Best Evidence Analyses and Commentary

New FDA Labeling Suggests Stopping bisphosphonates after 3 to 5 years in low risk patients
Eric Yeo, PharmD Candidate; Marcus Campbell, PharmD, BC-ADM

Osteoporosis is a disease associated with a reduction in bone mass and an increase in skeletal fragility. It affects 10 million Americans; another 34 million are considered at risk.1

Bisphosphonates have been shown to be effective in reducing the risk of osteoporotic fragility fractures, and are widely prescribed for that purpose. During the period from 2005 to 2009, 150 million prescriptions were dispensed in the United States outpatient setting for three popular oral bisphosphonates: alendronate (Fosamax®), risedronate (Actonel®) and ibandronate (Boniva®) in the US. Of these 150 million prescriptions, 5.1 million patients over the age of 55 received a prescription for bisphosphonates in 2008.2

The long-term safety and efficacy of bisphosphonate therapy for osteoporosis was evaluated by the FDA Advisory Committee for Reproductive Health Drugs and the Drug Safety and Risk Management committee. Rare but serious adverse events associated with long-term bisphosphonate use have been identified in post-marketing surveillance reports. Cases have included atypical femur fractures, osteonecrosis of the jaw, and esophageal cancer. The Committees jointly recommended that bisphosphonate labeling be updated.1

It is worth noting that bisphosphonates significantly accumulate in skeletal binding sites because the receptors are essentially unsaturable. A reservoir is formed and drug is continuously released for months to years, even after the drug is discontinued. This makes it possible for clinicians to consider a ‘drug holiday’ for patients on bisphosphonate therapy after a certain period of time.3

In September of 2011, the FDA held a hearing to review the long term safety and efficacy of bisphosphonates. Consequently, they recommended that clinicians reevaluate the need for continued bisphosphonate therapy beyond 3-5 years. They also stated that in patients at high risk, a drug holiday may not be advisable.3 Currently, all bisphosphonates approved by the FDA for the treatment of osteoporosis contain the following “Important Limitation of Use” statement: “The optimal duration of use has not been determined. All patients on bisphosphonate therapy should have the need for continued therapy re-evaluated on a periodic basis.” FDA scientist Theresa Kehoe, MD, testified that the agency’s own analysis concluded that there was no clear benefit or evidence of harm in women who continued bisphosphonate therapy after five years, nor was there a “clear and consistent” reduction in fracture risk.4

The committee recommended that the decision to continue treatment with bisphosphonates should be based on individual assessment of risks and benefits and patient preference. They indicated that patients that are at low risk for fractures, meaning those that are younger and without a history of fracture and a bone mineral density (BMD) near normal range, may be good candidates for bisphosphonate therapy lasting for 3-5 years. On the other hand, patients at increased risk of fractures, such as older patients with a history of fractures, or bone mineral density in the osteoporotic range, may benefit from continued bisphosphonate therapy.2

A double-blind, randomized, placebo-controlled trial called the Fracture Intervention Trial (FIT) was conducted to study the effects of alendronate treatment on fracture risk among 6459 postmenopausal women with low BMD. FIT enrolled 3236 women on alendronate who were followed for an average of 3.8 years. The investigators sought to determine if additional therapy with alendronate beyond this period would result in preservation or further gains in BMD following alendronate discontinuation.

Subsequently, they conducted a follow-up, double-blind, placebo-controlled extension trial to FIT, [FIT long-term extension (FLEX)] in which 1099 (39%) women from the FIT trial who had used alendronate for an average of 5 years were re-randomized. To be eligible for the FLEX study, women had to have been on alendronate for at least 3 years. Women were randomly assigned to alendronate 10 mg/day (30%) (n=333), alendronate 5 mg/day (30%) (n=329) or placebo (40%) (n=437) for a duration of 5 years. Randomization was stratified by fracture risk; women with at least one radiographic morphometric vertebral deformity identified by the end of FIT and/or who experienced a clinical fracture during FIT were assigned to the high-risk stratum. All participants were strongly encouraged to take a daily supplement containing calcium (500 mg) and vitamin D (250 IU). The percentage of participants receiving the supplement was 97.5%.5

BMD of the total hip and its sub-regions, together with the posterior-anterior lumbar spine, and the total body was measured at the FLEX baseline using DXA and then repeated at 36 months using the same densitometers. At FLEX baseline, the average age was 73 years and 97% of participants identified themselves as white. The average duration of alendronate treatment was 5 years. The mean BMD at the total hip corresponded to a T score of -1.9, mean BMD at the femoral neck corresponded to a T score of -2.2, and mean BMD at the lumbar spine corresponding to a T score of -1.3. Thirty-eight percent of participants were assigned to the high fracture risk stratum.5

The study showed lumbar spine BMD increased in the alendronate group compared to the placebo group (5.26% vs. 1.52%), a mean difference of 3.74% (95% CI, 3.03%-4.45%; P<0.001). Similarly, in terms of total body and forearm BMD, there was a statistically significant mean difference between the alendronate (1.28%) and placebo group (2.01%) with (P<0.001 for both). In regards to nonvertebral fractures, no significant difference was found between the pooled alendronate group and the placebo group. The percentage of fractures was 19% with placebo vs 18.9% with alendronate. Although there was a statistically significantly lower risk of clinical vertebral fractures in the alendronate group (5.3% with placebo vs 2.4% with alendronate; RR, 0.45; 95% CI, 0.24-0.85), post hoc subgroup fracture analysis did not indicate any significant trends with lower BMD or prevalent vertebral fractures at FLEX baseline for either nonvertebral or clinical vertebral fractures. However, both nonvertebral and clinical fractures were increased with lower baseline BMD or prevalent fractures. The RR reduction in those who continued to take alendronate was 55% and the absolute risk reduction was 2.9%. It is clinically significant to note that women with a history of vertebral fractures or very low BMD are at much higher risk of future vertebral fractures and have a higher absolute benefit for prevention of vertebral fractures. The authors of the study report that gains in BMD appeared to be better maintained after discontinuation of drugs in the bisphosphonate class, including alendronate, risedronate, pamidronate and eidronate than with seen in patients treated with estrogen, raloxifene or intermittent parathyroid hormones.6

Some of the limitations of this study include 1) limited power to detect modest differences in fracture rates, as reflected in wide CIs for fracture outcomes, 2) many FLEX participants were not diagnosed as having osteoporosis, either because they entered the FIT trial without osteoporosis or because they experienced gains in BMD during FIT trial; thus further reducing the power to detect a difference between groups, if one exists, 3) dose and duration was not consistent throughout the trial, 4) the average age of the participants at baseline was 73 years, causing the results to be non-generalizable to the general population (i.e. younger women, men or the very elderly).

During the trial, there were no reports of osteonecrosis of the jaw. There were no significant between-group differences in upper gastrointestinal tract or serious upper gastrointestinal adverse events.

The authors concluded that continuation of alendronate therapy for 10 years maintained both bone mass and reduced bone remodeling compared with discontinuation after 5 years. With that being said, even those who discontinued therapy after 5 years saw their BMD remain at or above baseline values and bone turnover was still somewhat reduced. Discontinuation of alendronate after 5 years did not increase the risk of nonvertebral fractures over the next 5 years. However, the risk of clinically diagnosed vertebral fractures was significantly increased among those who discontinued therapy. These results suggest that women at high risk of clinical vertebral fractures, such as those with vertebral fractures or very low BMD, may benefit by continuing bisphosphonate therapy beyond 5 years; and that discontinuation of alendronate after 5 years in women at low risk of fractures does not significantly increase fracture risk.6

The results of this study mirrors the recommendations of the FDA that patients on bisphosphonate therapy should be reevaluated after 3-5 years of therapy. Appropriateness of continued therapy based on an individual’s risks and benefits should be assessed during the reevaluation period. Patients at high risk of future vertebral fractures, such as patients with existing vertebral fractures, or patients with low BMD may benefit from continued bisphosphonate therapy.


1. Whitaker, M, Guo, J, Kehoe, T, Benson, G. Bisphosphonate for Osteoporosis—Where do we go from here? N. Engl J Med 366; 22. May 31, 2012

2. Division of Reproductive and Urologic Products, Office of New Drugs Division of Pharmacovigilance II, Office of Surveillance and Epidemiology, Office of Surveillance and Epidemiology Center for Drug Evaluation and Research Food and Drug Administration: Background Document for Meeting of Advisory Committee for Reproductive Health Drugs and Drug Safety and Risk Management Advisory Committee. September 9, 2011.

3. Diab, D, Watts, N. Bisphosphonates drug holidays: who, when and how long. Ther Adv Musculoskel Dis. (2013). (3): 107-111.

4. Rubin, R. FDA panel: Osteoporosis drugs need better labels. Time limits on the drugs are
suggested, but how much time is yet to be determined. WebMD. Accessed 07/16/2013.

5. Ensrud, K, Connor-Barrett, E, Schwartz, A, Santora, A, Bauer, D C, Suryawanshi, S, Feldstein, A, Haskell, W L, 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. Vol 19 (8), 2004: pp. 1259-1268.

6. Black, D, Schwart, AV, Ensrud, KE, Cauley, JA, Levis, S, Quandt, SA, Satterfiled, S, Wallace, RB, 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, 12/27/2006. Vol 296(24): pp 2927-2936.

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