RESUMO
Abaloparatide is a novel 34-amino acid peptide selected to be a potent and selective activator of the parathyroid hormone receptor (PTH1R) signaling pathway with 41% homology to PTH(1-34) and 76% homology to PTHrP(1-34). A 12-month treatment study was conducted in osteopenic ovariectomized (OVX) rats to characterize the mechanisms by which abaloparatide increases bone mass. Sprague-Dawley (SD) rats were subjected to OVX or sham surgery at age 6 months and left untreated for 3 months to allow OVX-induced bone loss. Ten OVX rats were euthanized after this bone depletion period, and the remaining OVX rats received daily subcutaneous injections of vehicle (n = 18) or abaloparatide at 1, 5, or 25 µg/kg/d (n = 18/dose level) for 12 months. Sham controls (n = 18) received vehicle daily. Bone densitometry and biochemical markers of bone formation and resorption were assessed longitudinally, and L3 vertebra and tibia were collected at necropsy for histomorphometry. Abaloparatide increased biochemical bone formation markers without increasing bone resorption markers or causing hypercalcemia. Abaloparatide increased histomorphometric indices of bone formation on trabecular, endocortical, and periosteal surfaces without increasing osteoclasts or eroded surfaces. Abaloparatide induced substantial increases in trabecular bone volume and density and improvements in trabecular microarchitecture. Abaloparatide stimulated periosteal expansion and endocortical bone apposition at the tibial diaphysis, leading to marked increases in cortical bone volume and density. Whole-body bone mineral density (BMD) remained stable in OVX-Vehicle controls while increasing 25% after 12 months of abaloparatide (25 µg/kg). Histomorphometry and biomarker data suggest that gains in cortical and trabecular bone mass were attributable to selective anabolic effects of abaloparatide, without evidence for stimulated bone resorption. © 2016 American Society for Bone and Mineral Research.
Assuntos
Reabsorção Óssea/tratamento farmacológico , Reabsorção Óssea/patologia , Osso e Ossos/patologia , Osteogênese , Ovariectomia , Proteína Relacionada ao Hormônio Paratireóideo/uso terapêutico , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Absorciometria de Fóton , Animais , Biomarcadores/sangue , Densidade Óssea/efeitos dos fármacos , Doenças Ósseas Metabólicas/sangue , Doenças Ósseas Metabólicas/complicações , Doenças Ósseas Metabólicas/tratamento farmacológico , Doenças Ósseas Metabólicas/patologia , Remodelação Óssea/efeitos dos fármacos , Reabsorção Óssea/sangue , Reabsorção Óssea/fisiopatologia , Osso e Ossos/efeitos dos fármacos , Densitometria , Tamanho do Órgão/efeitos dos fármacos , Osteogênese/efeitos dos fármacos , Proteína Relacionada ao Hormônio Paratireóideo/administração & dosagem , Proteína Relacionada ao Hormônio Paratireóideo/farmacologia , Ratos Sprague-DawleyRESUMO
Abaloparatide is a novel 34 amino acid peptide selected to be a potent and selective activator of the parathyroid hormone receptor 1 (PTHR1) signaling pathway. The effects of 12months of abaloparatide treatment on bone mass, bone strength and bone quality was assessed in osteopenic ovariectomized (OVX) rats. SD rats were subjected to OVX or sham surgery at 6months of age and left untreated for 3months to allow OVX-induced bone loss. Eighteen OVX rats were sacrificed after this bone depletion period, and the remaining OVX rats received daily s.c. injections of vehicle (n=18) or abaloparatide at 1, 5 or 25µg/kg/d (n=18/dose level) for 12months. Sham controls (n=18) received vehicle daily. Bone changes were assessed by DXA and pQCT after 0, 3, 6 or 12months of treatment, and destructive biomechanical testing was conducted at month 12 to assess bone strength and bone quality. Abaloparatide dose-dependently increased bone mass at the lumbar spine and at the proximal and diaphyseal regions of the tibia and femur. pQCT revealed that increased cortical bone volume at the tibia was a result of periosteal expansion and endocortical bone apposition. Abaloparatide dose-dependently increased structural strength of L4-L5 vertebral bodies, the femur diaphysis, and the femur neck. Increments in peak load for lumbar spine and the femur diaphysis of abaloparatide-treated rats persisted even after adjusting for treatment-related increments in BMC, and estimated material properties were maintained or increased at the femur diaphysis with abaloparatide. The abaloparatide groups also exhibited significant and positive correlations between bone mass and bone strength at these sites. These data indicate that gains in cortical and trabecular bone mass with abaloparatide are accompanied by and correlated with improvements in bone strength, resulting in maintenance or improvement in bone quality. Thus, this study demonstrated that long-term daily administration of abaloparatide to osteopenic OVX rats led to dose-dependent improvements in bone mass, geometry and strength.
Assuntos
Osso e Ossos/patologia , Osso e Ossos/fisiopatologia , Ovariectomia , Proteína Relacionada ao Hormônio Paratireóideo/farmacologia , Receptor Tipo 1 de Hormônio Paratireóideo/metabolismo , Animais , Fenômenos Biomecânicos , Osso e Ossos/diagnóstico por imagem , Osso e Ossos/efeitos dos fármacos , Densitometria , Feminino , Tamanho do Órgão/efeitos dos fármacos , Ratos Sprague-Dawley , Tomografia Computadorizada por Raios XRESUMO
Bimagrumab (BYM338) is a novel fully human monoclonal antibody that exerts strong promyogenic effects on skeletal muscle by blocking activin type II receptors (ActRII). We investigated whether such blockade of ActRII by bimagrumab manifests any detrimental effect on outcomes of bone healing in a rat fibula osteotomy model. Animals (n = 150) were divided into 11 groups and received weekly treatment with either bimagrumab (10 or 100 mg/kg) or vehicle. Progression and outcomes of bone healing were assessed by lateral radiographs in vivo as well as by peripheral quantitative computed tomography (pQCT), 4-point bending test, and microscopic examination of the excised fibula at Day 29 or later. The radiographic progression of bone healing showed no significant differences between treatment groups in any comparative setting. In 3-month-old animals, pQCT revealed slightly reduced immature callus size and bone mineral content in bimagrumab-treated animals compared with vehicle-treated animals at Day 29 (p < 0.05). There were, however, no differences in mature callus size, bone mineral density, or biomechanical competency. The aforementioned effects on immature callus size were not present when the treatment was initiated 4 weeks post osteotomy or when treating 6-month-old animals. In summary, these findings suggest that there is no major impact of ActRII blockade on overall fracture healing, and delayed treatment initiation can bypass the small and transient effect of the therapy on immature callus formation observed in younger animals. Verification of these findings in humans is the subject of an ongoing clinical trial on elderly hip fracture patients.