Orthopaedic journals and OrthoBuzz have devoted ample space to the apparent association between long-term bisphosphonate use and atypical femoral fractures. The latest insight into this relationship comes from Lim et al. in the December 7, 2016 edition of The Journal of Bone & Joint Surgery. The authors analyzed factors associated with delayed union or nonunion after surgical treatment of 109 atypical femoral fractures in patients who had an average 7.4-year history of bisphosphonate use.
Here’s what Lim et al. found among the 30% of patients studied who had delayed union or nonunion, relative to the 70% who had successful healing:
- Patient Factors: Patients who had problematic fracture healing had a higher BMI, longer duration of bisphosphonate exposure, and higher rate of prodromal symptoms.
- Radiographic/Fracture Factors: Supra-isthmic/subtrochanteric fracture location, femoral bowing of ≥10° in the coronal plane, and a lateral/medial cortical thickness ratio of ≥1.4 were predictive of problematic healing.
- Operative Factors: Iatrogenic cortical breakage around the fracture site and a ratio of ≥0.2 between the remaining gap and the cortical thickness on the anterior and lateral sides of the fracture site were associated with problematic fracture healing.
In an accompanying commentary on the study, Edward J. Harvey, MD notes that most trauma surgeons use cephalomedullary nails to treat atypical femoral fractures, but that “it is impossible from this manuscript to determine what effect the fixation technique had on the outcomes.” He therefore recommends a larger multicenter study using standardized therapy and bone biopsies to further improve understanding in this area.
We posted our first “Case Connections” article about bisphosphonate-related atypical femoral fractures (AFFs) one year ago. Since then, JBJS Case Connector has published three additional case reports on the same topic, suggesting that it’s time for a revisit. These three recent cases demonstrate that AFFs can occur despite prophylactic intramedullary (IM) nailing of an at-risk femur, that AFFs can present as periprosthetic fractures, and that men taking bisphosphonates—not just women—can experience AFFs.
Physicians worldwide frequently prescribe bisphosphonates such as alendronate (Fosamax) and ibandronate (Boniva) to treat osteoporosis and prevent fragility fractures. Unfortunately, long-term bisphosphonate use has been linked to an increased risk of atypical femoral fractures. In the March 3, 2015 edition of JBJS Reviews, Blood et al. offer some guidance on how to prevent such fractures.
The authors note that prodromal thigh pain and a radiolucent line on X-rays of patients with a history of chronic bisphosphonate use are strong indicators of an impending fracture. Among bisphosphonate users who have an incomplete fracture with little or no pain, the authors recommend a trial of discontinued bisphosphonates, protected weight-bearing, calcium and vitamin-D supplementation, and possible teriparatide (Forteo) therapy. They add that prophylactic fixation should be considered if there is no radiographic or symptomatic improvement after two to three months of that conservative approach. Blood et al. further recommend that patients at high risk for atypical femoral fracture, should consider discontinuing bisphosphonate therapy after five years of continuous use. They also encourage orthopaedists to assess the contralateral femur for signs of impending fracture in patients who have already had an atypical femoral fracture.
The recommendations by Blood et al. notwithstanding, we should stress that the absolute risk of atypical femoral fractures fractures is low (3.2 to 50 cases per 100,000 person-years among short-term bisphosphonate users and about 100 cases per 100,000 person-years among long-term users). Consequently, for most people with osteoporosis, the proven fragility-fracture risk-reduction benefits of bisphosphonates outweigh the risks of atypical femoral fracture.
In December 1996, a group of investigators reported the results of the Fracture Intervention Trial, a randomized controlled trial that compared the effect of alendronate plus calcium or calcium supplementation alone on the risk of fractures in women who already had evidence of vertebral fractures. The results showed that in patients managed with alendronate, there was a 51% decrease in the risk of hip fractures, a 46% decrease in the risk of vertebral fractures, and a 44% decrease in the risk of distal radial fractures when compared with patients managed with calcium alone. These results, as well as those from several other reports, supported the regulatory approval of alendronate (marketed under the trade name Fosamax) for the treatment of postmenopausal osteoporosis in the United States and many countries abroad. Alendronate thus became the first drug in a class of compounds known as the nitrogen-containing bisphosphonates to demonstrate these beneficial effects.
Approximately a decade later, and after millions of patients had undergone treatment, some disturbing reports suggested a potential suppression of bone turnover in association with long-term alendronate therapy. Bone biopsies from selected patients suggested diminished kinetic indices of bone formation. This was believed to lead to increased susceptibility to fracture and delayed healing of nonspinal fractures such as fractures of the femoral shaft. Additional reports suggested the occurrence of insufficiency or low-energy fractures in patients who used alendronate for several years. While epidemiological findings suggested that these fractures are very rare even among women who have been managed with bisphosphonates for as long as a decade, the American Society for Bone and Mineral Research convened a task force to understand the pathophysiology of these atypical fractures and to gain further information on the association of these fractures with bisphosphonates. The term “atypical femoral fracture” was adopted to distinguish this type of fracture as a unique entity in order to avoid a suggestion that it is exclusively associated with bisphosphonate use.
Atypical femoral fractures can occur anywhere along the shaft of the femur from just distal to the lesser trochanter to just proximal to the supracondylar flare of the distal femoral metaphysis. They may be transverse or short-oblique in configuration, are typically noncomminuted or minimally comminuted, are associated with minimal or no trauma, and may be associated with a medial spike. Incomplete fractures may involve only the lateral cortex. Because these fractures occur as a result of brittle failure while most osteoporotic patients show some ductility with deformation prior to failure, atypical femoral fractures most likely occur through bone that has undergone alterations in its mechanical and material properties. This further supports the notion that these fractures are unique and distinct from typical osteoporotic fractures of the femur.
While current evidence suggests a strong relationship between the use of bisphosphonates and the genesis of atypical femoral fractures, we now know that denosumab, a drug that inhibits osteoclastogenesis but is unrelated to the bisphosphonates, also may be associated with these fractures. Moreover, some patients who have never taken bisphosphonates or denosumab have presented with what appear to be atypical femoral fractures. Thus, atypical femoral fractures are not exclusive to patients who use osteoclast-inhibiting drugs, and this presents a more complicated picture regarding the etiology of this unique type of fracture.
In the March 2015 issue of JBJS Reviews, Blood et al. summarize current thinking regarding the evaluation and treatment of atypical femoral fractures. The authors note that these fractures can be treated successfully with intramedullary nailing and discontinuation of bisphosphonate therapy. However, there is a potential for a delay in healing. Prodromal thigh pain and radiographic evidence of a radiolucent line in patients with a history of atypical femoral fracture or chronic bisphosphonate use are strong indicators of impending fracture. In these patients, prophylactic fixation should be considered. In addition, patients with prodromal thigh pain who are receiving chronic bisphosphonate therapy but do not have radiographic evidence of incomplete fracture require further workup and may benefit from magnetic resonance imaging. For patients who have incomplete fractures and no pain, the authors recommend a trial of conservative therapy, including protected weight-bearing, discontinuation of bisphosphonate therapy, and supplementation with calcium and vitamin D (800 to 1000 IU) per day. While no recommendation currently exists regarding the duration of bisphosphonate therapy, most experts recommend discontinuation after five years. Moreover, as bisphosphonates are not the only class of compounds that may be associated with these fractures, further information is needed in order to make informed decisions regarding the use of specific drugs and the duration of their use. While treatment of atypical femoral fractures with an anabolic therapy such as parathyroid hormone has been proposed, there are no definitive data to support this suggestion at this time.
The use of bisphosphonates and denosumab to treat osteoporosis represents a major step forward. However, it is possible that there are specific subsets of patients who are more sensitive to pharmacological suppression of bone remodeling and who may not be candidates for this kind of therapy. Further investigation is required to understand the safety of prolonged use of osteoclast-inhibiting drugs.
Thomas A. Einhorn, MD, Editor
Click here for another OrthoBuzz post about this JBJS Reviews article.
BMJ recently published two studies of interest to orthopaedists:
- After analyzing data from more than 200 cardiovascular, orthopaedic, and neurologic devices approved in both the US and European Union (EU), Hwang et al. found that those approved in the EU first were nearly three times as likely to trigger a safety alert or experience a recall than those first approved in the US. Finding further that trial results were published for fewer than half of approved devices considered “major innovations,” the authors call for “greater regulatory transparency” so physicians and patients can make better-informed decisions. Interestingly, Figure 2 in this study showed that the FDA approval time for orthopaedic devices was faster than ortho-device approval times in the EU. However, a JBJS study earlier this year found that devices approved via the FDA’s “quick” 510(k) process were 11.5 times more likely to be recalled than those cleared through the longer and more stringent FDA pathway.
- In the second BMJ article, a registry-based case-control study, Abrahamsen et al. found that the long-term use of the bisphosphonate alendronate does not increase the risk for atypical femoral fractures (either subtrochanteric or femoral shaft), while protecting against hip fractures. After applying some sophisticated statistical analyses, the authors estimated that 38 patients with ≥5 years of alendronate adherence would need to be treated for an additional 5 years to prevent one hip fracture, while 1449 similar patients would need to be treated to cause an atypical femoral fracture. Click here for more OrthoBuzz coverage of the relationship between bisphosphonates and atypical femoral fractures.