# The role of GGPS1 and CYP1A1 mutations in atypical femoral fracture

> **NIH NIH R21** · HARVARD MEDICAL SCHOOL · 2021 · $220,850

## Abstract

Abstract
 Atypical Femoral Fractures (AFFs) are a major clinical problem, both for the patients that suffers them and
for the overall osteoporotic population because of their enormous impact on patients' willingness to be treated
with effective osteoporosis medications. Also, although AFF has been associated with long-term
bisphosphonates (BPs) treatment, a number of patients (up to 30%) who suffer AFF have never taken BPs.
This observation suggests the presence of rare genetic mutations that form the basis of this condition and/or
predispose certain patients to AFF by increasing their sensitivity to BPs. Identification of rare mutations that
predispose to AFF, in particular after treatment with BPs, would permit the prevention of many of these
fractures by selecting the appropriate treatment for such patients. Thus, understanding the genetic and
molecular basis of AFF and diaphyseal fragility is of the utmost clinical importance. As of today, little is
known about the pathogenesis of AFF and no animal model of AFF or of susceptibility to diaphyseal
fractures is available. Notably, a recent potential breakthrough by Dr. Diez-Perez group may offer the
opportunity to make initial steps in filling this knowledge gap. Specifically, exome sequencing in 3 sisters
treated with BPs who suffered AFFs has identified mutations, shown or predicted to impair function, in 3
components of the mevalonate pathway, the very pathway targeted by BPs to inhibit bone resorption.
Furthermore, 1 of 3 unrelated patients and a separate cohort showed mutations in CYP1A1, and mutations in
GGPS and Farnesyl pyrophosphatase synthase (FPPS) have also been identified in 2 patients with
Osteogenesis Imperfecta (OI) type V further suggesting a link between this pathway and bone fragility. The fact
that this pathway is the target of nitrogen-containing bisphosphonates strongly suggests that these
mutations, by mimicking/amplifying BPs action, may predispose patients to AFFs. Here, we will test the
hypothesis that mutations in one or more of the key enzymes involved in the mevalonate pathway predispose
to AFF, evidenced as increased diaphyseal fragility after BP treatment
Aim 1) In vitro: Determine whether and how replication of the Ggps1 and/or Cyp1A1 mutations
observed in the 3 sisters with AFF affect OC, OB and OCY differentiation and function and their
responses to nitrogen-containing bisphosphonates.
Aim 2) In vivo: Determine whether mice with heterozygous Ggps1 and/or Cyp1A1 deletion exhibit
diaphyseal fragility before and/or after OVX and treatment with NBPs.
Although mutations in this pathway probably constitute only a subset of the patients with AFF, this proposal
may validate the concept that specific genetic alterations form the background of AFFs and provide the first,
even though potentially imperfect, animal model to understand the mechanisms of these deleterious fractures.

## Key facts

- **NIH application ID:** 10222572
- **Project number:** 5R21AR076687-02
- **Recipient organization:** HARVARD MEDICAL SCHOOL
- **Principal Investigator:** ROLAND E BARON
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $220,850
- **Award type:** 5
- **Project period:** 2020-08-01 → 2024-07-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10222572

## Citation

> US National Institutes of Health, RePORTER application 10222572, The role of GGPS1 and CYP1A1 mutations in atypical femoral fracture (5R21AR076687-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10222572. Licensed CC0.

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