. Gynecol. Cancer 2008;18:1065-70).

There have been no previous reports quantifying the risk of malignancy in LSH in the setting of general practice. Dr. Taylor and her associates reviewed the charts of all consecutive women who underwent planned LSH at the Women's Hospital of Texas, Houston, between Jan. 1, 2002, and Dec. 31, 2008.

The 808 women had a median age of 44 years (range, 23-79 years), body mass index of 27 kg/m

Of the total 808, 96% (777) underwent LSH with or without bilateral salpingo-oophorectomy, whereas the other 31 patients were converted to other types of operations. Adhesions were the most common indication for conversion (17 of the 31).

Endometrial neoplasia was found in 2.5% of the 808 (20 patients), including 13 with endometrial hyperplasia, 3 with hyperplasia confined to a polyp, and 4 with uterine cancer (two endometrial cancers, one leiomyosarcoma, and one stromal carcinoma).

In all, the risk for cancer among the total 808 study population was 0.5%, Dr. Taylor reported.

By age, the incidence of neoplasia (including both hyperplasia and cancer) was 1.9% of the 212 women aged younger than 40 years, and 1.7% of 454 patients aged 40-49 years, compared with 5.6% of the 142 aged 50 years and older. The difference between women aged at least 50 vs. younger than 50 years was statistically significant, with an odds ratio of 3.25 and confidence interval that does not include one, suggesting that the two groups most likely do have different odds of neoplasia.

However, Dr. Taylor noted, “It's a pretty wide confidence interval. … Bottom line, if we had more cases, we might be more confident that the odds are truly greater in the older women.”

Neoplasia was found in 3.1% of the 548 women with abnormal bleeding (either menorrhagia or postmenopausal bleeding), compared with just 1.2% of the 260 without abnormal bleeding. That overall difference was not statistically significant.

But there was a relationship with age. Among the women aged younger than 40 years (none of whom had overt cancer), the risk for neoplasia with abnormal bleeding was 2.2%, compared with 1.4% without abnormal bleeding, an insignificant difference. Similarly, the neoplasia risk among those aged 40-49 (including three with overt cancer) was 2.1% with abnormal bleeding vs. 0.8% without, also not statistically different.

There were 58 patients identified as “menopausal” in a total of 142 who were aged 50 years and older, and there were 77 women aged 50 years and older with abnormal bleeding. In all, 26 women were coded as having postmenopausal bleeding, including 6 who were aged 40-49 years and 20 who were aged 50 and older. No neoplasias were found in the younger group, compared with five (19.2%) in the older group.

Thus, the incidence of neoplasia among women with postmenopausal bleeding was 25% (5 of 20) for those aged 50 and older vs. 0% (0 of 6) for those younger than 50. Among those aged 50 and older, the risk for neoplasia among those with abnormal bleeding was 9.1% (7 of 77), compared with just 1.5% for those without abnormal bleeding (1 of 65). Here, the difference between those aged at least 50 vs. younger than 50 was not statistically significant, but did represent a strong trend, Dr. Taylor said.

Of the total eight women aged 50 and older with neoplasia, six had hyperplasia, one had a polyp with hyperplasia, and one had overt cancer, she reported.

Taken together, she said, the findings suggest that there's a low risk for neoplasia with LSH among women who are younger than 40 even if they have abnormal bleeding, as well as among women aged 49 and younger who do not have abnormal bleeding.

In contrast, there's a high risk among women aged 40 and older with abnormal bleeding, and among those aged 50 and older whether they have bleeding or not. At greatest risk of all are those aged 50 and older with abnormal bleeding.

Dr. Taylor said she had no relevant financial disclosures.

Major Finding: Of 780 enterovirus RNA–negative CSF samples taken during 2006–2008, RT-PCR was detected HPeV in 2% of 218 samples from 2006, 17% of 320 from 2007, and in none of 242 from 2008. A separate case report found abdominal distension in six of eight infants with HPeV.

Data Source: Retrospective RT-PCR analysis of frozen CSF samples from a 3-year period in the larger study, and a case report of eight infants.

Disclosures: The Kansas City study was supported by research residual funds from Dr. Selvarangan. Dr. Selvarangan said he had no other relevant financial disclosures. Dr. Bangalore said he had no relevant financial disclosures.

Human parechovirus was found in 7.4% of nearly 800 cerebrospinal fluid samples taken from children seen at a Midwestern U.S. pediatric hospital over a 3-year period, Rangaraj Selvarangan, Ph.D., and his associates reported.

Sepsislike syndrome was the most common clinical presentation in that group, along with irritability, fever, and nonspecific rash. However, the combination of abdominal distension and an erythematous rash was a distinctive feature of human parechovirus (HPeV) among eight infants with sepsislike illness described in a separate case series report published in the same issue (PIDJ 2011;30:260–2; also available at http://journals.lww.com/pidj/Fulltext/2011/03000/Abdominal_Distension__An_Important_Feature_in.21.aspx

Human parechovirus (HPeV) is a newly classified genus (“Parechovirus”) that was previously classified as enterovirus within the family Picornaviridae. Detectable by specific (i.e., not enteroviral) real-time reverse-transcription polymerase chain reaction (RT-PCR) assay, HPeV has been associated with sepsislike illness and meningitis, particularly in young infants. Until now, epidemiologic data on HPeV illness have come from Europe, South America, and Asia, but not the United States, said Dr. Selvarangan and his associates at Children's Mercy Hospital, Kansas City, Mo. (PIDJ 2011;30:238–42; also available at http://journals.lww.com/pidj/Fulltext/2011/03000/Human_Parechovirus_3_Causing_Sepsis_like_Illness.13.aspx

Of 780 enterovirus RNA–negative cerebral spinal fluid (CSF) samples taken during 2006–2008, RT-PCR detected HPeV in 2% of 218 samples from 2006, 17% of 320 from 2007, and none of 242 from 2008.

Most samples were taken between June and October. The prevalence of enterovirus in CSF from children in the Kansas City area during the same time frame ranged from 20% to 33%, the investigators noted.

Most of those positive for HPeV were male (71%), with a mean age of 6.6 weeks (range 1 week to 7 months). Two-thirds (66%) presented with sepsislike syndrome, and 19% with suspected meningitis.

The most common symptoms were irritability (98%), fever (95%), and maculopapular rash (60%).

Mottling of the extremities was noted in 18%, and hypothermia in 9%.

Other signs included vomiting (19%), nonpurulent conjunctivitis (9%), neurologic symptoms (7%), abdominal distension (5%), and apnea (2%).

In contrast, among the eight infant cases reported in a separate article, five had abdominal distension – including one case so severe it was mistaken for a surgical condition – while six had an erythematous rash and four had both.

Definite neurologic symptoms, including seizures, hypotonia, and apnea, were also present in four infants, Dr. Harish Bangalore of Evelina Children's Hospital, London, reported.

In the larger Kansas City study, CSF pleocytosis was noted in only 7 of the 58 patients (12%), and abnormal CSF glucose and protein also were uncommon. Of the 54 patients with complete blood count data, the mean peripheral white blood cell count was 7,000/mm

Of 30 patients with viral cultures, all were negative and just 1 bacterial culture was positive. All but one patient was hospitalized, with a mean stay of 3.6 days (range 0–13 days).

Nearly all patients (57/58) were treated with IV antibacterials.

A limitation of the study was that it only included cases in which meningitis or sepsis was suspected, so that other clinical presentations of HPeV – such as upper respiratory infection – would not have been detected, Dr. Selvarangan and associates noted.

All of the eight case-reported infants (mean age 25 days) had lymphopenia at admission, combined in five infants with a failure to mount a C-reactive protein (CRP) response of more than 5 mg/L during their illness.

CSF was the source of the HPeV-positive sample in six of the eight, stool/rectal swabs in four, and blood in one, Dr. Bangalore and associates commented.

The “striking” clinical picture of prominent abdominal distension and a widespread erythematous rash in a young infant with sepsislike illness, along with fever, irritability, lymphopenia, and relative thrombocytopenia without CRP elevation, may assist in early diagnosis and avoid both confusion with surgical conditions and unnecessary broad-spectrum antibiotic use.

A specific RT-PCR assay is required for HPeV detection from blood, CSF, throat, or rectal swabs, rather than the standard enterovirus detection methods, Dr. Bangalore and associates noted.

The Kansas City investigators found a triad of fever, irritability, and rash as the most common presentation of HPeV in their study, with infections occurring in late summer or autumn with “strikingly variable annual prevalence.”

Dr. Selvarangan and his associates suggested “that HPeV CNS infection should be considered with sepsislike illness of infants even in the absence of CSF pleocytosis.

Addition of HPeV RT-PCR assay to the enterovirus RT-PCR assay on pediatric CSF specimens (particularly infants less than 6 months old) could reduce hospital stay, antibiotic usage, and hospitalization costs,” they commented

Major Finding: Of 780 enterovirus RNA–negative CSF samples taken during 2006–2008, RT-PCR was detected HPeV in 2% of 218 samples from 2006, 17% of 320 from 2007, and in none of 242 from 2008. A separate case report found abdominal distension in six of eight infants with HPeV.

Data Source: Retrospective RT-PCR analysis of frozen CSF samples from a 3-year period in the larger study, and a case report of eight infants.

Disclosures: The Kansas City study was supported by research residual funds from Dr. Selvarangan. Dr. Selvarangan said he had no other relevant financial disclosures. Dr. Bangalore said he had no relevant financial disclosures.

Human parechovirus was found in 7.4% of nearly 800 cerebrospinal fluid samples taken from children seen at a Midwestern U.S. pediatric hospital over a 3-year period, Rangaraj Selvarangan, Ph.D., and his associates reported.

Sepsislike syndrome was the most common clinical presentation in that group, along with irritability, fever, and nonspecific rash. However, the combination of abdominal distension and an erythematous rash was a distinctive feature of human parechovirus (HPeV) among eight infants with sepsislike illness described in a separate case series report published in the same issue (PIDJ 2011;30:260–2; also available at http://journals.lww.com/pidj/Fulltext/2011/03000/Abdominal_Distension__An_Important_Feature_in.21.aspx

Human parechovirus (HPeV) is a newly classified genus (“Parechovirus”) that was previously classified as enterovirus within the family Picornaviridae. Detectable by specific (i.e., not enteroviral) real-time reverse-transcription polymerase chain reaction (RT-PCR) assay, HPeV has been associated with sepsislike illness and meningitis, particularly in young infants. Until now, epidemiologic data on HPeV illness have come from Europe, South America, and Asia, but not the United States, said Dr. Selvarangan and his associates at Children's Mercy Hospital, Kansas City, Mo. (PIDJ 2011;30:238–42; also available at http://journals.lww.com/pidj/Fulltext/2011/03000/Human_Parechovirus_3_Causing_Sepsis_like_Illness.13.aspx

Of 780 enterovirus RNA–negative cerebral spinal fluid (CSF) samples taken during 2006–2008, RT-PCR detected HPeV in 2% of 218 samples from 2006, 17% of 320 from 2007, and none of 242 from 2008.

Most samples were taken between June and October. The prevalence of enterovirus in CSF from children in the Kansas City area during the same time frame ranged from 20% to 33%, the investigators noted.

Most of those positive for HPeV were male (71%), with a mean age of 6.6 weeks (range 1 week to 7 months). Two-thirds (66%) presented with sepsislike syndrome, and 19% with suspected meningitis.

The most common symptoms were irritability (98%), fever (95%), and maculopapular rash (60%).

Mottling of the extremities was noted in 18%, and hypothermia in 9%.

Other signs included vomiting (19%), nonpurulent conjunctivitis (9%), neurologic symptoms (7%), abdominal distension (5%), and apnea (2%).

In contrast, among the eight infant cases reported in a separate article, five had abdominal distension – including one case so severe it was mistaken for a surgical condition – while six had an erythematous rash and four had both.

Definite neurologic symptoms, including seizures, hypotonia, and apnea, were also present in four infants, Dr. Harish Bangalore of Evelina Children's Hospital, London, reported.

In the larger Kansas City study, CSF pleocytosis was noted in only 7 of the 58 patients (12%), and abnormal CSF glucose and protein also were uncommon. Of the 54 patients with complete blood count data, the mean peripheral white blood cell count was 7,000/mm

Of 30 patients with viral cultures, all were negative and just 1 bacterial culture was positive. All but one patient was hospitalized, with a mean stay of 3.6 days (range 0–13 days).

Nearly all patients (57/58) were treated with IV antibacterials.

A limitation of the study was that it only included cases in which meningitis or sepsis was suspected, so that other clinical presentations of HPeV – such as upper respiratory infection – would not have been detected, Dr. Selvarangan and associates noted.

All of the eight case-reported infants (mean age 25 days) had lymphopenia at admission, combined in five infants with a failure to mount a C-reactive protein (CRP) response of more than 5 mg/L during their illness.

CSF was the source of the HPeV-positive sample in six of the eight, stool/rectal swabs in four, and blood in one, Dr. Bangalore and associates commented.

The “striking” clinical picture of prominent abdominal distension and a widespread erythematous rash in a young infant with sepsislike illness, along with fever, irritability, lymphopenia, and relative thrombocytopenia without CRP elevation, may assist in early diagnosis and avoid both confusion with surgical conditions and unnecessary broad-spectrum antibiotic use.

A specific RT-PCR assay is required for HPeV detection from blood, CSF, throat, or rectal swabs, rather than the standard enterovirus detection methods, Dr. Bangalore and associates noted.

The Kansas City investigators found a triad of fever, irritability, and rash as the most common presentation of HPeV in their study, with infections occurring in late summer or autumn with “strikingly variable annual prevalence.”

Dr. Selvarangan and his associates suggested “that HPeV CNS infection should be considered with sepsislike illness of infants even in the absence of CSF pleocytosis.

Addition of HPeV RT-PCR assay to the enterovirus RT-PCR assay on pediatric CSF specimens (particularly infants less than 6 months old) could reduce hospital stay, antibiotic usage, and hospitalization costs,” they commented

Major Finding: Of 780 enterovirus RNA–negative CSF samples taken during 2006–2008, RT-PCR was detected HPeV in 2% of 218 samples from 2006, 17% of 320 from 2007, and in none of 242 from 2008. A separate case report found abdominal distension in six of eight infants with HPeV.

Data Source: Retrospective RT-PCR analysis of frozen CSF samples from a 3-year period in the larger study, and a case report of eight infants.

Disclosures: The Kansas City study was supported by research residual funds from Dr. Selvarangan. Dr. Selvarangan said he had no other relevant financial disclosures. Dr. Bangalore said he had no relevant financial disclosures.

Human parechovirus was found in 7.4% of nearly 800 cerebrospinal fluid samples taken from children seen at a Midwestern U.S. pediatric hospital over a 3-year period, Rangaraj Selvarangan, Ph.D., and his associates reported.

Sepsislike syndrome was the most common clinical presentation in that group, along with irritability, fever, and nonspecific rash. However, the combination of abdominal distension and an erythematous rash was a distinctive feature of human parechovirus (HPeV) among eight infants with sepsislike illness described in a separate case series report published in the same issue (PIDJ 2011;30:260–2; also available at http://journals.lww.com/pidj/Fulltext/2011/03000/Abdominal_Distension__An_Important_Feature_in.21.aspx

Human parechovirus (HPeV) is a newly classified genus (“Parechovirus”) that was previously classified as enterovirus within the family Picornaviridae. Detectable by specific (i.e., not enteroviral) real-time reverse-transcription polymerase chain reaction (RT-PCR) assay, HPeV has been associated with sepsislike illness and meningitis, particularly in young infants. Until now, epidemiologic data on HPeV illness have come from Europe, South America, and Asia, but not the United States, said Dr. Selvarangan and his associates at Children's Mercy Hospital, Kansas City, Mo. (PIDJ 2011;30:238–42; also available at http://journals.lww.com/pidj/Fulltext/2011/03000/Human_Parechovirus_3_Causing_Sepsis_like_Illness.13.aspx

Of 780 enterovirus RNA–negative cerebral spinal fluid (CSF) samples taken during 2006–2008, RT-PCR detected HPeV in 2% of 218 samples from 2006, 17% of 320 from 2007, and none of 242 from 2008.

Most samples were taken between June and October. The prevalence of enterovirus in CSF from children in the Kansas City area during the same time frame ranged from 20% to 33%, the investigators noted.

Most of those positive for HPeV were male (71%), with a mean age of 6.6 weeks (range 1 week to 7 months). Two-thirds (66%) presented with sepsislike syndrome, and 19% with suspected meningitis.

The most common symptoms were irritability (98%), fever (95%), and maculopapular rash (60%).

Mottling of the extremities was noted in 18%, and hypothermia in 9%.

Other signs included vomiting (19%), nonpurulent conjunctivitis (9%), neurologic symptoms (7%), abdominal distension (5%), and apnea (2%).

In contrast, among the eight infant cases reported in a separate article, five had abdominal distension – including one case so severe it was mistaken for a surgical condition – while six had an erythematous rash and four had both.

Definite neurologic symptoms, including seizures, hypotonia, and apnea, were also present in four infants, Dr. Harish Bangalore of Evelina Children's Hospital, London, reported.

In the larger Kansas City study, CSF pleocytosis was noted in only 7 of the 58 patients (12%), and abnormal CSF glucose and protein also were uncommon. Of the 54 patients with complete blood count data, the mean peripheral white blood cell count was 7,000/mm

Of 30 patients with viral cultures, all were negative and just 1 bacterial culture was positive. All but one patient was hospitalized, with a mean stay of 3.6 days (range 0–13 days).

Nearly all patients (57/58) were treated with IV antibacterials.

A limitation of the study was that it only included cases in which meningitis or sepsis was suspected, so that other clinical presentations of HPeV – such as upper respiratory infection – would not have been detected, Dr. Selvarangan and associates noted.

All of the eight case-reported infants (mean age 25 days) had lymphopenia at admission, combined in five infants with a failure to mount a C-reactive protein (CRP) response of more than 5 mg/L during their illness.

CSF was the source of the HPeV-positive sample in six of the eight, stool/rectal swabs in four, and blood in one, Dr. Bangalore and associates commented.

The “striking” clinical picture of prominent abdominal distension and a widespread erythematous rash in a young infant with sepsislike illness, along with fever, irritability, lymphopenia, and relative thrombocytopenia without CRP elevation, may assist in early diagnosis and avoid both confusion with surgical conditions and unnecessary broad-spectrum antibiotic use.

A specific RT-PCR assay is required for HPeV detection from blood, CSF, throat, or rectal swabs, rather than the standard enterovirus detection methods, Dr. Bangalore and associates noted.

The Kansas City investigators found a triad of fever, irritability, and rash as the most common presentation of HPeV in their study, with infections occurring in late summer or autumn with “strikingly variable annual prevalence.”

Dr. Selvarangan and his associates suggested “that HPeV CNS infection should be considered with sepsislike illness of infants even in the absence of CSF pleocytosis.

Addition of HPeV RT-PCR assay to the enterovirus RT-PCR assay on pediatric CSF specimens (particularly infants less than 6 months old) could reduce hospital stay, antibiotic usage, and hospitalization costs,” they commented

Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at both higher and lower risk for fracture, in a post-hoc analysis of data from a 3-year, phase III randomized trial in the Journal of Clinical Endocrinology & Metabolism.

The monoclonal antibody denosumab (Prolia) was approved in June 2010 for treatment of postmenopausal women who have a high risk of osteoporotic fractures. In phase II and III trials, denosumab rapidly decreased bone resorption markers and increased bone mineral density at all skeletal sites, compared with placebo, wrote Dr. S. Boonen of Leuven (Belgium) University and his associates (J. Clin. Endocrinol. Metab. 2011;96 [doi:10.1210/jc.2010-2784]).

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial enrolled 7,808 postmenopausal women aged 60-80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than –2.5 but not less than –4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

The new analysis compared high-risk and low-risk groups within the FREEDOM population. High-risk groups included women with two or more preexisting vertebral fractures of any degree of deformity, or one or more vertebral fractures of moderate or severe deformity, or both; a femoral neck BMD T score of -2.5 or less; or both multiple and/or moderate or severe vertebral deformities and a femoral neck BMD T score of –2.5 or less.

For hip fractures, the higher-risk subgroups included women who were age 75 years or older; had a femoral neck BMD T score of –2.5 or less; or were 75 years or older with a femoral neck BMD T score of –2.5 or less. Women who did not have those specified risk factors were included in the lower-risk subgroups.

Over 3 years, denosumab treatment was equally effective at reducing the risk of new vertebral fractures in women at both higher and lower risk for those types of fractures, similar to the overall FREEDOM population. Compared with placebo, denosumab reduced the incidence of vertebral fracture in the subgroups at higher risk by prevalent vertebral fracture status by 9.2% (16.6% placebo vs. 7.5% denosumab) among those at risk via baseline femoral neck BMD T score of –2.5 by 6.8% (9.9% vs. 3.1%), and among those with both risk factors by 12.3% (20.1% vs. 8.1%).

The numbers needed to treat to prevent one vertebral fracture in each of these higher-risk subgroups were 11, 15, and 12, respectively, Dr. Boonen and his associates said.

Similar results were seen for the lower-risk groups, including a 4.4% absolute risk reduction in those without prevalent vertebral fracture, 3.7% for those with BMD T score greater than –2.5, and 4.5% for those with without one or both risk factors. Subgroup results for hip fractures were also consistent with the findings from the overall FREEDOM population, with the same efficacy of denosumab consistent across patients with different levels of risk. Compared with placebo, denosumab treatment significantly reduced the incidence of hip fracture among those aged 75 years or older by 1.4% (2.3% placebo vs. 0.9% denosumab); those with a baseline femoral neck BMD T score of -2.5 or less by 1.4% (2.8% vs. 1.4%); and by 2.4% among those with both risk factors (4.1% vs. 1.7%).

"It is reassuring to see that the effect is similar across a range of fracture risk. ... The FDA-approved indication for denosumab is for ‘postmenopausal women at high risk of fracture,’ but the FREEDOM trial was not enriched with ‘women at high risk,’ " noted Dr. Nelson Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, in an interview. Risk reduction for hip fractures was low in the lower-risk subgroups because the incidence of hip fractures was low, and the difference between the denosumab and placebo groups was therefore not statistically significant. Adverse event incidences were also not statistically different between the treatment groups within any of the higher- and lower-risk subgroups, and were consistent with the adverse event incidences for the overall FREEDOM trial, the investigators said.

Overall mortality was lower – but not significantly so – among all the subgroups with denosumab. However, there was a significantly lower incidence of fatal adverse events with denosumab vs. placebo in the higher-risk group with prevalent vertebral fracture (1.8% vs. 4.9%) and in those with both prevalent vertebral fracture and low femoral neck BMD (1.6% vs. 7.1%). The difference in mortality among the higher-risk subgroups was greater than that of the lower-risk groups, they noted.

The reason for the mortality difference is unclear, Dr. Watts said. "This was not an end point in the main trail and only significant in a small subgroup of high risk patients. It’s clear that women who fracture have decreased survival, so it’s logical that preventing fracture would reduce mortality."

"Our analyses highlight the consistency of the antifracture efficacy of denosumab across subjects with differences in a variety of major risk factors for fractures at baseline. Our analyses suggests that denosumab reduces both new vertebral and hip fractures, regardless of the underlying risk and that the higher absolute fracture risk observed in the higher-risk subgroups is associated with greater absolute risk reduction. These analyses add to the evidence that denosumab is an effective option for the treatment of postmenopausal osteoporosis," Dr. Boonen and his associates concluded.

The study was funded by Amgen Inc. Dr. Boonen has received funding for serving as a trial investigator and as a member of the steering committee for Amgen, as well as consulting and lecture fees from the company. He is also senior clinical investigator of the Fund for Scientific Research in Flanders, Belgium. Four of the study’s coinvestigators are employees of Amgen, and the others disclosed relationships with Amgen and several other pharmaceutical companies. Dr. Watts is director, cofounder, and owner OsteoDynamics and holds stock and patents. He has received fees and/or honoraria from numerous drug companies including Amgen, Novartis, Warner Chilcott, Johnson & Johnson, Merck, and Takeda, Vivus, and Warner Chilcott. Through his university, he has research support from Amgen, Merck, and NPS.

Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at both higher and lower risk for fracture, in a post-hoc analysis of data from a 3-year, phase III randomized trial in the Journal of Clinical Endocrinology & Metabolism.

The monoclonal antibody denosumab (Prolia) was approved in June 2010 for treatment of postmenopausal women who have a high risk of osteoporotic fractures. In phase II and III trials, denosumab rapidly decreased bone resorption markers and increased bone mineral density at all skeletal sites, compared with placebo, wrote Dr. S. Boonen of Leuven (Belgium) University and his associates (J. Clin. Endocrinol. Metab. 2011;96 [doi:10.1210/jc.2010-2784]).

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial enrolled 7,808 postmenopausal women aged 60-80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than –2.5 but not less than –4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

The new analysis compared high-risk and low-risk groups within the FREEDOM population. High-risk groups included women with two or more preexisting vertebral fractures of any degree of deformity, or one or more vertebral fractures of moderate or severe deformity, or both; a femoral neck BMD T score of -2.5 or less; or both multiple and/or moderate or severe vertebral deformities and a femoral neck BMD T score of –2.5 or less.

For hip fractures, the higher-risk subgroups included women who were age 75 years or older; had a femoral neck BMD T score of –2.5 or less; or were 75 years or older with a femoral neck BMD T score of –2.5 or less. Women who did not have those specified risk factors were included in the lower-risk subgroups.

Over 3 years, denosumab treatment was equally effective at reducing the risk of new vertebral fractures in women at both higher and lower risk for those types of fractures, similar to the overall FREEDOM population. Compared with placebo, denosumab reduced the incidence of vertebral fracture in the subgroups at higher risk by prevalent vertebral fracture status by 9.2% (16.6% placebo vs. 7.5% denosumab) among those at risk via baseline femoral neck BMD T score of –2.5 by 6.8% (9.9% vs. 3.1%), and among those with both risk factors by 12.3% (20.1% vs. 8.1%).

The numbers needed to treat to prevent one vertebral fracture in each of these higher-risk subgroups were 11, 15, and 12, respectively, Dr. Boonen and his associates said.

Similar results were seen for the lower-risk groups, including a 4.4% absolute risk reduction in those without prevalent vertebral fracture, 3.7% for those with BMD T score greater than –2.5, and 4.5% for those with without one or both risk factors. Subgroup results for hip fractures were also consistent with the findings from the overall FREEDOM population, with the same efficacy of denosumab consistent across patients with different levels of risk. Compared with placebo, denosumab treatment significantly reduced the incidence of hip fracture among those aged 75 years or older by 1.4% (2.3% placebo vs. 0.9% denosumab); those with a baseline femoral neck BMD T score of -2.5 or less by 1.4% (2.8% vs. 1.4%); and by 2.4% among those with both risk factors (4.1% vs. 1.7%).

"It is reassuring to see that the effect is similar across a range of fracture risk. ... The FDA-approved indication for denosumab is for ‘postmenopausal women at high risk of fracture,’ but the FREEDOM trial was not enriched with ‘women at high risk,’ " noted Dr. Nelson Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, in an interview. Risk reduction for hip fractures was low in the lower-risk subgroups because the incidence of hip fractures was low, and the difference between the denosumab and placebo groups was therefore not statistically significant. Adverse event incidences were also not statistically different between the treatment groups within any of the higher- and lower-risk subgroups, and were consistent with the adverse event incidences for the overall FREEDOM trial, the investigators said.

Overall mortality was lower – but not significantly so – among all the subgroups with denosumab. However, there was a significantly lower incidence of fatal adverse events with denosumab vs. placebo in the higher-risk group with prevalent vertebral fracture (1.8% vs. 4.9%) and in those with both prevalent vertebral fracture and low femoral neck BMD (1.6% vs. 7.1%). The difference in mortality among the higher-risk subgroups was greater than that of the lower-risk groups, they noted.

The reason for the mortality difference is unclear, Dr. Watts said. "This was not an end point in the main trail and only significant in a small subgroup of high risk patients. It’s clear that women who fracture have decreased survival, so it’s logical that preventing fracture would reduce mortality."

"Our analyses highlight the consistency of the antifracture efficacy of denosumab across subjects with differences in a variety of major risk factors for fractures at baseline. Our analyses suggests that denosumab reduces both new vertebral and hip fractures, regardless of the underlying risk and that the higher absolute fracture risk observed in the higher-risk subgroups is associated with greater absolute risk reduction. These analyses add to the evidence that denosumab is an effective option for the treatment of postmenopausal osteoporosis," Dr. Boonen and his associates concluded.

The study was funded by Amgen Inc. Dr. Boonen has received funding for serving as a trial investigator and as a member of the steering committee for Amgen, as well as consulting and lecture fees from the company. He is also senior clinical investigator of the Fund for Scientific Research in Flanders, Belgium. Four of the study’s coinvestigators are employees of Amgen, and the others disclosed relationships with Amgen and several other pharmaceutical companies. Dr. Watts is director, cofounder, and owner OsteoDynamics and holds stock and patents. He has received fees and/or honoraria from numerous drug companies including Amgen, Novartis, Warner Chilcott, Johnson & Johnson, Merck, and Takeda, Vivus, and Warner Chilcott. Through his university, he has research support from Amgen, Merck, and NPS.

Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at both higher and lower risk for fracture, in a post-hoc analysis of data from a 3-year, phase III randomized trial in the Journal of Clinical Endocrinology & Metabolism.

The monoclonal antibody denosumab (Prolia) was approved in June 2010 for treatment of postmenopausal women who have a high risk of osteoporotic fractures. In phase II and III trials, denosumab rapidly decreased bone resorption markers and increased bone mineral density at all skeletal sites, compared with placebo, wrote Dr. S. Boonen of Leuven (Belgium) University and his associates (J. Clin. Endocrinol. Metab. 2011;96 [doi:10.1210/jc.2010-2784]).

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial enrolled 7,808 postmenopausal women aged 60-80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than –2.5 but not less than –4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

The new analysis compared high-risk and low-risk groups within the FREEDOM population. High-risk groups included women with two or more preexisting vertebral fractures of any degree of deformity, or one or more vertebral fractures of moderate or severe deformity, or both; a femoral neck BMD T score of -2.5 or less; or both multiple and/or moderate or severe vertebral deformities and a femoral neck BMD T score of –2.5 or less.

For hip fractures, the higher-risk subgroups included women who were age 75 years or older; had a femoral neck BMD T score of –2.5 or less; or were 75 years or older with a femoral neck BMD T score of –2.5 or less. Women who did not have those specified risk factors were included in the lower-risk subgroups.

Over 3 years, denosumab treatment was equally effective at reducing the risk of new vertebral fractures in women at both higher and lower risk for those types of fractures, similar to the overall FREEDOM population. Compared with placebo, denosumab reduced the incidence of vertebral fracture in the subgroups at higher risk by prevalent vertebral fracture status by 9.2% (16.6% placebo vs. 7.5% denosumab) among those at risk via baseline femoral neck BMD T score of –2.5 by 6.8% (9.9% vs. 3.1%), and among those with both risk factors by 12.3% (20.1% vs. 8.1%).

The numbers needed to treat to prevent one vertebral fracture in each of these higher-risk subgroups were 11, 15, and 12, respectively, Dr. Boonen and his associates said.

Similar results were seen for the lower-risk groups, including a 4.4% absolute risk reduction in those without prevalent vertebral fracture, 3.7% for those with BMD T score greater than –2.5, and 4.5% for those with without one or both risk factors. Subgroup results for hip fractures were also consistent with the findings from the overall FREEDOM population, with the same efficacy of denosumab consistent across patients with different levels of risk. Compared with placebo, denosumab treatment significantly reduced the incidence of hip fracture among those aged 75 years or older by 1.4% (2.3% placebo vs. 0.9% denosumab); those with a baseline femoral neck BMD T score of -2.5 or less by 1.4% (2.8% vs. 1.4%); and by 2.4% among those with both risk factors (4.1% vs. 1.7%).

"It is reassuring to see that the effect is similar across a range of fracture risk. ... The FDA-approved indication for denosumab is for ‘postmenopausal women at high risk of fracture,’ but the FREEDOM trial was not enriched with ‘women at high risk,’ " noted Dr. Nelson Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, in an interview. Risk reduction for hip fractures was low in the lower-risk subgroups because the incidence of hip fractures was low, and the difference between the denosumab and placebo groups was therefore not statistically significant. Adverse event incidences were also not statistically different between the treatment groups within any of the higher- and lower-risk subgroups, and were consistent with the adverse event incidences for the overall FREEDOM trial, the investigators said.

Overall mortality was lower – but not significantly so – among all the subgroups with denosumab. However, there was a significantly lower incidence of fatal adverse events with denosumab vs. placebo in the higher-risk group with prevalent vertebral fracture (1.8% vs. 4.9%) and in those with both prevalent vertebral fracture and low femoral neck BMD (1.6% vs. 7.1%). The difference in mortality among the higher-risk subgroups was greater than that of the lower-risk groups, they noted.

The reason for the mortality difference is unclear, Dr. Watts said. "This was not an end point in the main trail and only significant in a small subgroup of high risk patients. It’s clear that women who fracture have decreased survival, so it’s logical that preventing fracture would reduce mortality."

"Our analyses highlight the consistency of the antifracture efficacy of denosumab across subjects with differences in a variety of major risk factors for fractures at baseline. Our analyses suggests that denosumab reduces both new vertebral and hip fractures, regardless of the underlying risk and that the higher absolute fracture risk observed in the higher-risk subgroups is associated with greater absolute risk reduction. These analyses add to the evidence that denosumab is an effective option for the treatment of postmenopausal osteoporosis," Dr. Boonen and his associates concluded.

The study was funded by Amgen Inc. Dr. Boonen has received funding for serving as a trial investigator and as a member of the steering committee for Amgen, as well as consulting and lecture fees from the company. He is also senior clinical investigator of the Fund for Scientific Research in Flanders, Belgium. Four of the study’s coinvestigators are employees of Amgen, and the others disclosed relationships with Amgen and several other pharmaceutical companies. Dr. Watts is director, cofounder, and owner OsteoDynamics and holds stock and patents. He has received fees and/or honoraria from numerous drug companies including Amgen, Novartis, Warner Chilcott, Johnson & Johnson, Merck, and Takeda, Vivus, and Warner Chilcott. Through his university, he has research support from Amgen, Merck, and NPS.

Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at both higher and lower risk for fracture, in a post-hoc analysis of data from a 3-year, phase III randomized trial in the Journal of Clinical Endocrinology & Metabolism.

The monoclonal antibody denosumab (Prolia) was approved in June 2010 for treatment of postmenopausal women who have a high risk of osteoporotic fractures. In phase II and III trials, denosumab rapidly decreased bone resorption markers and increased bone mineral density at all skeletal sites, compared with placebo, wrote Dr. S. Boonen of Leuven (Belgium) University and his associates (J. Clin. Endocrinol. Metab. 2011;96 [doi:10.1210/jc.2010-2784]).

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial enrolled 7,808 postmenopausal women aged 60-80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than –2.5 but not less than –4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

The new analysis compared high-risk and low-risk groups within the FREEDOM population. High-risk groups included women with two or more preexisting vertebral fractures of any degree of deformity, or one or more vertebral fractures of moderate or severe deformity, or both; a femoral neck BMD T score of -2.5 or less; or both multiple and/or moderate or severe vertebral deformities and a femoral neck BMD T score of –2.5 or less.

For hip fractures, the higher-risk subgroups included women who were age 75 years or older; had a femoral neck BMD T score of –2.5 or less; or were 75 years or older with a femoral neck BMD T score of –2.5 or less. Women who did not have those specified risk factors were included in the lower-risk subgroups.

Over 3 years, denosumab treatment was equally effective at reducing the risk of new vertebral fractures in women at both higher and lower risk for those types of fractures, similar to the overall FREEDOM population. Compared with placebo, denosumab reduced the incidence of vertebral fracture in the subgroups at higher risk by prevalent vertebral fracture status by 9.2% (16.6% placebo vs. 7.5% denosumab) among those at risk via baseline femoral neck BMD T score of –2.5 by 6.8% (9.9% vs. 3.1%), and among those with both risk factors by 12.3% (20.1% vs. 8.1%).

The numbers needed to treat to prevent one vertebral fracture in each of these higher-risk subgroups were 11, 15, and 12, respectively, Dr. Boonen and his associates said.

Similar results were seen for the lower-risk groups, including a 4.4% absolute risk reduction in those without prevalent vertebral fracture, 3.7% for those with BMD T score greater than –2.5, and 4.5% for those with without one or both risk factors. Subgroup results for hip fractures were also consistent with the findings from the overall FREEDOM population, with the same efficacy of denosumab consistent across patients with different levels of risk. Compared with placebo, denosumab treatment significantly reduced the incidence of hip fracture among those aged 75 years or older by 1.4% (2.3% placebo vs. 0.9% denosumab); those with a baseline femoral neck BMD T score of -2.5 or less by 1.4% (2.8% vs. 1.4%); and by 2.4% among those with both risk factors (4.1% vs. 1.7%).

"It is reassuring to see that the effect is similar across a range of fracture risk. ... The FDA-approved indication for denosumab is for ‘postmenopausal women at high risk of fracture,’ but the FREEDOM trial was not enriched with ‘women at high risk,’ " noted Dr. Nelson Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, in an interview. Risk reduction for hip fractures was low in the lower-risk subgroups because the incidence of hip fractures was low, and the difference between the denosumab and placebo groups was therefore not statistically significant. Adverse event incidences were also not statistically different between the treatment groups within any of the higher- and lower-risk subgroups, and were consistent with the adverse event incidences for the overall FREEDOM trial, the investigators said.

Overall mortality was lower – but not significantly so – among all the subgroups with denosumab. However, there was a significantly lower incidence of fatal adverse events with denosumab vs. placebo in the higher-risk group with prevalent vertebral fracture (1.8% vs. 4.9%) and in those with both prevalent vertebral fracture and low femoral neck BMD (1.6% vs. 7.1%). The difference in mortality among the higher-risk subgroups was greater than that of the lower-risk groups, they noted.

The reason for the mortality difference is unclear, Dr. Watts said. "This was not an end point in the main trail and only significant in a small subgroup of high risk patients. It’s clear that women who fracture have decreased survival, so it’s logical that preventing fracture would reduce mortality."

"Our analyses highlight the consistency of the antifracture efficacy of denosumab across subjects with differences in a variety of major risk factors for fractures at baseline. Our analyses suggests that denosumab reduces both new vertebral and hip fractures, regardless of the underlying risk and that the higher absolute fracture risk observed in the higher-risk subgroups is associated with greater absolute risk reduction. These analyses add to the evidence that denosumab is an effective option for the treatment of postmenopausal osteoporosis," Dr. Boonen and his associates concluded.

The study was funded by Amgen Inc. Dr. Boonen has received funding for serving as a trial investigator and as a member of the steering committee for Amgen, as well as consulting and lecture fees from the company. He is also senior clinical investigator of the Fund for Scientific Research in Flanders, Belgium. Four of the study’s coinvestigators are employees of Amgen, and the others disclosed relationships with Amgen and several other pharmaceutical companies. Dr. Watts is director, cofounder, and owner OsteoDynamics and holds stock and patents. He has received fees and/or honoraria from numerous drug companies including Amgen, Novartis, Warner Chilcott, Johnson & Johnson, Merck, and Takeda, Vivus, and Warner Chilcott. Through his university, he has research support from Amgen, Merck, and NPS.

Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at both higher and lower risk for fracture, in a post-hoc analysis of data from a 3-year, phase III randomized trial in the Journal of Clinical Endocrinology & Metabolism.

The monoclonal antibody denosumab (Prolia) was approved in June 2010 for treatment of postmenopausal women who have a high risk of osteoporotic fractures. In phase II and III trials, denosumab rapidly decreased bone resorption markers and increased bone mineral density at all skeletal sites, compared with placebo, wrote Dr. S. Boonen of Leuven (Belgium) University and his associates (J. Clin. Endocrinol. Metab. 2011;96 [doi:10.1210/jc.2010-2784]).

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial enrolled 7,808 postmenopausal women aged 60-80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than –2.5 but not less than –4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

The new analysis compared high-risk and low-risk groups within the FREEDOM population. High-risk groups included women with two or more preexisting vertebral fractures of any degree of deformity, or one or more vertebral fractures of moderate or severe deformity, or both; a femoral neck BMD T score of -2.5 or less; or both multiple and/or moderate or severe vertebral deformities and a femoral neck BMD T score of –2.5 or less.

For hip fractures, the higher-risk subgroups included women who were age 75 years or older; had a femoral neck BMD T score of –2.5 or less; or were 75 years or older with a femoral neck BMD T score of –2.5 or less. Women who did not have those specified risk factors were included in the lower-risk subgroups.

Over 3 years, denosumab treatment was equally effective at reducing the risk of new vertebral fractures in women at both higher and lower risk for those types of fractures, similar to the overall FREEDOM population. Compared with placebo, denosumab reduced the incidence of vertebral fracture in the subgroups at higher risk by prevalent vertebral fracture status by 9.2% (16.6% placebo vs. 7.5% denosumab) among those at risk via baseline femoral neck BMD T score of –2.5 by 6.8% (9.9% vs. 3.1%), and among those with both risk factors by 12.3% (20.1% vs. 8.1%).

The numbers needed to treat to prevent one vertebral fracture in each of these higher-risk subgroups were 11, 15, and 12, respectively, Dr. Boonen and his associates said.

Similar results were seen for the lower-risk groups, including a 4.4% absolute risk reduction in those without prevalent vertebral fracture, 3.7% for those with BMD T score greater than –2.5, and 4.5% for those with without one or both risk factors. Subgroup results for hip fractures were also consistent with the findings from the overall FREEDOM population, with the same efficacy of denosumab consistent across patients with different levels of risk. Compared with placebo, denosumab treatment significantly reduced the incidence of hip fracture among those aged 75 years or older by 1.4% (2.3% placebo vs. 0.9% denosumab); those with a baseline femoral neck BMD T score of -2.5 or less by 1.4% (2.8% vs. 1.4%); and by 2.4% among those with both risk factors (4.1% vs. 1.7%).

"It is reassuring to see that the effect is similar across a range of fracture risk. ... The FDA-approved indication for denosumab is for ‘postmenopausal women at high risk of fracture,’ but the FREEDOM trial was not enriched with ‘women at high risk,’ " noted Dr. Nelson Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, in an interview. Risk reduction for hip fractures was low in the lower-risk subgroups because the incidence of hip fractures was low, and the difference between the denosumab and placebo groups was therefore not statistically significant. Adverse event incidences were also not statistically different between the treatment groups within any of the higher- and lower-risk subgroups, and were consistent with the adverse event incidences for the overall FREEDOM trial, the investigators said.

Overall mortality was lower – but not significantly so – among all the subgroups with denosumab. However, there was a significantly lower incidence of fatal adverse events with denosumab vs. placebo in the higher-risk group with prevalent vertebral fracture (1.8% vs. 4.9%) and in those with both prevalent vertebral fracture and low femoral neck BMD (1.6% vs. 7.1%). The difference in mortality among the higher-risk subgroups was greater than that of the lower-risk groups, they noted.

The reason for the mortality difference is unclear, Dr. Watts said. "This was not an end point in the main trail and only significant in a small subgroup of high risk patients. It’s clear that women who fracture have decreased survival, so it’s logical that preventing fracture would reduce mortality."

"Our analyses highlight the consistency of the antifracture efficacy of denosumab across subjects with differences in a variety of major risk factors for fractures at baseline. Our analyses suggests that denosumab reduces both new vertebral and hip fractures, regardless of the underlying risk and that the higher absolute fracture risk observed in the higher-risk subgroups is associated with greater absolute risk reduction. These analyses add to the evidence that denosumab is an effective option for the treatment of postmenopausal osteoporosis," Dr. Boonen and his associates concluded.

The study was funded by Amgen Inc. Dr. Boonen has received funding for serving as a trial investigator and as a member of the steering committee for Amgen, as well as consulting and lecture fees from the company. He is also senior clinical investigator of the Fund for Scientific Research in Flanders, Belgium. Four of the study’s coinvestigators are employees of Amgen, and the others disclosed relationships with Amgen and several other pharmaceutical companies. Dr. Watts is director, cofounder, and owner OsteoDynamics and holds stock and patents. He has received fees and/or honoraria from numerous drug companies including Amgen, Novartis, Warner Chilcott, Johnson & Johnson, Merck, and Takeda, Vivus, and Warner Chilcott. Through his university, he has research support from Amgen, Merck, and NPS.

Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at both higher and lower risk for fracture, in a post-hoc analysis of data from a 3-year, phase III randomized trial in the Journal of Clinical Endocrinology & Metabolism.

The monoclonal antibody denosumab (Prolia) was approved in June 2010 for treatment of postmenopausal women who have a high risk of osteoporotic fractures. In phase II and III trials, denosumab rapidly decreased bone resorption markers and increased bone mineral density at all skeletal sites, compared with placebo, wrote Dr. S. Boonen of Leuven (Belgium) University and his associates (J. Clin. Endocrinol. Metab. 2011;96 [doi:10.1210/jc.2010-2784]).

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial enrolled 7,808 postmenopausal women aged 60-80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than –2.5 but not less than –4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

The new analysis compared high-risk and low-risk groups within the FREEDOM population. High-risk groups included women with two or more preexisting vertebral fractures of any degree of deformity, or one or more vertebral fractures of moderate or severe deformity, or both; a femoral neck BMD T score of -2.5 or less; or both multiple and/or moderate or severe vertebral deformities and a femoral neck BMD T score of –2.5 or less.

For hip fractures, the higher-risk subgroups included women who were age 75 years or older; had a femoral neck BMD T score of –2.5 or less; or were 75 years or older with a femoral neck BMD T score of –2.5 or less. Women who did not have those specified risk factors were included in the lower-risk subgroups.

Over 3 years, denosumab treatment was equally effective at reducing the risk of new vertebral fractures in women at both higher and lower risk for those types of fractures, similar to the overall FREEDOM population. Compared with placebo, denosumab reduced the incidence of vertebral fracture in the subgroups at higher risk by prevalent vertebral fracture status by 9.2% (16.6% placebo vs. 7.5% denosumab) among those at risk via baseline femoral neck BMD T score of –2.5 by 6.8% (9.9% vs. 3.1%), and among those with both risk factors by 12.3% (20.1% vs. 8.1%).

The numbers needed to treat to prevent one vertebral fracture in each of these higher-risk subgroups were 11, 15, and 12, respectively, Dr. Boonen and his associates said.

Similar results were seen for the lower-risk groups, including a 4.4% absolute risk reduction in those without prevalent vertebral fracture, 3.7% for those with BMD T score greater than –2.5, and 4.5% for those with without one or both risk factors. Subgroup results for hip fractures were also consistent with the findings from the overall FREEDOM population, with the same efficacy of denosumab consistent across patients with different levels of risk. Compared with placebo, denosumab treatment significantly reduced the incidence of hip fracture among those aged 75 years or older by 1.4% (2.3% placebo vs. 0.9% denosumab); those with a baseline femoral neck BMD T score of -2.5 or less by 1.4% (2.8% vs. 1.4%); and by 2.4% among those with both risk factors (4.1% vs. 1.7%).

"It is reassuring to see that the effect is similar across a range of fracture risk. ... The FDA-approved indication for denosumab is for ‘postmenopausal women at high risk of fracture,’ but the FREEDOM trial was not enriched with ‘women at high risk,’ " noted Dr. Nelson Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, in an interview. Risk reduction for hip fractures was low in the lower-risk subgroups because the incidence of hip fractures was low, and the difference between the denosumab and placebo groups was therefore not statistically significant. Adverse event incidences were also not statistically different between the treatment groups within any of the higher- and lower-risk subgroups, and were consistent with the adverse event incidences for the overall FREEDOM trial, the investigators said.

Overall mortality was lower – but not significantly so – among all the subgroups with denosumab. However, there was a significantly lower incidence of fatal adverse events with denosumab vs. placebo in the higher-risk group with prevalent vertebral fracture (1.8% vs. 4.9%) and in those with both prevalent vertebral fracture and low femoral neck BMD (1.6% vs. 7.1%). The difference in mortality among the higher-risk subgroups was greater than that of the lower-risk groups, they noted.

The reason for the mortality difference is unclear, Dr. Watts said. "This was not an end point in the main trail and only significant in a small subgroup of high risk patients. It’s clear that women who fracture have decreased survival, so it’s logical that preventing fracture would reduce mortality."

"Our analyses highlight the consistency of the antifracture efficacy of denosumab across subjects with differences in a variety of major risk factors for fractures at baseline. Our analyses suggests that denosumab reduces both new vertebral and hip fractures, regardless of the underlying risk and that the higher absolute fracture risk observed in the higher-risk subgroups is associated with greater absolute risk reduction. These analyses add to the evidence that denosumab is an effective option for the treatment of postmenopausal osteoporosis," Dr. Boonen and his associates concluded.

The study was funded by Amgen Inc. Dr. Boonen has received funding for serving as a trial investigator and as a member of the steering committee for Amgen, as well as consulting and lecture fees from the company. He is also senior clinical investigator of the Fund for Scientific Research in Flanders, Belgium. Four of the study’s coinvestigators are employees of Amgen, and the others disclosed relationships with Amgen and several other pharmaceutical companies. Dr. Watts is director, cofounder, and owner OsteoDynamics and holds stock and patents. He has received fees and/or honoraria from numerous drug companies including Amgen, Novartis, Warner Chilcott, Johnson & Johnson, Merck, and Takeda, Vivus, and Warner Chilcott. Through his university, he has research support from Amgen, Merck, and NPS.

Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at both higher and lower risk for fracture, in a post-hoc analysis of data from a 3-year, phase III randomized trial in the Journal of Clinical Endocrinology & Metabolism.

The monoclonal antibody denosumab (Prolia) was approved in June 2010 for treatment of postmenopausal women who have a high risk of osteoporotic fractures. In phase II and III trials, denosumab rapidly decreased bone resorption markers and increased bone mineral density at all skeletal sites, compared with placebo, wrote Dr. S. Boonen of Leuven (Belgium) University and his associates (J. Clin. Endocrinol. Metab. 2011;96 [doi:10.1210/jc.2010-2784]).

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial enrolled 7,808 postmenopausal women aged 60-80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than –2.5 but not less than –4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

The new analysis compared high-risk and low-risk groups within the FREEDOM population. High-risk groups included women with two or more preexisting vertebral fractures of any degree of deformity, or one or more vertebral fractures of moderate or severe deformity, or both; a femoral neck BMD T score of -2.5 or less; or both multiple and/or moderate or severe vertebral deformities and a femoral neck BMD T score of –2.5 or less.

For hip fractures, the higher-risk subgroups included women who were age 75 years or older; had a femoral neck BMD T score of –2.5 or less; or were 75 years or older with a femoral neck BMD T score of –2.5 or less. Women who did not have those specified risk factors were included in the lower-risk subgroups.

Over 3 years, denosumab treatment was equally effective at reducing the risk of new vertebral fractures in women at both higher and lower risk for those types of fractures, similar to the overall FREEDOM population. Compared with placebo, denosumab reduced the incidence of vertebral fracture in the subgroups at higher risk by prevalent vertebral fracture status by 9.2% (16.6% placebo vs. 7.5% denosumab) among those at risk via baseline femoral neck BMD T score of –2.5 by 6.8% (9.9% vs. 3.1%), and among those with both risk factors by 12.3% (20.1% vs. 8.1%).

The numbers needed to treat to prevent one vertebral fracture in each of these higher-risk subgroups were 11, 15, and 12, respectively, Dr. Boonen and his associates said.

Similar results were seen for the lower-risk groups, including a 4.4% absolute risk reduction in those without prevalent vertebral fracture, 3.7% for those with BMD T score greater than –2.5, and 4.5% for those with without one or both risk factors. Subgroup results for hip fractures were also consistent with the findings from the overall FREEDOM population, with the same efficacy of denosumab consistent across patients with different levels of risk. Compared with placebo, denosumab treatment significantly reduced the incidence of hip fracture among those aged 75 years or older by 1.4% (2.3% placebo vs. 0.9% denosumab); those with a baseline femoral neck BMD T score of -2.5 or less by 1.4% (2.8% vs. 1.4%); and by 2.4% among those with both risk factors (4.1% vs. 1.7%).

"It is reassuring to see that the effect is similar across a range of fracture risk. ... The FDA-approved indication for denosumab is for ‘postmenopausal women at high risk of fracture,’ but the FREEDOM trial was not enriched with ‘women at high risk,’ " noted Dr. Nelson Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, in an interview. Risk reduction for hip fractures was low in the lower-risk subgroups because the incidence of hip fractures was low, and the difference between the denosumab and placebo groups was therefore not statistically significant. Adverse event incidences were also not statistically different between the treatment groups within any of the higher- and lower-risk subgroups, and were consistent with the adverse event incidences for the overall FREEDOM trial, the investigators said.

Overall mortality was lower – but not significantly so – among all the subgroups with denosumab. However, there was a significantly lower incidence of fatal adverse events with denosumab vs. placebo in the higher-risk group with prevalent vertebral fracture (1.8% vs. 4.9%) and in those with both prevalent vertebral fracture and low femoral neck BMD (1.6% vs. 7.1%). The difference in mortality among the higher-risk subgroups was greater than that of the lower-risk groups, they noted.

The reason for the mortality difference is unclear, Dr. Watts said. "This was not an end point in the main trail and only significant in a small subgroup of high risk patients. It’s clear that women who fracture have decreased survival, so it’s logical that preventing fracture would reduce mortality."

"Our analyses highlight the consistency of the antifracture efficacy of denosumab across subjects with differences in a variety of major risk factors for fractures at baseline. Our analyses suggests that denosumab reduces both new vertebral and hip fractures, regardless of the underlying risk and that the higher absolute fracture risk observed in the higher-risk subgroups is associated with greater absolute risk reduction. These analyses add to the evidence that denosumab is an effective option for the treatment of postmenopausal osteoporosis," Dr. Boonen and his associates concluded.

The study was funded by Amgen Inc. Dr. Boonen has received funding for serving as a trial investigator and as a member of the steering committee for Amgen, as well as consulting and lecture fees from the company. He is also senior clinical investigator of the Fund for Scientific Research in Flanders, Belgium. Four of the study’s coinvestigators are employees of Amgen, and the others disclosed relationships with Amgen and several other pharmaceutical companies. Dr. Watts is director, cofounder, and owner OsteoDynamics and holds stock and patents. He has received fees and/or honoraria from numerous drug companies including Amgen, Novartis, Warner Chilcott, Johnson & Johnson, Merck, and Takeda, Vivus, and Warner Chilcott. Through his university, he has research support from Amgen, Merck, and NPS.

Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at both higher and lower risk for fracture, in a post-hoc analysis of data from a 3-year, phase III randomized trial in the Journal of Clinical Endocrinology & Metabolism.

The monoclonal antibody denosumab (Prolia) was approved in June 2010 for treatment of postmenopausal women who have a high risk of osteoporotic fractures. In phase II and III trials, denosumab rapidly decreased bone resorption markers and increased bone mineral density at all skeletal sites, compared with placebo, wrote Dr. S. Boonen of Leuven (Belgium) University and his associates (J. Clin. Endocrinol. Metab. 2011;96 [doi:10.1210/jc.2010-2784]).

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial enrolled 7,808 postmenopausal women aged 60-80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than –2.5 but not less than –4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

The new analysis compared high-risk and low-risk groups within the FREEDOM population. High-risk groups included women with two or more preexisting vertebral fractures of any degree of deformity, or one or more vertebral fractures of moderate or severe deformity, or both; a femoral neck BMD T score of -2.5 or less; or both multiple and/or moderate or severe vertebral deformities and a femoral neck BMD T score of –2.5 or less.

For hip fractures, the higher-risk subgroups included women who were age 75 years or older; had a femoral neck BMD T score of –2.5 or less; or were 75 years or older with a femoral neck BMD T score of –2.5 or less. Women who did not have those specified risk factors were included in the lower-risk subgroups.

Over 3 years, denosumab treatment was equally effective at reducing the risk of new vertebral fractures in women at both higher and lower risk for those types of fractures, similar to the overall FREEDOM population. Compared with placebo, denosumab reduced the incidence of vertebral fracture in the subgroups at higher risk by prevalent vertebral fracture status by 9.2% (16.6% placebo vs. 7.5% denosumab) among those at risk via baseline femoral neck BMD T score of –2.5 by 6.8% (9.9% vs. 3.1%), and among those with both risk factors by 12.3% (20.1% vs. 8.1%).

The numbers needed to treat to prevent one vertebral fracture in each of these higher-risk subgroups were 11, 15, and 12, respectively, Dr. Boonen and his associates said.

Similar results were seen for the lower-risk groups, including a 4.4% absolute risk reduction in those without prevalent vertebral fracture, 3.7% for those with BMD T score greater than –2.5, and 4.5% for those with without one or both risk factors. Subgroup results for hip fractures were also consistent with the findings from the overall FREEDOM population, with the same efficacy of denosumab consistent across patients with different levels of risk. Compared with placebo, denosumab treatment significantly reduced the incidence of hip fracture among those aged 75 years or older by 1.4% (2.3% placebo vs. 0.9% denosumab); those with a baseline femoral neck BMD T score of -2.5 or less by 1.4% (2.8% vs. 1.4%); and by 2.4% among those with both risk factors (4.1% vs. 1.7%).

"It is reassuring to see that the effect is similar across a range of fracture risk. ... The FDA-approved indication for denosumab is for ‘postmenopausal women at high risk of fracture,’ but the FREEDOM trial was not enriched with ‘women at high risk,’ " noted Dr. Nelson Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, in an interview. Risk reduction for hip fractures was low in the lower-risk subgroups because the incidence of hip fractures was low, and the difference between the denosumab and placebo groups was therefore not statistically significant. Adverse event incidences were also not statistically different between the treatment groups within any of the higher- and lower-risk subgroups, and were consistent with the adverse event incidences for the overall FREEDOM trial, the investigators said.

Overall mortality was lower – but not significantly so – among all the subgroups with denosumab. However, there was a significantly lower incidence of fatal adverse events with denosumab vs. placebo in the higher-risk group with prevalent vertebral fracture (1.8% vs. 4.9%) and in those with both prevalent vertebral fracture and low femoral neck BMD (1.6% vs. 7.1%). The difference in mortality among the higher-risk subgroups was greater than that of the lower-risk groups, they noted.

The reason for the mortality difference is unclear, Dr. Watts said. "This was not an end point in the main trail and only significant in a small subgroup of high risk patients. It’s clear that women who fracture have decreased survival, so it’s logical that preventing fracture would reduce mortality."

"Our analyses highlight the consistency of the antifracture efficacy of denosumab across subjects with differences in a variety of major risk factors for fractures at baseline. Our analyses suggests that denosumab reduces both new vertebral and hip fractures, regardless of the underlying risk and that the higher absolute fracture risk observed in the higher-risk subgroups is associated with greater absolute risk reduction. These analyses add to the evidence that denosumab is an effective option for the treatment of postmenopausal osteoporosis," Dr. Boonen and his associates concluded.

The study was funded by Amgen Inc. Dr. Boonen has received funding for serving as a trial investigator and as a member of the steering committee for Amgen, as well as consulting and lecture fees from the company. He is also senior clinical investigator of the Fund for Scientific Research in Flanders, Belgium. Four of the study’s coinvestigators are employees of Amgen, and the others disclosed relationships with Amgen and several other pharmaceutical companies. Dr. Watts is director, cofounder, and owner OsteoDynamics and holds stock and patents. He has received fees and/or honoraria from numerous drug companies including Amgen, Novartis, Warner Chilcott, Johnson & Johnson, Merck, and Takeda, Vivus, and Warner Chilcott. Through his university, he has research support from Amgen, Merck, and NPS.

Denosumab reduced the incidence of new vertebral and hip fractures in postmenopausal women with osteoporosis at both higher and lower risk for fracture, in a post-hoc analysis of data from a 3-year, phase III randomized trial in the Journal of Clinical Endocrinology & Metabolism.

The monoclonal antibody denosumab (Prolia) was approved in June 2010 for treatment of postmenopausal women who have a high risk of osteoporotic fractures. In phase II and III trials, denosumab rapidly decreased bone resorption markers and increased bone mineral density at all skeletal sites, compared with placebo, wrote Dr. S. Boonen of Leuven (Belgium) University and his associates (J. Clin. Endocrinol. Metab. 2011;96 [doi:10.1210/jc.2010-2784]).

The Fracture Reduction Evaluation of Denosumab in Osteoporosis Every 6 Months (FREEDOM) trial enrolled 7,808 postmenopausal women aged 60-80 years with osteoporosis to receive either a subcutaneous injection of denosumab (60 mg) or placebo along with daily calcium and vitamin D supplements every 6 months. All subjects had bone mineral density (BMD) T scores of less than –2.5 but not less than –4.0 at the lumbar spine or total hip. At 36 months, denosumab was associated with reductions of 68% in vertebral fracture and 40% in hip fracture (N. Engl. J. Med. 2009;361:756-65).

The new analysis compared high-risk and low-risk groups within the FREEDOM population. High-risk groups included women with two or more preexisting vertebral fractures of any degree of deformity, or one or more vertebral fractures of moderate or severe deformity, or both; a femoral neck BMD T score of -2.5 or less; or both multiple and/or moderate or severe vertebral deformities and a femoral neck BMD T score of –2.5 or less.

For hip fractures, the higher-risk subgroups included women who were age 75 years or older; had a femoral neck BMD T score of –2.5 or less; or were 75 years or older with a femoral neck BMD T score of –2.5 or less. Women who did not have those specified risk factors were included in the lower-risk subgroups.

Over 3 years, denosumab treatment was equally effective at reducing the risk of new vertebral fractures in women at both higher and lower risk for those types of fractures, similar to the overall FREEDOM population. Compared with placebo, denosumab reduced the incidence of vertebral fracture in the subgroups at higher risk by prevalent vertebral fracture status by 9.2% (16.6% placebo vs. 7.5% denosumab) among those at risk via baseline femoral neck BMD T score of –2.5 by 6.8% (9.9% vs. 3.1%), and among those with both risk factors by 12.3% (20.1% vs. 8.1%).

The numbers needed to treat to prevent one vertebral fracture in each of these higher-risk subgroups were 11, 15, and 12, respectively, Dr. Boonen and his associates said.

Similar results were seen for the lower-risk groups, including a 4.4% absolute risk reduction in those without prevalent vertebral fracture, 3.7% for those with BMD T score greater than –2.5, and 4.5% for those with without one or both risk factors. Subgroup results for hip fractures were also consistent with the findings from the overall FREEDOM population, with the same efficacy of denosumab consistent across patients with different levels of risk. Compared with placebo, denosumab treatment significantly reduced the incidence of hip fracture among those aged 75 years or older by 1.4% (2.3% placebo vs. 0.9% denosumab); those with a baseline femoral neck BMD T score of -2.5 or less by 1.4% (2.8% vs. 1.4%); and by 2.4% among those with both risk factors (4.1% vs. 1.7%).

"It is reassuring to see that the effect is similar across a range of fracture risk. ... The FDA-approved indication for denosumab is for ‘postmenopausal women at high risk of fracture,’ but the FREEDOM trial was not enriched with ‘women at high risk,’ " noted Dr. Nelson Watts, director of the University of Cincinnati Bone Health and Osteoporosis Center, in an interview. Risk reduction for hip fractures was low in the lower-risk subgroups because the incidence of hip fractures was low, and the difference between the denosumab and placebo groups was therefore not statistically significant. Adverse event incidences were also not statistically different between the treatment groups within any of the higher- and lower-risk subgroups, and were consistent with the adverse event incidences for the overall FREEDOM trial, the investigators said.

Overall mortality was lower – but not significantly so – among all the subgroups with denosumab. However, there was a significantly lower incidence of fatal adverse events with denosumab vs. placebo in the higher-risk group with prevalent vertebral fracture (1.8% vs. 4.9%) and in those with both prevalent vertebral fracture and low femoral neck BMD (1.6% vs. 7.1%). The difference in mortality among the higher-risk subgroups was greater than that of the lower-risk groups, they noted.

The reason for the mortality difference is unclear, Dr. Watts said. "This was not an end point in the main trail and only significant in a small subgroup of high risk patients. It’s clear that women who fracture have decreased survival, so it’s logical that preventing fracture would reduce mortality."

"Our analyses highlight the consistency of the antifracture efficacy of denosumab across subjects with differences in a variety of major risk factors for fractures at baseline. Our analyses suggests that denosumab reduces both new vertebral and hip fractures, regardless of the underlying risk and that the higher absolute fracture risk observed in the higher-risk subgroups is associated with greater absolute risk reduction. These analyses add to the evidence that denosumab is an effective option for the treatment of postmenopausal osteoporosis," Dr. Boonen and his associates concluded.

The study was funded by Amgen Inc. Dr. Boonen has received funding for serving as a trial investigator and as a member of the steering committee for Amgen, as well as consulting and lecture fees from the company. He is also senior clinical investigator of the Fund for Scientific Research in Flanders, Belgium. Four of the study’s coinvestigators are employees of Amgen, and the others disclosed relationships with Amgen and several other pharmaceutical companies. Dr. Watts is director, cofounder, and owner OsteoDynamics and holds stock and patents. He has received fees and/or honoraria from numerous drug companies including Amgen, Novartis, Warner Chilcott, Johnson & Johnson, Merck, and Takeda, Vivus, and Warner Chilcott. Through his university, he has research support from Amgen, Merck, and NPS.

BOSTON – Unhealthy lifestyle habits are largely responsible for heart disease, diabetes, cancer, and lung disease in much of the world, but among the poorest people, much of the noncommunicable disease burden stems from infections and other endemic environmental factors.

Recognition of such fundamental differences in the etiology of noncommunicable diseases (NCDs) – and the endemic causes of those diseases among the world's poorest billion people – is needed as the United Nations forges ahead with plans to address NCDs on a global scale. That was the conclusion drawn by stakeholders at a meeting aimed at decreasing the burden of noncommunicable diseases in the so-called "bottom billion" – the world's population living on less than one dollar a day.

Photo credit: Ilvy Njiokiktjien

"The term 'endemic' is significant because it places the emphasis on the diseases that are already there in these populations, in addition to the epidemics of emerging NCDs.

We're expanding the notion of what 'noncommunicable disease' is," Dr. Gene Bukhman said at the meeting, which was sponsored by Partners In Health, an international nonprofit organization that provides direct health care services to people living in poverty around the world.

Over the last two decades, people and organizations have been clamoring for the inclusion of NCDs on the global health agenda. That movement has been newly energized by the United Nation's announcement last May that it will hold a General Assembly High-level Meeting on NCDs in September. It will be only the second such disease-related meeting that the UN has ever held. The first such meeting in 2001 focused on HIV/AIDS, and is credited with galvanizing global attention and fund-raising efforts for that cause.

Participants at the Partners In Health meeting are working to ensure that the upcoming UN meeting doesn't overlook the needs of the poorest people in the world.

The primary focus of the upcoming UN meeting will be on "noncommunicable disease" as defined by the World Health Organization in its 2008-2013 NCD action plan: cardiovascular diseases, diabetes, cancers, and chronic respiratory diseases related to the four shared risk factors – tobacco use, physical inactivity, unhealthy diets, and the harmful use of alcohol. Together, these conditions account for approximately 60% of all global deaths, of which 80% occur in low- and middle-income countries, according to WHO.

That "four-by-four" model, however, doesn't encompass the breadth of chronic conditions seen in the poorest countries, where infection, malnutrition, environmental toxins, and lack of access to care contribute much more to the NCD burden than do lifestyle factors. Taken together, "endemic NCDs" account for nearly 25% of disease among the world's poorest billion, said Dr. Bukhman, a cardiologist who serves as director of the Harvard Medical School Program in Non-Communicable Disease and Social Change, Boston, and also as the cardiology director for Partners In Health, working in Rwanda.

Infectious origins of many NCDs in poor countries highlight the "false dichotomy" view of NCDs as separate from infectious disease and that scarce resources need be divided between the two camps. "If we pit one set of interventions against another, we're not going to get very far," said Dr. Paul Farmer, director of Partners In Health.

Neglected Tropical Diseases. Neglected tropical diseases (NTDs) are a prime example of the blurred line between NCDs and infectious disease. The NTDs are not communicable from person to person, and they cause chronic illness that is not typically fatal in the short term but which can severely debilitate and reduce productive capacity, according to Dr. Peter Hotez, Distinguished Research Professor and Walter G. Ross Professor and Chair of the Department of Microbiology, Immunology, and Tropical Medicine at George Washington University, Washington.

Affecting approximately 1.4 billion people worldwide, the NTDs include chronic parasitic infections such as ascariasis, trichuriasis, hookworm, and schistosomiasis. Some of the NTDs cause NCDs, including cardiomyopathy due to Chagas disease, cor pulmonale from schistosomiasis, asthma due to toxocariasis, and inflammatory bowel disease from trichuriasis, said Dr. Hotez, who also serves as president of the Sabin Vaccine Institute, a nonprofit research and advocacy organization that is currently conducting trials on vaccines against hookworm, schistosomiasis, Chagas disease, and malaria.

Together, the NTD global burden in terms of disability-associated life-years is 56.6 million, greater than that of malaria (46.5 million) or tuberculosis (34.7 million), and two-thirds that of HIV/AIDS (84.5 million), Dr. Hotez and his associated reported (N. Engl. J. Med. 2007;357:1018-27).

Cardiovascular Diseases. The spectrum of cardiovascular diseases due to endemic causes in Africa represents another "neglected" set of conditions, according to Dr. Ana Mocumbi, a cardiologist and researcher at the Maputo Heart Institute in Mozambique.

Although Africa is seeing a rise in lifestyle-associated atherosclerosis and other conditions common in the developed world, there are also large numbers of people suffering from chronic heart conditions with infectious origins, including rheumatic heart disease arising from streptococcal infection, endomyocardial fibrosis, and tuberculous pericarditis.

Together, these conditions "can be considered neglected diseases because, despite considerable numbers of people, they have not been the subject of systematic research or structured control programs and did not benefit from translation of knowledge obtained in other areas of human knowledge," Dr. Mocumbi said.

Chronic Respiratory Disease. Chronic respiratory disease is another NCD area for which the picture is different among the bottom billion. While smoking is by far the most common cause of chronic obstructive pulmonary disease (COPD) in developed countries, emerging evidence suggests that other environmental factors may play a greater role in poor countries, where an estimated 25%-45% of COPD patients have never smoked, said Dr. Sundeep Salvi, director of the Chest Research Foundation, Pune, India.

About 3 billion people, half the world’s population, are exposed to smoke from biomass fuel, compared with 1.01 billion people who smoke tobacco, suggesting that exposure to biomass smoke might be the biggest risk factor for COPD globally, Dr. Salvi said (Lancet 2009;374:733-43).

A recently published meta-analysis of 25 studies identified significant associations between exposure to solid biomass fuels such as wood, dung, and charcoal and acute respiratory infection in children (pooled odds ratio 3.53), chronic bronchitis in women (OR 2.52), and chronic pulmonary disease in women (OR 2.40). No associations were seen with asthma (Thorax 2011;66:232-9).

Other NCDs include sickle cell anemia, diabetes (including that associated with malnutrition rather than obesity), mental illness, diseases requiring surgery, cervical cancer, epilepsy, and anemia, which is often a result of infectious diseases such as malaria and bacteremia in the developing world rather than iron deficiency.

A 'Diagonal' Approach. Experts at the meeting agreed that integrated approaches are necessary to address endemic NCDs, most of which are relatively uncommon individually, but together account for a large burden of disease among the bottom billion.

Dr. Julio Frenk, dean of Harvard’s School of Public Health, advocated in favor of taking a so-called "diagonal approach" as an alternative to the narrow, disease-specific "vertical approach" to care as has been used to address HIV/AIDS, malaria, and tuberculosis. A diagonal approach is also preferred, he said, to taking a broad, and often ineffectual, "horizontal" approach that generally aims at strengthening health systems.

"Global health in the 21st century should integrate vertical and horizontal programs, because we now know that, through what [Dr.] Jaime Sepulveda has called the 'diagonal approach,' we can use explicit intervention priorities to strengthen the overall structure and function of health systems," Dr. Frenk said.

Such an approach is now being used by Partners In Health in Rwanda, an effort that began in 2005 with the Rwandan government's request for support for rural health services. Also financed in part by the Clinton Foundation, the project provides building and renovations, supplementation of operational budgets, and staff training to three rural districts serving more than 750,000 in 2010.

The approach to chronic care in these regions follows a model similar to the way health systems were progressively decentralized to address HIV/AIDS in the 1990s: from tertiary referral centers to district hospitals, to local health centers, to community health workers. Under the model, primary care – typically delivered by nonphysician health care providers or trained laypeople – takes place at the community level, while increasingly specialized care takes place up the hierarchy of facilities, Dr. Bukhman explained.

District hospital leaders work closely with the staff of health centers, providing training, mentoring, and education, with the idea of reducing the need to transfer patients to referral centers. Each Partners In Health–supported district hospital in Rwanda has an advanced chronic care clinic for noninfectious diseases. Countries such as Rwanda that already have such integrated programs to address HIV/AIDS can more easily and less expensively integrate NCDs into their health systems, Dr. Bukhman noted.

Dr. Farmer, chair of the department of global health and social medicine at Harvard, stressed the need for "health systems strengthening" and for partnerships between governments, academia, nongovernmental organizations, private industry, and other stakeholders in order to tackle the complexity and heterogeneity of the endemic NCDs.

"It can't be diabetes versus mental health or rheumatic heart disease versus cancer. It has to be a very collaborative effort that draws on partnerships and synergies. ... In building platforms for the delivering of care for chronic disease, we need to do many things at once."

Dr. Hotez disclosed that he has a patent on a hookworm vaccine, but no relationships with pharmaceutical companies. Dr. Mocumbi stated that she has no disclosures. Dr. Salvi disclosed that he has received fees from Merck Pharmaceuticals as an advisory board member and speaker. Partners In Health receives funding from corporate donors, including several pharmaceutical companies.

BOSTON – Unhealthy lifestyle habits are largely responsible for heart disease, diabetes, cancer, and lung disease in much of the world, but among the poorest people, much of the noncommunicable disease burden stems from infections and other endemic environmental factors.

Recognition of such fundamental differences in the etiology of noncommunicable diseases (NCDs) – and the endemic causes of those diseases among the world's poorest billion people – is needed as the United Nations forges ahead with plans to address NCDs on a global scale. That was the conclusion drawn by stakeholders at a meeting aimed at decreasing the burden of noncommunicable diseases in the so-called "bottom billion" – the world's population living on less than one dollar a day.

Photo credit: Ilvy Njiokiktjien

"The term 'endemic' is significant because it places the emphasis on the diseases that are already there in these populations, in addition to the epidemics of emerging NCDs.

We're expanding the notion of what 'noncommunicable disease' is," Dr. Gene Bukhman said at the meeting, which was sponsored by Partners In Health, an international nonprofit organization that provides direct health care services to people living in poverty around the world.

Over the last two decades, people and organizations have been clamoring for the inclusion of NCDs on the global health agenda. That movement has been newly energized by the United Nation's announcement last May that it will hold a General Assembly High-level Meeting on NCDs in September. It will be only the second such disease-related meeting that the UN has ever held. The first such meeting in 2001 focused on HIV/AIDS, and is credited with galvanizing global attention and fund-raising efforts for that cause.

Participants at the Partners In Health meeting are working to ensure that the upcoming UN meeting doesn't overlook the needs of the poorest people in the world.

The primary focus of the upcoming UN meeting will be on "noncommunicable disease" as defined by the World Health Organization in its 2008-2013 NCD action plan: cardiovascular diseases, diabetes, cancers, and chronic respiratory diseases related to the four shared risk factors – tobacco use, physical inactivity, unhealthy diets, and the harmful use of alcohol. Together, these conditions account for approximately 60% of all global deaths, of which 80% occur in low- and middle-income countries, according to WHO.

That "four-by-four" model, however, doesn't encompass the breadth of chronic conditions seen in the poorest countries, where infection, malnutrition, environmental toxins, and lack of access to care contribute much more to the NCD burden than do lifestyle factors. Taken together, "endemic NCDs" account for nearly 25% of disease among the world's poorest billion, said Dr. Bukhman, a cardiologist who serves as director of the Harvard Medical School Program in Non-Communicable Disease and Social Change, Boston, and also as the cardiology director for Partners In Health, working in Rwanda.

Infectious origins of many NCDs in poor countries highlight the "false dichotomy" view of NCDs as separate from infectious disease and that scarce resources need be divided between the two camps. "If we pit one set of interventions against another, we're not going to get very far," said Dr. Paul Farmer, director of Partners In Health.

Neglected Tropical Diseases. Neglected tropical diseases (NTDs) are a prime example of the blurred line between NCDs and infectious disease. The NTDs are not communicable from person to person, and they cause chronic illness that is not typically fatal in the short term but which can severely debilitate and reduce productive capacity, according to Dr. Peter Hotez, Distinguished Research Professor and Walter G. Ross Professor and Chair of the Department of Microbiology, Immunology, and Tropical Medicine at George Washington University, Washington.

Affecting approximately 1.4 billion people worldwide, the NTDs include chronic parasitic infections such as ascariasis, trichuriasis, hookworm, and schistosomiasis. Some of the NTDs cause NCDs, including cardiomyopathy due to Chagas disease, cor pulmonale from schistosomiasis, asthma due to toxocariasis, and inflammatory bowel disease from trichuriasis, said Dr. Hotez, who also serves as president of the Sabin Vaccine Institute, a nonprofit research and advocacy organization that is currently conducting trials on vaccines against hookworm, schistosomiasis, Chagas disease, and malaria.

Together, the NTD global burden in terms of disability-associated life-years is 56.6 million, greater than that of malaria (46.5 million) or tuberculosis (34.7 million), and two-thirds that of HIV/AIDS (84.5 million), Dr. Hotez and his associated reported (N. Engl. J. Med. 2007;357:1018-27).

Cardiovascular Diseases. The spectrum of cardiovascular diseases due to endemic causes in Africa represents another "neglected" set of conditions, according to Dr. Ana Mocumbi, a cardiologist and researcher at the Maputo Heart Institute in Mozambique.

Although Africa is seeing a rise in lifestyle-associated atherosclerosis and other conditions common in the developed world, there are also large numbers of people suffering from chronic heart conditions with infectious origins, including rheumatic heart disease arising from streptococcal infection, endomyocardial fibrosis, and tuberculous pericarditis.

Together, these conditions "can be considered neglected diseases because, despite considerable numbers of people, they have not been the subject of systematic research or structured control programs and did not benefit from translation of knowledge obtained in other areas of human knowledge," Dr. Mocumbi said.

Chronic Respiratory Disease. Chronic respiratory disease is another NCD area for which the picture is different among the bottom billion. While smoking is by far the most common cause of chronic obstructive pulmonary disease (COPD) in developed countries, emerging evidence suggests that other environmental factors may play a greater role in poor countries, where an estimated 25%-45% of COPD patients have never smoked, said Dr. Sundeep Salvi, director of the Chest Research Foundation, Pune, India.

About 3 billion people, half the world’s population, are exposed to smoke from biomass fuel, compared with 1.01 billion people who smoke tobacco, suggesting that exposure to biomass smoke might be the biggest risk factor for COPD globally, Dr. Salvi said (Lancet 2009;374:733-43).

A recently published meta-analysis of 25 studies identified significant associations between exposure to solid biomass fuels such as wood, dung, and charcoal and acute respiratory infection in children (pooled odds ratio 3.53), chronic bronchitis in women (OR 2.52), and chronic pulmonary disease in women (OR 2.40). No associations were seen with asthma (Thorax 2011;66:232-9).

Other NCDs include sickle cell anemia, diabetes (including that associated with malnutrition rather than obesity), mental illness, diseases requiring surgery, cervical cancer, epilepsy, and anemia, which is often a result of infectious diseases such as malaria and bacteremia in the developing world rather than iron deficiency.

A 'Diagonal' Approach. Experts at the meeting agreed that integrated approaches are necessary to address endemic NCDs, most of which are relatively uncommon individually, but together account for a large burden of disease among the bottom billion.

Dr. Julio Frenk, dean of Harvard’s School of Public Health, advocated in favor of taking a so-called "diagonal approach" as an alternative to the narrow, disease-specific "vertical approach" to care as has been used to address HIV/AIDS, malaria, and tuberculosis. A diagonal approach is also preferred, he said, to taking a broad, and often ineffectual, "horizontal" approach that generally aims at strengthening health systems.

"Global health in the 21st century should integrate vertical and horizontal programs, because we now know that, through what [Dr.] Jaime Sepulveda has called the 'diagonal approach,' we can use explicit intervention priorities to strengthen the overall structure and function of health systems," Dr. Frenk said.

Such an approach is now being used by Partners In Health in Rwanda, an effort that began in 2005 with the Rwandan government's request for support for rural health services. Also financed in part by the Clinton Foundation, the project provides building and renovations, supplementation of operational budgets, and staff training to three rural districts serving more than 750,000 in 2010.

The approach to chronic care in these regions follows a model similar to the way health systems were progressively decentralized to address HIV/AIDS in the 1990s: from tertiary referral centers to district hospitals, to local health centers, to community health workers. Under the model, primary care – typically delivered by nonphysician health care providers or trained laypeople – takes place at the community level, while increasingly specialized care takes place up the hierarchy of facilities, Dr. Bukhman explained.

District hospital leaders work closely with the staff of health centers, providing training, mentoring, and education, with the idea of reducing the need to transfer patients to referral centers. Each Partners In Health–supported district hospital in Rwanda has an advanced chronic care clinic for noninfectious diseases. Countries such as Rwanda that already have such integrated programs to address HIV/AIDS can more easily and less expensively integrate NCDs into their health systems, Dr. Bukhman noted.

Dr. Farmer, chair of the department of global health and social medicine at Harvard, stressed the need for "health systems strengthening" and for partnerships between governments, academia, nongovernmental organizations, private industry, and other stakeholders in order to tackle the complexity and heterogeneity of the endemic NCDs.

"It can't be diabetes versus mental health or rheumatic heart disease versus cancer. It has to be a very collaborative effort that draws on partnerships and synergies. ... In building platforms for the delivering of care for chronic disease, we need to do many things at once."

Dr. Hotez disclosed that he has a patent on a hookworm vaccine, but no relationships with pharmaceutical companies. Dr. Mocumbi stated that she has no disclosures. Dr. Salvi disclosed that he has received fees from Merck Pharmaceuticals as an advisory board member and speaker. Partners In Health receives funding from corporate donors, including several pharmaceutical companies.

BOSTON – Unhealthy lifestyle habits are largely responsible for heart disease, diabetes, cancer, and lung disease in much of the world, but among the poorest people, much of the noncommunicable disease burden stems from infections and other endemic environmental factors.

Recognition of such fundamental differences in the etiology of noncommunicable diseases (NCDs) – and the endemic causes of those diseases among the world's poorest billion people – is needed as the United Nations forges ahead with plans to address NCDs on a global scale. That was the conclusion drawn by stakeholders at a meeting aimed at decreasing the burden of noncommunicable diseases in the so-called "bottom billion" – the world's population living on less than one dollar a day.

Photo credit: Ilvy Njiokiktjien

"The term 'endemic' is significant because it places the emphasis on the diseases that are already there in these populations, in addition to the epidemics of emerging NCDs.

We're expanding the notion of what 'noncommunicable disease' is," Dr. Gene Bukhman said at the meeting, which was sponsored by Partners In Health, an international nonprofit organization that provides direct health care services to people living in poverty around the world.

Over the last two decades, people and organizations have been clamoring for the inclusion of NCDs on the global health agenda. That movement has been newly energized by the United Nation's announcement last May that it will hold a General Assembly High-level Meeting on NCDs in September. It will be only the second such disease-related meeting that the UN has ever held. The first such meeting in 2001 focused on HIV/AIDS, and is credited with galvanizing global attention and fund-raising efforts for that cause.

Participants at the Partners In Health meeting are working to ensure that the upcoming UN meeting doesn't overlook the needs of the poorest people in the world.

The primary focus of the upcoming UN meeting will be on "noncommunicable disease" as defined by the World Health Organization in its 2008-2013 NCD action plan: cardiovascular diseases, diabetes, cancers, and chronic respiratory diseases related to the four shared risk factors – tobacco use, physical inactivity, unhealthy diets, and the harmful use of alcohol. Together, these conditions account for approximately 60% of all global deaths, of which 80% occur in low- and middle-income countries, according to WHO.

That "four-by-four" model, however, doesn't encompass the breadth of chronic conditions seen in the poorest countries, where infection, malnutrition, environmental toxins, and lack of access to care contribute much more to the NCD burden than do lifestyle factors. Taken together, "endemic NCDs" account for nearly 25% of disease among the world's poorest billion, said Dr. Bukhman, a cardiologist who serves as director of the Harvard Medical School Program in Non-Communicable Disease and Social Change, Boston, and also as the cardiology director for Partners In Health, working in Rwanda.

Infectious origins of many NCDs in poor countries highlight the "false dichotomy" view of NCDs as separate from infectious disease and that scarce resources need be divided between the two camps. "If we pit one set of interventions against another, we're not going to get very far," said Dr. Paul Farmer, director of Partners In Health.

Neglected Tropical Diseases. Neglected tropical diseases (NTDs) are a prime example of the blurred line between NCDs and infectious disease. The NTDs are not communicable from person to person, and they cause chronic illness that is not typically fatal in the short term but which can severely debilitate and reduce productive capacity, according to Dr. Peter Hotez, Distinguished Research Professor and Walter G. Ross Professor and Chair of the Department of Microbiology, Immunology, and Tropical Medicine at George Washington University, Washington.

Affecting approximately 1.4 billion people worldwide, the NTDs include chronic parasitic infections such as ascariasis, trichuriasis, hookworm, and schistosomiasis. Some of the NTDs cause NCDs, including cardiomyopathy due to Chagas disease, cor pulmonale from schistosomiasis, asthma due to toxocariasis, and inflammatory bowel disease from trichuriasis, said Dr. Hotez, who also serves as president of the Sabin Vaccine Institute, a nonprofit research and advocacy organization that is currently conducting trials on vaccines against hookworm, schistosomiasis, Chagas disease, and malaria.

Together, the NTD global burden in terms of disability-associated life-years is 56.6 million, greater than that of malaria (46.5 million) or tuberculosis (34.7 million), and two-thirds that of HIV/AIDS (84.5 million), Dr. Hotez and his associated reported (N. Engl. J. Med. 2007;357:1018-27).

Cardiovascular Diseases. The spectrum of cardiovascular diseases due to endemic causes in Africa represents another "neglected" set of conditions, according to Dr. Ana Mocumbi, a cardiologist and researcher at the Maputo Heart Institute in Mozambique.

Although Africa is seeing a rise in lifestyle-associated atherosclerosis and other conditions common in the developed world, there are also large numbers of people suffering from chronic heart conditions with infectious origins, including rheumatic heart disease arising from streptococcal infection, endomyocardial fibrosis, and tuberculous pericarditis.

Together, these conditions "can be considered neglected diseases because, despite considerable numbers of people, they have not been the subject of systematic research or structured control programs and did not benefit from translation of knowledge obtained in other areas of human knowledge," Dr. Mocumbi said.

Chronic Respiratory Disease. Chronic respiratory disease is another NCD area for which the picture is different among the bottom billion. While smoking is by far the most common cause of chronic obstructive pulmonary disease (COPD) in developed countries, emerging evidence suggests that other environmental factors may play a greater role in poor countries, where an estimated 25%-45% of COPD patients have never smoked, said Dr. Sundeep Salvi, director of the Chest Research Foundation, Pune, India.

About 3 billion people, half the world’s population, are exposed to smoke from biomass fuel, compared with 1.01 billion people who smoke tobacco, suggesting that exposure to biomass smoke might be the biggest risk factor for COPD globally, Dr. Salvi said (Lancet 2009;374:733-43).

A recently published meta-analysis of 25 studies identified significant associations between exposure to solid biomass fuels such as wood, dung, and charcoal and acute respiratory infection in children (pooled odds ratio 3.53), chronic bronchitis in women (OR 2.52), and chronic pulmonary disease in women (OR 2.40). No associations were seen with asthma (Thorax 2011;66:232-9).

Other NCDs include sickle cell anemia, diabetes (including that associated with malnutrition rather than obesity), mental illness, diseases requiring surgery, cervical cancer, epilepsy, and anemia, which is often a result of infectious diseases such as malaria and bacteremia in the developing world rather than iron deficiency.

A 'Diagonal' Approach. Experts at the meeting agreed that integrated approaches are necessary to address endemic NCDs, most of which are relatively uncommon individually, but together account for a large burden of disease among the bottom billion.

Dr. Julio Frenk, dean of Harvard’s School of Public Health, advocated in favor of taking a so-called "diagonal approach" as an alternative to the narrow, disease-specific "vertical approach" to care as has been used to address HIV/AIDS, malaria, and tuberculosis. A diagonal approach is also preferred, he said, to taking a broad, and often ineffectual, "horizontal" approach that generally aims at strengthening health systems.

"Global health in the 21st century should integrate vertical and horizontal programs, because we now know that, through what [Dr.] Jaime Sepulveda has called the 'diagonal approach,' we can use explicit intervention priorities to strengthen the overall structure and function of health systems," Dr. Frenk said.

Such an approach is now being used by Partners In Health in Rwanda, an effort that began in 2005 with the Rwandan government's request for support for rural health services. Also financed in part by the Clinton Foundation, the project provides building and renovations, supplementation of operational budgets, and staff training to three rural districts serving more than 750,000 in 2010.

The approach to chronic care in these regions follows a model similar to the way health systems were progressively decentralized to address HIV/AIDS in the 1990s: from tertiary referral centers to district hospitals, to local health centers, to community health workers. Under the model, primary care – typically delivered by nonphysician health care providers or trained laypeople – takes place at the community level, while increasingly specialized care takes place up the hierarchy of facilities, Dr. Bukhman explained.

District hospital leaders work closely with the staff of health centers, providing training, mentoring, and education, with the idea of reducing the need to transfer patients to referral centers. Each Partners In Health–supported district hospital in Rwanda has an advanced chronic care clinic for noninfectious diseases. Countries such as Rwanda that already have such integrated programs to address HIV/AIDS can more easily and less expensively integrate NCDs into their health systems, Dr. Bukhman noted.

Dr. Farmer, chair of the department of global health and social medicine at Harvard, stressed the need for "health systems strengthening" and for partnerships between governments, academia, nongovernmental organizations, private industry, and other stakeholders in order to tackle the complexity and heterogeneity of the endemic NCDs.

"It can't be diabetes versus mental health or rheumatic heart disease versus cancer. It has to be a very collaborative effort that draws on partnerships and synergies. ... In building platforms for the delivering of care for chronic disease, we need to do many things at once."

Dr. Hotez disclosed that he has a patent on a hookworm vaccine, but no relationships with pharmaceutical companies. Dr. Mocumbi stated that she has no disclosures. Dr. Salvi disclosed that he has received fees from Merck Pharmaceuticals as an advisory board member and speaker. Partners In Health receives funding from corporate donors, including several pharmaceutical companies.