Alendronate alters mineral composition and has potential to restore enthesis strength without preventing trabecular...

Prolonged unloading of the shoulder, most seen after stroke related hemiparesis, accelerates degeneration of the supraspinatus enthesis in part through localized bone loss at the tendon to bone interface. Because bisphosphonates are often used in populations experiencing disuse, it remains unclear whether they can mitigate bone deterioration at the supraspinatus enthesis. In this study, we examined how unloading and alendronate treatment influence bone architecture, mineral composition, cellular activity, and mechanical behavior at the supraspinatus enthesis using a 24-day murine model of botulinum toxin induced supraspinatus paralysis. Unloading produced significant trabecular deterioration, including reduced bone volume fraction and trabecular thickness, while fibrocartilage morphology and tendon area remained unchanged. Alendronate did not prevent structural bone loss, though it produced clear compositional changes such as increased carbonate substitution. Mineral to matrix ratio, crystallinity, and phosphate peak position did not differ significantly across any of the four treatment groups: under disuse- conditions, bisphosphonate treatment, or combined condition with bisphosphonate. Histomorphometry showed no differences in osteoblast or osteoclast number or surface, suggesting that bone loss occurs primarily through suppressed formation rather than elevated resorption. Because osteoclast number and surface were unchanged, elevated resorption is unlikely to account for observed bone loss. Osteoblast number and surface were similarly unaffected, indicating that any deficit in formation is more likely attributable to reduced activity per cell rather than to a reduction in osteoblast recruitment or abundance. Mechanical testing demonstrated that unloading reduced supraspinatus humerus complex strength and modulus. Although alendronate did not preserve trabecular structure, it produced a non-significant trend toward higher complex level strength, raising the possibility that material-level changes can influence failure independently of architecture. However, combined unloading and turnover suppression reduced post yield properties, highlighting tradeoffs for enthesis quality under low load conditions. These findings show that disuse induced bone loss at the supraspinatus enthesis is driven by formation and that bisphosphonates, while modifying mineral composition, do not prevent structural degeneration.