Novel Combination Therapy for Osteoporosis in Men

Summary

Osteoporotic fractures are a key health problem in older men. Although there are drugs approved to treat osteoporosis in men \[bisphosphonates, denosumab, and teriparatide (TPTD) or PTH(1-34)\], there is a lack of knowledge on how to use them effectively. TPTD is a potent bone anabolic drug, meaning that it builds bone mass. However, doctors do not know if it should only be used as single drug or whether it can be more effectively combined to achieve the most benefit? This trial will test a novel combination therapy for osteoporosis in men based on exciting laboratory findings in mice. TPTD works to raise bone mass and improve bone strength by stimulating PTH receptors (PTH-Rs) on the membranes of bone-forming cells or osteoblasts (OBs). Calcimimetics are drugs that activate calcium receptors (CaSRs) in OBs. CaSRs in OBs participate in new bone formation. Daily injections of TPTD, given along with a calcimimetic drug (called NPS-R568), over 6 weeks markedly improved bone mineral density (BMD) and structure in mice. This study will test whether the combined activation of PTH-Rs and CaSRs (by the combination treatment of TPTD+calcimimetic cinacalcet) in men will produce greater bone forming responses than PTH-R activation alone (TPTD+placebo). The study has two aims and will be done in 48 men with low bone mass: (1) to determine the effects of 11 months treatment with TPTD+cinacalcet vs TPTD+placebo on BMD and bone metabolism by assessing lumbar spine BMD (primary endpoint), femoral neck BMD, and levels of the bone formation marker serum N-terminal pro-peptide of type 1 collagen; (2) to determine the biochemical responses by blood tests in men who receive the combination of TPTD+cinacalcet compared to men who get TPTD+placebo treatment. This is done by quantifying acute and chronic changes in serum calcium and PTH levels right after these drugs are given and how much calcium is excreted in the urine over time, with both treatment regimens. This study will help to understand whether an effective combination therapy in mice will prove to be effective in men.

Conditions

• Male Osteoporosis

Interventions

DRUG

Teriparatide or human parathyroid hormone (PTH) 1-34

Teriparatide or PTH 1-34 is a 34 amino acid peptide derived by recombinant DNA technology from the authentic sequence of human parathyroid hormone. It is given by subcutaneous injection in the dosage of 20 micrograms per day in the trial in both treatment arms for the 48 weeks or 11 months of the trial.

DRUG

Cinacalcet

This drug is an orally active calcimimetic (drug that activates Ca-sensing receptors on target cells) that will be given daily orally to the men randomized to the Experimental Treatment Arm (#1). Cinacalcet tablets will be given simultaneously with the injection of PTH(1-34) or teriparatide. Cinacalcet will be given only once daily but given every single day of the trial starting with the Randomization Visit for the duration of 48 weeks or 11 months of the trial.

DRUG

placebo tablet

The placebo tablet in the trial will be purchased from Consolidated Midland Corporation in Brewster, NY. Each white tablet contains Lactose, Stearic Acid and Magnesium Stearate (330 mg total). Subjects randomized to the placebo arm or Placebo - Arm #2 - will take one tablet orally at the same time as he injects the teriparatide each day. Placebo tablets will be given only once daily but given every single day of the trial starting with the Randomization Visit for the duration of 48 weeks or 11 months of the trial.

DIETARY_SUPPLEMENT

Calcium citrate tablet

Ca citrate supplements (forms 200 or 250 mg elemental Ca/oral tablet) will be used in the study. Each subject will have average dietary Ca intake quantified by a Food Frequency Questionaire. Each subject will take sufficient Ca citrate supplements to make the total Ca intake equal \~1000 mg per day (diet+supplements). Ca supplements will be spread out during the day so that any amount of supplements over 500 mg will be taken at 2 different time-points. Ca citrate supplements will be sourced by our research pharmacist will be of high-quality and consistency. Ca supplements will be started at Screening Visit 2 and given for a 4-week run-in period. Once subjects are randomized to Arm 1 or Arm 2 of the trial, subjects will continue to take daily Ca supplements at the same dose and times as during the run-in period. That daily dosing will continue from day of Randomization through the end of 48 weeks or 11 months of the trial.

DIETARY_SUPPLEMENT

Vitamin D3

Subjects will be given 1000 IU vitamin D3 in tablet form to be taken orally once a day at any time during the day. Vitamin D3 supplements will be sourced by our research pharmacist and supplements selected for use in the trial will be of high quality and consistency. Vitamin D3 supplements will be started at Screening Visit 2 in the trial and given for a 4-week run-in period. Once subjects are randomized to Arm 1 or Arm 2 of the trial, subjects will continue to take daily vitamin D3 supplements at the same dose and timing as during the run-in period. That daily dosing will continue from the day of Randomization Visit through to the end of the 48 weeks or 11 months of the trial.

Sponsors & Collaborators

• University of California, San Francisco

  collaborator OTHER

• VA Office of Research and Development

  lead FED

Principal Investigators

• Dolores M. Shoback, MD · San Francisco VA Medical Center, San Francisco, CA

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

TRIPLE

Model

PARALLEL

Eligibility

Min Age

60 Years

Max Age

85 Years

Sex

MALE

Healthy Volunteers

No

Timeline & Regulatory

Start

2019-07-01

Primary Completion

2025-06-30

Completion

2026-06-30

FDA Drug

Yes

Countries

• United States

Study Locations