Low energy availability reduces bone mass and gonadal function in male mice

Abstract

Abstract In women, the female athlete triad, marked by low energy availability, functional hypothalamic amenorrhea and osteoporosis, is a recognized risk for stress fractures. Stress injuries also occur in men, but by contrast risks and mechanisms underlying them are less characterized. Here we propose that low energy availability puts men at risk for stress injuries as well. Male low energy availability model mice, established by limiting food intake, exhibited significantly reduced testicle weight, serum testosterone levels and bone mass. Such losses in bone mass were enhanced by exercise in food-restricted (FR) male mice. Histological analysis revealed that both bone-resorbing and -forming activities were significantly reduced in FR or FR plus exercise (FR+ex) mice, mimicking a state of low bone turnover. Significantly reduced bone mass in FR or FR+ex male mice was significantly rescued by treatment with 1,25(OH)2D3 (1.25) or ED71 (ED), both active vitamin D analogues, with significant restoration of osteoblastic activities. Serum levels of insulin-like growth factor I (IGF-I), which activates osteoblastic activities and is critical for bone remodeling, were significantly lower in FR versus control male mice, but restored by administration of either of vitamin D analogue. However, administration of recombinant IGF-I did not rescue reduced bone mass in FR male mice, and administration of either active vitamin D analogue could increase bone mass even in IGF-I conditional knockout FR male mice. Taken together, conditions comparable to the female athlete triad are also a risk for male stress injuries, and low energy availability is upstream of gonadal dysfunction and osteoporosis in males. Active vitamin D analogues could serve as therapeutic or preventive options for stress injuries in men.