Background
Bisphosphonate-associated femur fractures have been well described but the preoperative patient factors, treatment modalities, and complications of treatment are unclear.

Bisphosphonate-associated Femur Fractures Have High Complication Rates with Operative Fixation

Bisphosphonates (BPs) are highly effective in treating osteoporosis and reducing hip, vertebral, and other fractures by as much as 50% to 70%. However, since 2006, atypical femur fractures (AFFs) emerged as potential side effects of BPs and other treatments. These fractures have unusual radiologic features and occur with little trauma. Public concern has led to a >50% decrease in BP usage. AFFs are rare: for each AFF, >1200 fractures, including 135 hip fractures, are prevented. Case definition criteria were updated by the American Society of Bone and Mineral Research in 2014. Many epidemiologic studies have been reported, and although methodologically challenging, generally support a BP-AFF association. However, the magnitude of the association between BPs and AFFs is uncertain: estimates of relative risk for AFFs among BP users vs nonusers range from 1 to 65 with a meta-analysis estimate of 1.7. Although mechanistic studies have proposed several hypotheses explaining how BPs might decrease bone strength, AFF pathogenesis remains uncertain and cannot explain the paradox of efficacy of reduction of common fractures while increasing risk for rare fractures at one site. There are several consistent risk factors, including Asian race (in North America), femoral bowing, and glucocorticoid use, whereas others remain unclear. Consensus is emerging about strategies to prevent AFFs in BP users (including drug holidays after 5 years' use in some patients). In conclusion, AFFs can be devastating, but even under the most pessimistic assumptions, the benefit/risk ratio is highly positive for BPs, particularly during 3 to 5 years of use. As understanding of AFFs increases, it is becoming increasingly possible to maximize BP benefits while minimizing AFF risk.

Atypical Femur Fractures: Review of Epidemiology, Relationship to Bisphosphonates, Prevention, and Clinical Management.

Background
Several studies have identified a specific fracture in the proximal diaphysis of the femur in patients treated with bisphosphonates. The fractures typically are sustained after a low-energy mechanism with the presence of an existing characteristic stress fracture. However, it is unclear whether these patients are best treated nonoperatively or operatively.

Nonoperative versus Prophylactic Treatment of Bisphosphonate-associated Femoral Stress Fractures

Background: In the United States, hip fracture rates have declined by 30% coincident with bisphosphonate use. However, bisphosphonates are associated with sporadic cases of atypical femoral fracture. Atypical femoral fractures are usually atraumatic, may be bilateral, are occasionally preceded by prodromal thigh pain, and may have delayed fracture-healing. This study assessed the occurrence of bisphosphonate-associated nonhealing femoral fractures through a review of data from the U.S. FDA (Food and Drug Administration) Adverse Event Reporting System (FAERS) (1996 to 2011), published case reports, and international safety efforts.

Methods: We analyzed the FAERS database with use of the proportional reporting ratio (PRR) and empiric Bayesian geometric mean (EBGM) techniques to assess whether a safety signal existed. Additionally, we conducted a systematic literature review (1990 to February 2012).

Results: The analysis of the FAERS database indicated a PRR of 4.51 (95% confidence interval [CI], 3.44 to 5.92) for bisphosphonate use and nonhealing femoral fractures. Most cases (n = 317) were attributed to use of alendronate (PRR = 3.32; 95% CI, 2.71 to 4.17). In 2008, international safety agencies issued warnings and required label changes. In 2010, the FDA issued a safety notification, and the American Society for Bone and Mineral Research (ASBMR) issued recommendations about bisphosphonate-associated atypical femoral fractures.

Conclusions: Nonhealing femoral fractures are unusual adverse drug reactions associated with bisphosphonate use, as up to 26% of published cases of atypical femoral fractures exhibited delayed healing or nonhealing.

/pdf/bisphosphonates-and-nonhealing-femoral-fractures-analysis-of-128m8a4764.pdf

Bisphosphonates and nonhealing femoral fractures: analysis of the FDA Adverse Event Reporting System (FAERS) and international safety efforts: a systematic review from the Research on Adverse Drug Events And Reports (RADAR) project.

Aims Treatment guidelines for atypical femoral fractures associated
with bisphosphonates have not been established. We conducted a systematic
review of the treatment of atypical femoral fractures first, to
evaluate the outcomes of surgical fixation of complete atypical fractures
and secondly, to assess whether prophylactic surgery is necessary
for incomplete atypical fractures. Materials and Methods Case reports and series were identified from the PubMed database
and were included if they described the treatment of atypical femoral
fractures. In total, 77 publications met our inclusion criteria
and 733 patients with 834 atypical complete or incomplete femoral fractures
were identified. Results For complete fractures, internal fixation was predominantly achieved
by intramedullary nailing. The mean time to healing post-operatively
was 7.3 months (2 to 31). Revision surgery for nonunion or implant
failure was needed in 77 fractures (12.6%). A greater percentage
of fractures treated with plate fixation (31.3%) required revision
surgery than those treated with intramedullary nailing (12.9%) (p
 Non-operative treatment of incomplete fractures failed and surgery
was eventually needed in nearly half of the patients (47%), whereas
prophylactic surgery was successful and achieved a 97% rate of healing. Conclusion Intramedullary nailing is the first-line treatment for a complete
fracture, although the risk of delayed healing and revision surgery
seems to be higher than with a typical femoral fracture. Non-operative
treatment does not appear to be a reliable way of treating an incomplete
fracture: prophylactic intramedullary nailing should be considered
if the patient is in intractable pain. Radiographs of the opposite
side should be obtained routinely looking for an asymptomatic fracture.
Bisphosphonates must be discontinued but ongoing metabolic management
in the form of calcium and/or vitamin D supplements is advisable.
Teriparatide therapy can be considered as an alternative treatment. Cite this article: Bone Joint J 2017;99-B:295–302.

Atypical femoral fractures related to bisphosphonate treatment: issues and controversies related to their surgical management.

Background
Prolonged use of bisphosphonates in patients with osteoporosis reportedly induces femoral insufficiency fractures. However, the natural course of these fractures and how to treat them remain unknown.

/pdf/is-surgery-necessary-for-femoral-insufficiency-fractures-3kejnwsqfg.pdf

Ki Hong Park

Papers

Is Surgery Necessary for Femoral Insufficiency Fractures after Long-term Bisphosphonate Therapy?