Novel Combination Therapy for Osteoporosis in Men
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 40
- 试验地点
- 2
- 主要终点
- Effects of treatment with TPTD+cinacalcet compared to TPTD+PBO on lumbar spine BMD in men with low bone mass
研究概览
简要总结
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.
详细描述
NOVEL COMBINATION THERAPY FOR OSTEOPOROSIS IN MEN
- Background for the Study
What Is the Risk of Osteoporotic Fractures in Men and Why Do Men Lose Bone Mass? Osteoporosis is a neglected condition in men. Yet, men sustain approximately 30% of the 1.5 million fractures that occur annually in the US. Fractures are expensive. Estimated costs are at least $20 billion annually. This figure will no doubt rise substantially as the population ages. Plus, these costs do not take into account the personal and societal burden of fractures, especially hip fractures. One in 6 men will sustain a hip fracture by the time he reaches age 90 years. A man who fractures a hip at any age has greater disability following that fracture and is much less likely to regain his ability to walk and to live independently afterward. Men also have a greater risk of dying from the complications of hip fractures. Overall, one-year mortality for patients who sustain a hip fracture is ~20%. However, mortality in men with hip fractures is staggeringly high at ~37.5% in the first year.
The pathophysiology of bone loss in aging men differs in important ways from postmenopausal osteoporosis. Age-related bone loss in men begins in the 6th decade with nutritional and hormonal abnormalities playing important roles. Contributing factors include decreased intestinal Ca absorption, vitamin D deficiency or insufficiency, and secondary (2o) hyperparathyroidism (HPT). Testosterone levels decline with age in men, and as they do, estradiol levels also fall. Considerable evidence supports an important role for estradiol in maintaining bone mass in men as well as women. Men lose both trabecular and cortical bone mass with age. Trabecular bone thins out in men, rather than perforates, as it does in women, and excessive cortical bone remodeling is a dominant force in older men. In men, periosteal bone apposition does not keep pace with endosteal resorption, and the bones weaken. With minimal trauma, fragility fractures may result. Thus, reduced bone formation is a key mechanism underlying bone loss in men, more so than the high rates of bone resorption seen in postmenopausal estrogen deficiency. For these reasons, anabolic regimens that enhance bone formation may achieve better clinical outcomes in men compared to commonly used antiresorptive agents. This trial will test a novel anabolic combination therapy in men.
How Effective Are Current Treatments for Osteoporosis in Men? Several agents have been Food and Drug Administration (FDA)-approved to treat osteoporosis in men: bisphosphonates; denosumab; and teriparatide (TPTD) or parathyroid hormone (PTH) (1-34). In trials enrolling men, these agents were shown to increase bone mineral density (BMD) by dual energy Xray absorptiometry (DXA) at key skeletal sites, quantitatively similar to their effects in postmenopausal women. In only a few appropriately powered studies, there was a reduction in incident vertebral fractures in men at high risk and/or those on androgen deprivation therapy.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- Triple (Participant, Care Provider, Investigator)
盲法说明
All study personnel will be masked to treatment assignment and this group will include the DXA technicians, the study coordinators, and the lab technicians and lab supervisors who will analyze samples for study results.
入排标准
- 年龄范围
- 60 Years 至 85 Years（Adult, Older Adult）
- 性别
- Male
- 接受健康志愿者
- 否
入选标准
- •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)
排除标准
- •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
研究组 & 干预措施
Combination Therapy Arm: Teriparatide (TPTD) + the Calcimimetic Cinacalcet
Combination therapy arm: Men randomized to this arm will take daily subcutaneous injections of teriparatide [PTH (1-34)] (20 mcg per day) and at the same time swallow a 30-mg tablet of cinacalcet. Men in both arms of the study will take a total of approximately 1000 mg elemental Ca through their diets and study provided Ca supplements (Ca citrate) and approximately 1000 IU vitamin D3. Men will be followed and assessed throughout the entire study using the clinical (vital signs, adverse events), laboratory (blood and urine tests) and densitometric procedures (DXA BMD and TBS) outlined in the study protocol.
干预措施: Calcium citrate tablet (Dietary Supplement)
Monotherapy Arm: Teriparatide (TPTD) + Placebo
Monotherapy arm: Men randomized to this arm will take daily subcutaneous injections of teriparatide [PTH (1-34)] (20 mcg per day) and at the same time swallow a placebo tablet. Men in both arms of the study will take a total of approximately 1000 mg elemental Ca through their diets and study provided Ca supplements (Ca citrate) and approximately 1000 IU vitamin D3. Men will be followed and assessed throughout the entire study using the clinical (vital signs, adverse events), laboratory (blood and urine tests) and densitometric procedures (DXA BMD and TBS) outlined in the study protocol.
干预措施: placebo tablet (Drug)
Combination Therapy Arm: Teriparatide (TPTD) + the Calcimimetic Cinacalcet
Combination therapy arm: Men randomized to this arm will take daily subcutaneous injections of teriparatide [PTH (1-34)] (20 mcg per day) and at the same time swallow a 30-mg tablet of cinacalcet. Men in both arms of the study will take a total of approximately 1000 mg elemental Ca through their diets and study provided Ca supplements (Ca citrate) and approximately 1000 IU vitamin D3. Men will be followed and assessed throughout the entire study using the clinical (vital signs, adverse events), laboratory (blood and urine tests) and densitometric procedures (DXA BMD and TBS) outlined in the study protocol.
干预措施: Teriparatide or human parathyroid hormone (PTH) 1-34 (Drug)
Monotherapy Arm: Teriparatide (TPTD) + Placebo
Monotherapy arm: Men randomized to this arm will take daily subcutaneous injections of teriparatide [PTH (1-34)] (20 mcg per day) and at the same time swallow a placebo tablet. Men in both arms of the study will take a total of approximately 1000 mg elemental Ca through their diets and study provided Ca supplements (Ca citrate) and approximately 1000 IU vitamin D3. Men will be followed and assessed throughout the entire study using the clinical (vital signs, adverse events), laboratory (blood and urine tests) and densitometric procedures (DXA BMD and TBS) outlined in the study protocol.
干预措施: Calcium citrate tablet (Dietary Supplement)
Combination Therapy Arm: Teriparatide (TPTD) + the Calcimimetic Cinacalcet
Combination therapy arm: Men randomized to this arm will take daily subcutaneous injections of teriparatide [PTH (1-34)] (20 mcg per day) and at the same time swallow a 30-mg tablet of cinacalcet. Men in both arms of the study will take a total of approximately 1000 mg elemental Ca through their diets and study provided Ca supplements (Ca citrate) and approximately 1000 IU vitamin D3. Men will be followed and assessed throughout the entire study using the clinical (vital signs, adverse events), laboratory (blood and urine tests) and densitometric procedures (DXA BMD and TBS) outlined in the study protocol.
干预措施: Cinacalcet (Drug)
Monotherapy Arm: Teriparatide (TPTD) + Placebo
Monotherapy arm: Men randomized to this arm will take daily subcutaneous injections of teriparatide [PTH (1-34)] (20 mcg per day) and at the same time swallow a placebo tablet. Men in both arms of the study will take a total of approximately 1000 mg elemental Ca through their diets and study provided Ca supplements (Ca citrate) and approximately 1000 IU vitamin D3. Men will be followed and assessed throughout the entire study using the clinical (vital signs, adverse events), laboratory (blood and urine tests) and densitometric procedures (DXA BMD and TBS) outlined in the study protocol.
干预措施: Teriparatide or human parathyroid hormone (PTH) 1-34 (Drug)
Monotherapy Arm: Teriparatide (TPTD) + Placebo
Monotherapy arm: Men randomized to this arm will take daily subcutaneous injections of teriparatide [PTH (1-34)] (20 mcg per day) and at the same time swallow a placebo tablet. Men in both arms of the study will take a total of approximately 1000 mg elemental Ca through their diets and study provided Ca supplements (Ca citrate) and approximately 1000 IU vitamin D3. Men will be followed and assessed throughout the entire study using the clinical (vital signs, adverse events), laboratory (blood and urine tests) and densitometric procedures (DXA BMD and TBS) outlined in the study protocol.
干预措施: Vitamin D3 (Dietary Supplement)
Combination Therapy Arm: Teriparatide (TPTD) + the Calcimimetic Cinacalcet
Combination therapy arm: Men randomized to this arm will take daily subcutaneous injections of teriparatide [PTH (1-34)] (20 mcg per day) and at the same time swallow a 30-mg tablet of cinacalcet. Men in both arms of the study will take a total of approximately 1000 mg elemental Ca through their diets and study provided Ca supplements (Ca citrate) and approximately 1000 IU vitamin D3. Men will be followed and assessed throughout the entire study using the clinical (vital signs, adverse events), laboratory (blood and urine tests) and densitometric procedures (DXA BMD and TBS) outlined in the study protocol.
干预措施: Vitamin D3 (Dietary Supplement)
结局指标
主要结局
Effects of treatment with TPTD+cinacalcet compared to TPTD+PBO on lumbar spine BMD in men with low bone mass
时间窗: 48 weeks
Hypothesis 1a proposes that BMD responses to combined TPTD+cinacalcet are greater than those induced by TPTD+PBO. LS BMD typically responds quickly and robustly to TPTD and is the 1o endpoint of the trial. DXA measurements will be performed and analyzed by standard protocols at baseline and at the end of the trial. Subjects will be treated for 11 months (48 weeks). All subjects will receive Ca and vitamin D3 supplements throughout the trial. The percentage change in LS BMD from baseline to 48 week/11 months of treatment will be the variable/endpoint that is calculated.
Effects of Treatment With TPTD+Cinacalcet Compared to TPTD+PBO on Lumbar Spine BMD in Men With Low Bone Mass
时间窗: 48 weeks
Hypothesis 1a proposes that BMD responses to combined TPTD+cinacalcet are greater than those induced by TPTD+PBO. LS BMD typically responds quickly and robustly to TPTD and is the 1o endpoint of the trial. DXA measurements will be performed and analyzed by standard protocols at baseline and at the end of the trial. Subjects will be treated for 11 months (48 weeks). All subjects will receive Ca and vitamin D3 supplements throughout the trial. The percentage change in LS BMD from baseline to 48 week/11 months of treatment will be the variable/endpoint that is calculated.
次要结局
- Effects of treatment with TPTD+cinacalcet compared to TPTD+PBO on serum P1NP in men with low bone mass(48 weeks)
- Effects of treatment with TPTD+cinacalcet compared to TPTD+PBO on femoral neck BMD in men with low bone mass(48 weeks)
- Effects of Treatment With TPTD+Cinacalcet Compared to TPTD+PBO on Serum P1NP in Men With Low Bone Mass(12 weeks)
- Effects of Treatment With TPTD+Cinacalcet Compared to TPTD+PBO on Femoral Neck BMD in Men With Low Bone Mass(48 weeks)