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Osteoporosis in older men
clinicdCORNERSTONE
= OSTEOPOROSIS
1 Vol.2 No.6
Osteoporosis in Older Men Anne
Kenny,
MD
Assistant Professor of Medicine University of Connecticut Center on Aging University of Connecticut Health Center Farmington, Connecticut
PamelaTaxel,
MD
Assistant Professor of Medicine Division of Endocrinology and Metabolism University of Connecticut Health Center Farmington, Connecticut
Historically, the focus in osteoporosis has been on postmenopausal women. In the past few years, information about osteoporosis in other populations, including men, has begun to emerge. Although less common in older men, osteoporosis nonetheless represents a major health concern. Approximately 30% of hip fractures worldwide occur in men, resulting in significant mortality and loss of independence. The incidence of osteoporotic fractures in men is increasing. The reason for this is unclear, but improvement in longevity and better management of other chronic diseases most likely play a role. Two recent studies have addressed the question of fracture risk in men past middle age and have estimated that men >50 years of age have a 19% to 25% lifelong risk of osteoporotic fracture. Mortality is higher following hip fracture and pain is more intense in men than in women following severe vertebral fracture.
than it is in age-matched control or reference popu lations. In prospective studies, men with the lowest bone mineral density (BMD) at baseline were more likely to fracture during follow-up at 7 and 1 1
DETERMINANTS OF FRACTURE RISK The incidence of fragility fractures is lower in men than in women. Reasons for the difference include increased size of bone; thicker cortices, although density and trabecular architecture are similar to those of women; shorter life span; and lack of the abrupt decrease in sex hormone levels that occurs in women at menopause (Table). Nevertheless, several factors increase risk for bone loss and fracture in men, including low bone mass, genetic factors, changes in calcium absorption and osteoblast function with age, decreases in sex hormone levels, comorbid conditions, and lifestyle factors, such as smoking and excess alcohol consumption. These factors are similar to those for bone loss in women. A strong correlation is found between bone mass and fracture risk in women, and limited studies suggest a similar relationship in men. Bone mass is lower in men with hip or spine fracture
years. Like women, men achieve peak bone mass at age 25 to 30; however, the bone mass in men is higher due to the increased size of bone.
45
clinical CORNERSTONE
n
OSTEOPOROSIS
m Vol.2 No.6
Differences
Similarities l
Decreased calcium absorption with age
0 Thicker cortices in men
l
Decreased osteoblast function with age
0 Shorter life span in men
l
Life-style
l
Higher peak bone mass in men
0 No abrupt fall in hormonal
influences
(smoking and alcohol)
status in men
Genetic effects are present irrespective of gender. Twin studies have confirmed the heritability of bone mass, and men with a family history of osteoporosis or a mother who suffered a hip fracture have low BMD. However, the gene or genes associated with osteoporosis have not been clearly identified. Cross-sectional studies have detected a slower rate of bone loss in men compared with women, but in older populations, rates of femoral bone loss were equal in men and women. In a longitudinal study of men aged 30 to 90 years, the average bone loss per year in the radius and spine was 1%. Men do not have a period of accelerated bone loss that is equivalent to the acceleration in bone loss that
with rapid bone loss. Androgen levels fall with increasing age in men. Although total testosterone levels remain relatively stable, sex-hormone-binding globulin levels increase with a resultant decline in free or bioavailable testosterone levels at a rate of approximately 1% a year. Bioavailable testosterone levels are below the normal reference range of young adult men in approximately 50% of men >70 years of age. The role of this modest loss in sex hormones in aging men is not well understood. Several studies have evaluated the relationship between circulating estrogen and androgen levels and have found that low estrogen and androgen levels are associated with lower bone mass in men. Further research is required to better understand the roles of estrogen and testosterone in the maintenance of bone in older men. Likewise, the role of testosterone supplementation in the health of older men remains to be determined. The largest study in which men with testosterone levels in the lownormal range received supplemental testosterone found femoral bone density increased in the testosterone group but no effect on muscle strength. The effects of testosterone may be mediated directly or indirectly, following peripheral conversion of testosterone to estrogen via aromatase. Studies in animals suggest that the direct effect is to stimulate bone formation and that estrogen mediates an inhibition of bone resorption. Many conditions affect an individual’s risk of fracture. Hip fractures are associated with an increased risk of falling, but there are few prospective data in men to directly relate falls to subsequent fracture. Factors that increase fall risk, such as increased body sway, decreased strength, and neurologic disorders, probably increase risk factors for hip fracture in men. Lifestyle factors that con-
accompanies menopause, but there is continued steady loss with advancing age. Mechanisms outlined in previous articles, such as decreased calcium absorption and increased parathyroid hormone levels resulting in increased bone resorption, as well as decreased osteoblast function with consequent decrease in bone formation, are as significant in men as they are in women. Loss of sex steroids (menopause in women and severe hypogonadism in men) is associated
46
clinical CORNERSTONE
tribute to decreased bone mass and increased fracture risk include decreased weight, physical inactivity, self-described poor health, and excess alcohol and tobacco use. Finally, there is an association between idiopathic osteoporosis and low levels of both insulin-like growth factor-l and insulin-like growth factor-l binding protein-3.
.
OSTEOPOROSIS
1 Vol. 2 No. 6
Although diagnostic criteria for osteoporosis are not established, men with BMD measurements 2 standard deviations below the young adult normal range who have fractures or in whom other clinical conditions put them at risk for further bone loss should have a full evaluation for secondary causes of osteoporosis and be considered for treatment. Because secondary causes are thought to contribute to osteoporosis in 40% to 60% of men with the condition, a search for contributing factors is critical. Physicians should investigate medication use (especially thyroid replacement, glucocorticoid, anti-seizure, and gonadotropin-releasing hormone analogues) and social habits (excess alcohol consumption and tobacco use), and check for hypogonadism and malabsorptive conditions (eg, a history of gastric surgery). Laboratory evaluation should include testosterone, thyroid stimulating hormone, and vitamin D levels; serum protein electrophoresis (to exclude multiple myeloma); and urine test for calcium excretion (to exclude hypercalciuria). Biochemical markers of bone turnover have not been shown to be beneficial in the diagnosis of osteoporosis in men, although they may be used to assess therapeutic response to antiresorptive agents in high turnover states.
EVALUATION OF OSTEOPOROSIS The World Health Organization established criteria for the diagnosis of osteoporosis based on the relationship between risk of fracture and BMD for white women in 1994. Recently, there has been a movement for widespread screening for osteoporosis in postmenopausal women, but recommendations for BMD testing in men are less clear. Because fractures are less common and treatment
PREVENTION AND TREATMENT Few studies have been published to guide preventive programs in men; the NIH Consensus Conference recommended that men >65 years of age receive 1500 mg of calcium and 600 to 800 IU of vitamin D daily. A recent study of older individuals, including a large group of men, demonstrated decreased bone loss in those receiving 500 mg of supplemental calcium and 700 IU of vitamin D. In addition, weight-bearing exercise is recommended for prevention of bone loss and falls. Finally, patients should be counseled to avoid smoking and excess alcohol consumption. Similarly, young men should be counseled to consume adequate calcium (1000 mg/d) and vitamin D and to engage in weight-bearing exercise. There is no therapy specifically approved by the FDA for the treatment of osteoporosis in men. In men with severe hypogonadism, testosterone has been beneficial in increasing or restoring bone
for osteoporosis is less well established in men, it is difficult to justify widespread screening. Nevertheless, studies of risk factors for fracture in men and prospective studies of fracture risk in men indicate that low BMD is a strong predictor of fracture risk. Until more information is available, BMD measurement should be considered in men when a fracture occurs in the absence of significant trauma, when there are radiographic findings of low bone mass or vertebral deformity, or when clinical conditions are present that predispose to metabolic bone disease, such as glucocorticoid therapy or malabsorption. BMD will confirm the suspicion of low bone mass and can be used to monitor success of therapy.
47
clinicalCORNERSTONE
n
OSTEOPOROSIS
1 Vol.2 No. 6
CONCLUSIONS
mass. The typical replacement dosage of intramuscular testosterone is 200 to 300 mg every 2 to 3 weeks; alternatively, a daily scrotal or transdermal patch can be given. In men with low testosterone
Osteoporosis in men is a substantial public health issue that requires increased awareness from both clinicians and the patients at risk. Many characteristics of osteoporosis in men are similar to those found in women, but we need more information on diagnosis, pathogenesis, and therapy. As we gain information on the similarities and differences between osteoporosis in older men and postmenopausal women, it should be possible to establish better criteria for screening and diagnosis and more rational programs for prevention and treatment. Until that occurs, it is important to be alert to the possibility of osteoporosis in men and to follow the general guidelines for prevention and treatment presented here.
SUGGESTED
levels associated with aging and comorbidity, the use of testosterone therapy is not established. No studies have demonstrated fracture prevention in men receiving testosterone. In addition, the longterm effects of testosterone on the prostate and cardiovascular risk need further evaluation before replacement in older men can be recommended. Antiresorptive agents, such as bisphosphonates and calcitonin in doses given to women, have been used in men with osteoporosis. Preliminary data from a prospective trial in which >200 men with either low bone mass or fracture received alendronate 10 mg/d demonstrated increases in bone mass, including men with low testosterone levels. Men on glucocorticoid therapy may respond to bisphosphonate therapy as well as to testosterone.
ADVISORY
READING
Melton LJ III, Atkinson EJ, O’Connor MK, et al. Bone density and fracture risk in men. J Bone Miner Res. 1998;13:1915-1923. Poor G, Atkinson EJ, O’Fallon WM, Melton LJ III. Determinants of reduced survival following hip fractures in men. Clin Orthop. 1995;3 19:260-265. Khosla S, Melton LJ III, Atkinson EJ, et al. Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen. J Clin Endocrinol Metab. 1998;83:2266-2274. Center JR, Nhuyen TV, Sambrook PN, Eisman JA. Hormonal and biochemical parameters in the determination of osteoporosis in elderly men. J Clin Endocrinol Metab. 1999;84:3626-3635. Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab. 1999;84:1966-1972.
BOARD
for men as it is for women. The studies have been much smaller and fewer, but the trends look very similar. The problem is that nobody has decided what the cutoff points are for males. The World
How should clinicians use the T and Z scores in evaluating BMD in males?
Health Organization has made it pretty clear that a woman with a T score c-1 .O is at risk and a
KENNY
It appears that having a low BMD is just as bad
48
= OSTEOPOROSIS
1 Vol.2 No.6
Osteoporosis in Older Men Anne
Kenny,
MD
Assistant Professor of Medicine University of Connecticut Center on Aging University of Connecticut Health Center Farmington, Connecticut
PamelaTaxel,
MD
Assistant Professor of Medicine Division of Endocrinology and Metabolism University of Connecticut Health Center Farmington, Connecticut
Historically, the focus in osteoporosis has been on postmenopausal women. In the past few years, information about osteoporosis in other populations, including men, has begun to emerge. Although less common in older men, osteoporosis nonetheless represents a major health concern. Approximately 30% of hip fractures worldwide occur in men, resulting in significant mortality and loss of independence. The incidence of osteoporotic fractures in men is increasing. The reason for this is unclear, but improvement in longevity and better management of other chronic diseases most likely play a role. Two recent studies have addressed the question of fracture risk in men past middle age and have estimated that men >50 years of age have a 19% to 25% lifelong risk of osteoporotic fracture. Mortality is higher following hip fracture and pain is more intense in men than in women following severe vertebral fracture.
than it is in age-matched control or reference popu lations. In prospective studies, men with the lowest bone mineral density (BMD) at baseline were more likely to fracture during follow-up at 7 and 1 1
DETERMINANTS OF FRACTURE RISK The incidence of fragility fractures is lower in men than in women. Reasons for the difference include increased size of bone; thicker cortices, although density and trabecular architecture are similar to those of women; shorter life span; and lack of the abrupt decrease in sex hormone levels that occurs in women at menopause (Table). Nevertheless, several factors increase risk for bone loss and fracture in men, including low bone mass, genetic factors, changes in calcium absorption and osteoblast function with age, decreases in sex hormone levels, comorbid conditions, and lifestyle factors, such as smoking and excess alcohol consumption. These factors are similar to those for bone loss in women. A strong correlation is found between bone mass and fracture risk in women, and limited studies suggest a similar relationship in men. Bone mass is lower in men with hip or spine fracture
years. Like women, men achieve peak bone mass at age 25 to 30; however, the bone mass in men is higher due to the increased size of bone.
45
clinical CORNERSTONE
n
OSTEOPOROSIS
m Vol.2 No.6
Differences
Similarities l
Decreased calcium absorption with age
0 Thicker cortices in men
l
Decreased osteoblast function with age
0 Shorter life span in men
l
Life-style
l
Higher peak bone mass in men
0 No abrupt fall in hormonal
influences
(smoking and alcohol)
status in men
Genetic effects are present irrespective of gender. Twin studies have confirmed the heritability of bone mass, and men with a family history of osteoporosis or a mother who suffered a hip fracture have low BMD. However, the gene or genes associated with osteoporosis have not been clearly identified. Cross-sectional studies have detected a slower rate of bone loss in men compared with women, but in older populations, rates of femoral bone loss were equal in men and women. In a longitudinal study of men aged 30 to 90 years, the average bone loss per year in the radius and spine was 1%. Men do not have a period of accelerated bone loss that is equivalent to the acceleration in bone loss that
with rapid bone loss. Androgen levels fall with increasing age in men. Although total testosterone levels remain relatively stable, sex-hormone-binding globulin levels increase with a resultant decline in free or bioavailable testosterone levels at a rate of approximately 1% a year. Bioavailable testosterone levels are below the normal reference range of young adult men in approximately 50% of men >70 years of age. The role of this modest loss in sex hormones in aging men is not well understood. Several studies have evaluated the relationship between circulating estrogen and androgen levels and have found that low estrogen and androgen levels are associated with lower bone mass in men. Further research is required to better understand the roles of estrogen and testosterone in the maintenance of bone in older men. Likewise, the role of testosterone supplementation in the health of older men remains to be determined. The largest study in which men with testosterone levels in the lownormal range received supplemental testosterone found femoral bone density increased in the testosterone group but no effect on muscle strength. The effects of testosterone may be mediated directly or indirectly, following peripheral conversion of testosterone to estrogen via aromatase. Studies in animals suggest that the direct effect is to stimulate bone formation and that estrogen mediates an inhibition of bone resorption. Many conditions affect an individual’s risk of fracture. Hip fractures are associated with an increased risk of falling, but there are few prospective data in men to directly relate falls to subsequent fracture. Factors that increase fall risk, such as increased body sway, decreased strength, and neurologic disorders, probably increase risk factors for hip fracture in men. Lifestyle factors that con-
accompanies menopause, but there is continued steady loss with advancing age. Mechanisms outlined in previous articles, such as decreased calcium absorption and increased parathyroid hormone levels resulting in increased bone resorption, as well as decreased osteoblast function with consequent decrease in bone formation, are as significant in men as they are in women. Loss of sex steroids (menopause in women and severe hypogonadism in men) is associated
46
clinical CORNERSTONE
tribute to decreased bone mass and increased fracture risk include decreased weight, physical inactivity, self-described poor health, and excess alcohol and tobacco use. Finally, there is an association between idiopathic osteoporosis and low levels of both insulin-like growth factor-l and insulin-like growth factor-l binding protein-3.
.
OSTEOPOROSIS
1 Vol. 2 No. 6
Although diagnostic criteria for osteoporosis are not established, men with BMD measurements 2 standard deviations below the young adult normal range who have fractures or in whom other clinical conditions put them at risk for further bone loss should have a full evaluation for secondary causes of osteoporosis and be considered for treatment. Because secondary causes are thought to contribute to osteoporosis in 40% to 60% of men with the condition, a search for contributing factors is critical. Physicians should investigate medication use (especially thyroid replacement, glucocorticoid, anti-seizure, and gonadotropin-releasing hormone analogues) and social habits (excess alcohol consumption and tobacco use), and check for hypogonadism and malabsorptive conditions (eg, a history of gastric surgery). Laboratory evaluation should include testosterone, thyroid stimulating hormone, and vitamin D levels; serum protein electrophoresis (to exclude multiple myeloma); and urine test for calcium excretion (to exclude hypercalciuria). Biochemical markers of bone turnover have not been shown to be beneficial in the diagnosis of osteoporosis in men, although they may be used to assess therapeutic response to antiresorptive agents in high turnover states.
EVALUATION OF OSTEOPOROSIS The World Health Organization established criteria for the diagnosis of osteoporosis based on the relationship between risk of fracture and BMD for white women in 1994. Recently, there has been a movement for widespread screening for osteoporosis in postmenopausal women, but recommendations for BMD testing in men are less clear. Because fractures are less common and treatment
PREVENTION AND TREATMENT Few studies have been published to guide preventive programs in men; the NIH Consensus Conference recommended that men >65 years of age receive 1500 mg of calcium and 600 to 800 IU of vitamin D daily. A recent study of older individuals, including a large group of men, demonstrated decreased bone loss in those receiving 500 mg of supplemental calcium and 700 IU of vitamin D. In addition, weight-bearing exercise is recommended for prevention of bone loss and falls. Finally, patients should be counseled to avoid smoking and excess alcohol consumption. Similarly, young men should be counseled to consume adequate calcium (1000 mg/d) and vitamin D and to engage in weight-bearing exercise. There is no therapy specifically approved by the FDA for the treatment of osteoporosis in men. In men with severe hypogonadism, testosterone has been beneficial in increasing or restoring bone
for osteoporosis is less well established in men, it is difficult to justify widespread screening. Nevertheless, studies of risk factors for fracture in men and prospective studies of fracture risk in men indicate that low BMD is a strong predictor of fracture risk. Until more information is available, BMD measurement should be considered in men when a fracture occurs in the absence of significant trauma, when there are radiographic findings of low bone mass or vertebral deformity, or when clinical conditions are present that predispose to metabolic bone disease, such as glucocorticoid therapy or malabsorption. BMD will confirm the suspicion of low bone mass and can be used to monitor success of therapy.
47
clinicalCORNERSTONE
n
OSTEOPOROSIS
1 Vol.2 No. 6
CONCLUSIONS
mass. The typical replacement dosage of intramuscular testosterone is 200 to 300 mg every 2 to 3 weeks; alternatively, a daily scrotal or transdermal patch can be given. In men with low testosterone
Osteoporosis in men is a substantial public health issue that requires increased awareness from both clinicians and the patients at risk. Many characteristics of osteoporosis in men are similar to those found in women, but we need more information on diagnosis, pathogenesis, and therapy. As we gain information on the similarities and differences between osteoporosis in older men and postmenopausal women, it should be possible to establish better criteria for screening and diagnosis and more rational programs for prevention and treatment. Until that occurs, it is important to be alert to the possibility of osteoporosis in men and to follow the general guidelines for prevention and treatment presented here.
SUGGESTED
levels associated with aging and comorbidity, the use of testosterone therapy is not established. No studies have demonstrated fracture prevention in men receiving testosterone. In addition, the longterm effects of testosterone on the prostate and cardiovascular risk need further evaluation before replacement in older men can be recommended. Antiresorptive agents, such as bisphosphonates and calcitonin in doses given to women, have been used in men with osteoporosis. Preliminary data from a prospective trial in which >200 men with either low bone mass or fracture received alendronate 10 mg/d demonstrated increases in bone mass, including men with low testosterone levels. Men on glucocorticoid therapy may respond to bisphosphonate therapy as well as to testosterone.
ADVISORY
READING
Melton LJ III, Atkinson EJ, O’Connor MK, et al. Bone density and fracture risk in men. J Bone Miner Res. 1998;13:1915-1923. Poor G, Atkinson EJ, O’Fallon WM, Melton LJ III. Determinants of reduced survival following hip fractures in men. Clin Orthop. 1995;3 19:260-265. Khosla S, Melton LJ III, Atkinson EJ, et al. Relationship of serum sex steroid levels and bone turnover markers with bone mineral density in men and women: a key role for bioavailable estrogen. J Clin Endocrinol Metab. 1998;83:2266-2274. Center JR, Nhuyen TV, Sambrook PN, Eisman JA. Hormonal and biochemical parameters in the determination of osteoporosis in elderly men. J Clin Endocrinol Metab. 1999;84:3626-3635. Snyder PJ, Peachey H, Hannoush P, et al. Effect of testosterone treatment on bone mineral density in men over 65 years of age. J Clin Endocrinol Metab. 1999;84:1966-1972.
BOARD
for men as it is for women. The studies have been much smaller and fewer, but the trends look very similar. The problem is that nobody has decided what the cutoff points are for males. The World
How should clinicians use the T and Z scores in evaluating BMD in males?
Health Organization has made it pretty clear that a woman with a T score c-1 .O is at risk and a
KENNY
It appears that having a low BMD is just as bad
48