Giant cell tumor of the bone (GCTB) is a locally aggressive neoplasm where surgery is often curative. However, it can rarely give rise to distant metastases. Currently, the only available active therapeutic option for unresectable GCTB is denosumab, an anti-RANKL monoclonal antibody that dampens the aggressive osteolysis typically seen in this disease. For advanced/metastatic GCTB, denosumab should be continued lifelong, and although it is usually well tolerated, important questions may arise about the long-term safety of this drug. In fact, uncommon but severe toxicities can occur and eventually lead to denosumab discontinuation, such as atypical fracture of the femur (AFF). The optimal management of treatment-related AFF is a matter of debate, and to date, it is unknown whether reintroduction of denosumab at disease progression is a clinically feasible option, as no reports have been provided so far. Hereinafter, we present a case of a patient with metastatic GCTB who suffered from AFF after several years of denosumab; we describe the clinical features, orthopedic treatment, and oncological outcomes, finally providing the first evidence that denosumab rechallenge after AFF occurrence may be a safe and viable option at GCTB progression.

Osteoporosis leads to reduced bone mass and disrupted bone architecture. Bisphosphonates are used to treat osteoporosis by inhibiting bone resorption. Chronic bisphosphonate use has been associated with adverse effects including atypical femoral fractures (AFF). We report the case of a 63-year-old woman with a history of osteoporosis treated with alendronate, who presented with bilateral hip and groin pain. Radiography detected a chronic-appearing callus in the left hip concerning for a chronic stress fracture versus malignancy. Initial imaging could not rule out malignancy, prompting positron emission tomography (PET) and bone biopsy. PET scan was negative for malignancy and biopsy found changes consistent with chronic bisphosphonate use. This prompted prophylactic intramedullary nailing of the femur. This case highlights the importance of considering AFF in patients with a history of hip pain in the setting of chronic BPs use and reviews criteria within the literature to manage patients with AFFs.

Bisphosphonates are commonly used in patients with metastatic bone disease to prevent skeletal related events. Atypical femur fracture is a known complication of long-term bisphosphonate use but the incidence in cancer patients and pathogenesis are not well known. Several mechanisms of pathogenesis have been proposed including altered angiogenesis, altered bone mechanical properties, micro damage and bone remodeling suppression. Atypical femur fractures are atraumatic or minimally traumatic fractures in the sub trochanteric region or the femoral shaft. Awareness of atypical femur fractures is critical to diagnose and treat them in a timely manner. There is a paucity of data regarding the management of atypical femur fracture in patients with malignancy. Management options of atypical femur fractures include stopping bisphosphonates, initiating calcium/vitamin D supplementation and either surgery with internal fixation or conservative management. In the future, it will be important to explore the effect of continuous vs. intermittent exposure, cumulative dose and length of exposure on the incidence of this complication. Herein, we review the epidemiology, risk factors, management options and proposed mechanisms of pathogenesis of atypical femur fractures.

BACKGROUND: The use of bisphosphonates in treatment of osteoporosis declined significantly over the past decade. There is currently great concern, among patients and physicians, about two potential skeletal adverse effects associated with bisphosphonates- jaw osteonecrosis and atypical femur fractures. This has become a major public health issue since untreated osteoporosis carries a significant burden in terms of fracture-related morbidity and mortality, and bisphosphonates, considered first-line therapy for osteoporosis, have established efficacy in fracture and mortality reduction. Areas covered: In this review we discuss current literature on osteonecrosis of the jaw and atypical femur fractures in patients with osteoporosis treated with bisphosphonates, including case definition, pathogenesis, epidemiology, risk factors, clinical presentation, management and prevention. We conducted a literature search using PubMed and PubMed Central, using the search terms \'bisphosphonates\', \'osteonecrosis of the jaw\', and \'atypical fractures\'. We selected relevant articles including meta-analyses, clinical trials, observational studies, and major society guidelines published between 2010 and 2016, to be included in this review. A few articles published prior to 2010 were also included as references. Expert commentary: The rare skeletal side effects of bisphosphonates should not preclude their use in patients with osteoporosis and high fracture risk, as benefits significantly outweigh the risks.

Although there is strong evidence that bisphosphonates prevent certain types of osteoporotic fractures, there are concerns that these medications may be associated with rare atypical femoral fractures (AFF). Recent published studies examining this potential association are conflicting regarding the existence and strength of this association. We conducted a systematic review and meta-analysis of published studies examining the association of bisphosphonates with subtrochanteric, femoral shaft, and AFF. The random-effects model was used to calculate the pooled estimates of adjusted risk ratios (RR). Subgroup analysis was performed by study design, for studies that used validated outcome definitions for AFF, and for studies reporting on duration of bisphosphonate use. Eleven studies were included in the meta-analysis: five case-control and six cohort studies. Bisphosphonate exposure was associated with an increased risk of subtrochanteric, femoral shaft, and AFF, with adjusted RR of 1.70 (95% confidence interval [CI], 1.22-2.37). Subgroup analysis of studies using the American Society for Bone and Mineral Research criteria to define AFF suggests a higher risk of AFF, with bisphosphonate use with RR of 11.78 (95% CI, 0.39-359.69) as compared to studies using mainly diagnosis codes (RR, 1.62; 95% CI, 1.18-2.22), although there is a wide confidence interval and severe heterogeneity (I(2)  = 96.15%) in this subgroup analysis. Subgroup analysis of studies examining at least 5 years of bisphosphonate use showed adjusted RR of 1.62 (95% CI, 1.29-2.04). This meta-analysis suggests there is an increased risk of subtrochanteric, femoral shaft, and AFF among bisphosphonate users. Further research examining the risk of AFF with long-term use of bisphosphonates is indicated as there was limited data in this subgroup. The public health implication of this observed increase in AFF risk is not clear.