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      Fracture risk associated with continuation versus discontinuation of bisphosphonates after 5 years of therapy in patients with primary osteoporosis: a systematic review and meta-analysis

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          The risks and benefits of continuing bisphosphonate therapy beyond 5 years in patients with primary osteoporosis have not been well established.


          We searched MedLine, EMBase, CENTRAL, CINAHL, and AgeLine prior to February 2010. Bibliographies were also searched and experts in the field contacted. The ProQuest Dissertations and Theses database and relevant conference proceedings were searched to identify unpublished or ongoing studies. Two authors independently reviewed search results. Randomized controlled trials and comparative nonrandomized controlled trials examining post-menopausal women or men ≥50 years of age with primary osteoporosis assigned to continue versus discontinue bisphosphonate therapy after ≥5 years of therapy were included. Of 1188 identified articles, three studies (n = 1443) met criteria for inclusion in data synthesis. Data were extracted and risk of bias assessed by two independent reviewers using predefined criteria.


          No statistically significant association was found between fracture incidence and the discontinuation of therapy beyond 5 years for any type of fracture: clinical nonvertebral fracture (relative risk [RR] = 0.97; 95% confidence interval [CI] 0.77–1.23), clinical vertebral fracture (RR = 0.61; 95% CI 0.32–1.19), or morphometric vertebral fracture (RR = 0.90; 95% CI 0.5–1.64). No differences in adverse events were identified between the two groups.


          We found no significant difference in fracture risk or adverse events between postmenopausal women with primary osteoporosis who continued bisphosphonate therapy versus those who discontinued bisphosphonate therapy after 5 years of treatment. However, given the small number and limited quality of available studies, no firm conclusions or recommendations can be made.

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          Most cited references 28

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          Severely suppressed bone turnover: a potential complication of alendronate therapy.

          Alendronate, an inhibitor of bone resorption, is widely used in osteoporosis treatment. However, concerns have been raised about potential oversuppression of bone turnover during long-term use. We report on nine patients who sustained spontaneous nonspinal fractures while on alendronate therapy, six of whom displayed either delayed or absent fracture healing for 3 months to 2 yr during therapy. Histomorphometric analysis of the cancellous bone showed markedly suppressed bone formation, with reduced or absent osteoblastic surface in most patients. Osteoclastic surface was low or low-normal in eight patients, and eroded surface was decreased in four. Matrix synthesis was markedly diminished, with absence of double-tetracycline label and absent or reduced single-tetracycline label in all patients. The same trend was seen in the intracortical and endocortical surfaces. Our findings raise the possibility that severe suppression of bone turnover may develop during long-term alendronate therapy, resulting in increased susceptibility to, and delayed healing of, nonspinal fractures. Although coadministration of estrogen or glucocorticoids appears to be a predisposing factor, this apparent complication can also occur with monotherapy. Our observations emphasize the need for increased awareness and monitoring for the potential development of excessive suppression of bone turnover during long-term alendronate therapy.
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            Effects of continuing or stopping alendronate after 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.

            The optimal duration of treatment of women with postmenopausal osteoporosis is uncertain. To compare the effects of discontinuing alendronate treatment after 5 years vs continuing for 10 years. Randomized, double-blind trial conducted at 10 US clinical centers that participated in the Fracture Intervention Trial (FIT). One thousand ninety-nine postmenopausal women who had been randomized to alendronate in FIT, with a mean of 5 years of prior alendronate treatment. Randomization to alendronate, 5 mg/d (n = 329) or 10 mg/d (n = 333), or placebo (n = 437) for 5 years (1998-2003). The primary outcome measure was total hip bone mineral density (BMD); secondary measures were BMD at other sites and biochemical markers of bone remodeling. An exploratory outcome measure was fracture incidence. Compared with continuing alendronate, switching to placebo for 5 years resulted in declines in BMD at the total hip (-2.4%; 95% confidence interval [CI], -2.9% to -1.8%; P<.001) and spine (-3.7%; 95% CI, -4.5% to -3.0%; P<.001), but mean levels remained at or above pretreatment levels 10 years earlier. Similarly, those discontinuing alendronate had increased serum markers of bone turnover compared with continuing alendronate: 55.6% (P<.001) for C-telopeptide of type 1 collagen, 59.5% (P < .001) for serum n = propeptide of type 1 collagen, and 28.1% (P<.001) for bone-specific alkaline phosphatase, but after 5 years without therapy, bone marker levels remained somewhat below pretreatment levels 10 years earlier. After 5 years, the cumulative risk of nonvertebral fractures (RR, 1.00; 95% CI, 0.76-1.32) was not significantly different between those continuing (19%) and discontinuing (18.9%) alendronate. Among those who continued, there was a significantly lower risk of clinically recognized vertebral fractures (5.3% for placebo and 2.4% for alendronate; RR, 0.45; 95% CI, 0.24-0.85) but no significant reduction in morphometric vertebral fractures (11.3% for placebo and 9.8% for alendronate; RR, 0.86; 95% CI, 0.60-1.22). A small sample of 18 transilial bone biopsies did not show any qualitative abnormalities, with bone turnover (double labeling) seen in all specimens. Women who discontinued alendronate after 5 years showed a moderate decline in BMD and a gradual rise in biochemical markers but no higher fracture risk other than for clinical vertebral fractures compared with those who continued alendronate. These results suggest that for many women, discontinuation of alendronate for up to 5 years does not appear to significantly increase fracture risk. However, women at very high risk of clinical vertebral fractures may benefit by continuing beyond 5 years. clinicaltrials.gov Identifier: NCT 00398931.
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              Ten years' experience with alendronate for osteoporosis in postmenopausal women.

              Antiresorptive agents are widely used to treat osteoporosis. We report the results of a multinational randomized, double-blind study, in which postmenopausal women with osteoporosis were treated with alendronate for up to 10 years. The initial three-year phase of the study compared three daily doses of alendronate with placebo. Women in the original placebo group received alendronate in years 4 and 5 and then were discharged. Women in the original active-treatment groups continued to receive alendronate during the initial extension (years 4 and 5). In two further extensions (years 6 and 7, and 8 through 10), women who had received 5 mg or 10 mg of alendronate daily continued on the same treatment. Women in the discontinuation group received 20 mg of alendronate daily for two years and 5 mg daily in years 3, 4, and 5, followed by five years of placebo. Randomized group assignments and blinding were maintained throughout the 10 years. We report results for the 247 women who participated in all four phases of the study. Treatment with 10 mg of alendronate daily for 10 years produced mean increases in bone mineral density of 13.7 percent at the lumbar spine (95 percent confidence interval, 12.0 to 15.5 percent), 10.3 percent at the trochanter (95 percent confidence interval, 8.1 to 12.4 percent), 5.4 percent at the femoral neck (95 percent confidence interval, 3.5 to 7.4 percent), and 6.7 percent at the total proximal femur (95 percent confidence interval, 4.4 to 9.1 percent) as compared with base-line values; smaller gains occurred in the group given 5 mg daily. The discontinuation of alendronate resulted in a gradual loss of effect, as measured by bone density and biochemical markers of bone remodeling. Safety data, including fractures and stature, did not suggest that prolonged treatment resulted in any loss of benefit. The therapeutic effects of alendronate were sustained, and the drug was well tolerated over a 10-year period. The discontinuation of alendronate resulted in the gradual loss of its effects. Copyright 2004 Massachusetts Medical Society

                Author and article information

                Ther Clin Risk Manag
                Therapeutics and Clinical Risk Management
                Therapeutics and Clinical Risk Management
                Dove Medical Press
                09 May 2011
                : 7
                : 157-166
                [1 ]Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada;
                [2 ]Department of Medicine, McMaster University, Hamilton, Ontario, Canada
                Author notes
                Correspondence: Lisa-Ann Fraser, Division of Endocrinology and Metabolism, University of Western Ontario, St Joseph’s Health Care, 268 Grosvenor Street, London, Ontario N6A 4V2, Canada, Tel +1 519 646 6245, Fax +1 519 646 6067, Email lisaann.fraser@ 123456sjhc.london.on.ca
                © 2011 Fraser et al, publisher and licensee Dove Medical Press Ltd.

                This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited.

                Original Research


                bone mineral density, long-term follow-up, fracture, bisphosphonates


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