Inventing the Wheel: Understanding heterogeneity of response to skeletal muscle dysfunction interventions in women with COPD

Skeletal muscle dysfunction is arguably the most important manifestation of chronic obstructive pulmonary disease (COPD) to patients. It contributes to an inability to go about activities of daily living decreases quality of life, increases office visits and healthcare expenditure^1,2. It is only recently this extra-pulmonary complication of COPD has been given attention in terms of research and pharmacological interventions. However, the historical bias of a large body of medical research performed in men still overwhelms and limits our understanding of heterogeneity and sensitivity of responses to skeletal muscle dysfunction interventions in women.

Women with COPD have a higher prevalence of musculoskeletal comorbidities, muscle wasting and weakness than men^3,4. The sex hormones testosterone, estrogen and progesterone widely recognized for their role influencing the physical attributes of sexual dimorphism are also recognized for their influence on skeletal muscle homeostasis⁵. Despite this recognition, relatively little attention has been given to the role of sex hormone modulating life-course events on skeletal muscle dysfunction in women with COPD. Nonetheless, strides have been made recently in assessing the relationship between aspects of female reproductive health with risk of COPD and associated outcomes. In close to 300,000 women in the UK Biobank, parity > 3, late menarche and early menopause were associated with increased risk of COPD-related hospitalization and death⁶. A natural and much needed extension of this research is to investigate the role of sex hormone modulating life-course events on skeletal muscle dysfunction later in life in women with COPD.

Studies have suggested testosterone treatment may be efficacious in minimizing skeletal muscle dysfunction however, the benefits are overwhelmed by reports of increased adverse cardiovascular events in both males and females^5,7. For this reason, selective androgen receptor modulators (SARMs) have been considered as an attractive alternative to testosterone due to tissue-selective targeting of the androgen receptors. In the current issue of Thorax, Mohan et al, 2022, report the findings of a Phase 2A trial to evaluate the safety and efficacy of the SARM, GSK2881078, in conjunction with a home-based exercise program in 49 men and 47 postmenopausal women with COPD. In terms of safety, the SARM was well tolerated. In terms of efficacy, lean body mass was increased in both males and females with COPD which is highly encouraging. However, efficacy in terms of improvements in leg strength was only observed in males. The power and duration of the study may have limited observation of efficacy of the SARM in terms of efficacy in females in the study. In a Phase 1b RCT of GSK2881078, sex-related dosing differences for the SARM were observed with women gaining more muscle for the same dose⁸. In the current Phase 2b RCT, a 50% lower dose of the SARM was administered to women with COPD. However, other factors such as sex hormone modulating life-course events could account for heterogeneity of response to the SARM in terms of skeletal muscle dysfunction in women with COPD.

Overall, additional research in larger studies of females with COPD is needed to understand the role of sex hormone modulating life-course experiences on skeletal muscle dysfunction later in life. Deepening our understanding of the underlying etiology these life-course experiences influence may lead to discovery of biomarkers enabling precision dosing. This in turn has the potential to expand our understanding androgen sensitivity to mitigate the onset and progression of skeletal muscle dysfunction in COPD.