# Novel Combination Therapy for Osteoporosis in Men

> **NIH VA I01** · VETERANS AFFAIRS MED CTR SAN FRANCISCO · 2022 · —

## Abstract

In the US of the 1.5 million fractures that occur annually, one-third of them occur in men. Osteoporosis and
fracture-related disability are key health problems in older male veterans. Fractures also increase mortality.
Men who fracture their hips have twice the mortality of women sustaining those same hip fractures. Several
drugs are approved to treat osteoporosis in men [bisphosphonates, denosumab, and teriparatide (TPTD) or
PTH(1-34)], but we have little insight as to how to use them most effectively. TPTD has great appeal for
treating osteoporosis in men because it substantially improves bone mass, rebuilds the microarchitecture,
improves bone strength, and reduces fractures. Little is known about the best ways to employ TPTD in the
treatment of male osteoporosis. Should it be used only as monotherapy or does concurrent or sequential use
with other agents lead to the greatest benefit? The proposed clinical trial is an effort to test a novel
combination therapy for osteoporosis in men based on exciting preclinical findings in mice. It is known that
TPTD achieves its anabolic effects by stimulating PTH receptors (PTH-Rs) in cells of the osteoblast (OB)
lineage. Calcimimetics mimic the effects of high extracellular calcium concentrations ([Ca]e) by activating Ca-
sensing receptors (CaSRs) expressed in many cell types including OBs and osteoclasts in bone. Work by us
and other groups have found that CaSRs in OBs play an important role in controlling bone formation, OB
differentiation, and mineralization. In preclinical models in the lab, we found that daily injections of TPTD
given concurrently with an investigational calcimimetic agent (NPS-R568) in just 6 weeks markedly increased
bone mass and improved both trabecular and cortical microarchitecture of bone as assessed by both micro-
computed tomography and histomorphometry in adult male mice. Based on these results, we propose to test
the hypothesis that concurrent activation of PTH-Rs and CaSRs (TPTD+calcimimetic cinacalcet) in men with
low bone mineral density (BMD) produces greater anabolic responses than PTH-R activation alone
(TPTD+placebo). To test this hypothesis, we propose a randomized, double-blinded, {{placebo-controlled
clinical trial in 48 men with low bone mass}}. We plan two treatment arms. Aim 1 will determine the effects
of 11 months treatment with TPTD+cinacalcet compared to TPTD+placebo on BMD and bone metabolism in
men with low bone mass. We will assess responses in: (a) lumbar spine (LS) BMD (primary endpoint) and
femoral neck (FN) BMD; and (b) levels of the bone formation marker serum N-terminal pro-peptide of type 1
collagen (P1NP). Hypothesis 1a proposes that LS and FN BMD responses are greater with TPTD+cinacalcet
compared to TPTD+placebo. Hypothesis 1b proposes that serum P1NP increases are greater with
TPTD+cinacalcet compared to TPTD+placebo. Aim 2 will determine the pharmacodynamic responses to
TPTD+cinacalcet and to TPTD+placebo treatment in men with low bone mass....

## Key facts

- **NIH application ID:** 10409693
- **Project number:** 5I01CX001514-04
- **Recipient organization:** VETERANS AFFAIRS MED CTR SAN FRANCISCO
- **Principal Investigator:** DOLORES M. SHOBACK
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2019-07-01 → 2024-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10409693

## Citation

> US National Institutes of Health, RePORTER application 10409693, Novel Combination Therapy for Osteoporosis in Men (5I01CX001514-04). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10409693. Licensed CC0.

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