LAUSR

While the modern clich e “no pain, no gain”, is a commonly used exercise motto, earlier forms of this adage were related to work ethic. Over time, the meaning of this phrase has adapted so too has our understanding of biology and medicine. In this issue of EBioMedicine, Appelt and colleagues [1] demonstrated that a neuropeptide, calcitonin gene-related peptide (CGRP), which is known to be involved in the pathogenesis of migraines (pain), is essential in fracture repair (gain). This begs the question whether the converse is also true. Whether recently FDA approved antimigraine therapies (no pain), which block either CGRP or the CGRP receptor, may impair fracture healing (no gain). This important clinical question warrants examination, especially considering that women disproportionately suffer from both migraine and osteoporosis-related fractures. Migraine is a neurological disease defined by recurrent unprovoked headaches lasting over four hours with one or more disabling symptoms including nausea, vomiting, dizziness, and extreme sensitivity to sound and light. More than 1 billion people suffer from migraines worldwide [2]. Migraine disproportionately affects women with 85% of chronic migraine sufferers being women. Approximately 1 in 4 women will experience migraine in their lives. Fluctuations in estrogen levels are associated with severe and frequent attacks, which may explain why migraine is most common between the ages of 18 44, and in women (perimenopause typically begins when women are in their 40’s) [2]. CGRP levels significantly rise during migraine attacks, and injection of CGRP induces migraine-related symptoms [3]. Further CGRP, especially the a-isoform, is primarily thought to be involved in pain processes. Previous studies have suggested that CGRP-expressing dorsal root ganglia respond to noxious heat and