Osteoporosis represents the most common bone disease worldwide and results in a significantly increased fracture risk. Extrinsic and intrinsic factors implicated in the development of osteoporosis are also associated with delayed fracture healing and impaired bone regeneration. Based on a steadily increasing life expectancy in modern societies, the global implications of osteoporosis and impaired bone healing are substantial. Research in the last decades has revealed several molecular pathways that stimulate bone formation and could be targeted to treat both osteoporosis and impaired fracture healing. The identification and development of therapeutic approaches modulating bone formation, rather than bone resorption, fulfils an essential clinical need, as treatment options for reversing bone loss and promoting bone regeneration are limited. This review focuses on currently available and future approaches that may have the potential to achieve these aims.

Impaired fracture healing represents an ongoing clinical challenge, as treatment options remain limited. Calcitonin gene-related peptide (CGRP), a neuropeptide targeted by emerging anti-migraine drugs, is also expressed in sensory nerve fibres innervating bone tissue. Bone healing following a femoral osteotomy stabilized with an external fixator was analysed over 21 days in αCGRP-deficient and WT mice. Bone regeneration was evaluated by serum analysis, µCT analysis, histomorphometry and genome-wide expression analysis. Bone-marrow-derived osteoblasts and osteoclasts, as well as the CGRP antagonist olcegepant were employed for mechanistic studies. WT mice with a femoral fracture display increased CGRP serum levels. αCGRP mRNA expression after skeletal injury is exclusively induced in callus tissue, but not in other organs. On protein level, CGRP and its receptor, calcitonin receptor-like receptor (CRLR) complexing with RAMP1, are differentially expressed in the callus during bone regeneration. On the other hand, αCGRP-deficient mice display profoundly impaired bone regeneration characterised by a striking reduction in the number of bone-forming osteoblasts and a high rate of incomplete callus bridging and non-union. As assessed by genome-wide expression analysis, CGRP induces the expression of specific genes linked to ossification, bone remodeling and adipogenesis. This suggests that CGRP receptor-dependent PPARγ signaling plays a central role in fracture healing. This study demonstrates an essential role of αCGRP in orchestrating callus formation and identifies CGRP receptor agonism as a potential approach to stimulate bone regeneration. Moreover, as novel agents blocking CGRP or its receptor CRLR are currently introduced clinically for the treatment of migraine disorders, their potential negative impact on bone regeneration warrants clinical investigation. This work was funded by grants from the Else-Kröner-Fresenius-Stiftung (EKFS), the Deutsche Forschungsgemeinschaft (DFG), and the Berlin Institute of Health (BIH).

As brain and bone disorders represent major health issues worldwide, substantial clinical investigations demonstrated a bidirectional crosstalk on several levels, mechanistically linking both apparently unrelated organs. While multiple stress, mood and neurodegenerative brain disorders are associated with osteoporosis, rare genetic skeletal diseases display impaired brain development and function. Along with brain and bone pathologies, particularly trauma events highlight the strong interaction of both organs. This review summarizes clinical and experimental observations reported for the crosstalk of brain and bone, followed by a detailed overview of their molecular bases. While brain-derived molecules affecting bone include central regulators, transmitters of the sympathetic, parasympathetic and sensory nervous system, bone-derived mediators altering brain function are released from bone cells and the bone marrow. Although the main pathways of the brain-bone crosstalk remain ‘efferent’, signaling from brain to bone, this review emphasizes the emergence of bone as a crucial ‘afferent’ regulator of cerebral development, function and pathophysiology. Therefore, unraveling the physiological and pathological bases of brain-bone interactions revealed promising pharmacologic targets and novel treatment strategies promoting concurrent brain and bone recovery.

Traumatic brain injury (TBI) leads to skeletal changes, including bone loss in the unfractured skeleton, and paradoxically accelerates healing of bone fractures; however, the mechanisms remain unclear. TBI is associated with a hyperadrenergic state characterized by increased norepinephrine release. Here, we identified the β ₂ -adrenergic receptor (ADRB2) as a mediator of skeletal changes in response to increased norepinephrine. In a murine model of femoral osteotomy combined with cortical impact brain injury, TBI was associated with ADRB2-dependent enhanced fracture healing compared with osteotomy alone. In the unfractured 12-week-old mouse skeleton, ADRB2 was required for TBI-induced decrease in bone formation and increased bone resorption. Adult 30-week-old mice had higher bone concentrations of norepinephrine, and ADRB2 expression was associated with decreased bone volume in the unfractured skeleton and better fracture healing in the injured skeleton. Norepinephrine stimulated expression of vascular endothelial growth factor A and calcitonin gene–related peptide-α (αCGRP) in periosteal cells through ADRB2, promoting formation of osteogenic type-H vessels in the fracture callus. Both ADRB2 and αCGRP were required for the beneficial effect of TBI on bone repair. Adult mice deficient in ADRB2 without TBI developed fracture nonunion despite high bone formation in uninjured bone. Blocking ADRB2 with propranolol impaired fracture healing in mice, whereas the ADRB2 agonist formoterol promoted fracture healing by regulating callus neovascularization. A retrospective cohort analysis of 72 patients with long bone fractures indicated improved callus formation in 36 patients treated with intravenous norepinephrine. These findings suggest that ADRB2 is a potential therapeutic target for promoting bone healing.

Pharmacological application of teleost calcitonin (CT) has been shown to exert chondroprotective and anti-resorptive effects in patients with rheumatoid arthritis (RA). However, the role of endogenous CT that signals through the calcitonin receptor (CTR) remains elusive. Collagen II antibody-induced arthritis (CAIA) was stimulated in wild type (WT) and CTR-deficient (Calcr^−/−) mice. Animals were monitored over 10 or 48 days. Joint inflammation, cartilage degradation, and bone erosions were assessed by clinical arthritis score, histology, histomorphometry, gene expression analysis, and μ-computed tomography. CAIA was accompanied by elevated systemic CT levels and CTR expression in the articular cartilage. Inflammation, cartilage degradation, and systemic bone loss were more pronounced in Calcr^−/− CAIA mice. Expression of various pro-inflammatory, bone resorption, and catabolic cartilage markers were exclusively increased in Calcr^−/− CAIA mice. Endogenous CT signaling through the mammalian CTR has the potential to protect against joint inflammation, cartilage degradation, and excessive bone remodeling in experimental RA.

Recent studies on insulin, leptin, osteocalcin (OCN), and bone remodeling have evoked interest in the interdependence of bone formation and energy household. Accordingly, this study attempts to investigate trauma specific hormone changes in a murine trauma model and its influence on fracture healing. Thereunto 120 female wild type (WT) and leptin-deficient mice underwent either long bone fracture (Fx), traumatic brain injury (TBI), combined trauma (Combined), or neither of it and therefore served as controls (C). Blood samples were taken weekly after trauma and analyzed for insulin and OCN concentrations. Here, WT-mice with Fx and, moreover, with combined trauma showed a greater change in posttraumatic insulin and OCN levels than mice with TBI alone. In the case of leptin-deficiency, insulin changes were still increased after bony lesion, but the posttraumatic OCN was no longer trauma specific. Four weeks after trauma, hormone levels recovered to normal/basal line level in both mouse strains. Thus, WT- and leptin-deficient mice show a trauma specific hyperinsulinaemic stress reaction leading to a reduction in OCN synthesis and release. In WT-mice, this causes a disinhibition and acceleration of fracture healing after combined trauma. In leptin-deficiency, posttraumatic OCN changes are no longer specific and fracture healing is impaired regardless of the preceding trauma.