LAS VEGAS - When bisphosphonates are used appropriately, the benefit with respect to fracture reduction outweighs the risk of an atypical femoral fracture, according to the American Society for Bone and Mineral Research task force.
The decision to prescribe bisphosphonates depends on several factors, including dual-energy x-ray absorptiometry (DXA) results and patient factors, and consideration for a drug holiday is warranted in each patient’s care, Dr. Marcy B. Bolster of the Harvard Medical School and director of the rheumatology fellowship training program at Massachusetts General Hospital, both in Boston, said at the annual Perspectives in Rheumatic Diseases conference.
The ASBMR task force concluded, based on a review of the available literature, that a causal relationship between bisphosphonates and atypical femoral fractures has not been established; atypical femoral fractures also occur in patients who have not received bisphosphonates, as well as in some patients taking denosumab, but the task force noted that there is some evidence from radiograph-based studies to suggest a strong relationship between bisphosphonate use and atypical femoral fractures. Studies suggest that longer duration of therapy may contribute to the risk of atypical femoral fractures, Dr. Bolster said.
For example, in a Swedish study involving nearly 13,000 women, 1,271 subtrochanteric fractures had occurred and 59 of these were deemed atypical. Bisphosphonates were used by 78% of the case patients, compared with 10% of 263 controls who had had subtrochanteric fractures that did not have the characteristics of the atypical femoral fractures. The odds ratio for an atypical fracture was 1.3/100 daily doses, and in those who used bisphosphonates for 2-2.9 years, the adjusted odds ratio for a fracture was 61.7.
Further, after drug discontinuation, the odds ratio decreased by 70% per year since last use.
The number needed to harm (one atypical femoral fracture) was 2,000 per year (N. Engl. J. Med 2011;364:1728-37).
Most atypical fractures associated with bisphosphonate use in that study occurred within 1 year of the last prescription, and the risk reduction after stopping was similar whether treatment duration was less than or more than 2 years. Also, there was no increased risk of atypical femoral fractures in patients taking glucocorticoids or proton pump inhibitors, and the atypical fracture risk in bisphosphonate users did not differ based on age younger or older than 85 years.
In a Kaiser Permanente study of more than 1.8 million patients aged 45 years or older, 142 had atypical femoral fractures. Most (137) were women, 28 experienced bilateral fractures, and 128 (90%) had bisphosphonate exposure ranging from 1 month to 13 years (mean, 5.5 years) prior to the fracture.
Dr. Marcy B. Bolster
Age-adjusted incidence rates were 1.78/100,000 patient-years for those with up to 1.9 years of bisphosphonate use, and 113.1/100,000 patient-years in those with 8-9.9 years of use (J. Bone Miner. Res. 2012 [doi:10.1002/jbmr.1719]).
Increased rates of atypical femoral fractures occurred after 3-4 years of exposure – and more so with 6-10 years of exposure.
The findings beg the question of how long is long enough when it comes to bisphosphonate therapy for osteoporosis, Dr. Bolster said.
First, it is important to reassess the use of bisphosphonates for low bone mass. It has been well-established that patients with osteoporosis (a T score less than –2.5 or presence of a fragility fracture) warrant treatment. The National Osteoporosis Foundation guidelines have changed, however, for those with osteopenia, such that, previously, treatment was initiated in patients with osteopenia (a T score less than –2.0 or a T score less than –1.5 plus one risk factor), and it is now recommended that treatment decisions for patients with osteopenia incorporate the World Health Organization (WHO) FRAX tool to aid in determining which patients with osteopenia are at high risk for fracture. Treatment decisions are based on the presence of increased risk for fracture, she said.
Consider discontinuation of bisphosphonates in patients with osteopenia or in whom fracture risk is not determined to be increased, Dr. Bolster advised.
Given potential adverse effects, it is important to treat only those patients who are at increased risk for fracture. In those patients who warrant therapy, the duration of therapy and a drug holiday should also be considered because of the concern for potential risks associated with prolonged bisphosphonate therapy, she said.
If fracture risk is mild, treatment for about 5 years is warranted, and then bisphosphonates should be discontinued until bone mineral density decreases significantly (generally about 3-5 years) or until a fracture occurs.
For moderately increased fracture risk, published recommendations call for treating for 5-10 years, then discontinuing bisphosphonates for 2-3 years (or less if bone mineral density decreases or fracture occurs).