Conceptualizing patient-level adverse effects in implementation trials.

Duchenne muscular dystrophy (DMD) is a severe X-linked recessive neuromuscular disorder caused by mutations in the dystrophin gene, resulting in the absence of dystrophin, a protein essential for maintaining sarcolemmal integrity during muscle contraction. Loss of dystrophin leads to repeated myofiber injury, calcium influx, and progressive muscle degeneration with replacement by fat and connective tissue. Clinically, DMD presents in early childhood with progressive proximal weakness, calf pseudohypertrophy, and markedly elevated creatine kinase levels, followed by loss of ambulation and eventual cardiopulmonary failure, which remains the leading cause of mortality []. Glucocorticoids are a cornerstone of DMD management, shown to prolong ambulation, delay scoliosis, and preserve respiratory and cardiac function [,]. However, chronic steroid exposure during childhood has profound skeletal consequences. Glucocorticoids impair osteoblast activity, suppress bone formation, and disrupt normal bone accrual, resulting in reduced bone mineral density and osteoporosis. DMD itself already confers a baseline risk for fractures due to progressive muscle weakness, reduced mechanical stimulation of bone, and systemic inflammation, with studies showing a fourfold higher fracture incidence than in healthy individuals []. This risk increases further with long-term glucocorticoid therapy, with a 16-fold higher risk of first fracture than in steroid-naive boys with DMD []. Long-bone fractures are a well-established trigger for fat embolism syndrome (FES), a rare but potentially fatal condition characterized by acute hypoxemic respiratory failure, neurologic dysfunction, and systemic manifestations resulting from the dissemination of fat globules into the pulmonary and systemic microvasculature []. Patients with DMD may be uniquely susceptible to FES due to the convergence of severe osteopenia, chronic steroid use, expanded fatty marrow, and increased fracture risk. Intracardiac shunts, such as a patent foramen ovale (PFO), may further facilitate paradoxical cerebral embolization, leading to disproportionate neurologic injury.