# Musculoskeletal Project 2

> **NIH NIH U54** · EMORY UNIVERSITY · 2020 · $388,718

## Abstract

Project 2-Project Summary
HIV-infection causes bone loss that is paradoxically worsened by antiretroviral therapy (ART) leading to
significantly increased fracture rates in men and women. However, recent studies show that fracture incidence
is further exacerbated in HIV-infected women after the menopause, suggesting a collision between HIV/ART and
estrogen deficiency, aggravating skeletal deterioration. While the magnitude of bone loss may vary, all ART drug
classes cause bone loss and we have hypothesized that this is an indirect downstream effect of ART, driven by
immune-reconstitution and inflammatory events associated with the rekindling of adaptive immunity following T
cell reconstitution. We have demonstrated that an animal model of T cell reconstitution does indeed cause
significant inflammatory bone loss that closely mimics key features of ART-induced skeletal deterioration. In this
model, adaptive immune cells including lymphocytes and macrophages secrete the key osteoclastogenic
cytokines Receptor activator of NF-kB ligand (RANKL) and TNF which drives up basal bone resorption leading
to bone loss. Interestingly, postmenopausal osteoporosis, the archetypal bone disease of women, results from
estrogen decline after menopause that is also driven in part, by an inflammatory state characterized by B and T
cell production of RANKL and TNF by adaptive immune cells. Although the etiologies are different, because
bone loss in estrogen deficiency and in HIV/ART, both involve activation of adaptive immunity leading to the
development of chronic inflammatory states, we hypothesize that a collision between inflammatory bone loss
associated with HIV/ART may synergize with the inflammatory bone loss associated with estrogen deficiency.
Such events may account for exacerbated fracture in postmenopausal HIV-infected women and may portend a
looming epidemic of fracture in the rapidly aging female HIV community. Project 2 of this SCORE grant will study
whether HIV/ART- and estrogen deficiency-induced inflammatory events collide to additively or synergistically
augment inflammation and bone loss. We will employ animal models of ART- and estrogen deficiency-induced
inflammatory bone loss, and translational clinical studies in human HIV+ and HIV- women to quantify the
combined effects of HIV/ART and estrogen decline on bone structure and turnover in relation to adaptive immune
function and osteoclastogenesis. Our hypotheses, if validated, will significantly inform current understanding of
the collision between HIV/ART-induced skeletal decline with that of estrogen deficiency bone loss and the
underlying HIV-induced and estrogen deficiency induced immunological defects leading to bone loss and
establish whether these defects are additive or synergistic, or even diminished. This will have broad implications
for the future of HIV care especially as the population ages.

## Key facts

- **NIH application ID:** 9938414
- **Project number:** 5U54AG062334-03
- **Recipient organization:** EMORY UNIVERSITY
- **Principal Investigator:** Mervyn Neale Weitzmann
- **Activity code:** U54 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $388,718
- **Award type:** 5
- **Project period:** 2018-09-30 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9938414

## Citation

> US National Institutes of Health, RePORTER application 9938414, Musculoskeletal Project 2 (5U54AG062334-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9938414. Licensed CC0.

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