Endocrine Abstracts

Duchenne muscular dystrophy (DMD) is a relentlessly progressive dystrophinopathy arising from pathogenic, loss of function variants in the DMD gene. Corticosteroid (CS) monotherapy is the mainstay of DMD treatment in many countries around the world; even dystrophin-targeted treatments such as gene therapy do not relinquish patients from CS. On daily CS therapy, walking is prolonged by two years (with loss of ambulation typically experienced around 14 years of age), and life expectancy is typically extended into the late 20’s and early 30’s. Daily CS therapy is also characterized by well-known endocrine and bone co-morbidities including excess weight gain, short stature, delayed puberty, adrenal insufficiency, and bone fragility due to osteoporosis. In an effort to attenuate the adverse effects of CS therapy in DMD, regimens alternative to daily CS have been implemented (such as prednisone 10 days on/off); however, this saltatory approach comes at a cost to muscle strength. Recently, a novel steroid (vamorolone) has been studied in DMD. Data to nearly three years post-exposure suggest efficacy parity of high-dose vamorolone relative to classic CS regimens, along with improved growth velocity + serum bone turnover markers, and fewer vertebral fractures. However, excess weight gain, adrenal insufficiency and bone fragility can still occur on vamorolone, necessitating their ongoing, anticipatory prevention. DMD represents a serious secondary osteoporosis condition due to the high frequency of fractures, their devastating consequences, and limited potential for medication-unassisted recovery from osteoporosis. Lower extremity fractures are associated with premature, permanent loss of ambulation, while fat embolism syndrome after long bone injuries has been linked to acute respiratory distress syndrome and unexpected mortality. Vertebral fractures, often silent, occur at an alarmingly high rate in daily, classic CS-treated DMD, necessitating periodic surveillance with lateral spine imaging. Current management strategies centre around early detection of vertebral and non-vertebral fractures, with a single low-trauma vertebral or long bone fracture providing clear rationale for instituting bone protection therapy. At the same time, the high fracture rates of DMD combined with the devastating consequences of bone fragility have sparked interest in osteoporosis treatment prior to first fractures. Intravenous bisphosphonates remain the cornerstone of osteoporosis therapy in DMD. In an effort to improve the convenience of osteoporosis treatment and minimize first exposure adverse events, denosumab has been tried in this setting. However, even the low bone turnover of DMD does not protect against the denosumab-induced rebound phenomenon, leading to recommendations against the routine use of this agent in pediatric DMD. Overall, it is recognized that DMD is the ideal setting to consider not only prevention of first-ever fractures but also osteoanabolic agents, given the limitations of bisphosphonate monotherapy in low bone turnover states such as DMD. Strategic planning for primary osteoporosis prevention is currently underway by members of The OPTIMIZE DMD Consortium, an international working group dedicated to education, advocacy and research in endocrine and bone health care for people with DMD.