Atypical femoral fractures : a rare complication possibly due to the accumulation of rare genetic variants

ntiresorptive drugs, such as bisphosphonates and denosumab, are very effective in reducing the risk of vertebral and non-vertebral fractures in patients with osteoporosis. They can be administered conveniently, are generally well tolerated and the side effects are mild and infrequent. Occasionally, however, some patients may present complications peculiar to the treatment, such as atypical femoral fractures (FFA) and maxillary osteonecrosis. These complications occur very rarely, but are potentially serious and difficult to manage, so they are a source of concern for some doctors and many patients. This fear seems to have a negative influence, although not justified, on therapeutic compliance. Therefore, it would be extremely useful to identify the rare patients who are at risk of developing these complications. FFA is a particularly paradoxical case, since it involves fractures that appear associated with treatments that are given precisely to reduce the risk of fracture. The ASBMR (American Society for Bone and Mineral Research) has developed criteria to identify atypical fractures, which include a subtrochanteric or diaphyseal location, an origin in the outer cortex and a transverse or slightly oblique path, a minimal or absent comminution, a thickening Periosteal in the external cortex and the absence of high-impact trauma as a trigger. FFA has been related mainly to bisphosphonates, but cases associated with other antiresorptive drugs have also been reported. Likewise, the appearance of fractures with characteristics similar to FFA has been described in patients with some monogenic skeletal diseases, such as osteogenesis imperfecta, pycnodysostosis, osteopetrosis, hypophosphatemic rickets or hypophosphatasia, even without having received antiresorptive drugs. The frequency of FFA varies markedly from one study to another. Estimates range from 3 to 50 cases per 100,000 patient-years of bisphosphonate treatment. Prolonged treatment, for more than 5 years, seems to be associated with an increased risk, with the incidence reaching, in these cases, about 130 cases per 100,000 patient-years. In several studies, clinical factors associated with FFA have been explored. Among them, treatment with glucocorticoids together with bisphosphonates is the one that has been associated with an increased risk of FFA in a more consistent manner. As FFA is a complication that appears very rarely, only in a minority of patients treated with antiresorptives, it is thought that individual predisposition must be a significant factor. In favor of this is the fact that with a certain frequency the fractures are bilateral in the affected patients. Hence, several authors have analyzed whether these patients have any predisposing genetic characteristics. In this line, the work of Roca-Ayats et al., published in this issue of the journal, is particularly interesting because it includes three sisters with FFA. The family association reinforces the notion of genetic predisposition. The authors sequenced the exome, that is, the DNA coding regions. Most inherited diseases are due to mutations in these regions, although they only account for about 1% of the DNA. Roca-Ayats et al. They found several mutations in the 3 sisters studied, including some in genes that encode enzymes of the mevalonate pathway. These mutations are particularly interesting because this pathway is target of bisphosphonates, which gives biological plausibility to the causal relationship between these variants and the FFA associated with these antiresorptive drugs. However, the authors could not confirm that these mutations were involved in FFA suffered by other patients unrelated to the previous ones. In the Roca-Ayats study it was also observed that some patients had a mutation in the CYP1A1 gene, which metabolizes various hormones, eicosanoids and exogenous agents. Other studies have found mutations in genes that encode bone proteins such as alkaline phosphatase or collagen in some patients isolated with FFA. But in most of the cases analyzed, these mutations were not found. These results suggest that there is genetic heterogeneity, that is, the susceptibility genes vary from one patient to another. In silico analyses and some functional experiments suggest that these mutae-mail: rianchoj@unican.es