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Sclerostin is an Important Target for Stimulating Bone Formation, Restoring Bone Mass and Enhancing Fracture Healing
Abstracts / Bone 46 (2010) S9–S83
based assays, favorable pharmacokinetics in several preclinical species, and improved metabolic stability. Long term (21 months) treatment of ovx’d rhesus monkeys with ODN resulted in full protection of bone mineral density (BMD) loss at the spine and the hip, and maintenance of bone quality. Interestingly, ODN increases periosteal bone formation rate in the proximal femoral shaft and at the femoral neck. In clinical trials, ODN at 50 mg/week taken orally for three years increased lumbar spine and hip BMD in postmenopausal women with low bone mass. These results suggest that inhibition of Cat K may offer a novel therapeutic approach for treatment of post-menopausal osteoporosis. doi:10.1016/j.bone.2010.01.020
18. The Pathophysiology and Treatment of Glucocorticoid Induced Osteoporosis Nancy Lane Medicine, U.C. Davis, Sacramento, California, United States Glucocorticoid (GC) use results in rapid bone loss and an elevated risk of fracture. The excess bone fragility from GC treatment is multifactorial. GCs increase bone remodeling through reductions in gonadal hormones, elevations in PTH from a negative calcium balance, early stimulations of osteoclast maturation and activity, and delayed, sustained reductions in osteogenesis and osteoblast activity. In the presence of GCs, we have observed increased osteocyte lacunae size, with demineralization around the osteocyte and reduced elastic modulus, in both a mouse model and from clinical studies of GC induced bone loss. The etiology of the localized reduction in the material properties and increased osteocyte lacunae is under investigation, however our preliminary data demonstrate an initial response of the osteocytes to the stress of GCs is to undergo autophagy followed later by some apoptosis in a percentage of the cells. Our preclinical studies of mice that had developed glucocorticoidinduced osteoporosis (GIOP), and were treated with either risedronate or hPTH (1-34) for 28 days, improved bone mass and bone strength, through different biologic pathways. PTH overcame the GC induced suppression of osteogenesis by inhibiting the wnt signaling inhibitors (DKK-1 and Sclerostin and Wif1), while risedronate over came the GC induced suppression of bone mineralization through inhibition of the mineralization inhibitors (Dmp1, Phex, and Spp1). In clinical studies of GIOP, both bisphosphonates and hPTH (1-34) have demonstrated improvements in bone mass and reduction in incident vertebral fractures. In summary, GC effects on bone fragility are multi-factorial and additional studies are now underway to clarify how GCs alter osteocyte metabolism and result in reductions in localized bone strength through additional investigations of the response of osteocytes to GC exposure. doi:10.1016/j.bone.2010.01.021
19. Sclerostin is an Important Target for Stimulating Bone Formation, Restoring Bone Mass and Enhancing Fracture Healing David Ke, Desmond Padhi, Chris Paszty Amgen, Thousand Oaks, California, United States Sclerostin, a protein secreted by osteocytes, is a negative regulator of osteoblast differentiation/function and acts as an inhibitor of bone formation. Sclerostin knock-out mice demonstrate increased trabecular and cortical bone mineral density and bone strength by
S15
increased bone formation. To explore the therapeutic potential of sclerostin as a target for the anabolic treatment of diseases in which low bone mass is a significant component; we have developed a sclerostin neutralizing monoclonal antibody (Scl-Ab). In this presentation a summary of preclinical and clinical efficacy data will be reviewed to profile the effects of Scl-Ab on bone formation, bone resorption and the tissue-level mechanism of action such as bone modeling and remodeling. In vitro, Scl-Ab reversed the inhibitory effects of sclerostin on mineralization/osteoblasts differentiation. In an ovariectomy (OVX)-induced bone loss rat model, Scl-Ab increased modeling-based bone formation, restored trabecular and cortical bone mass and bone strength at multiple skeletal sites. Pre-treatment or co-treatment with anti-resorptive agents such as a bisphosphonate did not block the bone anabolic effects of Scl-Ab in OVX rats and the anabolic effects of Scl-Ab are reversible. In the aged male rat model with low bone turnover, Scl-Ab increased bone mass and bone strength by stimulating bone formation. In a disuse-induced bone loss rat model, Scl-Ab increased bone formation and decreased bone resorption leading to significant increases in trabecular and cortical bone mass. In a phase 1 trial in postmenopausal women with osteopenia, a single administration resulted in dose-dependent increases in serum bone formation markers (BSAP, osteocalcin, P1NP), and decreases in the serum bone resorption marker CTX1. These effects were associated with an increase in bone mineral density. In preclinical fracture healing and bone regeneration models (mouse, rat and non-human primate), Scl-Ab administrated by subcutaneous injection significantly decreases fracture healing time, improves bone strength, enhances implant fixation and heals critical size defect. Taken together, these data suggest sclerostin is an important target for stimulating bone formation, restoring bone mass in osteoporotic animal models and enhancing fracture healing in bone repair models, and inhibition of sclerostin is an attractive strategy for osteoporosis and fracture healing. doi:10.1016/j.bone.2010.01.022
20. Calcium supplement effects on vascular events - is it worth the risk? Ian Reid University of Auckland, Grafton, Auckland, New Zealand Calcium supplementation is widely used for the prevention of osteoporosis in postmenopausal women and in men. While there has been ongoing debate regarding its effectiveness in fracture prevention, the underlying assumption has been that, even if it was not particularly effective, at least it was safe. The recent finding of the Auckland Calcium Study that myocardial infarctions were more common in women randomised to calcium (BMJ 336:262), calls this assumption into question. We now report a meta-analysis of placebo-controlled trials of calcium supplementation (≥ 500 mg/day) with ≥ 100 participants and duration >1 year. 15 trials were eligible for inclusion, with patient-level data available for 5 studies (N = 8151), and triallevel data for 11 studies (N = 11921). HRs for myocardial infarction in those allocated to calcium were 1.31(1.02-1.67) and 1.27 (1.01-1.59), respectively, in these 2 groups of trials. Mean follow-up was 4 years. Cardiovascular (CVS) event data from the WHI have been published, and show an interaction between BMI and the CaD intervention. In non-obese women, the HR of a composite CVS endpoint was 1.24 (1.09-1.40) in those allocated to CaD. This study is also complicated by use of non-study Ca supplements in 56% of subjects. In those not self-administering Ca, the HR of this composite endpoint was 1.13 (0.99-1.30). It is already accepted that calcium supplements increase vascular risk in patients with renal compromise,
based assays, favorable pharmacokinetics in several preclinical species, and improved metabolic stability. Long term (21 months) treatment of ovx’d rhesus monkeys with ODN resulted in full protection of bone mineral density (BMD) loss at the spine and the hip, and maintenance of bone quality. Interestingly, ODN increases periosteal bone formation rate in the proximal femoral shaft and at the femoral neck. In clinical trials, ODN at 50 mg/week taken orally for three years increased lumbar spine and hip BMD in postmenopausal women with low bone mass. These results suggest that inhibition of Cat K may offer a novel therapeutic approach for treatment of post-menopausal osteoporosis. doi:10.1016/j.bone.2010.01.020
18. The Pathophysiology and Treatment of Glucocorticoid Induced Osteoporosis Nancy Lane Medicine, U.C. Davis, Sacramento, California, United States Glucocorticoid (GC) use results in rapid bone loss and an elevated risk of fracture. The excess bone fragility from GC treatment is multifactorial. GCs increase bone remodeling through reductions in gonadal hormones, elevations in PTH from a negative calcium balance, early stimulations of osteoclast maturation and activity, and delayed, sustained reductions in osteogenesis and osteoblast activity. In the presence of GCs, we have observed increased osteocyte lacunae size, with demineralization around the osteocyte and reduced elastic modulus, in both a mouse model and from clinical studies of GC induced bone loss. The etiology of the localized reduction in the material properties and increased osteocyte lacunae is under investigation, however our preliminary data demonstrate an initial response of the osteocytes to the stress of GCs is to undergo autophagy followed later by some apoptosis in a percentage of the cells. Our preclinical studies of mice that had developed glucocorticoidinduced osteoporosis (GIOP), and were treated with either risedronate or hPTH (1-34) for 28 days, improved bone mass and bone strength, through different biologic pathways. PTH overcame the GC induced suppression of osteogenesis by inhibiting the wnt signaling inhibitors (DKK-1 and Sclerostin and Wif1), while risedronate over came the GC induced suppression of bone mineralization through inhibition of the mineralization inhibitors (Dmp1, Phex, and Spp1). In clinical studies of GIOP, both bisphosphonates and hPTH (1-34) have demonstrated improvements in bone mass and reduction in incident vertebral fractures. In summary, GC effects on bone fragility are multi-factorial and additional studies are now underway to clarify how GCs alter osteocyte metabolism and result in reductions in localized bone strength through additional investigations of the response of osteocytes to GC exposure. doi:10.1016/j.bone.2010.01.021
19. Sclerostin is an Important Target for Stimulating Bone Formation, Restoring Bone Mass and Enhancing Fracture Healing David Ke, Desmond Padhi, Chris Paszty Amgen, Thousand Oaks, California, United States Sclerostin, a protein secreted by osteocytes, is a negative regulator of osteoblast differentiation/function and acts as an inhibitor of bone formation. Sclerostin knock-out mice demonstrate increased trabecular and cortical bone mineral density and bone strength by
S15
increased bone formation. To explore the therapeutic potential of sclerostin as a target for the anabolic treatment of diseases in which low bone mass is a significant component; we have developed a sclerostin neutralizing monoclonal antibody (Scl-Ab). In this presentation a summary of preclinical and clinical efficacy data will be reviewed to profile the effects of Scl-Ab on bone formation, bone resorption and the tissue-level mechanism of action such as bone modeling and remodeling. In vitro, Scl-Ab reversed the inhibitory effects of sclerostin on mineralization/osteoblasts differentiation. In an ovariectomy (OVX)-induced bone loss rat model, Scl-Ab increased modeling-based bone formation, restored trabecular and cortical bone mass and bone strength at multiple skeletal sites. Pre-treatment or co-treatment with anti-resorptive agents such as a bisphosphonate did not block the bone anabolic effects of Scl-Ab in OVX rats and the anabolic effects of Scl-Ab are reversible. In the aged male rat model with low bone turnover, Scl-Ab increased bone mass and bone strength by stimulating bone formation. In a disuse-induced bone loss rat model, Scl-Ab increased bone formation and decreased bone resorption leading to significant increases in trabecular and cortical bone mass. In a phase 1 trial in postmenopausal women with osteopenia, a single administration resulted in dose-dependent increases in serum bone formation markers (BSAP, osteocalcin, P1NP), and decreases in the serum bone resorption marker CTX1. These effects were associated with an increase in bone mineral density. In preclinical fracture healing and bone regeneration models (mouse, rat and non-human primate), Scl-Ab administrated by subcutaneous injection significantly decreases fracture healing time, improves bone strength, enhances implant fixation and heals critical size defect. Taken together, these data suggest sclerostin is an important target for stimulating bone formation, restoring bone mass in osteoporotic animal models and enhancing fracture healing in bone repair models, and inhibition of sclerostin is an attractive strategy for osteoporosis and fracture healing. doi:10.1016/j.bone.2010.01.022
20. Calcium supplement effects on vascular events - is it worth the risk? Ian Reid University of Auckland, Grafton, Auckland, New Zealand Calcium supplementation is widely used for the prevention of osteoporosis in postmenopausal women and in men. While there has been ongoing debate regarding its effectiveness in fracture prevention, the underlying assumption has been that, even if it was not particularly effective, at least it was safe. The recent finding of the Auckland Calcium Study that myocardial infarctions were more common in women randomised to calcium (BMJ 336:262), calls this assumption into question. We now report a meta-analysis of placebo-controlled trials of calcium supplementation (≥ 500 mg/day) with ≥ 100 participants and duration >1 year. 15 trials were eligible for inclusion, with patient-level data available for 5 studies (N = 8151), and triallevel data for 11 studies (N = 11921). HRs for myocardial infarction in those allocated to calcium were 1.31(1.02-1.67) and 1.27 (1.01-1.59), respectively, in these 2 groups of trials. Mean follow-up was 4 years. Cardiovascular (CVS) event data from the WHI have been published, and show an interaction between BMI and the CaD intervention. In non-obese women, the HR of a composite CVS endpoint was 1.24 (1.09-1.40) in those allocated to CaD. This study is also complicated by use of non-study Ca supplements in 56% of subjects. In those not self-administering Ca, the HR of this composite endpoint was 1.13 (0.99-1.30). It is already accepted that calcium supplements increase vascular risk in patients with renal compromise,