What is the optimal duration of bisphosphonate therapy?
ABSTRACTIt is reasonable to stop bisphosphonates after 5 years of use and then to follow patients with markers of bone turnover. As long as the levels of these markers remain reduced, adding an antiresorptive drug does not make physiologic sense.
KEY POINTS
- Bisphosphonates reduce the risk of osteoporotic fractures, including devastating hip and spine fractures.
- As with any drugs, bisphosphonates should not be used indiscriminately. They are indicated for patients at high risk of fracture, especially those with vertebral fractures or a hip bone density T score lower than −2.5.
- There is little evidence to guide physicians about the duration of bisphosphonate therapy beyond 5 years. One study with marginal power did not show any difference in fracture rates between those who continued taking alendronate and those who discontinued after 5 years (JAMA 2006; 296:2927–2938).
- Evidence is accumulating that the risk of atypical fracture of the femur increases after 5 years of bisphosphonate use.
- Anabolic drugs are needed; the only one currently available is teriparatide (Forteo), which can be used when fractures occur despite (or perhaps because of) bisphosphonate use.
BISPHOSPHONATES SHOULD BE USED WHEN THEY ARE INDICATED
The focus of this paper is on the duration of use, but concern about long-term use should not discourage physicians or patients from using these drugs when there is a high risk of an osteoporotic fracture within the next 10 years, particularly in elderly patients who have experienced a vertebral compression fracture or a hip fracture. Patients with a vertebral fracture have a one-in-five chance of fracturing another vertebra, which is a far higher risk than any of the known long-term side effects from treatment, and bisphosphonates are effective at reducing the risk.
Low bone density alone can be used as an indication for bisphosphonates if the hip T score is lower than −2.5. A cost-effectiveness study concluded that alendronate was beneficial in these cases.45 In the FIT patients without a vertebral fracture at baseline, the overall fracture rate was significantly decreased by 36% with alendronate in those with a hip T score lower than −2.5, but there was no difference between placebo and alendronate in those with T scores between −2 and −2.5, and a 14% (nonsignificant) higher fracture rate when the T score was better than −2.0.22
A new method of calculating the risk of an osteoporotic fracture is the FRAX prediction tool (https://www.shef.ac.uk/FRAX), and one group has suggested that treatment is indicated when the 10-year risk of a hip fracture is greater than 3%.46 Another group, from the United Kingdom, suggests using a sliding scale depending on the fracture risk and the age.47
It is not always clear what to do when the hip fracture risk is greater than 3% for the next decade but the T score is better than −2.5. These patients have other factors that contribute to fracture risk. Their therapy must be individualized, and if they are at risk of fracture because of low weight, smoking, or alcohol use, it makes more sense to focus the approach on those treatable factors.
Women who have osteopenia and have not had a fragility fracture are often treated with bisphosphonates with the intent of preventing osteoporosis in the distant future. This approach is based on hope, not evidence, and several editorial reviews have concluded that these women do not need drug therapy.48–50
MY RECOMMENDATION: STOP AFTER 5 YEARS
Bisphosphonates reduce the incidence of devastating osteoporotic fractures in patients with osteoporosis, but that does not mean they should be used indefinitely.
After 5 years, the overall fracture risk is the same in patients who keep taking bisphosphonates as in patients who discontinue them. Therefore, I think these drugs are no longer necessary after 5 years. The post hoc subgroup analysis that showed benefit in only one of six groups of the FLEX study does not provide compelling evidence to continue taking bisphosphonates.
While awaiting better studies, we use the approach shown in the algorithm in Figure 4.
Follow the patient with bone resorption markers
In patients who have shown some improvement in bone density during 5 years of bisphosphonate treatment and who have not had any fractures, I measure a marker of bone resorption at the end of 5 years.
The use of a biochemical marker to assess patients treated with anti-turnover drugs has not been studied in a formal trial, so we have no grade A evidence for recommending it. However, there have been many papers describing the effects of bisphosphonates on these markers, and it makes physiologic sense to use them in situations where decisions must be made when there is not enough evidence.
In FIT (a trial of alendronate), we reported that the change in bone turnover markers was significantly related to the reduction in fracture risk, and the effect was at least as strong as that observed with a 1-year change in bone density. Those with a 30% decrease in bone alkaline phosphatase had a significant reduction in fracture risk.51
Furthermore, in those patients who were compliant with bisphosphonate treatment, the reduction in fractures with alendronate treatment was significantly better in those who initially had a high bone turnover.52
Similarly, with risedronate, the change in NTx accounted for half of the effect on fracture reduction during the clinical trial, and there was little further improvement in fracture benefit below a decrease of 35% to 40%.10
The baseline NTx level in these clinical trials was about 70 nmol bone collagen equivalents per millimole of creatinine (nmol BCE/mmol Cr) in the risedronate study and 60 in the alendronate study, and in both the fracture reduction was seen at a level of about 40. The FLEX study measured NTx after 5 years, and the average was 19 nmol BCE/mmol Cr. This increased to 22 after 3 years without alendronate.53 At 5 years, the turnover markers had gradually increased but were still 7% to 24% lower than baseline.10
These markers have a diurnal rhythm and daily variation, but despite these limitations they do help identify low bone resorption.
In our hospital, NTx is the most economical marker, and my patients prefer a urine sample to a blood test. Therefore, we measure the NTx and consider values lower than 40 nmol BCE/mmol Cr to be satisfactory.
If the NTx is as low as expected, I discontinue the bisphosphonate. The patient remains on 1,200 mg/day of calcium and 1,000 U/day vitamin D supplementation and is encouraged to exercise.
Bone density tends to be stable for 1 or 2 years after stopping a bisphosphonate, and the biochemical markers of bone resorption remain reduced for several years. We remeasure the urine NTx level annually, and if it increases to more than 40 nmol BCE/mmol Cr an antiresorptive medication is given: either the bisphosphonate is restarted or raloxifene (Evista), calcitonin (Miacalcin), or denosumab (Prolia) is used.
