Abstract
Bone’s ability to adapt to mechanical demands is governed by mechanoregulation, the process by which cells sense and respond to mechanical stimuli to maintain skeletal integrity. In osteoporosis, increased bone resorption activity leads to structural deterioration and elevated fracture risk. While existing pharmacological therapies aim to restore bone mass to reduce fracture risk, it is unclear how they modulate mechanoregulation, especially when combined with physical interventions. Here, we investigate the joint effects of load-bearing physical and pharmacological treatment in a female mouse model of osteoporosis using longitudinal in vivo micro-computed tomography and computational mechanics. We demonstrate that mechanical loading additively and synergistically enhanced predicted strength, bone volume, and mechanoregulation parameters when combined with anabolic therapies (parathyroid hormone and sclerostin antibody) but not with anti-catabolic treatments (bisphosphonates). Increases in predicted strength are associated with reductions in bone resorption rates, shifts in the (re)modeling thresholds as anticipated by Frost in the mechanostat theory, and the modeling capacity of anabolic pharmacological treatments. These findings underscore the therapeutic potential of combining anabolic pharmacological therapies with load-bearing physical activity, particularly in early treatment phases, to optimize bone adaptation and fracture prevention in osteoporosis management.
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Data availability
The primary data supporting the findings of this study are available within the paper. The raw data generated during the study are available in a Zenodo repository (see link below). Source data are provided with this paper.
Code availability
All data and code are available in a Zenodo repository: https://doi.org/10.5281/zenodo.17256047.
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Acknowledgements
We acknowledge Kathleen Koch for assistance and performance of animal experiments of the PTH and BIS groups, and Dr. Ulrike Kettenberger for assistance and performance of animal experiments of the PTH group. Nirujan Pasupathy and Júlia van den Nest Molina have supported the analyses of modeling and mechanoregulation mechanisms. This work was funded by the European Union grant VPHOP (FP7-ICT-2008-223865; FAS, FML, CW, GAK) and the European Research Council ERC Advanced grant (MechAGE ERC-2016-ADG-741883; FCM, GAK).
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RM, GAK, and PJR designed the experiment. CW, GAK, MS, and FML performed the experiments. FAS, FCM, JG, CW, MS, FML, and GAK performed image processing and analysis. MK provided pharmacological agents. RM, GAK, PJR, and CK supervised the project. FAS wrote the original draft of the manuscript. All authors contributed to data interpretation, were involved in discussions throughout the study, and participated in manuscript revision and preparation.
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MK, PJR, and CK are employees of Novartis. The other authors declare they have no competing interests.
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Schulte, F.A., Marques, F.C., Griesbach, J.K. et al. Combined physical and pharmacological anabolic osteoporosis therapies increase bone response and mechanoregulation in female mice. Nat Commun (2026). https://doi.org/10.1038/s41467-026-70309-2
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DOI: https://doi.org/10.1038/s41467-026-70309-2
