Hidden impact of osteoporosis on the woven bone quality and formation

Osteoporosis significantly challenges fracture healing, particularly in the regeneration of critical-size bone defects. It remains unclear whether osteoporotic woven bone weakness results from impaired intrinsic quality, reduced formation rate, or both, including its effect on the adjacent bone tissue. To address this question in a translational context, we employed an osteoporotic sheep model, widely recognized as one of the closest animal analogs to human bone biology and physiology. Using an ex vivo multimodal characterization, this study analyzed the woven tissue formed within the distraction callus and the adjacent cortical bone. Bone samples were harvested at 40 and 100 days of osteoporotic bone regeneration and analyzed by nanoindentation, Raman spectroscopy, μCT and chemical composition analyses. Osteoporotic data were compared with non-osteoporotic references. Results revealed that the intrinsic elastic mechanical properties, microstructure and chemical quality of the regenerated osteoporotic woven bone were preserved at the tissue level. However, composition analysis indicated a significantly higher water content and significantly lower bone matrix volume, apparently delayed by the disease. In contrast, cortical tissue adjacent to the defect showed significant mineral loss, likely due to mineral mobilization to support woven tissue formation, although the remaining bone matrix appears to be unaltered. These findings suggest that osteoporotic impairment in bone regeneration is driven by a logistical failure in the woven formation rate and adjacent tissue degradation, rather than an intrinsic woven quality deficiency. Consequently, therapies should prioritize anabolic acceleration of woven bone formation and antiresorptive protection of the adjacent bone tissue, whose fixation is compromised. STATEMENT OF SIGNIFICANCE: Treating large fractures in patients with osteoporosis is challenging due to impaired bone regeneration. This study aimed to determine whether compromised healing results from impaired material quality of newly formed bone, reduced bone formation rate, or both, and to evaluate effects on adjacent bone tissue. Using an osteoporotic sheep model, we found that new bone quality is comparable to healthy bone, but bone formation occurs at a significantly reduced rate. Furthermore, adjacent bone deteriorates structurally, likely mobilizing minerals to support repair, becoming porous and fragile. These results suggest that treatments should focus on accelerating bone formation while preserving bone integrity.