OBJECTIVES: To investigate the relationship between duration of compliant bisphosphonate use and the risk of osteoporotic fractures.METHODS: The PHARMO database was used to identify new female bisphosphonate users, aged >/= 45 years or with diagnosd post-menopausal osteoporosis in the period of January 1996 – June 2004. Within this cohort a matched case-control study was performed. Cases were defined as patients who were hospitalized for an osteoporotic fracture and were matched to ten controls without a fracture by duration of follow-up. The duration of compliant bisphosphonate use (i.e., medication possession ratio >/= 80%) preceding the outcome date was determined.RESULTS: Of 14 760 new female bisphosphonate users, 387 fracture patients fulfilled the inclusion criteria. These cases were matched to 3950 controls. Increasing duration of compliant bisphosphonate use was associated with a decreased risk of fracture (trend p < 0.01). Adjusted for several cofactors, 1-2 years of compliant bisphosphonate use and 3-4 years of compliant bisphosphonate use decreased fracture risk by 12% and 46%, respectively, compared to < 1 year of compliant bisphosphonate use (OR 0.88; 95% CI 0.66-1.18 and OR 0.54; 95% CI 0.35-0.84, respectively). Unexpectedly, 5-6years of compliant bisphosphonate use was no longer associated with a decreased risk of fractures compared to < 1 year of compliant bisphosphonate use (OR 1.12, 95% CI 0.66-1.88).CONCLUSIONS: These results show a direct link between duration of compliantbisphosphonate use and fracture risk, and confirm the importance of continuing the use of bisphosphonates to maintain optimal bone protection. However, this link is inconclusive for bisphosphonate use for more than 4 years.