Abstract
Background: Oral bisphosphonates (BPs) are the standard therapy for osteoporosis and skeletal metastases, and exhibit anti-tumor properties in preclinical models. Observational studies assessing their impact on colorectal cancer (CRC) risk have yielded inconsistent results. We aimed to systematically review and meta-analyze the association between oral bisphosphonate use and CRC risk, applying a unified exposure definition. Methods: A systematic search was conducted in PubMed, Embase, and Scopus (January 1966-April 2025) to identify cohort, nested case-control, or population-based case-control studies reporting adjusted estimates of relative risk, 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). We assessed publication bias through Egger's test and the trim-and-fill method. Results: A total of eight studies published between 2010 and 2020, including 29,169 CRC cases, fulfilled the 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 bisphosphonate exposure is not significantly linked to CRC risk, prolonged use (≥1 year) appears to reduce risk. Prospective studies and randomized trials are needed to confirm these chemo-preventive effects and guide clinical recommendations.