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Latest results add to concern about atypical bisphosphonate-related femur fractures
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Bisphosphonates, a class of drugs developed to prevent the sometimes devastating fractures associated with osteoporosis, may be associated with atypical femur fractures in certain patients, based on several recent studies. With these findings, a clearer picture has emerged of the women and men taking bisphosphonates who are at the greatest risk for these atypical femoral fractures. But, more investigations are needed.
Physicians and patients now have more information about early signs of these fractures, such as localized thigh pain. Clinicians and researchers are also getting a better grasp on the role that the length of time a patient takes the medication has in atypical femoral fracture risk. Longer duration of bisphosphonate use — beyond 5 years in some studies — is reportedly highly associated with these fractures.
Per Aspenberg, MD, PhD, of Linköping University in Sweden, studied the relationship between bisphosphonate use and atypical femur fractures in a single county within Sweden and later in a nationwide study in Sweden published in 2011. Two key findings came out of his investigations.
“The risk of a stress fracture or so-called ‘atypical fracture’ decreases quickly when you have stopped taking the drug. The second thing is the role of corticosteroids and other drugs that people have been talking about could not be confirmed from our most recent study,” he told Orthopaedics Today Europe.
Although evidence for how to proceed in these cases remains limited concerning modifying or possibly discontinuing the osteoporosis medicine taken, but there is consensus the fractures should be treated with intramedullary (IM) nailing, even if they are incomplete.
Per Aspenberg, MD, PhD, noted that stopping bisphosphonates after a few years dramatically decreases the risk of atypical fractures.
Image: Peter Karlsson, Svarteld
Kristina Åkesson, MD, PhD, described the atypical femur fractures reported with bisphosphonate use as similar to stress fractures — the kind of fracture that is usually associated with bone that is loaded with not enough time to repair itself. In these bisphosphonate-related fractures, she said it is thought the proximal area of the femur that is stressed in these patients either has an impaired bone renewal mechanism or the bone repair is somehow impeded there.
Kristina Åkesson
“That stressed area in bone is in the proximal femur because it is curved and that is probably why we see it more there. But the possibility to have these fractures at other sites cannot be ruled out,” Åkesson, of Malmö, Sweden, told Orthopaedics Today Europe.
According to Karsten E. Dreinhöfer, MD, founding member of the Fragility Fracture Network, “There are a few case reports on atypical humerus fractures and a few more on atypical tibia fractures. However, there are still conflicting discussions if these are related to prolonged bisphosphonate use.”
Linked to drug duration
The main difficulty is definitively linking the atypical femur fractures in patients with osteoporotic bone with long-term bisphosphonate use, particularly beyond 3 years to 5 years, especially since bisphosphonates only reduce the risk of fracture in those individuals with osteoporosis by about 50%, Åkesson said. However, she noted, radiographs are invaluable for determining whether the fracture seen is an atypical “stress” fracture.
“You need to look at the X-rays,” she said, noting the best studies into this phenomenon, published by Aspenberg and colleagues in 2011, and Dell and colleagues this year in Bone and Mineral Research, for example, included radiographic findings. Although other large, notable studies in this area have been published without such imaging data, Åkesson said.
Sources who spoke with Orthopaedics Today Europe described the bisphosphonate-related atypical femur fractures as transverse proximal subtrochanteric fractures and said they are usually, but not always, preceded by local thigh pain that lasts for a few weeks before the fracture occurs.
Signs to predict a fracture
There are other signs that help clarify if the fracture can be classified as atypical, some of which are outlined in the American Society for Bone Mineral Research criteria for these fractures and often used in related studies.
“There is radiographic evidence of thickening of the cortex. One out of four [patients] suffers a contralateral fracture in the next 2 years” after the initial fracture, Dreinhöfer, an Orthopaedics Today Europe Editorial Board member, said. “The majority have taken bisphosphonates for 5 years or longer.”
A study of bisphosphonate-related fractures published in October 2012 found the mean duration of bisphosphonate treatment in the 81 patients studied was 9.5 years.
Raphael R.P. Meier, MD, and colleagues, of Geneva, studied hospitalized men and women who took bisphosphonates and had fractures afterwards. He told Orthopaedics Today Europe the risk of sustaining an atypical fracture compared to a classic fracture increased considerably over time. The odds ratios for atypical fractures were 47 for 2 years to 5 years, 117 for 5 years to 9 years, and 176 for more than 9 years of treatment, compared with no use.
Of the 477 patients aged 50 years or older that Meier and colleagues included in their study, 39 patients presented with a pattern that corresponds to atypical femoral fractures.
“We always have to consider that the fractures are rare. But, maybe since they are rare, and if we limit the [bisphosphonate] treatment, [then] you can avoid a lot of fractures of the rare type and end up with very few fractures overall,” Meier said.
All of the patients with the atypical fractures in Meier’s study, which included three men, were treated with IM nailing and bisphosphonates were discontinued. The postoperative course and the rest of the follow-up for the study cohort were typical, he said.
A drug switch?
Stopping bisphosphonates all together or taking them intermittently is as of yet unproven as a therapeutic approach or even a way to prevent atypical fractures. Dreinhöfer noted that a change to another drug, such as teriparatide or denosumab, should be discussed with the patient so that an informed decision can be made.
Karsten E. Dreinhöfer
According to Åkesson, “We don’t know exactly how we should select those who should not have the drug. My personal view is that it seems more common in women who have low bone density in the spine, but high or normal [density] in the hip. That’s my impression.
“We are still thinking it is not common in the very elderly women…so we are still prescribing bisphosphonates in elderly [patients] without necessarily doing DEXA,” she said.
Follow bisphosphonate indications
Aspenberg said, “One has to act on the data we have, and the data we have suggest that the risk of atypical fracture goes down rather quickly when you stop treatment and you know the protective effect lasts for quite some time. I am not an osteoporosis specialist. I am an orthopaedic surgeon, but one conclusion is very clear, and that is you should not prescribe bisphosphonates without a good indication. The most common indication is osteoporosis.”
In Sweden, osteoporosis is defined by bone density measurements and clinicians use the FRAX tool to assess patients, he said.
Aspenberg and colleagues have continued to study the mechanisms behind these atypical fractures, as have many other groups worldwide. Until more is known about the problem of atypical fractures, “the sign patients should be looking for is thigh pain. The sign radiologists should be looking for is cortical thickening. The sign surgeons should be looking for is the first fracture, indicating a high risk for a contralateral fracture,” Dreinhöfer said.
This approach will help ensure that more patients with osteoporosis are diagnosed and treated after the first femoral fracture occurs, he said.
According to Meier, much more needs to be learned about who is at greatest risk for atypical fractures with bisphosphonates. – by Susan M. Rapp
References:
Meier RP. Arch Intern Med. 2012;172:930-936.For more information:
Disclosures: Åkesson receives lecture fees, is on the advisory board or is a principal investigator for Merck, Amgen, Takeda and Eli Lilly. Aspenberg has shares in AdBio and receives various research support from Eli Lilly and Amgen. Dreinhöfer has received research funding and/or speaker honoraria from most pharmaceutical companies that market osteoporosis treatments. Meier has no relevant financial disclosures.
Should regulations be imposed to restrict the duration of bisphosphonate use due to the atypical femur fractures now being reported? Why?
Consider a bisphosphonate ‘holiday’
Given the difference in risk-benefit profiles of patients treated with bisphosphonates, I could argue on both the point and counterpoint side of this issue. In low to moderate risk patients for the typical hip and other osteoporosis-related fractures, I would strongly argue that 3 years to 5 years should be the point where a clinical decision should be made and in the majority of patients I would consider a drug “holiday” for 2 years with re-evaluation after the 2 year drug holiday.
Richard M. Dell
On the other hand, in patients with high risk for typical hip and other osteoporosis-related fractures, I would strongly argue that at 3 years to 5 years a clinical decision should be made. But in many patients I would continue using bisphosphonates while in other patients I would consider a drug holiday for 2 years with re-evaluation after the 2 year drug holiday.
The duration of treatment with a bisphosphonate appears to be a major risk factor for atypical femur fractures, but other factors also come into play such as race, sex, other medications (steroids), and other comorbidities, such as inflammatory arthritides. However of all risk factors, a prior atypical femur fracture on the contralateral femur is the highest risk factor and when a stress reaction or frank complete atypical femur fracture is present I strongly believe that the bisphosphonate should be discontinued immediately.
We are still learning a great deal about the effect of bisphosphonates on bone. We have strong evidence that bisphosphonates have led to a dramatic reduction in the rate of hip and other osteoporosis-related fractures. However, we also have growing evidence that bisphosphonates play some role in atypical femur fractures. The overall risk-benefit ratio continues to favor the use of bisphosphonates. We are rapidly gaining better knowledge of bisphosphonate use in terms of who to treat, when to start treatment, how long to treat, when to discontinue treatment if symptoms occur indicating stress reaction to bone, and how to better assess the patients’ overall risk-benefit ratio.
Richard M. Dell, MD, is a U.S. orthopaedic surgeon who has been with Southern California Kaiser Permanente for 25 years.
Disclosure: Dell has no relevant financial disclosures.
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Regulations are inappropriate
Mark Edwards
Cyrus Cooper
During the past few years, evidence has emerged that the long-term use of bisphosphonates is attended by an increased risk of atypical femoral diaphyseal fractures although their occurrence is rare. The efficacy of bisphosphonates has been well demonstrated up to 3 years to 5 years and thereafter investigators have compared the outcomes obtained by continuing with therapy or placebo. Overall, fracture rates tend to be similar over this period although vertebral fractures occur more frequently in the placebo group in some studies. Attempts have been made to quantify the relative benefits of treatment, in terms of fragility fracture prevention, against the risk of atypical fractures. Although estimates vary widely, the former tend to outweigh the latter by an order of magnitude.
From the available data, it seems reasonable to consider a drug “holiday” in those patients that are not deemed high risk either by virtue of previous hip or spine fractures or bone density that is either reducing despite treatment or in the osteoporotic range. However, at present we lack evidence to confirm the efficacy of such a drug holiday in resetting the clock on bone turnover suppression, thought to be the possible underlying cause of these atypical fractures. In patients who remain at high risk of fragility fracture, an alternative non-bisphosphonate therapy might seem the most appropriate choice.
Hence, regulations to restrict bisphosphonate use would not seem appropriate for two main reasons. Firstly, we do not have evidence to show that long-term bisphosphonate therapy is more likely to confer risk to the patient than benefit, and thus it cannot be deemed in all cases to be inappropriate. Secondly, if bisphosphonate therapy is curtailed, then the evidence is not available to guide alternative best practice.
Mark Edwards, BSc, MBChB, MRCP, is Clinical Research Fellow at MRC Lifecourse Epidemiology Unit in Southampton, United Kingdom.
Cyrus Cooper, MA, DM, FRCP, FFPH, FmedSci, is Director and Professor of Rheumatology, MRC Lifecourse Epidemiology Unit; Vice Dean, Faculty of Medicine, University of Southampton; and Professor of Musculoskeletal Science, University of Oxford; United Kingdom.
Disclosures: Edwards has no relevant financial disclosures. Cooper has received honoraria and consulting fees from Amgen, Eli Lilly, Medtronic, Merck, Novartis, and Servier.