Background/Purpose: 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 Dual Amylin Calcitonin Receptor Agonists (DACRAs) were characterized through a larger screening program; KBP-056 was found to be particular interesting for OA, by showing higher potency for the receptors than sCT. The objective of this study was to investigate the in vivo effect of KBP-056 on bone and cartilage turnover, as well as metabolic health.

Methods: Male Sprague Dawley rats (Taconic, Ry, Denmark) were given HFD for 10 weeks before they were treated with defined doses of KBP-056 (0.625, 1.25, 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 of 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. In addition, a similar study was performed using ovariectomy (OVX)-meniscectomy (MNX) Sprague Dawley rats.

Results: Serum levels of both CTX-I and -II decrease significantly 3 hours after treatment with KBP-056, 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. KBP-056 caused a 19% vehicle-corrected weight reduction for two highest doses at the end of the experiment. A similar weight reducing effect was observed in OVX-MNX rats.

Conclusion: The data presented here clearly indicate a protective effect of KBP-056 on both bone and cartilage in vivo, when evaluated by biochemical markers. Furthermore, KBP-056 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.