The crosstalk between bone remodeling and energy metabolism: A translational perspective

Abstract

Genetics in model organisms has progressively broken down walls that previously separated different disciplines of biology. One example of this holistic evolution is the recognition of the complex relationship that exists between the control of bone mass (bone remodeling) and energy metabolism in mammals. Numerous hormones orchestrate this crosstalk. In particular, the study of the leptin-mediated regulation of bone mass has not only revealed the existence of a central control of bone mass but has also led to the realization that sympathetic innervation is a major regulator of bone remodeling. This happened at a time when the use of drugs aiming at treating osteoporosis, the most frequent bone disease, has dwindled. This review will highlight the main aspects of the leptin-mediated regulation of bone mass and how this led to the realization that β-blockers, which block the effects of the sympathetic nervous system, may be a viable option to prevent osteoporosis.

Keywords: coordinated regulation of bone mass and energy metabolism; osteoporosis; sympathetic regulation of bone mass; β-blockers.

Figure 1.. Leptin signaling in the central nervous system recruits the sympathetic nervous system to inhibit bone mass accrual

Leptin, a hormone responsible for enforcing energy balance, is a powerful regulator of bone mass. Leptin signals in the dorsal raphe of the brainstem to inhibit serotonin synthesis by Tph2. Serotonergic neurons from the dorsal raphe synapse at several nuclei in the hypothalamus including the VMH. Htr2c signaling in the VMH inhibits sympathetic nervous system activity in the skeleton, thereby inhibiting bone mass accrual. Within the skeleton, the sympathetic nervous system releases norepinephrine, which signals on osteoblasts to stimulate bone resorption and inhibits bone formation. In mice, norepinephrine signals through Adrb2, but in humans, sympathetic norepinephrine signals through both Adrb1 and Adrb2. The effects of norepinephrine signaling on bone mass accrual are conserved between mice and humans. Altogether, this series of findings made several points. First, an energy metabolism hormone does regulate bone mass accrual, a process that consumes a great deal of energy. Second, the central nervous system controls bone mass. Third, the sympathetic nervous system is a powerful inhibitor of bone mass accrual.

Figure 2.. Energy metabolism endocrine systems calibrate the balance between bone quality and energy conservation

Bone remodeling is the lifelong creation and destruction of bone tissue that preserves bone quality. Because bone is one of the largest organs in the body and because bone remodeling is one of the only healthy biological processes that requires the active destruction of tissue, bone remodeling is one of the largest consumers of energy in bony vertebrates. For these reasons and others, it was proposed that there would be a coordinated regulation of organismal energy metabolism and bone remodeling. This concept stimulated the discovery that leptin inhibits bone formation and stimulates bone resorption by signaling through the brain to activate the sympathetic nervous system, which then signals through the β-adrenergic receptor in osteoblasts. Over the subsequent two decades, a host of energy metabolism hormones and metabolites, listed in this figure, have been shown to influence bone remodeling and, as hypothesized, help calibrate the balance between bone quality and energy conservation.

Figure 3.. Current clinical tools in the treatment of osteoporosis

There are several classes of drugs listed in this figure that can improve outcomes in osteoporosis. Each of these drug classes either inhibits bone resorption by osteoclasts or stimulates osteoblastic bone formation to improve bone mass and quality in osteoporotic patients. In addition to acting on only one arm of bone remodeling, each of these drugs has significant adverse side effects or limits on duration of use as represented in the figure. *The adverse side effects caused by each osteoporosis treatment.

Figure 4.. Effects of β-blockers on BMD and bone turnover markers in humans

Percent change from baseline following 20 weeks of treatment in (A) ultradistal radius and (B) distal radius BMD, as well as serum levels of (C) CTX and (D) total osteocalcin; ANCOVA p values are indicated, and when these were <0.05, individual groups were compared with placebo using the Dunnett’s two-tailed t test; *p < 0.05; **p < 0.01; ***p < 0.001. Data are mean ± SEM. Adapted from Khosla et al. (2018).

Figure 5.. Potential clinical niche for a β-blocker for the primary prevention of osteoporosis

Although the established osteoporosis drugs (bisphosphonates, denosumab, teriparatide, abaloparatide, and Romosozumab) are prescribed for the treatment of established osteoporosis, following the results of the Women’s Health Initiative, there is virtually no viable option for the primary prevention of osteoporosis. β-blockers could potentially fill this niche.