The Journal of Family Practice

With older women in the United States about 4 times more likely than their male counterparts to develop osteoporosis,^1,2 physicians often fail to screen for—or to treat—low bone mass in men. There are plenty of reasons why they should.

First and foremost: Osteoporosis is a leading cause of morbidity and mortality in the elderly.³ An estimated 8.8 million American men suffer from osteoporosis or osteopenia.³ And, although only about 20% of osteoporosis patients are male, men sustain between 30% and 40% of osteoporotic fractures.^1,2 What’s more, hip fracture in men has a mortality rate of up to 37.5%—2 to 3 times higher than that of women with hip fracture.^4,5

Clearly, then, it is crucial to be aware of the risks of osteoporosis faced by both men and women as they age. Here’s a look at what to consider, when to screen, and how to treat male patients who have, or are at risk for, osteoporosis.

Which men are at risk? 

The incidence of fractures secondary to osteoporosis varies with race/ethnicity and geography. The highest rates worldwide occur in Scandinavia and among Caucasians in the United States; black, Asian, and Hispanic populations have the lowest rates.^6,7 As with women, the risk of osteoporotic fracture in men increases with age. However, the peak incidence of fracture occurs about 10 years later in men than in women, starting at about age 70.⁸ Approximately 13% of white men older than 50 years will experience at least one osteoporotic fracture.⁹

There are 2 main types of osteoporosis: primary and secondary. Up to 40% of osteoporosis in men is primary,⁴ with bone loss due either to age (senile osteoporosis) or to an unknown cause (idiopathic osteoporosis).¹⁰ For men 70 years or older, osteoporosis is assumed to be age related. Idiopathic osteoporosis is diagnosed only in men younger than 70 who have no obvious secondary cause.¹⁰ There are numerous secondary causes, however, and most men with bone loss have at least one.⁴

Common secondary causes: Lifestyle, medical conditions, and meds

The most common causes of secondary osteoporosis in men are exposure to glucocorticoids, primary or secondary hypogonadism (low testosterone), diabetes, alcohol abuse, smoking, gastrointestinal (GI) disease, hypercalciuria, low body weight (body mass index <20 kg/m2), and immobility (TABLE 1).^4,5,8,10

Chronic use of corticosteroids, often used to treat chronic obstructive pulmonary disease (COPD), asthma, and rheumatoid arthritis, directly affects the bone, decreasing skeletal muscle, increasing immobility, and reducing intestinal absorption of calcium as well as serum testosterone levels.¹⁰ Men with androgen deficiency (which may be due to androgen deprivation therapy to treat prostate cancer) or chronic use of opioids are also at increased risk.^4,5,10-12

Diagnostic screening and criteria

The World Health Organization has established diagnostic criteria for osteoporosis using bone mineral density (BMD), reported as both T-scores and Z-scores as measured on dual-energy x-ray absorptiometry (DEXA) scan.¹³ The T-score represents the number of standard deviations above or below the mean BMD for young adults, matched for sex and race, but not age. It classifies individuals into 3 categories: normal; low (osteopenia), with a T-score between -1 and -2.5; and osteoporosis (T-score ≤-2.5).^4,14 The Z-score indicates the number of standard deviations above or below the mean for age, as well as sex and race. A Z-score of ≤-2.0 is below the expected range, indicating an increased likelihood of a secondary form of osteoporosis.¹⁴

Which men to screen?

The US Preventive Services Task Force has concluded that evidence is insufficient to assess the balance of benefits and harms of screening for osteoporosis in men. It therefore makes no recommendation to screen men who don't have evidence of previous fractures or secondary causes of osteoporosis.¹⁵

Other organizations agree that there is insufficient evidence to recommend routine screening for men without known osteoporotic fractures or secondary causes for osteoporosis. There are, however, some guidelines that are useful in clinical practice.

The most common causes of secondary osteoporosis in men include exposure to glucocorticoids, primary or secondary hypogonadism, diabetes, alcohol abuse, and smoking.

The Endocrine Society, American College of Physicians (ACP), and National Osteoporosis Foundation (NOF) recommend screening men ages 70 years or older, and men ages 50 to 69 who have risk factors for fracture and/or a history of fracture sustained after age 50.^5,16,17 (See “Did you know?”)^{1,2,4,5,9-12,16,17} Prior to screening, it is important to do a complete medical history and physical examination.

Screening considerations. The Endocrine Society, ACP, and NOF recommend a DEXA scan of the spine and hip for men who are at increased risk for osteoporosis and have no contraindications to drug therapy.^5,16,17 In patients who have degenerative changes of the spine and hip that would likely obscure DEXA outcomes, a scan of the radius may provide a more accurate assessment of bone status. Men receiving androgen deprivation therapy for prostate cancer will have a greater decline of bone density in the radius than in the hip or spine and are therefore ideal candidates for DEXA of the forearm, as well.^5,11 Keep in mind, however, that no studies have looked at how well, or whether, men with osteoporosis measured only in the radius respond to treatment.⁵

A DEXA scan is not always widely available, nor is it a perfect predictor of fracture risk. In addition, it is not always cost effective. For some patients, the use of a validated clinical predictive tool is preferable as an initial option.

The Male Osteoporosis Risk Estimation Score (MORES) uses age, weight, and history of COPD to identify men 60 years or older who are at risk for osteoporosis (TABLE 2).¹⁸ The score can be easily calculated during a clinical encounter and is beneficial for identifying men who should be referred for DEXA scan. A score of ≥6 has been found to yield an overall sensitivity of 0.93 (95% confidence interval [CI], 0.85-0.97) and a specificity of 0.59 (95% CI, 0.56-0.62), with a number needed to screen to prevent one additional hip fracture of 279.¹⁸

The Osteoporosis Self-assessment Tool (OST) (http://depts.washington.edu/osteoed/tools.php?type=ost) is a calculated value that uses age and weight to determine an individual’s risk for osteoporosis (risk score=weight [in kg] – age [in years]/5).^16,19 Although there is not a defined value to determine a positive OST risk score, scores of -1 to 3 have been used in a variety of studies.¹⁶ In a study of 181 American men, the OST predicted osteoporosis with a sensitivity of 93% and a specificity of 66% when using a cutoff score of 3.²⁰

Treating men at risk

Pharmacologic therapy is recommended for men at an increased risk for fracture. This includes men who have had a hip or vertebral fracture without major trauma, as well as those who have not had such a fracture but have a BMD of the spine, femoral neck, and/or total hip of ≤-2.5.^5,17 This standard also applies to the radius when used as an alternative site.

Several organizations recommend screening men ages ≥70 years and those ages 50 to 69 who have risk factors for fractures or who sustained a fracture after age 50.

The International Society for Clinical Densitometry and International Osteoporosis Foundation endorse the use of the Fracture Risk Assessment Tool (FRAX). Available at http://shef.ac.uk/FRAX/tool.aspx?country=9, FRAX is a computer-based calculator that uses risk factors and BMD of the femoral neck to estimate an individual’s 10-year fracture probability.²¹ Men who are 50 years or older, have a T-score between -1.0 and -2.5 in the spine, femoral neck, or total hip, and a 10-year risk of ≥20% of developing any fracture or ≥3% of developing a hip fracture based on FRAX, should be offered pharmacotherapy.^5,17

Bisphosphonates are first-line therapy

Although oral bisphosphonates are first-line therapy for men who meet these criteria,⁴ pharmacotherapy should be individualized based on factors such as fracture history, severity of osteoporosis, comorbidities (eg, peptic ulcer disease, malignancy, renal disease, or malabsorption), and cost (TABLE 3).^22,23

Alendronate once weekly has been proven to increase BMD and to reduce the risk of fracture in men.^24,25 A randomized, placebo-controlled trial of 241 men with osteoporosis found that alendronate increased BMD by 7.1% (±0.3) at the lumbar spine, 2.5% (±0.4) at the femoral neck, and 2% (±0.2) for the total body. Those in the placebo group had a 1.8% (±0.5) increase in BMD of the lumbar spine, with no significant change in femoral neck or total-body BMD—and a higher incidence of vertebral fractures (7.1% vs. 0.8% for those on alendronate; P=.02).²⁴

Risedronate once daily has also been proven to increase BMD in the lumbar spine and hip, with a reduction in vertebral fractures.²⁶ Another investigation—a 2-year, multicenter double-blind placebo-controlled study of 284 men with osteoporosis—found that risedronate given once a week increased BMD in the spine and hip, but did not reduce the incidence of either vertebral or nonvertebral fractures.²⁷

Because a DEXA scan is not always available or cost effective, a validated clinical predictive tool is preferred as an intial screening option.

Both alendronate and risedronate are effective for secondary causes of bone loss, such as corticosteroid use, androgen deprivation therapy/hypogonadism, and rheumatologic conditions.²⁸ Oral bisphosphonates may cause GI irritation, however. Abdominal pain associated with alendronate use is between 1% and 7%, vs 2% to 12% for risedronate.²³ Neither medication is recommended for use in patients with an estimated glomerular filtration rate <35 mL/min.²³ There is no clearly established duration of therapy for men.

Zoledronic acid infusions, given intravenously (IV) once a year, are available for men who cannot tolerate oral bisphosphonates. In a multicenter double-blind, placebocontrolled trial, zoledronic acid was found to reduce the risk of vertebral fractures in men with primary or hypogonadism-associated osteoporosis by 67% (1.6% vertebral fractures in the treatment group after 24 months vs 4.9% with placebo).²⁹ Given within 90 days of a hip fracture repair, zoledronic acid was associated with both a reduction in the rate of new fractures and an increased survival rate.³⁰

Adverse effects of zoledronic acid include diffuse bone pain (3%-9%), fever (9%-22%) and flu-like symptoms (1%-11%). Osteonecrosis of the jaw has been reported in <1% of patients.²³

Recombinant human parathyroid hormone stimulates bone growth

Pharmacotherapy should be individualized based on factors such as fracture history, severity of osteoporosis, comorbidities (eg, peptic ulcer disease, malignancy), and cost.

Teriparatide, administered subcutaneously (SC) once a day, directly stimulates bone formation. In a randomized placebo controlled trial of 437 men with a T-score of -2, teriparatide was found to increase BMD at the spine and femoral neck. Participants were randomized to receive teriparatide (20 or 40 mcg/d) or placebo. Those who received teriparatide had a doserelated increase in BMD from baseline at the spine (5.9% with 20 mcg and 9% with 40 mcg) and femoral neck (1.5% and 2.9%, respectively) compared with the placebo group.³¹ Teriparatide was shown to reduce vertebral fractures by 51% compared with placebo in a randomized study of 355 men with osteoporosis.³²

Teriparatide is indicated for men with severe osteoporosis and those for whom bisphosphonate treatment has been unsuccessful. Its use is limited to 2 years due to a dose-dependent risk of osteosarcoma. Teriparatide is contraindicated in patients with skeletal metastasis and has been associated with transient hypercalcemia 4 to 6 hours after administration.²³ Its use in combination with bisphosphonates is not recommended due to the lack of proven benefit, risk of adverse effects, and associated cost.⁵

Testosterone boosts bone density

Testosterone therapy is recommended for men with low levels of testosterone (<200 ng/dL), high risk for fracture, and contraindications to pharmacologic agents approved for the treatment of osteoporosis.⁵ Supplementation of testosterone to restore correct physiologic levels will decrease bone turnover and increase bone density.³³ In a meta-analysis of 8 trials with a total of 365 participants, testosterone administered intramuscularly was found to increase lumbar BMD by 8% compared with placebo. The effect on fractures is not known.¹²

Monoclonal antibody reduces fracture risk

Denosumab, a monoclonal antibody that prevents osteoclast formation leading to decreased bone resorption, is administered SC every 6 months.²³ In a placebo-controlled trial of 242 men with low bone mass, denosumab increased BMD at the lumbar spine (5.7%), total hip (2.4%), femoral neck (2.1%), trochanter (3.1%), and one-third radius (0.6%) compared with placebo after one year.³⁴ In men receiving androgen deprivation therapy for nonmetastatic prostate cancer, denosumab has been shown to increase BMD and reduce the incidence of vertebral fractures.³⁵

Adverse effects include hypocalcemia, hypophosphatemia, fatigue, and back pain.²³ No data exist on the ability of denosumab to reduce fracture risk in men without androgen deprivation.

Calcium and vitamin D for men at risk

Men who are at risk for or have osteoporosis should consume 1000 mg to 1200 mg of calcium per day. Ideally, this should come through dietary sources, but calcium supplementation may be added when diet is inadequate.⁵ The Institute of Medicine recommends a calcium intake of 1000 mg/d for men ages 51 to 70 years and 1200 mg/d for men ages 70 and older.³⁶

Supplementation of testosterone to restore correct physiologic levels in men with low testosterone will decrease bone turnover and increase bone density.

Men with vitamin D levels below 30 ng/mL should receive vitamin D supplementation to attain blood 25(OH) D levels of at least 30 ng/mL.⁵ The Institute of Medicine recommends a daily intake of 600 international units (IU) of vitamin D for men ages 51 to 70 and 800 IU for men 70 and older.³⁶ A recent Cochrane review on vitamin D and vitamin D analogues concluded that vitamin D alone was unlikely to prevent fractures in older people; when taken with calcium, however, it may have a preventive effect.³⁷

Counseling and follow-up

Lifestyle modification is an important means of primary prevention for osteoporosis. Advise men at risk for osteoporosis to limit alcohol consumption to 2 drinks daily.^4,5,8,10 Tell those who smoke that doing so increases their risk for osteoporotic fracture and refer them for smoking cessation counseling. Emphasize that weight-bearing exercise can improve BMD and should be done at least 3 days per week.^4,5,8,10 It is important, too, to do a medication review to look for drug-drug interactions and to discuss fall prevention strategies, such as gait training and an environmental assessment and removal of fall hazards.

A Cochrane review concluded that vitamin D alone was unlikely to prevent fractures in older people; when taken with calcium, however, it may have a preventive effect.

The evidence for monitoring treatment using BMD is not very strong.^5,14 However, the Endocrine Society recommends that response to treatment be monitored using DEXA scans every one to 2 years, with reduced frequency once the BMD has stabilized.⁵ Any patient found to have a decrease in BMD after treatment is initiated should undergo further evaluation to determine the cause of the decline.

CORRESPONDENCE
Bryan Farford, DO, Mayo Clinic Division of Regional Medicine, 742 Marsh Landing Parkway, Jacksonville Beach, FL 32250; farford.bryan@mayo.edu

With older women in the United States about 4 times more likely than their male counterparts to develop osteoporosis,^1,2 physicians often fail to screen for—or to treat—low bone mass in men. There are plenty of reasons why they should.

First and foremost: Osteoporosis is a leading cause of morbidity and mortality in the elderly.³ An estimated 8.8 million American men suffer from osteoporosis or osteopenia.³ And, although only about 20% of osteoporosis patients are male, men sustain between 30% and 40% of osteoporotic fractures.^1,2 What’s more, hip fracture in men has a mortality rate of up to 37.5%—2 to 3 times higher than that of women with hip fracture.^4,5

Clearly, then, it is crucial to be aware of the risks of osteoporosis faced by both men and women as they age. Here’s a look at what to consider, when to screen, and how to treat male patients who have, or are at risk for, osteoporosis.

Which men are at risk? 

The incidence of fractures secondary to osteoporosis varies with race/ethnicity and geography. The highest rates worldwide occur in Scandinavia and among Caucasians in the United States; black, Asian, and Hispanic populations have the lowest rates.^6,7 As with women, the risk of osteoporotic fracture in men increases with age. However, the peak incidence of fracture occurs about 10 years later in men than in women, starting at about age 70.⁸ Approximately 13% of white men older than 50 years will experience at least one osteoporotic fracture.⁹

There are 2 main types of osteoporosis: primary and secondary. Up to 40% of osteoporosis in men is primary,⁴ with bone loss due either to age (senile osteoporosis) or to an unknown cause (idiopathic osteoporosis).¹⁰ For men 70 years or older, osteoporosis is assumed to be age related. Idiopathic osteoporosis is diagnosed only in men younger than 70 who have no obvious secondary cause.¹⁰ There are numerous secondary causes, however, and most men with bone loss have at least one.⁴

Common secondary causes: Lifestyle, medical conditions, and meds

The most common causes of secondary osteoporosis in men are exposure to glucocorticoids, primary or secondary hypogonadism (low testosterone), diabetes, alcohol abuse, smoking, gastrointestinal (GI) disease, hypercalciuria, low body weight (body mass index <20 kg/m2), and immobility (TABLE 1).^4,5,8,10

Chronic use of corticosteroids, often used to treat chronic obstructive pulmonary disease (COPD), asthma, and rheumatoid arthritis, directly affects the bone, decreasing skeletal muscle, increasing immobility, and reducing intestinal absorption of calcium as well as serum testosterone levels.¹⁰ Men with androgen deficiency (which may be due to androgen deprivation therapy to treat prostate cancer) or chronic use of opioids are also at increased risk.^4,5,10-12

Diagnostic screening and criteria

The World Health Organization has established diagnostic criteria for osteoporosis using bone mineral density (BMD), reported as both T-scores and Z-scores as measured on dual-energy x-ray absorptiometry (DEXA) scan.¹³ The T-score represents the number of standard deviations above or below the mean BMD for young adults, matched for sex and race, but not age. It classifies individuals into 3 categories: normal; low (osteopenia), with a T-score between -1 and -2.5; and osteoporosis (T-score ≤-2.5).^4,14 The Z-score indicates the number of standard deviations above or below the mean for age, as well as sex and race. A Z-score of ≤-2.0 is below the expected range, indicating an increased likelihood of a secondary form of osteoporosis.¹⁴

Which men to screen?

The US Preventive Services Task Force has concluded that evidence is insufficient to assess the balance of benefits and harms of screening for osteoporosis in men. It therefore makes no recommendation to screen men who don't have evidence of previous fractures or secondary causes of osteoporosis.¹⁵

Other organizations agree that there is insufficient evidence to recommend routine screening for men without known osteoporotic fractures or secondary causes for osteoporosis. There are, however, some guidelines that are useful in clinical practice.

The most common causes of secondary osteoporosis in men include exposure to glucocorticoids, primary or secondary hypogonadism, diabetes, alcohol abuse, and smoking.

The Endocrine Society, American College of Physicians (ACP), and National Osteoporosis Foundation (NOF) recommend screening men ages 70 years or older, and men ages 50 to 69 who have risk factors for fracture and/or a history of fracture sustained after age 50.^5,16,17 (See “Did you know?”)^{1,2,4,5,9-12,16,17} Prior to screening, it is important to do a complete medical history and physical examination.

Screening considerations. The Endocrine Society, ACP, and NOF recommend a DEXA scan of the spine and hip for men who are at increased risk for osteoporosis and have no contraindications to drug therapy.^5,16,17 In patients who have degenerative changes of the spine and hip that would likely obscure DEXA outcomes, a scan of the radius may provide a more accurate assessment of bone status. Men receiving androgen deprivation therapy for prostate cancer will have a greater decline of bone density in the radius than in the hip or spine and are therefore ideal candidates for DEXA of the forearm, as well.^5,11 Keep in mind, however, that no studies have looked at how well, or whether, men with osteoporosis measured only in the radius respond to treatment.⁵

A DEXA scan is not always widely available, nor is it a perfect predictor of fracture risk. In addition, it is not always cost effective. For some patients, the use of a validated clinical predictive tool is preferable as an initial option.

The Male Osteoporosis Risk Estimation Score (MORES) uses age, weight, and history of COPD to identify men 60 years or older who are at risk for osteoporosis (TABLE 2).¹⁸ The score can be easily calculated during a clinical encounter and is beneficial for identifying men who should be referred for DEXA scan. A score of ≥6 has been found to yield an overall sensitivity of 0.93 (95% confidence interval [CI], 0.85-0.97) and a specificity of 0.59 (95% CI, 0.56-0.62), with a number needed to screen to prevent one additional hip fracture of 279.¹⁸

The Osteoporosis Self-assessment Tool (OST) (http://depts.washington.edu/osteoed/tools.php?type=ost) is a calculated value that uses age and weight to determine an individual’s risk for osteoporosis (risk score=weight [in kg] – age [in years]/5).^16,19 Although there is not a defined value to determine a positive OST risk score, scores of -1 to 3 have been used in a variety of studies.¹⁶ In a study of 181 American men, the OST predicted osteoporosis with a sensitivity of 93% and a specificity of 66% when using a cutoff score of 3.²⁰

Treating men at risk

Pharmacologic therapy is recommended for men at an increased risk for fracture. This includes men who have had a hip or vertebral fracture without major trauma, as well as those who have not had such a fracture but have a BMD of the spine, femoral neck, and/or total hip of ≤-2.5.^5,17 This standard also applies to the radius when used as an alternative site.

Several organizations recommend screening men ages ≥70 years and those ages 50 to 69 who have risk factors for fractures or who sustained a fracture after age 50.

The International Society for Clinical Densitometry and International Osteoporosis Foundation endorse the use of the Fracture Risk Assessment Tool (FRAX). Available at http://shef.ac.uk/FRAX/tool.aspx?country=9, FRAX is a computer-based calculator that uses risk factors and BMD of the femoral neck to estimate an individual’s 10-year fracture probability.²¹ Men who are 50 years or older, have a T-score between -1.0 and -2.5 in the spine, femoral neck, or total hip, and a 10-year risk of ≥20% of developing any fracture or ≥3% of developing a hip fracture based on FRAX, should be offered pharmacotherapy.^5,17

Bisphosphonates are first-line therapy

Although oral bisphosphonates are first-line therapy for men who meet these criteria,⁴ pharmacotherapy should be individualized based on factors such as fracture history, severity of osteoporosis, comorbidities (eg, peptic ulcer disease, malignancy, renal disease, or malabsorption), and cost (TABLE 3).^22,23

Alendronate once weekly has been proven to increase BMD and to reduce the risk of fracture in men.^24,25 A randomized, placebo-controlled trial of 241 men with osteoporosis found that alendronate increased BMD by 7.1% (±0.3) at the lumbar spine, 2.5% (±0.4) at the femoral neck, and 2% (±0.2) for the total body. Those in the placebo group had a 1.8% (±0.5) increase in BMD of the lumbar spine, with no significant change in femoral neck or total-body BMD—and a higher incidence of vertebral fractures (7.1% vs. 0.8% for those on alendronate; P=.02).²⁴

Risedronate once daily has also been proven to increase BMD in the lumbar spine and hip, with a reduction in vertebral fractures.²⁶ Another investigation—a 2-year, multicenter double-blind placebo-controlled study of 284 men with osteoporosis—found that risedronate given once a week increased BMD in the spine and hip, but did not reduce the incidence of either vertebral or nonvertebral fractures.²⁷

Because a DEXA scan is not always available or cost effective, a validated clinical predictive tool is preferred as an intial screening option.

Both alendronate and risedronate are effective for secondary causes of bone loss, such as corticosteroid use, androgen deprivation therapy/hypogonadism, and rheumatologic conditions.²⁸ Oral bisphosphonates may cause GI irritation, however. Abdominal pain associated with alendronate use is between 1% and 7%, vs 2% to 12% for risedronate.²³ Neither medication is recommended for use in patients with an estimated glomerular filtration rate <35 mL/min.²³ There is no clearly established duration of therapy for men.

Zoledronic acid infusions, given intravenously (IV) once a year, are available for men who cannot tolerate oral bisphosphonates. In a multicenter double-blind, placebocontrolled trial, zoledronic acid was found to reduce the risk of vertebral fractures in men with primary or hypogonadism-associated osteoporosis by 67% (1.6% vertebral fractures in the treatment group after 24 months vs 4.9% with placebo).²⁹ Given within 90 days of a hip fracture repair, zoledronic acid was associated with both a reduction in the rate of new fractures and an increased survival rate.³⁰

Adverse effects of zoledronic acid include diffuse bone pain (3%-9%), fever (9%-22%) and flu-like symptoms (1%-11%). Osteonecrosis of the jaw has been reported in <1% of patients.²³

Recombinant human parathyroid hormone stimulates bone growth

Pharmacotherapy should be individualized based on factors such as fracture history, severity of osteoporosis, comorbidities (eg, peptic ulcer disease, malignancy), and cost.

Teriparatide, administered subcutaneously (SC) once a day, directly stimulates bone formation. In a randomized placebo controlled trial of 437 men with a T-score of -2, teriparatide was found to increase BMD at the spine and femoral neck. Participants were randomized to receive teriparatide (20 or 40 mcg/d) or placebo. Those who received teriparatide had a doserelated increase in BMD from baseline at the spine (5.9% with 20 mcg and 9% with 40 mcg) and femoral neck (1.5% and 2.9%, respectively) compared with the placebo group.³¹ Teriparatide was shown to reduce vertebral fractures by 51% compared with placebo in a randomized study of 355 men with osteoporosis.³²

Teriparatide is indicated for men with severe osteoporosis and those for whom bisphosphonate treatment has been unsuccessful. Its use is limited to 2 years due to a dose-dependent risk of osteosarcoma. Teriparatide is contraindicated in patients with skeletal metastasis and has been associated with transient hypercalcemia 4 to 6 hours after administration.²³ Its use in combination with bisphosphonates is not recommended due to the lack of proven benefit, risk of adverse effects, and associated cost.⁵

Testosterone boosts bone density

Testosterone therapy is recommended for men with low levels of testosterone (<200 ng/dL), high risk for fracture, and contraindications to pharmacologic agents approved for the treatment of osteoporosis.⁵ Supplementation of testosterone to restore correct physiologic levels will decrease bone turnover and increase bone density.³³ In a meta-analysis of 8 trials with a total of 365 participants, testosterone administered intramuscularly was found to increase lumbar BMD by 8% compared with placebo. The effect on fractures is not known.¹²

Monoclonal antibody reduces fracture risk

Denosumab, a monoclonal antibody that prevents osteoclast formation leading to decreased bone resorption, is administered SC every 6 months.²³ In a placebo-controlled trial of 242 men with low bone mass, denosumab increased BMD at the lumbar spine (5.7%), total hip (2.4%), femoral neck (2.1%), trochanter (3.1%), and one-third radius (0.6%) compared with placebo after one year.³⁴ In men receiving androgen deprivation therapy for nonmetastatic prostate cancer, denosumab has been shown to increase BMD and reduce the incidence of vertebral fractures.³⁵

Adverse effects include hypocalcemia, hypophosphatemia, fatigue, and back pain.²³ No data exist on the ability of denosumab to reduce fracture risk in men without androgen deprivation.

Calcium and vitamin D for men at risk

Men who are at risk for or have osteoporosis should consume 1000 mg to 1200 mg of calcium per day. Ideally, this should come through dietary sources, but calcium supplementation may be added when diet is inadequate.⁵ The Institute of Medicine recommends a calcium intake of 1000 mg/d for men ages 51 to 70 years and 1200 mg/d for men ages 70 and older.³⁶

Supplementation of testosterone to restore correct physiologic levels in men with low testosterone will decrease bone turnover and increase bone density.

Men with vitamin D levels below 30 ng/mL should receive vitamin D supplementation to attain blood 25(OH) D levels of at least 30 ng/mL.⁵ The Institute of Medicine recommends a daily intake of 600 international units (IU) of vitamin D for men ages 51 to 70 and 800 IU for men 70 and older.³⁶ A recent Cochrane review on vitamin D and vitamin D analogues concluded that vitamin D alone was unlikely to prevent fractures in older people; when taken with calcium, however, it may have a preventive effect.³⁷

Counseling and follow-up

Lifestyle modification is an important means of primary prevention for osteoporosis. Advise men at risk for osteoporosis to limit alcohol consumption to 2 drinks daily.^4,5,8,10 Tell those who smoke that doing so increases their risk for osteoporotic fracture and refer them for smoking cessation counseling. Emphasize that weight-bearing exercise can improve BMD and should be done at least 3 days per week.^4,5,8,10 It is important, too, to do a medication review to look for drug-drug interactions and to discuss fall prevention strategies, such as gait training and an environmental assessment and removal of fall hazards.

A Cochrane review concluded that vitamin D alone was unlikely to prevent fractures in older people; when taken with calcium, however, it may have a preventive effect.

The evidence for monitoring treatment using BMD is not very strong.^5,14 However, the Endocrine Society recommends that response to treatment be monitored using DEXA scans every one to 2 years, with reduced frequency once the BMD has stabilized.⁵ Any patient found to have a decrease in BMD after treatment is initiated should undergo further evaluation to determine the cause of the decline.

CORRESPONDENCE
Bryan Farford, DO, Mayo Clinic Division of Regional Medicine, 742 Marsh Landing Parkway, Jacksonville Beach, FL 32250; farford.bryan@mayo.edu

With older women in the United States about 4 times more likely than their male counterparts to develop osteoporosis,^1,2 physicians often fail to screen for—or to treat—low bone mass in men. There are plenty of reasons why they should.

First and foremost: Osteoporosis is a leading cause of morbidity and mortality in the elderly.³ An estimated 8.8 million American men suffer from osteoporosis or osteopenia.³ And, although only about 20% of osteoporosis patients are male, men sustain between 30% and 40% of osteoporotic fractures.^1,2 What’s more, hip fracture in men has a mortality rate of up to 37.5%—2 to 3 times higher than that of women with hip fracture.^4,5

Clearly, then, it is crucial to be aware of the risks of osteoporosis faced by both men and women as they age. Here’s a look at what to consider, when to screen, and how to treat male patients who have, or are at risk for, osteoporosis.

Which men are at risk? 

The incidence of fractures secondary to osteoporosis varies with race/ethnicity and geography. The highest rates worldwide occur in Scandinavia and among Caucasians in the United States; black, Asian, and Hispanic populations have the lowest rates.^6,7 As with women, the risk of osteoporotic fracture in men increases with age. However, the peak incidence of fracture occurs about 10 years later in men than in women, starting at about age 70.⁸ Approximately 13% of white men older than 50 years will experience at least one osteoporotic fracture.⁹

There are 2 main types of osteoporosis: primary and secondary. Up to 40% of osteoporosis in men is primary,⁴ with bone loss due either to age (senile osteoporosis) or to an unknown cause (idiopathic osteoporosis).¹⁰ For men 70 years or older, osteoporosis is assumed to be age related. Idiopathic osteoporosis is diagnosed only in men younger than 70 who have no obvious secondary cause.¹⁰ There are numerous secondary causes, however, and most men with bone loss have at least one.⁴

Common secondary causes: Lifestyle, medical conditions, and meds

The most common causes of secondary osteoporosis in men are exposure to glucocorticoids, primary or secondary hypogonadism (low testosterone), diabetes, alcohol abuse, smoking, gastrointestinal (GI) disease, hypercalciuria, low body weight (body mass index <20 kg/m2), and immobility (TABLE 1).^4,5,8,10

Chronic use of corticosteroids, often used to treat chronic obstructive pulmonary disease (COPD), asthma, and rheumatoid arthritis, directly affects the bone, decreasing skeletal muscle, increasing immobility, and reducing intestinal absorption of calcium as well as serum testosterone levels.¹⁰ Men with androgen deficiency (which may be due to androgen deprivation therapy to treat prostate cancer) or chronic use of opioids are also at increased risk.^4,5,10-12

Diagnostic screening and criteria

The World Health Organization has established diagnostic criteria for osteoporosis using bone mineral density (BMD), reported as both T-scores and Z-scores as measured on dual-energy x-ray absorptiometry (DEXA) scan.¹³ The T-score represents the number of standard deviations above or below the mean BMD for young adults, matched for sex and race, but not age. It classifies individuals into 3 categories: normal; low (osteopenia), with a T-score between -1 and -2.5; and osteoporosis (T-score ≤-2.5).^4,14 The Z-score indicates the number of standard deviations above or below the mean for age, as well as sex and race. A Z-score of ≤-2.0 is below the expected range, indicating an increased likelihood of a secondary form of osteoporosis.¹⁴

Which men to screen?

The US Preventive Services Task Force has concluded that evidence is insufficient to assess the balance of benefits and harms of screening for osteoporosis in men. It therefore makes no recommendation to screen men who don't have evidence of previous fractures or secondary causes of osteoporosis.¹⁵

Other organizations agree that there is insufficient evidence to recommend routine screening for men without known osteoporotic fractures or secondary causes for osteoporosis. There are, however, some guidelines that are useful in clinical practice.

The most common causes of secondary osteoporosis in men include exposure to glucocorticoids, primary or secondary hypogonadism, diabetes, alcohol abuse, and smoking.

The Endocrine Society, American College of Physicians (ACP), and National Osteoporosis Foundation (NOF) recommend screening men ages 70 years or older, and men ages 50 to 69 who have risk factors for fracture and/or a history of fracture sustained after age 50.^5,16,17 (See “Did you know?”)^{1,2,4,5,9-12,16,17} Prior to screening, it is important to do a complete medical history and physical examination.

Screening considerations. The Endocrine Society, ACP, and NOF recommend a DEXA scan of the spine and hip for men who are at increased risk for osteoporosis and have no contraindications to drug therapy.^5,16,17 In patients who have degenerative changes of the spine and hip that would likely obscure DEXA outcomes, a scan of the radius may provide a more accurate assessment of bone status. Men receiving androgen deprivation therapy for prostate cancer will have a greater decline of bone density in the radius than in the hip or spine and are therefore ideal candidates for DEXA of the forearm, as well.^5,11 Keep in mind, however, that no studies have looked at how well, or whether, men with osteoporosis measured only in the radius respond to treatment.⁵

A DEXA scan is not always widely available, nor is it a perfect predictor of fracture risk. In addition, it is not always cost effective. For some patients, the use of a validated clinical predictive tool is preferable as an initial option.

The Male Osteoporosis Risk Estimation Score (MORES) uses age, weight, and history of COPD to identify men 60 years or older who are at risk for osteoporosis (TABLE 2).¹⁸ The score can be easily calculated during a clinical encounter and is beneficial for identifying men who should be referred for DEXA scan. A score of ≥6 has been found to yield an overall sensitivity of 0.93 (95% confidence interval [CI], 0.85-0.97) and a specificity of 0.59 (95% CI, 0.56-0.62), with a number needed to screen to prevent one additional hip fracture of 279.¹⁸

The Osteoporosis Self-assessment Tool (OST) (http://depts.washington.edu/osteoed/tools.php?type=ost) is a calculated value that uses age and weight to determine an individual’s risk for osteoporosis (risk score=weight [in kg] – age [in years]/5).^16,19 Although there is not a defined value to determine a positive OST risk score, scores of -1 to 3 have been used in a variety of studies.¹⁶ In a study of 181 American men, the OST predicted osteoporosis with a sensitivity of 93% and a specificity of 66% when using a cutoff score of 3.²⁰

Treating men at risk

Pharmacologic therapy is recommended for men at an increased risk for fracture. This includes men who have had a hip or vertebral fracture without major trauma, as well as those who have not had such a fracture but have a BMD of the spine, femoral neck, and/or total hip of ≤-2.5.^5,17 This standard also applies to the radius when used as an alternative site.

Several organizations recommend screening men ages ≥70 years and those ages 50 to 69 who have risk factors for fractures or who sustained a fracture after age 50.

The International Society for Clinical Densitometry and International Osteoporosis Foundation endorse the use of the Fracture Risk Assessment Tool (FRAX). Available at http://shef.ac.uk/FRAX/tool.aspx?country=9, FRAX is a computer-based calculator that uses risk factors and BMD of the femoral neck to estimate an individual’s 10-year fracture probability.²¹ Men who are 50 years or older, have a T-score between -1.0 and -2.5 in the spine, femoral neck, or total hip, and a 10-year risk of ≥20% of developing any fracture or ≥3% of developing a hip fracture based on FRAX, should be offered pharmacotherapy.^5,17

Bisphosphonates are first-line therapy

Although oral bisphosphonates are first-line therapy for men who meet these criteria,⁴ pharmacotherapy should be individualized based on factors such as fracture history, severity of osteoporosis, comorbidities (eg, peptic ulcer disease, malignancy, renal disease, or malabsorption), and cost (TABLE 3).^22,23

Alendronate once weekly has been proven to increase BMD and to reduce the risk of fracture in men.^24,25 A randomized, placebo-controlled trial of 241 men with osteoporosis found that alendronate increased BMD by 7.1% (±0.3) at the lumbar spine, 2.5% (±0.4) at the femoral neck, and 2% (±0.2) for the total body. Those in the placebo group had a 1.8% (±0.5) increase in BMD of the lumbar spine, with no significant change in femoral neck or total-body BMD—and a higher incidence of vertebral fractures (7.1% vs. 0.8% for those on alendronate; P=.02).²⁴

Risedronate once daily has also been proven to increase BMD in the lumbar spine and hip, with a reduction in vertebral fractures.²⁶ Another investigation—a 2-year, multicenter double-blind placebo-controlled study of 284 men with osteoporosis—found that risedronate given once a week increased BMD in the spine and hip, but did not reduce the incidence of either vertebral or nonvertebral fractures.²⁷

Because a DEXA scan is not always available or cost effective, a validated clinical predictive tool is preferred as an intial screening option.

Both alendronate and risedronate are effective for secondary causes of bone loss, such as corticosteroid use, androgen deprivation therapy/hypogonadism, and rheumatologic conditions.²⁸ Oral bisphosphonates may cause GI irritation, however. Abdominal pain associated with alendronate use is between 1% and 7%, vs 2% to 12% for risedronate.²³ Neither medication is recommended for use in patients with an estimated glomerular filtration rate <35 mL/min.²³ There is no clearly established duration of therapy for men.

Zoledronic acid infusions, given intravenously (IV) once a year, are available for men who cannot tolerate oral bisphosphonates. In a multicenter double-blind, placebocontrolled trial, zoledronic acid was found to reduce the risk of vertebral fractures in men with primary or hypogonadism-associated osteoporosis by 67% (1.6% vertebral fractures in the treatment group after 24 months vs 4.9% with placebo).²⁹ Given within 90 days of a hip fracture repair, zoledronic acid was associated with both a reduction in the rate of new fractures and an increased survival rate.³⁰

Adverse effects of zoledronic acid include diffuse bone pain (3%-9%), fever (9%-22%) and flu-like symptoms (1%-11%). Osteonecrosis of the jaw has been reported in <1% of patients.²³

Recombinant human parathyroid hormone stimulates bone growth

Pharmacotherapy should be individualized based on factors such as fracture history, severity of osteoporosis, comorbidities (eg, peptic ulcer disease, malignancy), and cost.

Teriparatide, administered subcutaneously (SC) once a day, directly stimulates bone formation. In a randomized placebo controlled trial of 437 men with a T-score of -2, teriparatide was found to increase BMD at the spine and femoral neck. Participants were randomized to receive teriparatide (20 or 40 mcg/d) or placebo. Those who received teriparatide had a doserelated increase in BMD from baseline at the spine (5.9% with 20 mcg and 9% with 40 mcg) and femoral neck (1.5% and 2.9%, respectively) compared with the placebo group.³¹ Teriparatide was shown to reduce vertebral fractures by 51% compared with placebo in a randomized study of 355 men with osteoporosis.³²

Teriparatide is indicated for men with severe osteoporosis and those for whom bisphosphonate treatment has been unsuccessful. Its use is limited to 2 years due to a dose-dependent risk of osteosarcoma. Teriparatide is contraindicated in patients with skeletal metastasis and has been associated with transient hypercalcemia 4 to 6 hours after administration.²³ Its use in combination with bisphosphonates is not recommended due to the lack of proven benefit, risk of adverse effects, and associated cost.⁵

Testosterone boosts bone density

Testosterone therapy is recommended for men with low levels of testosterone (<200 ng/dL), high risk for fracture, and contraindications to pharmacologic agents approved for the treatment of osteoporosis.⁵ Supplementation of testosterone to restore correct physiologic levels will decrease bone turnover and increase bone density.³³ In a meta-analysis of 8 trials with a total of 365 participants, testosterone administered intramuscularly was found to increase lumbar BMD by 8% compared with placebo. The effect on fractures is not known.¹²

Monoclonal antibody reduces fracture risk

Denosumab, a monoclonal antibody that prevents osteoclast formation leading to decreased bone resorption, is administered SC every 6 months.²³ In a placebo-controlled trial of 242 men with low bone mass, denosumab increased BMD at the lumbar spine (5.7%), total hip (2.4%), femoral neck (2.1%), trochanter (3.1%), and one-third radius (0.6%) compared with placebo after one year.³⁴ In men receiving androgen deprivation therapy for nonmetastatic prostate cancer, denosumab has been shown to increase BMD and reduce the incidence of vertebral fractures.³⁵

Adverse effects include hypocalcemia, hypophosphatemia, fatigue, and back pain.²³ No data exist on the ability of denosumab to reduce fracture risk in men without androgen deprivation.

Calcium and vitamin D for men at risk

Men who are at risk for or have osteoporosis should consume 1000 mg to 1200 mg of calcium per day. Ideally, this should come through dietary sources, but calcium supplementation may be added when diet is inadequate.⁵ The Institute of Medicine recommends a calcium intake of 1000 mg/d for men ages 51 to 70 years and 1200 mg/d for men ages 70 and older.³⁶

Supplementation of testosterone to restore correct physiologic levels in men with low testosterone will decrease bone turnover and increase bone density.

Men with vitamin D levels below 30 ng/mL should receive vitamin D supplementation to attain blood 25(OH) D levels of at least 30 ng/mL.⁵ The Institute of Medicine recommends a daily intake of 600 international units (IU) of vitamin D for men ages 51 to 70 and 800 IU for men 70 and older.³⁶ A recent Cochrane review on vitamin D and vitamin D analogues concluded that vitamin D alone was unlikely to prevent fractures in older people; when taken with calcium, however, it may have a preventive effect.³⁷

Counseling and follow-up

Lifestyle modification is an important means of primary prevention for osteoporosis. Advise men at risk for osteoporosis to limit alcohol consumption to 2 drinks daily.^4,5,8,10 Tell those who smoke that doing so increases their risk for osteoporotic fracture and refer them for smoking cessation counseling. Emphasize that weight-bearing exercise can improve BMD and should be done at least 3 days per week.^4,5,8,10 It is important, too, to do a medication review to look for drug-drug interactions and to discuss fall prevention strategies, such as gait training and an environmental assessment and removal of fall hazards.

A Cochrane review concluded that vitamin D alone was unlikely to prevent fractures in older people; when taken with calcium, however, it may have a preventive effect.

The evidence for monitoring treatment using BMD is not very strong.^5,14 However, the Endocrine Society recommends that response to treatment be monitored using DEXA scans every one to 2 years, with reduced frequency once the BMD has stabilized.⁵ Any patient found to have a decrease in BMD after treatment is initiated should undergo further evaluation to determine the cause of the decline.

CORRESPONDENCE
Bryan Farford, DO, Mayo Clinic Division of Regional Medicine, 742 Marsh Landing Parkway, Jacksonville Beach, FL 32250; farford.bryan@mayo.edu

In late 2013, there were 45 cases of acute liver failure (ALF) in Hawaii, and 29 of those people reported taking OxyELITE Pro (an herbal dietary supplement marketed for weight reduction and “fat-burning”) 60 days before illness onset. Of 8 initial cases, 2 patients needed urgent liver transplants, one died, and 5 eventually recovered.¹ The manufacturer of OxyELITE Pro voluntarily recalled the product after receiving a warning letter from the US Food and Drug Administration (FDA).

One way to prevent situations like this from occurring might be to ban the sale of weight loss or sports enhancement supplements unless they are rigorously tested and approved by the FDA. Voluntary reporting to the FDA is time-consuming and it takes time for the FDA to follow up on these reports.

As primary care physicians, we need to consistently ask patients about their use of supplements, educate them about the potential dangers, and identify those who are experiencing adverse reactions. While we can’t put a stop to the harm that some herbal dietary supplements might inflict on a public eager to embrace quick fixes for weight loss and improved strength, we can be the best first responders.

Linda L. Wong, MD
Honolulu, Hawaii

In late 2013, there were 45 cases of acute liver failure (ALF) in Hawaii, and 29 of those people reported taking OxyELITE Pro (an herbal dietary supplement marketed for weight reduction and “fat-burning”) 60 days before illness onset. Of 8 initial cases, 2 patients needed urgent liver transplants, one died, and 5 eventually recovered.¹ The manufacturer of OxyELITE Pro voluntarily recalled the product after receiving a warning letter from the US Food and Drug Administration (FDA).

One way to prevent situations like this from occurring might be to ban the sale of weight loss or sports enhancement supplements unless they are rigorously tested and approved by the FDA. Voluntary reporting to the FDA is time-consuming and it takes time for the FDA to follow up on these reports.

As primary care physicians, we need to consistently ask patients about their use of supplements, educate them about the potential dangers, and identify those who are experiencing adverse reactions. While we can’t put a stop to the harm that some herbal dietary supplements might inflict on a public eager to embrace quick fixes for weight loss and improved strength, we can be the best first responders.

Linda L. Wong, MD
Honolulu, Hawaii

In late 2013, there were 45 cases of acute liver failure (ALF) in Hawaii, and 29 of those people reported taking OxyELITE Pro (an herbal dietary supplement marketed for weight reduction and “fat-burning”) 60 days before illness onset. Of 8 initial cases, 2 patients needed urgent liver transplants, one died, and 5 eventually recovered.¹ The manufacturer of OxyELITE Pro voluntarily recalled the product after receiving a warning letter from the US Food and Drug Administration (FDA).

One way to prevent situations like this from occurring might be to ban the sale of weight loss or sports enhancement supplements unless they are rigorously tested and approved by the FDA. Voluntary reporting to the FDA is time-consuming and it takes time for the FDA to follow up on these reports.

As primary care physicians, we need to consistently ask patients about their use of supplements, educate them about the potential dangers, and identify those who are experiencing adverse reactions. While we can’t put a stop to the harm that some herbal dietary supplements might inflict on a public eager to embrace quick fixes for weight loss and improved strength, we can be the best first responders.

Linda L. Wong, MD
Honolulu, Hawaii

Hepatitis C virus (HCV) infection is a leading cause of chronic liver disease. Over the next few decades, the number of deaths per year due to complications of HCV such as liver failure and hepatocellular carcinoma (HCC) is predicted to more than triple to 36,000 by 2032.¹

Fortunately, major advances in drug therapy have made it possible to cure patients of HCV, and treatment is now less complex, of shorter duration, and better tolerated than it once was. To help family physicians maximize the care they provide to these patients, we’ve summarized screening recommendations from the Centers for Disease Control and Prevention (CDC), innovative alternatives to biopsy for staging liver disease, and counseling points to cover with patients.

A common, usually silent infection with potentially fatal complications

According to the National Health and Nutrition Examination Survey (NHANES), an estimated 2.7 to 3.9 million people in the United States are chronically infected with HCV, about threefourths of whom were born between 1945 and 1965 (the “baby boomer” generation).² However, by adding “unaccounted groups” (eg, incarcerated, homeless, and active duty military) to these estimates, the number of people with HCV is likely more than 5.2 million.³

HCV is a ribonucleic acid (RNA) virus capable of mutating at a high rate to escape detection and clearance by the host’s immune system.⁴ Most patients with HCV are asymptomatic during the acute and chronic phases of infection, and may have a silent infection for decades. In fact, 65% to 75% of patients with HCV are unaware of their infection.⁵

Approximately 20% of chronically infected patients develop cirrhosis after 20 years and, once they do, the annual rate of HCC and liver decompensation is about 5%.^6-8 Risk factors for advancement to cirrhosis includes male sex, alcohol consumption, co-infection with human immunodeficiency virus (HIV) or hepatitis B virus (HBV), immunosuppression, having had HCV infection for a long time, becoming infected with HCV after age 40, and not having responded to previous treatment.⁹

Chronic HCV infection can lead to extrahepatic manifestations such as essential mixed cryoglobulinemia, porphyria cutanea tarda, membranoproliferative glomerulonephritis, lymphoma, and glucose intolerance.¹⁰ There is also growing evidence that HCV infection affects cognitive function in the absence of fibrosis and hepatic encephalopathy. Several studies show that HCV-infected patients score poorly on neuropsychological testing for verbal learning, attention, memory, and executive function.¹¹ This may be related to the expression of receptors for HCV by the brain’s microvascular endothelial cells.¹²

Screening recommendations. Given the high prevalence of HCV infection among baby boomers, the CDC decided in 2012 to recommend one-time HCV screening for all patients born between 1945 and 1965.¹³ This is in addition to risk-based screening for all patients who have a history of injection drug use, those on long-term hemodialysis or with tattoos obtained in unregulated settings, offspring of HCV-infected mothers, and those with health-care associated exposures (TABLE¹³). In 2013, the US Preventive Services Task Force upgraded its recommendation to match those of the CDC.¹⁴

Despite these recommendations, which are expected to increase detection of HCV among asymptomatic persons who do not know they are infected, there remain significant barriers to HCV testing. These include poor access to primary care and preventive services, lack of knowledge and awareness of the disease among patients and providers, and a lack of studies that support a universal screening approach for HCV.^5,15,16 One tool that might help overcome some of these barriers and aid family physicians in the screening process is automatic reminders or standing lab orders for HCV testing in electronic medical records systems.

Screening for HCV can be done using any of the US Food and Drug Administration (FDA)-approved tests for the anti-HCV antibody, which have sensitivities and specificities greater than 99%.¹⁷ A positive screening result should be confirmed with an HCV RNA test. However, for practical purposes, ordering the anti-HCV test with reflex to the HCV RNA test decreases the number of blood draws and office visits required of the patient. The reflex confirmation allows the physician to deliver the patient’s full diagnosis and reduces the psychological distress associated with waiting for confirmatory results. The HCV RNA test (alone) should be used, however, in immunocompromised patients, those who may have had exposure to HCV in the past 6 months, and those suspected of having an HCV re-infection after having cleared the virus.¹⁸

Look for the evidence of liver disease

Family physicians should order several additional tests for patients found to have chronic HCV infection before referring such patients to a specialist (ALGORITHM). Work-up should include the complete blood count, HCV genotype (which will help guide treatment), liver function tests, international normalized ratio test, and ultrasound of the liver.¹⁸ In addition, all HCV-positive patients should be tested for HIV and HBV, because these co-infections may accelerate liver fibrosis.^19,20

All patients with chronic HCV infection should also be screened for the presence of fibrosis and cirrhosis, as this will influence treatment choice and duration. Signs of cirrhosis that may be evident on physical exam include jaundice, spider angiomata, palmar erythema, encephalopathy with asterixis, and fluid overload, especially ascites. Cirrhosis can be classified clinically as compensated (stage 1 with no varices present and stage 2 with varices present) and decompensated (stages 3 and 4), which is defined as cirrhosis with signs of severe portal hypertension (bleeding varices, ascites, hepatic encephalopathy) or liver insufficiency (jaundice).²¹ Patients with decompensated cirrhosis should be managed by a liver transplant center. For more on cirrhosis, see “Cirrhosis complications: Keeping them under control” (J Fam Pract. 2015;64:338-342).

Several noninvasive alternatives to liver biopsy

Historically, liver biopsy has been the gold standard for staging liver disease. The Metavir scoring system is a histological assessment of the degree of inflammatory activity and the stage of fibrosis.²² The degree of inflammation activity, which is a precursor of fibrosis, is scored from A0 (no activity) to A3 (severe activity). The staging of fibrosis involves a 5-stage scoring system: F0 (chronic hepatitis without fibrosis); F1 (portal fibrosis without septae); F2 (portal fibrosis with rare septae); F3 (many septae without cirrhosis); or F4 (cirrhosis).

That said, noninvasive tests have largely supplanted liver biopsy for fibrosis screening.

Up to 75% of patients with hepatitis C are unaware of their infection.

For example, the FibroSure test uses the patient’s age, gender, and a combination of 6 serum markers of liver function in a computational algorithm to generate a quantitative indicator of liver fibrosis, with a score of 0.0 to 1.0 that corresponds to the Metavir fibrosis score (F0-F4), and an inflammatory activity score (A0-A3).²³ Similarly, HepaScore uses several noninvasive markers to calculate a score from 0.00 to 1.00. A score ≤0.2 accurately excludes significant fibrosis. However, a score of ≥0.55 or higher corresponds to a Metavir score of at least F2, and in such cases further testing would be needed to evaluate for cirrhosis.²⁴

FDA-approved in 2013, transient elastography (FibroScan) is another noninvasive alternative to liver biopsy for determining the stage of liver disease. This bedside test uses ultrasound technology to measure liver stiffness and provides a score ranging from 0 to 75 kPA that correlates with the Metavir score. Although not yet widely available in the United States, FibroScan is becoming increasingly popular as a rapid and noninvasive screening tool for cirrhosis.²⁵

Identifying cirrhosis in patients who have HCV is crucial because such patients need prompt care from a specialist. In addition to receiving HCV treatment, patients with cirrhosis also need regular liver ultrasound exams to screen for HCC (every 6 months) and esophagogastroduodenoscopy to screen for esophageal and gastric varices.²⁶

Advise patients to avoid alcohol, lose weight

Counsel patients who test positive for HCV infection about making lifestyle changes to avoid further liver damage and transmission of HCV to others. Infectious diseases and hepatology society guidelines recommend vaccination against hepatitis A and B for all HCV-infected patients who are not immune to these viruses because acute co-infection could lead to severe acute liver injury.^18,27 Urge all HCV-infected patients to completely abstain from alcohol and, if necessary, refer them to an addiction specialist, because excess alcohol consumption is strongly associated with the development of cirrhosis and HCC.^28,29

Comorbid conditions such as metabolic syndrome, obesity, and hyperlipidemia can worsen the prognosis for HCV-infected patients; therefore, intense counseling on weight loss is recommended.³⁰ Statins are safe and beneficial for HCV patients with hypercholesterolemia and compensated cirrhosis.³¹

Teach patients that the primary mode of transmission of HCV is through infected blood. Sexual transmission of HCV has been well documented in HIV-positive men who have sex with men.³² Although the risk of transmission of HCV among heterosexual couples is extremely low, it is possible, and patients should be counseled accordingly.³³ Transmission of HCV from mother to the baby occurs in up to 6% of births and most commonly occurs during delivery.³⁴

Newer treatments are highly effective and well tolderated

HCV treatment has changed dramatically over the past few years. Previous treatments for HCV, particularly those containing interferon, were known for their poor tolerability due to adverse effects and low cure rates. Compared to previous therapies, the new interferon-free direct-acting antiviral (DAA) regimens are not only less complex but also shorter in duration, ranging from 8 to 24 weeks depending on the patient’s viral load, stage of liver disease, and previous treatment experience.¹⁸ The specific agents and dosages used in DAA regimens aren’t described here because these regimens are rapidly changing. However, continuously updated treatment recommendations from the American Association for the Study of Liver Diseases and the Infectious Diseases Society of America are available at http://www.hcvguidelines.org.

The goal of HCV treatment is cure as evidenced by a sustained virologic response (SVR), which is defined as the absence of HCV RNA 12 weeks or more after completing treatment.^35,36 In general, for the most common genotypes of HCV, treatment with a DAA regimen results in a SVR in ≥95% of patients.¹⁸ Achieving SVR is associated with a 50% reduction in all-cause mortality, a 90% reduction in liver-associated mortality, and a >70% reduction in the risk of developing HCC.^27,37,38 SVR also has been shown to have a significant effect on reducing extrahepatic manifestations of HCV infection, such as cryoglobulinemia and lymphoma.^39-41

The DAAs are well tolerated and have good safety profiles. In phase III clinical trials of today’s most commonly used DAA regimens, the discontinuation rate was <1% in non-cirrhotic patients and 2% in those with cirrhosis.¹⁸ The most commonly reported adverse effects were nausea, fatigue, and headache. DAAs may have drug-drug interactions; therefore, careful medication reconciliation should be performed before initiating treatment.¹⁸

Prioritizing treatment. Current evidence supports treatment for all patients with HCV except those with a life expectancy of <12 months.¹⁸ Evidence indicates that treatment becomes less effective as a patient’s liver injury progresses to cirrhosis. Due to the high cost of available treatments, however, many insurers have imposed strict criteria for coverage. (See “Barriers to HCV Treatment,” above.⁴²)

Ordering the anti-HCV test with reflex to hepatitis C virus RNA decreases the number of blood draws and office visits required of the patient.

The highest priority for treatment has been given to patients with advanced liver fibrosis, compensated cirrhosis, those who have received a liver transplant, and those with severe extrahepatic manifestations (eg, mixed cryoglobulinemia and end-organ disease such as nephropathy). Treatment is also prioritized for high-risk populations (eg, patients with HBV and HIV co-infection, diabetes mellitus) and patients who are at high risk of transmitting the virus (eg, individuals who inject drugs or are incarcerated, men who have sex with men, women of childbearing age, hemodialysis patients, and health care professionals who perform exposure-prone procedures).¹⁸

While it may eventually become feasible for family physicians to treat HCV-infected patients, the rapid evolution and significant cost of treatment, as well as the challenges in obtaining insurance coverage, have kept HCV treatment largely in the domain of specialists, at least for now. In the interim, family physicians play a crucial role by screening, diagnosing, and counseling patients with this infection, referring them to specialty care, and providing ongoing monitoring for signs of HCC and esophageal and gastric varices.

CORRESPONDENCE
Laura Wangensteen, MD, Department of Family Medicine, Drexel University, 3401 South Market Street #105 A, Philadelphia, PA 19104; laura.wangensteen@drexelmed.edu