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Original Investigation |

Fracture Prediction After Discontinuation of 4 to 5 Years of Alendronate Therapy:  The FLEX Study

Douglas C. Bauer, MD1,2; Ann Schwartz, PhD2; Lisa Palermo, MA, MS2; Jane Cauley, DrPH3; Marc Hochberg, MD4; Art Santora, MD5; Steven R. Cummings, MD6; Dennis M. Black, PhD2
[+] Author Affiliations
1Department of Medicine, University of California, San Francisco
2Department of Epidemiology and Biostatistics, University of California, San Francisco
3Department of Epidemiology, Graduate School of Public Health, University of Pittsburgh, Pittsburgh, Pennsylvania
4Department of Epidemiology and Public Health, University of Maryland School of Medicine, Baltimore
5Merck and Co, Inc, Rahway, New Jersey
6California Pacific Research Foundation, San Francisco, California
JAMA Intern Med. 2014;174(7):1126-1134. doi:10.1001/jamainternmed.2014.1232.
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Importance  Discontinuation of bisphosphonate therapy after 3 to 5 years is increasingly considered, but methods to monitor fracture risk after discontinuation have not been established.

Objective  To test methods of predicting fracture risk among women who have discontinued alendronate therapy after 4 to 5 years.

Design, Setting, and Participants  The prospective Fracture Intervention Trial Long-term Extension (FLEX) study randomized postmenopausal women aged 61 to 86 years previously treated with 4 to 5 years of alendronate therapy to 5 more years of alendronate or placebo from 1998 through 2003; the present analysis includes only the placebo group. Hip and spine dual-energy x-ray absorptiometry (DXA) were measured when placebo was begun (FLEX baseline) and after 1 to 3 years of follow-up. Two biochemical markers of bone turnover, urinary type 1 collagen cross-linked N-telopeptide (NTX) and serum bone-specific alkaline phosphatase (BAP), were measured at FLEX baseline and after 1 and 3 years.

Main Outcomes and Measures  Symptomatic spine and nonspine fractures occurring after the follow-up measurement of DXA or bone turnover.

Results  During 5 years of placebo, 94 of 437 women (22%) experienced 1 or more symptomatic fractures; 82 had fractures after 1 year. One-year changes in hip DXA, NTX, and BAP were not related to subsequent fracture risk, but older age and lower hip DXA at time of discontinuation were significantly related to increased fracture risk (lowest tertile of baseline femoral neck DXA vs other 2 tertiles relative hazard ratio, 2.17 [95% CI, 1.38-3.41]; total hip DXA relative hazard ratio, 1.87 [95% CI, 1.20-2.92]).

Conclusions and Relevance  Among postmenopausal women who discontinue alendronate therapy after 4 to 5 years, age and hip BMD at discontinuation predict clinical fractures during the subsequent 5 years. Follow-up measurements of DXA 1 year after discontinuation and of BAP or NTX 1 to 2 years after discontinuation are not associated with fracture risk and cannot be recommended.

Trial Registration  clinicaltrials.gov Identifier: NCT00398931

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Figure 1.
Design of Fracture Intervention Trial Long-term Extension (FLEX) Trial

FIT indicates Fracture Intervention Trial.

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Figure 2.
Proportion of Women With Any Clinical Fracture After Discontinuation of Alendronate Therapy

A, By tertile of hip bone mineral density (BMD) at Fracture Intervention Trial Long-term Extension (FLEX) baseline. P for trend < .001 for total hip BMD and for femoral neck BMD. B, By tertile of bone turnover marker at FLEX baseline. P for trend = .18 for urinary type 1 collagen cross-linked N-telopeptide to creatinine concentration ratio (NTX/Cr) and .40 for serum bone-specific alkaline phosphatase (BAP). C, By tertile of 1-year percent change in hip BMD. P for trend = .96 for total hip BMD and .81 for femoral neck BMD. D, By tertile of 1-year percent change in bone turnover marker. P for trend = .91 for NTX/Cr and .70 for BAP.

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