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Senneville, Canada

Kostenuik P.J.,Amgen Inc. | Smith S.Y.,Bone Research | Jolette J.,Bone Research | Schroeder J.,Amgen Inc. | And 2 more authors.
Bone | Year: 2011

This study examined the effects of denosumab, an anti-RANKL antibody that inhibits bone resorption, on bone histomorphometry in adult ovariectomized cynomolgus monkeys (OVX cynos). A month after surgery, OVX cynos were treated with subcutaneous vehicle (OVX-Veh) or denosumab (25 or 50mg/kg/month) for 16months (n=14-20/group). Sham controls were treated with vehicle (Sham-Veh; n=17). Areal and volumetric BMD, urine NTx, and serum osteocalcin were measured at baseline and months 3, 6, 12, and 16. Double fluorochrome labels were injected prior to iliac and rib biopsies at month 6 and month 12, and prior to sacrifice at month 16. Histomorphometry was performed on these biopsies, the tibial diaphysis, the L2 vertebra, and the proximal femur. Strength of humeral cortical beams, femur diaphysis, femur neck, and trabecular cores of L5-L6 vertebrae was determined by destructive biomechanical testing. There was no evidence of woven bone, osteomalacia, or other bone histopathologic changes with OVX or with denosumab. OVX-Veh animals exhibited significantly greater bone remodeling at all skeletal sites relative to Sham-Veh controls. Both doses of denosumab markedly inhibited bone remodeling at all sites, including significant reductions in trabecular eroded surfaces (48-86% lower than OVX-Veh controls), cortical porosity (28-72% lower), and dynamic parameters of bone formation (81-100% lower). Decreased fluorochrome labeling with denosumab was related to reductions in cortical porosity and trabecular eroded surfaces, and regression analyses suggested that these reductions contributed to denosumab-related increments in BMD and bone strength. Denosumab-treated animals with the lowest levels of fluorescent labeling exhibited the greatest structural bone strength values at each site. Intracortical remodeling had no relationship with material properties including ultimate strength, elastic modulus or toughness (r 2=0.00-0.01). These data suggest that remodeling inhibition with denosumab improved structural strength without altering material properties under these experimental conditions. Greater structural strength in the denosumab-treated animals can be primarily explained by the combined effects of increased trabecular and cortical bone mass, and reductions in trabecular eroded surfaces and cortical porosity. © 2011 Elsevier Inc.

Ominsky M.S.,Amgen Inc. | Stouch B.,Amgen Inc. | Schroeder J.,Amgen Inc. | Pyrah I.,Amgen Inc. | And 3 more authors.
Bone | Year: 2011

Denosumab is a fully human monoclonal antibody that inhibits RANKL, a protein essential for osteoclast formation, function, and survival. Osteoclast inhibition with denosumab decreased bone resorption, increased bone mineral density (BMD), and reduced fracture risk in osteoporotic women. The effects of 16months of continuous osteoclast inhibition on bone strength parameters were examined in adult ovariectomized (OVX) cynomolgus monkeys (cynos). One month after surgery, OVX cynos (n=14-20/group) were treated monthly with subcutaneous vehicle (OVX-Veh) or denosumab (25 or 50mg/kg). Sham-operated controls were treated with vehicle (n=17). OVX-Veh exhibited early and persistent increases in the resorption marker CTx, followed by similar increases in the formation marker BSAP, consistent with increased bone remodeling. Denosumab reduced CTx and BSAP throughout the study to levels significantly lower than in OVX-Veh or Sham-Veh, consistent with reduced remodeling. Increased remodeling in OVX-Veh led to absolute declines in areal BMD of 4.3-7.4% at the lumbar spine, total hip, femur neck, and distal radius (all p<0.05 vs baseline). Denosumab significantly increased aBMD at each site to levels exceeding baseline or OVX-Veh controls, and denosumab significantly increased cortical vBMC of the central radius and tibia by 7% and 14% (respectively) relative to OVX-Veh. Destructive biomechanical testing revealed that both doses of denosumab were associated with significantly greater peak load for femur neck (+19-34%), L3-L4 vertebral bodies (+54-55%), and L5-L6 cancellous cores (+69-82%) compared with OVX-Veh. Direct assessment of bone tissue material properties at cortical sites revealed no significant changes with denosumab. For all sites analyzed biomechanically, bone mass (BMC) and strength (load) exhibited strong linear correlations (r 2=0.59-0.85 for all groups combined). Denosumab did not alter slopes of load-BMC regressions at any site, and denosumab groups exhibited similar or greater load values at given BMC values compared with OVX-Veh or Sham. In summary, denosumab markedly reduced biochemical markers of bone remodeling and increased cortical and trabecular bone mass in adult OVX cynos. Denosumab improved structural bone strength parameters at all sites analyzed, and strength remained highly correlated with bone mass. There was no evidence for reduced material strength properties of cortical bone with denosumab over this time period, which approximates to 4years of remodeling in the slower-remodeling adult human skeleton. These data indicate that denosumab increased bone strength by increasing bone mass and preserving bone quality. © 2011 Elsevier Inc.

Kumar S.,Glaxosmithkline | Hoffman S.J.,Glaxosmithkline | Samadfam R.,Bone Research | Mansell P.,Charles River Laboratories | And 4 more authors.
Journal of Bone and Mineral Research | Year: 2013

Rosiglitazone (RSG) is an antidiabetic drug that has been associated with increased peripheral fractures, primarily in postmenopausal women. In this report, we investigated the underlying mechanisms of RSG-associated bone loss in ovariectomized (OVX) rats and determined whether changes in bone parameters associated with RSG administration are reversible on treatment cessation or preventable by coadministration with an antiresorptive agent. Nine-month-old Sprague-Dawley rats underwent OVX or sham operation. Sham-operated rats received oral vehicle only; OVX animals were randomized to receive vehicle, RSG, alendronate (ALN), or RSG plus ALN for 12 weeks. All treatment started the day after ovariectomy. After the 12-week treatment period, the OVX and RSG groups also underwent an 8-week treatment-free recovery period. Bone densitometry measurements, bone turnover markers, biomechanical testing, and histomorphometric analysis were conducted. Microcomputed tomography was also used to investigate changes in microarchitecture. RSG significantly increased deoxypyridinoline levels compared with OVX. Significant exacerbation of OVX-induced loss of bone mass, strength, and microarchitectural deterioration was observed in RSG-treated OVX animals compared with OVX controls. These effects were observed predominantly at sites rich in trabecular bone, with less pronounced effects in cortical bone. Coadministration of RSG and ALN prevented the bone loss associated with RSG treatment. Following cessation of RSG treatment, effects on bone mass and strength showed evidence of reversal. Thus, treatment of OVX rats with RSG results in loss of bone mass and strength, primarily at sites rich in trabecular bone, mainly due to increased bone resorption. These effects can be prevented by concomitant treatment with ALN and may be reversed following discontinuation of RSG. Copyright © 2013 American Society for Bone and Mineral Research.

Ominsky M.S.,Amgen Inc. | Li C.,Amgen Inc. | Li X.,Amgen Inc. | Tan H.L.,Amgen Inc. | And 15 more authors.
Journal of Bone and Mineral Research | Year: 2011

Therapeutic enhancement of fracture healing would help to prevent the occurrence of orthopedic complications such as nonunion and revision surgery. Sclerostin is a negative regulator of bone formation, and treatment with a sclerostin monoclonal antibody (Scl-Ab) results in increased bone formation and bone mass in animal models. Our objective was to investigate the effects of systemic administration of Scl-Ab in two models of fracture healing. In both a closed femoral fracture model in rats and a fibular osteotomy model in cynomolgus monkeys, Scl-Ab significantly increased bone mass and bone strength at the site of fracture. After 10 weeks of healing in nonhuman primates, the fractures in the Scl-Ab group had less callus cartilage and smaller fracture gaps containing more bone and less fibrovascular tissue. These improvements at the fracture site corresponded with improvements in bone formation, bone mass, and bone strength at nonfractured cortical and trabecular sites in both studies. Thus the potent anabolic activity of Scl-Ab throughout the skeleton also was associated with an anabolic effect at the site of fracture. These results support the potential for systemic Scl-Ab administration to enhance fracture healing in patients. © 2011 American Society for Bone and Mineral Research.

Smith S.Y.,Bone Research | Doyle N.,Bone Research | Boyer M.,Bone Research | Chouinard L.,Bone Research | Saito H.,Chugai Pharmaceutical Co.
Bone | Year: 2013

Vitamin D insufficiency is common in elderly people worldwide, and intake of supplementary calcium and vitamin D is recommended to those with a high risk of fracture. Several clinical studies and meta-analyses have shown that calcium and vitamin D supplementation reduces osteoporotic fractures, and a strong correlation exists between vitamin D status and fracture risk. Vitamin D supplementations improve calcium balance in the body; however, it remains unclear whether vitamin D directly affects bone metabolism. Recently, eldecalcitol (ELD), an active form of vitamin D analog, has been approved for the treatment of osteoporosis in Japan. A 3-year clinical trial showed ELD treatment increased lumbar spine bone mineral density (BMD) and reduced fracture risk in patients with osteoporosis. To evaluate the mechanism of ELD action in bone remodeling, ovariectomized cynomolgus monkeys were treated with 0.1 or 0.3. μg/day of ELD for 6. months. This treatment increased lumbar BMD by 4.4% and 10.2%, respectively, and suppressed ovariectomy-induced increases in bone turnover markers compared to OVX-vehicle control. Histomorphometric analysis of bone revealed that both bone formation parameters and bone resorption parameters in the trabecular bone of the lumbar vertebrae were suppressed by ELD treatment. ELD treatment also improved biomechanical properties of the lumbar vertebrae and the femoral neck in the ovariectomized cynomolgus monkeys. These results indicate that, in a bone-remodeling animal model, ELD increases BMD and improves bone biomechanical properties by normalizing bone turnover. Therefore, ELD has a direct and potentially beneficial effect on bone metabolism. © 2013 The Authors.

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