Sarcopenia is a geriatric syndrome characterized by the reduction of skeletal muscle mass, strength, and/or physical performance.^1-4) This condition leads to a range of adverse outcomes, including higher incidences of falls, increased hospital admissions, elevated mortality rates, diminished quality of life, and increased healthcare costs.^5-7) The etiological pathways involved in the onset and aggravation of sarcopenia remain partially elucidated, with numerous cellular and molecular factors implicated in its pathophysiology.^8,9) These factors include insulin-like growth factor 1 (IGF-1), forkhead box O (FoxO) transcription factors, and elements of the transforming growth factor-beta (TGF-β) superfamily, which are crucial in maintaining muscle homeostasis.^10,11) However, despite significant research efforts, there are currently no FDA-approved treatments specifically targeting the underlying pathophysiology of sarcopenia. Consequently, the identification of biomarkers for early screening of high-risk individuals and the development of effective interventions are imperative to maintain independence in older adults.^12-14)

Bone morphogenetic proteins (BMPs), originally identified in decalcified bone matrices,¹⁵⁾ are part of the TGF-β superfamily and interact with type I and type II serine-threonine kinase receptors to phosphorylate Smad proteins.¹⁶⁾ Among these, BMP-7 has been FDA-approved for its role in bone formation^17,18) and is also recognized as a myokine—a molecule produced by muscle fibers that exerts autocrine, paracrine, or endocrine effects.^19-21) Experimental studies in vitro and in animal models have shown that BMP-7 promotes hypertrophic signaling and protects against skeletal muscle diseases.²²⁾ Notably, BMP-7 has demonstrated efficacy in reducing muscle atrophy in denervated or diabetic mice^22,23) and normalizing aberrant cytokine expression in cultured muscle cells from patients with rheumatoid arthritis.²⁴⁾ Despite these promising experimental results, the role of BMP-7 in human muscle health remains to be clarified. This study aims to measure serum BMP-7 levels to explore their potential association with sarcopenia status and related physiological parameters.

Table 1 presents the baseline characteristics of the 182 study participants, divided into 37 sarcopenic cases and 145 non-sarcopenic controls. Among these, 70.3% (26 individuals) of the sarcopenic group and 60.7% (88 individuals) of the control group were women (p=0.343). The mean age was 76.2±7.0 years for the sarcopenic group and 71.1±7.0 years for the control group (p<0.001). Compared to the non-sarcopenic participants, those with sarcopenia had significantly lower body weight, height, BMI, ASM, SMI, handgrip strength, gait speed, and SPPB scores, along with slower times to complete five chair stands (p<0.001 to 0.039).

Differences in serum BMP-7 concentrations based on the presence of sarcopenia and its diagnostic components were evaluated using ANCOVA (Fig. 1). The analyses, performed before and after adjustments for sex, age, and BMI, revealed no statistically significant differences in BMP-7 levels between participants with and without sarcopenia, low muscle mass, weak muscle strength, or poor physical performance (p=0.089 to 0.681).

Linear regression analyses were performed to evaluate the associations between serum BMP-7 levels and the parameters assessing sarcopenia, including SMI, grip strength, gait speed, time required to complete five chair stands, and SPPB score (Table 2). In both the unadjusted and adjusted analyses, no significant correlations were found between serum BMP-7 concentrations and any of the sarcopenia assessment parameters (p=0.104 to 0.886). Consistently, there was no significant association between the increase in SD of circulating BMP-7 levels and the risk of sarcopenia, low muscle mass, weak muscle strength, or poor physical performance in the logistic regression analyses, regardless of adjustment models (p=0.093 to 0.712) (Table 3).

To investigate the potential existence of a threshold effect of circulating BMP-7 on human muscle phenotypes, participants were stratified into four quartiles based on their serum BMP-7 levels (Fig. 2). Analyses, both before and after adjusting for confounding factors, showed no significant differences in SMI, grip strength, gait speed, time required to complete five chair stands, or SPPB scores across the BMP-7 quartile groups (p=0.663 to 0.996).

This study analyzed 182 older Korean adults to explore a potential relationship between serum BMP-7 levels and sarcopenia, including its related parameters. Our findings revealed no significant differences in circulating BMP-7 levels among groups with or without sarcopenia, low muscle mass, weak muscle strength, or poor physical performance. Furthermore, there was no significant correlation between serum BMP-7 concentration and sarcopenia assessment metrics such as SMI, grip strength, gait speed, time to complete five chair stands, and SPPB score. These results remained consistent even after adjusting for age, sex, BMI, and threshold effects. To our knowledge, this is the first clinical study to investigate the association between circulating BMP-7 levels and muscle health in older adults.

Muscles and bones represent the largest tissues in humans and are intricately linked throughout the life cycle, including development, growth, and aging.²⁸⁾ Together, they form a mechanical unit essential for protecting organs and facilitating movement. Notably, sarcopenia, characterized by a decline in muscle strength, and osteoporosis, marked by decreased bone strength, often co-occur in aging individuals.^29,30) This phenomenon, known as coupling, underscores their recognition as concomitant age-related diseases potentially driven by shared etiological factors.^31,32) Indeed, myoblasts, pivotal in muscle formation, and osteoblasts, central to bone formation, both originate from mesenchymal stem cells and share similar cellular physiology.³³⁾ This suggests that identical factors may influence both muscle and bone metabolism simultaneously. The development of pharmacological interventions that target these common regulatory factors in muscle-bone interactions promises to simultaneously address two prevalent conditions in the elderly, potentially enhancing overall health outcomes in this population and thus garnering significant interest in aging research.

Among its varied biological functions, BMP-7 primarily facilitates the differentiation of mesenchymal stem cells into osteoblasts.³⁴⁾ Consequently, BMP-7 is extensively utilized in clinical settings to enhance the healing of complex fractures and in spinal fusion surgeries,^18,35) and it is considered a promising therapeutic target for osteoporosis due to its robust osteogenic properties. Interestingly, numerous studies involving cellular and animal models have demonstrated BMP-7’s beneficial effects on muscle metabolism, including the promotion of myogenesis and the reversal of muscle atrophy.^21-24) These findings position BMP-7 as a dual regulator of muscle and bone, highlighting its significance not only in fracture healing and osteoporosis management but also in the diagnosis and treatment of sarcopenia. However, despite these promising applications, research on the role of BMP-7 in human muscle health is limited; furthermore, our observational study of individuals aged 65 and older showed that serum BMP-7 levels did not correlate with any muscle phenotype or the risk of sarcopenia. While these results do not negate BMP-7’s potential as a therapeutic target for sarcopenia, its utility as a blood-based biomarker for predicting this condition in humans appears limited.

Despite the established role and plausible mechanisms of BMP-7 as a muscle anabolic factor in experimental research, our study did not find a significant association between circulating BMP-7 levels and sarcopenia status in older adults. While the exact reasons for this discrepancy remain unclear, several hypotheses can be considered. First, most prior experiments investigating BMP-7’s effects on skeletal muscle were conducted in biomolecular environments vastly different from those in the human body. For instance, one study treated muscle cells with 750 ng/mL of BMP-7,²⁴⁾ whereas our findings indicate mean serum concentrations of merely 11.1 pg/mL. Consequently, the magnitude of BMP-7’s effect on muscle homeostasis may not be as pronounced in humans as observed in vitro or in animal models. Secondly, despite their biological similarities to humans, mice exhibit significant differences in genetic regulation and chromatin organization,^36,37) which might account for their divergent responses to pharmacological interventions and variations in biological systems such as immunity and metabolism. These genetic differences may also contribute to the inconsistent results observed in the effects of BMP-7 on muscle homeostasis between humans and mice. Furthermore, the absence of an association between serum BMP-7 levels and sarcopenia may underscore the complex nature of sarcopenia, which is influenced by multiple pathways and factors, each contributing a relatively modest effect.^9,38) This complexity suggests that BMP-7 alone may not significantly impact sarcopenia. Therefore, additional research incorporating various other factors is essential, and a larger cohort might be necessary to detect the relatively subtle effects of BMP-7.

Compared to many prior studies that focused solely on specific muscle phenotypes, our study possesses significant strengths as it encompassed all critical factors necessary for diagnosing sarcopenia, including muscle mass, muscle strength, and physical performance. Moreover, we employed Asian-specific cutoffs to account for ethnic differences, enhancing the relevance and precision of our findings for this demographic. However, the interpretation of our results is subject to several limitations. The primary limitation of our study is its cross-sectional design, which inhibits our ability to establish causality or analyze the progression of sarcopenia. Additionally, being a single-center study involving older outpatient subjects, the results may be subject to selection bias and may not be generalizable to broader populations. Furthermore, the relatively modest sample size limited our ability to adjust for key confounding factors in the analysis, such as underlying comorbidities, which may have influenced our findings. Finally, we cannot rule out the possibility that uncontrolled variables, including specific medications that may impact blood BMP-7 levels or muscle metabolism, could have affected the results.

In summary, serum BMP-7 levels were not significantly different between older adults with and without sarcopenia, a result that remained consistent across various adjustment models. Additionally, whether analyzed as a continuous variable or categorized into quartiles, serum BMP-7 levels showed no association with skeletal muscle mass, grip strength, or different types of physical performance. These findings do not support the hypothesized role of BMP-7 in human muscle health, as suggested by prior experimental research. Consequently, further large-scale, prospective studies are required to determine the clinical significance of BMP-7 in assessing the risk of sarcopenia.