In this study, we examined the BMD and the correlation between Z-score or T-score and geometry parameters of the proximal femur. We found that three-fourths of MHE patients show a range of osteopenia or osteoporosis and that femoral neck width significantly correlates with Z-score and T-score. These results suggest that femoral neck width may be a reliable predicting factor of bone mineral density.
MHE is an autosomal dominant disorder mainly caused by germline and heterozygous mutations in EXT1 and EXT2. MHE exhibits formation of multiple exostoses and skeletal deformities, including limb length discrepancy, forearm bowing deformities, lower-limb valgus deformities, and scoliosis [1–4]. Several mice models for this disease were established recently and understanding of this disease has been gradually advancing [3, 17, 18]. Nozawa S et al. reported that heparan sulfate (HS) regulate bone mass by interacting with osteoprotegerin and reduced bone mineral density in mice model . However, there is few information about bone mineral density in MHE patients. Recently, Matsumoto et al. reported that MHE patients have low bone mass in the lumbar spine and femoral neck area . In this study, the bone mineral density of most MHE patients in their femoral neck area (31 out of 40 hips) were within osteopenia or osteoporosis range.
Osteoporosis is a common disease characterized by reduced bone mass. The primary pathogenic mechanism of osteoporosis is an imbalance between bone formation and bone resorption, which are mediated by osteoclasts and osteoblasts, respectively. Recently, Matsumoto et al. reported that serum osteocalcin and urine NTx, the markers of bone formation and bone resorption, respectively, are within normal range in almost all MHE patients . These results suggest low bone mass in this disease might not be due to the alterations in bone metabolism. Therefore, we hypothesized that the low bone mass in MHE patients may be due to developmental abnormalities, such as proximal femur deformities, caused by the development of exostoses.
Hip exostoses are present in a high percentage of MHE patients, mainly in the proximal femur, which they have been reported in 30% to 90% of patients [19-21]. Furthermore, Duque Orozco et al. reported that hip exostoses were found in 90% of patients, and their most common location was the femoral neck . In this study, we focused on the hip geometry parameters and examined the correlation between these parameters and Z-score or T-score. Interestingly, there was no significant correlation between Z-score or T-score and femoral neck axis length, femoral head width, femoral shaft width, and neck shaft angle. Only femoral neck width was found to have a significant correlation with Z-score and T-score. As we have mentioned above, femoral neck is the frequent site for exostoses. Taken together, these facts suggest that the low bone mass of MHE patients is not due to abnormal bone metabolism, but to the development of exostoses.
Although exostoses around the hip are often asymptomatic, they can produce various deformities including hip dysplasia, subluxation, impingement, and premature osteoarthritis [20, 23-25]. In this study, we focused on these characteristic deformities and examined the correlation between various hip geometry parameters and BMD. We found that the femoral neck width may be one reliable predictor of low bone mass. These results suggest that the wider the femoral neck is, the lower the bone mass. These data support the hypothesis that the low bone mass in MHE patients may be due to the deformities caused by exostoses. However, MHE patients show various deformities including hip dysplasia and subluxation. These deformities may alter normal weight bearing and may affect bone mineral density. The mechanisms that lead to low bone mass in MHE patients are still unclear and more evidence are needed to elucidate them.
There are several limitations in this study. First, there is a limited number of MHE patients from only one institution. Second, we did not evaluate the deformities in the lower legs which may affect the degree of low bone mass in these patients. However, this is the first report where the relationship between BMD and hip geometry parameters in MHE patients was examined in detail. When a wide femoral neck is observed, we should suspect low bone mass in the patients. These results could provide useful information in understanding the mechanisms of MHE.