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Abstract
Background Osteoarthritis (OA) may be segregated into different disease phenotypes based on disease drivers; cartilage damage, joint inflammation or subchondral bone remodelling. Each phenotype may require targeted treatments. Patients with a bone-driven OA may particularly benefit from a treatment with anti-resorptive and chondro-protective properties. Salmon calcitonin (sCT), a hormone acting through CT and amylin receptors, have in multiple preclinical models been demonstrated to improve bone homeostasis and attenuate joint destruction, in part through the anti-resorptive property. In addition, sCT have recently been shown to have a positive effect on obesity and diabetes, which may benefit certain OA subjects. Several CT analogues were characterized through a larger screening program; the KBP088 analogue was found to be particular interesting for OA, by showing higher potency for the receptors than sCT.
Objectives To investigate the effect of KBP088 on bone and cartilage turnover in vivo, and secondary investigate the effect on body weight in rats fed with high fat diet (HFD).
Methods Thirty male Sprague Dawley rats (Taconic, Ry, Denmark) were given HFD for 10 weeks before they were treated with defined doses of KBP088 (0.63, 1.3, 2.5, 5, 10 ug/Kg) or vehicle as subcutaneous injections. Blood was collected from overnight fasted rats immediately at baseline, 3 and 24 hours after first treatment. Rats were treated for 8 weeks. Body weight was recorded weekly. Biomarkers of bone and cartilage degradation were assessed in the blood using the ELISAs CTX-I (bone resorption) and CTX-II (cartilage degradation). CTX-I and -II were reported as fold change baseline levels, as means with standard error of mean (SEM) and compared using two-way ANOVA assuming normal distribution. Significance levels; *P<0.05, **P<0.01, ***P<0.001.
Results Serum levels of both CTX-I and -II decrease significantly 3 hours after treatment with KBP088, even at the lowest dose tested (P<0.05, fig. 1). Moreover, a dose-dependent response by CTX-I still remained 24 hours after treatment, suggesting increased potency. KBP088 caused a 19% vehicle-corrected weight reduction for two highest doses at the end of the experiment.
Conclusions The data presented here clearly indicate a protective effect of KBP088 on both bone and cartilage in vivo, when evaluated by biochemical markers. Furthermore, KBP088 has demonstrated positive effects on metabolic health (cause a weight decrease), and may therefore represent a possible treatment opportunity for bone-driven OA, with an unhealthy phenotype (e.g. high BMI). Many further studies are needed to match the optimal treatment opportunity with the right OA patient for a personalized health care approach for OA.
Disclosure of Interest : None declared
DOI 10.1136/annrheumdis-2014-eular.4027