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bioRxiv · 10.64898/2026.10.05.756707

Differential Adaptation of Osteocyte Lacunar Morphology at Bone (Re)modeling Sites under Mechanical Loading and Pharmacological Therapies in a Mouse Model of Osteoporosis

Lindenmann, S.·Li, Z.·Weigt, C.·Lambers, F. M.·Schulte, F. A.·Kuhn, G. A.·Mathavan, N.·Muller, R.
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Abstract

Postmenopausal osteoporosis is a highly prevalent disease characterized by low bone mass and structural deterioration of bone tissue leading to increased bone fragility and fracture risk. Osteocytes orchestrate local bone (re)modeling and therefore, characterizing their 3D morphological and spatial distribution across distinct (re)modeling microenvironments is essential for understanding the cellular mechanisms underlying divergent tissue-level responses. To address this, we used a 3D-3D multiscale registration framework mapping endpoint osteocyte lacunae onto dynamic, time-lapsed in vivo (re)modeling sites. Ovariectomized 15-week-old mice were subjected to 4 weeks of anabolic parathyroid hormone (PTH) or anti-catabolic bisphosphonate (BIS) treatment as monotreatment or combined with cyclic mechanical loading (ML). Biweekly in vivo micro-computed tomography (micro-CT) to identify (re)modeling sites and endpoint ultra-high resolution (ultra-HR) micro-CT to characterize osteocyte lacunae was performed. Osteocyte lacunae were characterized by lacunar density, volume and sphericity. Our findings showed that physical and pharmacological therapies differentially regulate the osteocyte lacunar network through distinct perilacunar adaptations across functional microenvironments. While BIS stabilizes local lacunar architecture, PTH drives asymmetrical lacunar expansion (increased volume with reduced sphericity) through perilacunar remodeling that supersedes any added ML effects. Crucially, estrogen loss disrupts the natural spatial maturation gradient by inducing rounding of lacunae in newly formed bone. Therapies counteract this disruption, restoring the healthy gradients in lacunar morphometry between spatially distinct microenvironments. Additionally, despite restoring tissue-level bone volume, physical and pharmacological osteoporosis therapies do not fully recover persistent lacunar density deficits. The overall lacunar morphological spatial signatures confirm active osteocytic tuning to endocrine, physical and matrix cues.

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Lindenmann, S., Li, Z., Weigt, C., Lambers, F. M., Schulte, F. A., Kuhn, G. A., Mathavan, N., Muller, R.. 2026-10-06. Differential Adaptation of Osteocyte Lacunar Morphology at Bone (Re)modeling Sites under Mechanical Loading and Pharmacological Therapies in a Mouse Model of Osteoporosis. https://doi.org/10.64898/2026.10.05.756707

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