Back to summary |Download this issue

Johann D. RINGE, MD
West German Osteoporosis
Center (WCO) and Department
of General Internal Medicine
Klinikum Leverkusen
University of Cologne
GERMANY

Osteoporosis in men is today recognized worldwide as an important and growing public health problem. Although osteoporosis is less prevalent in men, 30% of all hip fractures occur in males and the prevalence of vertebral fractures—half of that in women—is still substantial. Loss of trabecular bone in aging men is associated with changes in the insulinlike growth factor 1 (IGF-1) regulation system leading to trabecular thinning, rather than the reduced trabecular connectivity seen in women after the menopause. Cortical bone loss in men, however, starts later in life and is associated with a decrease in physical activity and bioavailability of both sex hormones. Alendronate was the first bisphosphonate to be approved for the treatment of male osteoporosis based on consistently positive effects on bone mineral density (BMD) and vertebral fractures from two independent studies in men on a daily dosage of 10 mg. Just two years ago, risedronate followed suit with its once weekly dosage and, recently, 5 mg zoledronic acid IV once yearly and teriparatide—as the first osteoanabolic agent for men—were approved. Up till now, etidronate and ibandronate have been insufficiently studied in men. Pilot study data show that the lumbar spine and total hip BMD increases seen with strontium ranelate are consistent with those found previously in postmenopausal women. A randomized, placebo-controlled trial testing this innovative dual-action drug in a purely male population has been set up to confirm these preliminary results and will soon be finished.

The rather exclusive focus on postmenopausal osteoporosis in the past has undoubtedly led to an underreporting of osteoporosis in men. Fifteen years ago, it was shown that 29% of men and 56% of women, if they are currently 60 years old and receive no preventive measures, will experience fractures during their remaining lifetime.¹ Only in the past decade has attention been focused upon the increasingly important problem of osteoporosis in men.^2-4 Efforts devoted to the issue have been successful. There is today a much better understanding of the disorder, and effective diagnostic, preventive, and therapeutic strategies have been developed.⁵ Today, osteoporosis in men is recognized as an important public health problem and has developed into a very active research issue. Male-female differences have been revealed that in turn have had positive effects on our understanding of bone biology in general. Drugs that have been developed primarily for the treatment of postmenopausal osteoporosis have been studied and approved for male osteoporosis with a typical delay of several years.

The magnitude of the problem

Although osteoporosis is less prevalent in men, it has been estimated that 30% of all hip fractures occur in males and that one in eight men older than 50 years will experience an osteoporotic fracture.^3,4 Moreover, studies have shown that the mortality rate after fracture in men is higher compared with that in women.^6,7 The reported prevalence is further increasing due to the increasing life expectancy of men, measuring bone mineral density more frequently in men with back pain, and probably due to general changes in nutrition and lifestyle with a negative impact on calciummetabolismand the skeleton.^5,8 In our outpatient department today, already 20% of patients presenting for diagnosis and treatment of osteoporosis are men. Nevertheless, the disease remains largely underdiagnosed and undertreated.^9,10

_ Epidemiology of fractures
The incidence of fractures is bimodal in both sexes with peaks of fracture incidence in adolescence and young adulthood, lower rates in middle age, and dramatic increases thereafter. Figure 1 clearly shows that men have a higher “juvenile peak”, possibly due to a higher risk of traumatic impacts. The sharp increase in later life in men is as dramatic as in women, but occurs about 10 years later in life.¹¹ In younger men, long bone fractures are more common, whereas vertebral and hip fractures predominate in the elderly, where skeletal fragility, frailty, and falls are major factors.¹² The age-adjusted incidence of hip fractures in men is one third to one half that of women. There is less information concerning vertebral fracture rates in men. According to data from the European Prospective Osteoporosis Study (EPOS), the age-adjusted incidence in men seems to be rather high, reaching 50% of that in women.¹³

_ Pathogenesis of male osteoporosis
According to results of longitudinal studies, bone loss accelerates in men after the age of 70 and rapid bone loss is more common with deficient testosterone and estradiol levels.^14,15 In contrast to women developing reduced trabecular connectivity due to a loss of trabeculae, men show trabecular thinning secondary to reduced osteoblastic formation.^16,17 The better preservation of spongy bone microstructure may explain their 50% lower lifetime risk of fractures.¹ The loss of trabecular bone in men starts after reaching peak bone mass in association with changes in the insulinlike growth factor 1 (IGF-1) regulation system. Cortical bone loss, however, starts later in life and is associated with decreasing physical activity and bioavailability of both sex hormones, causing increased bone remodeling. Up to 85% is lost after age 50.¹⁸ As important differences between men and women, it was always stated that men lose less bone than women from the endosteal envelope and that they gain more bone on the periosteal envelope with advancing age. Recent evidence challenges these observations and further research is requested.^19-21 Data from the MINOS study on 796 elderly men showed that low muscle mass in men is associated with narrower bones, thinner cortices, and a consequent decreased bending strength.¹²

Figure 1. Average annual fracture incidence.

The cause of osteoporosis in men is much more heterogeneous than in women; 50% to 60% of men with osteoporosis are diagnosed as secondary cases, ie, the disease is associated with one or more relevant medical conditions, medications, or lifestyle factors that may result in bone loss and reduced bone strength.^2,3,22 The reported pattern of identified risk factors in men varies largely between centers due to differences in the respective patient sources.²³ In our own earlier study on 500 unselectedmen, we found that 52%had primary idiopathic and 48% secondary osteoporosis.^2,8 Among the latter, we identified a subgroup of monoetiological (n=124) and another of polyetiological origin (n=116). In Table I, the frequency of risk factors in these 240 males is shown in terms of mono- and polyetiological subgroups. It becomes obvious that some factors are “strong” pathogenetic risks, which lead to secondary osteoporosis on their own (for example, numbers 1, 4, 5, 11, and 21 in Table I), while other “weak” risk fac- tors only cause osteoporosis when in combination (for example, numbers 2,3,6,7,8, and 10 in Table I). In an important fraction of osteoporotic men, hypercalciuria can be detected as an underlying disorder.24 In our study, we found this risk factor in 34 patients (Table I). Interestingly, idiopathic hypercalciuria is an uncommon risk factor in osteoporotic women.

Diagnosis of osteoporosis in men

There are important sexual differences in skeletal biology that may influence bone density measurement. In particular, bone size is larger in men. For diagnostic purposes, gender differences are addressed by the use of sex-specific T-scores, but this practice remains controversial.¹⁶ Epidemiologic data suggest that for any given absolute bone mineral density (BMD) value at the spine or hip, the risk of fracture is similar among women and men of the same age.^25-27 Since the prevalence of degenerative changes in men at the lumbar spine with increasing age is very high, measurements of bone mineral density at the femoral neck or total hip are preferable to spinal assessments. The average BMD in men who fracture a hip, however, is higher than in women, suggesting that other factors such as bone microarchitecture or trauma may contribute to fractures more in men than in women.¹⁶ Until safety data are available to confidently link fracture risk to BMD measurements in men, the use of male-specific reference ranges has to be adopted.⁵ Today in most guidelines, bone densitometry is recommended inmen aged 70 or older or earlier in men with major risk factors for osteoporotic fractures. That means male patients should be assessed routinely for risk factors for osteoporosis and for clinical symptoms of secondary osteoporosis.

Additional examinations to obtain a definite diagnosis of osteoporosis are not very different from the procedures used in women. When proving a BMD z-score below –2.0 (2 SD below the age-related mean), a clinical examination and further laboratory testing for secondary osteoporosis is indicated.²⁸In our osteoporosis center, we use a 25-question questionnaire as a first source of information. The answers are verified by taking a thorough personal history of the patient, with an evaluation of possible underlying diseases, medications, risk factors of lifestyle, and finally a physical examination. The results are a basis to judge the extent of additional blood and urine examinations and any further diagnostic program.² Since hypogonadism is often difficult to detect on the basis of a patient’s history and physical examination, measurement of total testosterone and sex hormone–binding globulin (SHBG) is recommended in all men with osteoporosis.¹⁶ 25-Hydroxyvitamin D should be measured in patients reporting little exposure to sunshine and/or with low-normal serum calcium, hypocalciuria, or increased parathyroid hormone. There are only limited data relating markers of bone turnover to fracture risk in men.²⁹ Because they show high biological variability, routine use of these markers cannot be recommended. They may, however, be useful in men with no apparent cause of osteoporosis and in men with very low BMD for detecting low levels of bone formation.

Table I. Risk factors in men with secondary osteoporosis.

Prevention of osteopenia and fractures in men

Measures to avoid bone loss and associated fractures in men are similar to those in women. In early life, a combination of good nutrition, regular exercise, and a healthy lifestyle should aim to produce a high peak bone mass. Reducing modifiable individual risk factors of diet and lifestyle, including alcohol, nicotine, and physical inactivity, remain important throughout life.³⁰

For men with one or more diseases or medical conditions associated with a high risk of developing secondary osteoporosis (Table I), early detection and counteracting measures are important. Examples include a reduction of glucocorticoid dosage if possible, substitution of androgen in hypogonadism, thiazides in idiopathic hypercalciuria, or early surgical treatment of primary hyperparathyroidism.^2,30

In the elderly at risk of falls (eg, reduced muscle strength, poor balance, frailty, and history of previous falls), attempts to increase strength and balance or the use of a hip protector may be beneficial. Due to positive effects on muscle mass and function, vitamin D supplementation of at least 800 IU per day reduces the risk of falls.^31,32 There are still conflicting data on the benefits of calciumand vitamin D in osteoporosis, butmore recent meta-analyses favor beneficial effects on falls and fractures.^33,34 Table II summarizes general recommendations for the prevention of bone loss and osteoporotic fractures in men.

Table II. General measures for prevention of bone loss and osteoporotic fractures in men.

_ The therapeutic dilemma of male osteoporosis
Even today, not all drugs available for women with postmenopausal osteoporosis are also approved treatments for osteoporosis in men. This is due to the fact that data from earlier trials on mixed female-male populations have not been accepted and that the requested randomized controlled studies on purely male cohorts are always smaller and often contain insufficient fracture reduction evidence.

Earlier drugs were approved for osteoporosis in general, without separate trials in men being asked for (eg, calcium, fluoride, calcitonin, and alfacalcidol). These are still available for treating osteoporosis in men in some countries. Starting with the bisphosphonates, health authorities only approved new substances for postmenopausal osteoporosis, arguing that the respective phase 3 trials had been performed in this population. Furthermore, it was suggested that significant differences in bone biologymight exist between the sexes, with consequent clinically relevant differences in therapeutic response.

Accordingly, nowadays the approval for using a new drug in men follows after several years’ delay in general or never, if the respective pharmaceutical company considers a new independent study in men as being too expensive given the limited time of their patent protection. This is a severe therapeutic disadvantage for men with osteoporosis. To prescribe innovative drugs to men with established osteoporosis “off label” is often difficult because insurers tend to be reluctant to reimburse the costs in many countries. Interestingly, so far for all drugs studied in men, similar therapeutic results to those seen in women in terms of BMD, bone turnover markers, and fracture-reducing potency have been reported, disproving the argument that relevant basic differences exist in the bone biology of the female and male skeleton.³⁰

Osteoporosis therapy in men

_ Causative therapy in secondary osteoporosis
Since about 50% of men are diagnosed as having secondary osteoporosis, an etiologically tailored treatment is more important in male than in postmenopausal osteoporosis. In hypogonadal men with secondary osteoporosis, androgen replacement therapy is effective.^35-37 We recommend a combination with calcium and vitamin D and found that subcutaneous or transdermal testosterone therapy, especially in advanced osteoporosis, is not sufficient per se to significantly improve BMD.² A combination with another bone turnover– modifying substance is very often mandatory. Contraindications for androgen use (lipid pattern, prostatic cancer risk) have to be taken into consideration.

Other examples of a causative therapy have been mentioned above under prevention. In glucocorticoid-induced osteoporosis, a premature reduction in corticoids may increase the risk of osteoporosis, since an insufficient immunosuppressive effect will favor further loss of bone tissue by proinflammatory cytokines.38 Furthermore, insufficient disease control is associated with less mobility. For the majority of secondary osteoporoses (see Table I), no causative therapies are available, ie, therapeutic strategy is the same as that for idiopathic osteoporosis.

_ Treatment of idiopathic osteoporosis
In men with secondary osteoporosis without options for etiology- related treatment and in all primary or idiopathic cases of osteoporosis, an individually tailored therapeutic strategy has to be planned. A prerequisite for devising this long-term strategy is information about the history and present situation of the respective patient (Table III). Since osteoporosis is a chronic disease requiring long-term therapy, it is important to inform the patient very carefully about the type of osteoporosis, its severity, modifiable risk factors, future fracture risk, the chance of alleviating pain, and the therapeutic mechanisms of available medications and their possible side effects. Only then can good compliance and adherence be expected.

Table III. Data for devising an optimal osteoporosis treatment strategy in men.

Figure 2 gives an overview of the options for an individually tailored treatment regimen in men with idiopathic or primary osteoporosis. With the exception of estrogen and raloxifene, the same specific drugs can be adopted in men as in women. But there are differences in the evidence of fracture reducing potency and in the approval status in different countries. As mentioned before, calcitonin, alfacalcidol, and fluoride are older substances without exclusions inmale osteoporosis and are often listed as second-line treatments. All bisphosphonates, strontium ranelate, and teriparatide are first-line treatments in postmenopausal osteoporosis, but only alendronate, risedronate, zoledronic acid, and teriparatide are also approved in men.³⁰

_ Calcitonin, fluoride, and alfacalcidol
There are only older case reports or small studies for these treatments in male osteoporosis. In a double-blind, placebocontrolled study testing the physiological osteoclast inhibitor calcitonin, 28 men received either 200 IU salmon calcitonin via nasal spray plus 500 mg calcium per day or placebo via nasal spray plus calcium. A significant lumbar spine BMD increase of 7.1% in the calcitonin group vs 2.4% in the controls was found in parallel with a higher decrease in bone resorption markers with calcitonin.³⁹

In a prospective controlled 3-year trial in 60 men with primary osteoporosis, we found a significantly lower vertebral fracture rate with low-dose intermittent fluoride therapy when compared with controls receiving only calcium plus vitamin D.⁴⁰ Further relevant studies with fluoride in men were not undertaken mainly due to the low cost of the substance and the lack of patent protection.

Only recently, it was shown that treatment with the active D-hormone analogue alfacalcidol plus calcium is superior to plain vitamin D plus calcium in male osteoporosis.⁴¹

_ Bisphosphonates
There are only two small uncontrolled studies using the typical intermittent cyclical therapeutic regimen with etidronate in men with osteoporosis that show significant effects on BMD, but no fracture results.^42,43

Alendronate was shown to be effective for the treatment of male osteoporosis and was the first bisphosphonate to be approved for this indication.⁴⁴ The positive evidence was mainly based on two large trials. The first trial was a two-year multicenter randomized placebo-controlled US study on 241 men with primary osteoporosis or secondary osteoporosis due to hypogonadism.⁴⁵ In the second trial, an open prospective controlled study by our group, 134 men with only idiopathic osteoporosis were treated over 3 years.⁴⁶ Both studies proved that the therapeutic results on BMD and fracture incidence with 10 mg alendronate daily are consistent with the effects known for postmenopausal osteoporosis. Although similar effects on BMD and significant decreases in bone turnover markers could be demonstrated with alendronate 70 mg once weekly, this dosage was never approved for male osteoporosis.⁴⁷

Figure 2. Therapeutic osteoporosis strategies in men.

The first evidence that risedronate is also effective in men came from a large subgroup of male patients with glucocorticoid- induced osteoporosis.⁴⁸ We were the first to investigate the therapeutic efficacy of risedronate in a purely male population (n=316) with primary and secondary osteoporosis.⁴⁹ Patients were randomized to risedronate or controls, stratified by the presence of prevalent vertebral fractures at baseline. All patients in the bisphosphonate treatment arm received 5 mg risedronate plus 1000 mg calcium and 800 IU vitamin D daily. Patients in the control group received 1 ìg alfacalcidol plus 500 mg calcium daily if they had prevalent vertebral fractures and 1000 IU plain vitamin D plus 800 mg calcium per day if they did not. After 12 and 24 months, we found significantly higher increases in lumbar spine and total hip BMD with risedronate compared with the combined controls. The relative risk reduction of patients with new vertebral fractures with risedronate was 60%after the first and 61% after the second year of intervention.⁵⁰

Figure 3. Effect of year-long osteoporosis therapy on BMD.

Risedronate 35 mg per week was studied in an international randomized placebo-controlled study. Some 192 patients received once weekly risedronate and 93, placebo. All patients received additional supplementation of 1000 mg calcium and 400-500 IU vitamin D.⁵¹ After 2 years, there was a significant increase in lumbar spine BMD of 5.8% in the risedronate group versus 1.2% in controls. Concerning all new fracture events documented as adverse events, there was a positive trend in favor of risedronate, but no significant difference (7.7% placebo vs 4.9% risedronate). Risedronate 35 mg once weekly was the second bisphosphonate to be approved for the treatment of men at high fracture risk, and its fracture reducing potency was recently underlined by a meta-analysis.⁵² There are no relevant studies on pamidronate and ibandronate in men. Zoledronic acid 5 mg once yearly by infusion, however, was approved recently for male osteoporosis. In a subset of 508 men from the Health Outcomes and Reduced Incidence with Zoledronic Acid ONce yearly (HORIZON) recurrent fracture trial, significant increases in total hip BMD and a reduction in the rate of new clinical fractures could be demonstrated.^53,54 A large purely male study comparing once yearly zoledronic acid versus placebo is currently being performed.

_ Teriparatide and strontium ranelate
There are two trials that have studied the osteoanabolic effect of parathyroid hormone (PTH) in men with osteoporosis. The first one was a small pilot study (n=23) with daily injections of 400 IU teriparatide (rhPTH[1-34]) in 10 patients and placebo injections in 13.⁵⁵ After 18months, average lumbar spine BMD had increased 13.5% in the PTH group and was unchanged in the placebo group (P<0.001). This mean rate of gain in BMD was consistent with the rate seen in the pivotal fracture trial in postmenopausal osteoporosis. A larger international trial of 437 men with osteoporosis (20 ìg or 40 ìg rhPTH daily or subcutaneous placebo) over 11 months plus 18 months’ follow-up found similar effects on BMD and a significantly lower rate of vertebral fractures for the pooled PTH groups.^56,57

With strontium ranelate in postmenopausal osteoporosis, significant effects on all fracture types over the whole age range fromearly postmenopausal to advanced age could be demonstrated. In the open-label, controlled, prospective CASIMO (Comparing Alendronate and Strontium ranelate In Male Osteoporosis) trial, we randomly included 152 men (mean age 59.8 years) with prevalent vertebral fractures and T-score values of lower than –3.0 SD at lumbar spine and lower than –2.5 SD at total hip. Patients of group A (n=76) received 2 g strontium ranelate plus 800 IU vitamin D and 1200 mg calcium per day. The 76 men of group B were treated with alendronate 70 mg once weekly and the same daily amounts of vitamin D and calcium.58 After 12 months, the average lumbar spine–bone mineral density (LS-BMD) increase was 5.8% and 4.5% in the strontium ranelate and alendronate patients, respectively. The corresponding mean changes at total hip amounted to 3.5% and 2.7%.

These increases were significantly higher for the strontium ranelate–treated patients compared with alendronate, at both sites (Figure 3), and were consistent with the respective average 12 month increases from the pivotal fracture studies with strontium ranelate in postmenopausal osteoporosis.⁵⁹ Interestingly, there was a significantly steeper reduction in back pain in strontium ranelate–treated patients.

We concluded from the CASIMO trial that strontium ranelate is at least as potent if not superior in men with established osteoporosis as alendronate, which has received approval for this indication. A multicenter international trial with strontium ranelate in men is due to finish soon.

Conclusion

Although the causes of osteoporosis are more heterogeneous in men than they are in women (about 50% of cases in men are diagnosed as secondary cases), the options for prevention and basic therapy of osteoporosis are the same as those in postmenopausal women. Initially, modifying and counteracting existing negative risk factors, especially those relating to diet, physical exercise, and calcium and vitamin D supplementation, is recommended. The current treatments available for male osteoporosis are alendronate, risedronate, and zoledronate, but strontium ranelate has good potential with some promising results. More news about strontium ranelate will shortly be available after the completion of an ongoing international multicenter study. _

References

1. Jones G, Nguyen TV, Sambrook PN, Kelly PJ, Bisman JA. Progressive femoral neck bone loss in the elderly: Longitudinal findings from the Dubbo Osteoporosis Epidemiology Study. BMJ. 1994;309:691-695.
2. Ringe JD. Osteoporosis in Men. In: Hosking D, Ringe J, eds. Treatment of metabolic bone disease. Management strategy and drug therapy. London, UK: Martin Dunitz; 2000.
3. Amin S, Felson DT. Osteoporosis in men. Osteoporos Int. 2001;27:19-47.
4. Campion JM, Maricic MJ. Osteoporosis in men. Am Fam Physician. 2003;67: 1521-1526.
5. Orwoll E, ed. Osteoporosis in Men. The effects of gender on skeletal health. San Diego, London, Boston: Academic Press; 2006.
6. Center JR, Nguyen TV, Schneider D, Sambrook PN, Eisman JA. Mortality after all major types of osteoporotic fracture in men and women: an observational study. Lancet. 1999;353:878-882.
7. Olszynski WP. Osteoporosis in men: epidemiology, diagnosis, prevention, and treatment. Clin Ther. 2004;26:15-28.
8. Ringe JD, Dorst AJ, Faber H. Osteoporosis in men—Clinical assessment of 400 patients and 205 controls by risk factor analysis, densitometry, and x-ray findings. Osteologie. 1997;6:81-86.
9. Kiebzak GM, Beinart GA, Perser K, Ambrose CG, Siff SJ, Heggeness MH. Undertreatment of osteoporosis in men with hip fracture. Arch Intern Med. 2002;162:2217-2222.
10. Nguyen TV, Center JR, Eisman JA. Osteoporosis: underrated, under-diagnosed and undertreated. Med J Aust. 2004;180(suppl 5):S18-S22.
11. Donaldson LJ, Cook A, Thomson RG. Pathogenesis of bone fragility in women and men in a geographically defined population. J Epi Comm Health. 1990;359: 1841-1850.
12. Szulc P, Beck TJ, Marchand F, Delmas PD. Low skeletal muscle mass is associated with poor structural parameters of bone and impaired balance in elderly men—The MINOS study. J Bone Miner Res. 2005;20:721-729.
13. Group EPOS. Incidence of vertebral fracture in Europe: Results from the European prospective osteoporosis study (EPOS). J Bone Miner Res. 2002;17: 716-724.
14. Szulc P, Delmas PD. Biochemical markers of bone turnover in men. Calcif Tissue Int. 2001;89:229-334.
15. Fink HA, Ewing SK, Ensrud KB, et al. Association of testosterone and estradiol deficiency with osteoporosis and rapid bone loss in older men. J Clin Endocrinol Metab. 2006;91:3908-3915.
16. Ebeling PR. Osteoporosis in men. N Engl J Med. 2008;358:1474-1482.
17. Khosla S. Riggs BL, Atkinson EJ. Effects of sex and age on bone microstructure at the ultradistal radius: a population-based noninvasive in vivo assessment. J Bone Miner Res. 2006;21:124-131.
18. Riggs BL, Melton LJ, Robb RA. A population-based assessment of rates of bone loss at multiple skeletal sites: evidence for substantial trabecular bone loss in young adult women and men. J Bone Miner Res. 2008;23:205-214.
19. Nieves JW, Formica C, Ruffing J, et al. Males have larger skeletal size and bone mass than females, despite comparable body size. J Bone Miner Res. 2005;20: 529-535.
20. Seeman E, Bianchi G, Khosla S, Kanis JA, Orwoll E. Bone fragility in men— where are we? Osteoporos Int. 2006:17:1577-1583.
21. Szulc P, Delmas PD. Bone loss in elderly men: increased endosteal bone loss and stable periosteal apposition: The prospective MINOS study. Osteoporos Int. 2007:18:495-503.
22. Orwoll E, Klein R. Osteoporosis in men. 2nd ed. San Diego, USA: Academic Press; 2001.
23. Nguyen TV, Eisman JA, Kelly PJ, Sambrook PN. Risk factors for osteoporotic fractures in elderly men. Amer J Epidemiol. 1996;144:258-261.
24. Pietschmann F, Breslau NA, Pak CYC. Reduced vertebral bone density in hypercalciuric nephrolithiasis. J Bone Miner Res. 1992;7:1383-1388.
25. The European Prospective Osteoporosis Study (EPOS) Group. The relationship between bone density and incident vertebral fractures in men and women. J Bone Miner Res. 2002;17:2214-2221.
26. De Laet CB, van der Klift M, Hofman A, Pols HA. Osteoporosis in men and women: A story about bone mineral density thresholds and hip fracture risk. J Bone Miner Res. 2002;17:2231-2236.
27. Johnell O, Kanis J, Gullberg G. Mortality, morbidity, and assessment of fracture risk in male osteoporosis. Calcif Tissue Int. 2001;69:182-184.
28. Orwoll ES. The clinical evaluation of osteoporosis in men. In: Orwoll E, ed. Osteoporosis in Men. The effects of gender on skeletal health. San Diego, London, Boston: Academic Press; 2006.
29. Meier C, Nguyen TV, Center JR, Seibel MJ, Eisman JA. Bone resorption and osteoporotic factures in elderly men: The Dubbo Osteoporosis Epidemiological Study. J Bone Miner Res. 2005;20:579-587.
30. Ringe JD. Treatment of osteoporosis in men. J Mens Health Gend. 2007;4: 326-333.
31. Bischoff HA, Stähelin HB, Urscheler N. Muscle strength in the elderly: its relation to vitamin D metabolites. Arch Phys Med Rehabil. 1999;80:54-58.
32. Binkley N, Ringe JD, Reed JI, et al. Alendronate/vitamin D3 70 mg/2800 IU with and without additional 2800 IU vitamin D3 for osteoporosis: Results of a randomized controlled trial. Bone. 2009;44:639-647.
33. Bischoff-Ferrari HA, Willet WC, Wong JB, Giovannucci E, Dietrich T, Dawson- Hughes B. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA. 2005;293:2257-2264.
34. Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A. Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet. 2007; 370:657-666.
35. Finkelstein JS, Klibanski A, Neer RM, et al. Increases in bone density during treatment of men with idiopathic hypogonadotropic hypogonadism. J Clin Endocrinol Metab. 1989;69:776-783.
36. Snyder PJ, Peachey H, Berlin JA, et al. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab. 2000;85:2670-2677.
37. Wang C, Swerdloff RS, Iranmanes A, et al. Effects of transdermal testosterone gel on bone turnover markers and bone mineral density in hypogonadal men. Clin Endocrinol. 2001;54:739-750.
38. Habib GS, Haj S. Bone mineral density in patients with early rheumatoid arthritis treated with corticoids. Clin Rheumatol. 2005;24:129-133.
39. Trovas GP, Lyritis, GP, Galanos A, Raptou P, Constantelou E. A randomized trial of nasal spray salmon calcitonin in men with idiopathic osteoporosis: effects on bone mineral density and bone markers. Bone Miner Res. 2002;17:521-527.
40. Ringe JD, Dorst A, Kipshoven C, Rovati LC, Setnikar I. Avoidance of vertebral fractures in men with idiopathic osteoporosis by a three year therapy with calcium and low-dose intermittent monofluorophosphate. Osteoporosis Int. 1998; 8:47-52.
41. Ringe JD, Farahmand P, Schacht E. Superiority of alfacalcidol over plain vitamin D in men with osteoporosis: A prospective, observational, single center, two year trial on 214 patients. J Bone Miner Res. 2008;23:S349.
42. Andersen FH, Francis RM, Bishop DJ, Rawlings D. Effect of intermittent cyclical disodium etidronate therapy on bone mineral density in men with vertebral fractures. Age Ageing. 1997;156:359-365.
43. Geusens P, Vanhoof J, Raus J, Dequeker J, Nijs J. Joly J. Treatment with etidronate for men with idiopathic osteoporosis. Ann Rheum Dis. 1997;56:280.
44. Ringe JD, Orwoll E, Daifotis A, Lombardi A. Treatment of male osteoporosis: Recent advances with alendronate. Osteoporos Int. 2002;13:195-199.
45. Orwoll E, Ettinger M, Weiss S, et al. Alendronate for the treatment of osteoporosis in men. N Engl J Med. 2000; 343:604-610.
46. Ringe JD, Dorst A, Faber H, Ibach K. Alendonate treatment of established primary osteoporosis in men: 3-year results of a prospective, comparative, twoarm study. Rheumatology Int. 2004;24:110-113.
47. Miller P. Treatment with alendronate 70 mg once weekly for 3 months de creases biochemical markers of bone turnover in men with osteoporosis. J Bone Miner Res. 2002;17(suppl 1):S369.
48. Reid DM, Adami S, Devogalaer JP, Chines AA. Risedronate increases bone density and reduces vertebral fracture risk within one year in men on corticosteroid therapy. Calcif Tissue Int. 2001;69:242-247.
49. Ringe JD, Faber H, Farahmand P, Dorst A. Efficacy of risedronate in men with primary and secondary osteoporosis. Results of a 1-year study. Rheumatol Int. 2006;26:427-431.
50. Ringe JD, Farahmand P, Faber H, Dorst A. Sustained efficacy of risedronate in men with primary and secondary osteoporosis: results of a 2-year study. Rheumatol Int. 2009;29:311-315.
51. Boonen S, Orwoll ES, Wenderoth D, Stoner KJ, Eusebio R, Delmas PD. Onceweekly risedronate in men with osteoporosis: results of a 2-year, placebo-controlled, double-blind, multicenter study. J Bone Miner Res. 2009;24:719-725.
52. Zhong ZM, Chen JT. Anti-fracture efficacy of risedronic acid in men. A metaanalysis of randomized controlled trials. Clin Drug Invest. 2009;29:349-357.
53. Lyles K, Colon-Emeric C, Magaziner J, et al. Zoledronic acid and clinical fractures and mortality after hip fracture. N Engl J Med. 2007;357:1799-1809.
54. Boonen S, Magaziner J, Lyles K, et al. Effect of once yearly iv zoledronic acid in men after hip fracture: Results from the HORIZON recurrent fracture trial. Osteoporos Int. 2009;20(suppl 1):S84.
55. Kurland ES, Cosman F, McMahon DJ, Rosen CJ, Lindsay R, Bilezikian JP. Parathyroid hormone as a therapy for idiopathic osteoporosis in men: effects on mineral density and bone markers. J Clin Endocrinol Metab. 2000;85:3069-3076.
56. Orwoll ES, Scheele WH, Paul S, et al. The effect of teriparatide [human parathyroid hormone (1-34)] therapy on bone density in men osteoporosis. J Bone Miner Res. 2003;18:9-17.
57. Kaufman JM, Orwoll ES, 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.
58. Ringe JD, Dorst A, Faber H, Farahmand P. Treatment of osteoporosis in men with strontium ranelate: Results of a prospective controlled trial in 152 patients. Osteoporos Int. 2008;19(suppl):S13.
59. Meunier PJ, Roux C, Seeman E, Ortolani S. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med. 2004;350:459-468.