How bisphosphonates affect bone matrix and remodeling: implications for atypical femoral fractures

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Project Summary / Abstract Atypical femoral fractures (AFFs) are a rare but devastating side effect of long-term bisphosphonate (BP) treatment. Despite the relatively low prevalence of AFFs, public awareness has considerably depressed osteoporosis medication adherence. The mechanisms driving BP associated AFFs remain elusive and several mechanisms have been proposed, including impaired bone remodeling, altered bone matrix maturation, and the accumulation of tissue microdamage. A critical barrier to understanding how BPs negatively affect skeletal integrity is the difficulty in separating the individual contributions of altered remodeling kinetics (suppressed resorption and formation) from bone matrix maturation. We will overcome this barrier with our recently validated rat model of induced cortical remodeling to investigate mechanism and treatment, based on robust preliminary work in the laboratories of the three multiPIs. The current proposal, submitted in response to a notice of special interest on AFF pathophysiology (NOT-AR-21-006), will test the central hypothesis that BPs degrade skeletal integrity by affecting both the initiation of bone formation and matrix maturation. In Aims 1 and 2, we will focus on alendronate because of its strong association with the development of AFFs and raloxifene as a potential mitigating treatment due to its reported positive effects on both the formation and matrix maturation processes. Specifically, we will investigate the effects of alendronate and raloxifene on the initiation of bone formation, concentrating on the role of reversal cells (Aim 1) and the remodeling independent effects of these two drugs on matrix maturation and fatigue life (Aim 2). To determine if BP molecular structure could play a role in AFF susceptibility, we will also compare how alendronate, zoledronate, risedronate, and ibandronate affect bone formation, matrix maturation, and fatigue life (Aim 3). We will utilize an innovative preclinical model and leverage the expertise of a highly qualified research team to address critical questions associated with AFFs. If successful, the project will (i) further the understanding of the consequences of BP usage on the skeleton by disentangling bone formation initiation and matrix maturation, identifying factors that contribute to BP-induced loss of fatigue life and (ii) examine raloxifene as a novel rapid treatment option for patients at risk for BP-induced AFF.