Expression of XBP1s in fibroblasts is critical for TiAl6V4 particle‐induced RANKL expression and osteolysis

Wear particle‐induced osteolysis is a major cause of aseptic loosening, which is one of the most common reasons for total hip arthroplasty (THA) failure. Previous studies have shown that the expression of Receptor activation of nuclear factor (NF)‐kB (RANKL) by fibroblasts in periprosthetic membrane played a crucial role in wear particle‐induced osteolysis. However, the underlying mechanism of RANKL expression remains largely unknown. In the present study, we investigated the effect of TiAl₆V₄ particle (TiPs)‐induced XBP1s (spliced form of X‐box binding protein 1) on RANKL expression and osteoclastogenesis both in vitro and in vivo. The levels of XBP1s in peri‐implant membrane, animal models, and TiPs‐stimulated fibroblasts were determined by western blots. To assess the effect of XBP1s on RANKL expression, fibroblasts were treated with both a small interfering RNA (siRNA) and an inhibitor of XBP1 prior to exposure to TiPs. The effect of XBP1s on osteoclasts formation was determined by tartrate‐resistant acid phosphatase (TRAP) staining in vitro osteoclastogenesis assay and in animal models. The resorption of bone was assessed by micro‐computed tomography (micro‐CT) with three‐dimensional reconstruction. Our results demonstrated that XBP1s was activated in periprosthetic membrane, mouse calvaria models, and TiPs‐stimulated human synovial fibroblasts. Further, inhibition of XBP1s decreased the expression of RANKL and osteoclasts formation in vitro. In mouse calvaria models, both of the osteoclastogenesis and osteolysis were inhibited XBP1s inhibitor. Our results suggested that XBP1s mediated TiPs‐induced of RANKL expression in fibroblasts, and down regulating XBP1s may represent a potential therapy for wear particle‐induced osteolysis. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:752–759, 2017.

     

Effects of sequential treatment with intermittent parathyroid hormone and zoledronic acid on particle‐induced implant loosening: Evidence from a rat model

Particle‐induced implant loosening is a major challenge to long‐term survival of joint prostheses. Administration of intermittent parathyroid hormone (PTH) has shown potential in the treatment of cases of early‐stage periprosthetic osteolysis, while sequential administration of intermittent PTH (iPTH) and bisphosphonates (Bps) has achieved significant effects on treatment of postmenopausal osteoporosis. The objective of this study was to determine whether sequential treatment could preserve bone mass and implant fixation during a pathological course of peri‐implant osteolysis in a rat model. Ninety male Sprague Dawley rats were randomly divided into nine groups, four of which were used for confirmation of establishment of the peri‐implant osteolysis model at two time points, while the other five were used to determine the efficiency of the sequential treatment on peri‐implant osteolysis. Implant fixation and peri‐implant bone mass were evaluated using biomechanical testing, micro‐CT analysis, and histology at 6 and 12 weeks postoperative. The biomechanical test demonstrated that the maximum loading force during a push‐out test was significantly elevated in the sequential treatment group compared to the osteolysis group and iPTH withdrawal group at 12 weeks. Peri‐implant bone morphology also indicated a robust increase in bone volume in the sequential treatment group. Sequential administration of iPTH and Bps was effective in preventing experimental peri‐implant osteolysis, resulting in improved implant fixation and increased peri‐implant bone volume. Clinical significance: The innovative application of sequential treatment in peri‐implant osteolysis could be used clinically to improve the prognosis of patients with early‐stage periprosthetic osteolysis. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:1489–1497, 2019.     

The effects of local and systemic alendronate delivery on wear debris‐induced osteolysis in vivo

We investigated the effects of locally and systemically administered alendronate on wear debris‐induced osteolysis in vivo. Endotoxin‐free titanium particles were injected into rabbit femurs, prior to insertion of a nonweight‐bearing polymethylmethacrylate plug into the distal femur canal. Then the particles were repeatedly injected into the knee 2, 4, and 6 weeks after the implantation. Alendronate was incorporated at three different concentrations (0.1, 0.5, and 1.0 wt %) into bone cement for local delivery. For systemic delivery, alendronate was subcutaneously injected (1.0 mg/kg/week) 1 week after the implantation and then once a week until sacrifice. Eight weeks postoperatively, there was significant evidence of osteolysis surrounding the plug in the control group compared with markedly blocked osteolysis in the 0.5 wt % and the 1.0 wt % groups, and the systemic group. There was a concentration‐dependent effect of alendronate‐loaded bone cement on the improvement of peri‐prosthetic bone stock. Notably, no significant differences were found between the 0.5 wt % and the systemic group in peri‐prosthetic bone stock and implant fixation. Collectively, although the biological efficacy after the systemic delivery of alendronate was slightly higher than that in the local treatment groups, alendronate‐loaded bone cement may be therapeutically effective in inhibiting titanium particle‐induced osteolysis in vivo. © 2010 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:893–899, 2010     

Local delivery of mutant CCL2 protein‐reduced orthopaedic implant wear particle‐induced osteolysis and inflammation in vivo

Total joint replacement (TJR) has been widely used as a standard treatment for late‐stage arthritis. One challenge for long‐term efficacy of TJR is the generation of ultra‐high molecular weight polyethylene wear particles from the implant surface that activates an inflammatory cascade which may lead to bone loss, prosthetic loosening and eventual failure of the procedure. Here, we investigate the efficacy of local administration of mutant CCL2 proteins, such as 7ND, on reducing wear particle‐induced inflammation and osteolysis in vivo using a mouse calvarial model. Mice were treated with local injection of 7ND or phosphate buffered saline (PBS) every other day for up to 14 days. Wear particle‐induced osteolysis and the effects of 7ND treatment were evaluated using micro‐CT, histology, and immunofluorescence staining. Compared with the PBS control, 7ND treatment significantly decreased wear particle‐induced osteolysis, which led to a higher bone volume fraction and bone mineral density. Furthermore, immunofluorescence staining showed 7ND treatment decreased the number of recruited inflammatory cells and osteoclasts. Together, our results support the feasibility of local delivery of 7ND for mitigating wear particle‐induced inflammation and osteolysis, which may offer a promising strategy for extending the life time of TJRs. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:58–64, 2016.     

Antisense oligonucleotide targeting TNF‐α can suppress co‐cr‐mo particle‐induced osteolysis

The most common cause of implant failure in joint replacement is aseptic loosening due to particle‐induced osteolysis. TNF‐α has been shown to be one of the key factors in the process of osteoclastogenesis. Anti‐TNF agents are useful in the treatment of joint inflammation related to osteolysis. This study investigated the effect of a single subcutaneous dose of an antisense oligonucleotide (ASO) on particle‐induced osteolysis. We utilized the murine calvaria osteolysis model in C57BL/J6 mice. Bone resorption was measured by the toluidine blue staining. Osteoclasts were detected by tartrate resistant acid phosphatase (TRAP) staining assay and were quantified by a TRAP quantification kit. Results show that bone resorption is 0.347 ± 0.09 mm² in mice with particle implantation, and decreased to 0.123 ± 0.05 mm² and 0.052 ± 0.02 mm² after ASO treatment with low and high doses, respectively. The number of osteoclasts in animal calvaria treated with ASO is reduced compared with that of untreated animals, and the quantification results indicate that about 90% of osteoclastogenesis is suppressed by the ASO. In addition, the osteoclastogenesis can be reestablished by the addition of TNF‐α. In conclusion, we demonstrate that the antisense oligonucleotide targeting to TNF‐α can suppress osteolysis induced by metal particles in a murine calvaria model. This new finding may be of value in the search for novel therapeutic methods for implant loosening. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:1114–1120, 2008     

Particle‐induced osteolysis is not accompanied by systemic remodeling but is reflected by systemic bone biomarkers

Particle‐induced osteolysis is caused by an imbalance in bone resorption and formation, often leading to loss of implant fixation. Bone remodeling biomarkers may be useful for identification of osteolysis and studying pathogenesis, but interpretation of biomarker data could be confounded if local osteolysis engenders systemic bone remodeling. Our goal was to determine if remote bone remodeling contributes to biomarker levels. Serum concentrations of eight biomarkers and bone remodeling rates at local (femur), contiguous (tibia), and remote (humerus and lumbar vertebra) sites were evaluated in a rat model of particle‐induced osteolysis. Serum CTX‐1, cathepsin K, PINP, and OPG were elevated and osteocalcin was suppressed in the osteolytic group, but RANKL, TRAP 5b, and sclerostin were not affected at the termination of the study at 12 weeks. The one marker tested longitudinally (CTX‐1) was elevated by 3 weeks. We found increased bone resorption and decreased bone formation locally, subtle differences in contiguous sites, but no differences remotely at 12 weeks. Thus, the skeletal response to local particle challenge was not systemic, implying that the observed differences in serum biomarker levels reflect differences in local remodeling. © 2014 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:967–973, 2014.     

Adverse local tissue reaction (ALTR) associated with corrosion products in metal‐on‐metal and dual modular neck total hip replacements is associated with upregulation of interferon gamma‐mediated chemokine signaling

Adverse local tissue reactions (ALTR) associated with tribocorrosion following total hip arthroplasty (THA) have become a significant clinical concern in recent years. In particular, implants featuring metal‐on‐metal bearing surfaces and modular femoral stems have been reported to result in elevated rates of ALTR. These tribocorrosion‐related tissue reactions are characterized by marked necrosis and lymphocytic infiltration, which contrasts sharply with the macrophagic and foreign body giant cell inflammation associated with polyethylene wear particle induced peri‐implant osteolysis. In this study, we characterize tribocorrosion‐associated ALTR at a molecular level. Gene expression profiling of peri‐implant tissue around failing implants identifies upregulation of numerous inflammatory mediators in ALTR, including several interferon gamma inducible factors, most notably the chemokines MIG/CXCL9 and IP‐10/CXCL10. This expression profile is distinct from that associated with polyethylene wear induced osteolysis, which is characterized by induction of markers of alternative macrophage activation, such as chitotriosidase (CHIT‐1). Importantly, MIG/CXCL9 and IP‐10/CXCL10 are also elevated at the protein level in the synovial fluid and, albeit more moderately, the serum, of ALTR patients, raising the possibility that these factors may serve as circulating biomarkers for the early detection of ALTR in at‐risk patients. © 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 33:1487–1497, 2015.     

Local bisphosphonate treatment increases fixation of hydroxyapatite‐coated implants inserted with bone compaction

It has been shown that fixation of primary cementless joint replacement can independently be enhanced by either: (1) use of hydroxyapatite (HA) coated implants, (2) compaction of the peri‐implant bone, or (3) local application of bisphosphonate. We investigated whether the combined effect of HA coating and bone compaction can be further enhanced with the use of local bisphosphonate treatment. HA‐coated implants were bilaterally inserted into the proximal tibiae of 10 dogs. On one side local bisphosphonate was applied prior to bone compaction. Saline was used as control on the contralateral side. Implants were evaluated with histomorphometry and biomechanical push‐out test. We found that bisphosphonate increased the peri‐implant bone volume fraction (1.3‐fold), maximum shear strength (2.1‐fold), and maximum shear stiffness (2.7‐fold). No significant difference was found in bone‐to‐implant contact or total energy absorption. This study indicates that local alendronate treatment can further improve the fixation of porous‐coated implants that have also undergone HA‐surface coating and peri‐implant bone compaction. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27:189–194, 2009     

miR‐21 expression is related to particle‐induced osteolysis pathogenesis

Previous studies have found that microRNA‐21 (miR‐21) is an important functional factor during osteoclast differentiation. Abnormal osteoclastogenesis induced by wear particles is the main cause of aseptic loosening in joint replacements. The aim of the present study is to investigate the possible role of miR‐21 in the pathogenesis of particle‐induced osteolysis (PIO). miR‐21 expression was examined in a PIO mouse model using real‐time (RT‐PCR). Osteoclastogenesis was determined by a tartrate resistant acid phosphatase (TRAP) quantification method. A toluidine blue staining assay was used to examine calvarial osteolysis. The results demonstrated that miR‐21 was significantly upregulated in the PIO animal model. Knocking out miR‐21 in the particle‐stimulated tissue could ameliorate osteolysis symptoms. Additionally, through our analysis of PDCD4 and AP‐1 expression, we suggest that the feedback loop of AP‐1, miR‐21, and PDCD4 might have an important influence on the development of PIO and that miR‐21 is a potential target for implant loosening therapies. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 30:1837–1842, 2012     

Particle bioreactivity and wear-mediated osteolysis

This review focuses on wear debris-mediated osteolysis, a major factor compromising the long-term success of total joint arthroplasty. Studies on retrieved implants and animal models, as well as in vitro studies on particle bioreactivity, suggest that wear-mediated periprosthetic osteolysis is unlikely to be caused solely by 1 particular cell type or particulate species, but is rather the cumulative consequence of a number of biological reactions. Our recent findings suggest 3 novel mechanisms of particle bioreactivity that may contribute to osteolysis: 1) exacerbated inflammation caused by elevated reactive oxygen species production by activated macrophages and osteoclasts, (2) impaired periprosthetic bone formation secondary to disrupted osteogenesis, and (3) compromised bone regeneration resulting from increased cytotoxic response of mesenchymal osteoprogenitor cells. Understanding the pathogenesis of wear-mediated osteolysis is needed to improve orthopedic implant biocompatibility and wear reduction, and to develop effective pharmacotherapies.     

Augmentation of peri‐implant bone improves implant stability: Quantification using simulated bone loss

Low bone quality, such as induced by osteoporosis, is considered a main factor leading to failure of fracture fixations. Peri‐implant bone augmentation has been proposed as a means of reducing failure rates in osteoporotic bone by improving implant stability. The beneficial effects of pharmacological augmentation of bone in the immediate vicinity of the implant have been demonstrated. Yet, a quantitative understanding of the role of peri‐implant bone in implant stability is lacking. Therefore, the aim of our study was to quantify the effects of bone loss and peri‐implant bone augmentation on implant stability using image‐based finite element analyses. Using a validated model, we simulated how osteoporotic bone loss would affect implant stability in human humeral heads. We also quantified how augmentation of peri‐implant bone can enhance implant stability. Our simulations revealed that a 30% reduction in bone mass led to a 50% decrease in implant stability. We also found that peri‐implant bone augmentation increased implant stability and that the efficiency of bone augmentation decreased with increasing peri‐implant distance. These findings highlight the strong effect that bone loss has on implant fixation and the potential of peri‐implant bone augmentation for improving implant anchorage in low quality bone. © 2011 Orthopaedic Research Society Published by Wiley Periodicals, Inc. J Orthop Res 30:178–184, 2012     

A novel in silico method to quantify primary stability of screws in trabecular bone

Insufficient primary stability of screws in bone leads to screw loosening and failure. Unlike conventional continuum finite‐element models, micro‐CT based finite‐element analysis (micro‐FE) is capable of capturing the patient‐specific bone micro‐architecture, providing accurate estimates of bone stiffness. However, such in silico models for screws in bone highly overestimate the apparent stiffness. We hypothesized that a more accurate prediction of primary implant stability of screws in bone is possible by considering insertion‐related bone damage. We assessed two different screw types and loading scenarios in 20 trabecular bone specimens extracted from 12 cadaveric human femoral heads (N = 5 for each case). In the micro‐FE model, we predicted specimen‐specific Young's moduli of the peri‐implant bone damage region based on morphometric parameters such that the apparent stiffness of each in silico model matched the experimentally measured stiffness of the corresponding in vitro specimen as closely as possible. The standard micro‐FE models assuming perfectly intact peri‐implant bone overestimated the stiffness by over 330%. The consideration of insertion related damaged peri‐implant bone corrected the mean absolute percentage error down to 11.4% for both loading scenarios and screw types. Cross‐validation revealed a mean absolute percentage error of 14.2%. We present the validation of a novel micro‐FE modeling technique to quantify the apparent stiffness of screws in trabecular bone. While the standard micro‐FE model overestimated the bone‐implant stiffness, the consideration of insertion‐related bone damage was crucial for an accurate stiffness prediction. This approach provides an important step toward more accurate specimen‐specific micro‐FE models. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2415–2424, 2017.

     

Healing in peri‐implant gap with BMP‐2 and systemic bisphosphonate is dependent on BMP‐2 dose—A canine study

The bone–implant interface of cementless orthopedic implants can be described as a series of uneven sized gaps with discontinuous areas of direct bone–implant contact. Bridging these voids and crevices by addition of an anabolic stimulus to increase new bone formation can potentially improve osseointegration of implants. Bone morphogenetic protein 2 (BMP‐2) stimulates osteoblast formation to increase new bone formation but also indirectly stimulates osteoclast activity. In this experiment, we investigate the hypothesis that osseointegration, defined as mechanical push‐out and histomorphometry, depends on the dose of BMP‐2 when delivered as an anabolic agent with systemic administration of the anti‐resorptive agent zoledronate to curb an increase in osteoclast activity. Four porous coated titanium implants (one with each of three doses of surface‐applied BMP‐2 (15 µg; 60 µg; 240 µg) and untreated) surrounded by a 0.75 mm empty gap, were inserted into the distal femurs of each of twelve canines. Zoledronate IV (0.1 mg/kg) was administered 10 days into the observation period of 4 weeks. Bone–implant specimens were evaluated by mechanical push‐out test and histomorphometry. The 15 µg implants had the best fixation on all mechanical parameters and largest surface area covered with new bone compared to the untreated, 60 and 240 µg implants, as well as the highest volume of new bone in the implant gap compared to 60 and 240 µg implants. The results in a canine implant model demonstrated that a narrow range of BMP‐2 doses have opposite effects in bridging an empty peri‐implant gap with bone, when combined with systemic zoledronate. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1406–1414, 2018.

     

Local delivery of zoledronate from a poly (d,l‐lactide)‐coating increases fixation of hydroxy‐coated implants

Initial secure implant fixation predicts long‐term survival. Bisphosphonates are anti‐resorptive agents. They have been shown to increase implant fixation. We investigated whether local delivery of zoledronate from a poly‐d ,l ‐lactide (PDLLA)‐coating could improve fixation and osseointegration of hydroxy‐apatite coated implants. Cylindrical hydroxy‐apatite coated implants were bilaterally inserted press‐fit into the proximal tibiae of 10 dogs. On one side the implant was coated with PDLLA containing zoledronate. The PDLLA coating was applied upon the hydroxy‐apatite coating. We used the contralateral implant as control. This implant was not coated with a poly‐d ,l ‐lactide. Observation period was 12 weeks. We evaluated implant fixation with histomorphometry and biomechanical push‐out test. Zoledronate resulted in an approximately threefold increase in all biomechanical parameters when comparing data with their respective controls. We found that zoledronate increased preservation of old lamellar bone and increased formation of new woven bone. This study indicates that local delivery of zoledronate from a PDDLA coating has the potential to increase implant fixation. Studies investigating different doses of zoledronate and longer follow‐up are needed. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:974–979, 2017.

     

Fully porous 3D printed titanium femoral stem to reduce stress‐shielding following total hip arthroplasty

Current hip replacement femoral implants are made of fully solid materials which all have stiffness considerably higher than that of bone. This mechanical mismatch can cause significant bone resorption secondary to stress shielding, which can lead to serious complications such as peri‐prosthetic fracture during or after revision surgery. In this work, a high strength fully porous material with tunable mechanical properties is introduced for use in hip replacement design. The implant macro geometry is based off of a short stem taper‐wedge implant compatible with minimally invasive hip replacement surgery. The implant micro‐architecture is fine‐tuned to locally mimic bone tissue properties which results in minimum bone resorption secondary to stress shielding. We present a systematic approach for the design of a 3D printed fully porous hip implant that encompasses the whole activity spectrum of implant development, from concept generation, multiscale mechanics of porous materials, material architecture tailoring, to additive manufacturing, and performance assessment via in vitro experiments in composite femurs. We show that the fully porous implant with an optimized material micro‐structure can reduce the amount of bone loss secondary to stress shielding by 75% compared to a fully solid implant. This result also agrees with those of the in vitro quasi‐physiological experimental model and the corresponding finite element model for both the optimized fully porous and fully solid implant. These studies demonstrate the merit and the potential of tuning material architecture to achieve a substantial reduction of bone resorption secondary to stress shielding. © 2016 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:1774–1783, 2017.

     

Supraphysiological loading induces osteocyte‐mediated osteoclastogenesis in a novel in vitro model for bone implant loosening

We aimed to develop an in vitro model for bone implant loosening, allowing analysis of biophysical and biological parameters contributing to mechanical instability‐induced osteoclast differentiation and peri‐implant bone loss. MLO‐Y4‐osteocytes were mechanically stimulated for 1 h by fluid shear stress using regimes simulating: (i) supraphysiological loading in the peri‐prosthetic interface (2.9 ± 2.9 Pa, 1 Hz, square wave); (ii) physiologic loading in the cortical bone (0.7 ± 0.7 Pa, 5 Hz, sinusoidal wave); and (iii) stress shielding. Cellular morphological parameters, membrane‐bound RANKL expression, gene expression influencing osteoclast differentiation, nitric oxide release and caspase 3/7‐activity were determined. Either Mouse bone marrow cells were cultured on top of loaded osteocytes or osteocyte‐conditioned medium was added to bone marrow cells. Osteoclast differentiation was assessed after 6 days. We found that osteocytes subjected to supraphysiological loading showed similar morphology and caspase 3/7‐activity compared to simulated physiological loading or stress shielding. Supraphysiological stimulation of osteocytes enhanced osteoclast differentiation by 1.9‐fold compared to physiological loading when cell‐to‐cell contact was permitted. In addition, it enhanced the number of osteoclasts using conditioned medium by 1.7‐fold, membrane‐bound RANKL by 3.3‐fold, and nitric oxide production by 3.2‐fold. The stimulatory effect of supraphysiological loading on membrane‐bound RANKL and nitric oxide production was higher than that achieved by stress shielding. In conclusion, the in vitro model developed recapitulated the catabolic biological situation in the peri‐prosthetic interface during instability that is associated with osteoclast differentiation and enhanced RANKL expression. The model thus provides a platform for pre‐clinical testing of pharmacological interventions with potential to stop instability‐induced bone implant loosening. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1425–1434, 2018.

     

Peri‐implant bone strains and micro‐motion following in vivo service: A postmortem retrieval study of 22 tibial components from total knee replacements

Biological adaptation following placement of a total knee replacements (TKRs) affects peri‐implant bone mineral density (BMD) and implant fixation. We quantified the proximal tibial bone strain and implant‐bone micro‐motion for functioning postmortem retrieved TKRs and assessed the strain/micro‐motion relationships with chronological (donor age and time in service) and patient (body weight and BMD) factors. Twenty‐two tibial constructs were functionally loaded to one body weight (60% medial/40% lateral), and the bone strains and tray/bone micro‐motions were measured using a digital image correlation system. Donors with more time in service had higher bone strains (p = 0.044), but there was not a significant (p = 0.333) contribution from donor age. Donors with lower peri‐implant BMD (p = 0.0039) and higher body weight (p = 0.0286) had higher bone strains. Long term implants (>11 years) had proximal bone strains 900 µ? that were almost twice as high as short term (<5 years) implants 570 µ?. Micro‐motion was greater for younger donors (p = 0.0161) and longer time in service (p = 0.0008). Increased bone strain with long term in vivo service could contribute to loosening of TKRs by failure of the tibial peri‐implant bone. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:355–361, 2014.

     

Blockade of JNK and NFAT pathways attenuates orthopedic particle‐stimulated osteoclastogenesis of human osteoclast precursors and murine calvarial osteolysis

Particles released from orthopedic implants attract immune host defense cells to the bone‐implant interface and contribute to development of inflammation. The inflammatory microenvironment supports recruitment and differentiation of osteoclasts, the primary culprit of osteolysis. Therefore, understanding the complex signals that contribute to osteoclastogenesis and osteolysis is a sensible approach to design strategies to inhibit bone loss. The signaling cascades that coordinate osteoclastogenesis have been widely investigated. These include MAP kinases, Akt/PI3K pathway, NF‐κB signal transduction pathway, and NFAT pathway. We have recently reported that polymethylmethacrylate (PMMA) particles activate the NFAT pathway in murine osteoclast precursors and that NFAT inhibitors dose‐dependently block PMMA‐induced osteoclastogenesis. In the current study, we examined the role of JNK and NFATc1 in mice in response to PMMA particles using murine calvaria model. We show that locally administered MAPK/JNK inhibitor SP600125 and calcineurin/NFAT inhibitor cyclosporine‐A effectively blocked PMMA‐induced osteolysis in murine calvaria. To buttress the clinical relevance of JNK/NFATc1‐based regulation of PMMA‐induced osteoclastogenesis, we evaluated the effect of PMMA using human macrophages. We demonstrate that SP600125 and cyclosporine‐A abolished particle‐induced osteoclastogenesis in human osteoclast progenitors retrieved from patients undergoing total hip replacement. Thus JNK and NFATc1 appear to act as significant mediators of orthopedic particle‐induced osteolysis in humans. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:67–72, 2012     

Strain shielding inspired re‐design of proximal femoral stems for total hip arthroplasty

A large number of hip prosthesis with different designs have been developed. However, the influence of hip implant design changes on the strains induced in the bone remains unclear. The purpose of this study is to better understand the mechanics of short stem total hip arthroplasty. Specifically, it investigates whether strain shielding can be avoided by changing implant shape and/or material properties. It is hypothesized that the re‐design of existing implant designs can result in further reduction of strain shielding and thus keep bone loss minimal following total hip replacement. Finite element methods were used to compare healthy and implanted models. The local mechanics strains/stresses in the intact and implanted femurs were determined under patient‐specific muscle and joint contact forces. Results suggest that small changes in implant geometry and material properties have no major effect on strain shielding. Furthermore, it was found that improvement depends on a dramatic re‐design of the original implant design. Whereas the benefit of this strategy of modification of the original geometry of a given short‐stemmed hip consists in reduced bone remodeling, care should be taken with regard to long‐term bone anchorage and implant fatigue strength. It is also shown that geometrical and material changes have a limited potential in avoiding strain shielding even in short‐stemmed implants. Finally, it is suggested that an understanding of the influence of these changes on the strain distribution within the bone can guide in the process of optimizing the current stem designs toward minimal strain shielding effects. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 35:2534–2544, 2017.

     

Quantification of regional variations in glenoid trabecular bone architecture and mineralization using clinical computed tomography images

The purpose of this study was to demonstrate feasibility of a clinical CT imaging and analysis technique to quantify regional variations in trabecular bone architecture and mineralization of glenoid bones. Specifically, our objective was to determine to what extent clinical CT imaging of intact upper extremities can describe variations of trabecular bone architectures at anatomic and peri‐implant regions by comparing trabecular bone architectures as measured by high‐resolution, micro CT imaging of same excised glenoid bones. Bone volume fraction (BVF), trabecular bone thickness (TbTh), number of trabecular bone (TbN), spacing (TbS), pattern factor (TbPf), bone surface area (BSA), and skeletal connectivity (Conn.), in addition to bone mineral content (BMC) and bone mineral density (BMD), were quantified from both clinical and micro CT images using whole bone, anatomic, and peri‐implant bone masks. Strong correlations of BVF, TbTh, TbSp, BMC, and BMD were found between clinical CT and micro CT imaging methods. The variations in BVF, TbTh, TbSp, TbN, BMC, and BMD at anatomical and peri‐implant regions were larger than those at whole bone regions. In this study, we have demonstrated that this clinical CT imaging methodology can be used to quantify variations of a patient's glenoid bone at anatomic and peri‐implant levels. Statement of Clinical Significance. An in vivo quantitative assessment of glenoid trabecular bone architecture in the anatomic and peri‐implant regions may improve our understanding on the role of bone quality on glenoid component loosening following total shoulder arthroplasty. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:85–96, 2018.