The Geometry of Lower Extremity and Atypical Femoral Fractures

Abstract

Osteoporosis is a systemic skeletal disease that is characterized by low bone mass and the structural deterioration of bone tissue leading to bone fragility and an increased risk of fracture. Fractures, most notably of the hip, are associated with significant morbidity and mortality. From a patient’s perspective, a hip fracture and the subsequent loss of mobility and autonomy often represent a major drop in the quality of life.

Although it had been thought to be a natural part of the aging process in women, osteoporosis is no longer considered age or sex dependent, and it is largely preventable due to the remarkable progress in the scientific understanding of its causes, diagnosis, and treatment. Bone strength primarily reflects the integration of bone density and bone quality. The treatment of osteoporosis seeks to increase the bone mass and, hopefully, to improve bone quality, resulting in the strengthening of the bone structure. As bone is a remodeling organ and because of recent developments in the field of bone biology, we have recently become able to increase bone mass and bone strength by modulating the bone remodeling processes. However, the goal of therapy is fracture prevention.

The bisphosphonates (BPs), a class of antiresorptive agents, are the current cornerstone of osteoporosis treatment and prevention. These nitrogen-containing compounds bind to the bone surface. Treatment with bisphosphonates reduces the rate of bone resorption, increases bone mineral density, and improves trabecular connectivity. These resultant effects serve to improve bone strength and reduce the risk of fracture. Denosumab, a fully human monoclonal antibody against the receptor activator of nuclear factor-κB ligand (RANKL), prevents the interaction of RANKL with RANK, its receptor, on osteoclasts and their precursors, thereby blocking the formation, function, and survival of osteoclasts. At the moment, these anti-bone-resorbing agents are only drugs that can reduce the incidence of osteoporotic hip fragility fractures in osteoporotic patients. However, treatments with these agents must be continued for 3–4 years in order to reduce the risk of both vertebral and non-vertebral fractures in osteoporotic women.

In spite of their clinical benefits, the long-term treatment with BPs has raised questions regarding their associations with rare but serious adverse events, including atypical femoral fractures (AFFs). Currently, the long-term use of BPs is considered to be linked to the occurrence of AFFs. Although the evidence had been controversial regarding the association between the occurrence of AFFs and the use of BPs, more recent studies with radiographic adjudication have supported that an association exists. However, the pathogenesis of AFFs is still not completely understood.

AFFs are characterized by unique radiographic features, such as a transverse fracture line, a periosteal callus formation at the fracture site and little or no comminution, and also by unique clinical features, such as prodromal pain and bilaterality, that resemble stress fractures or reactions. Based upon new information, an American Society for Bone and Mineral Research (ASBMR) task force reported the original case definition to highlight the unusual radiographic features that distinguish AFFs from ordinary osteoporotic typical femoral fractures (TFFs) and to provide more precise guidance on what is meant by transverse orientation. The epidemiological evidence for a relationship between BP use and AFFs has become more compelling. While AFFs appear to be more common in patients who have been exposed to the long-term use of BPs, every series includes patients who have not been treated with BPs, which suggests the possible presence of AFF “background factors” in osteoporosis patients. The majority of studies have found a significant association with glucocorticoid (GC) use or duration of use. Although the relative risks of AFFs are very high in patients who use BPs, ranging from 2.1 to 128, the absolute risk is extremely low, ranging from 3.2 to 50 cases per 100,000 person-years. Thus, these fractures are rare, particularly when considered against the incidence of common osteoporotic fractures of all types and of ordinary TFFs, all of which have been proven to decrease with BP therapy. In addition, increasing reports have suggested an association between denosumab and AFFs. Therefore, it becomes more important to know the “risk factors” and/or the “background factors” of AFF to treat patients with osteoporosis who are susceptible to osteoporotic fractures.

We previously reported that the incidence of AFFs in the Japanese population was similar to that in Caucasians and that the taking of BPs and GCs and the presence of collagen diseases were the risk factors for developing AFFs. We also reported that fracture sites of AFFs are associated with the standing lower limb alignment and that lower limb alignment is suggested to be one of the risk factors for AFFs. In this section, we focus on the epidemiology, pathology, and risk factors of AFFs and especially on the involvement of the geometry of the lower extremities as one of the risk factors of AFFs.