RESUMO
The effects of up to 26 weeks of sclerostin antibody (Scl-Ab) treatment were investigated in ovariectomized (OVX) rats. Two months after surgery, 6-month-old osteopenic OVX rats were treated with vehicle or Scl-Ab (25 mg/kg, sc, one time per week) for 6, 12, or 26 weeks. In vivo dual-energy x-ray absorptiometry analysis demonstrated that the bone mineral density of lumbar vertebrae and femur-tibia increased progressively through 26 weeks of Scl-Ab treatment along with progressive increases in trabecular and cortical bone mass and bone strength at multiple sites. There was a strong correlation between bone mass and maximum load at lumbar vertebra, femoral neck, and diaphysis at weeks 6 and 26. Dynamic histomorphometric analysis showed that lumbar trabecular and tibial shaft endocortical and periosteal bone formation rates (BFR/BS) increased and peaked at week 6 with Scl-Ab-treatment; thereafter trabecular and endocortical BFR/BS gradually declined but remained significantly greater than OVX controls at week 26, whereas periosteal BFR/BS returned to OVX control levels at week 26. In the tibia metaphysis, trabecular BFR/BS in the Scl-Ab treated group remained elevated from week 6 to week 26. The osteoclast surface and eroded surface were significantly lower in Scl-Ab-treated rats than in OVX controls at all times. In summary, bone mass and strength increased progressively over 26 weeks of Scl-Ab treatment in adult OVX rats. The early gains were accompanied by increased cortical and trabecular bone formation and reduced osteoclast activity, whereas later gains were attributed to residual endocortical and trabecular osteoblast stimulation and persistently low osteoclast activity.
Assuntos
Anticorpos Monoclonais/uso terapêutico , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Osso e Ossos/efeitos dos fármacos , Osteoporose/tratamento farmacológico , Animais , Anticorpos Monoclonais/farmacologia , Densidade Óssea/efeitos dos fármacos , Remodelação Óssea/efeitos dos fármacos , Avaliação Pré-Clínica de Medicamentos , Feminino , Marcadores Genéticos , Ovariectomia , Distribuição Aleatória , Ratos Sprague-Dawley , Microtomografia por Raio-XRESUMO
BACKGROUND: The Advanced Clinician Practitioner in Arthritis Care (ACPAC) program was developed in 2005 to prepare experienced physical and occupational therapists to function as extended role practitioners (ERPs) within models of arthritis care across Ontario, Canada. PURPOSE: To examine the system-level integration and clinical utilization of the ACPAC program-trained ERP. METHOD: A longitudinal survey was administered to all ACPAC graduates over a two-year period (n=30). RESULTS: The majority of ERPs were physical therapists working in urban settings. Family physicians or physician specialists referred the majority of patients. The longest median wait time to access ERPs' services was 22 days. Half of the ERPs triaged patients, and most of those who did triage (75%) worked under medical directives. Approximately half (51.6%) of the patients seen had a diagnosis of osteoarthritis, followed by rheumatoid arthritis (14.7%). CONCLUSION: Understanding the system-level impact of this unique human resource can help to shape healthcare planning and delivery of care.
Assuntos
Artrite/terapia , Atenção à Saúde/métodos , Terapia Ocupacional/organização & administração , Fisioterapeutas/organização & administração , Artrite/diagnóstico , Atenção à Saúde/organização & administração , Atenção à Saúde/normas , Prestação Integrada de Cuidados de Saúde/organização & administração , Prestação Integrada de Cuidados de Saúde/estatística & dados numéricos , Acessibilidade aos Serviços de Saúde/organização & administração , Acessibilidade aos Serviços de Saúde/estatística & dados numéricos , Humanos , Ontário , Papel Profissional , Avaliação de Programas e Projetos de Saúde , Encaminhamento e Consulta/estatística & dados numéricos , Listas de EsperaRESUMO
The purpose of this study was to evaluate the effects of sclerostin inhibition by treatment with a sclerostin antibody (Scl-AbII) on bone formation, bone mass, and bone strength in an aged, gonad-intact male rat model. Sixteen-month-old male Sprague-Dawley rats were injected subcutaneously with vehicle or Scl-AbII at 5 or 25 mg/kg twice per week for 5 weeks (9-10/group). In vivo dual-energy X-ray absorptiometry (DXA) analysis showed that there was a marked increase in areal bone mineral density of the lumbar vertebrae (L(1) to L(5) ) and long bones (femur and tibia) in both the 5 and 25 mg/kg Scl-AbII-treated groups compared with baseline or vehicle controls at 3 and 5 weeks after treatment. Ex vivo micro-computed tomographic (µCT) analysis demonstrated improved trabecular and cortical architecture at the fifth lumbar vertebral body (L(5) ), femoral diaphysis (FD), and femoral neck (FN) in both Scl-AbII dose groups compared with vehicle controls. The increased cortical and trabecular bone mass was associated with a significantly higher maximal load of L(5) , FD, and FN in the high-dose group. Bone-formation parameters (ie, mineralizing surface, mineral apposition rate, and bone-formation rate) at the proximal tibial metaphysis and tibial shaft were markedly greater on trabecular, periosteal, and endocortical surfaces in both Scl-AbII dose groups compared with controls. These results indicate that sclerostin inhibition by treatment with a sclerostin antibody increased bone formation, bone mass, and bone strength in aged male rats and, furthermore, suggest that pharmacologic inhibition of sclerostin may represent a promising anabolic therapy for low bone mass in aged men.
Assuntos
Envelhecimento/metabolismo , Anticorpos Monoclonais/imunologia , Densidade Óssea/fisiologia , Proteínas Morfogenéticas Ósseas/antagonistas & inibidores , Osso e Ossos/anatomia & histologia , Osso e Ossos/metabolismo , Osteogênese , Absorciometria de Fóton , Animais , Proteínas Morfogenéticas Ósseas/metabolismo , Osso e Ossos/citologia , Osso e Ossos/diagnóstico por imagem , Colágeno Tipo I/metabolismo , Marcadores Genéticos , Masculino , Tamanho do Órgão , Osteocalcina/sangue , Ratos , Ratos Sprague-Dawley , Serotonina/sangue , Tomografia Computadorizada por Raios XRESUMO
Humoral hypercalcemia of malignancy (HHM) is mediated primarily by skeletal and renal responses to tumor-derived PTHrP. PTHrP mobilizes calcium from bone by inducing the expression of receptor activator for nuclear factor-kappaB ligand (RANKL), a protein that is essential for osteoclast formation, activation, and survival. RANKL does not influence renal calcium reabsorption, so RANKL inhibition is a rational approach to selectively block, and thereby reveal, the relative contribution of bone calcium to HHM. We used the RANKL inhibitor osteoprotegerin (OPG) to evaluate the role of osteoclast-mediated hypercalcemia in two murine models of HHM. Hypercalcemia was induced either by sc inoculation of syngeneic colon (C-26) adenocarcinoma cells or by sc injection of high-dose recombinant PTHrP (0.5 mg/kg, s.c., twice per day). In both models, OPG (0.2-5 mg/kg) caused rapid reversal of established hypercalcemia, and the speed and duration of hypercalcemia suppression were significantly greater with OPG (5 mg/kg) than with high-dose bisphosphonates (pamidronate or zoledronic acid, 5 mg/kg). OPG also caused greater reductions in osteoclast surface and biochemical markers of bone resorption compared with either bisphosphonate. In both models, hypercalcemia gradually returned despite clear evidence of ongoing suppression of bone resorption by OPG. These data demonstrate that osteoclasts and RANKL are important mediators of HHM, particularly in the early stages of the condition. Aggressive antiresorptive therapy with a RANKL inhibitor therefore might be a rational approach to controlling HHM.