Black DM, Schwartz AV, Ensrud KE, et al. Effects of continuing or stopping alendronate after 5 years of treatment – The Fracture Intervention Trial long-term extension (FLEX): A randomized trial. Jama-Journal of the American Medical Association 2006;296:2927-38.
PubMed link: https://www.ncbi.nlm.nih.gov/pubmed/17190893
Full text article: https://jamanetwork.com/journals/jama/fullarticle/204789
Ensrud K, E., Barrett‐Connor E, L., Schwartz A, et al. Randomized Trial of Effect of Alendronate Continuation Versus Discontinuation in Women With Low BMD: Results From the Fracture Intervention Trial Long‐Term Extension. Journal of Bone and Mineral Research 2004;19(8):1259-69.
PubMed link: https://www.ncbi.nlm.nih.gov/pubmed/15231012
Full text article: https://asbmr.onlinelibrary.wiley.com/doi/full/10.1359/JBMR.040326
Schwartz AV, Bauer DC, Cummings SR, et al. Efficacy of Continued Alendronate for Fractures inWomen With and Without Prevalent Vertebral Fracture:The FLEX Trial. Journal of Bone and Mineral Research 2010;25(5):976–82-76–82.
PubMed link: https://www.ncbi.nlm.nih.gov/pubmed/20200926
Full text article: https://asbmr.onlinelibrary.wiley.com/doi/full/10.1002/jbmr.11
| Methods | Study design: Randomized double-blind controlled study with a parallel-design
Number of groups: Three groups |
| Participants | Number of participants: 1099 randomized, 759 completed
· Intervention deprescribing group: 437 enrolled, 299 completed · Continue alendronate 5mg group: 329 enrolled, 236 completed · Continue alendronate 10mg group: 333 enrolled, 224 completed Age: 73.7 ± 5.9 years Sex: 1099 female, 0 male Inclusion criteria: · Eligibility in deprescribing study (FLEX study) was limited to women assigned to receive alendronate during the drug treatment intervention study (FIT study) who completed at least 3 years of treatment during the trial and subsequent open-label period · Alendronate drug treatment intervention (FIT) study included o Aged between 55 and 81 years at baseline o Postmenopausal for at least two years o Femoral neck Bone Mass Density of 0·68 g/cm2 or less (QDR-2000 Hologic, Waltham, MA, USA), about 2·1 SDs below peak bone mass based on the manufacturer’s normative data Exclusion criteria: · Total hip Bone Mass Density at deprescribing baseline was less than 0.515 g/cm2 (T-score −3.5) 10; or · Total hip Bone Mass Density was lower than at commencement of alendronate treatment (baseline) were ineligible · Alendronate drug treatment intervention (FIT) study excluded: o Women with peptic-ulcer disease (a single hospital admission for upper gastrointestinalbleeding or two or more documented ulcers within the preceding 5 years) o Dyspepsia requiring daily treatment o Abnormal renal function (serum creatinine >144 μmol/L) o Major medical problems that would be likely to preclude participation for 3 years o Severe malabsorption syndrome o Uncontrolled hypertension (blood pressure >210 mm Hg systolic or >105 mm Hg diastolic) o Myocardial infarction during the previous 6 months o Unstable angina o Evidence of disturbed thyroid or parathyroid function o Taken estrogen or calcitonin within the preceding 6 months o Taken bisphosphonate or sodium fluoride (>1 mg daily for 2 weeks or longer) at any time Country: United States of America Setting: Community (11 metropolitan sites) |
| Interventions | Medicine: Alendronate
Withdrawal schedule: Not described Comparator: Placebo compared to continued medicine |
| Outcomes | Change in bone mineral density for duration of deprescribing
Biochemical markers of bone turnover Incidence of fracture Histomorphometry/micro–computed tomography Adverse events Anti-fracture efficacy of continued alendronate in subgroups defined by femoral neck T-score and vertebral fracture status |
| Dates | Dates: Not described
Follow-up duration: Ten years (five years treatment vs. ten years treatment) |
| Funding sources | Merck & Co “…designed jointly by the non-Merck investigators and Merck employees. Study drug was manufactured and packaged by Merck.” |
| Notes | Black 2006 includes a description of the funder’s role and declarations of conflicts of interest. There is insufficient room to include them here.
Black 2006 is the deprescribing trial Schwartz 2010 is a posthoc analysis of the deprescribing trial Note: we combined the two groups that continued alendronate for the analysis. |
Risk of bias table
| Bias | Authors’ judgment | Support for judgment |
| Random sequence generation (selection bias) | Unclear risk | “In each arm, women were randomized to alendronate, 5 mg/d for 2 years and 10 mg/d thereafter (n = 3236), or placebo (n = 3223).”
“Two randomization strata were defined: the higher-risk stratum included women with one or more morphometric vertebral deformities at the end of FIT or with a clinical fracture during FIT; all other women were randomized to the low-riskstratum.” Randomization was describedfor the parent study (FLEX), but not for this study. “At FLEX baseline, participants were randomly allocated (using a permuted- block design, stratified by study stratum and center) to receive alendronate, 10 mg/d (30%), alendronate, 5 mg/d (30%), or placebo (40%) for 5 years.” |
| Allocation concealment (selection bias) | Unclear risk | Concealment method is not described. |
| Blinding of participants and personnel (performance bias) | Low risk | Blinding participants and personnelwere undertaken. |
| Blinding of outcome assessment (detection bias) | High risk | “Participants and all study staff and investigators, except a senior statistician, remained blinded to treatment allocation and Bone Mass Density follow-up values throughout the study. The senior statistician created unblindedreports that were reviewed periodically by a data monitoring committee. The 3-year interim analysis was performedwithout unblinding of investigators to individual assignments.” |
| Incomplete outcome data (attrition bias) | Low risk | “Modified intention-to-treat analysis, using all available data from all participants assigned to treatment who had at least one follow-up measure, regardless of study medication adherence, was used for analysis of Bone Mass Density. If at least one post- randomization value was available, we carried forward values for later missing values. In addition, we performed sensitivity analyzeswithout carrying forward Bone Mass Density values or excluding women who discontinued study drug or used other bone-active medications.” |
| Selective reporting (reporting bias) | Low risk | Published protocol unavailable, however, intended outcomes described in the paper are all reported.
“As pre-specified, data from both alendronate dosage groups were pooled for primaryanalyzes; secondary analyzes for Bone Mass Density and biochemical markers were performedwithout pooling.” |
| Other bias | High risk | Industry-sponsoredstudy. |
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