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6 June 2011
Two recent observational studies (one in Canada and another in Sweden) have reported an increased risk of atypical femoral fractures in older women taking bisphosphonates, which increases with duration of use. However, in absolute terms, this risk is low. Following a Europe-wide review of the evidence on this adverse effect, the European Medicines Agency (EMA) concluded that whilst atypical femoral fractures are likely to be a class effect of bisphosphonates, they occur only rarely, and the benefits of bisphosphonates continue to outweigh the risks. The EMA recommended that the prescribing information for all bisphosphonate-containing medicines is updated to include this risk.
Level of evidence:
Level 2 (limited quality patient-oriented evidence) according to the SORT criteria.
Action
Healthcare professionals, and patients taking bisphosphonates, should follow the recommendations issued by the EMA in April 2011, noting that the benefits of bisphosphonates continue to outweigh the risks. Doctors should be aware that atypical fractures may occur rarely in the femur, especially after long-term use. If an atypical fracture is suspected in one leg then the other leg should be examined. Doctors who are prescribing these medicines for the prevention or treatment of osteoporosis should regularly review the need for continued treatment, especially after five or more years of use. Patients who are taking bisphosphonate-containing medicines need to be aware of the risk of atypical fracture of the thigh bone. They should report to their doctor any pain, weakness or discomfort in the thigh or groin area, as this may be an indication of a possible fracture. In addition, healthcare professionals should continue to follow the detailed guidance, issued by the MHRA on all other safety considerations with bisphosphonates.
Note: – this was the subject of a Drug Safety Update bulletin published by the MHRA in June 2011.
What is the background to this?
Bisphosphonates are widely prescribed for the prevention and treatment of bone-related conditions, in particular osteoporosis (see NICE Technology Appraisal Guidance 160 and 161). In 2008, following a Europe-wide review, the Committee for Medicinal Products for Human Use’s (CHMP’s) Pharmacovigilance Working Party of the EMA noted that alendronic acid was associated with an increased risk of atypical fracture of the femur that developed with low or no trauma. This led to specific recommendations from the MHRA in 2009, that patients taking alendronic acid, who develop atypical stress fractures, should discontinue the drug and receive no further bisphosphonate treatment unless the benefits of continued treatment are thought to clearly outweigh the risks to the individual. The product information for alendronic acid was updated to include a warning about this risk. However, limited data were available for the other bisphosphonates at this time. Following the availability of further data, in September 2010, the MHRA asked the CHMP to conduct a further review on all bisphosphonate-containing medicines. Recently, two epidemiological studies assessing this risk have been published in peer-reviewed journals.
Note: – this was the subject of a Drug Safety Update bulletin published by the MHRA in June 2011.
What do these studies claim?
The first study, was a Canadian population-based, nested case-control study of 205,466 women aged >68 years who started treatment with an oral bisphosphonate (alendronate, risedronate or etidronate). Of these, 716 women had a subtrochanteric or femoral shaft fracture and 9,723 women had a typical osteoporotic fracture (femoral neck or intertrochanteric region). Use of bisphosphonates for 5 years or longer more than doubled the risk of hospitalisation for subtrochanteric or femoral shaft fracture compared with transient (less than 100 days) use of bisphosphonates (the primary analysis; adjusted odds ratio (OR), 2.74; 95%CI 1.25 to 6.02). However, the absolute risk appears to be low; from 52,595 women with at least 5 years of bisphosphonate use, hospitalisation for these fractures occurred in 71 women (0.13%) during the subsequent year and 117 (0.22%) within two years.
The second study was a Swedish nationwide cohort study and a population-based case-control study which identified 12,777 women aged >55 years who had a facture of the femur in 2008, 59 of whom were classed as having atypical subtrochanteric or shaft fractures on x-ray. The age adjusted relative risk of atypical fracture with any use of bisphosphonates was 47.3 (95%CI 25.6 to 87.3), equivalent to an absolute risk increase of 5 cases per 10,000 patient-years (95% CI, 4 to 7) between users and non-users of bisphosphonates. However, again, the absolute risk is low, with the number needed to harm (NNH) for one case of atypical fracture estimated to be 2,000 per year of bisphosphonate use. In the case-control study, the multivariable adjusted OR for atypical fracture with bisphosphonate use (alendronate or risedronate) compared with no use was 33.3 (95%CI 14.3 to 77.8). This risk increased with duration of bisphosphonate use, but it fell after bisphosphonate withdrawal. No atypical fractures were associated with etidronate but few women were on this drug.
So what?
Both of these studies suggest that taking bisphosphonates is associated with an increased risk of atypical femoral fractures, which increases with duration of exposure. However, the absolute risk appears to be low and it is important to consider this in the context of the beneficial effects of bisphosphonates in osteoporosis. For example, the Cochrane review of alendronate for the primary and secondary prevention of osteoporotic fractures in postmenopausal women found statistically significant reductions in primary vertebral fractures and secondary vertebral, non-vertebral, hip and wrist fractures. The number needed to treat (NNT) with alendronate 10mg daily over 1 to 4 years to prevent one osteoporotic fracture ranged from 18 to 148 depending on fracture type and baseline risk. It is important to note that the absolute benefit of bisphosphonate treatment depends on a person’s baseline risk of osteoporotic fracture, and may be greater in those at highest risk. Further studies are needed to better understand the prognosis of subtrochanteric or femoral shaft fractures and to identify which patients taking bisphosphonates over a prolonged period are at the greatest risk.
These two studies have several limitations, particularly the observational nature of the data, which introduces several confounding factors that cannot easily be accounted for, such as differences in lifestyle. However, the conclusions from these studies are broadly similar to those made by the CHMP of the EMA in April 2011. The CHMP concluded that atypical femoral fractures are likely to be a class effect of bisphosphonates but they occur only rarely, and the benefits of bisphosphonates continue to outweigh the risks. The number of reports of atypical fractures of the femur in users of bisphosphonates had increased since the 2008 review. Therefore, the EMA recommended that the product information for all bisphosphonates should be updated to include a warning about this risk, and to advise doctors to periodically review bisphosphonates used in osteoporosis, particularly after five years or more.
Healthcare professionals, and patients taking bisphosphonates, should follow the specific recommendations issued by the EMA regarding bisphosphonate use (see Action). In addition, healthcare professionals should continue to follow the detailed guidance, issued by the MHRA on all other safety considerations with bisphosphonates. The safety of all bisphosphonates will continue to be monitored closely by the MHRA.
Study details –
Park-Wyllie LY, et al. Bisphosphonate use and the risk of subtrochanteric or femoral shaft fractures in older women. JAMA 2011;305:783–9
More information on bisphosphonates can be found in the osteoporosis section of the NPC website.
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