Primary osteoporosis in men: an unmet medical need

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. 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. Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/54234-29067 Discuss: You can discuss this article with its authors and other readers at https://www.fertstertdialog.com/users/16110-fertility-and-sterility/posts/54234-29067 Osteoporosis 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 (1Cooper C. Campion G. Melton 3rd, L.J. Hip fractures in the elderly: a world-wide projection.Osteoporos Int. 1992; 2: 285-289Crossref PubMed Scopus (2334) Google Scholar). 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 (2Wright N.C. Looker A.C. Saag K.G. Curtis J.R. Delzell E.S. Randall S. et al.The recent prevalence of osteoporosis and low bone mass in the United States based on bone mineral density at the femoral neck or lumbar spine.J Bone Miner Res. 2014; 29: 2520-2526Crossref PubMed Scopus (1019) Google Scholar). 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% (3Melton 3rd, L.J. Chrischilles E.A. Cooper C. Lane A.W. Riggs B.L. Perspective: how many women have osteoporosis?.J Bone Miner Res. 1992; 7: 1005-1010Crossref PubMed Scopus (1255) Google Scholar, 4Forsén L. Sogaard A.J. Meyer H.E. Edna T. Kopjar B. Survival after hip fracture: short- and long-term excess mortality according to age and gender.Osteoporos Int. 1999; 10: 73-78Crossref PubMed Scopus (287) Google Scholar). Furthermore, among patients suffering from fractures, male patients have higher mortality than their female counterparts (5Center J.R. Nguyen T.V. Schneider D. Sambrook P.N. Eisman J.A. Mortality after all major types of osteoporotic fracture in men and women: an observational study.Lancet. 1999; 353: 878-882Abstract Full Text Full Text PDF PubMed Scopus (1595) Google Scholar, 6Bliuc D. Nguyen N.D. Milch V.E. Nguyen T.V. Eisman J.A. Center J.R. Mortality risk associated with low-trauma osteoporotic fracture and subsequent fracture in men and women.JAMA. 2009; 301: 513-521Crossref PubMed Scopus (1183) Google Scholar, 7Haentjens P. Magaziner J. Colón-Emeric C.S. Vanderschueren D. Milisen K. Velkeniers B. Meta-analysis: excess mortality after hip fracture among older women and men.Ann Intern Med. 2010; 152: 380-390Crossref PubMed Scopus (908) Google Scholar). 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. A fragility fracture is defined as a fracture produced by a low energy impact (8World Health OrganizationGuidelines for preclinical evaluation and clinical trials in osteoporosis. World Health Organization, Geneva1998Google Scholar). Older adults are more prone to fragility fractures due to a higher number of falls and reduced bone strength (9Scott D. Seibel M.J. Cumming R. Naganathan V. Blyth F. Le Couteur D.G. et al.Associations of body composition trajectories with bone mineral density, muscle function, falls and fractures in older men: The Concord Health and Ageing in Men Project.J Gerontol A Biol Sci Med Sci. 2019 Aug 13; (Epub ahead of print)https://doi.org/10.1093/gerona/glz184Crossref Scopus (11) Google Scholar). Despite the lack of methods to directly quantify bone strength, dual-energy 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 (10Mazess R.B. Barden H.S. Measurement of bone by dual-photon absorptiometry (DPA) and dual-energy X-ray absorptiometry (DEXA).Ann Chir Gynaecol. 1988; 77: 197-203PubMed Google Scholar, 11Chun K.J. Bone densitometry.Semin Nucl Med. 2011; 41: 220-228Crossref PubMed Scopus (58) Google Scholar). 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 that is strongly associated with bone strength (11Chun K.J. Bone densitometry.Semin Nucl Med. 2011; 41: 220-228Crossref PubMed Scopus (58) Google Scholar). Multiple studies have shown the strong correlations between low BMD and the risk of fracture in both genders (12Marshall D. Johnell O. Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures.BMJ. 1996; 312: 1254-1259Crossref PubMed Scopus (2986) Google Scholar). 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 sub-populations (12Marshall D. Johnell O. Wedel H. Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures.BMJ. 1996; 312: 1254-1259Crossref PubMed Scopus (2986) Google Scholar). Osteoporosis (regardless of the gender) is defined as a spinal or hip reduction of BMD ≥ 2.5 standard deviations below the young adult female reference mean (T-score ≤ –2.5) (13Watts N.B. Leslie W.D. Foldes A.J. International Society for Clinical Densitometry Position Development Conference: Task Force on Normative Databases.J Clin Densitom. 2013; 16: 472-481Crossref PubMed Scopus (56) Google Scholar). 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 (14Binkley N. Adler R. Bilezikian J.P. Osteoporosis diagnosis in men: The T-score controversy revisited.Curr Osteoporos Rep. 2014; 12: 403-409Crossref PubMed Scopus (30) Google Scholar). This raises the concerns for underdiagnosing the fragility fracture risk of 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 (15De Laet C. Oden A. Johnell O. Jonsson B. Kanis J.A. The impact of the use of multiple risk factors on case finding strategies: a mathematical framework.Osteoporosis International. 2005; 16: 313-318Crossref PubMed Scopus (123) Google Scholar, 16Kanis J.A. Oden A. Johansson H. Borgström F. Ström O. McCloskey E. FRAX and its applications to clinical practice.Bone. 2009; 44: 734-743Crossref PubMed Scopus (556) Google Scholar). 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 (17Siris E.S. Adler R. Bilezikian J. Bolognese M. Dawson-Hughes B. Favus M.J. et al.The clinical diagnosis of osteoporosis: a position statement from the National Bone Health Alliance Working Group.Osteoporos Int. 2014; 25: 1439-1443Crossref PubMed Scopus (355) Google Scholar) (Table 1). Using this criterion applied to the NHANES data, 16% of U.S. men 50-years-old or older are osteoporotic (18Wright NC, Saag KG, Dawson-Hughes B, Khosla S, Siris ES. The impact of the new National Bone Health Alliance (NBHA) diagnostic criteria on the prevalence of osteoporosis in the USA. Osteoporos Int. 2017;28:3283-84.Google Scholar). 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.Table 1Recommendations of the National Bone Health Alliance Working Group for the diagnosis of osteoporosis in postmenopausal women and men over the age of 50 years (17Siris E.S. Adler R. Bilezikian J. Bolognese M. Dawson-Hughes B. Favus M.J. et al.The clinical diagnosis of osteoporosis: a position statement from the National Bone Health Alliance Working Group.Osteoporos Int. 2014; 25: 1439-1443Crossref PubMed Scopus (355) Google Scholar).BMD testingT-score of ≤ −2.5 at the spine or hipFractureLow trauma hip fracture regardless of T-scoreLow trauma fracture in vertebral, proximal humerus, or pelvis bones in patients with a T-score of -1.0 to <-2.5aIn some cases, distal forearm fractures.FRAX scoreElevated risk of fracturesbCut 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.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 = bone mineral density; FRAX = 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. Open table in a new tab 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 = bone mineral density; FRAX = fracture risk assessment tool. 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 (19Watts N.B. Adler R.A. Bilezikian J.P. Drake M.T. Eastell R. Orwoll E.S. et al.Endocrine society. Osteoporosis in men: an endocrine society clinical practice guide-line.J Clin Endocrinol Metab. 2012; 97: 1802-1822Crossref PubMed Scopus (374) Google Scholar). 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. Osteoporotic fractures in men account for 39% of all the osteoporosis-related fractures (20Cooper C. Cole Z.A. Holroyd C.R. Earl S.C. Harvey N.C. Dennison E.M. et al.Secular trends in the incidence of hip and other osteoporotic fractures.Osteoporos Int. 2011; 22: 1277-1288Crossref PubMed Scopus (607) Google Scholar, 21Amin S. Achenbach S.J. Atkinson E.J. Khosla S. Melton III, L.J. Trends in fracture incidence: a population-based study over 20 years.J Bone Miner Res. 2014; 29: 581-589Crossref PubMed Scopus (217) Google Scholar). 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 (21Amin S. Achenbach S.J. Atkinson E.J. Khosla S. Melton III, L.J. Trends in fracture incidence: a population-based study over 20 years.J Bone Miner Res. 2014; 29: 581-589Crossref PubMed Scopus (217) Google Scholar). 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 (21Amin S. Achenbach S.J. Atkinson E.J. Khosla S. Melton III, L.J. Trends in fracture incidence: a population-based study over 20 years.J Bone Miner Res. 2014; 29: 581-589Crossref PubMed Scopus (217) Google Scholar). 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 (22Solomon D.H. Johnston S.S. Boytsov N.N. McMorrow D. Lane J.M. Krohn K.D. Osteoporosis medication use after hip fracture in U.S. patients between 2002 and 2011.J Bone Miner Res. 2014; 29: 1929-1937Crossref PubMed Scopus (239) Google Scholar). Therefore, efforts in early recognition and treatment have largely fallen short of addressing this dramatically unmet medical need. 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 hormones and cytokines, but also by muscle and bone signaling molecules triggered by mechanical stimuli (23Vezeridis P.S. Semeins C.M. Chen Q. Klein-Nulend J. Osteocytes subjected to pulsating fluid flow regulate osteoblast proliferation and differentiation.Biochem Biophys Res Commun. 2006; 348: 1082-1088Crossref PubMed Scopus (117) Google Scholar, 24You L. Temiyasathit S. Lee P. Kim C.H. Tummala P. Yao W. et al.Osteocytes as mechanosensors in the inhibition of bone resorption due to mechanical loading.Bone. 2008; 42: 172-179Crossref PubMed Scopus (261) Google Scholar). 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 (25Klein-Nulend J. Bakker A.D. Bacabac R.G. Vatsa A. Weinbaum S. Mechanosensation and transduction in osteocytes.Bone. 2013; 54: 182-190Crossref PubMed Scopus (329) Google Scholar, 26Juffer P. Jaspers R.T. Klein-Nulend J. Bakker A.D. Mechanically loaded myotubes affect osteoclast formation.Calcif Tissue Int. 2014; 94: 319-326Crossref Scopus (20) Google Scholar). Stimulation of these receptors triggers sclerostin dependent and independent osteogenic responses. Conversely, the lack of mechanical load stimulates receptor activator of nuclear factor kappa-Β ligand (RANKL) production by osteocytes (27Kulkarni R.N. Bakker A.D. Everts V. Klein-Nulend J. Inhibition of osteoclastogenesis by mechanically loaded osteocytes: involvement of MEPE.Calcif Tissue Int. 2010; 87: 461-468Crossref PubMed Scopus (71) Google Scholar, 28Uda Y. Azab E. Sun N. Shi C. Pajevic P.D. Osteocyte mechanobiology.Curr Osteoporos Rep. 2017; 15: 318-325Crossref PubMed Scopus (103) Google Scholar). 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" (29Binkley N. Krueger D. Buehring B. What's in a name revisited: should osteoporosis and sarcopenia be considered components of "dysmobility syndrome?".Osteoporos Int. 2013; 24: 2955-2959Crossref PubMed Scopus (98) Google Scholar). Muscle health is measured by appendicular lean mass, grip strength, and other functional measures such as gait speed (30Wong R.M.Y. Wong H. Zhang N. Chow S.K.H. Chau W.W. Wang J. et al.The relationship between sarcopenia and fragility fracture-a systematic review.Osteoporos Int. 2019; 30: 541-553Crossref Scopus (63) Google Scholar, 31Cruz-Jentoft A.J. Bahat G. Bauer J. Boirie Y. Bruyere O. Cederholm T. et al.Sarcopenia: revised European consensus on definition and diagnosis.Age Ageing. 2019; 48: 16-31Crossref PubMed Scopus (4317) Google Scholar, 32Studenski S.A. Peters K.W. Alley D.E. Cawthon P.M. McLean R.R. Harris T.B. et al.The FNIH sarcopenia project: rationale, study description, conference recommendations, and final estimates.J Gerontol A Biol Sci Med Sci. 2014; 69: 547-558Crossref PubMed Scopus (1250) Google Scholar, 33Fielding R.A. Vellas B. Evans W.J. Bhasin S. Morley J.E. Newman A.B. et al.Sarcopenia: an undiagnosed condition in older adults. Current consensus definition: prevalence, etiology, and consequences. International working group on sarcopenia.J Am Med Dir Assoc. 2011; 12: 249-256Abstract Full Text Full Text PDF PubMed Scopus (1975) Google Scholar). 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 (34Laurent MR, Dedeyne L, Dupont J, Mellaerts B, Dejaeger M, Mauritas GE. Age-related bone loss and sarcopenia in men. Maturitas 2019;22:51-6.Google Scholar). 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. In addition to advanced aged and sarcopenia, estrogen deficiency is the most important factor conditioning the development of osteoporosis in men (35Almeida M. Laurent M.R. Dubois V. Claessens F. O'Brien C.A. et al.Estrogens and androgens in skeletal physiology and pathophysiology.Physiol Rev. 2017; 97: 135-187Crossref PubMed Scopus (402) Google Scholar). Estrogen deficiency and 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 (36Ucer S. Iyer S. Kim H.N. Han L. Rutlen C. Allison K. et al.The effects of aging and sex steroid deficiency on the murine skeleton are independent and mechanistically distinct.J Bone Miner Res. 2017; 32: 560-574Crossref PubMed Scopus (73) Google Scholar). In men, estradiol (E2) is produced by testicles (15%) and by peripheral aromatization (85%), from testosterone (37Gennari L. Merlotti D. Martini G. Gonnelli S. Franci B. Campagna S. et al.Longitudinal association between sex hormone levels, bone loss, and bone turnover in elderly men.J Clin Endocrinol Metab. 2003; 88: 5327-5333Crossref PubMed Scopus (216) Google Scholar). 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 (35Almeida M. Laurent M.R. Dubois V. Claessens F. O'Brien C.A. et al.Estrogens and androgens in skeletal physiology and pathophysiology.Physiol Rev. 2017; 97: 135-187Crossref PubMed Scopus (402) Google Scholar, 38Finkelstein J.S. Lee H. Burnett-Bowie S.A. Pallais J.C. Yu E.W. Borges L.F. et al.Gonadal steroids and body composition, strength, and sexual function in men.N Engl J Med. 2013; 369: 1011-1022Crossref PubMed Scopus (451) Google Scholar). 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 (35Almeida M. Laurent M.R. Dubois V. Claessens F. O'Brien C.A. et al.Estrogens and androgens in skeletal physiology and pathophysiology.Physiol Rev. 2017; 97: 135-187Crossref PubMed Scopus (402) Google Scholar). Estrogens and androgens link the bone estrogen receptor α or β (also termed NR3A1 and NR3A2) and the androgen receptor (AR), also known as NR3C4, respectively (35Almeida M. Laurent M.R. Dubois V. Claessens F. O'Brien C.A. et al.Estrogens and androgens in skeletal physiology and pathophysiology.Physiol Rev. 2017; 97: 135-187Crossref PubMed Scopus (402) Google Scholar, 39Pihlajamaa P. Sahu B. Janne O.A. Determinants of receptor and tissue specifications in androgen signaling.Endocr Rev. 2015; 36: 357-384Crossref PubMed Scopus (83) Google Scholar). The receptors mentioned above form homodimers binding DNA sequences called "hormone response elements" (EREs or AREs) (40Claessens F. Denayer S. Van T.N. Kerkhofs S. Helsen C. Haelens A. Diverse roles of Androgenreceptor (AR) domains in AR-mediated signaling.Nucl Recept Signa. 2008; l6: e008Google Scholar). The direct target genes of ERES/ARES are poorly characterized in bone tissue (41Krum S.A. Direct transcriptional targets of sex steroid hormones in bone.J Cell Biochem. 2011; 112: 401-408Crossref PubMed Scopus (60) Google Scholar), but it has been postulated that multiple cytokines including TGF-β, 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 (35Almeida M. Laurent M.R. Dubois V. Claessens F. O'Brien C.A. et al.Estrogens and androgens in skeletal physiology and pathophysiology.Physiol Rev. 2017; 97: 135-187Crossref PubMed Scopus (402) Google Scholar, 41Krum S.A. Direct transcriptional targets of sex steroid hormones in bone.J Cell Biochem. 2011; 112: 401-408Crossref PubMed Scopus (60) Google Scholar, 42Manolagas S.C. Kousteni S. Jilka R.L. Sex steroids and bone.Recent Prog Horm Res. 2002; 57: 385-409Crossref PubMed Scopus (451) Google Scholar, 43Weitzmann M.N. Pacifici R. Estrogen deficiency and bone loss: an inflammatory tale.J Clin Invest. 2006; 116: 1186-1194Crossref PubMed Scopus (652) Google Scholar, 44Lee N.K. Choi Y.G. Baik J.Y. Han S.Y. Jeong D.W. Bae Y.S. et al.A crucial role for reactive oxygen species in RANKL-induced osteoclast differentiation.Blood. 2005; 106: 852-859Crossref PubMed Scopus (672) Google Scholar). 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 (45Callewaert F. Sinnesael M. Gielen E. Boonen S. Vanderschueren D. Skeletal sexual dimorphism: relative contribution of sex steroids, GH-IGF1, and mechanical loading.J Endocrinol. 2010; 207: 127-134Crossref PubMed Scopus (157) Google Scholar); and lower metabolism of osteoblasts and osteocytes affecting mainly the trabecular bone (35Almeida M. Laurent M.R. Dubois V. Claessens F. O'Brien C.A. et al.Estrogens and androgens in skeletal physiology and pathophysiology.Physiol Rev. 2017; 97: 135-187Crossref PubMed Scopus (402) Google Scholar). 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 (46Nordstrom P. Eklund F. Bjornstig U. Nordstrom A. Lorentzon R. Siavanen H. et al.Do both areal BMD and injurious falls explain the higher incidence of fractures in women than in men?.Calcif Tissue Int. 2011; 89: 203-210Crossref PubMed Scopus (17) Google Scholar). 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 (47Dubois V. Laurent M.R. Sinnesael M. Cielen N. Helsen C. Clinckemalie L. et al.A satellite cell-specific knockout of the androgen receptor reveals myostatin as a direct androgen target in skeletal muscle.FASEB J. 2014; 28: 2979-2994Crossref PubMed Scopus (74) Google Scholar). Also, it has been proposed that stimulation of brain dopamine pathways contributes to an increase in exercise activity as suggested by animal models (48Jardí F. Laurent M.R. Kim N. Khalil R. De Bundel D. Van Eeckhaut A. et al.Testosterone boosts physical activity in male mice via dopaminergic pathways.Sci Rep. 2018; 8: 957Crossref PubMed Scopus (28) Google Scholar). 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 (49Cui Y. Zong H. Yang C. Yan H. Zhang Y. The effect of 5α-reductase inhibitors on prostate growth in men receiving testosterone replacement therapy: a systematic review and meta-analysis.Int Urol Nephrol. 2013; 45: 979-987Crossref Scopus (5) Google Scholar). However, testosterone therapy for 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) (34Laurent MR, Dedeyne L, Dupont J, Mellaerts B, Dejaeger M, Mauritas GE. Age-related bone loss and sarcopenia in men. Maturitas 2019;22:51-6.Google Scholar). Secondary osteoporosis seems to be more frequent in males than female patients (50Gennari L. Bilezikian J.P. Osteoporosis in men.Endocrinol Metab Clin N Am. 2007; 36: 399-419Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 51Khosla S. Amin S. Orwoll E. Osteoporosis in men.Endocr Rev. 2008; 29: 441-464Crossref PubMed Scopus (296) Google Scholar) but this very high prevalence, reaching up to 50% of the cohorts, can be associated with an underdiagnoses of primary osteoporosis (52Gennari L. Bilezikian J.P. New and developing pharmacotherapy for osteoporosis in men.Expert Opin Pharmacother. 2018; 19: 253-264Crossref Scopus (22) Google Scholar). Alcohol abuse, use of corticosteroids, hypogonadism, endogenous hypercortisolemia and diabetes mellitus are the most common primary co-morbidities (52Gennari L. Bilezikian J.P. New and developing pharmacotherapy for osteoporosis in men.Expert Opin Pharmacother. 2018; 19: 253-264Crossref Scopus (22) Google Scholar, 53Napoli N. Chandran M. Pierroz D.D. Abrahamsen B. Schwartz A.V. Ferrari S.L. et al.IOF bone and diabetes working group. Mechanisms of diabetes mellitus-induced bone fragility.Nat Rev Endocrinol. 2017; 13: 208-219Crossref PubMed Scopus (492) Google Scholar). 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. 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) (19Watts N.B. Adler R.A. Bilezikian J.P. Drake M.T. Eastell R. Orwoll E.S. et al.Endocrine society. Osteoporosis in men: an endocrine society clinical practice guide-line.J Clin Endocrinol Metab. 2012; 97: 1802-1822Crossref PubMed Scopus (374) Google Scholar, 54Black D.M. Cummings S.R. Karpf D.B