# Bone Formation and the Immuno-Skeletal Interface

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2020 · —

## Abstract

Osteoporosis is endemic in the US and other Western societies and fractures are a serious medical problem
among aging Veterans and their peers in the general population with 1 in 2 females and 1 in 4 males over the
age of 50 projected to suffer an osteoporosis related bone fracture in their lifetimes. Fractures lead to huge
healthcare expenditures, loss of mobility and significant morbidity. Hip fractures almost always require major
surgery and mortality rates are extremely high in aged individuals following surgery, approaching 24% in the
general population and reaching as high as 32% in male veterans. Historically, anti-resorptive drugs (such as
bisphosphonates) have been the mainstay of anti-osteoporosis therapy/fracture prevention and although these
agents stall further bone degeneration and lead to an increase in bone mineral density, they are inefficient at
restoring high quality, remodelled bone and many patients treated with these drugs ultimately still go on to sustain
a fracture. Compliance in taking anti-resorptive agents is furthermore extremely poor with multiple large
population studies conducted in major healthcare systems all reporting abysmal patient compliance with typically
75% of patients discontinuing their anti-resorptive medications within a year of initiation, due to inconvenient
administration schedules, side-effects and costs. Recently, rare but potentially serious complications of long term
anti-resorptive use have led to hysteria among the public and an unprecedented and alarming retreat from
pharmacological fracture prevention therapy is now underway. This has led to a "call for action" by the ASBMR
leadership, however clearly, other pharmacological alternatives are now even more urgently needed. In contrast
to anti-catabolic agents, drugs based on parathyroid hormone (PTH) such as Teriparatide (PTH (1-34)) and
Preotact (PTH (1-84)), are the only FDA approved bone anabolic therapies capable of stimulating bone formation
and reversing bone loss, thus reducing the odds of fracture. Although additional bone anabolic drugs are in
development, potential side-effects have indefinitely delayed final FDA approval of Amgen’s anti-sclerostin
antibody Romosozumab. PTH-based anabolics, like Teriparatide, are thus likely to remain the only available
bone anabolic agents for the near future. Teriparatide however, has significant limitations of its own that have
constrained its wider application, including inconvenient daily injection and rapidly waning efficacy. During the
tenure of this Merit program we made the unexpected discovery that the pharmacological T cell
immunosuppressant Abatacept (CTLA4-Ig), used in the therapy of inflammatory diseases, such as rheumatoid
arthritis, mediates a bone anabolic signal. When Abatacept renders T cells dormant (anergic), it transforms them
into Wnt10b secreting cells. Wnt10b is a ligand for the Wnt-signal transduction pathway, that promotes bone
formation by stimulating differentiation and ac...

## Key facts

- **NIH application ID:** 9815347
- **Project number:** 5I01BX000105-10
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Mervyn Neale Weitzmann
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2020
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2009-04-01 → 2022-09-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9815347

## Citation

> US National Institutes of Health, RePORTER application 9815347, Bone Formation and the Immuno-Skeletal Interface (5I01BX000105-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9815347. Licensed CC0.

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