Low-intensity pulsed ultrasound increases blood vessel size during fracture healing in patients with a delayed-union of the osteotomized fibula.

Disturbed vascularity leads to impaired fracture healing. Since low-intensity pulsed ultrasound (LIPUS) increases new bone formation in delayed-unions, we investigated whether LIPUS increases blood supply in delayed-unions of the osteotomized fibula, and if LIPUS-increased bone formation is correlated to increased blood supply. Blood vessel parameters were analysed using histology, immunohistochemistry, and histomorphometric analysis as well as their correlation with bone formation and resorption parameters. Fibular biopsies of thirteen patients with a delayed-union of the osteotomized fibula treated for 2-4 months with or without LIPUS originating from a randomized prospective double-blind placebo-controlled clinical trial were studied. In histological sections of the fibular biopsies parameters of blood vessel formation were measured and were related to histomorphometric bone characteristics of newly formed bone of the same samples analysed in our previously published study on the effects of LIPUS on bone healing at the tissue level in delayed-unions. LIPUS-treated delayed-unions and sham-treated delayed-unions as well as healed delayed-unions and failed-to-heal delayed-unions were compared. The volume density of blood vessels was increased in LIPUS-treated delayed-unions compared to sham-treated controls. LIPUS did not change blood vessel number, but significantly increased blood vessel size. Healed delayed-unions as well as LIPUS-treated and sham-treated delayed-unions showed significant correlations between blood vessel size and osteoid volume. LIPUS increases blood vessel size, essential for fracture healing, in bone from patients with a delayed-union of the osteotomized fibula. The increased osteoid volume in delayed-unions can largely be explained by increased blood supply and perfusion.

A histomorphometric and micro-computed tomography study of bone regeneration in the maxillary sinus comparing biphasic calcium phosphate and deproteinized cancellous bovine bone in a human split-mouth model.

OBJECTIVE: The gain of mineralized bone was compared between deproteinized bovine bone allograft (DBA) and biphasic calcium phosphate (BCP) for dental implant placement. STUDY DESIGN: Five patients with atrophic maxillae underwent bilateral sinus elevation with DBA (Bio-Oss) and BCP (Straumann BoneCeramic). After 3 to 8 months, 32 Camlog implants were placed, and biopsies were retrieved. Bone and graft volume, degree of bone mineralization, and graft degradation gradient were determined using micro-computed tomography, and bone formation and resorption parameters were measured using histomorphometry. Implant functioning and peri-implant mucosa were evaluated up to 4 years. RESULTS: Patients were prosthetically successfully restored. All but one of the implants survived, and peri-implant mucosa showed healthy appearance and stability. Bone volume, graft volume, degree of bone mineralization, and osteoclast and osteocyte numbers were similar, but BCP-grafted biopsies had relatively more osteoid than DBA-grafted biopsies. CONCLUSIONS: The BCP and DBA materials showed similar osteoconductive patterns and mineralized bone, although signs of more active bone formation and remodeling were observed in BCP- than in DBA-grafted biopsies.

The Src inhibitor AZD0530 reversibly inhibits the formation and activity of human osteoclasts.

Tumor cells in the bone microenvironment are able to initiate a vicious cycle of bone degradation by mobilizing osteoclasts, multinucleated cells specialized in bone degradation. c-Src is highly expressed both in tumors and in osteoclasts. Therefore, drugs like AZD0530, designed to inhibit Src activity, could selectively interfere with both tumor and osteoclast activity. Here we explored the effects of AZD0530 on human osteoclast differentiation and activity. The effect on osteoclasts formed in vivo was assessed in mouse fetal calvarial explants and in isolated rabbit osteoclasts, where it dose-dependently inhibited osteoclast activity. Its effect on formation and activity of human osteoclasts in vitro was determined in cocultures of human osteoblasts and peripheral blood mononuclear cells. AZD0530 was most effective in inhibiting osteoclast-like cell formation when present at the onset of osteoclastogenesis, suggesting that Src activity is important during the initial phase of osteoclast formation. Formation of active phosphorylated c-Src, which was highly present in osteoclast-like cells in cocultures and in peripheral blood mononuclear cell monocultures, was significantly reduced by AZD0530. Furthermore, it reversibly prevented osteoclast precursor migration from the osteoblast layer to the bone surface and subsequent formation of actin rings and resorption pits. These data suggest that Src is pivotal for the formation and activity of human osteoclasts, probably through its effect on the distribution of the actin microfilament system. The reversible effect of AZD0530 on osteoclast formation and activity makes it a promising candidate to temper osteoclastic bone degradation in bone diseases with enhanced osteoclast activity such as osteolytic metastatic bone disease.

Low-intensity pulsed ultrasound increases bone volume, osteoid thickness and mineral apposition rate in the area of fracture healing in patients with a delayed union of the osteotomized fibula.

INTRODUCTION: Low-intensity pulsed ultrasound (LIPUS) accelerates impaired fracture healing, but the exact mechanism is unknown. The aim of this study was to investigate how LIPUS affects bone healing at the tissue level in patients with a delayed union of the osteotomized fibula, by using histology and histomorphometric analysis to determine bone formation and bone resorption parameters. MATERIALS AND METHODS: Biopsies were obtained from 13 patients (9 female, 4 male; age 42-63) with a delayed union of the osteotomized fibula after a high tibial osteotomy, treated for 2-4 months with or without LIPUS in a randomized prospective double-blind placebo-controlled trial. In the histological sections of the delayed union biopsies, 3 areas of interest were distinguished, i.e. 1) area of new bone formation at the fracture ends, 2) area of cancellous bone, and 3) area of cortical bone. Histomorphometrical analysis was performed to determine bone formation and bone resorption parameters (as well as angiogenesis). RESULTS: In LIPUS-treated delayed unions, endosteal callus formation by direct bone formation without a cartilage intermediate as well as indirect bone formation was observed, while in untreated controls only indirect bone formation was observed. In the area of new bone formation, LIPUS significantly increased osteoid thickness by 47%, mineral apposition rate by 27%, and bone volume by 33%. No increase in the number of blood vessels was seen in the newly formed bony callus. In the area of cancellous bone, bone volume was significantly increased by 17% whereas no effect on osteoid thickness and mineral apposition rate was seen. LIPUS did not affect osteoid volume, osteoid maturation time, number of osteocytes, osteocyte lacunae, or osteoclast-like cells in any of the areas of interest. CONCLUSIONS: Our results suggest that LIPUS accelerates clinical fracture healing of delayed unions of the fibula by increasing osteoid thickness, mineral apposition rate, and bone volume, indicating increased osteoblast activity, at the front of new bony callus formation. Improved stability and/or increased blood flow, but probably not increased angiogenesis, might explain the differences in ossification modes between LIPUS-treated delayed unions and untreated controls.