When to Stop the Bisphosphonate

Charles P. Vega, MD


May 31, 2019

Door Number…

I choose to provide a drug holiday and reassess at 2-3 years. This choice is based on limited evidence from clinical research and expert opinion. However, it is also substantially influenced by this patient's motivation to take fewer medications.

Postmenopausal osteoporosis is common and has potentially devastating consequences for patients and their loved ones. It is estimated that 1 in every 2-3 women will experience a fragility fracture at some point.[1,2]

Bisphosphonates can lower this risk substantially. Most clinical trials of bisphosphonates that measured fracture prevention have documented reductions in fracture rates, though it should be noted that the majority were less than 4 years in duration. Depending on the drug, skeletal site, and the unique risk factors of any individual, reductions in the following ranges are reported[2]:

  • Vertebral fractures: 40%-70%;

  • Hip fractures: 20%-50%; and

  • Other nonvertebral fractures: 15%-39%.

A review of extension trials looking at prolonged use of bisphosphonates (6-10 years) conducted by the US Food and Drug Administration (FDA) found that alendronate, risedronate, and zoledronic acid all maintained gains in bone mineral density (BMD) of the femoral neck over 5 years. These agents also promoted continued improvement in BMD in the lumbar spine during this treatment period.[3] After discontinuation, BMD in the femoral neck declined modestly for 1-2 years and then stabilized; BMD in the lumbar spine continued to increase.

However, as the FDA pointed out in their analysis, fracture is a much more patient-centered and clinically relevant outcome than BMD. The extension trials were generally underpowered to detect this outcome over the long term. Fracture rates were fairly similar in patients treated with bisphosphonates and placebo during the extension studies. Moreover, there is little data to identify which patients might benefit most from prolonged treatment with bisphosphonates.

While the long-term benefit associated with bisphosphonates is questionable, there are certain serious risks associated with therapy. Esophagitis with oral bisphosphonates has been well-understood for years. It is usually avoidable through precautions by the patient in taking the drug.

Bisphosphonates should be avoided among patients with an eGFR less than 30 mL/min/m2, and our current patient does not meet this level of severity.

Osteonecrosis of the jaw is very rare among patients receiving bisphosphonates for postmenopausal osteoporosis, adding up to possibly several cases per 100,000 patient-years of treatment.[4] Subtrochanteric atypical fractures of the femur in patients taking bisphosphonates is also highly unlikely and counterbalanced by the known benefits for vertebral and nonvertebral fractures associated with these agents. In addition, this risk declines rapidly after withdrawal of the drug.[4]

Nonetheless, these side effects are severe and can ruin a patient's quality of life. So it is worth it to consider suspending bisphosphonate therapy among women with a low BMD and few, if any, other risk factors for fracture. Women with a previous history of fragility fracture should most likely receive treatment beyond 5 years. Women with other risk factors for fracture (prolonged use of steroids, low body weight, smoking, high fall risk) should be considered for prolonged therapy as well.

I am also concerned regarding the patient's desire to reduce her total medication load. What if she stops her treatments for hypertension or diabetes instead of osteoporosis? The consequences could potentially be more damaging. Understanding her agenda in this regard is critical.

In line with that patient-centered objective of lowering pill burden, you'll note I did not suggest switching her to romosozumab, a newly approved, first in its class agent for the treatment of osteoporosis. This drug is approved for use in postmenopausal women at high risk for fracture. Its exact place in the osteoporosis armamentarium is yet to be determined. It was initially rejected by the FDA because of questions about its cardiovascular safety. Those questions, plus the fact that this patient has no history of previous fracture, make romosozumab less attractive as a treatment option in this case. And let's not forget that, as is the case for many new drugs only available as patented agents, this new drug is going to be expensive and potentially not covered under many insurance plans.

What is your best practice? What would you do in this case? Please provide comments, and I will share a reasonable algorithm focused on long-term treatment with bisphosphonates, in line with recent guidelines, in approximately 1 month.

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