Is Atypical Bisphosphonate Treatment Response a Risk Factor for Atypical Femoral Fracture? (2017)

Commentary Dual x-ray absorptiometry (DX+A) measurements of hip and lumbar spine areal bone mineral density (BMD) remain the clinical gold standard for osteoporosis diagnosis and the evaluation of treatment effect. These measures are typically expressed as a standardized value (T-score) relative to a young healthy reference cohort and are used to classify a patient according to the World Health Organization (WHO) criteria as osteoporotic (T-score below −2.5), osteopenic (T-score between −1.0 and −2.5), or normal (T-score of more than −1.0). It is not uncommon for different regions or subregions under analysis to fall into different classification categories, and the International Society for Clinical Densitometry recommends using the lower of the T-scores for diagnostic purposes1. Bisphosphonates are commonly used to treat osteoporosis because they significantly increase BMD and reduce the incidence of fragility fracture. However, atypical femoral fractures (AFFs) have been widely publicized as a risk associated with bisphosphonate use. Despite their low incidence (3.2 to 50 cases/100,000 person-years)2, the elevated perception of AFF risk has contributed to a 50% drop in the use of bisphosphonate therapy between 2008 and 20123. As a result, considerable effort has been focused on identifying risk factors associated with AFF, developing early detection schemes, and identifying mechanisms that contribute to their development. In their article, Lee and colleagues compared DXA data from 48 patients who experienced AFF while being treated with bisphosphonates with those from 114 patients with (typical) intertrochanteric femoral fracture. They found that T-score discordance was significantly more prevalent in patients with AFF, and that the average T-scores in this subgroup with discordance (n = 34) indicated osteoporosis in the spine but only osteopenia in the proximal part of the femur. In contrast, the patients with AFF who had concordant T-scores (n = 14) generally exhibited osteoporosis at both sites. Why would this be the case, and what could it mean? In this study, DXA data were obtained after the AFFs were identified and, therefore, reflect data post-bisphosphonate treatment in this group. The relatively common combination of low spine BMD and age-normal (osteopenic) proximal femoral BMD observed in the AFF group raises questions about whether the bisphosphonate treatment preferentially affected the femur instead of the spine in this patient group. A comparison can be made with participants in the Fracture Intervention Trial (FIT), which prospectively investigated the effects of alendronate treatment in postmenopausal women with low femoral neck BMD (T score of −1.6 or lower)4. In that group, the increase in spine BMD resulting from alendronate treatment was approximately double the increase in hip BMD4. This suggests that the low spine/age-normal proximal femoral BMD pattern observed in the AFF cohort in the study by Lee et al. may not represent a typical treatment response to bisphosphonates. If that is the case, then perhaps a large discrepancy between proximal femoral and lumbar spine responses to bisphosphonate treatment serves as an early indicator of AFF risk. On the other hand, this pattern of lower T-scores in the spine than in the hip appears to be fairly common among individuals with discordant T-scores in general. An alternate possibility is that individuals with low spine/high femoral BMD are predisposed to AFF for some other anatomic reason. The pre-bisphosphonate DXA data that were available for 9 of the patients in the study by Lee et al. suggest that perhaps the T-score discordance preceded the bisphosphonate therapy, although the sample is too small to draw any conclusions. Nevertheless, other anatomic features that would manifest as high proximal femoral BMD have been associated with AFF, such as increased cortical thickness and decreased femoral neck width5. From a mechanics perspective, increased cortical thickness would be considered an indicator of strength, raising questions about the quality of bone material in these patients. More research is needed to understand the mechanisms by which these specific anatomic features, or a femur-specific bisphosphonate treatment response, might contribute to T-score discordance and AFF risk. The limitations of the data presented by Lee and colleagues also underscore the need for high-quality longitudinal data to examine potential predictors of AFF. Finally, the findings highlight the potential value of evaluating BMD measurements at multiple anatomic sites rather than focusing on a single site of interest or diagnostic category.