From Bone Health to Gut Shield: A Reanalysis & Meta‑Analysis of Long‑Term Oral Bisphosphonates in Colorectal Cancer Prevention

Background: Oral bisphosphonates (BP) are standard therapy for osteoporosis and skeletal metastases and exhibit anti tumor properties in preclinical models. Observa-tional studies assessing their impact on colorectal cancer (CRC) risk have yielded in-consistent results. We aimed to systematically review and meta analyze the association between oral bisphosphonate use and CRC risk, applying a unified exposure definition. Methods: We searched PubMed, Embase and Scopus (January 1966–April 2025) for cohort, nested or population based case control studies reporting adjusted relative risks, odds ratios (ORs) or hazard ratios (HRs) for CRC among oral bisphosphonate users. Two reviewers independently screened studies, extracted data and assessed quality using the Newcastle–Ottawa Scale. Random effects meta analyses pooled risk estimates for “any use” of bisphosphonates, with subgroup analyses by duration of use (< 1, 1–3, >3 years). Publication bias was evaluated via Egger’s test and trim and fill. Results: Eight studies (29169 CRC cases) met inclusion criteria. Any bisphosphonate use was not significantly associated with CRC risk (pooled OR 0.97; 95% C.I., 0.90–1.03). However, 1–3 years of use conferred a protective effect (OR 0.86; 95% C.I., 0.73–0.99), as did >3 years (OR 0.91; 95% C.I., 0.85–0.97). Heterogeneity was moderate and no significant publication bias was detected. Conclusions: While overall oral bisphos-phonate exposure is not significantly linked to CRC risk, prolonged use (≥1 year) ap-pears to reduce risk. Prospective studies and randomized trials are needed to confirm these chemo preventive effects and guide clinical recommendations.