Osteoporosis in Men

Pamela B. Sheets, MD
The Polyclinic, Seattle, WA, USA

Clinical Characteristics
Osteoporosis is under-recognized and under-treated. The problem is compounded in men because of the misconception that osteoporosis is a disease of women. A gender-specific approach to screening, diagnosis, and treatment should reduce the morbidity and mortality of the disease, particularly in men over 70. Fractures are common in men, with a dramatic increase after age 70, typically beginning 5-10 years later in life compared to women (1). The incidence of hip fracture is one-third to one-half that in women with 20-25% of all hip fractures occurring in men. Peak bone mass is achieved somewhat later in boys than girls. They develop thicker cortices and larger bones than do girls. This may in part explain some of the reasons for the lower fracture risk in men later in life. Lower fracture risk in males may also be the result of differences in the microarchitectural loss of trabecular bone in males vs. females. Men have primarily trabecular thinning, whereas women have trabecular thinning and dropout (due to loss of connectivity). Aging in both sexes results in loss of cortical thickness. However, men have a greater compensatory periosteal expansion of their cortical bone than women resulting in larger overall cortical diameter (bigger bones). Despite the differences in fracture risk, elderly men are more likely to die and suffer disability than women after a fracture, and they are less likely than women to be treated with antiresorptive therapy after hip fracture (2, 3).

Men with osteoporosis usually present with low-trauma fractures or radiographic osteopenia discovered incidentally during evaluation for musculoskeletal pain (e.g. back pain). Osteoporosis should be suspected in men with diseases or treatments known to be associated with bone loss such as hypogonadism, inflammatory bowel disease, or glucocorticoid therapy. The same disorders that cause osteoporosis in women can cause osteoporosis in men, including endocrine diseases, gastrointestinal disorders, connective tissue diseases, drugs, and hematologic conditions. Most osteoporotic men have secondary causes of bone loss, especially alcohol abuse, excess glucocorticoid therapy and hypogonadism (4). One of the most important causes of severe hypogonadism is androgen deprivation therapy for prostate cancer. Those with idiopathic disease can present at any age, but are most dramatic in younger men.

Evaluation
A careful history and physical exam should be done, recording risk factors associated with bone loss, looking for kyphosis and measuring for height loss. Bone density should be assessed in men presenting with fracture and those with risk factors. Indications for bone mass measurement in men have been published. They include those who have suffered a low trauma fracture and those with known secondary causes of bone loss, including men on glucocorticoids or other medications associated with osteoporosis, men with hypogonadism, and those with alcoholism. Measurement of bone mineral density (BMD) should be considered in men who have lost more than 1.5 inches in height. It is the position of the ISCD to screen men aged 70 and older with BMD testing (5).

Laboratory evaluation is indicated in osteoporotic men, looking for correctable causes of bone loss. A basic evaluation includes measurement of serum calcium, phosphorus, creatinine, alkaline phosphatase, liver function tests, complete blood count, 25-hydroxyvitamin D, PTH, serum testosterone and LH, and serum protein electrophoresis in those 50 or older. Additional testing may include thyroid function tests, 24-hour urine cortisol and bone turnover markers.

Diagnosis
Interpretation of BMD measures in men has been controversial. Data suggesting that the risk of fracture is similar in men and women at the same absolute level of BMD has led some to recommend that the definition of osteoporosis based on T-scores be the same for both sexes (6). However, this approach results in fewer men over age 50 being identified as at risk. The ISCD Position Development Conference held in July 2003 reviewed this controversy and recommends using a combination of risk factors and T-scores (7). In men age 65 and older, T-scores should be used and osteoporosis diagnosed if the T-score is -2.5 or below the young normal mean for men. Between age 50 and 65, T-scores may be used and osteoporosis diagnosed if both the T-score is equal to or less than -2.5 and other risk factors for fracture are identified. Men at any age with secondary causes of low BMD may be diagnosed clinically with osteoporosis supported by findings of low BMD. The diagnosis of osteoporosis in men under age 50 years should not be made on the basis of densitometric criteria alone. The diagnosis in men under age 50 must be made on clinical grounds. Longitudinal studies are needed to better define the BMD-fracture risk relationship in men.

Treatment
Principles of fracture prevention in men are similar to those in women. Good nutrition and exercise have positive effects on bone mass. Avoidance of poor lifestyle choices (e.g., alcohol excess, smoking, sedentary lifestyle, etc.) remain important throughout life. Calcium and vitamin D recommendations are similar to women: 1000 mg calcium for those age 30-50 and 1200 mg after age 50; vitamin D intakes of 800-1000 IU. Secondary causes of osteoporosis should be treated appropriately.

Prospective fracture intervention trials are not as extensive in men as in women, although the therapies appear to be equally effective. Support comes from a controlled trial comparing calcium alone to alendronate 10 mg/day in 241 men with osteoporosis. At the end of two years, men treated with alendronate had significantly greater gains in lumbar spine BMD and femoral neck BMD compared to placebo. Radiographs were available at baseline and two years for 209 of the men. Using quantitative methods, the incidence of vertebral fractures was less in the alendronate group (0.8%) than the placebo group (7.1%) (P=0.02). The number of non-vertebral fractures was small and similar in both groups (5/95 in placebo and 6/146 in alendronate, P=0.8) (8). Another study of alendronate in 134 men with primary osteoporosis produced similar results (9). Alendronate is FDA approved for use in males. There is no data with risedronate in men except in the setting of glucocorticoid-induced osteoporosis. Bisphosphonates have been shown to prevent bone loss in men undergoing androgen deprivation therapy for treatment of prostate cancer. In a 48-week, open-label study of 47 men with advanced prostate cancer randomly assigned to receive either leuprolide alone or leuprolide and pamidronate (60 mg IV every 12 weeks), BMD did not change significantly at any skeletal site in the pamidronate-treated group. Those on leuprolide alone had a mean decrease in BMD of 3.3% at the spine and 1.8% at the hip when measured by DXA and 8.5% in the spine when measured by quantitative computed tomography (10). Zoledronic acid (4 mg every three months for one year) not only prevents bone loss but also increases BMD in the hip and spine compared to placebo in men receiving androgen deprivation therapy (11). Oral bisphosphonates have not been evaluated in this specific subgroup of men.

Teriparatide (1-34 recombinant human PTH) is FDA-approved for men at high risk for fracture. The first controlled, randomized, double blind study of PTH in men was conducted in 23 subjects with idiopathic osteoporosis. After 18 months the PTH treated men showed a significant increase in lumbar spine and femoral neck BMD (13.5% and 2.9%) compared to placebo (12). In the largest randomized, placebo controlled trial to date, 437 osteoporotic men received PTH for a median duration of 11 months (13). Spine and femoral neck BMD increased significantly in the treated group compared to placebo. No fracture data from this study is available. The result of combining alendronate with PTH has been unexpectedly disappointing. In a randomized trial of 83 men with low BMD, more significant increases were observed in the lumbar spine and femoral neck BMD in men treated with parathyroid hormone alone (40 mcg SQ daily) than those treated with alendronate alone (10 mg daily), or the combination (alendronate 10 mg daily for 30 months and PTH 40 mcg SQ daily starting at six months) (14). Alendronate appears to impair the ability of PTH to increase BMD at the lumbar spine and femoral neck in men. Testosterone replacement increases BMD in hypogonadal men, but there is no data on fracture risk reduction (15). Hormone replacement in older men with less severe gonadal hypofunction is unproven. Benefits of correcting low testosterone levels must be weighed against unknown long-term risks of treatment. A bisphosphonate or parathyroid hormone is suggested.

Summary
Men with osteoporosis have been largely neglected. The diagnosis is frequently not considered, even in the presence of a devastating fracture. Diagnostic criteria are evolving. Testing for secondary, correctable causes is imperative. Treatments are available and include bisphosphonates and PTH. Double-blind controlled treatment trials suggest similar efficacy to those in women. Testosterone replacement should be reserved for treating overt hypogonadal syndrome. Development of a gender-directed approach to diagnosis and treatment should reduce the morbidity and high mortality of this disease.

References
1. Farmer ME, White LR, Brody JA, et al. Race and sex differences in hip fracture incidence. AM J Public Health 1984;74:1374-80.
2. Diamond, TH, Thornley SW, Sekel, R, et al. Hip fracture in elderly men: prognostic factors and outcomes. Med J Aust 1997;167:412-5.
3. Kiebzak GM, Beinart GA, Perser K, et al. Undertreatment of osteoporosis in men with hip fracture. Arch Intern Med 2002;162:2217-22.
4. Klein RF, Orwoll ES. Bone loss in men: pathogenesis and therapeutic considerations. Endocrinologist 1994;4:252.
5. Leib ES, Lewiecki EM, Binkley N, et al. Official positions of the ISCD. J Clin Densitom. 2004;7:1-6.
6. De Laet CE, van Hout BA, Burger H, et al. Hip fracture prediction in elderly men and women: validation of the Rotterdam study. J Bone Miner Res 1998;13:1587-93.
7. The Writing Group for the ISCD Position Development Conference. International Society for Clinical Densitometry Position Development Conference. Diagnosis of osteoporosis in men, premenopausal women, and children. J Clin Densitom. 2004;7:17-26.
8. Orwoll E, Ettinger M, Weiss S, et al. Alendronate for the treatment of osteoporosis in men. N Engl J Med 2000;343:604-10.
9. Ringe JD, Faber H, Dorst A. Alendronate treatment of established primary osteoporosis in men: results of a 2-year prospective study. J Clin Endocrinol Metab 2001;86:5252-5.
10. Smith MR, McGovern FJ, Zietman AL, et al. Pamidronate to prevent bone loss during androgen-deprivation therapy for prostate cancer. N Engl J Med 2001;345:948-55.
11. Smith MR, Eastham J, Gleason DM, et al. Randomized controlled trial of zoledronic acid to prevent bone loss in men receiving androgen deprivation therapy for nonmetastatic prostate cancer. J Urol 2003;169:2008-12.
12. Kurland ES, Cosman F, McMahon DJ, et al. Parathyroid hormone as a therapy for idiopathic osteoporosis in men: effects on bone mineral density and bone markers. J Clin Endocrinol Metab 2000;85: 3069-76.
13. Orwoll ES, Scheele WH, Paul S, et al. The effect of teriparatide Human Parathyroid Hormone (1-34) therapy on bone density in men with osteoporosis. J Bone Miner Res 2003;18:9-17.
14. Finkelstein JS, Hayes A, Hunzelman JL, et al. The effects of parathyroid hormone, alendronate, or both in men with osteoporosis. N Engl J Med. 2003 Sep 25; 349(13): 1216-26.
15. Katznelson L. Therapeutic role of androgens in the treatment of osteoporosis in men. Ballieres Clin Endocrinol Metab 1998;12:453-70.

Last modified: December 17, 2012