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Little D.G.,Orthopaedic Research and Biotechnology | Kim H.K.W.,Texas Scottish Rite Hospital for Children
Journal of Pediatric Orthopaedics | Year: 2011

Background: The observation that the pathogenesis of femoral head deformity in Legg-Calve-Perthes disease (LCPD) relates to bone resorption without subsequent coupled bone formation leads quickly to the hypothesis that antiresorptive agents may provide a useful adjunctive avenue for therapy. Robust bone catabolism in the absence of anabolism can only lead to femoral head deformity. Methods: The published data on bisphosphonate use in models of LCPD was reviewed. Results: Multiple animal studies support the further investigation of bisphosphonates and other anticatabolic agents in LCPD. Clinical data is only now starting to be gathered on the basis of animal and safety data.Rodent studies of traumatic and spontaneous osteonecrosis confirm that femoral head shape can be preserved by systemic bisphosphonate administration. Large animal piglet studies also show better preservation of the femoral head shape with systemic and local bisphosphonate administration, and also illustrate that systemic therapy requires initial revascularization of the necrotic head before its distribution within the head-a potential drawback of systemic therapy. Timing of effective dosing is likely to be very important. If the goal of treatment is to prevent deformity, then the window of therapy may be limited to an early stage of the disease before the significant collapse of the head.Although limiting bone resorption and preserving femoral head shape with bisphosphonates or other anticatabolic drugs may be of use, anabolic stimulation to speed up healing and new bone formation may also be desirable. Physical factors such as weight relief and activity modification may be important as the mechanical properties of the necrotic femoral head are significantly compromised during healing. The inflammatory nature of early LCPD is likely to also play a role in pathogenesis. These factors cannot be addressed by the use of antiosteoclastic therapy alone. Clinical Relevance: Further basic science and clinical studies are required to clarify the role of bisphosphonates as adjunctive therapy in LCPD. Copyright © 2011 by Lippincott Williams & Wilkins.

Ravarian R.,University of Sydney | Murphy C.M.,Orthopaedic Research and Biotechnology | Murphy C.M.,University of Sydney | Schindeler A.,Orthopaedic Research and Biotechnology | And 4 more authors.
RSC Advances | Year: 2015

Poly(methyl methacrylate) (PMMA) is broadly used for bone fixation. One of the major concerns of using this polymer is the lack of post-implantation integration with the host tissue. We have produced a novel hybrid ceramic-thermoplastic composite manufactured by a sol-gel method via covalent bonding between bioactive glass and PMMA to address this shortcoming. The uniform distribution of bioactive glass promoted the bioactivity of PMMA and substantially improved the biological properties. In this paper, we describe a refinement of the synthesis process of a previously manufactured PMMA-bioactive glass hybrid resulting in significantly more rapid fabrication. Key innovations were the replacement of tetrahydrofuran with ethanol as a more biologically benign reaction solvent, and the addition of sodium bicarbonate as a non-toxic catalyst. Our results showed that the gelation time was decreased 100-fold by increasing the reaction temperature from 25°C to 70°C, which also increased the rate of hardening 7-fold. The resulting hybrid monoliths displayed a more condensed structure with an 80% increase in network connectivity and 6-fold more resistance to degradation. These favorable biophysical properties of the new class of hybrids also enhanced the osteoblast adhesion and proliferation compared with the previously developed hybrids. This bioactive glass-PMMA hybrid has great potential to be used as a bone filler. © The Royal Society of Chemistry 2015.

Tagil M.,Orthopaedic Research and Biotechnology | Tagil M.,Lund University | McDonald M.M.,Orthopaedic Research and Biotechnology | Morse A.,Orthopaedic Research and Biotechnology | And 7 more authors.
Bone | Year: 2010

Intermittent Parathyroid Hormone (PTH)(1-34) has an established place in osteoporosis treatment, but also shows promising results in models of bone repair. Previous studies have been dominated by closed fracture models, where union is certain. One of the major clinical needs for anabolic therapies is the treatment of open and high energy fractures at risk of non-union. In the present study we therefore compared PTH(1-34) treatment in models of both open and closed fractures.108 male Wistar rats were randomly assigned to undergo standardized closed fractures or open osteotomies with periosteal stripping. 27 rats in each group were treated s.c. with PTH(1-34) at a dose of 50 μg/kg 5 days a week, the other 27 receiving saline. Specimens were harvested at 6 weeks for mechanical testing (n=17) or histological analysis (n=10).In closed fractures, union by any definition was 100% in both PTH(1-34) and saline groups at 6 weeks. In open fractures, the union rate was significantly lower (p<0.05), regardless of treatment. In open fractures the mechanically defined union rate was 10/16 (63%) in saline and 11/17 (65%) in PTH(1-34) treated fractures. By histology, the union rate was 3/9 (33%) with saline and 5/10 (50%) with PTH(1-34). Radiological union was seen in 13/25 (52%) for saline and 15/26 (58%) with PTH(1-34).Open fractures were associated with decreases in bone mineral content (BMC) and volumetric bone mineral density (vBMD) on quantitative computerized tomography (QCT) analysis compared to closed fractures. PTH(1-34) treatment in both models led to significant increases in callus BMC and volume as well as trabecular bone volume/total volume (BV/TV), as assessed histologically (p<0.01). In closed fractures, PTH(1-34) had a robust effect on callus size and strength, with a 60% increase in peak torque (p<0.05). In the open fractures that united and could be tested, PTH(1-34) treatment also increased peak torque by 49% compared to saline (p<0.05).In conclusion, intermittent PTH(1-34) produced significant increases in callus size and strength in closed fractures, but failed to increase the rate of union in an open fracture model. In the open fractures that did unite, a muted response to PTH was seen compared to closed fractures. Further research is required to determine if PTH(1-34) is an appropriate anabolic treatment for open fractures. © 2009 Elsevier Inc.

Morse A.,Orthopaedic Research and Biotechnology | Morse A.,University of Sydney | McDonald M.M.,Garvan Institute of Medical Research | Kelly N.H.,Cornell University | And 8 more authors.
Journal of Bone and Mineral Research | Year: 2014

Sclerostin, encoded by the Sost gene, is an important negative regulator of bone formation that has been proposed to have a key role in regulating the response to mechanical loading. To investigate the effect of long-term Sclerostin deficiency on mechanotransduction in bone, we performed experiments on unloaded or loaded tibiae of 10 week old female Sost-/-and wild type mice. Unloading was induced via 0.5U botulinum toxin (BTX) injections into the right quadriceps and calf muscles, causing muscle paralysis and limb disuse. On a separate group of mice, increased loading was performed on the left tibiae through unilateral cyclic axial compression of equivalent strains (+1200 μe) at 1200 cycles/day, 5 days/week. Another cohort of mice receiving equivalent loads (-9.0 N) also were assessed. Contralateral tibiae served as normal load controls. Loaded/unloaded and normal load tibiae were assessed at day 14 for bone volume (BV) and formation changes. Loss of BV was seen in the unloaded tibiae of wild type mice, but BV was not different between normal load and unloaded Sost-/- tibiae. An increase in BV was seen in the loaded tibiae of wild type and Sost-/- mice over their normal load controls. The increased BV was associated with significantly increased mid-shaft periosteal mineralizing surface/bone surface (MS/BS), mineral apposition rate (MAR), and bone formation rate/bone surface (BFR/BS), and endosteal MAR and BFR/BS. Notably, loading induced a greater increase in periosteal MAR and BFR/BS in Sost-/- mice than in wild type controls. Thus, long-term Sclerostin deficiency inhibits the bone loss normally induced with decreased mechanical load, but it can augment the increase in bone formation with increased load. © 2014 American Society for Bone and Mineral Research.

Murphy C.M.,Orthopaedic Research and Biotechnology | Murphy C.M.,University of Sydney | Schindeler A.,Orthopaedic Research and Biotechnology | Schindeler A.,University of Sydney | And 6 more authors.
Journal of Bone and Mineral Research | Year: 2015

Bisphosphonates (BP) are antiresorptive drugs with a high affinity for bone. Despite the therapeutic success in treating osteoporosis and metabolic bone diseases, chronic BP usage has been associated with reduced repair of microdamage and atypical femoral fracture (AFF). The latter has a poor prognosis, and although anabolic interventions such as teriparatide (PTH(1-34)) have been suggested as treatment options, there is a limited evidence base in support of their efficacy. Because PTH(1-34) acts to increase bone turnover, we hypothesized that it may be able to increase BP in turnover in the skeleton, which, in turn, may improve bone healing. To test this, we employed a mixture of fluorescent Alexa647-labelled pamidronate (Pam) and radiolabeled 14C-ZA (zoledronic acid). These traceable BPs were dosed to Wistar rats in models of normal growth and closed fracture repair. Rats were cotreated with saline or 25 μg/kg/d PTH(1-34), and the effects on BP liberation and bone healing were examined by X-ray, micro-CT, autoradiography, and fluorescent confocal microscopy. Consistent with increased BP remobilization with PTH(1-34), there was a significant decrease in fluorescence in both the long bones and in the fracture callus in treated animals compared with controls. This was further confirmed by autoradiography for 14C-ZA. In this model of acute BP treatment, callus bone volume (BV) was significantly increased in fractured limbs, and although we noted significant decreases in callus-bound BP with PTH(1-34), these were not sufficient to alter this BV. However, increased intracellular BP was noted in resorbing osteoclasts, confirming that, in principle, PTH(1-34) increases bone turnover as well as BP turnover. © 2015 American Society for Bone and Mineral Research. © 2015 American Society for Bone and Mineral Research.

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