Introduction 1 2 3 3 4 5 5 8 6 9 10 11 Patients and methods Setting Data were obtained from the PHARMO Record Linkage System (PHARMO RLS) which includes several databases, among which drug dispensing and hospitalization data of more than two million residents of the Netherlands. The drug dispensing histories contain data on the dispensed drug, the type of prescriber, the dispensing date, the amount dispensed, the prescribed dose regimens, and the duration of use. All drugs are coded according to the Anatomical Therapeutic Chemical (ATC) Classification. The hospital records include detailed information concerning the primary and secondary diagnoses, procedures, and dates of hospital admission and discharge. All diagnoses are coded according to the International Classification of Diseases, 9th Revision, Clinical Modification (ICD-9-CM). Study cohort The source population included all new users of bisphosphonates in the period from January 1999 until July 2004. These patients were not dispensed any anti-osteoporotic drugs (bisphosphonates, raloxifene, tibolone, estrogens, hormone replacement therapy, calcitonin or teriparatide) for at least one year before their first bisphosphonate dispensing. All female new users of alendronate (10 mg daily or 70 mg weekly) or risedronate (5 mg daily or 35 mg weekly) (i.e. the dosages indicated for the prevention or treatment of postmenopausal osteoporosis), aged ≥45 years or with diagnosed postmenopausal osteoporosis (ICD-9-CM code 733.01), without gaps in registration in PHARMO RLS, and with a registration of at least one year before and one year after starting bisphosphonate treatment were included in the study cohort. All study patients were followed from the first bisphosphonate dispensing until the occurrence of the outcome of interest, death, end of registration in PHARMO RLS or end of the study period, whichever event was earliest. Compliance Compliance with bisphosphonates during follow-up may change and was measured over 90-day intervals using the Medication Possession Ratio (MPR). MPR was defined as the sum of days’ supply of all alendronate and risedronate dispensings during or overlapping the 90-day interval divided by 90 potential days of bisphosphonate therapy. For each dispensing only the days’ supply covering a specific interval were counted. E.g. of a 100-days supply dispensed at follow-up day 60, only 30 days were counted when calculating the MPR over the first interval (day 0–90) and 70 days for the MPR over the second interval (day 91–180). The maximum value of a MPR was set at 1. Subdividing follow-up in larger intervals was assumed too rough and subdividing in smaller intervals was not feasible regarding the usual prescription length of 90 days. Osteoporotic fractures The outcome variable osteoporotic fracture was defined as hospitalisation for an osteoporotic fracture during follow-up. Hospitalisations were selected based on primary discharge diagnosis for probable (ICD-9-CM codes 805.2 (vertebral thoracic), 805.4 (vertebral lumbar), 820 (proximal femur), 812 (proximal humerus), 813.4 (distal radius/ulna), 814 (carpus)) or possible (ICD-9-CM codes 823.0 (proximal tibia/fibula), 807.0 (rib), 807.2 (sternum), 808.0 (pelvis)) osteoporotic fractures. Covariates 12 14 15 17 Statistical analyses The association between low compliance with bisphosphonates and the risk of fractures was analysed univariately and multivariately using time-dependent Cox regression analysis to account for changing compliance over time. In this analysis, at the time of each fracture, the cumulative compliance up to and including the corresponding 90-day interval of women who had experienced a fracture was compared to the cumulative compliance of those women who remained fracture-free at this time. The cumulative compliance of the fracture-free patients was measured up to the interval of corresponding fracture. 11 The multiple regression models included age, history of fracture and all covariates that were univariately associated with the risk of fractures and significantly contributed to the multivariate model, i.e. inclusion of the covariate resulted in a change of the compliance hazard ratio (HR) of 5% or over, starting with the most potent covariate. HRs and 95% confidence intervals (CI) were estimated using SAS V8.2 UNIX (Cary, NC, USA). Results 1 Table 1 General characteristics of new bisphosphonate users between 1 January 1999 and 30 June 2004 (N = 8,822) Characteristic N % Age class (years) 45–54 889 10.1  55–69 3,225 36.5  ≥70 4,708 53.4 Mean age (years) ± sd   69.4 ± 10.3  Year of start 1999 / 2000 2,250 25.5  2001 / 2002 2,769 31.4  2003 / 2004 3,803 43.1 Initial bisphosphonate Daily bisphosphonate 4,222 47.9  Weekly bisphosphonate 4,600 52.1 First prescriber General practitioner 5,704 64.7  Internist, rheumatologist, orthopedist 2,313 26.2  Other prescribers 805 9.1 Hospitalization for an osteoporotic fracture in the year before start   197 2.2 Use of corticosteroids in the year before start (irrespective of quantity)  2,389 27.1 Follow-up time (months) 12–23 2,939 33.3  24–35 2,268 25.7  ≥36 3,615 41.0 During follow-up, 216 patients (2%) experienced an osteoporotic fracture, of which 40 patients during the first six months and 78 during the first year. About two third of all osteoporotic fractures were located at the proximal femur. 1 Fig. 1 Compliance with bisphosphonates, classified in five MPR categories, after six months, one year, two years and three years of follow-up. MPR: medication possession ratio  2 Table 2 six months   Fracture patients (N) Fracture-free patients (N)  N % N % crude 95% CI Total 176 100 8,606 100   Age (years) at start        45–54 7 4.0 879 10.2 1.00 reference  55–69 29 16.5 3,189 37.1 1.16 0.51–2.66  ≥70 140 79.5 4,538 52.7 4.28 2.00–9.15 Year of start        1999/2000 86 48.9 2,158 25.1 1.68 1.04–2.71  2001/2002 63 35.8 2,691 31.3 1.55 0.97–2.49  2003/2004 27 15.3 3,757 43.6 1.00 reference History of osteoporotic fracture 5 2.8 190 2.2 1.52 0.63–3.70 1        Analgesics 68 38.6 2,136 24.8 1.82 1.34–2.46  Benzodiazepines 80 45.5 3,324 38.6 1.30 0.96–1.74  Antidepressants 29 16.5 1,046 12.2 1.52 1.02–2.26  ß-blockers 47 26.7 1,929 22.4 1.35 0.97–1.89 HR: hazard ratio, CI: confidence interval 1 2 Fig. 2 half  Discussion This study indicates that non-compliant bisphosphonate users had an approximately 50% higher likelihood of osteoporotic fracture compared to compliant users. Classifying compliance into five categories, fracture risk gradually increased with poorer compliance to an 80% risk increase with very low compliance compared to very high compliance. These results emphasize the importance of treatment compliance in obtaining maximal treatment benefit. 18 19 11 20 21 20 21 11 22 5 5 23 7 24 25 26 6 8 9 27 28 25 In conclusion, the results of this study show a statistically significant association between level of compliance with bisphosphonates and level of fracture risk, emphasizing the importance of treatment compliance in obtaining maximal bone protection.