Sclerostin, a glycoprotein, plays a pivotal role in impeding the processes associated with bone formation and stands as a key factor in diminishing osteoblast function. Additionally, sclerostin upregulates the expression of proteolytic enzymes in osteoclasts [21]. Several studies have demonstrated a direct association between BMD and sclerostin concentration in both healthy humans and individuals with spinal cord injuries [22–24]. Consistent with findings from previous studies, we identified significant positive correlations between circulating sclerostin levels and BMD measurements in postmenopausal females with GIO. These studies suggest that sclerostin concentration might serve as a complementary or potentially alternative indicator to densitometric testing. One suggested rationale for this positive association between sclerostin and BMD posits that circulating sclerostin levels are contingent upon the number and activity of osteocytes, theoretically correlating with the overall bone mass. Elevated BMD might lead to an increased number of osteocytes, consequently resulting in higher levels of circulating sclerostin.
Nevertheless, Patalong-Wojcik and collaborators found no discernible disparity in sclerostin levels between groups with normal and diminished BMD. Moreover, there was an absence of correlation between sclerostin concentration and lumbar vertebrae BMD in young adult women [2]. The observed disparity could potentially be attributed to variations in population characteristics, including factors such as gender, menopausal status, and notably, the age range of the study cohort.
A few studies suggested that sclerostin may be associated with marrow adiposity [4, 10]. Ma et al. reported that vertebral marrow adiposity was greater in elderly men with higher serum sclerostin levels in models adjusted for age, BMI and diabetes, but not in women [10]. There were a few limitations to that study, such as the age of the population, which included only older white adults (mean age 79 years). Additionally, the factors used for adjustment were different from those used in our study and did not include eGFR, BMD, and the duration and doses of glucocorticoids treatment, which may have influenced the results. However, the complex interplay between the marrow adipose depot and osteocytes, along with osteocyte-derived molecules like sclerostin, remains largely unexplored. Fairfield and colleagues shed light on this relationship by demonstrating that sclerostin not only promotes adipocyte differentiation in pre-adipocyte cell lines but also in primary MSCs obtained from both mouse and human, exerting its effects at the expense of osteoblastogenesis. Reinforcing their findings with two in vivo models designed to inhibit sclerostin, the research unequivocally affirms that the induction of BMAT is orchestrated by sclerostin and is diminished in the absence of sclerostin, achieved through either knockout or neutralization using a specific antibody [4, 9].
However, others reported that no substantial correlations were found between circulating sclerostin and marrow proton density fat fraction in the lumbar spine, femoral neck, and femoral diaphysis in both postmenopausal women with fragility fractures and controls (postmenopausal women with osteoarthritis). This lack of correlation persisted both before and after accounting for factors such as age, eGFR, and BMD [1].
The correlation between vertebral marrow fat fraction in our study cohort and BMD values demonstrated an inverse relationship, consistent with previously published data highlighting the negative association between bone marrow adipocytes and BMD in GIO [5]. The primary discovery from our study reveals a negative association between sclerostin serum concentrations and marrow adiposity in postmenopausal females with GIO. In the literature, conflicting findings arise when investigating the regulation of sclerostin by glucocorticoids. Several previous studies have indicated that both the administration of synthetic glucocorticoids and exposure to endogenous glucocorticoids led to elevated systemic sclerostin levels in mice [13, 25]. Intriguingly, in animal models, skeletal sclerostin expression either witnessed an increase [26] or displayed no discernible difference [13, 27] following glucocorticoid treatment.
Differing from observations in animal studies, the regulation of sclerostin in the human system demonstrated increased consistency, marked by a reduction observed after glucocorticoid treatment in human bone marrow stromal cells. Additionally, patients undergoing glucocorticoid therapy for conditions such as rheumatoid arthritis, polymyalgia rheumatica and chronic inflammatory diseases exhibited a noteworthy decrease in sclerostin levels [13, 28, 29]. The regulation of sclerostin shows variations in individuals with hypercortisolism. One study documented reduced sclerostin levels in those with endogenous hypercortisolism compared to healthy controls [30], whereas another reported increased sclerostin levels [31, 32]. The contrasting results could be linked to differing methodologies, including variations in the timing of blood sample collection, the differentiation between non-fasting and fasting blood samples, discrepancies in study populations, or differences in the methods used to assess blood sclerostin levels.
Despite its strengths, our study has limitations, primarily associated with its cross-sectional nature and the absence of a designated control group. Examining the temporal correlation between circulating sclerostin and BMAT proved impractical. Additionally, our study focused solely on postmenopausal women aged 50 years and older, potentially constraining the applicability of our findings to younger women or men. Notable strengths, however, include the comprehensive assessment of marrow fat across all subjects in the study and the homogeneity of the patient group, as all individuals were undergoing chronic glucocorticoid treatment with a daily dose of ≥ 5 mg. These factors contribute to the robustness of our study.
In conclusion, we have established a correlation between circulating sclerostin levels and marrow adiposity in postmenopausal females with GIO. These findings imply that sclerostin may play significant roles in the pathogenesis of GIO.