A soluble activin receptor Type IIA fusion protein (ACE-011) increases bone mass via a dual anabolic-antiresorptive effect in Cynomolgus monkeys.
ABSTRACT Activin A belongs to the TGF-beta superfamily and plays an important role in bone metabolism. It was reported that a soluble form of extracellular domain of the activin receptor type IIA (ActRIIA) fused to the Fc domain of murine IgG, an activin antagonist, has an anabolic effect on bone in intact and ovariectomized mice. The present study was designed to examine the skeletal effect of human ActRIIA-IgG1-Fc (ACE-011) in non-human primates. Young adult female Cynomolgus monkeys were given a biweekly subcutaneous injection of either 10mg/kg ACE-011 or vehicle (VEH) for 3months. Treatment effects were evaluated by histomorphometric analysis of the distal femur, femoral midshaft, femoral neck and 12th thoracic vertebrae, by muCT analysis of femoral neck and by biomarkers of bone turnover. Compared to VEH, at the distal femur ACE-011-treated monkeys had significantly increased cancellous bone volume (+93%), bone formation rate per bone surface (+166%) and osteoblast surface (+196%) indicating an anabolic action. Monkeys treated with ACE-011 also had decreased osteoclast surface and number. No differences were observed in parameters of cortical bone at the midshaft of the femur. Similar to distal femur, ACE-011-treated monkeys had significantly greater cancellous bone volume, bone formation rate and osteoblast surface at the femoral neck relative to VEH. A significant increase in bone formation rate and osteoblast surface with a decrease in osteoclast surface was observed in thoracic vertebrae. muCT analysis of femoral neck indicated more plate-like structure in ACE-011-treated monkeys. Monkeys treated with ACE-011 had no effect on serum bone-specific alkaline phosphatase and CTX at the end of the study. These observations demonstrate that ACE-011 is a dual anabolic-antiresorptive compound, improving cancellous bone volume by promoting bone formation and inhibiting bone resorption in non-human primates. Thus, soluble ActRIIA fusion protein may be useful in the prevention and/or treatment of osteoporosis and other diseases involving accelerated bone loss.
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ABSTRACT: Osteoporosis is a major public health problem that is characterized by microarchitectural deterioration, low bone mass, and increased risk of fractures. Currently, many women and men affected with this disease are not diagnosed or treated. As osteoporosis is often clinically silent, risk-factor assessment and measurement of BMD are needed to identify those who may benefit from osteoporosis therapy. Although adequate daily intake of calcium and vitamin D, and regular weight-bearing exercise are important for skeletal health, they are not adequate treatments for individuals with osteoporosis. Therapies approved for treatment and/or prevention of osteoporosis in the United States include oral bisphosphonates (alendronate, ibandronate and risedronate), calcitonin, estrogens, teriparatide (parathyroid hormone fragment [1-34]), and raloxifene. For most patients, oral bisphosphonates are the treatment of choice, given the large-scale randomized-trial data demonstrating efficacy in fracture reduction, although bisphosphonates that reduce spine and nonspine fractures (e.g. alendronate and risedronate) are preferred. For high-risk patients (those with very low bone density, or with fractures), teriparatide therapy for 2 years should be considered. The treatment paradigm for osteoporosis will evolve further as promising new treatments progress through clinical development.Nature Clinical Practice Endocrinology & Metabolism 01/2007; 2(12):670-80. · 7.55 Impact Factor
Article: Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis.[show abstract] [hide abstract]
ABSTRACT: Once-daily injections of parathyroid hormone or its amino-terminal fragments increase bone formation and bone mass without causing hypercalcemia, but their effects on fractures are unknown. We randomly assigned 1637 postmenopausal women with prior vertebral fractures to receive 20 or 40 microg of parathyroid hormone (1-34) or placebo, administered subcutaneously by the women daily. We obtained vertebral radiographs at base line and at the end of the study (median duration of observation, 21 months) and performed serial measurements of bone mass by dual-energy x-ray absorptiometry. New vertebral fractures occurred in 14 percent of the women in the placebo group and in 5 percent and 4 percent, respectively, of the women in the 20-microg and 40-microg parathyroid hormone groups; the respective relative risks of fracture in the 20-microg and 40-microg groups, as compared with the placebo group, were 0.35 and 0.31 (95 percent confidence intervals, 0.22 to 0.55 and 0.19 to 0.50). New nonvertebral fragility fractures occurred in 6 percent of the women in the placebo group and in 3 percent of those in each parathyroid hormone group (relative risk, 0.47 and 0.46, respectively [95 percent confidence intervals, 0.25 to 0.88 and 0.25 to 0.861). As compared with placebo, the 20-microg and 40-microg doses of parathyroid hormone increased bone mineral density by 9 and 13 more percentage points in the lumbar spine and by 3 and 6 more percentage points in the femoral neck; the 40-microg dose decreased bone mineral density at the shaft of the radius by 2 more percentage points. Both doses increased total-body bone mineral by 2 to 4 more percentage points than did placebo. Parathyroid hormone had only minor side effects (occasional nausea and headache). Treatment of postmenopausal osteoporosis with parathyroid hormone (1-34) decreases the risk of vertebral and nonvertebral fractures; increases vertebral, femoral, and total-body bone mineral density; and is well tolerated. The 40-microg dose increased bone mineral density more than the 20-microg dose but had similar effects on the risk of fracture and was more likely to have side effects.New England Journal of Medicine 06/2001; 344(19):1434-41. · 53.30 Impact Factor
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ABSTRACT: An important, unfilled clinical need is the development of new approaches to improve fracture healing and to treat osteoporosis by increasing bone mass. Recombinant forms of bone morphogenetic protein 2 (BMP2) and BMP7 are FDA approved to promote spinal fusion and fracture healing, respectively, and the first FDA-approved anabolic drug for osteoporosis, parathyroid hormone, increases bone mass when administered intermittently but can only be given to patients in the US for two years. As we discuss here, the tremendous explosion over the last two decades in our fundamental understanding of the mechanisms of bone remodeling has led to the prospect of mechanism-based anabolic therapies for bone disorders.Journal of Clinical Investigation 03/2008; 118(2):421-8. · 15.39 Impact Factor