PURPOSE: Atypical femur fractures represent a potential complication of chronic oral bisphosphonate therapy in women with osteoporosis, but the risk of atypical femur fractures among cancer patients receiving intravenous bisphosphonates at higher cumulative doses remains unclear. We examined femur fractures occurring in cancer patients treated with intravenous bisphosphonates (IVBP) to determine whether a subset may be atypical fractures. METHODS: Between 2005 and 2010, we identified patients with known IVBP therapy for multiple myeloma or metastatic breast cancer, who subsequently sustained a femur fracture based on hospitalization, oncology, pharmacy and chemotherapy visit records. Radiographs were examined by an orthopedic surgeon to determine anatomic fracture site and pattern. An atypical fracture was defined as a transverse or short oblique fracture occurring below the lesser trochanter with evidence of focal hypertrophy of the lateral cortex and absence of biopsy-proven malignancy or radiation therapy at the fracture site. RESULTS: A total of 62 patients with breast cancer (N=39) or multiple myeloma (N=23) with femur fracture and prior IVBP treatment for bone malignancy were identified. There were 30 proximal hip, 18 subtrochanteric and 14 femoral shaft fractures. Intraoperative bone samples were sent in 29 of 58 fracture cases undergoing operative repair, with 76% positive for malignancy. Six cases (4 breast cancer, 2 multiple myeloma) of atypical femur fracture were identified, two with negative intraoperative pathology and four with no bone biopsy samples sent. Five of the six patients with atypical fracture had bilateral femur findings, including two with transverse fracture in the contralateral femur and three with focal hypertrophy of the contralateral cortex. Two atypical fracture cases also experienced osteonecrosis of the jaw compared to 3 in the remaining cohort (33% vs. 5%, p=0.07). Patients with atypical fracture received more IVBP (median 55 vs. 15 doses) and zoledronic acid (32 vs. 12 doses) and had longer treatment duration (median 5.9 vs. 1.6 years) compared to patients without atypical fracture (all p=0.01). CONCLUSIONS: Among 62 patients who received IVBP for skeletal malignancy and experienced a femur fracture, we identified six cases of atypical fracture. While fractures in this population are often assumed to be pathologic, prospective studies investigating fracture pattern, microscopic bone pathology and pharmacologic exposures should be conducted to further examine the association of IVBP and atypical femur fractures.