# Neurogenic bone loss after SCI: skeletal rehabilitation via Wnt and exercise interactions

> **NIH VA I01** · RLR VA MEDICAL CENTER · 2022 · —

## Abstract

The purpose of this application is to identify a long-term rehabilitative solution to skeletal fragility associated
with spinal cord injury (SCI). SCI is one of the most debilitating medical conditions among the veteran
population. Neurogenic osteopenia is a major complicating factor for SCI rehabilitation efforts, and there is
currently a paucity of options for treating bone wasting associated with SCI. Thus, an urgent need exists to
develop new rehabilitative strategies for preserving and/or restoring bone lost to SCI. This is particularly true
given that significant advances are being made in neuromuscular rehabilitation (e.g., harnessing motoneuron
plasticity and sprouting/regeneration mechanisms) for functional restoration; all of those efforts are in jeopardy
if they are not accompanied by restoration of bone structure and strength, as fractures can nullify progress
made in neurological rehabilitation. Although neurogenic bone loss is a different disease than standard
postmenopausal osteoporosis (PMO) or senile osteoporosis, there are no approved therapies that specifically
target the sequelae of SCI-induced bone loss. The closest drug option for SCI-induced bone loss is the
sclerostin neutralizing antibody Romosozumab (“Romo”), due to its potent anabolic action and efficacy in
mouse models of SCI. However, Romo received a black box warning from the FDA cautioning its use in
patients at higher risk for cardiovascular disease and stroke, two risk factors that are significantly elevated in
SCI patients. Therefore, while the bone-building effects of Romo are beneficial in SCI, its use at full strength is
not suitable for SCI patients. We have found a combination therapy (sclerostin and Dkk1 neutralization) that
reduces the sclerostin antibody dose by 83% (and total drug dose by 75%) yet still maintains all of the
osteoanabolic action of full strength sclerostin antibody. Our overall goal is to is capitalize on the interaction
between a very specific and novel osteoanabolic therapy (identified in our lab), and the powerful, lasting effects
of mechanical stimulation (exercise), to define a rehabilitative strategy for neurogenic bone loss that will have
lasting effects beyond the short-lived windows of most pharmaceutical options. Our approach takes into
consideration the risk factors associated with SCI (e.g., elevated cardiovascular complications and stroke) and
the beneficial effects of exercise to both the skeleton and to motor function to design a more tailored and
focused approach to skeletal rehabilitation after SCI. In the first aim, we will determine whether an optimized
ratio of sclerostin/Dkk1 antibody treatment can restore skeletal density, size, and strength after neurogenic
bone loss from SCI. In the second aim, we will determine whether optimized sclerostin/Dkk1 antibody
treatment can sensitize bone to the effects of mechanical exercise after SCI, producing a more robust and
fracture-resistant skeleton. In the third aim, we will de...

## Key facts

- **NIH application ID:** 10317142
- **Project number:** 1I01RX003714-01A1
- **Recipient organization:** RLR VA MEDICAL CENTER
- **Principal Investigator:** ALEXANDER G ROBLING
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 1
- **Project period:** 2021-11-01 → 2026-10-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10317142

## Citation

> US National Institutes of Health, RePORTER application 10317142, Neurogenic bone loss after SCI: skeletal rehabilitation via Wnt and exercise interactions (1I01RX003714-01A1). Retrieved via AI Analytics 2026-05-31 from https://api.ai-analytics.org/grant/nih/10317142. Licensed CC0.

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