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 µCT before and after the period of stimulation and the biomechanical 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 effect of zoledronate plus the effect of mechanical loading. Interpretations: The results of this study suggested that a negative interaction between zoledronate and mechanical loading might exist at high level of strain

Microstimulations at the bone implant interface upregulate osteoclast activation pathway

Peri-implant bone resorption after total joint arthroplasty is a key parameter in aseptic loosening. Implant wear debris and biomechanical aspects have both been demonstrated to be part of the bone resorption process. However, neither of these two parameters has been clearly identified as the primary initiator of peri-implant bone resorption. For the biomechanical parameters, micromotions were measured at the bone implant interface during normal gait cycles. The amplitude of the micromotions was shown to trigger differentiation of bone tissues. So far no data exists directly quantifying the effect of micromotion and compression on human bone. We hypothesize that micromotion and compression at the bone implant interface may induce direct activation of bone resorption around the implant through osteoblasts- osteoclasts cell signaling in human bone. This hypothesis was tested with an ex vivo loading system developed to stimulate trabecular bone cores and mimic the micromotions arising at the bone-implant interface. Gene expression of RANKL, OPG, TGFB2, IFNG and CSF-1 were analyzed after no mechanical stimulation (control), exposure to static compression or exposure to micromotions. We observed an 8-fold upregulation of RANKL after exposure to micromotions, and down regulation of OPG, IFNG and TGFB2. The RANK:OPG ratio was up regulated 24 fold after micromotions. This suggests that the micromotions arising at the bone-implant interface during normal gait cycles induce a bone resorption response after only one hour, which occurs before any wear debris particles enter the system

3D strain map of axially loaded mouse tibia: a numerical analysis validated by experimental measurements

A combined experimental/numerical study was performed to calculate the zone of highest strain in a rat tibia loaded axially. This study is motivated by the fact that the bone remodeling analysis in this in vivo rat model should be performed at the zone of highest mechanical stimulus to maximize the measured effects. Accordingly, it is proposed that quantification of bone remodeling should be performed at the tibial crest and at the distal diaphysis. The numerical model could also be used to furnish a more subtle analysis as a precise correlation between local strain and local biological response can be obtained with the experimentally validated numerical model

Fatigue as the missing link between bone fragility and fracture

The prevention of fragility fractures in bone—pathologic fractures resulting from daily activity and mostly occurring in the elderly population—has been a long-term clinical quest. Recent research indicating that falls in the elderly might be the conse- quence of fracture rather than its cause has raised fundamental questions about the origin of fragility fractures. Is day-to-day cyclic loading, instead of a single-load event such as a fall, the main cause of progressively growing fractures? Are fragility fractures predominantly affected by bone quality rather than bone mass, which is the clinical indicator of fracture risk? Do osteocytes actively participate in the bone repair process? In this Perspective, we discuss the central role of cyclic fatigue in bone fragility fracture

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 orthopedic 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 remodeling 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 400µm 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

Prediction of bone density around orthopedic implants delivering bisphosphonate

The fixation of an orthopedic implant depends strongly upon its initial stability. Peri-implant bone may resorb shortly after the surgery. This resorbtion is directly followed by new bone formation and implants fixation strengthening, the so-called secondary fixation. If the initial stability is not reached, the resorbtion continues and the implant fixation weakens, which leads to implant loosening. Studies with rats and dogs have shown that a solution to prevent peri-implant resorbtion is to deliver bisphosphonate from the implant surface. The aims of the study were, first, to develop a model of bone remodeling around an implant delivering bisphosphonate, second, to predict the bisphosphonate dose that would induce the maximal peri- implant bone density, and third to verify in vivo that peri-implant bone density is maximal with the calculated dose. The model consists of a bone remodeling equation and a drug diffusion equation. The change in bone density is driven by a mechanical stimulus and a drug stimulus. The drug stimulus function and the other numerical parameters were identified from experimental data. The model predicted that a dose of 0.3µg of zolderonate on the implant would induce a maximal bone density. Implants with 0.3µg of zoledronate were then implanted in rat femurs for 3, 6 and 9 weeks. We measured that peri-implant bone density was 4% greater with the calculated dose compared to the dose empirically described as best. The approach presented in this paper could be used in the design and analysis processes of experiments in local delivery of drug such as bisphosphonate

Orbital floor repair using patient specific osteoinductive implant made by stereolithography

The orbital floor (OF) is an anatomical location in the craniomaxillofacial (CMF) region known to be highly variable in shape and size. When fractured, implants commonly consisting of titanium meshes are customized by plying and crude hand-shaping. Nevertheless, more precise customized synthetic grafts are needed to meticulously reconstruct the patients’ OF anatomy with better fidelity. As alternative to titanium mesh implants dedicated to OF repair, we propose a flexible patient-specific implant (PSI) made by stereolithography (SLA), offering a high degree of control over its geometry and architecture. The PSI is made of biodegradable poly(trimethylene carbonate) (PTMC) loaded with 40 wt % of hydroxyapatite (called Osteo-PTMC). In this work, we developed a complete work-flow for the additive manufacturing of PSIs to be used to repair the fractured OF, which is clinically relevant for individualized medicine. This work-flow consists of (i) the surgical planning, (ii) the design of virtual PSIs and (iii) their fabrication by SLA, (iv) the monitoring and (v) the biological evaluation in a preclinical large-animal model. We have found that once implanted, titanium meshes resulted in fibrous tissue encapsulation, whereas Osteo-PMTC resulted in rapid neovascularization and bone morphogenesis, both ectopically and in the OF region, and without the need of additional biotherapeutics such as bone morphogenic proteins. Our study supports the hypothesis that the composite osteoinductive Osteo-PTMC brings advantages compared to standard titanium mesh, by stimulating bone neoformation in the OF defects. PSIs made of Osteo-PTMC represent a significant advancement for patients whereby the anatomical characteristics of the OF defect restrict the utilization of traditional hand-shaped titanium mesh

The Origins of Concentric Demyelination: Self-Organization in the Human Brain

Baló's concentric sclerosis is a rare atypical form of multiple sclerosis characterized by striking concentric demyelination patterns. We propose a robust mathematical model for Baló's sclerosis, sharing common molecular and cellular mechanisms with multiple sclerosis. A reconsideration of the analogies between Baló's sclerosis and the Liesegang periodic precipitation phenomenon led us to propose a chemotactic cellular model for this disease. Rings of demyelination appear as a result of self-organization processes, and closely mimic Baló lesions. According to our results, homogeneous and concentric demyelinations may be two different macroscopic outcomes of a single fundamental immune disorder. Furthermore, in chemotactic models, cellular aggressivity appears to play a central role in pattern formation