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Differential effects of angiotensin II-receptor blockade on vascular and skeletal manifestations of Marfan syndrome
Abstracts / Bone 46 (2010) S9–S83
50. SCLEROSTIN NEUTRALIZING ANTIBODY ENHANCES BONE HEALING DURING DISTRACTION OSTEOGENESIS IN RATS Michelle McDonald1, Lauren Peacock1, Kathy Mikulec1, Oliver Birke1, Min Liu2, Scott Wasserman2, Hua Zhu “David” Ke2, David Little1 1 Orthopaedic Research Dept, The Children's Hospital Westmead, Westmead, New South Wales, Australia 2 Amgen, Thousand Oaks, California, United States Sclerostin (Scl) is a negative regulator of osteoblast differentiation and bone formation. The high specificity for bone and potent antagonism of formation has made sclerostin a logical target for intervention. Distraction osteogenesis (DO) is utilized widely in limb lengthening and reconstruction. Complications include disuse osteopenia and poor anabolic response, both of which would benefit from pro-anabolic therapy. A sclerostin antibody (Scl-Ab) was recently reported to stimulate bone formation and restore bone mass and strength in aged OVX rats and enhanced fracture healing in a rat model. We sought to examine the effects of this agent in a rat model of DO. An osteotomy in the femur was stabilised with an external fixator in male Sprague Dawley rats. The gap was distracted 0.25 mm twice daily to a total 7 mm. Saline or Scl-Ab was administered twice weekly throughout distraction and up to 4 or 6 weeks post commencement of distraction. Three groups were examined, Saline, Delayed Scl-Ab (D Scl-Ab, post distraction only) and Continuous Scl-Ab (Cont Scl-Ab). Radiographs were assessed for union rates. DEXA scans of the regenerate were performed at 2, 4 and 6 week time points and all samples were scanned using Micro CT (μCT) for analysis of bone volume.Radiographs demonstrated a trend for increased union rates with Scl-Ab treatment at 6 weeks with 20% unions for Saline, 50% unions for D Scl-Ab and 50% for Cont Scl-Ab. DEXA scans at 2 weeks revealed a 63% increase in regenerate BMD in Cont Scl-Ab group (p < 0.01) and a 41% increase in the D Scl-Ab group (p < 0.05), compared to Saline. In addition an increase of 116% in BMC was seen in the Cont Scl-Ab group compared to Saline (p < 0.01). At 6 weeks regenerate bone area was increased 18% in D Scl-Ab and 23 % Cont Scl-Ab compared to Saline (p < 0.05). μCT scans of the regenerate revealed an 89% increase in bone volume with Cont Scl-Ab and an 85% increase with D Scl-Ab treatment compared to Saline at 6 weeks (p < 0.05). Bone volume ratio (BV/TV) was increased 77% with Cont Scl-Ab treatment and 82% with D Scl-Ab, and bone surface was increased 62% with Cont Scl-Ab treatment at 6 weeks compared to Saline (p < 0.05). Scl-Ab treatment enhanced the amount of bone formed in this rat distraction model, when given either throughout or post distraction. Histological assessment of dynamic bone formation parameters will reveal the mechanism behind the enhanced bone repair, and its mechanical consequences will be examined. doi:10.1016/j.bone.2010.01.053
51. Differential effects of angiotensin II-receptor blockade on vascular and skeletal manifestations of Marfan syndrome Harikiran Nistala1, Aaron Rifkin2, Sui Lee Arteaga1, Maria del Solar1, Luca Carta1, Francesco Ramirez1 1 Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York, United States 2 Princeton University, Princeton, New Jersey, United States Progressive aortic root enlargement and dissection are the main causes of morbidity and mortality in patients with Marfan syndrome (MFS) and have causally been linked to promiscuous activation of latent TGFβ. Recent results have underscored the clinical efficacy of angiotensin II-receptor blockers, specifically losartan, in attenuating
S27
aneurysm progression in mouse models of MFS and a small cohort of pediatric patients. Skeletal overgrowth and osteopenia are also cardinal manifestations of MFS, the etiology of which is only starting to be elucidated. In the present study we investigated the effect of losartan (at human equivalent dosage) on skeletal metabolism during post natal growth in mice underexpressing fibrillin-1 that progressively develop severe MFS. Consistent with previous observations, losartan coordinated significant therapeutic benefits in the vasculature. By contrast, skeletal overgrowth and osteopenia in fibrillin-1 deficient mice remained unmitigated as assessed by microCT and histomorphometry. In concurrent bisphosphonate treated group, alendronate significantly improved multiple aspects of bone quality, including trabecular bone architecture and bone volume fraction. Taken together, these results point to the differential effects of angiotensin II-receptor blockade on vascular and skeletal manifestations of MFS, implicitly arguing for tissue specific pathogenetic programs requiring a multimodal treatment regimen. doi:10.1016/j.bone.2010.01.054
52. Effect of Denosumab on the Incidence of Hip and New Vertebral Fractures in Postmenopausal Women With High Fracture Risk: A Subanalysis of the FREEDOM Study Kurt Lippuner1, Jonathan Adachi2, Steven Cummings3, Zulema Man4, Jordi Farrerons5, Ove Törring6, John Gallagher7, Mike McClung8, Nathalie Franchimont9, Javier San Martin10, Andrea Wang10, Steven Boonen11 1 University of Bern, Bern, Switzerland 2 Charlton Medical Center, Hamilton, Ontario, Canada 3 SFCC, CPMC Research Institute, & UCSF, San Francisco, California, United States 4 Centro TIEMPO, Buenos Aires, Argentina 5 Hospital de la Santa Creu I Sant Pau, Barcelona, Spain 6 Karolinska Institutet Sodersjukhuset, Stockholm, Sweden 7 Creighton University Medical Center, Omaha, Nebraska, United States 8 Oregon Osteoporosis Center, Portland, Oregon, United States 9 Amgen (Europe) GmbH, Zug, Switzerland 10 Amgen Inc, Thousand Oaks, California, United States 11 University of Leuven, Leuven, Belgium Purpose: In the FREEDOM trial, denosumab (DMAb) significantly reduced the risk of hip and new vertebral fractures by 40% (95% CI:3%-63%) and 68% (95% CI: 59%-74%), respectively, over 3 years (Cummings NEJM 2009;361:756). In this post-hoc analysis, we examined the hip and new vertebral fracture incidence and risk reduction in subgroups of women with a higher baseline risk for fracture.Methods: The FREEDOM trial was a 3-year, randomized, blinded phase 3 trial in postmenopausal women with PMO aged 6090 years old with a spine or hip bone mineral density T-score <-2.5 and not <-4.0. Women were randomized to receive twice-yearly DMAb (60 mg) or placebo injections, with daily calcium and vitamin D supplements. The subgroups at high-risk for hip fractures were age ≥75 years, baseline femoral neck T-score ≤-2.5, and both factors. The subgroups at high-risk for new vertebral fractures were age ≥75 years and ≥2 prevalent vertebral fractures, or a moderate/severe prevalent vertebral fracture, or both. Results: After 3 years of treatment, DMAb significantly reduced the incidence and risk of hip and new vertebral fractures in all subgroups compared with placebo (Table). Conclusions: DMAb reduced hip and new vertebral fracture incidence and risk in subgroups of women from the FREEDOM trial who are at especially high risk for fracture. The risk reductions in these higher risk subgroups were consistent with the risk reduction observed in the overall population.
50. SCLEROSTIN NEUTRALIZING ANTIBODY ENHANCES BONE HEALING DURING DISTRACTION OSTEOGENESIS IN RATS Michelle McDonald1, Lauren Peacock1, Kathy Mikulec1, Oliver Birke1, Min Liu2, Scott Wasserman2, Hua Zhu “David” Ke2, David Little1 1 Orthopaedic Research Dept, The Children's Hospital Westmead, Westmead, New South Wales, Australia 2 Amgen, Thousand Oaks, California, United States Sclerostin (Scl) is a negative regulator of osteoblast differentiation and bone formation. The high specificity for bone and potent antagonism of formation has made sclerostin a logical target for intervention. Distraction osteogenesis (DO) is utilized widely in limb lengthening and reconstruction. Complications include disuse osteopenia and poor anabolic response, both of which would benefit from pro-anabolic therapy. A sclerostin antibody (Scl-Ab) was recently reported to stimulate bone formation and restore bone mass and strength in aged OVX rats and enhanced fracture healing in a rat model. We sought to examine the effects of this agent in a rat model of DO. An osteotomy in the femur was stabilised with an external fixator in male Sprague Dawley rats. The gap was distracted 0.25 mm twice daily to a total 7 mm. Saline or Scl-Ab was administered twice weekly throughout distraction and up to 4 or 6 weeks post commencement of distraction. Three groups were examined, Saline, Delayed Scl-Ab (D Scl-Ab, post distraction only) and Continuous Scl-Ab (Cont Scl-Ab). Radiographs were assessed for union rates. DEXA scans of the regenerate were performed at 2, 4 and 6 week time points and all samples were scanned using Micro CT (μCT) for analysis of bone volume.Radiographs demonstrated a trend for increased union rates with Scl-Ab treatment at 6 weeks with 20% unions for Saline, 50% unions for D Scl-Ab and 50% for Cont Scl-Ab. DEXA scans at 2 weeks revealed a 63% increase in regenerate BMD in Cont Scl-Ab group (p < 0.01) and a 41% increase in the D Scl-Ab group (p < 0.05), compared to Saline. In addition an increase of 116% in BMC was seen in the Cont Scl-Ab group compared to Saline (p < 0.01). At 6 weeks regenerate bone area was increased 18% in D Scl-Ab and 23 % Cont Scl-Ab compared to Saline (p < 0.05). μCT scans of the regenerate revealed an 89% increase in bone volume with Cont Scl-Ab and an 85% increase with D Scl-Ab treatment compared to Saline at 6 weeks (p < 0.05). Bone volume ratio (BV/TV) was increased 77% with Cont Scl-Ab treatment and 82% with D Scl-Ab, and bone surface was increased 62% with Cont Scl-Ab treatment at 6 weeks compared to Saline (p < 0.05). Scl-Ab treatment enhanced the amount of bone formed in this rat distraction model, when given either throughout or post distraction. Histological assessment of dynamic bone formation parameters will reveal the mechanism behind the enhanced bone repair, and its mechanical consequences will be examined. doi:10.1016/j.bone.2010.01.053
51. Differential effects of angiotensin II-receptor blockade on vascular and skeletal manifestations of Marfan syndrome Harikiran Nistala1, Aaron Rifkin2, Sui Lee Arteaga1, Maria del Solar1, Luca Carta1, Francesco Ramirez1 1 Pharmacology and Systems Therapeutics, Mount Sinai School of Medicine, New York, New York, United States 2 Princeton University, Princeton, New Jersey, United States Progressive aortic root enlargement and dissection are the main causes of morbidity and mortality in patients with Marfan syndrome (MFS) and have causally been linked to promiscuous activation of latent TGFβ. Recent results have underscored the clinical efficacy of angiotensin II-receptor blockers, specifically losartan, in attenuating
S27
aneurysm progression in mouse models of MFS and a small cohort of pediatric patients. Skeletal overgrowth and osteopenia are also cardinal manifestations of MFS, the etiology of which is only starting to be elucidated. In the present study we investigated the effect of losartan (at human equivalent dosage) on skeletal metabolism during post natal growth in mice underexpressing fibrillin-1 that progressively develop severe MFS. Consistent with previous observations, losartan coordinated significant therapeutic benefits in the vasculature. By contrast, skeletal overgrowth and osteopenia in fibrillin-1 deficient mice remained unmitigated as assessed by microCT and histomorphometry. In concurrent bisphosphonate treated group, alendronate significantly improved multiple aspects of bone quality, including trabecular bone architecture and bone volume fraction. Taken together, these results point to the differential effects of angiotensin II-receptor blockade on vascular and skeletal manifestations of MFS, implicitly arguing for tissue specific pathogenetic programs requiring a multimodal treatment regimen. doi:10.1016/j.bone.2010.01.054
52. Effect of Denosumab on the Incidence of Hip and New Vertebral Fractures in Postmenopausal Women With High Fracture Risk: A Subanalysis of the FREEDOM Study Kurt Lippuner1, Jonathan Adachi2, Steven Cummings3, Zulema Man4, Jordi Farrerons5, Ove Törring6, John Gallagher7, Mike McClung8, Nathalie Franchimont9, Javier San Martin10, Andrea Wang10, Steven Boonen11 1 University of Bern, Bern, Switzerland 2 Charlton Medical Center, Hamilton, Ontario, Canada 3 SFCC, CPMC Research Institute, & UCSF, San Francisco, California, United States 4 Centro TIEMPO, Buenos Aires, Argentina 5 Hospital de la Santa Creu I Sant Pau, Barcelona, Spain 6 Karolinska Institutet Sodersjukhuset, Stockholm, Sweden 7 Creighton University Medical Center, Omaha, Nebraska, United States 8 Oregon Osteoporosis Center, Portland, Oregon, United States 9 Amgen (Europe) GmbH, Zug, Switzerland 10 Amgen Inc, Thousand Oaks, California, United States 11 University of Leuven, Leuven, Belgium Purpose: In the FREEDOM trial, denosumab (DMAb) significantly reduced the risk of hip and new vertebral fractures by 40% (95% CI:3%-63%) and 68% (95% CI: 59%-74%), respectively, over 3 years (Cummings NEJM 2009;361:756). In this post-hoc analysis, we examined the hip and new vertebral fracture incidence and risk reduction in subgroups of women with a higher baseline risk for fracture.Methods: The FREEDOM trial was a 3-year, randomized, blinded phase 3 trial in postmenopausal women with PMO aged 6090 years old with a spine or hip bone mineral density T-score <-2.5 and not <-4.0. Women were randomized to receive twice-yearly DMAb (60 mg) or placebo injections, with daily calcium and vitamin D supplements. The subgroups at high-risk for hip fractures were age ≥75 years, baseline femoral neck T-score ≤-2.5, and both factors. The subgroups at high-risk for new vertebral fractures were age ≥75 years and ≥2 prevalent vertebral fractures, or a moderate/severe prevalent vertebral fracture, or both. Results: After 3 years of treatment, DMAb significantly reduced the incidence and risk of hip and new vertebral fractures in all subgroups compared with placebo (Table). Conclusions: DMAb reduced hip and new vertebral fracture incidence and risk in subgroups of women from the FREEDOM trial who are at especially high risk for fracture. The risk reductions in these higher risk subgroups were consistent with the risk reduction observed in the overall population.