Exploring the therapeutic synergy of drug-lifestyle interventions in fluorosis: a randomized trial on cardiovascular metabolic outcomes from the China fluorosis cohort (CFC)

Introduction Skeletal fluorosis patients face a markedly elevated risk of cardiovascular metabolic abnormalities, including endothelial dysfunction, excessive oxidative stress, and impaired calcium-phosphate metabolism. Current clinical interventions for this condition are limited to symptomatic analgesia and conventional anti-osteoporotic treatments, and lack targeted therapeutic strategies for the “kidney deficiency and blood stasis” pathogenesis of skeletal fluorosis that can synergistically protect both the skeletal and cardiovascular systems. Methods This multicenter randomized controlled trial was conducted on 1,480 skeletal fluorosis patients from the China Fluorosis Cohort (CFC), to investigate the synergistic therapeutic effects of three traditional Chinese medicine (TCM) combinations— Ginkgo biloba combined with Epimedium (Drug 1), Xianling Gubao combined with Eucommia ulmoides (Drug 2), and Gusongbao combined with Rosa roxburghii (Drug 3)—in conjunction with lifestyle modifications on cardiovascular metabolic outcomes. Results Smoking and alcohol consumption were identified as independent risk factors for reduced therapeutic efficacy in skeletal fluorosis patients with comorbid cardiovascular metabolic abnormalities (OR = 2.755, 95% CI: 1.400 –5.421). Among the three TCM combinations, Drug 2 and Drug 3 significantly counteracted these adverse risk factors, reducing the risk of treatment failure by 53.9% (OR = 0.461) and 57.0% (OR = 0.430), respectively. Drug 3 exhibited superior efficacy in reducing diastolic blood pressure ( β = −2.263, P = 0.010), while its systolic blood pressure-lowering effect diminished with increasing age. Drug 2 showed synergistic benefits with improved sleep quality ( β = 1.596, P = 0.002) and healthy dietary habits ( β = −1.180, P = 0.001), which enhanced its antihypertensive effects and led to a significant reduction in low-density lipoprotein cholesterol (LDL-C) levels ( P < 0.05). Additionally, the interaction models outperformed the main-effect models, confirming the dynamic synergistic effect between lifestyle interventions and TCM pharmacotherapy. Discussion These findings highlight the clinical necessity of integrating behavioral interventions with pharmacotherapy to optimize cardiovascular metabolic safety in the clinical management of skeletal fluorosis. Based on these results, we propose a novel theoretical framework—Personalized Behavioral-Integrated Therapy (PBIT)—which guides the incorporation of patient-specific behavioral and demographic factors into tailored treatment strategies, thereby improving the precision and clinical outcomes of skeletal fluorosis treatment.