ASM  Vol.3 No.3 A , August 2013
Low Testosterone—An Important Predictor of Low Mineral Bone Density in Young Men—Our Own Experience and a Review of Literature
Abstract: Urologists and reproductive endocrinologists have become the first contact physicians for young men of reproductive age and have the unique opportunity to positively affect men’s health and quality of life. Growing evidence indicates that a significant proportion of men presenting with infertility or sexual dysfunction are hypogonadal. One hundred ninety nine men were enrolled in our center, and mean total testosterone was <300 ng/dl. Patients were divided into three groups based on their DEXA scan results; normal bone density (n = 122, 57%), osteopenia (n = 69, 39%) and osteoporosis (n = 8, 4%). There were no differences in the mean age (p < 0.64), height (p < 0.99) and weight (p < 0.06) among the three groups (ANOVA), but men with osteopenia had statistically significant lower weights (p < 0.02). Our results indicate that hypogonadism is one of the main risk factors for osteopenia and osteoporosis which can be found in 8% of hypogonadal men younger than 50 years of age. Testosterone replacement therapy may be indicated in most men with hypogonadism and low bone mineral density (BMD); however the benefits of testosterone treatment in eugonadal men are unproven. Selective estradiol and androgen receptor modulators expand our treatment modalities in men of reproductive age when suppression of gonadotropins may interfere with reproductive plans. Early detection of hypogonadism and osteoporosis may lower the risk of hip and vertebral fractures in some men. Further prospective RCTs are needed to prove cost-effectiveness of detection and the best treatment of osteoporosis in hypogonadal men of reproductive age. Urologists have the opportunity to be at the forefront of greater awareness of this clinical problem due to their frequent contact with this population of patients.
Cite this paper: M. Funaro, A. Bolyakov, E. Gimenez, M. Herman and D. Paduch, "Low Testosterone—An Important Predictor of Low Mineral Bone Density in Young Men—Our Own Experience and a Review of Literature," Advances in Sexual Medicine, Vol. 3 No. 3, 2013, pp. 19-33. doi: 10.4236/asm.2013.33A003.

[1]   L. Gennari and J. P. Bilezikian, “Osteoporosis in Men: Pathophysiology and Treatment,” Current Rheumatology Reports, Vol. 9, No. 1, 2007, pp. 71-77. doi:10.1007/s11926-007-0025-y

[2]   L. J. Melton 3rd, E. A. Chrischilles, C. Cooper, A. W. Lane and B. L. Riggs, “Perspective How Many Women Have Osteoporosis?” Journal of Bone and Mineral Research, Vol. 7, No. 9, 1992, pp. 1005-1010. doi:10.1002/jbmr.5650070902

[3]   L. Gennari and J. P. Bilezikian, “Osteoporosis in Men,” Endocrinology and Metabolism Clinics of North America, Vol. 36, No. 2, 2007, pp. 399-419. doi:10.1016/j.ecl.2007.03.008

[4]   C. Cooper, G. Campion and L. J. Melton 3rd, “Hip Fractures in the Elderly: A World-Wide Projection,” Osteoporosis International, Vol. 2, No. 6, 1992, pp. 285-289. doi:10.1007/BF01623184

[5]   E. Seeman, G. Bianchi, S. Khosla, J. A. Kanis and E. Orwoll, “Bone Fragility in Men—Where Are We?” Osteoporosis International, Vol. 17, No. 11, 2006, pp. 1577-1583. doi:10.1007/s00198-006-0160-8

[6]   A. A. Abbasi, D. Rudman, C. R. Wilson, P. J. Drinka, S. N. Basu, D. E. Mattson and T. J. Richardson, “Observations on Nursing Home Residents with a History of Hip Fracture,” The American Journal of the Medical Sciences, Vol. 310, No. 6, 1995, pp. 229-234.

[7]   T. J. Allain, “Prostate Cancer, Osteoporosis and Fracture Risk,” Gerontology, Vol. 52, 2006, pp. 107-110. doi:10.1159/000090956

[8]   N. McLeod, C. C. Huynh and P. Rashid, “Osteoporosis from Androgen Deprivation Therapy in Prostate Cancer Treatment,” Australian Family Physician, Vol. 35, No. 4, 2006, pp. 243-245.

[9]   J. A. Kanis, O. Johnell, A. Oden, C. De Laet and D. Mellstrom, “Diagnosis of Osteoporosis and Fracture Threshold in Men,” Calcified Tissue International, Vol. 69, No. 4, 2001, pp. 218-221. doi:10.1007/s00223-001-1046-6

[10]   A. C. Looker, E. S. Orwoll, C. C. Johnston Jr., R. L. Lindsay, H. W. Wahner, W. L. Dunn, M. S. Calvo, T. B. Harris and S. P. Heyse, “Prevalence of Low Femoral Bone Density in Older U.S. Adults from NHANES III,” Journal of Bone and Mineral Research, Vol. 12, No. 11, 1997, pp. 1761-1768. doi:10.1359/jbmr.1997.12.11.1761

[11]   L. J. Melton 3rd, “The Prevalence of Osteoporosis: Gender and Racial Comparison,” Calcified Tissue International, Vol. 69, No. 4, 2001, pp. 179-181. doi:10.1007/s00223-001-1043-9

[12]   L. M. Marshall, J. M. Zmuda, B. K. Chan, E. Barrett-Connor, J. A. Cauley, K. E. Ensrud, T. F. Lang and E. S. Orwoll, “Race and Ethnic Variation in Proximal Femur Structure and BMD among Older Men,” Journal of Bone and Mineral Research, Vol. 23, No. 1, 2008, pp. 121-130. doi:10.1359/jbmr.070908

[13]   C. Cooper, “The Crippling Consequences of Fractures and Their Impact on Quality of Life,” The American Journal of Medicine, Vol. 103, No. 2A, 1997, pp. 12S-17S, discussion 17S-19S.

[14]   L. Forsen, A. J. Sogaard, H. E. Meyer, T. Edna and B. Kopjar, “Survival after Hip Fracture: Short-and Long-Term Excess Mortality according to Age and Gender,” Osteoporosis International, Vol. 10, No. 1, 1999, pp. 73-78. doi:10.1007/s001980050197

[15]   C. Becker, “Pathophysiology and Clinical Manifestations of Osteoporosis,” Clinical Cornerstone, Vol. 8, No. 1, 2006, pp. 19-27. doi:10.1016/S1098-3597(06)80062-1

[16]   E. L. Smith and D. M. Raab, “Osteoporosis and Physical Activity,” Acta Medica Scandinavica Supplementum, Vol. 711, 1986, pp. 149-156.

[17]   P. Garnero and P. D. Delmas, “New Developments in Biochemical Markers for Osteoporosis,” Calcified Tissue International, Vol. 59, No. 1, 1996, pp. S2-S9. doi:10.1007/s002239900168

[18]   L. You, S. Temiyasathit, P. Lee, C. H. Kim, P. Tummala, W. Yao, W. Kingery, A. M. Malone, R. Y. Kwon and C. R. Jacobs, “Osteocytes as Mechanosensors in the Inhibition of Bone Resorption Due to Mechanical Loading,” Bone, Vol. 42, No. 1, 2008, pp. 172-179. doi:10.1016/j.bone.2007.09.047

[19]   G. Silvestrini, P. Ballanti, M. Sebastiani, M. Leopizzi, M. Di Vito and E. Bonucci, “OPG and RANKL mRNA and Protein Expressions in the Primary and Secondary Metaphyseal Trabecular Bone of PTH-Treated Rats Are Independent of That of SOST,” Journal of Molecular Histology, Vol. 39, No. 2, 2008, pp. 237-242. doi:10.1007/s10735-007-9158-6

[20]   H. Kaji, T. Sugimoto, M. Kanatani, M. Nasu and K. Chihara, “Estrogen Blocks Parathyroid Hormone (PTH)-Stimulated Osteoclast-Like Cell Formation by Selectively Affecting PTH-Responsive Cyclic Adenosine Monophosphate Pathway,” Endocrinology, Vol. 137, No. 6, 1996, pp. 2217-2224. doi:10.1210/en.137.6.2217

[21]   K. H. Lau and D. J. Baylink, “Vitamin D Therapy of Osteoporosis: Plain Vitamin D Therapy versus Active Vitamin D Analog (D-Hormone) Therapy,” Calcified Tissue International, Vol. 65, No. 4, 1999, pp. 295-306. doi:10.1007/s002239900702

[22]   Y. Jayasinghe, S. R. Grover and M. Zacharin, “Current Concepts in Bone and Reproductive Health in Adolescents with Anorexia Nervosa,” BJOG: An International Journal of Obstetrics & Gynaecology, Vol. 115, No. 3, 2008, pp. 304-315. doi:10.1111/j.1471-0528.2007.01601.x

[23]   C. Cooper, N. Harvey, K. Javaid, M. Hanson and E. Dennison, “Growth and Bone Development,” In: D. J. P. Barker, R. L. Bergmann and P. L. Ogra, Eds., The Window of Opportunity: Pre-Pregnancy to 24 Months of Age, Karger, Basel, 2008, pp. 53-68. doi:10.1159/000113170

[24]   P. R. Ebeling “Osteoporosis in Men. New Insights into Aetiology, Pathogenesis, Prevention and Management,” Drugs & Aging, Vol. 13, No. 6, 1998, pp. 421-434. doi:10.2165/00002512-199813060-00002

[25]   M. A. Yialamas and F. J. Hayes, “Androgens and the Ageing Male and Female,” Best Practice & Research Clinical Endocrinology & Metabolism, Vol. 17, No. 2, 2003, pp. 223-236. doi:10.1016/S1521-690X(03)00018-6

[26]   E. J. Samelson and M. T. Hannan, “Epidemiology of Osteoporosis,” Current Rheumatology Reports, Vol. 8, No. 1, 2006, pp. 76-83. doi:10.1007/s11926-006-0030-6

[27]   R. Kaaks, S. Rinaldi, T. J. Key, F. Berrino, P. H. Peeters, C. Biessy, L. Dossus, A. Lukanova, S. Bingham, K. T. Khaw, N. E. Allen, H. B. Bueno-de-Mesquita, C. H. van Gils, D. Grobbee, H. Boeing, P. H. Lahmann, G. Nagel, J. Chang-Claude, F. Clavel-Chapelon, A. Fournier, A. Thiebaut, C. A. Gonzalez, J. R. Quiros, M. J. Tormo, E. Ardanaz, P. Amiano, V. Krogh, D. Palli, S. Panico, R. Tumino, P. Vineis, A. Trichopoulou, V. Kalapothaki, D. Trichopoulos, P. Ferrari, T. Norat, R. Saracci and E. Riboli, “Postmenopausal Serum Androgens, Oestrogens and Breast Cancer Risk: The European Prospective Investigation into Cancer and Nutrition,” Endocrine-Related Cancer, Vol. 12, 2005, pp. 1071-1082. doi:10.1677/erc.1.01038

[28]   D. Vanderschueren, L. Vandenput, S. Boonen, M. K. Lindberg, R. Bouillon and C. Ohlsson, “Androgens and Bone,” Endocrine Reviews, Vol. 25, No. 3, 2004, pp. 389-425. doi:10.1210/er.2003-0003

[29]   G. E. Krassas and P. Papadopoulou, “Oestrogen Action on Bone Cells,” Journal of Musculoskeletal & Neuronal Interactions, Vol. 2, No. 2, 2001, pp. 143-151.

[30]   S. Chowdhury, L. M. Pickering and P. A. Ellis, “Adjuvant Aromatase Inhibitors and Bone Health,” Menopause International, Vol. 12, No. 3, 2006, pp. 97-103. doi:10.1258/136218006778234020

[31]   S. Carreau, “Estrogens—Male Hormones?” Folia Histochemica et Cytobiologica, Vol. 41, No. 3, 2003, pp. 107-111.

[32]   S. E. Bulun, “Aromatase Deficiency and Estrogen Resistance: From Molecular Genetics to Clinic,” Seminars in Reproductive Medicine, Vol. 18, No. 1, 2000, pp. 31-39. doi:10.1055/s-2000-13481

[33]   M. E. Jones, W. C. Boon, J. Proietto and E. R. Simpson, “Of Mice and Men: The Evolving Phenotype of Aromatase Deficiency,” Trends in Endocrinology and Metabolism, Vol. 17, No. 2, 2006, pp. 55-64.

[34]   Q. Wang, M. Alen, P. H. Nicholson, J. M. Halleen, S. L. Alatalo, C. Ohlsson, H. Suominen and S. Cheng, “Differential Effects of Sex Hormones on Peri-and Endocortical Bone Surfaces in Pubertal Girls,” The Journal of Clinical Endocrinology and Metabolism, Vol. 91, No. 1, 2006, pp. 277-282.

[35]   G. R. Frank, “Role of Estrogen and Androgen in Pubertal Skeletal Physiology,” Medical and Pediatric Oncology, Vol. 41, No. 3, 2003, pp. 217-221. doi:10.1002/mpo.10340

[36]   C. Martel, M. H. Melner, D. Gagne, J. Simard and F. Labrie, “Widespread Tissue Distribution of Steroid Sulfatase, 3 Beta-Hydroxysteroid Dehydrogenase/Delta 5-Delta 4 Isomerase (3 Beta-HSD), 17 Beta-HSD 5 Alpha-Reductase and Aromatase Activities in the Rhesus Monkey,” Molecular and Cellular Endocrinology, Vol. 104, No. 1, 1994, pp. 103-111. doi:10.1016/0303-7207(94)90056-6

[37]   P. G. Blanchard and V. Luu-The, “Differential Androgen and Estrogen Substrates Specificity in the Mouse and Primates Type 12 17beta-Hydroxysteroid Dehydrogenase,” Journal of Endocrinology, Vol. 194, 2007, pp. 449-455. doi:10.1677/JOE-07-0144

[38]   T. Yanase, S. Suzuki, K. Goto, M. Nomura, T. Okabe, R. Takayanagi and H. Nawata, “Aromatase in Bone: Roles of Vitamin D3 and Androgens,” The Journal of Steroid Biochemistry and Molecular Biology, Vol. 86, No. 3-5, 2003, pp. 393-397. doi:10.1016/S0960-0760(03)00349-2

[39]   J. M. Janssen, R. Bland, M. Hewison, M. W. Coughtrie, S. Sharp, J. Arts, H. A. Pols and J. P. van Leeuwen, “Estradiol Formation by Human Osteoblasts via Multiple Pathways: Relation with Osteoblast Function,” Journal of Cellular Biochemistry, Vol. 75, No. 3, 1999, pp. 528-537. doi:10.1002/(SICI)1097-4644(19991201)75:3<528::AID-JCB16>3.0.CO;2-3

[40]   A. M. Cleton-Jansen, H. M. van Beerendonk, H. J. Baelde, J. V. Bovee, M. Karperien and P. C. Hogendoorn, “Estrogen Signaling Is Active in Cartilaginous Tumors: Implications for Antiestrogen Therapy as Treatment Option of Metastasized or Irresectable Chondrosarcoma,” Clinical Cancer Research, Vol. 11, 2005, pp. 8028-8035. doi:10.1158/1078-0432.CCR-05-1253

[41]   K. Venken, F. Schuit, L. Van Lommel, K. Tsukamoto, J. J. Kopchick, K. Coschigano, C. Ohlsson, S. Moverare, S. Boonen, R. Bouillon and D. Vanderschueren, “Growth without Growth Hormone Receptor: Estradiol Is a Major Growth Hormone-Independent Regulator of Hepatic IGF-I Synthesis,” Journal of Bone and Mineral Research, Vol. 20, No. 12, 2005, pp. 2138-2149. doi:10.1359/JBMR.050811

[42]   L. Savendahl, “Hormonal Regulation of Growth Plate Cartilage,” Hormone Research, Vol. 64, Suppl. 2, 2005, pp. 94-97. doi:10.1159/000087764

[43]   S. A. Krum, G. A. Miranda-Carboni, P. V. Hauschka, J. S. Carroll, T. F. Lane, L. P. Freedman and M. Brown, “Estrogen Protects Bone by Inducing Fas Ligand in Osteoblasts to Regulate Osteoclast Survival,” The EMBO Journal, Vol. 27, 2008, pp. 535-545. doi:10.1038/sj.emboj.7601984

[44]   D. Vanderschueren, J. Gaytant, S. Boonen and K. Venken, “Androgens and Bone,” Current Opinion in Endocrinology, Diabetes & Obesity, Vol. 15, No. 3, 2008, pp. 250-254. doi:10.1097/MED.0b013e3282fe6ca9

[45]   C. H. Kasperk, G. K. Wakley, T. Hierl and R. Ziegler, “Gonadal and Adrenal Androgens Are Potent Regulators of Human Bone Cell Metabolism in Vitro,” Journal of Bone and Mineral Research, Vol. 12, No. 3, 1997, pp. 464-471. doi:10.1359/jbmr.1997.12.3.464

[46]   H. Kaji, T. Sugimoto, M. Kanatani, K. Nishiyama, M. Nasu and K. Chihara, “Insulin-Like Growth Factor-I Mediates Osteoclast-Like Cell Formation Stimulated by Parathyroid Hormone,” Journal of Cellular Physiology, Vol. 172, No. 1, 1997, pp. 55-62. doi:10.1002/(SICI)1097-4652(199707)172:1<55::AID-JCP6>3.0.CO;2-C

[47]   Y. Wang, S. Nishida, B. M. Boudignon, A. Burghardt, H. Z. Elalieh, M. M. Hamilton, S. Majumdar, B. P. Halloran, T. L. Clemens and D. D. Bikle, “IGF-I Receptor Is Required for the Anabolic Actions of Parathyroid Hormone on Bone,” Journal of Bone and Mineral Research, Vol. 22, No. 9, 2007, pp. 1329-1337. doi:10.1359/jbmr.070517

[48]   T. Niu and C. J. Rosen, “The Insulin-Like Growth Factor-I Gene and Osteoporosis: A Critical Appraisal,” Gene, Vol. 361, 2005, pp. 38-56.

[49]   H. Michael, P. L. Harkonen, H. K. Vaananen and T. A. Hentunen, “Estrogen and Testosterone Use Different Cellular Pathways to Inhibit Osteoclastogenesis and Bone Resorption,” Journal of Bone and Mineral Research, Vol. 20, No. 12, 2005, pp. 2224-2232. doi:10.1359/JBMR.050803

[50]   D. Vanderschueren, E. Van Herck, P. Schot, E. Rush, T. Einhorn, P. Geusens and R. Bouillon, “The Aged Male Rat as a Model for Human Osteoporosis: Evaluation by Nondestructive Measurements and Biomechanical Testing,” Calcified Tissue International, Vol. 53, No. 5, 1993, pp. 342-347. doi:10.1007/BF01351841

[51]   D. Vanderschueren, E. Van Herck, R. De Coster and R. Bouillon, “Aromatization of Androgens Is Important for Skeletal Maintenance of Aged Male Rats,” Calcified Tissue International, Vol. 59, No. 3, 1996, pp. 179-183. doi:10.1007/s002239900106

[52]   V. C. Jordan, “SERMs: Meeting the Promise of Multifunctional Medicines,” Journal of the National Cancer Institute, Vol. 99, No. 5, 2007, pp. 350-356. doi:10.1093/jnci/djk062

[53]   C Jochems, U. Islander, A. Kallkopf, M. Lagerquist, C. Ohlsson and H. Carlsten, “Role of Raloxifene as a Potent Inhibitor of Experimental Postmenopausal Polyarthritis and Osteoporosis,” Arthritis & Rheumatism, Vol. 56, No. 10, 2007, pp. 3261-3270. doi:10.1002/art.22873

[54]   D. Mellstrom, O. Johnell, O. Ljunggren, A. L. Eriksson, M. Lorentzon, H. Mallmin, A. Holmberg, I. Redlund-Johnell, E. Orwoll and C. Ohlsson, “Free Testosterone Is an Independent Predictor of BMD and Prevalent Fractures in Elderly Men: MrOS Sweden,” Journal of Bone and Mineral Research, Vol. 21, No. 4, 2006, pp. 529-535.

[55]   A. Rapado, F. Hawkins, L. Sobrinho, M. Diaz-Curiel, A. Galvao-Telles, S. Arver, J. Melo Gomes, N. Mazer, J. Garcia e Costa, H. C. Orcajada, E. Lopez-Gavilanes, M. Mascarenhas, K. Papapietro, M. B. Lopez Alvarez, M. C. Pereira, G. Martinez, I. Valverde, J. J. Garcia, J. J. Carb allal and I. Garcia, “Bone Mineral Density and Androgen Levels in Elderly Males,” Calcified Tissue International, Vol. 65, No. 6, 1999, pp. 417-421. doi:10.1007/s002239900726

[56]   M. J. Diver, “Analytical and Physiological Factors Affecting the Interpretation of Serum Testosterone Concentration in Men,” Annals of Clinical Biochemistry, Vol. 43, 2006, pp. 3-12. doi:10.1258/000456306775141803

[57]   W. Rosner, R. J. Auchus, R. Azziz, P. M. Sluss and H. Raff, “Position Statement: Utility, Limitations, and Pitfalls in Measuring Testosterone: An Endocrine Society Position Statement,” The Journal of Clinical Endocrinology & Metabolism, Vol. 92, No. 2, 2007, pp. 405-413. doi:10.1210/jc.2006-1864

[58]   K. Bay, A. M. Andersson and N. E. Skakkebaek, “Estradiol Levels in Prepubertal Boys and Girls—Analytical Challenges,” International Journal of Andrology, Vol. 27, No. 5, 2004, pp. 266-273. doi:10.1111/j.1365-2605.2004.00487.x

[59]   M. M. Kushnir, A. L. Rockwood, W. L. Roberts, E. G. Pattison, A. M. Bunker, R. L. Fitzgerald and A. W. Meikle, “Performance Characteristics of a Novel Tandem Mass Spectrometry Assay for Serum Testosterone,” Clinical Chemistry, Vol. 52, No. 1, 2006, pp. 120-128. doi:10.1373/clinchem.2005.052167

[60]   R. Keen, “Osteoporosis: Strategies for Prevention and Management,” Best Practice & Research Clinical Rheumatology, Vol. 21, No. 1, 2007, pp. 109-122. doi:10.1016/j.berh.2006.10.004

[61]   N. E. Lane, “An Update on Glucocorticoid-Induced Osteoporosis,” Rheumatic Disease Clinics of North America, Vol. 27, No. 1, 2001, pp. 235-253. doi:10.1016/S0889-857X(05)70196-4

[62]   R. T. Turner, “Skeletal Response to Alcohol,” Alcoholism: Clinical and Experimental Research, Vol. 24, No. 11, 2000, pp. 1693-1701. doi:10.1111/j.1530-0277.2000.tb01971.x

[63]   Z. Yuan, N. Dawson, G. S. Cooper, D. Einstadter, R. Cebul and A. A. Rimm, “Effects of Alcohol-Related Disease on Hip Fracture and Mortality: A Retrospective Cohort Study of Hospitalized Medicare Beneficiaries,” American Journal of Public Health, Vol. 91, No. 7, 2001, pp. 1089-1093. doi:10.2105/AJPH.91.7.1089

[64]   H. M. Perry 3rd and J. E. Morley, “Osteoporosis in Men: Are We Ready to Diagnose and Treat?” Current Rheumatology Reports, Vol. 3, No. 3, 2001, pp. 240-244. doi:10.1007/s11926-001-0024-3

[65]   E. Orwoll, J. B. Blank, E. Barrett-Connor, J. Cauley, S. Cummings, K. Ensrud, C. Lewis, P. M. Cawthon, R. Marcus, L. M. Marshall, J. McGowan, K. Phipps, S. Sherman, M. L. Stefanick and K. Stone, “Design and Baseline Characteristics of the Osteoporotic Fractures in Men (MrOS) Study—A Large Observational Study of the Determinants of Fracture in Older Men,” Contemporary Clinical Trials, Vol. 26, No. 5, 2005, pp. 569-585. doi:10.1016/j.cct.2005.05.006

[66]   J. Placide and M. G. Martens, “Comparing Screening Methods for Osteoporosis,” Current Women’s Health Report, Vol. 3, No. 3, 2003, pp. 207-210.

[67]   M. C. Hochberg, “Recommendations for Measurement of Bone Mineral Density and Identifying Persons to be Treated for Osteoporosis,” Rheumatic Diseases Clinics of North America, Vol. 32, No. 4, 2006, pp. 681-689. doi:10.1016/j.rdc.2006.09.002

[68]   D. C. Bauer, S. K. Ewing, J. A. Cauley, K. E. Ensrud, S. R. Cummings and E. S. Orwoll, “Quantitative Ultrasound Predicts Hip and Non-Spine Fracture in Men: The MrOS Study,” Osteoporosis International, Vol. 18, No. 6, 2007, pp. 771-777. doi:10.1007/s00198-006-0317-5

[69]   E. Orwoll, “Assessing Bone Density in Men,” Journal of Bone and Mineral Research, Vol. 15, No. 10, 2000, pp. 1867-1870. doi:10.1359/jbmr.2000.15.10.1867

[70]   M. Z. Allende-Vigo, “The Use of Biochemical Markers of Bone Turnover in Osteoporosis,” Puerto Rico Health Sciences Journal, Vol. 26, No. 2, 2007, pp. 91-95.

[71]   V. Rochira, A. Balestrieri, B. Madeo, L. Zirilli, A. R. Granata and C. Carani, “Osteoporosis and Male Age-Related Hypogonadism: Role of Sex Steroids on Bone (Patho)Physiology,” European Journal of Endocrinology, Vol. 169, No. 2, 2006, pp. 175-185. doi:10.1530/eje.1.02088

[72]   H. W. Daniell, “Osteoporosis Due to Androgen Deprivation Therapy in Men with Prostate Cancer,” Urology, Vol. 58, No. 2, 2001, pp. 101-107. doi:10.1016/S0090-4295(01)01251-1

[73]   R. M. Francis, “The Effects of Testosterone on Osteoporosis in Men,” Clinical Endocrinology, Vol. 50, No. 4, 1999, pp. 411-414.

[74]   H. K. Kamel, “Male Osteoporosis: New Trends in Diagnosis and Therapy,” Drugs & Aging, Vol. 22, No. 9, 2005, pp. 741-748. doi:10.2165/00002512-200522090-00003

[75]   H. M. Behre, S. Kliesch, E. Leifke, T. M. Link and E. Nieschlag, “Long-Term Effect of Testosterone Therapy on Bone Mineral Density in Hypogonadal Men,” The Journal of Clinical Endocrinology & Metabolism, Vol. 82, No. 8, 1997, pp. 2386-2390. doi:10.1210/jc.82.8.2386

[76]   P. J. Snyder, H. Peachey, P. Hannoush, J. A. Berlin, L. Loh, J. H. Holmes, A. Dlewati, J. Staley, J. Santanna, S. C. Kapoor, M. F. Attie, J. G. Haddad Jr. and B. L. Strom, “Effect of Testosterone Treatment on Bone Mineral Density in Men over 65 Years of Age,” The Journal of Clinical Endocrinology & Metabolism, Vol. 84, No. 6, 1999, pp. 1966-1972. doi:10.1210/jc.84.6.1966

[77]   J. D. Scott, P. R. Wolfe, P. Anderson, G. R. Cohan and A. Scarsella, “Prospective Study of Topical Testosterone Gel (AndroGel) Versus Intramuscular Testosterone in Testosterone-Deficient HIV-Infected Men,” HIV Clinical Trials, Vol. 8, No. 6, 2007, pp. 412-420. doi:10.1310/hct0806-412

[78]   A. Fabbri, E. Giannetta, A. Lenzi and A. M. Isidori, “Testosterone Treatment to Mimic Hormone Physiology in Androgen Replacement Therapy. A View on Testosterone Gel and Other Preparations Available,” Expert Opinion on Biological Therapy, Vol. 7, No. 7, 2007, pp. 1093-1106. doi:10.1517/14712598.7.7.1093

[79]   L. Katznelson, J. S. Finkelstein, D. A. Schoenfeld, D. I. Rosenthal, E. J. Anderson and A. Klibanski, “Increase in Bone Density and Lean Body Mass during Testosterone Administration in Men with Acquired Hypogonadism,” The Journal of Clinical Endocrinology & Metabolism, Vol. 81, No. 12, 1996, pp. 4358-4365. doi:10.1210/jc.81.12.4358

[80]   C. Y. Guo, T. H. Jones and R. Eastell, “Treatment of Isolated Hypogonadotropic Hypogonadism Effect on Bone Mineral Density and Bone Turnover,” The Journal of Clinical Endocrinology & Metabolism, Vol. 82, No. 2, 1997, pp. 658-665. doi:10.1210/jc.82.2.658

[81]   M. Horowitz, J. M. Wishart, P. D. O’Loughlin, H. A. Morris, A. G. Need and B. E. Nordin, “Osteoporosis and Klinefelter’s Syndrome,” Clinical Endocrinology, Vol. 36, No. 1, 1992, pp. 113-118. doi:10.1111/j.1365-2265.1992.tb02910.x

[82]   J. P. van den Bergh, A. R. Hermus, A. I. Spruyt, C. G. Sweep, F. H. Corstens and A. G. Smals, “Bone Mineral Density and Quantitative Ultrasound Parameters in Patients with Klinefelter’s Syndrome after Long-Term Testosterone Substitution,” Osteoporosis International, Vol. 12, No. 1, 2001, pp. 55-62. doi:10.1007/s001980170158

[83]   C. Wang, G. Cunningham, A. Dobs, A. Iranmanesh, A. M. Matsumoto, P. J. Snyder, T. Weber, N. Berman, L. Hull and R. S. Swerdloff, “Long-Term Testosterone Gel (AndroGel) Treatment Maintains Beneficial Effects on Sexual Function and Mood, Lean and Fat Mass, and Bone Mineral Density in Hypogonadal Men,” The Journal of Clinical Endocrinology & Metabolism, Vol. 89, No. 5, 2004, pp. 2085-2098. doi:10.1210/jc.2003-032006

[84]   D. von Muhlen, G. A. Laughlin, D. Kritz-Silverstein, J. Bergstrom and R. Bettencourt, “Effect of Dehydroepian-drosterone Supplementation on Bone Mineral Density, Bone Markers, and Body Composition in Older Adults: The DAWN Trial,” Osteoporosis International, Vol. 19, No. 5, 2008, pp. 699-707. doi:10.1007/s00198-007-0520-z

[85]   B. Lunenfeld, “Androgen Therapy in the Aging Male,” World Journal of Urology, Vol. 21, No. 5, 2003, pp. 292- 305. doi:10.1007/s00345-003-0366-8

[86]   A. M. Kenny and K. M. Prestwood, “Osteoporosis. Pathogenesis, Diagnosis, and Treatment in Older Adults,” Rheumatic Disease Clinics of North America, Vol. 26, No. 3, 2000, pp. 569-591. doi:10.1016/S0889-857X(05)70157-5

[87]   M. R. Smith, “Treatment-Related Osteoporosis in Men with Prostate Cancer,” Clinical Cancer Research, Vol. 12, 2006, pp. 6315s-6319s. doi:10.1158/1078-0432.CCR-06-0846

[88]   D. Kastelan, Z. Giljevic, I. Kraljevic and M. Korsic, “Selective Estrogen Receptor Modulators: A Possible New Treatment of Osteoporosis in Males,” Medical Hypotheses, Vol. 67, No. 5, 2006, pp. 1052-1053. doi:10.1016/j.mehy.2006.04.040

[89]   M. R. Smith, “The Role of Bisphosphonates in Men with Prostate Cancer Receiving Androgen Deprivation Therapy,” Oncology, Vol. 18, No. 5, 2004, pp. 21-25.

[90]   N. H. Bell and R. H. Johnson, “Bisphosphonates in the Treatment of Osteoporosis,” Endocrine, Vol. 6, No. 2, 1997, pp. 203-206. doi:10.1007/BF02738966

[91]   H. Fleisch, “Bisphosphonates: A New Class of Drugs in Diseases of Bone and Calcium Metabolism,” Recent Results in Cancer Research, Vol. 116, 1989, pp. 1-28. doi:10.1007/978-3-642-83668-8_1

[92]   C. MacLean, S. Newberry, M. Maglione, M. McMahon, V. Ranganath, M. Suttorp, W. Mojica, M. Timmer, A. Alexander, M. McNamara, S. B. Desai, A. Zhou, S. Chen, J. Carter, C. Tringale, D. Valentine, B. Johnsen and J. Grossman, “Systematic Review: Comparative Effectiveness of Treatments to Prevent Fractures in Men and Women with Low Bone Density or Osteoporosis,” Annals of Internal Medicine, Vol. 148, No. 3, 2008, pp. 197-213. doi:10.7326/0003-4819-148-3-200802050-00198

[93]   R. G. Russell, “Bisphosphonates: Mode of Action and Pharmacology,” Pediatrics, Vol. 119, Suppl. 2, 2007, pp. S150-S162. doi:10.1542/peds.2006-2023H

[94]   P. Valverde, “Pharmacotherapies to Manage Bone Loss-Associated Diseases: A Quest for the Perfect Benefit-to-Risk Ratio,” Current Medicinal Chemistry, Vol. 15, No. 3, 2008, pp. 284-304. doi:10.2174/092986708783497274

[95]   R. G. Russell, N. B. Watts, F. H. Ebetino and M. J. Rogers, “Mechanisms of Action of Bisphosphonates: Similarities and Differences and Their Potential Influence on Clinical Efficacy,” Osteoporosis International, Vol. 19, No. 6, 2008, pp. 733-759. doi:10.1007/s00198-007-0540-8

[96]   M. C. Hochberg and R. Rizzoli, “Long-Term Experience with Alendronate in the Treatment of Osteoporosis,” Expert Opinion on Pharmacotherapy, Vol. 7, No. 9, 2006, pp. 1201-1210. doi:10.1517/14656566.7.9.1201

[97]   S. P. Tuck and H. K. Datta, “Osteoporosis in the Aging Male: Treatment Options,” Clinical Interventions in Aging, Vol. 2, No. 4, 2007, pp. 521-536.

[98]   P. N. Sambrook, “How to Prevent Steroid Induced Osteoporosis,” Annals of Rheumatic Diseases, Vol. 64, No. 2, 2005, pp. 176-178. doi:10.1136/ard.2003.018556

[99]   M. Q. Lacy, A. Dispenzieri, M. A. Gertz, P. R. Greipp, K. L. Gollbach, S. R. Hayman, S. Kumar, J. A. Lust, S. V. Rajkumar, S. J. Russell, T. E. Witzig, S. R. Zeldenrust, D. Dingli, P. L. Bergsagel, R. Fonseca, C. B. Reeder, A. K. Stewart, V. Roy, R. J. Dalton, A. B. Carr, D. Kademani, E. E. Keller, C. F. Viozzi and R. A. Kyle, “Mayo Clinic Consensus Statement for the Use of Bisphosphonates in Multiple Myeloma,” Mayo Clinic Proceedings, Vol. 81, No. 8, 2006, pp. 1047-1053. doi:10.4065/81.8.1047

[100]   M. Pazianas, P. Miller, W. A. Blumentals, M. Bernal and P. Kothawala, “A Review of the Literature on Osteonecrosis of the Jaw in Patients with Osteoporosis Treated with Oral Bisphosphonates: Prevalence, Risk Factors, and Clinical Characteristics,” Clinical Therapeutics, Vol. 29, No. 8, 2007, pp. 1548-1558. doi:10.1016/j.clinthera.2007.08.008

[101]   M. H. Vieillard, J. M. Maes, G. Penel, T. Facon, L. Magro, J. Bonneterre and B. Cortet, “Thirteen Cases of Jaw Osteonecrosis in Patients on Bisphosphonate Therapy,” Joint Bone Spine, Vol. 75, No. 1, 2008, pp. 34-40. doi:10.1016/j.jbspin.2007.05.003

[102]   D. Agnusdei and R. Gentilella, “GH and IGF-I as Therapeutic Agents for Osteoporosis,” Journal of Endocrinological Investigation, Vol. 28, Suppl. 8, 2005, pp. 32-36.

[103]   A. Toogood, “Safety and Efficacy of Growth Hormone Replacement Therapy in Adults,” Expert Opinion on Drug Safety, Vol. 4, No. 6, 2005, pp. 1069-1082. doi:10.1517/14740338.4.6.1069

[104]   E. Canalis, A. Giustina and J. P. Bilezikian, “Mechanisms of Anabolic Therapies for Osteoporosis,” The New England Journal of Medicine, Vol. 357, 2007, pp. 905-916.

[105]   K. Briot, F. Tremollieres, T. Thomas and C. Roux, “How Long Should Patients Take Medications for Postmenopausal Osteoporosis? Joint Bone Spine, Vol. 74, No. 1, 2007, pp. 24-31. doi:10.1016/j.jbspin.2006.05.011

[106]   D. Bodenner, C. Redman and A. Riggs, “Teriparatide in the Management of Osteoporosis,” Clinical Intervention in Aging, Vol. 2, No. 4, 2007, pp. 499-507.