# Influence of sex and sex hormones on modeling- and remodeling-based bone formation

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2022 · $162,500

## Abstract

Project Summary
The healthy skeleton continuously renews itself throughout the lifespan via closely coupled bone resorption
and remodeling-based bone formation (RBF). In contrast, modeling-based bone formation (MBF), i.e., de novo
bone formation without prior activation of bone resorption, is less commonly found in adults. However, MBF
has been identified as an important mechanism by which anabolic agents for osteoporosis, e.g., intermittent
parathyroid hormone (PTH) and PTH related peptide (PTHrP), and sclerostin antibody (Scl-Ab), rapidly elicit
new bone formation. Despite the potent effect of anabolic agents on increasing bone mass, their treatment
benefit can be reversed upon discontinuation. Nevertheless, osteoporosis is a life-long chronic condition and
there is a pressing need for novel therapeutic regimens to enhance and maintain treatment efficacy and extend
the treatment duration. Our recent investigation unexpectedly discovered that intact female and estrogen-
deficient female rats had distinct responses to the discontinuation of PTH treatment. No adverse effect was
observed in intact female rats, which sustained treatment benefit long after discontinuation, in contrast to the
significant bone loss and bone microarchitecture deterioration observed in estrogen-deficient rats and pre-
pubertal male rats after PTH discontinuation. These motivate the new objectives proposed in this supplement
to further elucidate the influence of sex and gonadal function on the cellular mechanisms of MBF and RBF,
which have been demonstrated to play important roles in determining skeletal responses to anabolic treatment
and discontinuation. This critical knowledge will then be used to guide the novel design of a cyclic
administration regimen of anabolic agents with and without intervening anti-resorptive agents to achieve the
greatest treatment benefit by considering patient’s sex and gonadal function. Ovariectomized (OVX) rats will be
used to simulate post-menopausal osteoporosis and orchiectomized (ORX) rats will be used to simulate
hypogonadism in aged men. Age-matched, intact male and female rats will be used as young adults with intact
gonadal function. We hypothesize that skeletal responses to anabolic treatment discontinuation and cyclic
administration regimen are influenced by both sex and sex hormones. In the Aim 1, we will elucidate the
influence of sex and sex hormones on the cellular mechanisms behind the dynamic responses of MBF and
RBF to anabolic treatment discontinuation. In the Aim 2, we will optimize cyclic administration regimens of
anabolic agents with and without an intervening anti-resorptive agent to achieve the best treatment efficacy
based on sex and gonadal function. The proposed studies will supplement essential data regarding the
influence of sex and gonadal function on development and retention of MBF and RBF to improve personalized,
long-term clinical care for osteoporosis by considering patient sex and gonadal functions.

## Key facts

- **NIH application ID:** 10556506
- **Project number:** 3R01AR077598-02S1
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Xiaowei Sherry Liu
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $162,500
- **Award type:** 3
- **Project period:** 2022-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10556506

## Citation

> US National Institutes of Health, RePORTER application 10556506, Influence of sex and sex hormones on modeling- and remodeling-based bone formation (3R01AR077598-02S1). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10556506. Licensed CC0.

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