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.
