Abstract: Introduction: While the impact of COVID-19 on bone metabolism has been extensively studied, the inverse relationship remains less understood. This study investigates whether impaired bone metabolism is associated with an increased risk of COVID-19 infection.
Methods: We conducted a nested case-control study within a population-based cohort, incorporating Kaplan-Meier analysis (KMA) to assess time to infection (TTI) differences. Propensity score matching (1:2) was performed and validated through standardized mean differences (<0.10), variance ratio (=1), and McFadden's pseudo-R2 (=0), ensuring balanced covariates. Bone status was evaluated using a composite index (AOMI), which included five components: P1NP and CTX (bone turnover markers), total hip bone mineral density (BMD-TH), trabecular bone score (TBS), and integral volumetric BMD (IvBMD). Inflammation and insulin resistance (IR) were assessed by albumin-to-globulin ratio (AGR <1.50) and the TG/HDL ratio (>2.50 in women and >2.80 in men), respectively.
Results: We analysed 294 COVID-19 cases and 528 controls. AOMI+ individuals had a higher prevalence of COVID-19 (41.5% vs. 33.2%; p = 0.031), an adverse lipid pattern ("A" profile: high ApoB, LDL and TC) and pronounced bone changes (higher P1NP and CTX, lower BMD-TH, TBS, and IvBMD). AOMI - individuals were more likely to have metabolic syndrome, displayed a different lipid profile ("B" profile: elevated TG, AIP, and TG/HDL ratio), fewer bone alterations, and lower COVID-19 prevalence. TG/HDL ratio was 1.66 ± 1 in "A" profile, while it was 2.85 ± 1.4 in "B" profile individuals (p = 0.0001). Age acted as an effect modifier, and lowest tercile significantly increased COVID-19 risk associated with AOMI+ [Mantel-Haenszel OR = 1.42 (95%CI: 1.08-1.9); p = 0.022]. KMA identified AOMI+ men and individuals of both sexes in lowest age tercile, as groups with shorter TTI: These younger individuals had high CTX (women), low TBS (men), and high ApoB (both). In multivariable analyses, plasma CTX levels negatively correlated with TTI (adjusted ?= -0.325; p = 0.0001). AOMI+ status was associated with increased COVID-19 risk after controlling for confounders, including IR (adjusted OR = 1.51; 95%CI: 1.04-2.10; p = 0.027), although this association weakened when adjusting for AGR (95%CI: 0.99-2.28; p = 0.055). ANCOVA-estimated adjusted TBS means were lower in COVID-19 cases compared to controls (1.259 vs. 1.294; p = 0.013).
Conclusions: Impaired bone metabolism was found to be associated with increased COVID-19 risk, in a relationship potentially mediated by underlying inflammation. Elevated osteoclastic activity and a defined lipid profile with high ApoB, TC, LDL levels, played a crucial role in the results. Bone quality parameters more accurately captured COVID-19-related bone changes than BMD.
