RELATIONSHIP BETWEEN HOMOCYSTEINE LEVELS AND BONE QUALITY IN HEALTHY ADULTS - A SYSTEMATIC REVIEW AND META-ANALYSIS.

Background and aims: Patients with elevated homocysteine (Hcy) levels are associated with an increased risk of fracture. B-vitamin supplementation studies have consistently shown an ability to reduce Hcy levels but have had no or marginal effect on bone mineral density (BMD), which led us to hypothesize that hyperhomocysteinemia may increase fracture risk by altering bone quality outcome measures beyond BMD. The aim of our systematic review was to investigate the association between Hcy and bone quality outcome measures, i.e. bone turnover, bone microarchitecture, collagen crosslinks and micro damage accumulation, in healthy adults.

Methods: A systematic search was performed on Pubmed, Embase, and Scopus from the date of inception to 30^th of September^, 2024. Studies were included that had sufficient data to identify the pooled relationship between plasma Hcy and at least one domain of bone quality, such as bone microarchitecture, bone turnover, advanced glycation product (AGE) pentosidine levels, collagen crosslinks, or micro damage accumulation. Studies involving patients who were on medications or had conditions affecting plasma Hcy or bone health were excluded. Osteoporotic patients were included only if they had not been treated.

Results: Twenty-seven studies were included in our systematic review. Our meta-analysis found a significant positive correlation between Hcy and osteocalcin [Pearson's coefficient of correlation (r) = 0.39, significance value (p) = 0.023, 95% Confidence Interval (CI) = 0.36 - 0.42]. No significant correlation was observed between Hcy and Procollagen type-1 N propeptide (P1NP), C-terminal telopeptide of type 1 collagen (CTX-1), or Bone-specific alkaline phosphatase (Bone ALP). Additionally, we found a strong positive correlation between Hcy and the AGE serum pentosidine [r = 0.72, p = 0.020, 95% CI = 0.67 - 0.76], a molecule linked to increased non-enzymatic collagen cross-linkage. Further, two studies measured collagen-crosslinking in the bone, and both reported elevated Hcy to be associated with higher non-enzymatic crosslinks and reduced enzymatic crosslinks.

Conclusion: Our results suggest that elevated Hcy impacts bone quality outcome measures. The effect is possibly mediated via increased bone turnover and accumulation of non-enzymatic collagen crosslinking, resulting in decreased bone strength. PROSPERO Registration No.: CRD42024595870.