September 5, 2022 By spierarchitectur Off

Bone. anti-sclerostin antibody plus calcium. Non-diseased, untreated littermates served as controls. Vertebral bone morphology (trabecular and cortical) and mechanical properties (structural and material-level) were assessed at 35 weeks of age by microCT and mechanical testing, respectively. Results CKD with high PTH resulted in 6-fold higher bone formation rate, significant reductions in the amount of trabecular and cortical bone, and compromised whole bone mechanical properties in the vertebra compared to normal animals. Treatments that reduced bone remodeling were effective in normalizing vertebral structure and mechanical properties only if the treatment reduced serum PTH. Similarly, treatment with anti-sclerostin antibody was effective in enhancing bone mass and mechanical properties but only if combined with PTH-suppressive treatment. Conclusions CKD significantly altered both cortical and trabecular bone properties in the vertebra resulting in compromised mechanical properties and these changes can be normalized by interventions that involve reductions in PTH levels. strong class=”kwd-title” Keywords: spine, zoledronic acid, CKD-MBD, anti-sclerostin antibody, PTH, chronic kidney disease INTRODUCTION Patients with chronic kidney diseasemineral and bone disorder (CKD-MBD) have a significantly higher fracture risk than the general population [1-3]. This population also displays differences in fracture rates between long bones and vertebrae [3], suggesting that these two skeletal sites may be differentially affected by the disease. A study of Japanese men on dialysis who underwent screening lumbar spine imaging studies demonstrated that 20.9% of prevalent SNS-032 (BMS-387032) dialysis patients had evidence of spine fractures [4]. High resolution CT data have revealed significant increases in cortical porosity in the distal limbs with variable responses in trabecular bone [5]. Because vertebral elements are primarily composed of trabecular bone, the influence of secondary hyperparathyroidism on these sites could be potentially different than in long bone cortices [6]. Furthermore, the thin cortical shell of the vertebrae bears nearly 50% of the load [7]; thus, cortical bone changes at this site would also have dramatic effects on mechanical properties and fracture risk Several animal models of CKD have revealed significant detriments in SNS-032 (BMS-387032) the biomechanical properties of long bones [8-10]. For example, rodent models indicate that animals with CKD exhibit lower strength and stiffness compared to their normal counterparts [11-13]. While much of the decline in mechanical integrity can be attributed to structural changes resulting from high parathyroid hormone (PTH) and high turnover rates, recent studies indicate that bone quality also plays a role [9]. Unfortunately, vertebral bone in CKD models has yet to be examined at any of these levels. The goal of this study was to assess the effects of progressive CKD on vertebral bone structure and mechanics and to determine the effects of treatment with either anti-remodeling medications (bisphosphonates) or anabolic treatments (anti-sclerostin antibody). We hypothesized that a significant phenotype would exist in the vertebrae of CKD animals and that treatment would restore structural mechanical properties but not the material-level mechanical properties. METHODS Animal model Cy/+ rats exhibit the progressive onset of polycystic kidney disease due to transmission of an autosomal dominant missense mutation in the geneAnks6, which codes for the protein SamCystin [14-16]. Anks6 has been shown to be important in childhood recessive cystic kidney disease although heterozygote parents have no manifestations [17-19]. The course of kidney disease progression in the Cy/+ rats parallels the course of human CKD-Mineral Bone Disorder (CKD-MBD) [16]. A colony of these animals is maintained at the Indiana University School of Medicine. All procedures were reviewed and approved by the Indiana University School of Medicine Institutional Animal Care and Use Committee. Experimental design The animals described in this work were part of a large experiment that included numerous treatment and control groups. Male Cy/+ rats began SNS-032 (BMS-387032) the study at 25 weeks of age PI4K2A at which time animals were fed a casein-based diet (Purina AIN-76A, Purina Animal Nutrition, Shreevport, LA, USA); 0.53% Ca and 0.56% P) in order to accentuate the disease. Subsets of Cy/+ animals were divided into the following groups (Figure 1): Open in a separate window.