Novel Combination Therapy for Osteoporosis in Men

• Status: Recruiting
• Trial end date: 2024-06-30
• Target enrollment: 0
• Participant gender: Male

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.

• Phase: Phase 4
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: VA Office of Research and Development
• Collaborator: University of California, San Francisco
• Treatments: Calcium; Calcium, Dietary; Cholecalciferol; Cinacalcet; Citric Acid; Ergocalciferols; Hormones; Parathyroid Hormone; Sodium Citrate; Teriparatide; Vitamin D; Vitamins

Criteria

Inclusion Criteria:

• DXA BMD T-score < or = -2.0 at either lumbar spine (LS), femoral neck (FN) or total hip (TH) sites; or DXA BMD T-score < or = -1.5 with at least one additional important clinical risk factor for osteoporotic fracture [e.g., fragility fracture after age 50 years; parental history of hip fracture; history of hypogonadism, prior glucocorticoid therapy (>3 months prior), current smoking, prevalent vertebral fracture(s), or prior hyperthyroidism on stable treatment]

• At least 2 LS vertebral levels with reliable BMD values (i.e., at least 2 without compression or hardware)

Exclusion Criteria:

• Metabolic bone disease other than osteoporosis (e.g., Paget's disease, hyperparathyroidism)

• Any osteoporosis drug therapy within 12 months; any prior course of TPTD for > or = 3 months; any history of IV bisphosphonate therapy; oral bisphosphonate therapy exceeding 3 months in past 2 years; oral bisphosphonate treatment exceeding 2 years ever; or use of denosumab (within the past 3 years or > 3 or = injections ever).

• Oral glucocorticoid use (> or = 5 mg prednisone) taken within 3 months prior to enrollment

• Hypercalcemia (albumin-corrected serum [Ca] >10.2 mg/dL), hypocalcemia (albumin-corrected serum [Ca] <8.8 mg/dL), elevated intact PTH level, or hypercalciuria (urinary Ca >300 mg/24 hours) at screening

• 25 OH vitamin D levels <20 ng/ml or >80 ng/ml at screening

• Estimated glomerular filtration rate < 30 ml/min (chronic kidney disease (CKD) stage 4 or 5)

• Cancer within past 5 years except for non-melanomatous skin cancers

• History of skeletal radiation, prior history of osteosarcoma or bone metastases

• Substance abuse (>3 drinks/day), liver disease or impaired liver function (abnormal liver function tests defined as greater than 3 times the upper limit of normal), known cirrhosis, malabsorption

• Poorly controlled diabetes (A1c >9.0%) or current thiazolidinedione therapy

• Drugs metabolized through CYP2D6 (e.g., flecainide, tricyclic antidepressants) and strong inducers or inhibitors of CYP3A4 (e.g., itraconazole, ketoconazole)

• Testosterone therapy with dose change within last 12 months; or androgen deprivation therapy within 12 months

• Thyrotropin (TSH) level < 0.01

• Congenital long QT syndrome, history of QT interval prolongation, family history of long QT syndrome or sudden cardiac death, and other conditions that predispose to QT interval prolongation and ventricular arrhythmia

• Hypersensitivity to teriparatide or any excipients in Forteo

• Use of other Ca-lowering drugs (e.g., calcitonin, bisphosphonates, denosumab)

• Moderate to severe hepatic impairment

• High risk for active urolithiasis, defined as having passed a kidney stone clinically within the last 5 years

• Upper gastrointestinal (GI) bleeding with a history of a clinical episode of upper GI bleeding within last 10 years that was note definitively treated by a surgical procedure

• Orthostatic hypotension or a known history of orthostatic hypotension documented in the chart or provided by the patient upon clinical history-taking

• Impaired cardiac function either diagnosed symptomatic heart failure requiring medical therapy