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Sex Steroids and the Construction and Conservation of the Adult Skeleton

Division of Endocrinology and Metabolism (B.L.R., S.K., L.J.M.), Department of Internal Medicine, and Section of Clinical Epidemiology (L.J.M.), Department of Health Sciences Research, Mayo Clinic and Mayo Foundation, 200 First Street SW, Rochester, Minnesota 55905

Correspondence: Address all correspondence and requests for reprints to: B. Lawrence Riggs, M.D., Mayo Clinic and Mayo Foundation, 200 First Street SW, North 6 Plummer, Rochester, Minnesota 55905.

Here we review and extend a new unitary model for the pathophysiology of involutional osteoporosis that identifies estrogen (E) as the key hormone for maintaining bone mass and E deficiency as the major cause of age-related bone loss in both sexes. Also, both E and testosterone (T) are key regulators of skeletal growth and maturation, and E, together with GH and IGF-I, initiate a 3- to 4-yr pubertal growth spurt that doubles skeletal mass. Although E is required for the attainment of maximal peak bone mass in both sexes, the additional action of T on stimulating periosteal apposition accounts for the larger size and thicker cortices of the adult male skeleton. Aging women undergo two phases of bone loss, whereas aging men undergo only one. In women, the menopause initiates an accelerated phase of predominantly cancellous bone loss that declines rapidly over 4–8 yr to become asymptotic with a subsequent slow phase that continues indefinitely. The accelerated phase results from the loss of the direct restraining effects of E on bone turnover, an action mediated by E receptors in both osteoblasts and osteoclasts. In the ensuing slow phase, the rate of cancellous bone loss is reduced, but the rate of cortical bone loss is unchanged or increased. This phase is mediated largely by secondary hyperparathyroidism that results from the loss of E actions on extraskeletal calcium metabolism. The resultant external calcium losses increase the level of dietary calcium intake that is required to maintain bone balance. Impaired osteoblast function due to E deficiency, aging, or both also contributes to the slow phase of bone loss. Although both serum bioavailable (Bio) E and Bio T decline in aging men, Bio E is the major predictor of their bone loss. Thus, both sex steroids are important for developing peak bone mass, but E deficiency is the major determinant of age-related bone loss in both sexes.

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				E. Bonnelye and J. E. Aubin Estrogen Receptor-Related Receptor {alpha}: A Mediator of Estrogen Response in Bone J. Clin. Endocrinol. Metab., May 1, 2005; 90(5): 3115 - 3121. [Abstract] [Full Text] [PDF]

				K. E. Ensrud, R. L. Fullman, E. Barrett-Connor, J. A. Cauley, M. L. Stefanick, H. A. Fink, C. E. Lewis, E. Orwoll, and for the Osteoporotic Fractures in Men Study Resear Voluntary Weight Reduction in Older Men Increases Hip Bone Loss: The Osteoporotic Fractures in Men Study J. Clin. Endocrinol. Metab., April 1, 2005; 90(4): 1998 - 2004. [Abstract] [Full Text] [PDF]

				S. Bonadonna, A. Burattin, M. Nuzzo, G. Bugari, E. A. Rosei, D. Valle, N. Iori, J. P Bilezikian, J. D Veldhuis, and A. Giustina Chronic glucocorticoid treatment alters spontaneous pulsatile parathyroid hormone secretory dynamics in human subjects Eur. J. Endocrinol., February 1, 2005; 152(2): 199 - 205. [Abstract] [Full Text] [PDF]

				P. V. Nantermet, P. Masarachia, M. A. Gentile, B. Pennypacker, J. Xu, D. Holder, D. Gerhold, D. Towler, A. Schmidt, D. B. Kimmel, et al. Androgenic Induction of Growth and Differentiation in the Rodent Uterus Involves the Modulation of Estrogen-Regulated Genetic Pathways Endocrinology, February 1, 2005; 146(2): 564 - 578. [Abstract] [Full Text] [PDF]

				J. M. Lean, C. J. Jagger, B. Kirstein, K. Fuller, and T. J. Chambers Hydrogen Peroxide Is Essential for Estrogen-Deficiency Bone Loss and Osteoclast Formation Endocrinology, February 1, 2005; 146(2): 728 - 735. [Abstract] [Full Text] [PDF]

				D. A. M. Salih, S. Mohan, Y. Kasukawa, G. Tripathi, F. A. Lovett, N. F. Anderson, E. J. Carter, J. E. Wergedal, D. J. Baylink, and J. M. Pell Insulin-Like Growth Factor-Binding Protein-5 Induces a Gender-Related Decrease in Bone Mineral Density in Transgenic Mice Endocrinology, February 1, 2005; 146(2): 931 - 940. [Abstract] [Full Text] [PDF]

				C. J. Jagger, J. M. Lean, J. T. Davies, and T. J. Chambers Tumor Necrosis Factor-{alpha} Mediates Osteopenia Caused by Depletion of Antioxidants Endocrinology, January 1, 2005; 146(1): 113 - 118. [Abstract] [Full Text] [PDF]

				A Martinetti, E Bajetta, L Ferrari, N Zilembo, E Seregni, M Del Vecchio, R Longarini, I La Torre, L Toffolatti, D Paleari, et al. Osteoprotegerin and osteopontin serum values in postmenopausal advanced breast cancer patients treated with anastrozole Endocr. Relat. Cancer, December 1, 2004; 11(4): 771 - 779. [Abstract] [Full Text] [PDF]

				L. Gennari, R. Nuti, and J. P. Bilezikian Aromatase Activity and Bone Homeostasis in Men J. Clin. Endocrinol. Metab., December 1, 2004; 89(12): 5898 - 5907. [Abstract] [Full Text] [PDF]

				Y. Gao, W.-P. Qian, K. Dark, G. Toraldo, A. S. P. Lin, R. E. Guldberg, R. A. Flavell, M. N. Weitzmann, and R. Pacifici Estrogen prevents bone loss through transforming growth factor {beta} signaling in T cells PNAS, November 23, 2004; 101(47): 16618 - 16623. [Abstract] [Full Text] [PDF]

				K. B. Markou, P. Mylonas, A. Theodoropoulou, A. Kontogiannis, M. Leglise, A. G. Vagenakis, and N. A. Georgopoulos The Influence of Intensive Physical Exercise on Bone Acquisition in Adolescent Elite Female and Male Artistic Gymnasts J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4383 - 4387. [Abstract] [Full Text] [PDF]

				M. Muir, G. Romalo, L. Wolf, W. Elger, and H.-U. Schweikert Estrone Sulfate Is a Major Source of Local Estrogen Formation in Human Bone J. Clin. Endocrinol. Metab., September 1, 2004; 89(9): 4685 - 4692. [Abstract] [Full Text] [PDF]

				H. W. Goderie-Plomp, M. van der Klift, W. de Ronde, A. Hofman, F. H. de Jong, and H. A. P. Pols Endogenous Sex Hormones, Sex Hormone-Binding Globulin, and the Risk of Incident Vertebral Fractures in Elderly Men and Women: The Rotterdam Study J. Clin. Endocrinol. Metab., July 1, 2004; 89(7): 3261 - 3269. [Abstract] [Full Text] [PDF]

				F. Stossi, D. H. Barnett, J. Frasor, B. Komm, C. R. Lyttle, and B. S. Katzenellenbogen Transcriptional Profiling of Estrogen-Regulated Gene Expression via Estrogen Receptor (ER) {alpha} or ER{beta} in Human Osteosarcoma Cells: Distinct and Common Target Genes for These Receptors Endocrinology, July 1, 2004; 145(7): 3473 - 3486. [Abstract] [Full Text] [PDF]

				D. Vanderschueren, L. Vandenput, S. Boonen, M. K. Lindberg, R. Bouillon, and C. Ohlsson Androgens and Bone Endocr. Rev., June 1, 2004; 25(3): 389 - 425. [Abstract] [Full Text] [PDF]

				U. I. L. Modder, A. Sanyal, A. E. Kearns, J. D. Sibonga, E. Nishihara, J. Xu, B. W. O'Malley, E. L. Ritman, B. L. Riggs, T. C. Spelsberg, et al. Effects of Loss of Steroid Receptor Coactivator-1 on the Skeletal Response to Estrogen in Mice Endocrinology, February 1, 2004; 145(2): 913 - 921. [Abstract] [Full Text] [PDF]

				J. Somner, S. McLellan, J. Cheung, Y. T. Mak, M. L. Frost, K. M. Knapp, A. S. Wierzbicki, M. Wheeler, I. Fogelman, S. H. Ralston, et al. Polymorphisms in the P450 c17 (17-Hydroxylase/17,20-Lyase) and P450 c19 (Aromatase) Genes: Association with Serum Sex Steroid Concentrations and Bone Mineral Density in Postmenopausal Women J. Clin. Endocrinol. Metab., January 1, 2004; 89(1): 344 - 351. [Abstract] [Full Text] [PDF]

				S. Bhasin, W. E. Taylor, R. Singh, J. Artaza, I. Sinha-Hikim, R. Jasuja, H. Choi, and N. F. Gonzalez-Cadavid The Mechanisms of Androgen Effects on Body Composition: Mesenchymal Pluripotent Cell as the Target of Androgen Action J. Gerontol. A Biol. Sci. Med. Sci., December 1, 2003; 58(12): M1103 - 1110. [Abstract] [Full Text] [PDF]

				Y. Kasukawa, D. J. Baylink, J. E. Wergedal, Y. Amaar, A. K. Srivastava, R. Guo, and S. Mohan Lack of Insulin-Like Growth Factor I Exaggerates the Effect of Calcium Deficiency on Bone Accretion in Mice Endocrinology, November 1, 2003; 144(11): 4682 - 4689. [Abstract] [Full Text] [PDF]

				S. Cenci, G. Toraldo, M. N. Weitzmann, C. Roggia, Y. Gao, W. P. Qian, O. Sierra, and R. Pacifici Estrogen deficiency induces bone loss by increasing T cell proliferation and lifespan through IFN-{gamma}-induced class II transactivator PNAS, September 2, 2003; 100(18): 10405 - 10410. [Abstract] [Full Text] [PDF]

				H. Kawano, T. Sato, T. Yamada, T. Matsumoto, K. Sekine, T. Watanabe, T. Nakamura, T. Fukuda, K. Yoshimura, T. Yoshizawa, et al. Suppressive function of androgen receptor in bone resorption PNAS, August 5, 2003; 100(16): 9416 - 9421. [Abstract] [Full Text] [PDF]

				M. Faustini-Fustini, A. Balestrieri, V. Rochira, and C. Carani The Apparent Paradox of Tall Stature with Hypopituitarism: New Insights from an Old Story J. Clin. Endocrinol. Metab., August 1, 2003; 88(8): 4002 - 4003. [Full Text]

				I. Van Pottelbergh, S. Goemaere, and J. M. Kaufman Bioavailable Estradiol and an Aromatase Gene Polymorphism Are Determinants of Bone Mineral Density Changes in Men over 70 Years of Age J. Clin. Endocrinol. Metab., July 1, 2003; 88(7): 3075 - 3081. [Abstract] [Full Text] [PDF]

				K.-i. Hirose, H. Tomiyama, R. Okazaki, T. Arai, Y. Koji, G. Zaydun, S. Hori, and A. Yamashina Increased Pulse Wave Velocity Associated with Reduced Calcaneal Quantitative Osteo-sono Index: Possible Relationship Between Atherosclerosis and Osteopenia J. Clin. Endocrinol. Metab., June 1, 2003; 88(6): 2573 - 2578. [Abstract] [Full Text] [PDF]