The Food and Drug Administration has approved the Pentax ED34-i10T model duodenoscope, the first with a disposable distal cap, according to an FDA press release.

A disposable distal cap will improve the ability to clean and reprocess the duodenoscope. Without being thoroughly cleaned and disinfected, contaminated tissue can remain and potentially can be transmitted to other patients.

lfranki@frontlinemedcom.com

The Food and Drug Administration has approved the Pentax ED34-i10T model duodenoscope, the first with a disposable distal cap, according to an FDA press release.

A disposable distal cap will improve the ability to clean and reprocess the duodenoscope. Without being thoroughly cleaned and disinfected, contaminated tissue can remain and potentially can be transmitted to other patients.

lfranki@frontlinemedcom.com

The Food and Drug Administration has approved the Pentax ED34-i10T model duodenoscope, the first with a disposable distal cap, according to an FDA press release.

A disposable distal cap will improve the ability to clean and reprocess the duodenoscope. Without being thoroughly cleaned and disinfected, contaminated tissue can remain and potentially can be transmitted to other patients.

lfranki@frontlinemedcom.com

Caffeine consumption has no significant impact on motor skills in patients with Parkinson’s disease, based on data from a double-blind, randomized, placebo-controlled trial of 121 adults. The findings were published online Sept. 27 in Neurology.

Data from previous studies have suggested a link between caffeine consumption and reduced risk of Parkinson’s disease, wrote Ronald B. Postuma, MD, of McGill University in Montreal, and his colleagues (Neurology. 2017 Sep 27. doi: 10.1212/WNL.0000000000004568). In addition, Dr. Postuma and his coauthors found a small impact of caffeine on motor skills in patients with existing Parkinson’s as a secondary outcome in a 2012 study on the role of caffeine on daytime sleepiness. Based on these findings, they designed a multicenter, randomized, controlled trial of 121 adults with Parkinson’s to assess the impact of caffeine. The average age of the patients was 62 years and the average disease duration was 4 years.

Caffeine consumption has no significant impact on motor skills in patients with Parkinson’s disease, based on data from a double-blind, randomized, placebo-controlled trial of 121 adults. The findings were published online Sept. 27 in Neurology.

Data from previous studies have suggested a link between caffeine consumption and reduced risk of Parkinson’s disease, wrote Ronald B. Postuma, MD, of McGill University in Montreal, and his colleagues (Neurology. 2017 Sep 27. doi: 10.1212/WNL.0000000000004568). In addition, Dr. Postuma and his coauthors found a small impact of caffeine on motor skills in patients with existing Parkinson’s as a secondary outcome in a 2012 study on the role of caffeine on daytime sleepiness. Based on these findings, they designed a multicenter, randomized, controlled trial of 121 adults with Parkinson’s to assess the impact of caffeine. The average age of the patients was 62 years and the average disease duration was 4 years.

Caffeine consumption has no significant impact on motor skills in patients with Parkinson’s disease, based on data from a double-blind, randomized, placebo-controlled trial of 121 adults. The findings were published online Sept. 27 in Neurology.

Data from previous studies have suggested a link between caffeine consumption and reduced risk of Parkinson’s disease, wrote Ronald B. Postuma, MD, of McGill University in Montreal, and his colleagues (Neurology. 2017 Sep 27. doi: 10.1212/WNL.0000000000004568). In addition, Dr. Postuma and his coauthors found a small impact of caffeine on motor skills in patients with existing Parkinson’s as a secondary outcome in a 2012 study on the role of caffeine on daytime sleepiness. Based on these findings, they designed a multicenter, randomized, controlled trial of 121 adults with Parkinson’s to assess the impact of caffeine. The average age of the patients was 62 years and the average disease duration was 4 years.

CHICAGO – Adding the oral kinase inhibitor nintedanib to pemetrexed/cisplatin resulted in substantial improvements in outcomes in patients with unresectable malignant pleural mesothelioma in phase 2 of the randomized, placebo-controlled phase 2/3 LUME-Meso study.

The effects were particularly pronounced among those with epithelioid histology, Jose Barrueco, PhD, of Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conn., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

Progression-free survival – the primary endpoint of the study – was improved in 44 patients randomized to receive up to six cycles of pemetrexed/cisplatin plus nintedanib, compared with 43 patients who received pemetrexed/cisplatin plus placebo (median 9.4 vs. 5.7 months; hazard ratio, 0.54), Dr. Barrueco said.

In the 89% of patients with epithelioid malignant pleural mesothelioma, progression-free survival was a median of 9.7 vs. 5.7 months with nintedanib vs. placebo (HR, 0.49).

There was a trend toward improved overall survival in the nintedanib group vs. the placebo group, (median 18.3 vs. 14.2 months; HR, 0.77; P = .319), and overall survival was slightly better in those with epithelioid histology (median 20.6 vs. 15.2 months ; HR, 0.70; P = .197).

Consistent with these results, the adjusted mean change in forced vital capacity at cycle eight also favored nintedanib over placebo (+10.0 vs. +2.8 for a mean treatment difference of 7.2 overall, and +14.1 vs. +4.2 for a mean treatment difference of 9.9 in those with epithelioid histology).

“Overall frequency of adverse events was consistent with the known safety profile of nintedanib,” Dr. Barrueco said, noting that most adverse events were reversible with dose reduction.

Study participants were chemotherapy-naive patients with a mean age of 67 years and Eastern Cooperative Oncology Group performance status of 0-1. They received pemetrexed at a dose of 500 mg/m² and cisplatin at a dose of 75 mg/m² on day 1 plus either nintedanib at a dose of 200 mg twice daily on days 2-21 or placebo, followed by monotherapy with nintedanib or placebo until progression or unacceptable toxicity.

“In conclusion, nintedanib plus pemetrexed/cisplatin demonstrated a signal for clinical benefit in the first-time treatment of patients with malignant pleural mesothelioma. This was evident in all endpoints of the trial, and consistently showed benefit for the nintedanib group,” Mr. Barrueco said, noting that phase 3 of the LUME-Meso study is now recruiting.

sworcester@frontlinemedcom.com

CHICAGO – Adding the oral kinase inhibitor nintedanib to pemetrexed/cisplatin resulted in substantial improvements in outcomes in patients with unresectable malignant pleural mesothelioma in phase 2 of the randomized, placebo-controlled phase 2/3 LUME-Meso study.

The effects were particularly pronounced among those with epithelioid histology, Jose Barrueco, PhD, of Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conn., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

Progression-free survival – the primary endpoint of the study – was improved in 44 patients randomized to receive up to six cycles of pemetrexed/cisplatin plus nintedanib, compared with 43 patients who received pemetrexed/cisplatin plus placebo (median 9.4 vs. 5.7 months; hazard ratio, 0.54), Dr. Barrueco said.

In the 89% of patients with epithelioid malignant pleural mesothelioma, progression-free survival was a median of 9.7 vs. 5.7 months with nintedanib vs. placebo (HR, 0.49).

There was a trend toward improved overall survival in the nintedanib group vs. the placebo group, (median 18.3 vs. 14.2 months; HR, 0.77; P = .319), and overall survival was slightly better in those with epithelioid histology (median 20.6 vs. 15.2 months ; HR, 0.70; P = .197).

Consistent with these results, the adjusted mean change in forced vital capacity at cycle eight also favored nintedanib over placebo (+10.0 vs. +2.8 for a mean treatment difference of 7.2 overall, and +14.1 vs. +4.2 for a mean treatment difference of 9.9 in those with epithelioid histology).

“Overall frequency of adverse events was consistent with the known safety profile of nintedanib,” Dr. Barrueco said, noting that most adverse events were reversible with dose reduction.

Study participants were chemotherapy-naive patients with a mean age of 67 years and Eastern Cooperative Oncology Group performance status of 0-1. They received pemetrexed at a dose of 500 mg/m² and cisplatin at a dose of 75 mg/m² on day 1 plus either nintedanib at a dose of 200 mg twice daily on days 2-21 or placebo, followed by monotherapy with nintedanib or placebo until progression or unacceptable toxicity.

“In conclusion, nintedanib plus pemetrexed/cisplatin demonstrated a signal for clinical benefit in the first-time treatment of patients with malignant pleural mesothelioma. This was evident in all endpoints of the trial, and consistently showed benefit for the nintedanib group,” Mr. Barrueco said, noting that phase 3 of the LUME-Meso study is now recruiting.

sworcester@frontlinemedcom.com

CHICAGO – Adding the oral kinase inhibitor nintedanib to pemetrexed/cisplatin resulted in substantial improvements in outcomes in patients with unresectable malignant pleural mesothelioma in phase 2 of the randomized, placebo-controlled phase 2/3 LUME-Meso study.

The effects were particularly pronounced among those with epithelioid histology, Jose Barrueco, PhD, of Boehringer Ingelheim Pharmaceuticals, Ridgefield, Conn., reported at the Chicago Multidisciplinary Symposium in Thoracic Oncology.

Progression-free survival – the primary endpoint of the study – was improved in 44 patients randomized to receive up to six cycles of pemetrexed/cisplatin plus nintedanib, compared with 43 patients who received pemetrexed/cisplatin plus placebo (median 9.4 vs. 5.7 months; hazard ratio, 0.54), Dr. Barrueco said.

In the 89% of patients with epithelioid malignant pleural mesothelioma, progression-free survival was a median of 9.7 vs. 5.7 months with nintedanib vs. placebo (HR, 0.49).

There was a trend toward improved overall survival in the nintedanib group vs. the placebo group, (median 18.3 vs. 14.2 months; HR, 0.77; P = .319), and overall survival was slightly better in those with epithelioid histology (median 20.6 vs. 15.2 months ; HR, 0.70; P = .197).

Consistent with these results, the adjusted mean change in forced vital capacity at cycle eight also favored nintedanib over placebo (+10.0 vs. +2.8 for a mean treatment difference of 7.2 overall, and +14.1 vs. +4.2 for a mean treatment difference of 9.9 in those with epithelioid histology).

“Overall frequency of adverse events was consistent with the known safety profile of nintedanib,” Dr. Barrueco said, noting that most adverse events were reversible with dose reduction.

Study participants were chemotherapy-naive patients with a mean age of 67 years and Eastern Cooperative Oncology Group performance status of 0-1. They received pemetrexed at a dose of 500 mg/m² and cisplatin at a dose of 75 mg/m² on day 1 plus either nintedanib at a dose of 200 mg twice daily on days 2-21 or placebo, followed by monotherapy with nintedanib or placebo until progression or unacceptable toxicity.

“In conclusion, nintedanib plus pemetrexed/cisplatin demonstrated a signal for clinical benefit in the first-time treatment of patients with malignant pleural mesothelioma. This was evident in all endpoints of the trial, and consistently showed benefit for the nintedanib group,” Mr. Barrueco said, noting that phase 3 of the LUME-Meso study is now recruiting.

sworcester@frontlinemedcom.com

Take-Home Points

• Analysis of patients in the Medicare database showed that each successive ESI decreased the risk of an osteoporotic spine fracture by 2%, and that each successive LJSI decreases it by 4%.

• Although statistically significant, this may not be clinically relevant.

• Successive ESI did not influence the risk of developing an osteoporotic hip or wrist fracture, but that each additional LJSI reduced the risk.

• Prolonged steroid exposure was found to increase the risk of spine fracture for ESI and LJSI patients.

• Acute exposure to exogenous steroids via the epidural space, transforaminal space, or large joints does not seem to increase the risk of an osteoporotic fracture of the spine, hip, or wrist.

Epidural steroid injections (ESIs) are widely used in the nonoperative treatment of low back pain, radicular leg pain, and spinal stenosis. The treatment rationale is that locally injected anti-inflammatory drugs, such as steroids, reduce inflammation by inhibiting formation and release of inflammatory cytokines, leading to pain reduction.^1,2 According to 4 systematic reviews, the best available evidence of the efficacy of ESIs is less than robust.^3-6 These reviews were limited by the heterogeneity of patient selection, delivery mode, type and dose of steroid used, number and frequency of ESIs, and outcome measures.

The association of chronic oral steroid use and the development of osteoporosis was previously established.^7,8 One concern is that acute exposure to steroids in the form of lumbar ESIs may also lead to osteoporosis and then a pathologic fracture of the vertebra. Several studies have found no association between bone mineral density and cumulative steroid dose,^9,10 mean number of ESIs, or duration of ESIs,¹⁰ though other studies have found lower bone mineral density in postmenopausal women treated with ESIs.^11-13

In a study of 3000 ESI patients propensity-matched to a non-ESI cohort, Mandel and colleagues¹⁴ found that each successive ESI increased the risk of osteoporotic spine fracture by 21%. This clinically relevant 21% increased risk might lead physicians to stop prescribing or using this intervention. However, the association between osteoporotic fractures and other types of steroid injections remains poorly understood and underinvestigated. 

To further evaluate the relationship between steroid injections and osteoporotic fracture risk, we analyzed Medicare administrative claims data on both large-joint steroid injections (LJSIs) into knee and hip and transforaminal steroid injections (TSIs), as well as osteoporotic hip and wrist fractures. Our hypothesis was that a systemic effect of steroid injections would increase fracture risk in all skeletal locations regardless of injection site, whereas a local effect would produce a disproportionate increased risk of spine fracture with spine injection.

Materials and Methods

Medicare is a publicly funded US health insurance program for people 65 years old or older, people under age 65 years with certain disabilities, and people (any age) with end-stage renal disease or amyotrophic lateral sclerosis. The 5% Medicare Part B (physician, carrier) dataset contains individual claims records for a random sample of Medicare beneficiaries (~2.4 million enrollees). Patients who received steroid injections were identified from 5% Medicare claims made between January 1, 2004 and December 31, 2011. LJSIs were identified by Current Procedural Terminology (CPT) code 20610 and any of 16 other CPT codes: J0702, J1020, J1030, J1040, J1094, J1100, J1700, J1710, J1720, J2650, J2920, J2930, J3300, J3301, J3302, and J3303. ESIs were identified by CPT code 62310, 62311, 62318, or 62319, and TSIs by CPT code 64479, 64480, 64483, or 64484. Patients were followed in their initial injection cohort. For example, a patient who received an ESI initially and later received an LJSI remained in the ESI cohort.

Several groups of patients were excluded from the study: those who received Medicare coverage because of their age (under 65 years) and disabilities; those who received Medicare health benefits through health maintenance organizations (healthcare expenses were not submitted to the Centers for Medicare & Medicaid Services for payment, and therefore claims were not in the database or were incomplete); those with a prior claim history of <12 months (incomplete comorbidity history); and those who received a diagnosis of osteoporotic fracture (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 733.1x) before the initial steroid injection.

We determined the incidence of osteoporotic wrist, hip, and spine fractures within 1, 2, and 8 years after LJSI, ESI, and TSI. Wrist, hip, and spine fractures were identified by ICD-9-CM diagnosis codes 733.12, 733.13, and 733.14, respectively. We also determined the number of steroid injections given before wrist, hip, or spine fracture or, if no fracture occurred, before death or the end of the data period.

Statistical Analysis

Multivariate Cox regression analysis was performed to evaluate the risk factors for wrist, spine, and hip fractures. The covariates in this model included age, sex, race, census region, Medicare buy-in status, Charlson Comorbidity Index (CCI),¹⁵ year, and number of steroid injections before fracture, death, or end of data period. Medicare buy-in status, which indicates whether the beneficiary received financial assistance in paying insurance premiums, was used as a proxy for socioeconomic status. CCI is used as a composite score of a patient’s general health status in terms of comorbidities.^15,16 Four previously established categories¹⁷ were used to group CCIs in this study: 0 (none), 1 to 2 (low), 3 to 4 (moderate), and 5 or more (high). In addition, several diagnoses made within the 12 months before initial steroid injection were considered: osteoporosis (ICD-9-CM codes 733.0x, V82.81), Cushing syndrome (ICD-9-CM code 255.0), long-term (current) use of bisphosphonates (ICD-9-CM code V58.68), asymptomatic postmenopausal status (ICD-9-CM code V49.81), postmenopausal hormone replacement therapy (ICD-9-CM code V07.4), and long-term (current) use of steroids (ICD-9-CM code V58.65). The comparison of relative risk between any groups was reported as the adjusted hazard ratio (AHR), which is the ratio of the hazard rates of that particular outcome, taking into account inherent patient characteristics such as age, sex, and race as covariates. AHR of 1 corresponds to equivalent risk, AHR of >1 to elevated risk, and AHR of <1 to reduced risk.

Results

Using the 5% Medicare data for 2004 to 2011, we identified 275,999 Medicare beneficiaries who underwent LJSI, 93,943 who underwent ESI, and 32,311 who underwent TSI. During this period, TSI use increased, ESI use decreased, and LJSI use was relatively stable (Figure).

The risk for osteoporotic spine fracture 1, 2, and 8 years after ESI, TSI, or LJSI was affected by age, race, sex, and CCI (P < .001 for all; Tables 2-4).

The risk for osteoporotic hip fracture after 1 and 2 years was affected by age and number of LJSIs and TSIs but not by number of ESIs. Sex and CCI were also risk factors for hip fracture at 1 and 2 years for ESI and LJSI patients, as was race for LJSI patients. Risk for osteoporotic wrist fracture at 1 and 2 years was affected by sex and race for ESI and LJSI patients; age, race, CCI, and long-term steroid use were risk factors for TSI patients at all time points. Higher number of LJSIs, but not ESIs or TSIs, was associated with lower wrist fracture risk.

Discussion

ESIs continue to be used in the nonoperative treatment of low back pain, radicular leg pain, and spinal stenosis. Although the present study found ESI use increased in the Medicare population between 1994 and 2001,¹⁸ the trend is reversing, decreasing by 25%, with rates of 264 per 10,000 Medicare enrollees in 2004 and 194 per 10,000 enrollees in 2011. ESI use may have changed after systematic reviews revealed there was no clear evidence of the efficacy of ESIs in managing low back pain and radicular leg pain^3,5,6 or spinal stenosis.⁴

Nevertheless, ESIs are widely used because of the perceived benefit balanced against the perceived rarity of adverse events.⁶ Even if patients recognize a low likelihood of significant benefit, they may accept ESI as preferable to surgery. In addition, most private payers require extensive nonoperative treatment before they will approve surgery as a treatment option.

In a study by Mandel and colleagues,¹⁴ ESI increased the risk of vertebral compression fractures by 21%, which in turn increased the risk of death.¹⁹ If accurate, these findings obviously would challenge the perception that ESI is a low-risk intervention. In contrast to the Mandel study,¹⁴ the present analysis of the Medicare population revealed no clinically relevant change in risk of osteoporotic spine fracture with each successive ESI after the initial injection. After the initial injection, each successive ESI decreased the relative risk of osteoporotic spine fracture by 2%, and each successive LJSI decreased it by 4%. Although statistically significant, the small change in relative risk may not be clinically relevant. However, taken cumulatively over a number of successive injections, these effects may be clinically relevant.

The data also showed that, after the initial injection, each successive ESI had no effect on risk of osteoporotic hip or wrist fracture, and each successive LJSI reduced the risk. Similar to earlier findings,^20,21 long-term steroid use increased the risk of spine fracture in ESI and LJSI patients. Prolonged exposure to steroids may be necessary to reduce bone formation and increase bone breakdown.¹²

Although the study by Mandel and colleagues¹⁴ and our study both used administrative databases and survival analysis methods, conclusions differed. First, Mandel and colleagues¹⁴ used a study inclusion criterion of spine-related steroid injections, whereas we used a criterion of any steroid injection. Second, they used 50 years as the lower age for study inclusion, and we used 65 years. Third, to control for patients who had osteoporosis before study entry, they excluded those who had a fracture in an adjacent vertebra after kyphoplasty and vertebroplasty. It is unclear if patients who had osteoporotic fractures at other sites were excluded as well. Thus, the 2 cohorts may not be directly comparable.

Whereas Mandel and colleagues¹⁴ based their definition of osteoporotic spine fracture on a keyword search of a radiology database, we used a specific reportable ICD-9-CM diagnosis code. As a result, they may have overreported osteoporotic spine fractures, and we may have underreported. Finally, our sample was much larger than theirs. Given the relative rarity of osteoporotic fractures, a study with a larger sample may have more power to detect differences. In addition, unlike Mandel and colleagues,¹⁴ we focused on an injection cohort. We did not include or make comparisons with a no-injection cohort because our study hypothesis involved the potential systemic effects of steroid injections based on injection site. Although chronic steroid use was found to have a significant effect in our study, it is unclear to what extent the diagnosis code was used, during the comorbidity assessment or only in the event of steroid-related complications.

Our study also found that, after the initial injection, each successive LJSI decreased the risk of osteoporotic wrist fracture by 10%, and each successive TSI decreased the risk of osteoporotic hip fracture by 5%. It is plausible these injections allowed improved mobility, mitigating the effects of osteoporosis induced by inactivity and lack of resistance training. It is also possible that improved mobility limited falls.

In summary, this analysis of the Medicare claims database revealed that ESI, TSI, and LJSI decreased osteoporotic spine fracture risk. However, the effect was small and may not be clinically meaningful. After the initial injection, successive ESIs had no effect on the risk of osteoporotic hip or wrist fracture, and successive LJSIs reduced the risk of osteoporotic wrist fracture, perhaps because of improved mobility. Prolonged oral steroid use increased spine fracture risk in ESI and LJSI patients. More studies are needed to evaluate the risk-benefit profile of steroid injections.

Take-Home Points

• Analysis of patients in the Medicare database showed that each successive ESI decreased the risk of an osteoporotic spine fracture by 2%, and that each successive LJSI decreases it by 4%.

• Although statistically significant, this may not be clinically relevant.

• Successive ESI did not influence the risk of developing an osteoporotic hip or wrist fracture, but that each additional LJSI reduced the risk.

• Prolonged steroid exposure was found to increase the risk of spine fracture for ESI and LJSI patients.

• Acute exposure to exogenous steroids via the epidural space, transforaminal space, or large joints does not seem to increase the risk of an osteoporotic fracture of the spine, hip, or wrist.

Epidural steroid injections (ESIs) are widely used in the nonoperative treatment of low back pain, radicular leg pain, and spinal stenosis. The treatment rationale is that locally injected anti-inflammatory drugs, such as steroids, reduce inflammation by inhibiting formation and release of inflammatory cytokines, leading to pain reduction.^1,2 According to 4 systematic reviews, the best available evidence of the efficacy of ESIs is less than robust.^3-6 These reviews were limited by the heterogeneity of patient selection, delivery mode, type and dose of steroid used, number and frequency of ESIs, and outcome measures.

The association of chronic oral steroid use and the development of osteoporosis was previously established.^7,8 One concern is that acute exposure to steroids in the form of lumbar ESIs may also lead to osteoporosis and then a pathologic fracture of the vertebra. Several studies have found no association between bone mineral density and cumulative steroid dose,^9,10 mean number of ESIs, or duration of ESIs,¹⁰ though other studies have found lower bone mineral density in postmenopausal women treated with ESIs.^11-13

In a study of 3000 ESI patients propensity-matched to a non-ESI cohort, Mandel and colleagues¹⁴ found that each successive ESI increased the risk of osteoporotic spine fracture by 21%. This clinically relevant 21% increased risk might lead physicians to stop prescribing or using this intervention. However, the association between osteoporotic fractures and other types of steroid injections remains poorly understood and underinvestigated. 

To further evaluate the relationship between steroid injections and osteoporotic fracture risk, we analyzed Medicare administrative claims data on both large-joint steroid injections (LJSIs) into knee and hip and transforaminal steroid injections (TSIs), as well as osteoporotic hip and wrist fractures. Our hypothesis was that a systemic effect of steroid injections would increase fracture risk in all skeletal locations regardless of injection site, whereas a local effect would produce a disproportionate increased risk of spine fracture with spine injection.

Materials and Methods

Medicare is a publicly funded US health insurance program for people 65 years old or older, people under age 65 years with certain disabilities, and people (any age) with end-stage renal disease or amyotrophic lateral sclerosis. The 5% Medicare Part B (physician, carrier) dataset contains individual claims records for a random sample of Medicare beneficiaries (~2.4 million enrollees). Patients who received steroid injections were identified from 5% Medicare claims made between January 1, 2004 and December 31, 2011. LJSIs were identified by Current Procedural Terminology (CPT) code 20610 and any of 16 other CPT codes: J0702, J1020, J1030, J1040, J1094, J1100, J1700, J1710, J1720, J2650, J2920, J2930, J3300, J3301, J3302, and J3303. ESIs were identified by CPT code 62310, 62311, 62318, or 62319, and TSIs by CPT code 64479, 64480, 64483, or 64484. Patients were followed in their initial injection cohort. For example, a patient who received an ESI initially and later received an LJSI remained in the ESI cohort.

Several groups of patients were excluded from the study: those who received Medicare coverage because of their age (under 65 years) and disabilities; those who received Medicare health benefits through health maintenance organizations (healthcare expenses were not submitted to the Centers for Medicare & Medicaid Services for payment, and therefore claims were not in the database or were incomplete); those with a prior claim history of <12 months (incomplete comorbidity history); and those who received a diagnosis of osteoporotic fracture (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 733.1x) before the initial steroid injection.

We determined the incidence of osteoporotic wrist, hip, and spine fractures within 1, 2, and 8 years after LJSI, ESI, and TSI. Wrist, hip, and spine fractures were identified by ICD-9-CM diagnosis codes 733.12, 733.13, and 733.14, respectively. We also determined the number of steroid injections given before wrist, hip, or spine fracture or, if no fracture occurred, before death or the end of the data period.

Statistical Analysis

Multivariate Cox regression analysis was performed to evaluate the risk factors for wrist, spine, and hip fractures. The covariates in this model included age, sex, race, census region, Medicare buy-in status, Charlson Comorbidity Index (CCI),¹⁵ year, and number of steroid injections before fracture, death, or end of data period. Medicare buy-in status, which indicates whether the beneficiary received financial assistance in paying insurance premiums, was used as a proxy for socioeconomic status. CCI is used as a composite score of a patient’s general health status in terms of comorbidities.^15,16 Four previously established categories¹⁷ were used to group CCIs in this study: 0 (none), 1 to 2 (low), 3 to 4 (moderate), and 5 or more (high). In addition, several diagnoses made within the 12 months before initial steroid injection were considered: osteoporosis (ICD-9-CM codes 733.0x, V82.81), Cushing syndrome (ICD-9-CM code 255.0), long-term (current) use of bisphosphonates (ICD-9-CM code V58.68), asymptomatic postmenopausal status (ICD-9-CM code V49.81), postmenopausal hormone replacement therapy (ICD-9-CM code V07.4), and long-term (current) use of steroids (ICD-9-CM code V58.65). The comparison of relative risk between any groups was reported as the adjusted hazard ratio (AHR), which is the ratio of the hazard rates of that particular outcome, taking into account inherent patient characteristics such as age, sex, and race as covariates. AHR of 1 corresponds to equivalent risk, AHR of >1 to elevated risk, and AHR of <1 to reduced risk.

Results

Using the 5% Medicare data for 2004 to 2011, we identified 275,999 Medicare beneficiaries who underwent LJSI, 93,943 who underwent ESI, and 32,311 who underwent TSI. During this period, TSI use increased, ESI use decreased, and LJSI use was relatively stable (Figure).

The risk for osteoporotic spine fracture 1, 2, and 8 years after ESI, TSI, or LJSI was affected by age, race, sex, and CCI (P < .001 for all; Tables 2-4).

The risk for osteoporotic hip fracture after 1 and 2 years was affected by age and number of LJSIs and TSIs but not by number of ESIs. Sex and CCI were also risk factors for hip fracture at 1 and 2 years for ESI and LJSI patients, as was race for LJSI patients. Risk for osteoporotic wrist fracture at 1 and 2 years was affected by sex and race for ESI and LJSI patients; age, race, CCI, and long-term steroid use were risk factors for TSI patients at all time points. Higher number of LJSIs, but not ESIs or TSIs, was associated with lower wrist fracture risk.

Discussion

ESIs continue to be used in the nonoperative treatment of low back pain, radicular leg pain, and spinal stenosis. Although the present study found ESI use increased in the Medicare population between 1994 and 2001,¹⁸ the trend is reversing, decreasing by 25%, with rates of 264 per 10,000 Medicare enrollees in 2004 and 194 per 10,000 enrollees in 2011. ESI use may have changed after systematic reviews revealed there was no clear evidence of the efficacy of ESIs in managing low back pain and radicular leg pain^3,5,6 or spinal stenosis.⁴

Nevertheless, ESIs are widely used because of the perceived benefit balanced against the perceived rarity of adverse events.⁶ Even if patients recognize a low likelihood of significant benefit, they may accept ESI as preferable to surgery. In addition, most private payers require extensive nonoperative treatment before they will approve surgery as a treatment option.

In a study by Mandel and colleagues,¹⁴ ESI increased the risk of vertebral compression fractures by 21%, which in turn increased the risk of death.¹⁹ If accurate, these findings obviously would challenge the perception that ESI is a low-risk intervention. In contrast to the Mandel study,¹⁴ the present analysis of the Medicare population revealed no clinically relevant change in risk of osteoporotic spine fracture with each successive ESI after the initial injection. After the initial injection, each successive ESI decreased the relative risk of osteoporotic spine fracture by 2%, and each successive LJSI decreased it by 4%. Although statistically significant, the small change in relative risk may not be clinically relevant. However, taken cumulatively over a number of successive injections, these effects may be clinically relevant.

The data also showed that, after the initial injection, each successive ESI had no effect on risk of osteoporotic hip or wrist fracture, and each successive LJSI reduced the risk. Similar to earlier findings,^20,21 long-term steroid use increased the risk of spine fracture in ESI and LJSI patients. Prolonged exposure to steroids may be necessary to reduce bone formation and increase bone breakdown.¹²

Although the study by Mandel and colleagues¹⁴ and our study both used administrative databases and survival analysis methods, conclusions differed. First, Mandel and colleagues¹⁴ used a study inclusion criterion of spine-related steroid injections, whereas we used a criterion of any steroid injection. Second, they used 50 years as the lower age for study inclusion, and we used 65 years. Third, to control for patients who had osteoporosis before study entry, they excluded those who had a fracture in an adjacent vertebra after kyphoplasty and vertebroplasty. It is unclear if patients who had osteoporotic fractures at other sites were excluded as well. Thus, the 2 cohorts may not be directly comparable.

Whereas Mandel and colleagues¹⁴ based their definition of osteoporotic spine fracture on a keyword search of a radiology database, we used a specific reportable ICD-9-CM diagnosis code. As a result, they may have overreported osteoporotic spine fractures, and we may have underreported. Finally, our sample was much larger than theirs. Given the relative rarity of osteoporotic fractures, a study with a larger sample may have more power to detect differences. In addition, unlike Mandel and colleagues,¹⁴ we focused on an injection cohort. We did not include or make comparisons with a no-injection cohort because our study hypothesis involved the potential systemic effects of steroid injections based on injection site. Although chronic steroid use was found to have a significant effect in our study, it is unclear to what extent the diagnosis code was used, during the comorbidity assessment or only in the event of steroid-related complications.

Our study also found that, after the initial injection, each successive LJSI decreased the risk of osteoporotic wrist fracture by 10%, and each successive TSI decreased the risk of osteoporotic hip fracture by 5%. It is plausible these injections allowed improved mobility, mitigating the effects of osteoporosis induced by inactivity and lack of resistance training. It is also possible that improved mobility limited falls.

In summary, this analysis of the Medicare claims database revealed that ESI, TSI, and LJSI decreased osteoporotic spine fracture risk. However, the effect was small and may not be clinically meaningful. After the initial injection, successive ESIs had no effect on the risk of osteoporotic hip or wrist fracture, and successive LJSIs reduced the risk of osteoporotic wrist fracture, perhaps because of improved mobility. Prolonged oral steroid use increased spine fracture risk in ESI and LJSI patients. More studies are needed to evaluate the risk-benefit profile of steroid injections.

Take-Home Points

• Analysis of patients in the Medicare database showed that each successive ESI decreased the risk of an osteoporotic spine fracture by 2%, and that each successive LJSI decreases it by 4%.

• Although statistically significant, this may not be clinically relevant.

• Successive ESI did not influence the risk of developing an osteoporotic hip or wrist fracture, but that each additional LJSI reduced the risk.

• Prolonged steroid exposure was found to increase the risk of spine fracture for ESI and LJSI patients.

• Acute exposure to exogenous steroids via the epidural space, transforaminal space, or large joints does not seem to increase the risk of an osteoporotic fracture of the spine, hip, or wrist.

Epidural steroid injections (ESIs) are widely used in the nonoperative treatment of low back pain, radicular leg pain, and spinal stenosis. The treatment rationale is that locally injected anti-inflammatory drugs, such as steroids, reduce inflammation by inhibiting formation and release of inflammatory cytokines, leading to pain reduction.^1,2 According to 4 systematic reviews, the best available evidence of the efficacy of ESIs is less than robust.^3-6 These reviews were limited by the heterogeneity of patient selection, delivery mode, type and dose of steroid used, number and frequency of ESIs, and outcome measures.

The association of chronic oral steroid use and the development of osteoporosis was previously established.^7,8 One concern is that acute exposure to steroids in the form of lumbar ESIs may also lead to osteoporosis and then a pathologic fracture of the vertebra. Several studies have found no association between bone mineral density and cumulative steroid dose,^9,10 mean number of ESIs, or duration of ESIs,¹⁰ though other studies have found lower bone mineral density in postmenopausal women treated with ESIs.^11-13

In a study of 3000 ESI patients propensity-matched to a non-ESI cohort, Mandel and colleagues¹⁴ found that each successive ESI increased the risk of osteoporotic spine fracture by 21%. This clinically relevant 21% increased risk might lead physicians to stop prescribing or using this intervention. However, the association between osteoporotic fractures and other types of steroid injections remains poorly understood and underinvestigated. 

To further evaluate the relationship between steroid injections and osteoporotic fracture risk, we analyzed Medicare administrative claims data on both large-joint steroid injections (LJSIs) into knee and hip and transforaminal steroid injections (TSIs), as well as osteoporotic hip and wrist fractures. Our hypothesis was that a systemic effect of steroid injections would increase fracture risk in all skeletal locations regardless of injection site, whereas a local effect would produce a disproportionate increased risk of spine fracture with spine injection.

Materials and Methods

Medicare is a publicly funded US health insurance program for people 65 years old or older, people under age 65 years with certain disabilities, and people (any age) with end-stage renal disease or amyotrophic lateral sclerosis. The 5% Medicare Part B (physician, carrier) dataset contains individual claims records for a random sample of Medicare beneficiaries (~2.4 million enrollees). Patients who received steroid injections were identified from 5% Medicare claims made between January 1, 2004 and December 31, 2011. LJSIs were identified by Current Procedural Terminology (CPT) code 20610 and any of 16 other CPT codes: J0702, J1020, J1030, J1040, J1094, J1100, J1700, J1710, J1720, J2650, J2920, J2930, J3300, J3301, J3302, and J3303. ESIs were identified by CPT code 62310, 62311, 62318, or 62319, and TSIs by CPT code 64479, 64480, 64483, or 64484. Patients were followed in their initial injection cohort. For example, a patient who received an ESI initially and later received an LJSI remained in the ESI cohort.

Several groups of patients were excluded from the study: those who received Medicare coverage because of their age (under 65 years) and disabilities; those who received Medicare health benefits through health maintenance organizations (healthcare expenses were not submitted to the Centers for Medicare & Medicaid Services for payment, and therefore claims were not in the database or were incomplete); those with a prior claim history of <12 months (incomplete comorbidity history); and those who received a diagnosis of osteoporotic fracture (International Classification of Diseases, Ninth Revision, Clinical Modification [ICD-9-CM] code 733.1x) before the initial steroid injection.

We determined the incidence of osteoporotic wrist, hip, and spine fractures within 1, 2, and 8 years after LJSI, ESI, and TSI. Wrist, hip, and spine fractures were identified by ICD-9-CM diagnosis codes 733.12, 733.13, and 733.14, respectively. We also determined the number of steroid injections given before wrist, hip, or spine fracture or, if no fracture occurred, before death or the end of the data period.

Statistical Analysis

Multivariate Cox regression analysis was performed to evaluate the risk factors for wrist, spine, and hip fractures. The covariates in this model included age, sex, race, census region, Medicare buy-in status, Charlson Comorbidity Index (CCI),¹⁵ year, and number of steroid injections before fracture, death, or end of data period. Medicare buy-in status, which indicates whether the beneficiary received financial assistance in paying insurance premiums, was used as a proxy for socioeconomic status. CCI is used as a composite score of a patient’s general health status in terms of comorbidities.^15,16 Four previously established categories¹⁷ were used to group CCIs in this study: 0 (none), 1 to 2 (low), 3 to 4 (moderate), and 5 or more (high). In addition, several diagnoses made within the 12 months before initial steroid injection were considered: osteoporosis (ICD-9-CM codes 733.0x, V82.81), Cushing syndrome (ICD-9-CM code 255.0), long-term (current) use of bisphosphonates (ICD-9-CM code V58.68), asymptomatic postmenopausal status (ICD-9-CM code V49.81), postmenopausal hormone replacement therapy (ICD-9-CM code V07.4), and long-term (current) use of steroids (ICD-9-CM code V58.65). The comparison of relative risk between any groups was reported as the adjusted hazard ratio (AHR), which is the ratio of the hazard rates of that particular outcome, taking into account inherent patient characteristics such as age, sex, and race as covariates. AHR of 1 corresponds to equivalent risk, AHR of >1 to elevated risk, and AHR of <1 to reduced risk.

Results

Using the 5% Medicare data for 2004 to 2011, we identified 275,999 Medicare beneficiaries who underwent LJSI, 93,943 who underwent ESI, and 32,311 who underwent TSI. During this period, TSI use increased, ESI use decreased, and LJSI use was relatively stable (Figure).

The risk for osteoporotic spine fracture 1, 2, and 8 years after ESI, TSI, or LJSI was affected by age, race, sex, and CCI (P < .001 for all; Tables 2-4).

The risk for osteoporotic hip fracture after 1 and 2 years was affected by age and number of LJSIs and TSIs but not by number of ESIs. Sex and CCI were also risk factors for hip fracture at 1 and 2 years for ESI and LJSI patients, as was race for LJSI patients. Risk for osteoporotic wrist fracture at 1 and 2 years was affected by sex and race for ESI and LJSI patients; age, race, CCI, and long-term steroid use were risk factors for TSI patients at all time points. Higher number of LJSIs, but not ESIs or TSIs, was associated with lower wrist fracture risk.

Discussion

ESIs continue to be used in the nonoperative treatment of low back pain, radicular leg pain, and spinal stenosis. Although the present study found ESI use increased in the Medicare population between 1994 and 2001,¹⁸ the trend is reversing, decreasing by 25%, with rates of 264 per 10,000 Medicare enrollees in 2004 and 194 per 10,000 enrollees in 2011. ESI use may have changed after systematic reviews revealed there was no clear evidence of the efficacy of ESIs in managing low back pain and radicular leg pain^3,5,6 or spinal stenosis.⁴

Nevertheless, ESIs are widely used because of the perceived benefit balanced against the perceived rarity of adverse events.⁶ Even if patients recognize a low likelihood of significant benefit, they may accept ESI as preferable to surgery. In addition, most private payers require extensive nonoperative treatment before they will approve surgery as a treatment option.

In a study by Mandel and colleagues,¹⁴ ESI increased the risk of vertebral compression fractures by 21%, which in turn increased the risk of death.¹⁹ If accurate, these findings obviously would challenge the perception that ESI is a low-risk intervention. In contrast to the Mandel study,¹⁴ the present analysis of the Medicare population revealed no clinically relevant change in risk of osteoporotic spine fracture with each successive ESI after the initial injection. After the initial injection, each successive ESI decreased the relative risk of osteoporotic spine fracture by 2%, and each successive LJSI decreased it by 4%. Although statistically significant, the small change in relative risk may not be clinically relevant. However, taken cumulatively over a number of successive injections, these effects may be clinically relevant.

The data also showed that, after the initial injection, each successive ESI had no effect on risk of osteoporotic hip or wrist fracture, and each successive LJSI reduced the risk. Similar to earlier findings,^20,21 long-term steroid use increased the risk of spine fracture in ESI and LJSI patients. Prolonged exposure to steroids may be necessary to reduce bone formation and increase bone breakdown.¹²

Although the study by Mandel and colleagues¹⁴ and our study both used administrative databases and survival analysis methods, conclusions differed. First, Mandel and colleagues¹⁴ used a study inclusion criterion of spine-related steroid injections, whereas we used a criterion of any steroid injection. Second, they used 50 years as the lower age for study inclusion, and we used 65 years. Third, to control for patients who had osteoporosis before study entry, they excluded those who had a fracture in an adjacent vertebra after kyphoplasty and vertebroplasty. It is unclear if patients who had osteoporotic fractures at other sites were excluded as well. Thus, the 2 cohorts may not be directly comparable.

Whereas Mandel and colleagues¹⁴ based their definition of osteoporotic spine fracture on a keyword search of a radiology database, we used a specific reportable ICD-9-CM diagnosis code. As a result, they may have overreported osteoporotic spine fractures, and we may have underreported. Finally, our sample was much larger than theirs. Given the relative rarity of osteoporotic fractures, a study with a larger sample may have more power to detect differences. In addition, unlike Mandel and colleagues,¹⁴ we focused on an injection cohort. We did not include or make comparisons with a no-injection cohort because our study hypothesis involved the potential systemic effects of steroid injections based on injection site. Although chronic steroid use was found to have a significant effect in our study, it is unclear to what extent the diagnosis code was used, during the comorbidity assessment or only in the event of steroid-related complications.

Our study also found that, after the initial injection, each successive LJSI decreased the risk of osteoporotic wrist fracture by 10%, and each successive TSI decreased the risk of osteoporotic hip fracture by 5%. It is plausible these injections allowed improved mobility, mitigating the effects of osteoporosis induced by inactivity and lack of resistance training. It is also possible that improved mobility limited falls.

In summary, this analysis of the Medicare claims database revealed that ESI, TSI, and LJSI decreased osteoporotic spine fracture risk. However, the effect was small and may not be clinically meaningful. After the initial injection, successive ESIs had no effect on the risk of osteoporotic hip or wrist fracture, and successive LJSIs reduced the risk of osteoporotic wrist fracture, perhaps because of improved mobility. Prolonged oral steroid use increased spine fracture risk in ESI and LJSI patients. More studies are needed to evaluate the risk-benefit profile of steroid injections.

Robot-assisted radical prostatectomy shows better early postoperative outcomes than does laparoscopic radical prostatectomy, but the differences between the two surgical approaches disappeared by the 6-month follow-up.

Dr. Hiroyuki Koike and his colleagues at Wakayama (Japan) Medical University Hospital conducted a study of two groups of patients treated for localized prostate cancer. One group of 229 patients underwent laparoscopic radical prostatectomy (LRP) between July 2007 and July 2013. The other group of 115 patients had robot-assisted radical prostatectomy (RARP) between December 2012 and August 2014 (J Robot Surg. 2017;11[3]:325-31).

Master Video/Shutterstock

“The RARP group showed significantly better scores in urinary summary and all urinary subscales at postoperative 3-month follow-up. However, these differences disappeared at postoperative 6 and 12-month follow-up,” the investigators wrote. For the urinary summary score, LRP significantly underperformed, compared with RARP, with scores of 63.3 vs. 75.8, respectively, after 3 months. In addition, the bowel function score was superior for RARP, compared with LRP, at 96.9 vs. 92.9, respectively. Sexual function results were similar, with RARP and LRP scores of 2.8 vs. 0.

The general measures of the PCS and MCS also favored RARP. At the 3-month follow-up, PCS (51.3 vs. 48.1) and MCS (50 vs. 47.8) scores were higher for RARP, compared with LRP.

“It is unclear why our superiority of urinary function in RARP was observed only in early period. However, we can speculate several reasons for better urinary function in RARP group. First, we were able to treat the apex area more delicately with RARP. Second, some of the new techniques which we employed after the introduction of RARP could influence the urinary continence recovery,” the investigators wrote.

The authors had no relevant financial disclosures.

ilacy@frontlinemedcom.com

Robot-assisted radical prostatectomy shows better early postoperative outcomes than does laparoscopic radical prostatectomy, but the differences between the two surgical approaches disappeared by the 6-month follow-up.

Dr. Hiroyuki Koike and his colleagues at Wakayama (Japan) Medical University Hospital conducted a study of two groups of patients treated for localized prostate cancer. One group of 229 patients underwent laparoscopic radical prostatectomy (LRP) between July 2007 and July 2013. The other group of 115 patients had robot-assisted radical prostatectomy (RARP) between December 2012 and August 2014 (J Robot Surg. 2017;11[3]:325-31).

Master Video/Shutterstock

“The RARP group showed significantly better scores in urinary summary and all urinary subscales at postoperative 3-month follow-up. However, these differences disappeared at postoperative 6 and 12-month follow-up,” the investigators wrote. For the urinary summary score, LRP significantly underperformed, compared with RARP, with scores of 63.3 vs. 75.8, respectively, after 3 months. In addition, the bowel function score was superior for RARP, compared with LRP, at 96.9 vs. 92.9, respectively. Sexual function results were similar, with RARP and LRP scores of 2.8 vs. 0.

The general measures of the PCS and MCS also favored RARP. At the 3-month follow-up, PCS (51.3 vs. 48.1) and MCS (50 vs. 47.8) scores were higher for RARP, compared with LRP.

“It is unclear why our superiority of urinary function in RARP was observed only in early period. However, we can speculate several reasons for better urinary function in RARP group. First, we were able to treat the apex area more delicately with RARP. Second, some of the new techniques which we employed after the introduction of RARP could influence the urinary continence recovery,” the investigators wrote.

The authors had no relevant financial disclosures.

ilacy@frontlinemedcom.com

Robot-assisted radical prostatectomy shows better early postoperative outcomes than does laparoscopic radical prostatectomy, but the differences between the two surgical approaches disappeared by the 6-month follow-up.

Dr. Hiroyuki Koike and his colleagues at Wakayama (Japan) Medical University Hospital conducted a study of two groups of patients treated for localized prostate cancer. One group of 229 patients underwent laparoscopic radical prostatectomy (LRP) between July 2007 and July 2013. The other group of 115 patients had robot-assisted radical prostatectomy (RARP) between December 2012 and August 2014 (J Robot Surg. 2017;11[3]:325-31).

Master Video/Shutterstock

“The RARP group showed significantly better scores in urinary summary and all urinary subscales at postoperative 3-month follow-up. However, these differences disappeared at postoperative 6 and 12-month follow-up,” the investigators wrote. For the urinary summary score, LRP significantly underperformed, compared with RARP, with scores of 63.3 vs. 75.8, respectively, after 3 months. In addition, the bowel function score was superior for RARP, compared with LRP, at 96.9 vs. 92.9, respectively. Sexual function results were similar, with RARP and LRP scores of 2.8 vs. 0.

The general measures of the PCS and MCS also favored RARP. At the 3-month follow-up, PCS (51.3 vs. 48.1) and MCS (50 vs. 47.8) scores were higher for RARP, compared with LRP.

“It is unclear why our superiority of urinary function in RARP was observed only in early period. However, we can speculate several reasons for better urinary function in RARP group. First, we were able to treat the apex area more delicately with RARP. Second, some of the new techniques which we employed after the introduction of RARP could influence the urinary continence recovery,” the investigators wrote.

The authors had no relevant financial disclosures.

ilacy@frontlinemedcom.com

The Food and Drug Administration has approved pembrolizumab (Keytruda) for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, in cases where tests confirm that the tumors contain programmed death–ligand 1 and where the disease is progressing on or after two or more prior lines of therapy.

Pembrolizumab has been approved in the United States since 2014 for the treatment of melanoma, with subsequent approvals for treatment of non–small-cell lung cancer, head and neck squamous cell carcinoma, Hodgkin lymphoma, and several other advanced cancers.

dwatson@frontlinemedcom.com

The Food and Drug Administration has approved pembrolizumab (Keytruda) for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, in cases where tests confirm that the tumors contain programmed death–ligand 1 and where the disease is progressing on or after two or more prior lines of therapy.

Pembrolizumab has been approved in the United States since 2014 for the treatment of melanoma, with subsequent approvals for treatment of non–small-cell lung cancer, head and neck squamous cell carcinoma, Hodgkin lymphoma, and several other advanced cancers.

dwatson@frontlinemedcom.com

The Food and Drug Administration has approved pembrolizumab (Keytruda) for the treatment of patients with recurrent locally advanced or metastatic gastric or gastroesophageal junction (GEJ) adenocarcinoma, in cases where tests confirm that the tumors contain programmed death–ligand 1 and where the disease is progressing on or after two or more prior lines of therapy.

Pembrolizumab has been approved in the United States since 2014 for the treatment of melanoma, with subsequent approvals for treatment of non–small-cell lung cancer, head and neck squamous cell carcinoma, Hodgkin lymphoma, and several other advanced cancers.

dwatson@frontlinemedcom.com

To date, efforts to translate exciting laboratory findings into clinical trials for Parkinson’s disease have not met with much success. However, the latest exenatide study results offer another chance for improving this situation. This randomized, placebo-controlled trial also highlights how a medication already in human use might be repurposed for a novel application.

Whether this study actually proved its concept will require confirmation by further clinical investigation. The biggest challenge presented by this study has to do with studying patients with Parkinson’s disease who already are receiving symptomatic therapy with dopaminergic drugs. The study plan was to eliminate this effect by an overnight washout of Parkinson’s disease drugs. But waiting for a day or two after stopping medication, even for a short-acting drug like levodopa, does not necessarily abolish all of its symptomatic effects. If exenatide acted by enhancing the temporary relief of parkinsonism offered by medications rather than by protecting against further neurodegeneration, study ratings would not be able to discern this difference. Similarly, if exenatide exerts a trophic effect on striatal dopamine transporters, the observed reduction of decline in dopamine transporter (DAT) scan readings would not necessarily reflect sparing of further dopaminergic neuron loss.

Another potentially confounding factor was that during the course of the trial, the exenatide group increased its concomitant dopaminergic therapy more than the placebo-treated controls did. In a study of only 62 subjects who were already advanced in the course of Parkinson’s disease and experiencing motor fluctuations, any imbalance between treatment and placebo groups might impart uncertainties for which it may be difficult to correct.

Despite all the reasonable objections that might detract from a definitive interpretation of this study, its results make a credible argument for a neuroprotection outcome. The happenstance of two seemingly independent indicators of disease modification—in this case, the washout ratings of parkinsonian features and the DAT scan results—provides grounds for optimism. In the quest for halting the advance of Parkinson’s disease, the perfect study has yet to emerge. The exenatide investigators’ careful attention to detail and collection of other study information and biomarker specimens will serve well the next researchers who explore the potential for glucagon-like peptide-1 treatments.

—Peter A. LeWitt, MD
Professor of Neurology
Wayne State University School of Medicine
Director, Parkinson's Disease and Movement Disorders Program
Henry Ford Hospital West Bloomfield
West Bloomfield, Michigan

To date, efforts to translate exciting laboratory findings into clinical trials for Parkinson’s disease have not met with much success. However, the latest exenatide study results offer another chance for improving this situation. This randomized, placebo-controlled trial also highlights how a medication already in human use might be repurposed for a novel application.

Whether this study actually proved its concept will require confirmation by further clinical investigation. The biggest challenge presented by this study has to do with studying patients with Parkinson’s disease who already are receiving symptomatic therapy with dopaminergic drugs. The study plan was to eliminate this effect by an overnight washout of Parkinson’s disease drugs. But waiting for a day or two after stopping medication, even for a short-acting drug like levodopa, does not necessarily abolish all of its symptomatic effects. If exenatide acted by enhancing the temporary relief of parkinsonism offered by medications rather than by protecting against further neurodegeneration, study ratings would not be able to discern this difference. Similarly, if exenatide exerts a trophic effect on striatal dopamine transporters, the observed reduction of decline in dopamine transporter (DAT) scan readings would not necessarily reflect sparing of further dopaminergic neuron loss.

Another potentially confounding factor was that during the course of the trial, the exenatide group increased its concomitant dopaminergic therapy more than the placebo-treated controls did. In a study of only 62 subjects who were already advanced in the course of Parkinson’s disease and experiencing motor fluctuations, any imbalance between treatment and placebo groups might impart uncertainties for which it may be difficult to correct.

Despite all the reasonable objections that might detract from a definitive interpretation of this study, its results make a credible argument for a neuroprotection outcome. The happenstance of two seemingly independent indicators of disease modification—in this case, the washout ratings of parkinsonian features and the DAT scan results—provides grounds for optimism. In the quest for halting the advance of Parkinson’s disease, the perfect study has yet to emerge. The exenatide investigators’ careful attention to detail and collection of other study information and biomarker specimens will serve well the next researchers who explore the potential for glucagon-like peptide-1 treatments.

—Peter A. LeWitt, MD
Professor of Neurology
Wayne State University School of Medicine
Director, Parkinson's Disease and Movement Disorders Program
Henry Ford Hospital West Bloomfield
West Bloomfield, Michigan

To date, efforts to translate exciting laboratory findings into clinical trials for Parkinson’s disease have not met with much success. However, the latest exenatide study results offer another chance for improving this situation. This randomized, placebo-controlled trial also highlights how a medication already in human use might be repurposed for a novel application.

Whether this study actually proved its concept will require confirmation by further clinical investigation. The biggest challenge presented by this study has to do with studying patients with Parkinson’s disease who already are receiving symptomatic therapy with dopaminergic drugs. The study plan was to eliminate this effect by an overnight washout of Parkinson’s disease drugs. But waiting for a day or two after stopping medication, even for a short-acting drug like levodopa, does not necessarily abolish all of its symptomatic effects. If exenatide acted by enhancing the temporary relief of parkinsonism offered by medications rather than by protecting against further neurodegeneration, study ratings would not be able to discern this difference. Similarly, if exenatide exerts a trophic effect on striatal dopamine transporters, the observed reduction of decline in dopamine transporter (DAT) scan readings would not necessarily reflect sparing of further dopaminergic neuron loss.

Another potentially confounding factor was that during the course of the trial, the exenatide group increased its concomitant dopaminergic therapy more than the placebo-treated controls did. In a study of only 62 subjects who were already advanced in the course of Parkinson’s disease and experiencing motor fluctuations, any imbalance between treatment and placebo groups might impart uncertainties for which it may be difficult to correct.

Despite all the reasonable objections that might detract from a definitive interpretation of this study, its results make a credible argument for a neuroprotection outcome. The happenstance of two seemingly independent indicators of disease modification—in this case, the washout ratings of parkinsonian features and the DAT scan results—provides grounds for optimism. In the quest for halting the advance of Parkinson’s disease, the perfect study has yet to emerge. The exenatide investigators’ careful attention to detail and collection of other study information and biomarker specimens will serve well the next researchers who explore the potential for glucagon-like peptide-1 treatments.

—Peter A. LeWitt, MD
Professor of Neurology
Wayne State University School of Medicine
Director, Parkinson's Disease and Movement Disorders Program
Henry Ford Hospital West Bloomfield
West Bloomfield, Michigan

Exenatide improves motor function in patients with Parkinson’s disease, according to research published online ahead of print August 3 in Lancet. The improvements may persist for months after treatment exposure.

Exenatide, an analogue of glucagon-like peptide-1, is used to treat type 2 diabetes. In rodent models of Parkinson’s disease, exenatide had neuroprotective effects and improved motor performance, behavior, learning, and memory. The drug also provided motor and cognitive benefits in a proof-of-concept study including patients with Parkinson’s disease.

Active Group Was Slightly Older

Dilan Athauda, MBBS, Senior Clinical Research Associate at University College London, and colleagues conducted a double-blind study to assess exenatide’s potential disease-modifying effects. At screening for study entry, patients with idiopathic Parkinson’s disease underwent physical and neurologic examinations, assessments of mood and cognition, and blood sampling. The investigators randomized eligible participants to subcutaneous injections of exenatide (2 mg) or placebo once weekly for 48 weeks. Participants continued to take their regular medications. Investigators examined patients in an off-medication state and collected blood and urine at baseline and weeks 12, 24, 36, and 48. Study drugs were withdrawn after 48 weeks, and the final follow-up visit was at week 60.

The primary outcome was change in Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part 3 score at 60 weeks. Secondary outcomes included differences between exenatide and placebo in each subsection of the MDS-UPDRS in the on-medication state, and the Mattis Dementia Rating Scale at weeks 48 and 60.

In all, 62 participants were randomized. Patients assigned to exenatide were slightly older, had higher baseline MDS-UPDRS part 3 scores, and had lower levodopa equivalent dose than did controls. Average age was about 62 in the exenatide group and about 58 among controls. About 26% of the population was female, and the mean disease duration at baseline was 6.4 years. Approximately 97% of the population were between Hoehn and Yahr stage 1 and 2 at baseline.

Exenatide Yielded Motor Improvement

At week 60, off-medication MDS-UPDRS part 3 scores had worsened by 2.1 points in the placebo group and improved by 1.0 point in the exenatide group, yielding a significant adjusted difference of –3.5 points. At week 48, scores among controls had deteriorated by 1.7 points, and those in the exenatide group had improved by 2.3 points, resulting in a significant adjusted between-group difference of –4.3 points.

On-medication scores on MDS-UPDRS parts 1 through 4 did not differ significantly between groups at weeks 48 or 60. The researchers also did not observe a significant difference between groups in Mattis Dementia Rating Scale score at those time points. The frequency of adverse events was similar between groups.

“Exenatide could have a longer-lasting effect on disease severity beyond conventional drug effects on dopaminergic receptors,” said the researchers. “Whether exenatide affects the underlying disease pathophysiology or simply induces long-lasting symptomatic effects is uncertain. Exenatide represents a major new avenue for investigation in Parkinson’s disease, and effects on everyday symptoms should be examined in longer-term trials.”

—Erik Greb

Suggested Reading

Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet. 2017 Aug 3 [Epub ahead of print].

Exenatide improves motor function in patients with Parkinson’s disease, according to research published online ahead of print August 3 in Lancet. The improvements may persist for months after treatment exposure.

Exenatide, an analogue of glucagon-like peptide-1, is used to treat type 2 diabetes. In rodent models of Parkinson’s disease, exenatide had neuroprotective effects and improved motor performance, behavior, learning, and memory. The drug also provided motor and cognitive benefits in a proof-of-concept study including patients with Parkinson’s disease.

Active Group Was Slightly Older

Dilan Athauda, MBBS, Senior Clinical Research Associate at University College London, and colleagues conducted a double-blind study to assess exenatide’s potential disease-modifying effects. At screening for study entry, patients with idiopathic Parkinson’s disease underwent physical and neurologic examinations, assessments of mood and cognition, and blood sampling. The investigators randomized eligible participants to subcutaneous injections of exenatide (2 mg) or placebo once weekly for 48 weeks. Participants continued to take their regular medications. Investigators examined patients in an off-medication state and collected blood and urine at baseline and weeks 12, 24, 36, and 48. Study drugs were withdrawn after 48 weeks, and the final follow-up visit was at week 60.

The primary outcome was change in Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part 3 score at 60 weeks. Secondary outcomes included differences between exenatide and placebo in each subsection of the MDS-UPDRS in the on-medication state, and the Mattis Dementia Rating Scale at weeks 48 and 60.

In all, 62 participants were randomized. Patients assigned to exenatide were slightly older, had higher baseline MDS-UPDRS part 3 scores, and had lower levodopa equivalent dose than did controls. Average age was about 62 in the exenatide group and about 58 among controls. About 26% of the population was female, and the mean disease duration at baseline was 6.4 years. Approximately 97% of the population were between Hoehn and Yahr stage 1 and 2 at baseline.

Exenatide Yielded Motor Improvement

At week 60, off-medication MDS-UPDRS part 3 scores had worsened by 2.1 points in the placebo group and improved by 1.0 point in the exenatide group, yielding a significant adjusted difference of –3.5 points. At week 48, scores among controls had deteriorated by 1.7 points, and those in the exenatide group had improved by 2.3 points, resulting in a significant adjusted between-group difference of –4.3 points.

On-medication scores on MDS-UPDRS parts 1 through 4 did not differ significantly between groups at weeks 48 or 60. The researchers also did not observe a significant difference between groups in Mattis Dementia Rating Scale score at those time points. The frequency of adverse events was similar between groups.

“Exenatide could have a longer-lasting effect on disease severity beyond conventional drug effects on dopaminergic receptors,” said the researchers. “Whether exenatide affects the underlying disease pathophysiology or simply induces long-lasting symptomatic effects is uncertain. Exenatide represents a major new avenue for investigation in Parkinson’s disease, and effects on everyday symptoms should be examined in longer-term trials.”

—Erik Greb

Suggested Reading

Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet. 2017 Aug 3 [Epub ahead of print].

Exenatide improves motor function in patients with Parkinson’s disease, according to research published online ahead of print August 3 in Lancet. The improvements may persist for months after treatment exposure.

Exenatide, an analogue of glucagon-like peptide-1, is used to treat type 2 diabetes. In rodent models of Parkinson’s disease, exenatide had neuroprotective effects and improved motor performance, behavior, learning, and memory. The drug also provided motor and cognitive benefits in a proof-of-concept study including patients with Parkinson’s disease.

Active Group Was Slightly Older

Dilan Athauda, MBBS, Senior Clinical Research Associate at University College London, and colleagues conducted a double-blind study to assess exenatide’s potential disease-modifying effects. At screening for study entry, patients with idiopathic Parkinson’s disease underwent physical and neurologic examinations, assessments of mood and cognition, and blood sampling. The investigators randomized eligible participants to subcutaneous injections of exenatide (2 mg) or placebo once weekly for 48 weeks. Participants continued to take their regular medications. Investigators examined patients in an off-medication state and collected blood and urine at baseline and weeks 12, 24, 36, and 48. Study drugs were withdrawn after 48 weeks, and the final follow-up visit was at week 60.

The primary outcome was change in Movement Disorders Society Unified Parkinson’s Disease Rating Scale (MDS-UPDRS) part 3 score at 60 weeks. Secondary outcomes included differences between exenatide and placebo in each subsection of the MDS-UPDRS in the on-medication state, and the Mattis Dementia Rating Scale at weeks 48 and 60.

In all, 62 participants were randomized. Patients assigned to exenatide were slightly older, had higher baseline MDS-UPDRS part 3 scores, and had lower levodopa equivalent dose than did controls. Average age was about 62 in the exenatide group and about 58 among controls. About 26% of the population was female, and the mean disease duration at baseline was 6.4 years. Approximately 97% of the population were between Hoehn and Yahr stage 1 and 2 at baseline.

Exenatide Yielded Motor Improvement

At week 60, off-medication MDS-UPDRS part 3 scores had worsened by 2.1 points in the placebo group and improved by 1.0 point in the exenatide group, yielding a significant adjusted difference of –3.5 points. At week 48, scores among controls had deteriorated by 1.7 points, and those in the exenatide group had improved by 2.3 points, resulting in a significant adjusted between-group difference of –4.3 points.

On-medication scores on MDS-UPDRS parts 1 through 4 did not differ significantly between groups at weeks 48 or 60. The researchers also did not observe a significant difference between groups in Mattis Dementia Rating Scale score at those time points. The frequency of adverse events was similar between groups.

“Exenatide could have a longer-lasting effect on disease severity beyond conventional drug effects on dopaminergic receptors,” said the researchers. “Whether exenatide affects the underlying disease pathophysiology or simply induces long-lasting symptomatic effects is uncertain. Exenatide represents a major new avenue for investigation in Parkinson’s disease, and effects on everyday symptoms should be examined in longer-term trials.”

—Erik Greb

Suggested Reading

Athauda D, Maclagan K, Skene SS, et al. Exenatide once weekly versus placebo in Parkinson’s disease: a randomised, double-blind, placebo-controlled trial. Lancet. 2017 Aug 3 [Epub ahead of print].

Social media is now being used by surgeons for interaction among peers, informal learning, exchange of technical information, and diffusion of ideas.

A study has examined posting and membership data from a closed Facebook page, the “Robotic Surgery Collaboration,” created by surgeons who practice robotic-assisted procedures. Overall, the findings show exponential growth in membership in January 2015 through August 2016, some signs of stagnating engagement, and use of the platform for peer-to-peer learning and discussion.

audioundwerbung/iStockphoto

acruz@frontlinemedcom.com

Social media is now being used by surgeons for interaction among peers, informal learning, exchange of technical information, and diffusion of ideas.

A study has examined posting and membership data from a closed Facebook page, the “Robotic Surgery Collaboration,” created by surgeons who practice robotic-assisted procedures. Overall, the findings show exponential growth in membership in January 2015 through August 2016, some signs of stagnating engagement, and use of the platform for peer-to-peer learning and discussion.

audioundwerbung/iStockphoto

acruz@frontlinemedcom.com

Social media is now being used by surgeons for interaction among peers, informal learning, exchange of technical information, and diffusion of ideas.

A study has examined posting and membership data from a closed Facebook page, the “Robotic Surgery Collaboration,” created by surgeons who practice robotic-assisted procedures. Overall, the findings show exponential growth in membership in January 2015 through August 2016, some signs of stagnating engagement, and use of the platform for peer-to-peer learning and discussion.

audioundwerbung/iStockphoto

acruz@frontlinemedcom.com

A key factor that impacts the efficacy and the toxicity of biologics used for rheumatic diseases is their immunogenicity, and this factor doesn’t appear to be any different for biosimilars in studies conducted so far.

In a meta-analysis of 63 studies of tumor necrosis factor (TNF) inhibitors, investigators including Daniel E. Furst, MD, professor of rheumatology at the University of Washington, Seattle, who also is affiliated with the University of California, Los Angeles, and the University of Florence, Italy, found that antidrug antibodies developed in 17% of patients (BioDrugs 2015;29:241-58).

“That doesn’t sound too bad, but does it differ by medication?” asked Dr. Furst, who spoke at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “For infliximab, 30% of the time, there are antidrug antibodies. So if that has a clinical effect, that’s a big deal. For certolizumab ... it’s only 6%, so there is a huge difference within the TNF inhibitors.” At the same time, antidrug antibodies developed in patients on adalimumab 23% of the time, followed by certolizumab (6%), golimumab (4%), and etanercept (2%).

dbrunk@frontlinemedcom.com

A key factor that impacts the efficacy and the toxicity of biologics used for rheumatic diseases is their immunogenicity, and this factor doesn’t appear to be any different for biosimilars in studies conducted so far.

In a meta-analysis of 63 studies of tumor necrosis factor (TNF) inhibitors, investigators including Daniel E. Furst, MD, professor of rheumatology at the University of Washington, Seattle, who also is affiliated with the University of California, Los Angeles, and the University of Florence, Italy, found that antidrug antibodies developed in 17% of patients (BioDrugs 2015;29:241-58).

“That doesn’t sound too bad, but does it differ by medication?” asked Dr. Furst, who spoke at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “For infliximab, 30% of the time, there are antidrug antibodies. So if that has a clinical effect, that’s a big deal. For certolizumab ... it’s only 6%, so there is a huge difference within the TNF inhibitors.” At the same time, antidrug antibodies developed in patients on adalimumab 23% of the time, followed by certolizumab (6%), golimumab (4%), and etanercept (2%).

dbrunk@frontlinemedcom.com

A key factor that impacts the efficacy and the toxicity of biologics used for rheumatic diseases is their immunogenicity, and this factor doesn’t appear to be any different for biosimilars in studies conducted so far.

In a meta-analysis of 63 studies of tumor necrosis factor (TNF) inhibitors, investigators including Daniel E. Furst, MD, professor of rheumatology at the University of Washington, Seattle, who also is affiliated with the University of California, Los Angeles, and the University of Florence, Italy, found that antidrug antibodies developed in 17% of patients (BioDrugs 2015;29:241-58).

“That doesn’t sound too bad, but does it differ by medication?” asked Dr. Furst, who spoke at the annual Perspectives in Rheumatic Diseases held by Global Academy for Medical Education. “For infliximab, 30% of the time, there are antidrug antibodies. So if that has a clinical effect, that’s a big deal. For certolizumab ... it’s only 6%, so there is a huge difference within the TNF inhibitors.” At the same time, antidrug antibodies developed in patients on adalimumab 23% of the time, followed by certolizumab (6%), golimumab (4%), and etanercept (2%).

dbrunk@frontlinemedcom.com