Journal of Osteoporosis for bone. Mice with overexpression of IGF-1 show higher cortical tissue properties. In men, increasing IGF-1 levels are associated with increasing femoral neck density [15]. The expression of IGF-1 in muscle tissue may be associated with the positive skeletal eﬀects of exercise in both young and elderly men, and the age-related decrease of IGF-1 levels may lead to decreased mechanosensitivity as reﬂected in the lower eﬀects of exercise on bone in elderly men. Androgens play a signiﬁcant role in the development and maintenance of muscle and of skeletal integrity in both men and women. Androgens stimulate the skeletal modeling process by inhibition of RANKL action on osteoclasts both through their own receptors and through aromatization to estrogen. In the growth process, androgens are responsible for large increases in formation of trabecular bone and are in particular associated with bone size, in both men and women [16]. Androgen loss has a particularly important eﬀect in men; eugonadal men undergo severe bone loss, which can be partially recovered through androgen replacement therapy. Androgens also have a particularly important role in skeletal muscle in men. Increased testosterone levels are associated with increased muscle mass in men, and low levels of an- drogen lead to loss of muscle mass and reduced growth of muscle mass in boys. Androgens are also important for skeletal and skeletal muscle development in women. Women with low testosterone levels show higher degrees of menopause-related bone loss, a condition that can be counteracted through androgen supplementation [17]. While estrogen is central to skeletal growth and mainte- nance of skeletal integrity in women, it is also a signiﬁcant factor for men. Estrogen inhibits the action of proresorption cytokines. Decrease in estrogen levels, in both genders, results in increased bone resorption, but low levels of estro- gen also aﬀect the skeleton by decreasing mechanosensitivity. Thus, as with androgens, estrogens aﬀect the muscle bone system by decreasing the eﬀect of muscle contractions on bone, leading potentially to decreased eﬃcacy of resistance exercise in men as well as women with increasing age. 5. Molecular Signaling between Muscle and Bone Emerging research indicates that muscles release factors that are detected by bones and that may aﬀect bone structure and strength independently of mechanical loads. In a study of mice lacking a muscle-speciﬁc phosphatase (MIP/MTMR14;MIPKO), Brotto et al. reported increases in intracellular phosphate accompanied by impaired calcium homeostasis, decreases in the function of skeletal, cardiac, and smooth muscle, as well as deterioration of trabecular structure with no eﬀect on cortical bone [18]. The skeletal eﬀects of ablation of MIP were gender-speciﬁc. Female knockout mice of 12–14 months showed severe trabecular bone loss, but this knockout did not appear to have a similar eﬀect on male mice. Further investigation in this area is underway, and a potential gender diﬀerence in muscle-bone signaling, which is independent of the mechanical loads on 3 bone exerted by muscle, may have importance for gender- speciﬁc strategies for prevention of muscle and bone loss. 6. Summary In conclusion, the interaction between bone and muscle, in the process of growth and development and in the process of aging, diﬀers between men and women. In females, the growth process is characterized by increased mass and strength of bone relative to that of muscle, whereas in men, increases in testosterone fuel large increases in muscle, resulting in muscle forces that coincide with a large growth in bone dimensions and strength. In both genders, aging causes pronounced losses in both tissues, but the large decrease in estrogen levels in women appears to diminish the skeleton’s responsiveness to exercise more than in men. In contrast, the aging of the muscle-bone axis in men is a function of age- related declines in both hormones. The gender diﬀerences in the acquisition and age-related loss in bone and muscle tis- sues may be important for developing gender-speciﬁc strat- egies for using exercise to reduce bone loss with aging. References [1] H. M. Frost, “Bone “mass” and the “mechanostat”: a pro- posal,” Anatomical Record, vol. 219, no. 1, pp. 1–9, 1987. [2] H. M. Frost, “Muscle, bone, and the Utah paradigm: a 1999 overview,” Medicine and Science in Sports and Exercise, vol. 32, no. 5, pp. 911–917, 2000. [3] O. Fricke and E. Schoenau, “The “Functional Muscle-Bone Unit”: probing the relevance of mechanical signals for bone development in children and adolescents,” Growth Hormone and IGF Research, vol. 17, no. 1, pp. 1–9, 2007. [4] E. Schoenau, “From mechanostat theory to development of the ‘functional muscle-bone-unit’,” Journal of Musculoskeletal Neuronal Interactions, vol. 5, no. 3, pp. 232–238, 2005. [5] I. Zˇofkova´, “Hormonal aspects of the muscle-bone unit,” Physiological Research, vol. 57, supplement 1, pp. S159–S169, 2008. [6] B. L. Riggs, L. J. Melton III, R. A. Robb et al., “Population- based study of age and sex diﬀerences in bone volumetric density, size, geometry, and structure at diﬀerent skeletal sites,” Journal of Bone and Mineral Research, vol. 19, no. 12, pp. 1945– 1954, 2004. [7] H. Macdonald, S. Kontulainen, M. Petit, P. Janssen, and H. McKay, “Bone strength and its determinants in pre- and early pubertal boys and girls,” Bone, vol. 39, no. 3, pp. 598–608, 2006. [8] A. Arabi, H. Tamim, M. Nabulsi et al., “Sex diﬀerences in the eﬀect of body-composition variables on bone mass in healthy children and adolescents,” The American Journal of Clinical Nutrition, vol. 80, no. 5, pp. 1428–1435, 2004. [9] A. Guadalupe-Grau, T. Fuentes, B. Guerra, and J. A. L. Calbet, “Exercise and bone mass in adults,” Sports Medicine, vol. 39, no. 6, pp. 439–468, 2009. [10] M. J. Delmonico, T. B. Harris, M. Visser et al., “Longitudinal study of muscle strength, quality, and adipose tissue inﬁltra- tion,” American Journal of Clinical Nutrition, vol. 90, no. 6, pp. 1579–1585, 2009. [11] T. M. Keaveny, D. L. Kopperdahl, L. J. Melton III et al., “Age- dependence of femoral strength in white women and men,”