Effects of Non-Weight-Bearing on the Immature Femoral Head Following Ischemic Osteonecrosis: An Experimental Investigation in Immature Pigs

Authors

Harry K.W. Kim, Olumide Aruwajoye, Jeffrey Stetler, Alec Stall

Abstract

Local non-weight-bearing as a treatment for Legg-Calvé-Perthes disease remains controversial since a clear scientific basis for this treatment is lacking. The purpose of this study was to determine the effects of non-weight-bearing on decreasing the femoral head deformity following ischemic osteonecrosis and to investigate its biological effects. Unilateral femoral head ischemia was induced in sixteen piglets by placing a ligature around the femoral neck and transecting the ligamentum teres. Eight animals received a hind-limb amputation to prevent weight-bearing on the ischemic side (NWB group). The remaining eight piglets were allowed to bear weight as tolerated (WB group). The contralateral femoral heads of the WB group were used as normal controls. All animals were killed at eight weeks after induction of ischemia, when a deformity is expected in this model. Radiographic, microcomputed tomographic (micro-CT), and histomorphometric assessments were performed. Radiographic and micro-CT assessments showed significantly greater flattening of the infarcted epiphysis in the WB group compared with the NWB group. The mean epiphyseal quotient (ratio of femoral head height to diameter) was significantly lower in the WB group (0.29 ± 0.06) compared with the NWB group (0.41 ± 0.06, p < 0.001). Histomorphometric analyses showed that the mean percentage revascularization of the infarcted epiphysis was significantly greater in the NWB group (95% ± 14%) compared with the WB group (34% ± 33%, p < 0.0004), suggesting that revascularization was more rapid in the NWB group. Both histomorphometric and micro-CT analyses of trabecular bone parameters showed significantly decreased bone volume and decreased trabecular number in the infarcted epiphysis of the NWB group compared with the WB group (p < 0.05). Local non-weight-bearing decreased the deformity following ischemic femoral head osteonecrosis and increased the rates of revascularization and resorption of the infarcted epiphysis. Local non-weight-bearing was mechanically protective but biologically suboptimal following ischemic osteonecrosis since it increased the imbalance of bone resorption and formation.

Link to Article

http://dx.doi.org/10.2106/JBJS.L.00300

Microcrack Density and Nanomechanical Properties in the Subchondral Region of the Immature Piglet Femoral Head following Ischemic Osteonecrosis

Authors

Olumide O. Aruwajoye, Mihir K. Patel, Matthew R. Allen, David B. Burr, Pranesh B. Aswath, Harry K.W. Kim

Abstract

Development of a subchondral fracture is one of the earliest signs of structural failure of the immature femoral head following ischemic osteonecrosis, and this eventually leads to a flattening deformity of the femoral head. The mechanical and mineralization changes in the femoral head preceding subchondral fracture have not been elucidated. We hypothesized that ischemic osteonecrosis leads to early material and mechanical alterations in the bone of the subchondral region. The purpose of this investigation was to assess the bone of the subchondral region for changes in the histology of bone cells, microcrack density, mineral content, and nanoindentation properties at an early stage of ischemic osteonecrosis in a piglet model. This large animal model has been shown to develop a subchondral fracture and femoral head deformity resembling juvenile femoral head osteonecrosis. The unoperated, left femoral head of each piglet (n = 8) was used as a normal control, while the right side had a surgical ischemia induced by disrupting the femoral neck vessels with a ligature. Hematoxylin and eosin (H&E) staining and TUNEL assay were performed on femoral heads from 3 piglets. Quantitative backscattered electron imaging, nanoindentation, and microcrack assessments were performed on the subchondral region of both control and ischemic femoral heads from 5 piglets. H&E staining and TUNEL assay showed extensive cell death and an absence of osteoblasts in the ischemic side compared to the normal control. Microcrack density in the ischemic side (3.2 ± 0.79 cracks/mm2) was significantly higher compared to the normal side (0.27 ± 0.27 cracks/mm2) in the subchondral region (p < 0.05). The weighted mean of the weight percent distribution of calcium (CaMean) also was significantly higher in the ischemic subchondral region (p < 0.05). Furthermore, the nanoindentation modulus within localized areas of subchondral bone was significantly increased in the ischemic side (16.8 ± 2.7 GPa) compared to the normal control (13.3 ± 3.2 GPa) (p < 0.05). Taken together, these results support the hypothesis that the nanoindentation modulus of the subchondral trabecular bone is increased in the early stage of ischemic osteonecrosis of the immature femoral head and makes it more susceptible to microcrack formation. We postulate that continued loading of the hip joint when there is a lack of bone cells to repair the microcracks due to ischemic osteonecrosis leads to microcrack accumulation and subsequent subchondral fracture.

Link to Article

http://dx.doi.org/10.1016/j.bone.2012.07.028

Ovariectomy stimulates and bisphosphonates inhibit intracortical remodeling in the mouse mandible

Authors

DJ Kubek, DB Burr, MR Allen

Abstract

The pathophysiology of osteonecrosis of the jaw (ONJ) is thought to be linked to suppression of intracortical remodeling. The aim of this study was to determine whether mice, which normally do not undergo appreciable amounts of intracortical remodeling, could be stimulated by ovariectomy to remodel within the cortex of the mandible and if bisphosphonates (BPs) would suppress this intracortical remodeling. Skeletally mature female C3H mice were either ovariectomized (OVX) or SHAM operated and treated with two intravenous doses of zoledronic acid (ZOL, 0.06 mg/kg body weight) or vehicle (VEH). This ZOL dose corresponds to the dose given to patients with cancer on a mg/kg basis, adjusted for body weight. Calcein was administered prior to sacrifice to label active formation sites. Dynamic histomorphometry of the mandible and femur was performed. Vehicle-treated OVX animals had significantly higher (eightfold) intracortical remodeling of the alveolar portion of the mandible compared to sham – this was significantly suppressed by ZOL treatment. At all skeletal sites, overall bone formation rate was lower with ZOL treatment compared to the corresponding VEH group. Under normal conditions, the level of intracortical remodeling in the mouse mandible is minimal but in C3H mice it can be stimulated to appreciable levels with ovariectomy. Based on this, if the suppression of intracortical remodeling is found to be part of the pathophysiology of ONJ, the ovariectomized C3H mouse could serve as a useful tool for studying this condition.

Link to Article

http://dx.doi.org/10.1111/j.1601-6343.2010.01497.x