The non-steroidal anti-inflammatory drug carprofen negatively impacts new bone formation and antibiotic efficacy in a rat model of orthopaedic-device-related infection.

Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used for pain management during recovery from orthopaedic surgery. NSAID use is associated with increased risk of bone healing complications but it is currently unknown whether NSAIDs increase the risk of developing an orthopaedic-device-related infection (ODRI) and/or affects its response to antibiotic therapy. The present study aimed to determine if administration of the NSAID carprofen [a preferential cyclooxygenase-2 (COX-2) inhibitor] negatively affected Staphylococcus epidermidis (S. epidermidis) bone infection, or its subsequent treatment with antibiotics, in a rodent ODRI model. Sterile or S. epidermidis-contaminated screws (~ 1.5 x 106 CFU) were implanted into the proximal tibia of skeletally mature female Wistar rats, in the absence or presence of daily carprofen administration. A subset of infected animals received antibiotics (rifampicin plus cefazolin) from day 7 to 21, to determine if carprofen affected antibiotic efficacy. Bone changes were monitored using in vivo µCT scanning and histological analysis. The risk of developing an infection with carprofen administration was assessed in separate animals at day 9 using a screw contaminated with 10² CFU S. epidermidis. Quantitative bacteriological analysis assessed bacterial load at euthanasia. In the 28-day antibiotic treatment study, carprofen reduced osteolysis but markedly diminished reparative bone formation, although total bacterial load was not affected at euthanasia. Antibiotic efficacy was negatively affected by carprofen (carprofen: 8/8 infected; control: 2/9 infected). Finally, carprofen increased bacterial load and diminished bone formation following reduced S. epidermidis inoculum (10² CFU) at day 9. This study suggests that NSAIDs with COX-2 selectivity reduce antibiotic efficacy and diminish reparative responses to S. epidermidis ODRI.

Medication-related osteonecrosis of the jaw in a minipig model: Parameters for developing a macroscopic, radiological, and microscopic grading scheme.

OBJECTIVES: To devise a macroscopic, radiological, and histological scale for assessing pathological changes associated with medication-related osteonecrosis of the jaw in a minipig model. MATERIALS AND METHODS: Medication-related osteonecrosis of the jaw was induced in Göttingen minipigs by weekly intravenous administration of bisphosphonate (zoledronic acid) combined with a tooth extraction procedure. Controls either did not receive zoledronic acid or did not undergo tooth extraction. After 20 weeks, minipigs were euthanized and underwent computed tomography and micro-computed tomography scanning. The mandible underwent additional histological examination. RESULTS: The most consistent macroscopic findings in animals that had developed bisphosphonate-related osteonecrosis of the jaw (BRONJ) were necrotic, denuded bone, and formation of fistula and pus. Under radiological examination, impaired extraction socket healing, decrease in attenuation of bone beneath the extraction site, and periosteal reaction were observed. Under histological examination, demineralization of the extracellular bone matrix, denuding of bone, and osteonecrosis were recorded. CONCLUSION: These parameters were used to develop a scoring system for grading BRONJ.

Implants delivering bisphosphonate locally increase periprosthetic bone density in an osteoporotic sheep model. A pilot study.

It is a clinical challenge to obtain a sufficient orthopaedic implant fixation in weak osteoporotic bone. When the primary implant fixation is poor, micromotions occur at the bone-implant interface, activating osteoclasts, which leads to implant loosening. Bisphosphonate can be used to prevent the osteoclastic response, but when administered systemically its bioavailability is low and the time it takes for the drug to reach the periprosthetic bone may be a limiting factor. Recent data has shown that delivering bisphosphonate locally from the implant surface could be an interesting solution. Local bisphosphonate delivery increased periprosthetic bone density, which leads to a stronger implant fixation, as demonstrated in rats by the increased implant pullout force. The aim of the present study was to verify the positive effect on periprosthetic bone remodelling of local bisphosphonate delivery in an osteoporotic sheep model. Four implants coated with zoledronate and two control implants were inserted in the femoral condyle of ovariectomized sheep for 4 weeks. The bone at the implant surface was 50% higher in the zoledronate-group compared to control group. This effect was significant up to a distance of 400mum from the implant surface. The presented results are similar to what was observed in the osteoporotic rat model, which suggest that the concept of releasing zoledronate locally from the implant to increase the implant fixation is not species specific. The results of this trial study support the claim that local zoledronate could increase the fixation of an implant in weak bone.

Surface-enrichment with hydroxyapatite nanoparticles in stereolithography-fabricated composite polymer scaffolds promotes bone repair.

Fabrication of composite scaffolds using stereolithography (SLA) for bone tissue engineering has shown great promises. However, in order to trigger effective bone formation and implant integration, exogenous growth factors are commonly combined to scaffold materials. In this study, we fabricated biodegradable composite scaffolds using SLA and endowed them with osteopromotive properties in the absence of biologics. First we prepared photo-crosslinkable poly(trimethylene carbonate) (PTMC) resins containing 20 and 40wt% of hydroxyapatite (HA) nanoparticles and fabricated scaffolds with controlled macro-architecture. Then, we conducted experiments to investigate how the incorporation of HA in photo-crosslinked PTMC matrices improved human bone marrow stem cells osteogenic differentiation in vitro and kinetic of bone healing in vivo. We observed that bone regeneration was significantly improved using composite scaffolds containing as low as 20wt% of HA, along with difference in terms of osteogenesis and degree of implant osseointegration. Further investigations revealed that SLA process was responsible for the formation of a rich microscale layer of HA corralling scaffolds. To summarize, this work is of substantial importance as it shows how the fabrication of hierarchical biomaterials via surface-enrichment of functional HA nanoparticles in composite polymer stereolithographic structures could impact in vitro and in vivo osteogenesis. STATEMENT OF SIGNIFICANCE: This study reports for the first time the enhance osteopromotion of composite biomaterials, with controlled macro-architecture and microscale distribution of hydroxyapatite particles, manufactured by stereolithography. In this process, the hydroxyapatite particles are not only embedded into an erodible polymer matrix, as reported so far in the literature, but concentrated at the surface of the structures. This leads to robust in vivo bone formation at low concentration of hydroxyapatite. The reported 3D self-corralling composite architecture provides significant opportunities to develop functional biomaterials for bone repair and tissue engineering.

Injectable calcium phosphate cement for augmentation around cancellous bone screws. In vivo biomechanical studies.

In lower cancellous apparent bone density, it can be difficult to achieve adequate screw fixation and hence stable fracture fixation. Different strategies have been proposed, one of them is through augmentation using calcium phosphate cement in the region at or close to the screw thread itself. To support the hypothesis of an improved screw fixation technique by augmentation of the bone surrounding the implanted screw, in vivo biomechanical and densitometric studies are performed on rabbit specimen where normal and simulated weak bone quality are considered. In particular, the evolution of screw stability till 12 weeks following the implantation is quantified. A statistical significance in the pull out force for augmented versus non-augmented screws was found for the shorter time periods tested of ≤ 5 days whilst the pull out force was found to increase with time for both augmented and non-augmented screws during the 12 week course of the study. The results of the study demonstrate that the use of an injectable calcium phosphate cement which sets in vivo can significantly improve screw pull out strength at and after implantation for normal and simulated weak bone quality.

Combined effects of zoledronate and mechanical stimulation on bone adaptation in an axially loaded mouse tibia.

BACKGROUND: local bisphosphonate delivery may be a solution to prevent periprosthetic bone loss and improve orthopedic implants fixation. In load-bearing implants, periprosthetic bone is exposed to high mechanical demands, which in normal conditions induce an adaptation of bone. In this specific mechanical situation, the modulation of the bone response by bisphosphonate remains uncertain. METHODS: we assessed the combined effects of zoledronate and mechanical loading on bone adaptation using an in-vivo axial compression model of the mouse tibia and injections of zoledronate. Bone structure was quantified with in-vivo microCT before and after the period of stimulation and the mechanical properties of the tibias were evaluated with 3 point-bending tests after sacrifice. FINDINGS: axial loading induced a localized increase of cortical thickness and bone area. Zoledronate increased cortical thickness, bone perimeter, and bone area. At the most loaded site of the tibia, the combined effect of zoledronate and mechanical stimulation was significantly smaller than the sum of the individual effects measured at the same site in the control groups. INTERPRETATIONS: the results of this study suggested that a negative interaction between zoledronate and mechanical loading might exist at high level of strain.