Letters to the Editor: Serum Markers of Bone Metabolism Show Bone Loss in Hibernating Bears

To the Editor:

In the article published by Donahue et al,¹ they stated that hibernating black bears have biologic mechanisms that allow them to minimize bone loss during the inactivity associated with hibernation, as indicated by serial measures of markers of bone formation and resorption during hibernation and active summer period.¹ Such mechanisms maintain bone formation during hibernation at a greater level than one would expect based on the significant reduction of physical activity and body weight. The specific biologic factor(s) responsible for maintaining bone formation during hibernation have not been identified. We propose that a decrease in leptin may be the biologic factor responsible for minimizing bone loss during hibernation. This phenomenon may be caused by a steep drop in leptin levels around the time of hibernation, which would remove the inhibitory influence of leptin on the osteoblast, rather than by an increase in stimulatory mechanical inputs to this cell, as hypothesized by Donahue et al. Consistent with this hypothesis is their observation that bone loss in hibernating bears is minimized by maintaining osteoblastic function rather than by inhibiting osteoclast function, as indicated by measurements of carboxy-terminal cross-linked telopeptide, and the carboxy-terminal propeptide of Type I collagen, which are markers of bone resorption and formation, respectively.

In addition to its roles in the regulation of body weight and appetite control, it was reported that leptin exerts an inhibitory effect on bone formation in the ob/ob mouse, which is specifically mediated at the hypothalamic level by the sympathetic system.^2,7 This suppressive effect of leptin on bone mass has been regarded as paradoxic because leptin is produced by fat. Typically, mechanical load at the skeleton favors bone accretion, therefore low body weight is associated, across species, with lower bone mineral density, especially at weightbearing sites.⁵ Leptin levels are in large part determined by fat deposits, therefore caloric intake. However, the amount of fat present in the body is not the only determinant of circulating leptin. Seasonal changes in leptin levels, independent of fat content, have been reported in several hibernating species, including the common shrew and the blue fox.⁴ In the raccoon dog there is a steep decline in leptin levels at the beginning of hibernation when the fat deposits are at their peak.⁴ Such a decline in leptin levels therefore is independent of changes in fat mass. We propose that a similar drop in leptin also may occur in the bear in winter and trigger the removal of an inhibitory brake on the osteoblast preserving bone mass (Fig 1). Later throughout the winter, as fat deposits are used and leptin levels continue to decline, the inhibitory tone on the osteoblast continues to decline, thereby additionally limiting bone loss.

Fig 1.: A–B. This diagram shows the putative mechanisms at play during (A), nonhibernation disuse osteopenia and (B), hibernation disuse osteopenia, a condition during which bone mass is somewhat preserved in the black bear. We hypothesize there may be a decline in leptin levels at the beginning of hibernation that is triggered by unknown mechanisms, unrelated to the decrease in adiposity (fat levels are at a peak at this time). Such a decline removed the inhibitory brake that leptin tonically exerts on the osteoblast through the sympathetic system, therefore maintaining bone mass in the context of minimal weightbearing activity. This is based on observations that leptin acts on hypothalamic neurons to regulate bone mass. Specifically, the leptin-activated hypothalamic neurons stimulate sympathetic fibers, innervating the osteoblast, to release noradrenaline. Noradrenaline then binds to beta-2 adrenergic receptors which inhibit the osteoblast.

Hibernation is a means of adaptation to scarce food conditions as often found in nature. We hypothesize that the fall in the inhibitory effect of leptin on bone is part of the neuroendocrine adaptation to winter hibernation, a condition similar to starvation characterized by the minimal caloric intake and physical inactivity. In addition, as in starvation, it also would involve an inhibition of the sympathoadrenal system, reproductive and thyroid axes, and activation of the hypothalamic pituitary adrenal axis. Plasma cortisol levels were twofold to threefold higher during the denning period than during the active period, an effect observed in males and females with and without cubs. However, as stated by Donahue et al,¹ hypercortisolism did not suppress osteoblast activity thereby suggesting a degree of cortisol resistance during hibernation. Similarly, during hibernation there is a relative resistance to the effect of leptin on the centers of satiety and hunger. In addition to maintaining bone formation during hibernation, at the beginning of the active period there was a fourfold to fivefold increase in bone formation in two bears, indicating that recovery of bone mass after hibernation also may be efficient in this species. This phenomenon is reminiscent of the recovery of bone mass after pregnancy and lactation.³ It would be interesting to establish whether similar mechanisms are activated in these two physiologic conditions to preserve bone mass. Identification of these mechanisms may provide important clues for preventing bone loss in humans during prolonged periods of immobilization.

It is unclear whether leptin exerts any substantial effect on bone mass in humans. Administration of leptin for 6 months to two human subjects with a null mutation of the leptin gene did not result in any change in biochemical markers of bone turnover.⁶ Therefore, it is possible that the effects of leptin on bone mass in humans may be minimal. Seasonal changes in hormonal levels in humans tend to vanish because of artificial light, heating, and ample food which minimize changes in environmental conditions.⁸ However, most animal species still are vulnerable to seasonal changes, therefore the compensatory biologic mechanisms for adaptation still are apparent. In bears, where the period of inactivity is similar to the months of activity, hormonal changes may be necessary to minimize bone loss during hibernation. It is important to elucidate the mechanisms by which changes in leptin, independent of changes in adiposity, may preserve bone mass. We propose that leptin may be one of the biologic factors responsible for minimizing bone loss during hibernation.

Giovanni Cizza, MD, PhD

Clinical Endocrinology Branch, National Institute of Diabetes & Digestive & Kidney Disease, Bethesda, MD

Sejal Mistry, BS

National Institute of Diabetes & Digestive & Kidney Disease, Clinical Endocrinology Branch, National Institutes of Health, Bethesda, MD

Terry Phillips

Ultramicro Analytical Immunochemistry Resource Division of Bioengineering & Physical Science, Office of Research Services, National Institutes of Health, Bethesda, MD