Effects of long-term pharmacological inhibition of CGRP signaling on bone and glucose metabolism

Objectives The neuropeptide Calcitonin gene-related peptide (CGRP) and its receptor, Calcitonin receptor like receptor (CRLR) have been shown to be crucially involved in the pathogenesis of migraine. This has resulted in the development and recent approval of novel migraine drugs that inhibit CGRP signaling.

Beside its role in migraine, CGRP plays a pivotal role in regulating bone turnover, and has also been suggested to contribute to the development of the metabolic syndrome in obesity. As there are only few data regarding the long-term effects of CGRP antagonism, our study was designed to characterize its impact on bone and glucose metabolism in a preclinical model of diet-induced obesity (DIO).

Methods 4-week-old wildtype mice (C57BL/6 J, female, n = 20) were fed a high-fat diet (HFD) over 8 weeks. Then mice received a subcutaneous pellet releasing either 0.02 mg/day of the CRLR antagonist olcegepant (OL) or vehicle as control. HFD was continued for additional 8 weeks. Thereafter, animals were sacrificed and tissue and serum specimens were harvested. DIO was assessed by body- and organ weights, oral glucose tolerance (OGT), plasma lipids, and tissue gene-expression studies.

Histomorphometry of non-decalcified bone sections was performed. Serum analysis of beta-crosslaps and procollagen I N-terminal propeptide (PINP) was assessed by ELISA. Statistical analyses (p < 0.05 considered significant) were performed using students t-test or Man-Whitney-U test, respectively. All experiments were approved by the local ethic authorities.

Results and Conclusion Assessing glucose metabolism, long-term OL treatment did not alter the course of body weight gain or organ weight of liver, white and brown adipose tissue during DIO. Furthermore, the levels of plasma lipids including triacylglycerol, cholesterol, and high-density lipoprotein were not affected by OL treatment. After 8 weeks of treatment, OL led to a slight but significant improvement of OGT. This was accompanied by an increased expression of pro-inflammatory markers and Stearoyl-CoA desaturase in the liver, a key enzyme regulating fatty acid metabolism.

In skeletal tissue, OL treatment resulted in reduced bone volume and higher trabecular separation in the lumbar spine. In the proximal tibia, bone volume and trabecular thickness were significantly reduced in the OL group. OL treatment was associated with reduced osteoblast numbers while osteoclast parameters were not affected. Serum analysis revealed decreased concentrations of the bone formation marker PINP and unaltered levels of the bone resorption marker beta-crosslaps in the OL group.

Taken together, our results indicate that long-term inhibition of CGRP signaling only moderately affects glucose metabolism during DIO but significantly impairs bone formation. As novel agents blocking CGRP or its respective receptor CRLR are currently introduced clinically for the treatment of migraine disorders, their potential negative impact on bone metabolism warrants further investigations.

Stichwörter bone; bone quality; metabolism; cgrp; calcrl; gepant; migraine; side effects;

Publication History

Article published online:
15 October 2020