# Senile Osteoporosis as a Neuroskeletal Disease

> **NIH NIH R01** · BAYLOR COLLEGE OF MEDICINE · 2021 · $396,250

## Abstract

Project Abstract
Osteoporosis is a well known consequence of sex-hormone deficiency, but bone loss starts in the 30s and
continues steadily after gonadal failure. There are thus several causes for the bone loss associated with aging.
In this application, we ask whether osteoporosis might have a neuroskeletal component.
 The proposal stems from an increasing amount of preclinical data suggesting that sympathetic nerves,
which richly innervate the skeleton, control the process of bone remodeling. We and others have shown that
activation of sympathetic nerves in mice causes the release of norepinephrine (NE) and the stimulation of the
β2-adrenergic receptors (β2AR) in osteoblasts, leading to a Rankl-dependent increase in bone resorption and
to a Clock-dependent reduction in bone formation, hence to bone loss. However, the clinical relevance of these
findings remains unclear.
 Three critical observations are at the core of this proposal: 1) parasympathetic and sympathetic outflow
changes in an inverse manner with age and these changes correlate with bone accrual and bone loss,
respectively; 2) bone loss occurs prematurely in patients with Alzheimer disease (AD), at early stage of the
disease, prior to reduced locomotor activity and skeletal unloading typical of late-stage AD, and this is also
associated with low parasympathetic and high sympathetic tone; 3) our data support the existence of an
endogenous homeostatic system, driven by the norepinephrine transporter (NET) in osteocytes, controlling the
skeleton’s response to overt activity of sympathetic nerves, which become dysfunctional upon aging. Based on
these observations, the main hypothesis of this proposal is that a shift from a dominant parasympathetic tone
in young individuals to a dominant sympathetic tone in older individuals contributes to age-related bone loss.
 We have designed experiments to determine if a high central parasympathetic tone is beneficial for bone
density accrual, and if a premature or overt reduction in parasympathetic tone during aging leads to bone loss
(Aim 1). In Aim 2, we will determine if a reduction in NE uptake activity in osteocytes with age reduces the
capacity of the skeleton to handle NE released from sympathetic nerves and contributes to age-related
osteoporosis. Genetic and pharmacological approaches will be used in both aims to alter crucial components
of the autonomic nervous system, in presynaptic neurons versus post-synaptic bone cells, and in young versus
aging mice. This work will for the first time put previous findings related to the autonomic nervous system and
bone into the clinically relevant context of aging. It could impact the management of osteoporosis by supporting
the use of approaches that counteract not only the negative effect of sex hormone deficiency on bone but also
the early, progressive and sustained effects of the autonomic nervous system on bone homeostasis.

## Key facts

- **NIH application ID:** 10166748
- **Project number:** 5R01AG055394-05
- **Recipient organization:** BAYLOR COLLEGE OF MEDICINE
- **Principal Investigator:** Florent Elefteriou
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $396,250
- **Award type:** 5
- **Project period:** 2017-07-15 → 2023-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10166748

## Citation

> US National Institutes of Health, RePORTER application 10166748, Senile Osteoporosis as a Neuroskeletal Disease (5R01AG055394-05). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10166748. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*