Disuse uncouples bone formation from resorption, leading to increased porosity, decreased bone geometrical properties, and decreased bone mineral content which compromises bone mechanical properties and increases fracture risk. However, black bear bone properties are not adversely affected by aging despite annual periods of disuse (i.e., hibernation), which suggests that bears either prevent bone loss during disuse or lose bone and subsequently recover it at a faster rate than other animals. Here we show decreased cortical bone turnover during hibernation with balanced formation and resorption in grizzly bear femurs. Hibernating grizzly bear femurs were less porous and more mineralized, and did not demonstrate any changes in cortical bone geometry or whole bone mechanical properties compared to active grizzly bear femurs. The activation frequency of intracortical remodeling was 75% lower during hibernation than during periods of physical activity, but the normalized mineral apposition rate was unchanged. These data indicate bone turnover decreases during hibernation, but osteons continue to refill at normal rates. There were no changes in regional variation of porosity, geometry, or remodeling indices in femurs from hibernating bears, indicating that hibernation did not preferentially affect one region of the cortex. Thus, grizzly bears prevent bone loss during disuse by decreasing bone turnover and maintaining balanced formation and resorption, which preserves bone structure and strength. These results support the idea that bears possess a biological mechanism to prevent disuse osteoporosis.

SUMMARY Mechanical unloading of bone causes an imbalance in bone formation and resorption leading to bone loss and increased fracture risk. Black bears(Ursus americanus) are inactive for up to six months during hibernation, yet bone mineral content and strength do not decrease with disuse or aging. To test whether hibernating bears have biological mechanisms to prevent disuse osteoporosis, we measured the serum concentrations of hormones and growth factors involved in bone metabolism and correlated them with the serum concentration of a bone formation marker (osteocalcin). Serum was obtained from black bears over a 7-month duration that included periods of activity and inactivity. Both resorption and formation markers increased during hibernation, suggesting high bone turnover occurred during inactivity. However, bone formation appeared to be balanced with bone resorption. The serum concentration of parathyroid hormone (PTH) was higher in the hibernation(P=0.35) and post-hibernation (P=0.006) seasons relative to pre-hibernation levels. Serum leptin was lower (P<0.004)post-hibernation relative to pre-hibernation and hibernation periods. Insulin-like growth factor I (IGF-I) decreased (P<0.0001) during hibernation relative to pre-hibernation and reached its highest value during remobilization. There was no difference (P=0.64) in 25-OH vitamin D between the three seasons. Serum osteocalcin (bone formation marker) was significantly correlated with PTH, but not with leptin, IGF-I or 25-OH vitamin D. Osteocalcin and PTH were positively correlated when samples from all seasons were pooled and when only hibernation samples were considered, raising the possibility that the anabolic actions of PTH help maintain bone formation to prevent disuse osteoporosis. Prostaglandin E2 (PGE2)release from MC3T3 osteoblastic cells was significantly affected by treatment with bear serum from different seasons (i.e. hibernation versus active periods). The seasonal changes in PGE2 release showed trends similar to the seasonal changes in serum IGF-I. Since both PGE2 and IGF-I are associated with collagenous bone formation, it is possible that seasonal changes in a circulating factor influence IGF-I levels in vivo in bears and PGE2 release in osteoblastic cells in vitro. The significant decrease in serum leptin following arousal from hibernation may promote bone formation during remobilization, assuming there is a similar decrease in intracerebroventricular leptin. These findings support the idea that seasonal changes in the concentration of circulating molecules help regulate bone formation activity and may be important for preventing disuse osteoporosis in bears.

Bone adaptation to mechanical loading is dependent on age and the frequency and magnitude of loading. It is believed that load-induced fluid flow in the porous spaces of bone is an important signal that influences bone cell metabolism and bone adaptation. We used fluid flow-induced shear stress as a mechanical stimulus to study intracellular calcium (Ca) signaling in rat osteoblastic cells (ROB) isolated from young, mature, and old animals. Fluid flow produced higher magnitude and more abundant [Ca(2+)](i) oscillations than spontaneous oscillations, suggesting that flow-induced Ca signaling encodes a different cellular message than spontaneous oscillations. ROB from old rats showed less basal [Ca(2+)](i) activity and were less responsive to fluid flow. Cells were more responsive to 0.2 Hz than to 1 or 2 Hz and to 2 Pa than to 1 Pa. These data suggest that the frequency and magnitude of mechanical loading may be encoded by the percentage of cells displaying [Ca(2+)](i) oscillations but that the ability to transduce this information may be altered with age.

Bone evolved to serve many mechanical and physiological functions. Osteocytes and bone remodeling first appeared in the dermal skeleton of fish, and subsequently adapted to various challenges in terrestrial animals occupying diverse environments. This review discusses the physiology of bone and its role in mechanical and calcium homeostases from an evolutionary perspective. We review how bone physiology responds to changing environments and the adaptations to unique and extreme physiological conditions.

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