Is bisphosphonate use a risk factor for atypical periprosthetic/peri-implant fractures? - A metanalysis of retrospective cohort studies and systematic review of the current evidence.

INTRODUCTION: Atypical periprosthetic/peri-implant fractures are not recognised in any widely used classification and therefore little focus is given to them. Multiple case reports and case series demonstrate these fractures exist and are related to bisphosphonate (BP) use. HYPOTHESIS: Are patients taking long-term BPs at an increased risk of developing an atypical periprosthetic/peri-implant fracture? Is a particular BP drug causing an increased risk of fracture? Is there a correlation between the time of BP use and the incidence of fractures? Do vitamin D analogues or parathyroid hormones reduce the time to union? MATERIAL AND METHODS: Systematic review of all available evidence on the existence of periprosthetic/peri-implant atypical fractures in patients taking long-term BPs and metanalysis of available retrospective cohort studies. Selected 1 systematic review, 7 retrospective cohort studies (5 used for metanalysis) and 32 case reports. RESULTS: Metanalysis reported a risk ratio of 14.1, p=0.25, suggesting bisphosphonates are a risk factor in the development of periprosthetic/peri-implant atypical fractures. The secondary outcomes couldn't be reliably identified due to the small size of available studies and risk of significant bias. DISCUSSION: Atypical periprosthetic/peri-implant fractures are an entity and seem to be associated with the use of bisphosphonates. The benefits of bisphosphonates use outweigh the risks, but clinicians should be aware of atypical fractures and actively search for them when patients on long-term bisphosphonates attend with non-specific pain close to the implant/prosthesis or reduced mobility. LEVEL OF EVIDENCE: II, Systematic review and metanalysis.

Periprosthetic atypical femoral fractures exist and are associated with duration of bisphosphonate therapy.

AIMS: Currently, periprosthetic fractures are excluded from the American Society for Bone and Mineral Research (ASBMR) definition of atypical femoral fracture (AFFs). This study aims to report on a series of periprosthetic femoral fractures (PFFs) that otherwise meet the criteria for AFFs. Secondary aims were to identify predictors of periprosthetic atypical femoral fractures (PAFFs) and quantify the complications of treatment. PATIENTS AND METHODS: This was a retrospective case control study of consecutive patients with periprosthetic femoral fractures between 2007 and 2017. Two observers identified 16 PAFF cases (mean age 73.9 years (44 to 88), 14 female patients) and 17 typical periprosthetic fractures in patients on bisphosphonate therapy as controls (mean age 80.7 years (60 to 86, 13 female patients). Univariate and multivariate analysis was performed to identify predictors of PAFF. Management and complications were recorded. RESULTS: Interobserver agreement for the PAFF classification was excellent (kappa = 0.944; p < 0.001). On univariate analysis compared with controls, patients with PAFFs had higher mean body mass indices (28.6 kg/m2 (sd 8.9) vs 21.5 kg/m2 (sd 3.3); p = 0.009), longer durations of bisphosphonate therapy (median 5.5 years (IQR 3.2 to 10.6) vs 2.4 years (IQR 1.0 to 6.4); p = 0.04), and were less likely to be on alendronate (50% vs 94%; p = 0.02) with an indication of secondary osteoporosis (19% vs 0%; p = 0.049). Duration of bisphosphonate therapy was an independent predictor of PAFF on multivariate analysis (R2 = 0.733; p = 0.05). Following primary fracture management, complication rates were higher in PAFFs (9/16, 56%) than controls (5/17, 29%; p = 0.178) with a relative risk of any complication following PAFF of 1.71 (95% confidence interval (CI) 0.77 to 3.8) and of reoperation 2.56 (95% CI 1.3 to 5.2). CONCLUSION: AFFs do occur in association with prostheses. Longer duration of bisphosphonate therapy is an independent predictor of PAFF. Complication rates are higher following PAFFs compared with typical PFFs, particularly of reoperation and infection. Cite this article: Bone Joint J 2019;101-B:1285-1291.

Prevalence and Characteristics of Atypical Periprosthetic Femoral Fractures.

Bisphosphonate use has been associated with atypical femoral fractures (AFFs), defined by the American Society of Bone and Mineral Research (ASBMR) Task Force criteria, which currently exclude periprosthetic fractures. The objectives of this study were to establish the prevalence of atypical periprosthetic femoral fractures (APFFs) in patients with hip and knee arthroplasties and to determine the clinical and radiological risk factors associated with these fractures. We performed a retrospective radiological review of all femoral fractures between January 1, 2006, and March 31, 2015, in Quebec City, Canada. Patients who sustained a periprosthetic femoral fracture (PFF) were identified and included in this study. We used the ASBMR Task Force criteria to identify atypical fractures and establish their prevalence. Data from medical records and radiological assessments of the femoral anatomy, the characteristics of the fracture, and the positioning of the prosthesis were collected. The prevalence of APFFs among PFFs was 8.3% (11/133). A strong association with bisphosphonates (p = 0.007) was observed, as well as an increased risk of APFFs among alendronate users compared to risedronate users (p = 0.04). A transverse fracture (p < 0.0001), a periosteal thickening of the lateral cortex at the fracture (p < 0.0001), a unicortical fracture (p = 0.02), and prodromal symptoms (p = 0.03) were associated with APFFs. The type of implant, its positioning, and the femoral geometry did not appear to be risk factors for APFFs compared to PFFs. © 2018 American Society for Bone and Mineral Research.

Atypical periprosthetic femoral fracture: a case report.

We report an 82-year-old woman who underwent fixation with a long-spanning cable-plate for a bisphosphonate-induced Vancouver B1 periprosthetic femoral fracture. Non-union and breakage of the plate occurred at 16 months and necessitated revision surgery using a long-stem femoral prosthesis augmented with a cable-plate construct. Bone union was achieved eventually after 10 months.

Periprosthetic Atypical Femoral Fractures in Patients on Long-term Bisphosphonates: A Multicenter Retrospective Review.

OBJECTIVES: To define the characteristics of periprosthetic atypical femoral fractures (PAFFs) in patients on long-term bisphosphonate treatment and to provide a guide to the diagnosis and long-term treatment of these patients based on the literature. DESIGN: Multicenter retrospective review. SETTING: Fifteen orthopaedic centers in the United States and Canada, including members of the Canadian Orthopaedic Trauma Society. PATIENTS/PARTICIPANTS: Patients on long-term bisphosphonates who presented with either periprosthetic fractures or femoral fractures, over a 10-year period. MAIN OUTCOME MEASUREMENTS: Time to union and complications. RESULTS: Clinically significant differences were identified in time to union, mortality, and complications. There was a statistically significant difference in complications. Imaging review demonstrated identical features in both atypical femoral fractures (AFFs) and PAFFs. CONCLUSIONS: This is the largest comparative case series reported on PAFFS and AFFs and provides compelling evidence that PAFFs in patients on long-term bisphosphonates are indeed a subset of periprosthetic fractures that exhibit atypical femoral fracture (AFF) characteristics. As such, these fractures pose serious diagnostic and management challenges to trauma and arthroplasty surgeons. LEVEL OF EVIDENCE: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence.

Lower Total Knee Arthroplasty Revision Risk Associated With Bisphosphonate Use, Even in Patients With Normal Bone Density.

BACKGROUND: Bisphosphonates (BPs) are associated with lower total knee arthroplasty (TKA) revision risk, but the effect of bone mineral density has not been evaluated. METHODS: A cohort of 34,116 primary TKA patients was evaluated with revision surgery and periprosthetic fractures as end points. BP usage was the exposure of interest. Bone quality (normal, osteopenia, and osteoporosis) and patient age (<65 vs ≥65 years) were evaluated as effect modifiers of risk estimates. RESULTS: Of the patients, 19.6% were BP users. In BP users, 0.5% underwent an aseptic revision; and 0.6%, a periprosthetic fracture. In non-BP users, 1.6% underwent aseptic revision; and 0.1%, a periprosthetic fracture. CONCLUSION: Bisphosphonate use was associated with lower risk of revision in all bone quality categories in those older than 65 years. The risk of periprosthetic fractures was higher for patients on BP.

Rare non-traumatic periprosthetic femoral fracture with features of an atypical femoral fracture: a case report.

INTRODUCTION: Atypical femoral fractures have emerged as one of the potential complications of bisphosphonates during the past decade. The American Society for Bone and Mineral Research published a Task Force report on atypical femoral fractures in 2010 and a second report in 2014. Although the current definition of atypical femoral fractures in these reports excludes periprosthetic fractures, each of three published case reports describe a bisphosphonate-associated atypical femoral fracture that occurred around the stem of a total hip arthroplasty. We report a rare case of an atypical femoral fracture that occurred at the stem tip of a total hip arthroplasty that fulfills the major criteria defined by the second American Society for Bone and Mineral Research Task Force report for an atypical femoral fracture and that was associated with prolonged use of bisphosphonate. CASE PRESENTATION: A 69-year-old Japanese woman with a right cementless total hip arthroplasty undertaken 44 months previously had a right femoral shaft fracture that occurred without trauma. She related that the bone fractured while she was standing, after which she fell down. Radiographs showed a noncomminuted transverse fracture located at the tip of the stem with localized periosteal thickening of the lateral cortex. The fracture was complete, extending through both cortices, and was associated with a medial spike. Her history revealed that she had been taking prednisolone to treat dermatomyositis and interstitial pneumonia for approximately 15 years. Alendronate was administered for more than 7 years. We performed open reduction and internal fixation using a locking plate with cable grip. The latest follow-up was performed 2 years after the fracture surgery. Bony union was successful. She regained the ability to walk, although her activity was limited by her comorbidities. CONCLUSIONS: Although the current definition of an atypical femoral fracture excludes periprosthetic fractures, there may be a periprosthetic fracture with the same or similar pathology as that of an atypical femoral fracture. We must be vigilant and aware of this type of fracture, especially in patients with prolonged bisphosphonate use.

Association of Bisphosphonate Use and Risk of Revision After THA: Outcomes From a US Total Joint Replacement Registry.

BACKGROUND: Total hip arthroplasty (THA) is often performed in patients who are older and may take bisphosphonates to treat a variety of conditions, most commonly osteoporosis. However, the clinical effects of bisphosphonate use on patients who have undergone THA are not well described. QUESTIONS/PURPOSES: (1) Is bisphosphonate use in patients with osteoarthritis undergoing primary THA associated with a change in the risk of all-cause revision, aseptic revision, or periprosthetic fracture compared with patients not treated with bisphosphonates? (2) Does the risk of bisphosphonate use and revision and periprosthetic fracture vary by patient bone mineral density and age? METHODS: A retrospective cohort study of 12,878 THA recipients for the diagnosis of osteoarthritis was conducted; 17.8% of patients were bisphosphonate users. Data sources for this study included a joint replacement registry (93% voluntary participation) and electronic health records and an osteoporosis screening database with complete capture of cases as part of the Kaiser Permanente integrated healthcare system. The endpoints for this study were revision surgery for any cause, aseptic revision, and periprosthetic fracture. The exposure of interest was bisphosphonate use; patients were considered users if prescriptions were continuously refilled for a period equal to or longer than 6 months. Bone quality (based on dual-energy x-ray absorptiometery ordered based on the National Osteoporosis Foundation's clinical guidelines taken within 5 years of the THA) and patient age (< 65 versus ≥ 65 years) were evaluated as effect modifiers. Patient, surgeon, and hospital factors were evaluated as confounders. Cox proportional hazards models were used. Hazard ratios (HRs) and 95% confidence intervals (CIs) were determined. RESULTS: Age- and sex-adjusted risks of all-cause (HR, 0.50; 95% CI, 0.33-0.74; p < 0.001) and aseptic revision (HR, 0.53; 95% CI, 0.34-0.81; p = 0.004) was lower in bisphosphonate users than in nonusers. The adjusted risk of periprosthetic fractures in patients on bisphosphonates was higher than in patients not on bisphosphonates (HR, 1.92; 95% CI, 1.13-3.27; p = 0.016). Lower risks of all-cause revision and aseptic revision were observed in patients with osteopenia (HR, 0.49; 95% CI, 0.29-0.84; and HR, 0.53; 95% CI, 0.29-0.99, respectively) and osteoporosis (HR, 0.22; 95% CI, 0.08-0.62; and HR, 0.33; 95% CI, 0.11-0.99, respectively). CONCLUSIONS: Patients considered bisphosphonate users who underwent THA had a lower risk for revision surgery. Bisphosphonate use was associated with a higher risk of periprosthetic fractures in younger patients with normal bone quantity. Evaluation of bone quality and bisphosphonate use for the diagnosis of osteoporosis is encouraged in patients with osteoarthritis who are candidates for primary THA. Further research is required to determine the optimal duration of therapy because long-term bisphosphonate use has been associated with atypical femur fractures. LEVEL OF EVIDENCE: Level III, therapeutic study.

Bisphosphonate-associated peri-implant fractures: a new clinical entity? A series of 10 patients with 11 fractures.

BACKGROUND AND PURPOSE: The current definition of atypical femoral fractures (AFFs) associated with bisphosphonate use includes only de novo fractures. However, in recent years reports of bisphosphonate-associated periprosthetic fractures involving stemmed arthroplasty implants have emerged. In a case series of peri-implant fractures in femurs with plate/screw constructs, we aimed to assess similarities with classical AFFs and how their location may have implications for the pathogenesis and management of AFFs. PATIENTS AND METHODS: We retrospectively identified 10 patients with 11 peri-implant fractures. RESULTS: The patients were ambulant women, mean age 80 (70-92) years. Mean duration of bisphosphonate use was 5 (1-10) years. The peri-implant fractures were sustained an average of 4 years (6 months to 9 years) from the time of index surgery. They were all associated with low-energy mechanisms. 8 fractures occurred near the tip of a plate, while 3 traversed the penultimate screwhole of a plate. The peri-implant fractures showed clinical and radiological features of atypicality such as lateral cortical thickening, simple fracture pattern, and lack of comminution. The patients underwent revision surgery, with bone grafting used in all but 1 case. Radiological union was evident after 2-4 months. INTERPRETATION: Atypical peri-implant fractures of the femur associated with bisphosphonate use may be a new entity. Stress lesions and atypical fractures may tend to develop over stress risers along the operated femur. This finding has implications for the pathogenesis and clinical management of AFFs.

Spontaneous acetabular periprosthetic fracture in a patient continuously having zoledronic acid.

Zoledronic acid has been used for prevention of osteolytic and osteoblastic bone metastasis. This case report illustrates an undesirable consequence from prolonged usage of zoledronic acid in bone metastasis prevention. Periprosthetic acetabular fracture in a patient treated with zoledronic acid for 7 years was reported. The clinical presentation, radiographic and pathological results were described. This is a rare complication after total hip arthroplasty which should not be ignored especially in patients who received long term bisphosphonate.

Spontaneous Acetabular Periprosthetic Fracture in a Patient Continuously Having Zoledronic Acid

Zoledronic acid has been used for prevention of osteolytic and osteoblastic bone metastasis. This case report illustrates an undesirable consequence from prolonged usage of zoledronic acid in bone metastasis prevention. Periprosthetic acetabular fracture in a patient treated with zoledronic acid for 7 years was reported. The clinical presentation, radiographic and pathological results were described. This is a rare complication after total hip arthroplasty which should not be ignored especially in patients who received long term bisphosphonate.

A rare case of a bisphosphonate-induced peri-prosthetic femoral fracture.

An 81-year-old woman presented with a fracture in the left femur. She had well-fixed bilateral hip replacements and had received long-term bisphosphonate treatment. Prolonged bisphosphonate use has been recently linked with atypical subtrochanteric and diaphyseal femoral fractures. While the current definition of an atypical fracture of the femur excludes peri-prosthetic fractures, this case suggests that they do occur and should be considered in patients with severe osteopenia. Union of the fracture followed cessation of bisphosphonates and treatment with teriparatide. Thus, this case calls into question whether prophylactic intramedullary nailing is sufficient alone to treat early or completed atypical femoral fractures.