Low-intensity pulsed ultrasound (LIPUS) has been shown to accelerate fracture healing in both animal models and clinical trials, but the mechanism of action remains unclear. In fracture healing, various consecutive cellular reactions occurred until repair. We investigated whether the advanced effects of LIPUS depended on the duration and timing of LIPUS treatment in a rat closed femoral fracture model to determine the target of LIPUS in the healing process. Sixty-nine Long-Evans male rats that have bilateral closed femoral fractures were used. The right femur was exposed to LIPUS (30 mW/cm 2 spatial and temporal average [SATA], for 20 minutes/day), and the left femur was used as a control. Rats were divided into four groups according to timing and duration of treatment (Ph-1, days 1-8; Ph-2, days 9 -16; Ph-3, days 17-24; throughout [T], days 1-24 after the fracture). Animals were killed on day 25. After radiographs and microfocus X-ray computed tomography (CT) tomograms were taken, the hard callus area (HCA), bone mineral content (BMC) at the fracture site, and mechanical torsion properties were measured, and histological analysis was conducted. Interestingly, the maximum torque of the LIPUS-treated femur was significantly greater than that of the controls in all groups without any changes in HCA and BMC. The multiviewing of three-dimensional (3D) CT reconstructions and histology supported our findings that the partial LIPUS treatment time was able to accelerate healing, but longer treatment was more effective. These results suggest that LIPUS acts on some cellular reactions involved in each phase of the healing process such as inflammatory reaction, angiogenesis, chondrogenesis, intramembranous ossification, endochondral ossification, and bone remodeling. (J Bone Miner Res 2001;16:671-680)

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Fibroblast growth factor 2 (FGF-2) is a potent mitogen for mesenchymal cells, and a local application of recombinant human FGF-2 (rhFGF-2) in a gelatin hydrogel has been reported to accelerate bone union in our animal studies and preparatory dose-escalation trial on patients with surgical osteotomy. We have performed a randomized, double-blind, placebo-controlled trial in which patients with fresh tibial shaft fractures of transverse or short oblique type were randomly assigned to three groups receiving a single injection of the gelatin hydrogel containing either placebo or 0.8 mg (low-dosage group) or 2.4 mg (high-dosage group) of rhFGF-2 into the fracture gap at the end of an intramedullary nailing surgery. Of 194 consecutive patients over 2 years, 85 met the eligibility criteria, and 70 (24 in the placebo group and 23 each in low-and high-dosage groups) completed the 24-week study. The cumulative percentages of patients with radiographic bone union were higher in the rhFGF-2-treated groups ( p ¼ .031 and .009 in low-and high-dosage group, respectively) compared with the placebo group, although there was no significant difference between low-and high-dosage groups ( p ¼ .776). At 24 weeks, 4, 1, and 0 patients in the placebo, low-dosage, and high-dosage groups, respectively, continued to show delayed union. No patient underwent a secondary intervention, and the time to full weight bearing without pain was not significantly different among the three groups ( p ¼ .567). There also was no significant difference in the profiles of adverse events among the groups. In conclusion, a local application of the rhFGF-2 hydrogel accelerated healing of tibial shaft fractures with a safety profile. ß

In patients with developmental dysplasia of the hip, acetabular retroversion results from relatively deficient coverage by the posterior portion of the acetabulum. Developmental dysplasia with acetabular retroversion is associated with an earlier onset of pain than is developmental dysplasia with anteversion, suggesting a correlation between deficiency of the posterior acetabular wall and the earlier onset of pain.

Objective. To investigate the effects of combination treatment with an anticoagulant (warfarin) plus a lipid-lowering agent (probucol) on the prevention of steroid-induced osteonecrosis (ON) in rabbits.Methods. Adult male Japanese white rabbits were injected once intramuscularly with 20 mg/kg of methylprednisolone acetate into the right gluteus medius muscle. The rabbits were then divided into 4 groups and treated as follows: one group received warfarin plus probucol (WP; n ‫؍‬ 25), one received probucol alone (PA; n ‫؍‬ 30), one received warfarin alone (WA; n ‫؍‬ 26), and one received no treatment (nonprophylactic [NP]; n ‫؍‬ 20). Two weeks after the steroid injection, the femora and humeri were examined histopathologically for the presence of ON. The sizes of the bone marrow fat cells were examined morphologically. Hematologic examinations were performed before and after the steroid injection.Results. The incidence of ON in the WP group (5%) was significantly lower than that observed in the NP group (70%). While the incidence rates of ON in the PA (38%) and WA (33%) groups were also significantly lower than that in the NP group, they were significantly higher than that observed in the WP group. The sizes of the bone marrow fat cells in both the WP (53.5 ؎ 4.1 m) and the PA (52.0 ؎ 5.0 m) groups were significantly smaller than those in the NP group (60.0 ؎ 4.0 m). We also observed a prolongation of the prothrombin time and a reduction in the plasma lipid levels in the WP group during the study.Conclusion. This study experimentally confirmed that the combined use of an anticoagulant and a lipidlowering agent helps prevent steroid-induced ON in rabbits.

Bilateral femurs of 12-week-old female Sprague-Dawley rats were fractured, and the fractured femurs were harvested 36 h, 3, 7, 10, and 14 days after the fracture. Localization of cell proliferation in the fracture calluses was investigated using immunohistochemistry with antiproliferating cell nuclear antigen (PCNA) monoclonal antibodies. Thirty-six hours after the fracture, many PCNA-positive cells were observed in the whole callus. The change was not limited to mesenchymal cells at the fracture site where the inflammatory reaction had occurred, but extended in the periosteum along almost the entire femoral diaphysis where intramembranous ossification was initiated. On day 3, periosteal cells or premature osteoblasts in the newly formed trabecular bone during intramembranous ossification still displayed intense staining. On day 7, many premature chondrocytes and proliferating chondrocytes were PCNA positive. Endochondral ossification appeared on days 10 and 14, and the premature osteoblasts and endothelial cells in the endochondral ossification front were stained with anti-PCNA antibodies. Quantification of PCNA-positive cells was carried out using an image analysis computer system, obtaining a PCNA score for each cellular event. The highest score was observed in the periosteum early after the fracture near the fracture site. Immunohistochemistry using anti-PCNA antibodies showed that the distribution of proliferating cells and the degree of cell proliferation varied according to the time lag after the fracture, suggesting the existence of local regulatory factors such as growth factors, and that significant cell proliferation was observed at the beginning of each cellular event. (J Bone Miner Res 1997;12:96-102)