# An ounce of prevention: stopping menopausal bone loss before it starts

> **NIH NIH R21** · YALE UNIVERSITY · 2022 · $182,408

## Abstract

Summary
 The aphorism “an ounce of prevention is worth a pound of cure” very much applies to postmenopausal
osteoporosis. Immediately following menopause, bone loss rates can reach as high as 3-4% per year. At present,
there is no acceptable way to prevent this. A good prevention strategy would abrogate the increase in bone loss
without over-suppressing bone turnover and without off-target effects. Estrogen replacement therapy effectively
prevents menopausal bone loss, but the Women’s Health Initiative exposed the risks of ERT and it has largely
been abandoned as a preventive strategy. SERMs like ERT increase the risk of DVT. The long-term use of
bisphosphonates increases the risk of atypical fracture. To address this treatment gap, we propose a bold new
strategy, based on the biology of Colony Stimulating Factor 1.
 Colony Stimulating Factor 1 (CSF1) is the principal colony stimulating factor released by osteoblasts and, in
addition to RANKL, is absolutely required for osteoclast formation. There are two major isoforms of CSF1, a
membrane-bound isoform (mCSF1) and a soluble, or circulating, isoform (sCSF1). The sCSF1 isoform has a
unique carboxy-terminus extension. Withdrawal of estrogen selectively up-regulates sCSF1 in osteoblasts, while
mCSF1 is unchanged. Importantly, an isoform-indiscriminate neutralizing antibody to CSF1 completely prevents
ovariectomy (OVX)-induced bone loss in mice. However, blocking both isoforms of CSF1 is not a viable
preventive strategy for estrogen-deficiency bone loss, because CSF1 is required for normal osteoclastogenesis.
We found that selectively deleting sCSF1 in vivo causes no phenotype, does not change the basal rate of bone
turnover, but protects mice against OVX-induced bone loss. These data point to sCSF1 as a novel therapeutic
target to prevent estrogen-deficiency bone loss. This R21 will test the hypothesis that selective inhibition of
the soluble isoform of CSF1 protects against estrogen-deficiency bone loss without affecting normal
bone remodeling or bone quality. In Specific Aim 1, phage display antibody selection will be employed to
rapidly develop an antibody that selectively inhibits sCSF1 by targeting the unique 73 amino acid c-terminus of
that isoform. In Specific Aim 2, the dose and timing of neutralizing antibody administration that completely
prevents bone loss in OVX wild type mice will first be determined using serial in vivo DXA bone density
measurements in OVX wild type mice. OVX animals treated with estrogen and OVX-sCSF1-/- mice will serve as
controls. Using the protocol that prevents a change in BMD from baseline, OVX and Sham-OVX wild type animals
will be treated with neutralizing antibody or isotype matched control antibody for 4 weeks. Comprehensive BMD
and body composition measurements, as well as ex vivo microCT, biochemical, biomechanical and
histomorphometric analyses will be undertaken. To ensure adequate rigor, these studies will be performed in
two different strains of mice. I...

## Key facts

- **NIH application ID:** 10324591
- **Project number:** 5R21AR078538-02
- **Recipient organization:** YALE UNIVERSITY
- **Principal Investigator:** KARL Leonard INSOGNA
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $182,408
- **Award type:** 5
- **Project period:** 2021-01-15 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10324591

## Citation

> US National Institutes of Health, RePORTER application 10324591, An ounce of prevention: stopping menopausal bone loss before it starts (5R21AR078538-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10324591. Licensed CC0.

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