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Primary osteoporosis in men: an unmet medical need
Primary osteoporosis in men: an unmet medical need Fabian A. Mendoza, M.D.,a,b Michelle Le Roux, B.S.,c and Intekhab Ahmed, M.D.d a Division of Rheumatology, Department of Medicine; b Jefferson Institute of Molecular Medicine; c Sidney Kimmel Medical College; and d Division of Endocrinology, Department of Medicine, Thomas Jefferson University, Philadelphia, Pennsylvania
Osteoporosis is a skeletal disease characterized by loss of bone strength and increased risk of fractures. Even though fracture prevalence is higher in women, fractures also constitute a significant public health issue in older men. Men are screened less and more frequently undertreated than female patients. It is the goal of this review, to summarize updated information about the current understanding of pathophysiology and clinical aspects of diagnosis and treatment of osteoporosis in men. (Fertil SterilÒ 2019;112:791–8. Ó2019 by American Society for Reproductive Medicine.) Key Words: Osteoporosis, men, fracture, bone mass Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertilityand-sterility/posts/54234-29067
O
steoporosis is a skeletal disease characterized by loss of bone strength and increased risk of fractures. It is calculated that worldwide 200 million people have this disease (1). Considering a prevalence of 10.3% in this population, a recent study calculates that more than 10 million adults over 50-years-old have this condition in the U.S. There is an even higher prevalence of adults with low bone mass, affecting near 44% of the older adult population (2). Older adults with osteoporosis have a high lifelong cumulative prevalence of fragility fractures. Among fragility fractures, hip fractures carry a high morbidity and mortality. Even though fracture prevalence is higher in women, fractures also constitute a significant public health issue in older men with a fracture lifetime prevalence of up to 15% to 30% (3, 4). Furthermore, among patients suffering from fractures, male patients have higher mortality than their female counterparts (5–7). In addition, men are screened less and more frequently undertreated than female patients. It is
the goal of this review, to summarize updated information about the current understanding of pathophysiology and clinical aspects of diagnosis and treatment of osteoporosis in men.
DEFINITIONS AND DIAGNOSIS A fragility fracture is defined as a fracture produced by a low energy impact (8). Older adults are more prone to fragility fractures due to a higher number of falls and reduced bone strength (9). Despite the lack of methods to directly quantify bone strength, dualenergy X-ray absorption (DXA) is a highly cost-effective, safe, and clinically widely used surrogate measurement of bone strength. DXA quantifies the bone mineral density (BMD) in specific bone areas prone to fractures such as the spine and hip (10, 11). It has replaced prior techniques (i.e., dual-photon absorptiometry) due to its higher precision and lower radiation exposure. BMD provides an indirect measurement of total bone mass
Received October 1, 2019; accepted October 1, 2019. F.A.M. has nothing to disclose. M.L. has nothing to disclose. I.A. has nothing to disclose. Correspondence: Intekhab Ahmed, Division of Endocrinology, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107 (E-mail: [email protected]). Fertility and Sterility® Vol. 112, No. 5, November 2019 0015-0282/$36.00 Copyright ©2019 American Society for Reproductive Medicine, Published by Elsevier Inc. https://doi.org/10.1016/j.fertnstert.2019.10.003 VOL. 112 NO. 5 / NOVEMBER 2019
that is strongly associated with bone strength (11). Multiple studies have shown the strong correlations between low BMD and the risk of fracture in both genders (12). Extensive data on the normal range of BMD for age, sex, and many different ethnicities have been developed and decisively used to calculate a more accurate estimate for risk fracture risk in different subpopulations (12). Osteoporosis (regardless of the gender) is defined as a spinal or hip reduction of BMD R 2.5 standard deviations below the young adult female reference mean (T-score % –2.5) (13). This recent endorsement of a female Caucasian referent database for T-score calculation in men was not without controversy. Data showed that at the same absolute BMD (g/cm2), men and women have a very similar fracture risk. Therefore, using the same database to derive the T-score in men and women is reasonable. However, we should keep in mind that with this new definition, men suffering from fragility fractures have higher T-score values than if a male control database were used. Furthermore, many men developing fragility fractures have T-scores considered ‘‘normal’’ as per current calculations (14). This raises the concerns for underdiagnosing the fragility fracture risk of 791
VIEWS AND REVIEWS men when only using the T-score. Consequently, it is crucial to not rely solely on DXA-BMD T-score to identify men with osteoporosis but also to consider additional clinical risk factors. The FRAX score, a fracture risk assessment tool integrating clinical risk factors and BMD, has proven valuable to recognize patients at risk for fragility fractures (15, 16). This clinical tool highlights the importance of diagnosing osteoporosis by combining the BMD with the presence or absence of other risk factors. Recently a new diagnostic strategy developed by the National Bone Health Alliance has included the above mentioned and added the presence of fractures and FRAX score in addition to BMD. The new criteria take into consideration the classic T-score cut point by DXA but also a FRAX score showing a risk of more than 20% for any fracture or 3% for hip fracture in the upcoming 10 years (17) (Table 1). Using this criterion applied to the NHANES data, 16% of U.S. men 50-years-old or older are osteoporotic (18). We endorse this approach of considering multiple variables to diagnose osteoporosis in men, but even risk fracture scores like FRAX are less validated in men than in women. The Endocrine Society guidelines recommend performing a DXA scan at the hip and spine for all men above 70-years-old or for men between 50- to 69-years-old with a history of fracture or having other risk factors (19). We should also keep in mind that the risk of fracture is not only defined by the BMD or risk factors for decreased bone strength but also by the risk of falls since fractures occur when external forces surpass the bone’s biomechanical competence. Risk of falls is associated with other aging-related factors such as decreased muscle strength.
OSTEOPOROSIS-RELATED FRACTURES IN MEN Osteoporotic fractures in men account for 39% of all the osteoporosis-related fractures (20, 21). For example, the incidence of the spine, wrist, and humerus fractures in the Mayo Clinic catchment area in residents over age 50 is approximately 26,000/100,000-person-years in women and around 16,000/100,000-person-years in men (21). However, more importantly, while the incidence of fracture is declining in female patients, no significant decline was observed from 1989 to 1991 and 2009 to 2011 among men in the Rochester cohort (21). This sustained high prevalence is likely associated with underscreening and undertreatment in men. This was evidenced by a review of the Medicare database showing that only 9% of men received osteoporosis treatment within one year of sustaining a hip fracture (22). Therefore, efforts in early recognition and treatment have largely fallen short of addressing this dramatically unmet medical need.
PHYSIOLOGICAL BASIS OF OSTEOPOROSIS IN MEN Bone is continuously under a dynamic metabolic equilibrium by the parallel action of bone-resorbing osteoclasts and bone producing osteoblasts. This dynamic process reflects the physiological basis for avoiding fatigue-related micro-damage and allowing adaptation of the bone mass and structure to changes in our body weight and muscle mass. The balance between the amount of bone resorption and bone formation is determined by autocrine and paracrine effects of circulating 792
TABLE 1 Recommendations of the National Bone Health Alliance Working Group for the diagnosis of osteoporosis in postmenopausal women and men over the age of 50 years (17). BMD testing Fracture
FRAX score
T-score of £ L2.5 at the spine or hip Low trauma hip fracture regardless of T-score Low trauma fracture in vertebral, proximal humerus, or pelvis bones in patients with a T-score of -1.0 to <-2.5a Elevated risk of fracturesb
Note: Modified from Siris ES, Adler R, Bilezikian J, Bolognese M, Dawson-Hughes B, Favus MJ et al. The clinical diagnosis of osteoporosis: a position statement from the National Bone Health Alliance Working Group. Osteoporos Int. 2014;25:1439–43. BMD ¼ bone mineral density; FRAX ¼ fracture risk assessment tool. a In some cases, distal forearm fractures. b Cut point for treatment has been considered as a 10-year risk of major osteoporotic fracture of at least 20% or a 3% risk of hip fracture. Mendoza. Primary osteoporosis in men. Fertil Steril 2019.
hormones and cytokines, but also by muscle and bone signaling molecules triggered by mechanical stimuli (23, 24).
Muscle and Mechanical Loading As a part of the musculoskeletal system, bones, tendons, and muscles have a coordinated function in growth and locomotion and share a close metabolic interdependence. Bone resists a combination of multiple vectorial forces and gravity. This mechanical load triggers osteocytes and osteoblast proliferation and at the same time, releases cytokines produced by the muscle (myokines), and muscle-derived growth factors. Osteocytes can respond to mechanical forces by sensing them by mechanoreceptors (primary cilia) in their lacunocanalicular network that are able to react to strain-related flow changes of interstitial fluid (25, 26). Stimulation of these receptors triggers sclerostin dependent and independent osteogenic responses. Conversely, the lack of mechanical load stimulates receptor activator of nuclear factor kappa-B ligand (RANKL) production by osteocytes (27, 28). Loss of muscle mass and muscle strength (sarcopenia) is seen in aging men. The association of sarcopenia with falls, fragility fractures, and inability to perform usual activities has been termed ‘‘dysmobility syndrome’’ (29). Muscle health is measured by appendicular lean mass, grip strength, and other functional measures such as gait speed (30–33). There is a high prevalence of sarcopenia in elderly patients with fragility fractures and a correlation between muscle mass and function, and fractures have been postulated (34). However, it seems than the muscle mass and BMD are tightly correlated, and when corrected for BMD, the fracture association disappears. On the other hand, low muscle strength and poor physical performance are an independent risk for fracture and non-related to scores and BMD values.
Hormonal Factors In addition to advanced aged and sarcopenia, estrogen deficiency is the most important factor conditioning the development of osteoporosis in men (35). Estrogen deficiency and VOL. 112 NO. 5 / NOVEMBER 2019
Fertility and Sterility® aging co-occur, and it is difficult to assign exact cause/effect relationships in humans. Studies in animals demonstrated that aging and hormonal deficiency are two different phenomena affecting bones with independent effects (36). In men, estradiol (E2) is produced by testicles (15%) and by peripheral aromatization (85%), from testosterone (37). As opposed to women, the E2 production in men does not experience an abrupt decline and overall E2 concentrations over their lifetime are enough to maintain bone homeostasis (35, 38). Bioavailability is controlled by the high-affinity binding sex hormone-binding globulin since less than 5% is unbounded to sex hormone-binding globulin and biologically active (35).
Hormones and Inflammatory Cytokines Estrogens and androgens link the bone estrogen receptor a or b (also termed NR3A1 and NR3A2) and the androgen receptor (AR), also known as NR3C4, respectively (35, 39). The receptors mentioned above form homodimers binding DNA sequences called ‘‘hormone response elements’’ (EREs or AREs) (40). The direct target genes of ERES/ARES are poorly characterized in bone tissue (41), but it has been postulated that multiple cytokines including TGF-b, IL-1, IL-6, IL-17, OPG, RANKL, and CXCL12, among others are direct targets of bone-forming effects of sex-hormones. From those cytokines and growth factors, the RANKL is crucial for the generation, survival, and function of osteoclasts, and thereby for bone resorption driven by the deficiency of sex steroid hormones (35, 41–44). It is important to stress that the hormonal influence in osteoporosis differs in men and women. The decline in estrogen levels associated with menopause causes bone loss in both the trabecular and the cortical bone. Post-menopausal bone loss is associated with a high bone turnover rate with metabolically very active osteoclasts driving this turnover. Conversely, in men low androgen levels cause bone loss by two mechanisms: reduced levels of estrogens from testosterone aromatization (45); and lower metabolism of osteoblasts and osteocytes affecting mainly the trabecular bone (35). These hormonal differences are likely associated with the structural differences between male and female bones. It is essential to mention that the main factor in explaining higher bone strength in men is their wider bone constitution. Other previously proposed factors such as the greater bone mass or presence of more cortical bone have been disproven as explanations (46). In addition, hormones have a significant effect on the muscle. Androgens induce a greater gain in muscle mass than muscle strength by direct effects in muscle fibroblasts (47). Also, it has been proposed that stimulation of brain dopamine pathways contributes to an increase in exercise activity as suggested by animal models (48). Interestingly, testosterone in muscle does not require conversion into dihydrotestosterone by 5-alpha reduction to exert its effects. Thus, a combination of testosterone with 5-alpha reductase inhibitors are a safe alternative for older patients with testosterone deficiency but on treatment for prostate hypertrophy (49). However, testosterone therapy for VOL. 112 NO. 5 / NOVEMBER 2019
osteo-sarcopenia is not a good therapeutic option due to the associated high cardiovascular risk in both genders and virilization in women. Tor this reason there is a therapeutic opportunity for the development of new molecules with specific action on androgen receptors (selective androgen receptor modulators) (34).
SECONDARY OSTEOPOROSIS IN MEN Secondary osteoporosis seems to be more frequent in males than female patients (50, 51) but this very high prevalence, reaching up to 50% of the cohorts, can be associated with an underdiagnoses of primary osteoporosis (52). Alcohol abuse, use of corticosteroids, hypogonadism, endogenous hypercortisolemia and diabetes mellitus are the most common primary co-morbidities (52, 53). It is beyond the scope of this review to provide a detailed discussion of secondary osteoporosis, but this should be ruled out in men diagnosed with osteoporosis.
DRUGS FOR OSTEOPOROSIS IN MEN Osteoporotic treatment studies in women support multiple classes of medications as effective and safe for reducing the risk of vertebral and non-vertebral fractures. Evidence supporting the efficacy and safety of osteoporotic drugs for men is comparatively limited, with most studies to date relying on BMD end-points and bone turnover markers as surrogates for risk of fracture. Drug approval and recommendations for use in men are based on smaller trials that show similar effects on surrogates for fracture risk as those seen in studies of women that demonstrated reductions in fractures (Table 2) (19, 54–67) Medications currently approved for use in men include oral bisphosphonates alendronate and risedronate, intravenous bisphosphonate zoledronic acid, RANKL monoclonal antibody denosumab, and synthetic parathyroid hormone (PTH) analogue teriparatide.
Bisphosphonates Nitrogen-containing bisphosphonates (alendronate, risedronate, ibandronate, and zoledronate) exert antiresorptive effects via inhibition of farnesyl pyrophosphate synthase in osteoclasts, a key enzyme in the pathway that produces isoprenoid lipids utilized for post-translational modification of small guanosine triphosphate-binding proteins essential for osteoclasts, resulting in cellular toxicity (68). Bisphosphonates are recommended as the first line for treatment of osteoporosis in postmenopausal women and men by multiple organizations, including American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) and the Endocrine Society (19, 69). Large, placebo-controlled randomized controlled trials (RCTs) of alendronate, risedronate, and zoledronic acid in postmenopausal women have shown reductions in fractures at the vertebral and non-vertebral sites including hip (54, 55, 58, 61, 70), and extension trials have shown sustained efficacy and residual benefits after discontinuation (71–73). Trials of alendronate, risedronate, and zoledronic acid in osteoporotic men have shown increasing BMD with use. 793
VIEWS AND REVIEWS
TABLE 2 FDA-approved drugs for treatment of osteoporosis in men: data from pivotal trials for women and men.
Drug Alendronate Women Men Risedronate Women
Study
Primary endpoint(s)
Non-vertebral fractures (ARR, RRR), %
Black, 1996 (54) Cummings, 1998 (55) Orwoll, 2000 (56) Miller, 2004 (57)
2,027 4,432 241 167
New vertebral fractures Clinical fractures Lumbar spine BMD BMD
7, 47 1.7, 44.7 5.0, 61.70 NA
2.8, 19.0 1.5, 11.2 NA NA
Reginster, 2000 (58) Harris, 1999 (59) Boonen, 2009 (60)
1,226 2,458 284
New vertebral fractures New vertebral fractures Lumbar spine BMD
10.9, 37.6 5.0, 30.6 NA
5.1, 31.9 3.2, 38.1 NA
7,765
7.6, 69.7
2.7, 25.2
NA NA
3.1, 28.9 NA
Men Zoledronic acid Women Black, 2007 (61)
Men Denosumab Women Men Teriparatide Women Men
Patients enrolled, n
Vertebral fractures (ARR, RRR), %
Lyles, 2007 (62) Orwoll, 2010 (63)
1,065 (men/women) 302
New vertebral fracture (population with no concomitant medications); hip fracture (all population) New clinical fractures Lumbar spine BMD
Cummings, 2009 (64) Orwoll, 2012 (65)
7,868 242
New vertebral fracture Lumbar spine BMD
4.9, 68.1 NA
1.5, 18.8 NA
Neer, 2001 (66) Orwoll, 2003 (67)
1,637 437
New vertebral fracture Lumbar spine BMD
10, 71 NA
3, 50 NA
Note: ARR ¼ absolute risk reduction; BMD ¼ bone mineral density; NA ¼ not applicable; RRR ¼ relative risk reduction. Mendoza. Primary osteoporosis in men. Fertil Steril 2019.
However, with the sole exception of zoledronic acid, quality data of fracture risk is lacking. Only one RCT to date reported fracture incidence as a primary endpoint in men with osteoporosis (74), highlighting the need for more rigorous studies. To date, there are currently no data to suggest that side effect profiles are different in men compared to women, including rare occurrences such as osteonecrosis of the jaw and atypical femur fracture. Adverse events did not differ significantly between placebo and treatment in most trials in men described here (56, 60, 63); however, data are limited. Oral bisphosphonates: alendronate and risedronate. Alendronate was Food and Drug Administration (FDA) approved for men with osteoporosis following two double-blind RCTs with BMD as primary endpoints. The first, a trial of 241 eugonadal and hypogonadal men, showed greater spinal, femoral neck and total body BMD with alendronate use compared to placebo at two years, as well as a lower incidence of radiographic vertebral fractures (0.8% vs. 7.1% in the placebo group, P ¼ .02) (56). In another pivotal trial of 167 men, compared to placebo men treated with alendronate had higher BMD and lower bone turnover markers at 12 months but the study was underpowered to assess fracture risk (57). Similarly, FDA approval of risedronate followed an RCT trial of 284 men, which showed increased spinal and proximal femur BMD with use compared to placebo at 24 months (60); however, fracture efficacy was not demonstrated. An openlabel trial of risedronate has shown reduced vertebral fracture incidence with use at 1 year (5.1% vs. 12.7, P ¼ .028) and both vertebral (9.2% vs. 23.6%, P ¼ .0026) and non-vertebral (11.8 vs. 22.3%; P ¼ .032 fracture incidence at 2 years, but data are not as robust due to absence of blinding (75, 76). 794
Subsequent meta-analysis showed a reduced risk of vertebral fractures with use of alendronate (2 studies, risk ratio 0.328, 95% confidence internal 0.155-0.692) and risedronate (2 studies, risk ratio 0.428, 95% confidence internal 0.245-0.746), but not vertebral fractures (77). However, authors combined RCTs and open-label studies for the analysis, diminishing significantly the quality of data. In the same study, authors found a reduced risk of vertebral and nonvertebral fractures with use of bisphosphonates (alendronate, risedronate, ibandronate, and zoledronic acid) as a category. However, not all bisphosphonates have demonstrated uniform efficacy, particularly ibandronate (78), also diminishing the quality of reported data. Intravenous bisphosphonates: zoledronic acid. Intravenous zoledronic acid is the best-studied drug for the efficacy of fracture risk reduction in men with osteoporosis. In a study of 508 men and 1619 women with hip fracture repair, zoledronic acid reduced both new clinical fractures (8.6% vs. 13.9%, P ¼ .001) and clinical vertebral fractures (1.7% vs. 3.8%, P ¼ .02) as primary endpoints, as well as mortality compared to placebo (60). Subset analysis of men in the trial showed increased BMD compared to placebo; however, fracture incidence was low among men and no statistically significant effect was seen (60, 79). FDA approval for zoledronic acid for men followed a comparative study that showed zoledronic acid to have similar efficacy to alendronate using BMD endpoint in men (63). More recently, in the only trial in men to date reporting fracture incidence as a primary endpoint, among 1,199 eugonadal and hypogonadal men with osteoporosis, those treated with zoledronic acid had lower vertebral fracture incidence VOL. 112 NO. 5 / NOVEMBER 2019
Fertility and Sterility® compared to placebo (1.6% vs. 4.9%, P ¼ .002) as well significantly higher BMD (74). Ibandronate. The bisphosphonate ibandronate (oral or intravenous) is approved for use in osteoporotic women but is currently not recommended as the first-line due to questionable efficacy for non-vertebral fractures (78). Ibandronate is currently not approved for use in men, though in a trial of 132 men ibandronate was shown to increase BMD (80).
RANKL inhibitors: Denosumab Denosumab is a human monoclonal antibody that inhibits the binding of RANKL to the RANK receptor expressed on the cell surface of osteoclast precursors, an essential step for differentiation (81). The U.S. FDA approved denosumab for treatment in postmenopausal women with osteoporosis based on a 36month trial that demonstrated reduced vertebral, nonvertebral, and hip fractures with use in 7,868 women. It is only approved for use in women and men at high risk of fracture and is currently recommended by AACE/ACE as first-line for this group due to greater BMD gains showed in trials comparing denosumab to bisphosphonates in women (82– 83). Unfortunately, trials of women have shown the rapid decline of BMD following discontinuation of therapy, and risk of fracture increases to that of untreated (84). Therefore, antiresorptive therapy is recommended after stopping therapy from preventing new fractures. The risk of posttreatment rebound has not been evaluated in men. In a pivotal RCT of 242 males with low bone mass without secondary causes, denosumab increased BMD at all sites measured at 12 months compared to placebo (65), from which FDA approval followed. Continued efficacy at 24 months was shown in an open-label phase of the trial. However, the study was underpowered to assess fracture risk (1 vertebral fracture, 3 clinical fractures reported in total) (85). Fracture risk efficacy using denosumab has been shown, however, in a double-blind multicenter study of 1,468 men receiving androgen deprivation therapy for prostate cancer (FDA approved use) over 3 years which showed lower incidence of vertebral fractures (3.9% vs. 1.5% cumulative incidence), but not non-vertebral or hip fractures (86). No studies in men to date have investigated BMD changes following discontinuation of therapy. Rare but severe adverse events associated with denosumab use include hypocalcemia, and osteonecrosis of the jaw and atypical femur fracture. No reports of hypocalcemia, osteonecrosis of the jaw, fracture, or atypical femoral fracture were observed in men in the studies cited here, and the overall incidence of serious adverse effects did not differ significantly between placebo and control (65, 85).
Anabolic Agents Teriparatide. Teriparatide, a synthetic analogue of PTH, is approved for the treatment of osteoporosis in postmenopausal women and men with high fracture risk. It acts via PPTH/ PTHrP receptors expressed on the surface of osteoblasts, osteocytes, and renal tubule cells. Intermittent stimulation preferentially enhances bone formation whereas prolonged receptor stimulation enhances its effects on bone resorption, thus VOL. 112 NO. 5 / NOVEMBER 2019
intermittent stimulation seems to be required for its desired effect (87). Approval in women was granted by the US FDA following a trial of 1637 postmenopausal women with osteoporosis in which teriparatide administration reduced vertebral and non-vertebral fracture risk as primary outcome measures over a median of 21 months (66). Approval in men followed a one-year RCT of 437 men with primary and hypogonadal osteoporosis, which showed teriparatide increases spinal and proximal femur BMD (67). Similar to women (88), a trial showed that antiresorptive therapy is needed to maintain benefit following bone anabolic therapy with teriparatide (89). No RCT trials have demonstrated a significant reduction in fracture incidence, though one observational study demonstrated that teriparatide reduced the risk of vertebral fracture compared to placebo after teriparatide treatment was discontinued (90). Adverse events associated with teriparatide include arthralgia, pain, and nausea, and potential increased risk of osteosarcoma. In the pivotal trial of men, transient hypercalcemia occurred with increased frequency in the drug group, but other adverse effects did not differ between placebo- and risedronate- treated men, and there were no reports of osteosarcoma (14). Abaloparatide. Abaloparatide is a synthetic analogue of PTH-related peptide (PTHrP), which similarly to PTHanalogue acts to increase bone formation (87). It is currently approved for the treatment of osteoporosis in postmenopausal women only following a study that showed a lower risk of vertebral and non-vertebral fractures compared with placebo as well as non-inferiority when compared with teriparatide. The study showed a lower incidence of major osteoporotic fractures (defined as fractures of the upper arm, wrist, hip, or clinical spine) with abaloparatide use compared with teriparatide (91). There are few trials to date that support its use in men.
Testosterone Data on the effects of testosterone therapy in men with osteoporosis are limited. Treatment with testosteronereplacement therapy has been shown to increase BMD in men with hypogonadism and normal BMD (92) but not in eugonadal men (93). Testosterone therapy for men with normal testosterone levels is not advised due to potential adverse effects and lack of demonstrated benefit. However, the Endocrine Society recommends the combined use of anti-fracture treatment with testosterone therapy for men at high risk of fracture and low testosterone (<200 ng/dl) (19). Bisphosphonates have been shown to improve BMD largely independent of testosterone levels (56, 60, 74), supporting a role in the treatment of men with hypogonadism. Moreover, bisphosphonates alendronate and zolendronic acid, and denosumab have been shown to increase lumbar spine BMD in men on androgen deprivation therapy (85, 94, 95).
Romosozumab Romosozumab is a monoclonal antibody that binds to and inhibits sclerostin, an endogenous inhibitor of Wnt signaling 795
VIEWS AND REVIEWS that is crucial to both bone development and the regulation of bone mass (96). It was recently approved for use in women following a trial of 1,226 postmenopausal women over three years that demonstrated reduced fracture risk with use compared to placebo (97). A RCT of 245 men with osteoporosis designed as a bridging study for approval demonstrated significant improvement of the lumbar spine and total hip BMD at 1 year for those treated with Romosozumab (98). Romosozumab is currently not approved for use in men.
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Osteoporosis is a skeletal disease characterized by loss of bone strength and increased risk of fractures. Even though fracture prevalence is higher in women, fractures also constitute a significant public health issue in older men. Men are screened less and more frequently undertreated than female patients. It is the goal of this review, to summarize updated information about the current understanding of pathophysiology and clinical aspects of diagnosis and treatment of osteoporosis in men. (Fertil SterilÒ 2019;112:791–8. Ó2019 by American Society for Reproductive Medicine.) Key Words: Osteoporosis, men, fracture, bone mass Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertilityand-sterility/posts/54234-29067
O
steoporosis is a skeletal disease characterized by loss of bone strength and increased risk of fractures. It is calculated that worldwide 200 million people have this disease (1). Considering a prevalence of 10.3% in this population, a recent study calculates that more than 10 million adults over 50-years-old have this condition in the U.S. There is an even higher prevalence of adults with low bone mass, affecting near 44% of the older adult population (2). Older adults with osteoporosis have a high lifelong cumulative prevalence of fragility fractures. Among fragility fractures, hip fractures carry a high morbidity and mortality. Even though fracture prevalence is higher in women, fractures also constitute a significant public health issue in older men with a fracture lifetime prevalence of up to 15% to 30% (3, 4). Furthermore, among patients suffering from fractures, male patients have higher mortality than their female counterparts (5–7). In addition, men are screened less and more frequently undertreated than female patients. It is
the goal of this review, to summarize updated information about the current understanding of pathophysiology and clinical aspects of diagnosis and treatment of osteoporosis in men.
DEFINITIONS AND DIAGNOSIS A fragility fracture is defined as a fracture produced by a low energy impact (8). Older adults are more prone to fragility fractures due to a higher number of falls and reduced bone strength (9). Despite the lack of methods to directly quantify bone strength, dualenergy X-ray absorption (DXA) is a highly cost-effective, safe, and clinically widely used surrogate measurement of bone strength. DXA quantifies the bone mineral density (BMD) in specific bone areas prone to fractures such as the spine and hip (10, 11). It has replaced prior techniques (i.e., dual-photon absorptiometry) due to its higher precision and lower radiation exposure. BMD provides an indirect measurement of total bone mass
Received October 1, 2019; accepted October 1, 2019. F.A.M. has nothing to disclose. M.L. has nothing to disclose. I.A. has nothing to disclose. Correspondence: Intekhab Ahmed, Division of Endocrinology, Department of Medicine, Thomas Jefferson University, Philadelphia, PA 19107 (E-mail: [email protected]). Fertility and Sterility® Vol. 112, No. 5, November 2019 0015-0282/$36.00 Copyright ©2019 American Society for Reproductive Medicine, Published by Elsevier Inc. https://doi.org/10.1016/j.fertnstert.2019.10.003 VOL. 112 NO. 5 / NOVEMBER 2019
that is strongly associated with bone strength (11). Multiple studies have shown the strong correlations between low BMD and the risk of fracture in both genders (12). Extensive data on the normal range of BMD for age, sex, and many different ethnicities have been developed and decisively used to calculate a more accurate estimate for risk fracture risk in different subpopulations (12). Osteoporosis (regardless of the gender) is defined as a spinal or hip reduction of BMD R 2.5 standard deviations below the young adult female reference mean (T-score % –2.5) (13). This recent endorsement of a female Caucasian referent database for T-score calculation in men was not without controversy. Data showed that at the same absolute BMD (g/cm2), men and women have a very similar fracture risk. Therefore, using the same database to derive the T-score in men and women is reasonable. However, we should keep in mind that with this new definition, men suffering from fragility fractures have higher T-score values than if a male control database were used. Furthermore, many men developing fragility fractures have T-scores considered ‘‘normal’’ as per current calculations (14). This raises the concerns for underdiagnosing the fragility fracture risk of 791
VIEWS AND REVIEWS men when only using the T-score. Consequently, it is crucial to not rely solely on DXA-BMD T-score to identify men with osteoporosis but also to consider additional clinical risk factors. The FRAX score, a fracture risk assessment tool integrating clinical risk factors and BMD, has proven valuable to recognize patients at risk for fragility fractures (15, 16). This clinical tool highlights the importance of diagnosing osteoporosis by combining the BMD with the presence or absence of other risk factors. Recently a new diagnostic strategy developed by the National Bone Health Alliance has included the above mentioned and added the presence of fractures and FRAX score in addition to BMD. The new criteria take into consideration the classic T-score cut point by DXA but also a FRAX score showing a risk of more than 20% for any fracture or 3% for hip fracture in the upcoming 10 years (17) (Table 1). Using this criterion applied to the NHANES data, 16% of U.S. men 50-years-old or older are osteoporotic (18). We endorse this approach of considering multiple variables to diagnose osteoporosis in men, but even risk fracture scores like FRAX are less validated in men than in women. The Endocrine Society guidelines recommend performing a DXA scan at the hip and spine for all men above 70-years-old or for men between 50- to 69-years-old with a history of fracture or having other risk factors (19). We should also keep in mind that the risk of fracture is not only defined by the BMD or risk factors for decreased bone strength but also by the risk of falls since fractures occur when external forces surpass the bone’s biomechanical competence. Risk of falls is associated with other aging-related factors such as decreased muscle strength.
OSTEOPOROSIS-RELATED FRACTURES IN MEN Osteoporotic fractures in men account for 39% of all the osteoporosis-related fractures (20, 21). For example, the incidence of the spine, wrist, and humerus fractures in the Mayo Clinic catchment area in residents over age 50 is approximately 26,000/100,000-person-years in women and around 16,000/100,000-person-years in men (21). However, more importantly, while the incidence of fracture is declining in female patients, no significant decline was observed from 1989 to 1991 and 2009 to 2011 among men in the Rochester cohort (21). This sustained high prevalence is likely associated with underscreening and undertreatment in men. This was evidenced by a review of the Medicare database showing that only 9% of men received osteoporosis treatment within one year of sustaining a hip fracture (22). Therefore, efforts in early recognition and treatment have largely fallen short of addressing this dramatically unmet medical need.
PHYSIOLOGICAL BASIS OF OSTEOPOROSIS IN MEN Bone is continuously under a dynamic metabolic equilibrium by the parallel action of bone-resorbing osteoclasts and bone producing osteoblasts. This dynamic process reflects the physiological basis for avoiding fatigue-related micro-damage and allowing adaptation of the bone mass and structure to changes in our body weight and muscle mass. The balance between the amount of bone resorption and bone formation is determined by autocrine and paracrine effects of circulating 792
TABLE 1 Recommendations of the National Bone Health Alliance Working Group for the diagnosis of osteoporosis in postmenopausal women and men over the age of 50 years (17). BMD testing Fracture
FRAX score
T-score of £ L2.5 at the spine or hip Low trauma hip fracture regardless of T-score Low trauma fracture in vertebral, proximal humerus, or pelvis bones in patients with a T-score of -1.0 to <-2.5a Elevated risk of fracturesb
Note: Modified from Siris ES, Adler R, Bilezikian J, Bolognese M, Dawson-Hughes B, Favus MJ et al. The clinical diagnosis of osteoporosis: a position statement from the National Bone Health Alliance Working Group. Osteoporos Int. 2014;25:1439–43. BMD ¼ bone mineral density; FRAX ¼ fracture risk assessment tool. a In some cases, distal forearm fractures. b Cut point for treatment has been considered as a 10-year risk of major osteoporotic fracture of at least 20% or a 3% risk of hip fracture. Mendoza. Primary osteoporosis in men. Fertil Steril 2019.
hormones and cytokines, but also by muscle and bone signaling molecules triggered by mechanical stimuli (23, 24).
Muscle and Mechanical Loading As a part of the musculoskeletal system, bones, tendons, and muscles have a coordinated function in growth and locomotion and share a close metabolic interdependence. Bone resists a combination of multiple vectorial forces and gravity. This mechanical load triggers osteocytes and osteoblast proliferation and at the same time, releases cytokines produced by the muscle (myokines), and muscle-derived growth factors. Osteocytes can respond to mechanical forces by sensing them by mechanoreceptors (primary cilia) in their lacunocanalicular network that are able to react to strain-related flow changes of interstitial fluid (25, 26). Stimulation of these receptors triggers sclerostin dependent and independent osteogenic responses. Conversely, the lack of mechanical load stimulates receptor activator of nuclear factor kappa-B ligand (RANKL) production by osteocytes (27, 28). Loss of muscle mass and muscle strength (sarcopenia) is seen in aging men. The association of sarcopenia with falls, fragility fractures, and inability to perform usual activities has been termed ‘‘dysmobility syndrome’’ (29). Muscle health is measured by appendicular lean mass, grip strength, and other functional measures such as gait speed (30–33). There is a high prevalence of sarcopenia in elderly patients with fragility fractures and a correlation between muscle mass and function, and fractures have been postulated (34). However, it seems than the muscle mass and BMD are tightly correlated, and when corrected for BMD, the fracture association disappears. On the other hand, low muscle strength and poor physical performance are an independent risk for fracture and non-related to scores and BMD values.
Hormonal Factors In addition to advanced aged and sarcopenia, estrogen deficiency is the most important factor conditioning the development of osteoporosis in men (35). Estrogen deficiency and VOL. 112 NO. 5 / NOVEMBER 2019
Fertility and Sterility® aging co-occur, and it is difficult to assign exact cause/effect relationships in humans. Studies in animals demonstrated that aging and hormonal deficiency are two different phenomena affecting bones with independent effects (36). In men, estradiol (E2) is produced by testicles (15%) and by peripheral aromatization (85%), from testosterone (37). As opposed to women, the E2 production in men does not experience an abrupt decline and overall E2 concentrations over their lifetime are enough to maintain bone homeostasis (35, 38). Bioavailability is controlled by the high-affinity binding sex hormone-binding globulin since less than 5% is unbounded to sex hormone-binding globulin and biologically active (35).
Hormones and Inflammatory Cytokines Estrogens and androgens link the bone estrogen receptor a or b (also termed NR3A1 and NR3A2) and the androgen receptor (AR), also known as NR3C4, respectively (35, 39). The receptors mentioned above form homodimers binding DNA sequences called ‘‘hormone response elements’’ (EREs or AREs) (40). The direct target genes of ERES/ARES are poorly characterized in bone tissue (41), but it has been postulated that multiple cytokines including TGF-b, IL-1, IL-6, IL-17, OPG, RANKL, and CXCL12, among others are direct targets of bone-forming effects of sex-hormones. From those cytokines and growth factors, the RANKL is crucial for the generation, survival, and function of osteoclasts, and thereby for bone resorption driven by the deficiency of sex steroid hormones (35, 41–44). It is important to stress that the hormonal influence in osteoporosis differs in men and women. The decline in estrogen levels associated with menopause causes bone loss in both the trabecular and the cortical bone. Post-menopausal bone loss is associated with a high bone turnover rate with metabolically very active osteoclasts driving this turnover. Conversely, in men low androgen levels cause bone loss by two mechanisms: reduced levels of estrogens from testosterone aromatization (45); and lower metabolism of osteoblasts and osteocytes affecting mainly the trabecular bone (35). These hormonal differences are likely associated with the structural differences between male and female bones. It is essential to mention that the main factor in explaining higher bone strength in men is their wider bone constitution. Other previously proposed factors such as the greater bone mass or presence of more cortical bone have been disproven as explanations (46). In addition, hormones have a significant effect on the muscle. Androgens induce a greater gain in muscle mass than muscle strength by direct effects in muscle fibroblasts (47). Also, it has been proposed that stimulation of brain dopamine pathways contributes to an increase in exercise activity as suggested by animal models (48). Interestingly, testosterone in muscle does not require conversion into dihydrotestosterone by 5-alpha reduction to exert its effects. Thus, a combination of testosterone with 5-alpha reductase inhibitors are a safe alternative for older patients with testosterone deficiency but on treatment for prostate hypertrophy (49). However, testosterone therapy for VOL. 112 NO. 5 / NOVEMBER 2019
osteo-sarcopenia is not a good therapeutic option due to the associated high cardiovascular risk in both genders and virilization in women. Tor this reason there is a therapeutic opportunity for the development of new molecules with specific action on androgen receptors (selective androgen receptor modulators) (34).
SECONDARY OSTEOPOROSIS IN MEN Secondary osteoporosis seems to be more frequent in males than female patients (50, 51) but this very high prevalence, reaching up to 50% of the cohorts, can be associated with an underdiagnoses of primary osteoporosis (52). Alcohol abuse, use of corticosteroids, hypogonadism, endogenous hypercortisolemia and diabetes mellitus are the most common primary co-morbidities (52, 53). It is beyond the scope of this review to provide a detailed discussion of secondary osteoporosis, but this should be ruled out in men diagnosed with osteoporosis.
DRUGS FOR OSTEOPOROSIS IN MEN Osteoporotic treatment studies in women support multiple classes of medications as effective and safe for reducing the risk of vertebral and non-vertebral fractures. Evidence supporting the efficacy and safety of osteoporotic drugs for men is comparatively limited, with most studies to date relying on BMD end-points and bone turnover markers as surrogates for risk of fracture. Drug approval and recommendations for use in men are based on smaller trials that show similar effects on surrogates for fracture risk as those seen in studies of women that demonstrated reductions in fractures (Table 2) (19, 54–67) Medications currently approved for use in men include oral bisphosphonates alendronate and risedronate, intravenous bisphosphonate zoledronic acid, RANKL monoclonal antibody denosumab, and synthetic parathyroid hormone (PTH) analogue teriparatide.
Bisphosphonates Nitrogen-containing bisphosphonates (alendronate, risedronate, ibandronate, and zoledronate) exert antiresorptive effects via inhibition of farnesyl pyrophosphate synthase in osteoclasts, a key enzyme in the pathway that produces isoprenoid lipids utilized for post-translational modification of small guanosine triphosphate-binding proteins essential for osteoclasts, resulting in cellular toxicity (68). Bisphosphonates are recommended as the first line for treatment of osteoporosis in postmenopausal women and men by multiple organizations, including American Association of Clinical Endocrinologists (AACE)/American College of Endocrinology (ACE) and the Endocrine Society (19, 69). Large, placebo-controlled randomized controlled trials (RCTs) of alendronate, risedronate, and zoledronic acid in postmenopausal women have shown reductions in fractures at the vertebral and non-vertebral sites including hip (54, 55, 58, 61, 70), and extension trials have shown sustained efficacy and residual benefits after discontinuation (71–73). Trials of alendronate, risedronate, and zoledronic acid in osteoporotic men have shown increasing BMD with use. 793
VIEWS AND REVIEWS
TABLE 2 FDA-approved drugs for treatment of osteoporosis in men: data from pivotal trials for women and men.
Drug Alendronate Women Men Risedronate Women
Study
Primary endpoint(s)
Non-vertebral fractures (ARR, RRR), %
Black, 1996 (54) Cummings, 1998 (55) Orwoll, 2000 (56) Miller, 2004 (57)
2,027 4,432 241 167
New vertebral fractures Clinical fractures Lumbar spine BMD BMD
7, 47 1.7, 44.7 5.0, 61.70 NA
2.8, 19.0 1.5, 11.2 NA NA
Reginster, 2000 (58) Harris, 1999 (59) Boonen, 2009 (60)
1,226 2,458 284
New vertebral fractures New vertebral fractures Lumbar spine BMD
10.9, 37.6 5.0, 30.6 NA
5.1, 31.9 3.2, 38.1 NA
7,765
7.6, 69.7
2.7, 25.2
NA NA
3.1, 28.9 NA
Men Zoledronic acid Women Black, 2007 (61)
Men Denosumab Women Men Teriparatide Women Men
Patients enrolled, n
Vertebral fractures (ARR, RRR), %
Lyles, 2007 (62) Orwoll, 2010 (63)
1,065 (men/women) 302
New vertebral fracture (population with no concomitant medications); hip fracture (all population) New clinical fractures Lumbar spine BMD
Cummings, 2009 (64) Orwoll, 2012 (65)
7,868 242
New vertebral fracture Lumbar spine BMD
4.9, 68.1 NA
1.5, 18.8 NA
Neer, 2001 (66) Orwoll, 2003 (67)
1,637 437
New vertebral fracture Lumbar spine BMD
10, 71 NA
3, 50 NA
Note: ARR ¼ absolute risk reduction; BMD ¼ bone mineral density; NA ¼ not applicable; RRR ¼ relative risk reduction. Mendoza. Primary osteoporosis in men. Fertil Steril 2019.
However, with the sole exception of zoledronic acid, quality data of fracture risk is lacking. Only one RCT to date reported fracture incidence as a primary endpoint in men with osteoporosis (74), highlighting the need for more rigorous studies. To date, there are currently no data to suggest that side effect profiles are different in men compared to women, including rare occurrences such as osteonecrosis of the jaw and atypical femur fracture. Adverse events did not differ significantly between placebo and treatment in most trials in men described here (56, 60, 63); however, data are limited. Oral bisphosphonates: alendronate and risedronate. Alendronate was Food and Drug Administration (FDA) approved for men with osteoporosis following two double-blind RCTs with BMD as primary endpoints. The first, a trial of 241 eugonadal and hypogonadal men, showed greater spinal, femoral neck and total body BMD with alendronate use compared to placebo at two years, as well as a lower incidence of radiographic vertebral fractures (0.8% vs. 7.1% in the placebo group, P ¼ .02) (56). In another pivotal trial of 167 men, compared to placebo men treated with alendronate had higher BMD and lower bone turnover markers at 12 months but the study was underpowered to assess fracture risk (57). Similarly, FDA approval of risedronate followed an RCT trial of 284 men, which showed increased spinal and proximal femur BMD with use compared to placebo at 24 months (60); however, fracture efficacy was not demonstrated. An openlabel trial of risedronate has shown reduced vertebral fracture incidence with use at 1 year (5.1% vs. 12.7, P ¼ .028) and both vertebral (9.2% vs. 23.6%, P ¼ .0026) and non-vertebral (11.8 vs. 22.3%; P ¼ .032 fracture incidence at 2 years, but data are not as robust due to absence of blinding (75, 76). 794
Subsequent meta-analysis showed a reduced risk of vertebral fractures with use of alendronate (2 studies, risk ratio 0.328, 95% confidence internal 0.155-0.692) and risedronate (2 studies, risk ratio 0.428, 95% confidence internal 0.245-0.746), but not vertebral fractures (77). However, authors combined RCTs and open-label studies for the analysis, diminishing significantly the quality of data. In the same study, authors found a reduced risk of vertebral and nonvertebral fractures with use of bisphosphonates (alendronate, risedronate, ibandronate, and zoledronic acid) as a category. However, not all bisphosphonates have demonstrated uniform efficacy, particularly ibandronate (78), also diminishing the quality of reported data. Intravenous bisphosphonates: zoledronic acid. Intravenous zoledronic acid is the best-studied drug for the efficacy of fracture risk reduction in men with osteoporosis. In a study of 508 men and 1619 women with hip fracture repair, zoledronic acid reduced both new clinical fractures (8.6% vs. 13.9%, P ¼ .001) and clinical vertebral fractures (1.7% vs. 3.8%, P ¼ .02) as primary endpoints, as well as mortality compared to placebo (60). Subset analysis of men in the trial showed increased BMD compared to placebo; however, fracture incidence was low among men and no statistically significant effect was seen (60, 79). FDA approval for zoledronic acid for men followed a comparative study that showed zoledronic acid to have similar efficacy to alendronate using BMD endpoint in men (63). More recently, in the only trial in men to date reporting fracture incidence as a primary endpoint, among 1,199 eugonadal and hypogonadal men with osteoporosis, those treated with zoledronic acid had lower vertebral fracture incidence VOL. 112 NO. 5 / NOVEMBER 2019
Fertility and Sterility® compared to placebo (1.6% vs. 4.9%, P ¼ .002) as well significantly higher BMD (74). Ibandronate. The bisphosphonate ibandronate (oral or intravenous) is approved for use in osteoporotic women but is currently not recommended as the first-line due to questionable efficacy for non-vertebral fractures (78). Ibandronate is currently not approved for use in men, though in a trial of 132 men ibandronate was shown to increase BMD (80).
RANKL inhibitors: Denosumab Denosumab is a human monoclonal antibody that inhibits the binding of RANKL to the RANK receptor expressed on the cell surface of osteoclast precursors, an essential step for differentiation (81). The U.S. FDA approved denosumab for treatment in postmenopausal women with osteoporosis based on a 36month trial that demonstrated reduced vertebral, nonvertebral, and hip fractures with use in 7,868 women. It is only approved for use in women and men at high risk of fracture and is currently recommended by AACE/ACE as first-line for this group due to greater BMD gains showed in trials comparing denosumab to bisphosphonates in women (82– 83). Unfortunately, trials of women have shown the rapid decline of BMD following discontinuation of therapy, and risk of fracture increases to that of untreated (84). Therefore, antiresorptive therapy is recommended after stopping therapy from preventing new fractures. The risk of posttreatment rebound has not been evaluated in men. In a pivotal RCT of 242 males with low bone mass without secondary causes, denosumab increased BMD at all sites measured at 12 months compared to placebo (65), from which FDA approval followed. Continued efficacy at 24 months was shown in an open-label phase of the trial. However, the study was underpowered to assess fracture risk (1 vertebral fracture, 3 clinical fractures reported in total) (85). Fracture risk efficacy using denosumab has been shown, however, in a double-blind multicenter study of 1,468 men receiving androgen deprivation therapy for prostate cancer (FDA approved use) over 3 years which showed lower incidence of vertebral fractures (3.9% vs. 1.5% cumulative incidence), but not non-vertebral or hip fractures (86). No studies in men to date have investigated BMD changes following discontinuation of therapy. Rare but severe adverse events associated with denosumab use include hypocalcemia, and osteonecrosis of the jaw and atypical femur fracture. No reports of hypocalcemia, osteonecrosis of the jaw, fracture, or atypical femoral fracture were observed in men in the studies cited here, and the overall incidence of serious adverse effects did not differ significantly between placebo and control (65, 85).
Anabolic Agents Teriparatide. Teriparatide, a synthetic analogue of PTH, is approved for the treatment of osteoporosis in postmenopausal women and men with high fracture risk. It acts via PPTH/ PTHrP receptors expressed on the surface of osteoblasts, osteocytes, and renal tubule cells. Intermittent stimulation preferentially enhances bone formation whereas prolonged receptor stimulation enhances its effects on bone resorption, thus VOL. 112 NO. 5 / NOVEMBER 2019
intermittent stimulation seems to be required for its desired effect (87). Approval in women was granted by the US FDA following a trial of 1637 postmenopausal women with osteoporosis in which teriparatide administration reduced vertebral and non-vertebral fracture risk as primary outcome measures over a median of 21 months (66). Approval in men followed a one-year RCT of 437 men with primary and hypogonadal osteoporosis, which showed teriparatide increases spinal and proximal femur BMD (67). Similar to women (88), a trial showed that antiresorptive therapy is needed to maintain benefit following bone anabolic therapy with teriparatide (89). No RCT trials have demonstrated a significant reduction in fracture incidence, though one observational study demonstrated that teriparatide reduced the risk of vertebral fracture compared to placebo after teriparatide treatment was discontinued (90). Adverse events associated with teriparatide include arthralgia, pain, and nausea, and potential increased risk of osteosarcoma. In the pivotal trial of men, transient hypercalcemia occurred with increased frequency in the drug group, but other adverse effects did not differ between placebo- and risedronate- treated men, and there were no reports of osteosarcoma (14). Abaloparatide. Abaloparatide is a synthetic analogue of PTH-related peptide (PTHrP), which similarly to PTHanalogue acts to increase bone formation (87). It is currently approved for the treatment of osteoporosis in postmenopausal women only following a study that showed a lower risk of vertebral and non-vertebral fractures compared with placebo as well as non-inferiority when compared with teriparatide. The study showed a lower incidence of major osteoporotic fractures (defined as fractures of the upper arm, wrist, hip, or clinical spine) with abaloparatide use compared with teriparatide (91). There are few trials to date that support its use in men.
Testosterone Data on the effects of testosterone therapy in men with osteoporosis are limited. Treatment with testosteronereplacement therapy has been shown to increase BMD in men with hypogonadism and normal BMD (92) but not in eugonadal men (93). Testosterone therapy for men with normal testosterone levels is not advised due to potential adverse effects and lack of demonstrated benefit. However, the Endocrine Society recommends the combined use of anti-fracture treatment with testosterone therapy for men at high risk of fracture and low testosterone (<200 ng/dl) (19). Bisphosphonates have been shown to improve BMD largely independent of testosterone levels (56, 60, 74), supporting a role in the treatment of men with hypogonadism. Moreover, bisphosphonates alendronate and zolendronic acid, and denosumab have been shown to increase lumbar spine BMD in men on androgen deprivation therapy (85, 94, 95).
Romosozumab Romosozumab is a monoclonal antibody that binds to and inhibits sclerostin, an endogenous inhibitor of Wnt signaling 795
VIEWS AND REVIEWS that is crucial to both bone development and the regulation of bone mass (96). It was recently approved for use in women following a trial of 1,226 postmenopausal women over three years that demonstrated reduced fracture risk with use compared to placebo (97). A RCT of 245 men with osteoporosis designed as a bridging study for approval demonstrated significant improvement of the lumbar spine and total hip BMD at 1 year for those treated with Romosozumab (98). Romosozumab is currently not approved for use in men.
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