Novel Combination Therapy for Osteoporosis in Men

NOVEL COMBINATION THERAPY FOR OSTEOPOROSIS IN MEN 1. 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. Intermittent injections of TPTD are appealing as a treatment for osteoporosis in men because the agent has potent anabolic actions. TPTD increases bone formation, reflected by enhanced biochemical markers of osteoblast (OB) activity, such as N-terminal propeptide of type 1 collagen (P1NP) and bone specific alkaline phosphatase (BSAP) in the blood, and by direct histomorphometric quantification of bone formation, and mineral apposition rates. TPTD also improves the microarchitecture of bone by micro-CT (trabecular thickness and connectivity) and increases the maturation or number of circulating osteogenic precursors and stem cells in blood in postmenopausal women. TPTD in vitro stimulates the proliferation of mesenchymal stem cells and their commitment to the OB lineage as osteoprogenitors. PTH (1-34) also increases differentiation of early OBs and matrix production, blocks apoptosis of OBs and osteocytes, and reduces production of the Wnt inhibitor sclerostin by osteocytes. The anabolic actions of PTH treatment within a defined time-frame (18 to 24 months in humans) -- called the "anabolic window" -- improve bone strength and ultimately reduce spine and nonvertebral fractures. Over time, however, PTH stimulates receptor activator of nuclear factor kappa B ligand (RANK-L) production by early OB lineage cells, and RANK-L enhances osteoclast (OC) production. This increases bone resorption, which limits further gains in BMD with PTH. The challenge in designing optimal treatment regimens with PTH is maximizing its anabolic activity, while taming its catabolic effects on bone. Clinical trials with TPTD \[recombinant human PTH (1-34)\] or synthetic human PTH (1-34) in men are limited to a few studies with small numbers of men. Orwoll and colleagues randomized 437 men into 3 groups: placebo (PBO) vs 20 (the dose subsequently FDA-approved) or 40 ug TPTD daily. However, they completed only an average of 11 months on treatment. Kurland and colleagues randomized 23 men to synthetic PTH (1-34) (400 IU or \~25 ug/day; N=10) or PBO (N=13) for 18 months. Finkelstein and colleagues, as part of a combination study, randomized 27 men to synthetic PTH (1-34) for 24 months (37 ug/day). Thus, that study used twice the approved dose of PTH (1-34). Walker and colleagues randomized men to risedronate (35 mg/week) (N=10), TPTD (20 ug/day) (N=9), or the combination (N=10) for 18 months. In these studies, BMD rose by \~6-14% at the lumbar spine and by \~2-4% at femoral neck with 11-18 months treatment \[with 20 or 25 ug PTH (1-34)/day\]. Higher doses of PTH (1-34) (37 or 40 ug/day) produced even greater responses at both sites (2-3 fold more). This indicates that stronger anabolic effects are feasible to achieve in men within these short time-frames. However, these doses are less tolerated, and the investigators do not plan to use them. Rather, the trial proposed will use the FDA-approved dose of TPTD (20 ug/d) by daily subcutaneous injection. Combination studies of PTH (1-34) with alendronate or TPTD with risedronate did not convincingly show synergistic effects on BMD in men. A trial combining TPTD and denosumab showed additive effects of the combination, but it was done in women. Several important questions about TPTD treatment in men have never been addressed. Among them, can TPTD be advantageously combined with another "bone-active" drug that has a similar or a different mechanism of action? Investigators in the field only know that adding PTH (1-34) to alendronate in men does not produce additive effects. This trial will test the hypothesis that concurrent CaSR activation (by calcimimetic) synergizes with PTH-R activation (by TPTD) to produce greater anabolic effects in men, reflected by changes in BMD and bone turnover markers (BTMs), compared to TPTD alone. This is a novel combination therapy that is well-supported in preclinical studies. 2. Scientific Premise for the Planned Intervention This is a first in human study of a combination therapy for osteoporosis. Both of the drugs that will be used in the trial have been FDA-approved for many years and have been used in the clinic in hundreds of thousands of patients worldwide: TPTD for the treatment of osteoporosis in women and men, and cinacalcet for the treatment of various forms of HPT in women and men. The two agents to be used in the trial have not been as yet tested in the combination format that will be done in this study. Summarized below are preclinical data from young (12-week old) and elderly (12-month old) male and female mice. Preclinical Studies: Combined PTH(1-34) and Calcimimetic Produce Marked Anabolic Effects on Bone in Mice Both extracellular Ca-sensing receptors (CaSRs) and PTH receptors (PTH-Rs) play central roles in the control of bone remodeling. In conditional (or tissue-specific) knockout mice, CaSRs have been shown to play key roles in skeletal development and in OB and osteocyte function by several groups. Such work supports the idea that high extracellular \[Ca\] (\[Ca\]e), acting through CaSRs, is an "anabolic pathway" in bone, akin to intermittent PTH (1-34) stimulation of PTH-R signaling in bone. Several groups have found that direct CaSR activation in OC lineage cells reduced their survival, gene expression, and resorptive function. This suggested that enhanced OB and suppressed OC function might be accomplished through activation of CaSRs in different bone cell populations. Based on this work in mice and the known role of PTH peptides as bone anabolic agents in humans, studies were done in mice to test the hypothesis that concurrent activation of PTH-Rs and of CaSRs has synergistic effects on bone mass. Adult male mice given intermittent subcutaneous (SC) injections of PTH(1-34) (40-80 ug/kg) and the calcimimetic NPS-R568 (20 umole/kg) for 4-6 weeks showed dramatic synergistic anabolic effects on bone mass and strength. PTH (1-34) injections alone significantly increased trabecular (Tb) bone mass \[Tb bone volume/tissue volume (BV/TV)\] by micro-CT in the distal femur as well as Tb thickness (TbTh) (p\<0.05). Co-injections of PTH (1-34) and NPS-R568 produced significantly greater effects on Tb BV/TV and TbTh (by \~21%; p\<0.01), while NPS-R568 injections alone had no effect. These are large effects on bone mass, as determined by highly sensitive methods - micro CT and bone histomorphometry. The latter is the gold-standard for testing the effects of an intervention on dynamic bone metabolic processes. This combination therapy also produced bone microarchitectural changes (more plate-like trabeculi), compatible with mechanically stronger bone. Cortical (Ct) bone is typically less affected by PTH (1-34) treatment. However, in these experiments when Ct bone at the tibiofibular junction (TFJ) was assessed by micro-CT, it was clear that combined injections of PTH (1-34) and NPS-R568 produced dramatic increases in CtTV, CtBV, and CtTh…