Background 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. Method 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. Findings 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. Interpretation 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. Funding This work was funded by grants from the Else-Kröner-Fresenius-Stiftung (EKFS), the Deutsche Forschungsgemeinschaft (DFG), and the Berlin Institute of Health (BIH).

This study emphasises the long-term negative impact of tibial nonunions on patient QoL, even after successful surgical treatment.

PurposeThe aim of this study was to demonstrate, whether the degree of limb alignment correction in varus knee osteoarthritis correlated with an increase in ankle symptoms and to define a cut‐off value concerning the degree of correction above which to expect ankle problems. MethodsNinety‐nine consecutive patients with preoperative intraarticular varus knee deformities who underwent total knee arthroplasty were retrospectively analyzed. Patients were examined clinically (Knee Society Score, Forgotten Joint Score, Foot Function Index, Range of Motion of the knee and ankle joint, pain scales) as well as radiologically. The mean follow‐up time was 57 months. ResultsThe degree of operative limb alignment correction strongly correlated with the Foot Function Index (R = 0.91, p < 0.05). Given this, higher degrees of knee malalignment corrections were associated with worse postoperative outcomes in the knee and ankle joint—despite postoperative improved joint line orientations. Subsequently, a cut‐off value for arthritic varus deformities (14.5°) could be calculated, above which the prevalence of ankle symptoms increased manifold [OR = 15.6 (3.2–77.2 95% CI p < 0.05)]. Furthermore, ROM restrictions in the subtalar joint were associated with a worse outcome in the ankle joint. ConclusionsWhen correcting excessive intraarticular varus knee osteoarthritis, surgeons have to be aware of possible postoperative ankle symptoms and should consider ankle deformities or decreased subtalar ROM before operative procedures. Level of evidenceIII.

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