MASLD and Bone Markers in Postmenopause: Highlighting the Critical Gap of Vitamin D Status and the Need for Targeted Supplementation Trials

My colleagues and I read with great interest the cross-sectional study by Maharjan and colleagues, titled “Metabolic Dysfunction Associated Steatotic Liver Disease and Bone Turnover Markers in Postmenopausal Women: A Cross-Sectional Study in Central Nepal,” published in Health Science Reports. The authors are commended for their timely investigation into the link between MASLD and bone metabolism in a vulnerable population. Their finding of altered serum calcium, phosphorus, and alkaline phosphatase (ALP) levels in postmenopausal women with MASLD provides a crucial clinical signal, reinforcing the concept of interconnected metabolic disorders. However, the study's methodology and conclusions powerfully illuminate several critical, unresolved issues in this field. We wish to elaborate on these points to guide more definitive future research. First, the study's cross-sectional design, while efficient for hypothesis generation, inherently limits causal inference. The observed association between MASLD and altered bone markers (low calcium, high phosphorus, high ALP) is profoundly confounded by the significantly higher body mass index and waist circumference in the MASLD group [1]. The authors correctly note that these anthropometric factors significantly influence bone metabolic disorders. However, the lack of multivariate analysis to adjust for these potent confounders means the reported biochemical changes may largely reflect the shared pathophysiology of obesity and metabolic syndrome, rather than an independent effect of hepatic steatosis. This leaves a fundamental question unanswered: Is MASLD itself a driver of bone metabolism disturbance, or merely a fellow traveler with central adiposity? This ambiguity leads directly to the study's most significant methodological gap: the absence of vitamin D status assessment [2, 3]. Vitamin D is a central regulator of calcium–phosphate homeostasis and bone health. Its deficiency is exceptionally common in individuals with obesity and MASLD, as evidenced by robust literature showing strong inverse correlations between serum 25-hydroxyvitamin D [25(OH)D] levels and NAFLD/MASLD severity [3, 4]. The biochemical pattern reported by Maharjan and colleagues—hypocalcemia, hyperphosphatemia, and elevated ALP—is classic for secondary hyperparathyroidism, a direct and common consequence of vitamin D deficiency. Therefore, a highly plausible explanation for their findings is a high prevalence of vitamin D deficiency within the MASLD cohort, mediated by their adiposity and metabolic state [5]. Without measuring 25(OH)D and parathyroid hormone (PTH), the study cannot determine whether the bone marker alterations are a direct consequence of MASLD or are secondary to a co-existing, treatable endocrine abnormality. This gap touches upon a major clinical and public health conundrum. For the public and many clinicians, maintaining adequate vitamin D levels is perceived as a simple and effective strategy for supporting bone health. The willingness to engage in long-term supplementation is often driven by the well-established link between severe vitamin D deficiency and poor bone outcomes like osteomalacia. However, as your study implicitly demonstrates, the direct evidence chain for routine vitamin D supplementation in preventing osteoporosis in community-dwelling adults, particularly when deficiency is not severe, is complex and not definitively linear. Furthermore, the study relies on nonspecific blood markers. The sensitivity and specificity of serum calcium, phosphorus, and total ALP for predicting actual bone loss or fracture risk are limited; they are indirect signals, not measures of bone strength or architecture [5]. We propose that the path forward requires bridging this critical evidential gap through targeted intervention research. The shared pathophysiology of MASLD and bone loss—chronic low-grade inflammation and oxidative stress—provides a compelling mechanistic rationale. Vitamin D possesses well-documented pleiotropic effects, including anti-inflammatory and antioxidant properties. Correcting deficiency could therefore simultaneously ameliorate the metabolic milieu harming both the liver and bone. Thus, we strongly advocate for future research to move beyond associative studies and directly test this integrative hypothesis. Specifically, we call for targeted randomized controlled trials (RCTs) designed to answer a clear clinical question: Does vitamin D supplementation (with adequate calcium) improve bone health outcomes and/or MASLD parameters in postmenopausal women with confirmed vitamin D insufficiency and MASLD? The ideal trial would: (1) Precisely Define the Cohort: Enroll postmenopausal women with ultrasonography-confirmed MASLD and biochemically confirmed vitamin D insufficiency (e.g., 25(OH)D < 20 ng/mL). (2) Employ Robust Outcomes: Measure not only standard bone turnover markers but also bone mineral density (BMD) via DXA as a primary endpoint, alongside liver-specific outcomes such as liver fat fraction quantified by MRI-PDFF or transient elastography-controlled attenuation parameter. (3) Incorporate Mechanistic Insights: Include measurements of inflammatory cytokines (e.g., IL-6, TNF-α) and oxidative stress markers to explore the biological pathways through which supplementation may exert its effects. In conclusion, the valuable study by Maharjan and colleagues succeeds not only in highlighting an association but, perhaps more importantly, in exposing a critical missing piece in the puzzle: vitamin D status. We manage the whole patient and see the confluence of obesity, metabolic liver disease, and concerns about bone health daily. The solution requires moving from observing nonspecific markers to testing targeted, mechanism-informed interventions. We urge the research community to undertake the RCTs necessary to determine if correcting the widespread vitamin D deficiency in this high-risk population is a key to unlocking dual benefits for metabolic and skeletal health. Xiao Wen: investigation, writing – original draft. Kong Qingfei: conceptualization, investigation, supervision, writing – original draft, writing – review and editing. All authors have read and approved the final version of the manuscript. The authors have nothing to report. The authors have nothing to report. The authors declare no conflicts of interest. Data sharing is not applicable to this article as no data sets were generated or analyzed during the current study. Kong Qingfei had full access to all of the data in this study and takes complete responsibility for the integrity of the data and the accuracy of the data analysis.