2 In order to understand gender diﬀerences in fracture risk in elderly subjects, it is important to understand the gender diﬀerences in the conditions of accrual of peak bone strength during childhood and adolescence. The achievement of peak bone strength is a function both of accrual bone of mass and changes in bone geometry, and this diﬀers strongly in males and females in relation to patterns of skeletal muscle growth. The idea of the bone-muscle unit, derived from the mechanostat theory [1, 2], has been widely employed to account for gender-speciﬁc trends in acquisition of peak bone strength in relation to growth of muscle area [3, 4]. From this point of view, bone structure evolves to match in- creased tissue strains occurring as a function of growth. During the period of rapid growth in adolescence, bone structure constantly adapts to maintain stability in the pres- ence of mechanical loads and a rapidly changing hormonal environment. In this phase, changes in mechanical loads occur as bones grow longitudinally, resulting in higher lever arms and increasing bending moments. The increasing size and strength of muscles result in larger deformation forces on bone. The increased mechanical stimulation due to the com- bination of longitudinal growth and muscle contraction results in bone growth primarily due to periosteal bone formation. Gender diﬀerences in the relation of muscle and bone growth are generally not evident in early childhood, and studies show little to any diﬀerences in the relation of muscle to bone area. However, gender-variant patterns emerge during adolescence, reﬂecting the diﬀerent musculoskeletal eﬀects of testosterone and estrogen in males and females [5]. In males, the changes of bone and muscle during puberty are dominated by the increasing levels of testosterone and IGF- 1, which result in increased muscle mass and strength. The combination of higher deformation forces and the higher bending moments due to longitudinal growth leads to a bone growth pattern dominated by periosteal apposition. Thus, in men, the growth in muscle and bone is more parallel in nature and the peak values of cortical area and muscle cross- sectional area tend to coincide within half a year in men. In girls, with lower levels of testosterone, and higher levels of estrogen, bone mass, but not total cross-sectional area, tends to increase more rapidly in relation to muscle area. The increase in bone mass appears to take the form of increased endosteal apposition, rather than periosteal apposition. A study examining gender diﬀerences in bone structure in young men and women at the hip, distal tibia, and distal radius found that men have higher total and cortical bone cross-sectional area, but volumetric density values similar to those observed in women [6]. When the data are adjusted for diﬀerences in body height, gender diﬀerences in cortical thickness and area are highly attenuated, but diﬀerences in total bone cross-sectional area remain large. The higher total bone area is consistent with higher muscle cross-sectional area found in young men compared to young women. In young adulthood, there are apparent gender diﬀerences in the correlation of muscle area to bone area. In men, more of the variation in bone dimensions is explained by muscle area in men [7]. Women have higher values of bone in relation Journal of Osteoporosis to muscle, but a lower percentage of the variation in cortical area in women is explained by muscle mass [8]. 3. Aging, Physical Activity, and Skeletal Integrity After attainment of peak bone and muscle strength, both men and women begin to lose both bone and muscle tissue with age. In women, age-related bone loss begins in the early to mid-thirties. This process is greatly accentuated by the rapid decrease of estrogen levels occurring as a result of the menopause. Men have a lower rate of bone loss that continues throughout the lifespan that is also inﬂuenced by age-related decreases in estradiol levels. Both men and wom- en undergo age-related muscle loss associated with decline in testosterone levels, with men undergoing a larger lifetime loss of muscle mass and strength. In the aging process, the bone-muscle relationship is aﬀected by gender diﬀerences in the rate of loss of bone and muscle and in the mechanosensitivity of bone. In males, aging is characterized by large declines in testosterone, and men experience cross-sectional and longitudinal losses of muscle strength and mass that are twice what is observed in women [9, 10]. Women, on the other hand, experience an over 50% larger lifetime loss of bone mass and strength, driven by loss of age- and menopause-related loss of estrogen [6, 11]. Although bone and muscle show sharply diﬀerent age-related changes in men and women, the critical factor for the bone muscle relationship is the change in bone mechanosensitivity that occurs in women as a function of estrogen loss. At the cellular level, mechanical loading involves a series of molecular events that depend on the estrogen receptor alpha (ER-α). ER-α number declines with menopause, reducing the ability of mechanical loading to induce an osteogenic response [12]. This picture is consistent with gender diﬀerences in the relationship of muscle mass with bone density, with men tending to show higher correlations between muscle mass and areal bone density [13]. It is also consistent with observations that the eﬀect of strenuous exercise on bone mineral density is attenuated in older compared to younger women and that among older subjects, evidence seems to point to more robust exercise eﬀects on bone in men. Overall, the relationship of muscle mass to bone structure and strength is more preserved in men than in women. While exercise can be of high relevance in reducing the rate of age-related bone loss in both genders, the eﬀect is especially important in men. 4. Muscle and Bone Tissues as Individual Targets of Systemic Hormone Action IGF-1 is a hormone that targets both muscle and bone tissue and is considered to be of particularly high importance in the development of osteoporosis and sarcopenia in males. IGF- 1 stimulates the proliferation of muscle progenitor cells and their integration with existing ﬁbers during the muscle repair process [14]. It also aﬀects pathways controlling the calcium- induced contractility of muscle ﬁbers. IGF-1 is also anabolic