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Clinical Cases in mineral and bone metabolism

Atypical femur fractures

Mini-Review, 43 - 59
doi: 10.11138/ccmbm/2018.15.1.043
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Already from the late 1970s, some fractures of the subtrochanteric and diaphyseal region of the femur were defined “atypical” and described as “fatigue” fractures. In 2005, Odvina reported an unusual type of femoral fracture after the administration of alendronate as a result of a severely repressed bone turnover and Lenart defined femoral fractures occurring on the subtrocanteric or diaphyseal region in post-menopause women after alendronate therapy as “atypical” (AFFs). Hence the hypothesis that these fractures could be associated with the use of bisphosphonates (BP). Even with a “normal” dose of BP, the risk of fracture is highest if therapy lasts more than 5 years, although cases have recently been reported with short-term therapies.
However, many of the studies on this association did not consider the radiographic patterns and the atypical or typical radiographic definition did not evaluate the BP doses used and patient compliance; they just state if there was an association or not, and this had led to an underestimation of the real incidence of these fractures. It is the latest revision of the diagnostic criteria made in 2013 by the American Society for Bone and Mineral Research (ASBMR) Task Force to determine that to be defined as AFF, a fracture localized along the femoral diaphysis just distal from the small trochanter to just proximal to the supracondylar region must have certain clinical and radiographic patterns. They also defined exclusion and minor criteria.
In general, incidence is still low. Considering the incidence of all femoral fractures of about 460/100,000 people-year, the sub-trochanteric ones represent 7 to 10% of these, and atypical ones are even rarer: 32 per million people-year and 5, 9 per 100,000 person-years in a retrospective study from 1996 to 2009. Morbidity and mortality are similar to neck or intertrochanteric femoral fractures.
However, AFF was also found in patients who had never used BP, so BP therapy could not be the only risk factor. Among them, recent attention has been given to hypoposphatasia, picnodisostosis with mutant catepsin gene, osteopetrosis, tumors, use of glucocorticoids (GC), high body mass index (BMI) and use of proton pump inhibitors (PPI).
About pathogenesis it seems that the accumulation of microlesions, the increase of mineralization with reduced heterogeneity of mineralization, accumulation of
Advanced Glycation End-products (AGEs), reduced vascularization and reduced antiangiogenic effects, alterations of normal collagen reticulation and maturation variations of crosslinks of collagen are all factors involved.
Histological studies have demonstrated how these stress fractures occur: at the fracture site there are thin cracks that even micro-movements can distort and bring to their enlargement. In presence of predisposing conditions (femoral conformation, hypophosphatasia, use of GC ...) in BP patients, these cracks are trapped in free mineral deposits at the site of the fracture, particularly at intracortical level and act longer by suppressing just in that site where the remodeling processes are essential to healing. Initial alteration occurs precisely on the lateral cortex, which is subjected to increased stress in the subtrochanteric and diaphyseal region, causing a femur bending.
This observation has led to studies that have shown how femoral conformation plays a role in determining an increased risk of AFF. With a same BP therapy duration, for conformation characteristics, more is the lateral curvature of the femur and greater the knee valgus and more frequent are the AFFs; these features are more common in some breeds (Asiatic).
Recently AFF case reports have also been published with denosumab, a monoclonal antibody that similarly to BP has an anti-resorptive effect. Some Authors and the ASBMR themselves have outlined guidelines for AFF diagnosis and management. Following
patients who are taking BP therapy with DEXA is useful: evidence of certain pre-lesions to DEXA and the presence of prodromal symptoms are strong predictors of a subsequent fracture. Also useful is the dosage and monitoring of biochemical markers of bone remodeling.
With regard to surgical strategy, the use of an intramedullary nail is the best treatment. In cases of particularly curved femur it is more appropriate to use angular stability plates because in the case of incomplete fracture the use of a nail may turn it into complete and
because even in the case of complete fractures, the risk of non-union is higher. To date, even stopping of BP alone in the AFF suspect and the use of teriparatide as supportive drug therapy are two key elements to enable proper AFF healing.

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