Osteoporosis in Men: the Forgotten Reality

MAY 18, 2007
M. Y. Zaman, MD, LACASA Health Center, Clovis, NM, and Zia Salam, MD, FACE, Atlantic City Medical Center, Atlantic City, NJ
M. Y. Zaman, MD
Primary Care Physician
LACASA Health Center
Clovis, NM

Zia Salam, MD, FACE
Internal Medicine Program Director
Atlantic City Medical Center
Atlantic City, NJ

Osteoporosis is characterized by reduced bone strength, diminished bone density, and altered macrogeometry and microscopic architecture of bone. Although both men and women can have osteoporosis, the risk in men is often unrecognized and remains undiagnosed for years. The resultant morbidity, mortality, and healthcare costs could all be avoided with timely intervention. No clear-cut guidelines are available for the management of osteoporosis in men. A silent disease until the catastrophic end result, osteoporosis is underdiagnosed and undertreated in men and women but is even less managed in men. With appropriate therapy, the disease can be arrested before any fracture occurs.

Osteoporosis is generally considered a women?s health issue, as evidenced by a substantial body of literature on this topic. However, according to the National Osteoporosis Foundation, approximately one fifth of patients with symptomatic osteoporosis are men.1 Even though osteoporosis is more common in women, the associated morbidity and mortality are greater in men. This is because osteoporosis is unrecognized in men and therefore the resulting fractures in men are associated with more complications. It is high time that primary care physicians evaluate all men starting at age 70 or those at high risk.

PRACTICE POINTS
About one fifth of all patients with symptomatic osteoporosis are men.
? The morbidity and mortality associated with osteoporosis is greater in men than in women.

? In men older than 70, osteoporosis results from decreases in calcium intake/ absorption, vitamin D activation, sex hormone concentration, and declining functioning of osteoblasts.

? Evaluate all men older than 70 regularly for osteoporosis using dual-energy x-ray absorptiometry testing.

? Treatment options for primary disease include bisphosphonates, parathyroid hormone, androgens, and nonpharmacologic interventions, including diet and calcium and vitamin D supplementation.

Epidemiology
Available data suggest that 2 million American men already have osteoporosis, and another 12 million men are at risk.2 Among men aged 50 years and older, an estimated 7% of non-Hispanic white and Asian men have osteoporosis, and another 35% have low bone mass. The respective numbers are 4% and 19% for non-Hispanic black men and 3% and 23% for Hispanic men.1 One fourth of men aged 50 and older will have an osteoporosis-related fracture during their lives, and thus men account for a substantial portion of the estimated $18 billion spent on the management of osteoporotic fractures each year in the United States.1

In persons 60 years and older, the rate of osteoporotic hip fracture is 759 per 100,000 person-years in women and 329 per 100,000 person-years in men.3 But with advancing age, this gender gap narrows; the female-to-male ratio is 4.5:1 in those aged 60 to 69 years, 1.5:1 in those aged 70 to 79, and 1.9:1 in those aged 80 years and older.3

Evidence suggests that hip fracture?related morbidity and mortality are significantly greater in men than in women. In a study of 565 community-dwelling adults aged 60 and older, men were more than 5 times more likely than women to be institutionalized with a hip fracture or to have died from it within 2 years.4 Recent data indicate that only about one third of men aged 50 and older are still alive 2 years after suffering a low-trauma hip fracture.5

Risk Factors
The skeletal system consists of trabecular bone and cortical bone. The vertebrae and pelvic bones contain high quantities of trabecular and cancellous tissue, whereas the long bones have a relatively high amount of cortical bone. Any alteration in the 3-dimensional microarchitecture of skeletal tissue compromises its structural integrity and strength. Thus, inadequate peak bone mass, bone loss, impaired bone strength, and trauma all predispose to osteoporosis (Figure).

Certain gender differences help explain why osteoporosis is more common in women, beginning with the accelerated bone loss that women undergo during menopause. In addition, men have larger bones and greater peak bone mass at skeletal maturity, which provide added protection.6

Although differences in patterns of bone loss account for the differences in bone quality between men and women, they share many of the risk factors for osteoporosis. Common risk factors include increasing age, poor diet, smoking, excessive alcohol use, family history, various diseases, and the use of certain medications (Table 1).1,2

In men older than 70 years, osteoporosis is often the result of decreased intake and/or absorption of calcium, reduced activation of vitamin D, reduced level of sex hormone concentration, and the declining lifespan and functioning of osteoblasts.7,8

Osteoporosis in men younger than 70 is more likely to be secondary to another medical condition, but in a substantial number of such men the cause remains elusive after testing for osteoporosis, and the condition is classified as idiopathic. Some evidence suggests that genetics play a major role in the pathogenesis of idiopathic osteoporosis in men.9

Diagnosing Osteoporosis in Men
The diagnosis of osteoporosis can be made with the help of central dual-energy x-ray absorptiometry (DEXA). The technique is called ?central? because it measures bone in the central skeleton areas?spine and hip?that show the earliest signs of bone loss. Although quantitative computed tomography could also be helpful for diagnosis, it is rarely used because of its high cost and higher radiation exposure.

The World Health Organization (WHO) classification of bone mineral density (BMD) for the diagnosis of osteoporosis in women can also be applied to men (Table 2).10 However, because there may be between-gender differences in the relationship between BMD and fracture risk, it is recommended that T scores in men be based on a male normative database.11

The WHO classification, which was derived from a reference population, is a subject of current debate. The position statement of the International Society for Clinical Densitometry (ISCD) recommends modifications in the WHO classification for men.12 Although the ISCD does advocate using a T score at or below ?2.5 to diagnose osteoporosis in men aged 65 years and older, it recommends that other risk factors also be present before making the diagnosis in men aged 50 to 64 years. It should be noted, however, that clinical trials of pharmacotherapy have used male reference data to determine T-score criteria.13

Once the diagnosis is established, the next question to address is whether the condition is primary or secondary (Table 3). Laboratory tests that can help rule out secondary etiologies include serum testosterone, thyroid-stimulating hormone, calcium, alkaline phosphatase, 25-hydroxyvitamin D, parathyroid hormone (PTH), liver function, complete blood cell count, erythrocyte sedimentation rate, and protein electrophoresis; and urine calcium and creatinine measurements.

Not all these tests are necessary; the actual tests ordered should be guided by the history and physical examination findings. Measurements of markers of bone formation and resorption have little diagnostic value.

Drug Therapy
If osteoporosis is determined to be secondary in origin, addressing the underlying cause will improve bone health. For example, treatment for hyperthyroidism, hypogonadism, or hyperparathyroidism can increase BMD by 10% to 20%.14 For primary disease, 4 options are available?bisphosphonates, PTH, androgens, and nonpharmacologic interventions (Table 4). Combining a bisphosphonate with PTH therapy is not recommended, based on a study that showed that alendronate (Fosamax) interfered with the ability of PTH to increase lumbar and femoral neck BMD.15

Bisphosphonates
Of the currently available bisphosphonates approved for the treatment of osteoporosis in women, only alendronate and risedronate (Actonel) have been approved for the treatment of osteoporosis in men. Risedronate was approved for this indication in August 2006.

A meta-analysis of randomized, placebo-controlled trials of men with primary osteoporosis demonstrated that 10 mg/day alendronate treatment reduced the risk of vertebral fracture by 56%, but the analysis yielded insufficient data on alendronate?s ability to reduce nonvertebral fractures.16 Recent studies that included more than 300 men with osteoporosis showed that 12 months of treatment with alendronate increases lumbar BMD by 4.3% to 5.8%.17,18

The new indication for risedronate, 35 mg/week, for the treatment of osteoporosis in men was based on a 2-year, double-blind, placebo-controlled trial of 284 men with osteoporosis. Use of risedronate, 35 mg once weekly, resulted in a significant increase in BMD of the lumbar spine at 6, 12, and 24 months. Significant reductions in bone turnover markers were also seen.19

Side effects are possible with bisphosphonates, most frequently gastrointestinal disturbances that can range from dyspepsia to severe reflux disease. Bisphosphonates should be avoided in patients with a creatinine clearance less than 30 mL/min.

Parathyroid hormone
The Food and Drug Administration has approved PTH in the form of teriparatide injection (Forteo) for men at high risk for fracture?those who have not responded to previous treatment, have a history of low-trauma fractures, or have multiple risk factors for fracture.20 A study of 437 men with spine or hip BMD more than 2 SD below the young adult male mean showed that self-injections of teriparatide, 20 or 40 ?g/day, increased spine BMD by up to 9% at an average follow-up of 11 months.13

This therapy, however, is very expensive and requires daily injections. The maximum duration of treatment is 2 years, after which antiresorptive therapy can be started to prevent BMD declines and continue BMD gains. A recent study that included 355 men found that men who took antiresorptive agents after stopping teriparatide had an 83% lower risk of moderate or severe vertebral fractures compared with men who took placebo.21

Teriparatide should not be used in patients with severe hypercalcemia or with Paget?s disease or in those who have a history of bone radiation treatment, skeletal malignancy, or metastases. Drug therapy also involves safety concerns, with experimental studies showing that high doses caused osteosarcoma in rats. More recent evidence suggests that these neoplasms can be avoided with shorter duration of lower-dose teriparatide treatment.22

Androgens
Androgens, key hormones in men, play a major role in skeletal homeostasis, from inhibiting osteoclasts to stimulating osteoblasts. Continuous, long-term testosterone replacement therapy can increase BMD in hypogonadal men and maintain BMD within the normal range.23 However, the role of such therapy in men without overt hypogonadism remains controversial. A recent meta-analysis of 8 randomized, placebo-controlled trials demonstrated that intramuscular testosterone therapy resulted in a modest 8% improvement in lumbar BMD and a nonsignificant 4% gain in femoral neck BMD, leading the authors to conclude that the efficacy evidence was weak.24 Clearly, more research is needed.

When prescribing testosterone replacement therapy, prostate-specific antigen levels must be monitored. Side effects of testosterone therapy include hypertension, benign prostatic hyperplasia, and gynecomastia.

Nonpharmacologic Interventions
All men who have or who are at risk for osteoporosis should be counseled on the need to modify specific behaviors, such as smoking and high alcohol consumption, that increase the risk for osteoporosis. They should also be informed of the importance of adequate intake of calcium (1000 mg/day) and vitamin D (800 IU/day). Despite the availability of vitamin D from exposure to sunlight, about one third of adult white men in the United States have low serum levels of this vitamin, and black and Hispanic men are thought to have an even higher incidence of hypovitaminosis D.25 Weight-bearing exercises, 30 to 45 minutes for at least 3 days weekly, can increase BMD by about 2.6% in the sites loaded by the exercise.26 Fall-precaution measures should also be discussed, such as gait training, the use of assistive devices, avoiding psychotropic medications if possible, and eliminating environmental hazards.27

When to Refer
Referral to a specialist should be considered for men with osteoporosis who have complex comorbidities; have severe osteoporosis at age younger than 50 years; have a history of multiple or recurrent fractures; do not respond to therapy; have problems with or cannot tolerate treatment; or those who present with an acute spinal fracture that may be amenable to treatment with percutaneous vertebroplasty.28

Conclusion
As primary care physicians we have to realize that osteoporosis is a growing healthcare concern in men, and the associated morbidity and mortality burden is greater in men than in women. Hence male patients, especially those older than 70, should be regularly evaluated for risk factors for osteoporosis, screened regularly using DEXA testing where necessary, and if affected, treated appropriately.

Self-assessment test
1. Which of the following statements about osteoporosis is NOT true?
A. Men account for one fifth of all cases
B. Men are at greater risk of osteoporotic fracture than women
C. Morbidity after hip fracture is greater in men than in women
D. Mortality after hip fracture is greater in men than in women

2. Osteoporosis is less common in men than in women for all the following reasons, except:
A. Male bone-loss pattern
B. Larger bones in men
C. Greater peak bone mass at skeletal maturity
D. Nicotine use

3. Risk factors for osteoporosis in men include all the following, except:
A. Smoking
B. Maternal history of osteoporosis
C. Age under 60 years
D. Insufficient calcium/vitamin D intake

4. All these conditions are secondary causes of osteoporosis in men, except:
A. Type 2 diabetes
B. Inflammatory bowel disease
C. Thyrotoxicosis
D. Alcohol abuse

5. Which of the following drugs is NOT indicated for the treatment of primary osteoporosis in men?
A. Risedronate
B. Ibandronate
C. Alendronate
D. Teriparatide

(Answers at end of reference list)

References
1. National Osteoporosis Foundation. Fast Facts on Osteoporosis. Available at www.nof.org/osteoporosis/diseasefacts.htm. Accessed August 1, 2006.

2. National Osteoporosis Foundation. Osteoporosis in Men. Available at www.nof.org/men/index.htm. Accessed August 3, 2006.

3. Chang KP, Center JR, Nguyen TV, et al. Incidence of hip and other osteoporotic fractures in elderly men and women: Dubbo Osteoporosis Epidemiology Study. J Bone Miner Res. 2004; 19:532-536.

4. Fransen M, Woodward M, Norton R, et al. Excess mortality or institutionalization after hip fracture: men are at greater risk than women. J Am Geriatr Soc. 2002; 50: 685-690.

5. Pande I, Scott DL, O?Neill TW, et al. Quality of life, morbidity, and mortality after low trauma hip fracture in men. Ann Rheum Dis. 2006; 65:87-92.

6. Seeman E. Pathogenesis of bone fragility in women and men. Lancet. 2002; 359:1841-1850.

7. Boonen S, Vanderschueren D, Cheng XG, et al. Age-related (type II) femoral neck osteoporosis in men: biochemical evidence for both hypovitaminosis D- and androgen deficiency-induced bone resorption. J Bone Miner Res. 1997; 12: 2119-2126.

8. Szulc P, Munoz F, Claustrat B, et al. Bioavailable estradiol may be an important determinant of osteoporosis in men: the MINOS study. J Clin Endocrinol Metab. 2001; 86: 192-199.

9. Van Pottelbergh I, Goemaere S, Zmierczak H, et al. Deficient acquisition of bone during maturation underlies idiopathic osteoporosis in men: evidence from a three-generation family study. J Bone Miner Res. 2003;18:303-311.

10. World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: report of a WHO Study Group. World Health Organ Tech Rep Ser. 1994; 843:1-129.

11. Binkley NC, Schmeer P, Wasnich RD, et al, for the International Society for Clinical Densitometry Position Development Panel and Scientific Advisory Committee. What are the criteria by which a densitometric diagnosis of osteoporosis can be made in males and non-Caucasians? J Clin Densitom. 2002; 5(suppl):S19-S27.

12. Lewiecki EM, Watts NB, McClung MR, et al, for the International Society for Clinical Densitometry. Official positions of the International Society for Clinical Densitometry. J Clin Endocrinol Metab. 2004; 89:3651-3655.

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. Francis RM. Male osteoporosis. Rheumatology. 2000; 39:1055-1059.

15. 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; 349:1216-1226.

16. Sawka AM, Papaioannou A, Adachi JD, et al. Does alendronate reduce the risk of fracture in men? A meta-analysis incorporating prior knowledge of anti-fracture efficacy in women. BMC Musculoskelet Disord. 2005; 6:39.

17. Olszynski WP, Davison KS, Ioannidis G, et al. Effectiveness of alendronate and etidronate in the treatment of osteoporosis in men: a prospective observational study. Osteoporos Int. 2006; 17:217-224.

18. Iwamoto J, Takeda T, Sato Y, et al. Comparison of the effect of alendronate on lumbar bone mineral density and bone turnover in men and postmenopausal women with osteoporosis. Clin Rheumatol. 2006; March 25 [published online ahead of print].

19. The US Food and Drug Administration approves Actonel for broader use in men with osteoporosis [press release]. Cincinnati, Ohio, Bridgewater, NJ: The Alliance for Better Bone Health; August 14, 2006.

20. Forteo [prescribing information]. Indianapolis, Ind: Eli Lilly; 2004.

21. Kaufman JM, Orwoll E, Goemaere S, et al. Teriparatide effects on vertebral fractures and bone mineral density in men with osteoporosis: treatment and discontinuation of therapy. Osteoporos Int. 2005; 16:510-516.

22. Vahle JL, Long GG, Sandusky G, et al. Bone neoplasms in F344 rats given teriparatide [rhPTH(1-34)] are dependent on duration of treatment and dose. Toxicol Pathol. 2004;32:426-438.

23. Behre HM, Kliesch S, Leifke E, et al. Long-term effect of testosterone therapy on bone mineral density in hypogonadal men. J Clin Endocrinol Metab. 1997; 82:2386-2390.

24. Tracz MJ, Sideras K, Bolona ER, et al. Testosterone use in men and its effects on bone health. A systematic review and meta-analysis of randomized placebo-controlled trials. J Clin Endocrinol Metab. 2006; 91:2011-2016.

25. Zadshir A, Tareen N, Pan D, et al. The prevalence of hypovitaminosis D among US adults: data from the NHANES III. Ethn Dis. 2005;15(suppl 5):S97-S101.

26. Kelley GA, Kelley KS, Tran ZV. Exercise and bone mineral density in men: a meta-analysis. J Appl Physiol. 2000; 88:1730-1736.

27. American Geriatrics Society, British Geriatrics Society, and American Academy of Orthopaedic Surgeons Panel on Falls Prevention. Guideline for the prevention of falls in older persons. J Am Geriatr Soc. 2001; 49:664-672.

28. Diamond T, Sambrook P, Williamson M, et al. Guidelines for treatment of osteoporosis in men. Aust Fam Physician. 2001; 30:787-791.

Answers: 1. B; 2. D; 3. C; 4. A; 5. B.

Online Resources for Patients
? The National Osteoporosis Foundation Information specifics for men: www.nof.org/menindex.htm

? The International Osteoporosis Foundation A 20-page publication on osteoporosis in men: www.osteofound.org/publications/pdf/
osteoporosis_in_men.pdf


? The National Institute of Arthritis and Musculoskeletal and Skin Diseases A web page devoted to osteoporosis in men: www.niams.nih.gov/bone/hi/osteoporosis_men.htm

? Information for men on risedronate: www.actonel.com/patientinformation/patientInfo.jsp


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