Aims. Osteoporosis is characterized by decreased trabecular bone volume, and microarchitectural deterioration in the medullary cavity. Interleukin-19 (IL-19), a member of the IL-10 family, is an anti-inflammatory cytokine produced primarily by macrophages. The aim of our study was to investigate the effect of IL-19 on osteoporosis. Methods. Blood and femoral bone marrow suspension IL-19 levels were first measured in the lipopolysaccharide (LPS)-induced bone loss model. Small interfering RNA (siRNA) was applied to knock down IL-19 for further validation. Thereafter, osteoclast production was stimulated with IL-19 in combination with mouse macrophage colony-stimulating factor (M-CSF) and receptor activator of nuclear factor-κB ligand (RANKL). The effect of IL-19 was subsequently evaluated using tartrate-resistant acid phosphatase (TRAP) staining and quantitative real-time polymerase chain reaction (RT-qPCR). The effect of IL-19 on osteoprotegerin (OPG) was then assessed using in vitro recombinant IL-19 treatment of primary osteoblasts and MLO-Y4 osteoblast cell line. Finally, transient transfection experiments and chromatin immunoprecipitation (ChIP) experiments were used to examine the exact mechanism of action. Results. In the LPS-induced bone loss mouse model, the levels of IL-19 in peripheral blood serum and femoral bone marrow suspension were significantly increased. The in vivo results indicated that global IL-19 deletion had no significant effect on RANKL content in the serum and bone marrow, but could increase the content of OPG in serum and femoral bone marrow, suggesting that IL-19 inhibits OPG expression in bone marrow mesenchymal stem cells (BMSCs) and thus increases bone resorption. Conclusion. IL-19 promotes bone resorption by suppressing OPG expression in BMSCs in a LPS-induced bone loss mouse model, which highlights the potential benefits and side effects of IL-19 for future clinical applications. Cite this article: Bone Joint Res 2023;12(11):691–701

Aims. Transcription factor nuclear factor kappa B (NF-κB) plays a major role in the pathogenesis of chronic inflammatory diseases in all organ systems. Despite its importance, NF-κB targeted drug therapy to mitigate chronic inflammation has had limited success in preclinical studies. We hypothesized that sex differences affect the response to NF-κB treatment during chronic inflammation in bone. This study investigated the therapeutic effects of NF-κB decoy oligodeoxynucleotides (ODN) during chronic inflammation in male and female mice. Methods. We used a murine model of chronic inflammation induced by continuous intramedullary delivery of lipopolysaccharide-contaminated polyethylene particles (cPE) using an osmotic pump. Specimens were evaluated using micro-CT and histomorphometric analyses. Sex-specific osteogenic and osteoclastic differentiation potentials were also investigated in vitro, including alkaline phosphatase, Alizarin Red, tartrate-resistant acid phosphatase staining, and gene expression using reverse transcription polymerase chain reaction (RT-PCR). Results. Local delivery of NF-κB decoy ODN in vivo increased osteogenesis in males, but not females, in the presence of chronic inflammation induced by cPE. Bone resorption activity was decreased in both sexes. In vitro osteogenic and osteoclastic differentiation assays during inflammatory conditions did not reveal differences among the groups. Receptor activator of nuclear factor kappa Β ligand (Rankl) gene expression by osteoblasts was significantly decreased only in males when treated with ODN. Conclusion. We demonstrated that NF-κB decoy ODN increased osteogenesis in male mice and decreased bone resorption activity in both sexes in preclinical models of chronic inflammation. NF-κB signalling could be a therapeutic target for chronic inflammatory diseases involving bone, especially in males. Cite this article: Bone Joint Res 2024;13(1):28–39

Aseptic loosening is currently the leading cause of failure of total hip arthroplasty. The aetiology of periprosthetic bone resorption is currently under intense investigation. Wear particles are produced from the articulating surface of the femoral and acetabular components. These particles gain access to the bone-cement interface where they are phagocytosed by macrophages. Particle stimulated macrophages differentiate into bone resorping osteoclasts. This leads to periprosthetic bone resorption and subsequent implant loosening. Nuclear factor kappa B (NFκB) is a transcription factor known to be activated by pathogenic stimuli in a variety of cells. The activation of NFkB would appear to be the primary event in the activation of particle stimulated macrophages in the periprosthetic membrane. NFκB subsequently causes a cascade of events leading to the release of bone resorbing cytokines, namely interleukin-6 (IL-6) and tumour necrosis factor α (TNFα). The aim of our study was to ascertain if bone resorption could be prevented in vitro by the addition of PDTC, an NFkB inhibitor to particle stimulated macrophages. Human monocytes were isolated and cultured from healthy volunteers. The monocyte/macrophage cell line was differentiated into osteoclasts by the addition of alumina particles and allowed to adhere onto bone slices. The NFkB inhibitor, PDTC, has added to the cultured osteoclasts. Bone resorption was analysed by counting the number of resorption pits in each bone slice. The addition of PDTC to stimulated macrophages reduced the number of resorption pits by greater than 40% compared to control. This is a unique and promising finding that may offer a future therapeutic strategy for the prevention of periprosthetic bone resorption and therefore aseptic loosening in total hip arthoplasty

Osteoclastic bone resorption is a highly dynamic process that requires the tight ordering of intracellular trafficking events in order to maintain the structural and functional polarization of the ruffled border and basolateral domains. Rab3 proteins are a subfamily of GTPases, known to mediate membrane transport in eukaryotic cells and play a role in exocytosis. Our recent data indicates that Rab3D modulates a post-TGN trafficking step that is required for osteoclastic bone resorption (1). Here, to identify down-stream regulatory molecules of Rab3D, we have performed a yeast two-hybrid screen. Amongst several candidate Rab3D-interacting proteins identified, Rab3D was found to associate with calmodulin, an established regulator of osteoclastic bone resorption. As an initial effort to better define the interaction between Rab3D and calmodulin, we generated several mutants of Rab3D which interfere with the GDP/GTP nucleotide exchange (Rab3DQ81L, Rab3DN135I) and/or membrane attachment of Rab3D (Rab3D-CXC). By in vivo bioluminescence resonance energy transfer (BRET) assay, Calmodulin was found to associate equivalently with wild type Rab3D as well as Rab3DN135I and Rab-3DCXC variants. Over expression of constitutively active Rab3D (Rab3DQ81L) enhanced this interaction suggesting that the active form of Rab3D (i.e. GTP-bound) might recruit additional effector molecules which further potentiate it’s binding to calmodulin. In an attempt to address the impact of calmodulin activity on Rab3D-calmodulin interaction and osteoclastic bone resorption, we performed complementary BRET and in vitro bone resorption assays in the presence of the calmodulin inhibitor, calmidazolium chloride. Interestingly, we show that suppression of calmodulin activity via calmidazolium chloride impairs the association of Rab3D with calmodulin, an affect that correlates with a disruption in osteoclastic bone resorption. We propose that the recruitment of calmodulin by Rab3D might be an important requirement for osteoclast-mediated bone resorption

Bone remodeling effects is a significant issue in predicting long term stability of hip arthroplasty. It has been frequently observed around the femoral components especially with the implantation of prosthesis stem. Presence of the stiffer materials into the femur has altering the stress distribution and induces changes in the architecture of the bone. Phenomenon of bone resorption and bone thickening are the common reaction in total hip arthroplasty (THA) which leading to stem loosening and instability. The objectives of this study are (i) to develop inhomogeneous model of lower limbs with hip osteoarthritis and THA and (ii) to predict the bone resorption behavior of lower limbs for both cases. Biomechanical evaluations of lower limbs are established using the finite element method in predicting bone remodeling process. Lower limbs CT-based data of 79 years old female with hip osteoarthritis (OA) are used in constructing three dimensional inhomogenous models. The FE model of lower limbs was consisted of sacrum, left and right ilium and both femur shaft. Bond between cartilage, acetabulum and femoral head, sacrum and ilium were assumed to be rigidly connected. The inhomogeneous material properties of the bone are determined from the Hounsfield unit of the CT image using commercial biomedical software. A load case of 60kg body weight was considered and fixed at the distal cut of femoral shaft. For THA lower limbs model, the left femur which suffering for hip OA was cut off and implanted with prosthesis stem. THA implant is designed to be Titanium alloy and Alumina for stem and femoral ball, respectively. Distribution of young modulus of cross-sectional inhomogeneous model is presented in Fig. 2 while model of THA lower limbs also shown in Fig. 2. Higher values of young modulus at the outer part indicate hard or cortical bone. Prediction of bone resorption is discussed with the respect of bone mineral density (BMD). Changes in BMD at initial age to 5 years projection were simulated for hip OA and THA lower limbs models. The results show different pattern of stress distribution and bone mineral density between hip OA lower limbs and THA lower limbs. Stress is defined to be dominant at prosthesis stem while femur experienced less stress and leading to bone resorption. Projection for 5 years follow up shows that the density around the greater tronchanter appears to decrease significantly

Recently, concerns arose over the medial tibial bone resorption of a novel cobalt-chromium (CoCr) implant. This study aimed to investigate the effects of tibial component material, design, and patient factors on periprosthetic bone resorption and to determine its association with clinical outcomes after total knee arthroplasty (TKA). A total of 462 primary TKAs using five types of implants were included. To evaluate tibial periprosthetic bone resorption, we assessed radiolucent lines (RLL) and change in bone mineral density at the medial tibial condyle (BMDMT). Factors related to bone resorption were assessed using regression analysis. Clinical outcomes were also evaluated with respect to periprosthetic bone resorption. Compared to titanium (Ti) implants, CoCr implants showed a higher incidence of complete RLL (23.1% vs. 7.9% at two years post-TKA) and a greater degree of BMDMT reduction. However, there was no significant difference between the implants made of the same material. Increased medial tibial bone resorption was associated with male sex, osteoporosis, larger preoperative varus deformity, longer follow-up period, and lower body mass index. The periprosthetic bone resorption was not associated with clinical outcomes including changes in range of motion and WOMAC score. Furthermore, no cases warranted additional surgery. Periprosthetic bone resorption was associated with implant material but not with implant design. Moreover, patient factors were related to the medial tibial bone resorption post-TKA. However, the periprosthetic bone resorption was not associated with short-term clinical outcomes. We contend that researchers should incorporate integrative considerations when developing and assessing novel implants

Introduction. Revision total knee arthroplasy (TKA) has been often used with a metal block augmentation for patients with poor bone quality. However, bone resorption beneath metal block augmentation has been still reported and little information about the reasons of the occurrence of bone resorption is available. The aim of the current study is to identify a possibility of the potential occurrence of bone resorption beneath metal block augmentation, through evaluation of strain distribution beneath metal block augmentation in revision TKA with metal block augmentation, during high deep flexion. Materials and Method. LOSPA, revision TKA with a metal block augmentation (Baseplate size #5, Spacer size #5, Stem size Φ9, L30, Augment #5 T5) was considered in this study. For the test, the tibia component of LOSPA was implanted to the tibia sawbone (left, #3401, Sawbones EuropeAB, Malmö, Sweden), which was corresponded to a traditional TKR surgical guideline. The femoral component of LOSPA was mounted to a customized jig attached to the Instron 8872 (Instron, Norwood, MA, USA), which was designed specially to represent the angles ranged from 0° to 140° with consideration of a rollback of knee joint (Figure. 1). Here, a compressive load of 1,600N (10N/s) was applied for each angle. Strain distribution was then measured from rossete strain gauge (Half Bridge type, CAS, Seoul, Korea) together (Figure 1). Results and Discussions. The strain distribution on the cortical bone of the tibia was shown in Figure 2. The results showed that the strains on the posterior region were gradually increased from extension to high deep of the knee joint and generally larger than the other regions. In contrast to the results on the posterior region, the strains on the medial region were gradually decreased after 60° or 90° flexion position and relatively lower than the other regions. Particularly, the strains on the medial region were generally lower than 50–100 µstrain, which is known as critical value range able to inducing bone resorption, during high deep flexion. This fact indicate that a possibility of the potential bone resorption occurrence in revision TKA used with a metal block augmentation may be relatively increased in patients who are frequently exposed to a personal lifestyle history with the loading conditions of the high flexion. This study may be valuable by identifying for the first time a possibility of the potential bone resorption occurrence through evaluation of the strain distribution beneath metal block augmentation in revision TKA used with a metal block augmentation during high deep flexion. Conclusion. A possibility of the potential bone resorption occurrence in revision TKA used with a metal block augmentation may be dependent on loading patterns applied on the knee joint related to personal lifestyle history. Particularly, it may be relatively increased in patients who are frequently exposed to a personal lifestyle history with the loading conditions of the high flexion. Acknowledgements. This study was supported by a grant from the New Technology Product Evaluation Technical Research project, Ministry of Food and Drug Safety (MFDS), Republic of Korea

Summary Statement. In this study it has been considered an alternative therapeutic approach to bone resorption diseases by using plant decoctions to improve adherence from patients to the treatment. In this context, Hemidesmus indicus represents a possible therapeutic or adjuvant natural compound. Introduction. The acceleration of bone remodelling, with an excessive osteoclastogenesis or activation of mature osteoclasts, causes the loss of bone mass which is implicated in bone resorption diseases. Conventional therapies are expensive and limited by systemic toxicity and low drug bioavailability. Alternative treatments that are not only effective but also administered employing formulations and dosages different from conventional ones, may improve adherence to therapy, having a positive influence on clinical outcomes. Experimental evidence have attributed antiproliferative and apoptosis inducing activity on different cell lines (including osteoclast precursors or mature osteoclasts) to four plants used in Ayurvedic medicine: Asparagus racemosus (AR), Emblica officinalis (EO), Hemidesmus indicus (HI) and Rubia cordifolia (RC) These properties could be helpful in the treatment of some bone resorption diseases. In order to clarify the possible therapeutic effects of these compounds, the anti-osteoclast activity of their decoctions were evaluated. Methods. The anti-osteoclast activity of natural compounds was evaluated on primary cultures of human osteoclasts generated by isolating peripheral blood monocytes from buffy coat and treating cells with medium supplemented with differentiating factors. To evaluate the effect on osteoclastogenesis, osteoclast precursors were treated with different concentrations of plant decoctions and characterised by the formation of multinucleated cells and the expression of tartrate-resistant acid phosphatase. To evaluate the osteoclasts apoptosis inducing activity mature osteoclasts were treated with the compounds and stained with Hoechst 33258, to make clear the possible nuclear pyknosis, and phalloidin-TRITC to highlight the structure of the typical osteoclast actin ring. The toxicity of compounds on osteogenic precursors was evaluated by the Alamar Blue assay after 7 days of cells treatment with bioactive concentrations of decoctions. Results. At the higher concentrations, all the decoctions had inhibited osteoclastogenesis with an effect similar to that of alendronate (positive control), but only HI was effective like alendronate at lower concentrations. The percentage of apoptotic osteoclasts was very low in control cultures (30 ± 2%), but increased significantly when cells were exposed to the highest concentration of EO (P < 0.001), HI (P < 0.001), and RC (P < 0.05). It was not observed the same effect when cells were exposed to the highest concentration of AR. At the highest concentrations AR has completely inhibited the proliferation of osteogenic precursors, EO was toxic at all tested concentrations, while RC was toxic only at the highest ones. On the contrary, HI showed absence of toxicity on osteogenic precursors at all tested concentrations. Conclusion. An ideal anti-resorption drug should exert an anti-osteoclastic activity without interfering with the proliferative capacity of osteogenic precursors. For these reasons, among all the plants evaluated in this study, HI represents a possible therapeutic candidate. In fact, it demonstrated the greater effectiveness of anti-osteoclast activity, both in terms of inhibition of osteoclastogenesis that induction of apoptosis, but showed no toxicity on osteogenic precursors

Summary Statement. Obovatol inhibits receptor activator of nuclear factor kappa B ligand (RANKL)-induced osteoclastogenesis and prevents inflammatory bone loss in mice. Introduction. Adult skeletal mass and integrity are maintained by balancing osteoclast-mediated bone resorption and osteoblast-induced bone formation during bone remodeling. Abnormal increases in osteoclastic bone resorption can lead to excessive bone destruction as observed in osteoporosis, rheumatoid arthritis, and metastatic cancers Therefore, Modulation of osteoclast formation and function is a promising strategy for the treatment of bone-destructive diseases. To search for compounds that inhibit osteoclast formation, we tested the effect of obovatol, a natural product isolated from the medicinal plant Magnolia obovata, on osteoclastogenesis and inflammatory bone loss. Methods. Osteoclastogenesis was assessed using bone marrow-derived macrophages. RANKL signaling was assessed by immunoblotting and apoptosis by cell death ELISA assay. Actin ring staining and resorption pit assay was performed. Bone morphometric parameters were determined using a microcomputed tomography system. Results. We found that obovatol strongly inhibited osteoclast formation from bone marrow-derived macrophages in a dose-dependent manner without cytotoxicity. Obovatol significantly suppressed RANKL-induced activation of NF-κB, JNK, and ERK signaling pathways. Obovatol also inhibited RANKL-induced expression of the genes c-Fos and nuclear factor of activated T cells c1, which are transcription factors important for osteoclastogenesis. In addition to osteoclast differentiation, obovatol blocked cytoskeletal organization and abrogated the bone resorbing activity of mature osteoclast. Obovatol also accelerated osteoclast apoptosis through the induction of caspase-3 activation. Consistent with its in vitro anti-resorptive effect, obovatol prevented bone loss induced by lipopolysaccharide (LPS) in vivo. Conclusion. Our findings demonstrate that obovatol, a natural compound isolated from Magnolia obovata, suppresses the differentiation, function, and survival of osteoclasts. Furthermore, obovatol protected against LPS-induced bone loss in vivo. Therefore, we suggest that obovatol may have therapeutic potential for the treatment of bone-destructive diseases characterised by increased osteoclast number and/or activity

Mast cells (MC), the tissue-based effector cells in allergic diseases, have many functions. Within bone tissue, they have been linked with new blood vessel formation and marrow fibrosis and it has been proposed that they are capable of promoting osteoclastic bone resorption. MC numbers are known to increase in a number of osteolytic conditions e.g. osteoporosis, hyperparathyroidism and periodontitis. In fracture callus, too, large numbers of MC are present, especially during the onset of remodelling where it is believed they may be responsible for osteoclast recruitment and/or differentiation. The aim of this study was to look for further evidence of mast cell (MC) involvement in pathological bone resorption. MC activity was assessed in tissue sections of osteolytic conditions including Paget’s disease of bone, rheumatoid arthritis and fibrous dysplasia together with several benign and malignant bone tumours. MCs were identified by toluidine blue staining and by immunostaining with a commercial antibody against MC tryptase. Extensive infiltration of mast cells was observed in fibrous dysplasia, rheumatoid arthritis and Paget’s disease of bone and mast cell accumulation was seen at the bone resorbing margin of a number of enlarging bone tumours including osteosarcoma, giant cell tumour of bone, osteoma and osteoid osteoma. MCs, along with other inflammatory cells, are known to accumulate at the margins of soft tissue tumours where they are thought to promote tumour growth. The current findings are consistent with a similar role for mast cells in the primary bone tumours examined. In each of the conditions studied, an additional role for MC may be that of promoting bone lysis. MC are known to contain numerous factors including TNF-alpha and IL-1, which are potent stimulators of osteoclast formation and activity. It is concluded that MCs may contribute to the fibrosis, angiogenesis and increased bone resorption seen in certain metabolic bone diseases. MC activity may also be an important factor contributing to the lysis that occurs in numerous other pathological situations including at the margins of aggressive primary bone tumours and skeletal metastases, leading to the expansion of these lesions

Introduction: Tumor necrosis factor-alpha (TNF-a) has been shown to be a potent stimulator of bone resorption in vitro and in vivo, and has been identified as an important factor in aseptic loosening of total joint replacements. In order to investigate the effects of TNF-a at the bone-cement interface, we developed a rabbit model in which a slow-release pellet containing a known amount of TNF-a was inserted adjacent to a polymethylmethacryate (PMMA) implant in the distal femur. Methods: 25 male New Zealand white rabbits were used in this IACUC-approved study. After routine exposure of the distal femur, a 3 mm drill bit was used to drill through the intercondylar region into the medullary canal of the distal femur. A resorbable pellet containing 0, 420, 4200, 42 000 or 420 000 pg of TNF-a (n=5 animals per dose level) was inserted into the drill hole, immediately followed by a cylindrical PMMA implant (20 mm long). Animals were euthanized 42 days after surgery. The right femora were excised, radiographed, and processed for histology. Ground sections were prepared at the level of the proximal implant. Semi-automated image analysis was used to quantify cortical bone area, porosity and fractional surfaces (quiescent, osteoid and eroded). Data from control and treatment animals were compared with a one-way analysis of variance (ANOVA) using p< 0.05. Results: All of the animals recovered well after surgery. Radiographically, all of the implants appeared to be stable, with no evidence of linear or cystic osteolysis. Local delivery of TNF-a for 6 weeks had no effect on cortical bone area or porosity. However, TNF-a stimulated bone resorption and decreased new bone formation at the endosteal surface (p< 0.05); these effects were not dose-dependent but were seen in all of the TNF-a groups. Discussion: Our data provide direct evidence that local release of TNF-a is capable of inducing endosteal bone resorption in vivo. Additional studies are now needed to determine the effects of other proinflammatory cytokines in this animal model. However, based on these results, it appears that targeted blockade of TNF-a release or activity may provide a rational therapeutic approach to osteolysis and aseptic loosening

Introduction: A collar can be defined as any projection from the surface of the proximal third of the femoral stem that interferes with the capacity of the stem to move distally within the cement mantle and provide optimal load distribution along the calcar area. Contraversy exists concerning the usage of a collared or collarless prosthesis and the ability of the collar to perform its effect on the medial femoral neck. The purpose of this study is to compare the proximal femoral bone resorption and aseptic loosening in cases that had poor or good contact between the collar and the proximal medial femoral neck. Materials& Methods: 102 hybrid total hip arthroplasties which were done for severe hip joint disease were analyzed radiographically in the current study. Pre-operative, immediate post operative and the last follow-up anteroposterior and lateral pelvis radiographies were examined. The medial femoral neck-collar contact was considered to be ideal if the medial femoral neck was fully covered by the prosthesis (group A). Contact was deamed to be poor if the medial femoral neck was partially uncovered (group B) or there was cement interposition between the bone and the prosthesis (group C) Cortical femoral bone thickness of the femoral neck was measured on the immediate post-operative and the latest follow-up radiograph as well as the thicker area of bone in Gruen Zone 7. The medial femoral neck height was measured from the superior border of the lesser trochanter. Results: The mean follow up was 4.86 years. The good contact between the collar and the medial femoral neck was achieved for most of the patients. 55 hips were in group A. 30 hips were in group B and 17 hips were in group C at the latest follow-up. The mean loss in the height of the medial femoral neck was 4.21 mm for group A, 4.26mm for group B and 3.05mm for group C. The difference among the groups was not statiscally significant (p=0.545). As we evaluate the relation between the transverse bone loss in the Gruen Zone 7; the loss was 2.49 for group A, 2.26 for group B and 1.58 for group C. The difference among the groups was not statistically significant (p=0.246). Discussion: Unloading of the proximal femur leads resorption of the medial femoral neck and the proximal support of the prosthesis can be lost ultimately leading to aseptic failure due to excessive stresses on the proximal cement and debonding. Although the main purpose of using a collared femoral stem is to transfer load to the medial femoral neck and to prevent bone resorption, in the current study the collar did not prevent calcar resorption even when ideal contact was achieved between the collar and proximal medial femoral neck. Revision rate seems to be unchanged whether the collar had good or bad contact

Introduction. Stress shielding is one of the major concerns of load bearing implants (e.g. hip prostheses). Stiff implants cause stress shielding, which is thought to contribute to bone resorption1. On the contrary, low-stiffness implants generate high interfacial stresses that have been related to pain and interfacial micro-movements². Different attempts have been made to reduce these problems by optimizing either the stem design3 or using functionally graded implants (FGI) where the stem's mechanical properties are optimized4. In this way, new additive manufacturing technologies allow fabricating porous materials with well-controlled mesostructure, which allows tailoring their mechanical properties. In this work, Finite Element (FE) simulations are used to develop an optimization methodology for the shape and material properties of a FGI hip stem. The resorbed bone mass fraction and the stem head displacement are used as objective functions. Methodology. The 2D-geometry of a femur model (Sawbones®) with an implanted Profemur-TL stem (Wright Medical Technology Inc.) was used for FE simulations. The stem geometry was parameterized using a set of 8 variables (Figure 1-a). To optimize the stem's material properties, a grid was generated with equally spaced points for a total of 96 points (Figure 1-b). Purely elastic materials were used for the stem and the bone. Two bone qualities were considered: good (Ecortical=20 GPa, Etrabecular=1.5 GPa) and medium (Ecortical=15 GPa, Etrabecular=1 GPa). Poisson ratio was fixed to v=0.3. Loading corresponded to stair climbing. Hip contact force along with abductors, vastus lateralis and vastus medialis muscles were considered5 for a bodyweight of 847 N. The resorbed bone mass fraction was evaluated from the differences in strain energy densities between the intact bone and the implanted bone2. The displacement of the load point on the femoral head was computed. The optimization problem was formulated as the minimization of the resorbed bone mass fraction and the head displacement. It was solved using a genetic algorithm. Results. For the Profemur-TL design, bone resorption was around 36% and 56% for good and medium bone qualities, respectively (Fig. 2). The corresponding head displacements were 11.75 mm and 21.19 mm. Optimized solutions showed bone resorption from 15% to 26% and from 44% to 65% for good and medium bone qualities, respectively. Corresponding head displacements ranged from 11.85 mm to 12.25 mm and from 16.9 mm to 22.6 mm. Conclusion. The obtained set of solutions constitutes an improvement of the implant performance for this functionally graded implant (FGI) compared to the original implant for both bone qualities. From these simulations, the final solution for the FGI could be chosen based on manufacturing restrictions or another performance indicator

Introduction: Many claim that an inflammatory reaction to wear debris particles is the main cause for prosthetic loosening. We have rat model in which bone resorption can be induced both by fluid pressure and particles. We compared the bone resorptive potency of particles and fluid pressure. Materials and Methods: The rats received a titanium plate at the proximal tibia. A central plug was inserted. After 5 weeks of osseointegration, the central plug was changed to a piston or a hollow plug with 20mg titanium particles. Commercially pure titanium particles with 90 % of particles lesser than 3,6 microns were used. The pressure piston was subjected to a transcutanous force of 5N. Each episode of pressure comprised 20 pressure cycles at 0.17 Hz, applied twice a day. 60 rats were randomized to 6 groups for particle treatment. One group had particle implantation both at day 1 and 7. Additionally 15 rats were randomized into 3 groups with for pressure treatment. All rats were killed after 5 or 14 days. Bone resorption underneath the piston was evaluated blindedly in hematoxlyin/eosine sections and scored as 0 – 5. Differences between groups were analyzed by Kruskal Wallis and Mann-Whitney U-tests. Results: Many specimens with titanium particles showed no visible resorption at al, and a few showed dramatic osteolysis. After 14 days, the osteolytic effect was significant. Partice refill made no difference. Titanium particles over 10 μm had minor effect. Fluid pressure always caused bone resorption, and significantly more so than particles both after 5 and 14 days. Discussion: There was lesser variability in fluid pressure induced osteolysis, which might be due to a different signalling pathway. Titanium particles have an osteolytic effect in this model, but in spite of the massive amount of particles, the effect was less predictable than with pressure

INTRODUCTION. Bone resorption around hip stems, in particular periprosthetic bone loss, is a common observation post-operatively. A number of factors influence the amount of bone loss over time and the mechanical environment following total hip replacement (THR) is important; conventional long stem prostheses have been shown to transfer loads distally, resulting in bone loss of the proximal femur. More conservative, short stems have been recently introduced to attempt to better replicate the physiological load distribution in the femur. The aim of this study was to evaluate the bone mineral density (BMD) change over time, in a femur implanted with either a short or a long stem. METHODS. Finite element models of two implants, a short (Minihip, Corin, UK) and long (Metafix, Corin, UK) hip stem were used to simulate bone remodeling under a physiological load condition (stair climbing). The magnitudes and directions of the muscle forces and joint reaction force were obtained from Heller et al (2001, 2005). An unimplanted femur was also simulated. A strain-adaptive remodelling theory (Scannel & Prendergast 2009) was utilised to simulate remodelling in the bone after virtual implantation. COMSOL Multiphysics software was used for the analysis. The strain component of the remodelling stimulus was strain energy density per unit mass. This was calculated in the continuum model from the strain energy density, and apparent density. Bone mass was adapted using a site-specific approach in an attempt to return the local remodelling stimulus to the equilibrium stimulus level (calculated from the unimplanted femur). The minimal inhibitory signal proposed by Frost (1964), was included in the model and described by a ‘lazy zone’, where no bone remodelling occurred. The three dimensional geometry of the femur was constructed from computed tomography data of the donor (female, 44 years old, right side). Elemental bone properties were assigned from the Hounsfield Unit values of the CT scans. The elastic modulus of the bone was assumed to be isotropic and was determined using a relationship to the apparent bone density (Frost 1964, Rho 1995). The Poisson's ratio for the bone regions varied between 0.2 and 0.32 depending on the apparent density of the bone (Stulpner 1997). The period of implantation analysed was 2 years. The muscle forces and joint contact loads applied were ramped linearly from zero to full load over a period of two weeks, representing the estimated post operative rest period of a patient. RESULTS AND DISCUSSION. The overall percentage BMD change observed for Gruen zones 1 through to 7, were −14%, +4%, +40%, +12%, +4%, 0%, 12% respectively at 2 years for the Minihip. The corresponding overall percentage BMD change observed for Gruen zones 1 through to 7 for the Metafix were −8%, −2%, 18%, 26%, +12%, −9%, −42% respectively (Figure 1,2). CONCLUSIONS. Considerably more bone resorption occurs in Gruen zone 7 with the long stem. Long stem designs distrupt the mechanical environment more than short stems, and lead to a greater bone mineral reduction over time

Aims

The association of auraptene (AUR), a 7-geranyloxycoumarin, on osteoporosis and its potential pathway was predicted by network pharmacology and confirmed in experimental osteoporotic mice.

Aims: To examine the relationship between the Interleukin 6 (IL-6) −174 G> C promoter polymorphism and exercise-induced femoral cortical bone resorption. Methods: The skeletal response to exercise was assessed in 130 male Caucasian army recruits. Five cross-sectional magnetic resonance images of the right femur were obtained before and after a 10 week period of basic physical training, and changes in cross-sectional cortical area calculated. Recruits were genotyped for the −174 G> C IL-6 promoter polymorphism. Results: Genotype frequencies (GG 36%, GC 47%, CC 22 17%) were in Hardy-Weinberg Equilibrium. The mean percentage change in proximal femoral cross sectional cortical area was strongly IL-6 genotype-dependent, with GG homozygotes losing 6.8 ± 3.82% in cortical area, GC gaining +5.5 ± 4.88%, and CC gaining +17.3 ± 9.46% (p=0.007 for linear trend). These changes persisted throughout the right femur and were significant in the femur as a whole (p=0.03). Conclusion: This study demonstrates a linear relationship between a functional polymorphism in the IL-6 gene and femoral cortical remodelling during strenuous physical exercise. Previous studies have suggested an important role for IL-6 in the regulation of bone mass in postmenopausal women, and in the invasion of bone by metastatic tumour deposits. These data extend these observations to the regulation of bone mass in healthy males, supporting a fundamental role for IL-6 in the regulation of bone mass and bone remodelling in humans

Abstract

Introduction: In a rat model, fluid pressure causes more bone resorption than particles. Does pressure also cause more inflammation?. Materials and Methods: Rats received a titanium plate at the proximal tibia. A central plug was inserted. After 5 weeks of osseointegration, the central plug was changed to either a piston or a hollow plug with titanium particles. Commercially pure titanium particles with 90% of particles lesser than 3,6 microns were used. The pressure piston was subjected to a transcutanous force of 8N. Each episode of pressure comprised 20 pressure cycles at 0.17 Hz, applied twice a day. 39 rats were randomized to 3 groups: Titanium particles (n=13), fluid pressure (n=13) and controls with neither particles nor fluid pressure (n=13). The rats were killed after 3 days. 6 rats in each group were used for histology and the others for gene expression. Extraction of total RNA was performed using the TRIspin method. Primers for cat K, RANK, RANKL, OPG IL-1, IL-b, TNF-a, iNOS and COX-2 were used. Each sample was normalized to 18S rRNA. Histology was evaluated qualitatively. Differences between the groups were analyzed by Kruskal Wallis and Mann-Whitney U-test. Results: Both particles and fluid pressure increased the expression of osteoclastic genes. Particles induced an elevated expression of IL-6 and RANK compared to both controls and fluid pressure. There was a tendency that particles induced more expression of other inflammatory genes compared to fluid pressure. Histology: The controls showed only few osteoclasts at the bone surface. The particle group showed osteoclasts at the surface towards the particles. In contrast, the pressure group showed resorption cavities spread out inside the bone. Discussion: Although there was more resorption in the pressure group, there was a lesser inflammatory response. This suggests that pressure-induced resorption is mediated via different pathways

A common location for radius fracture is the proximal radial head. With the arm in neutral position, the fracture usually happens in the anterolateral quadrant (Lacheta et al., 2019).

If traditional surgeries are not enough to induce bone stabilization and vascularization, or the fracture can be defined grade III or grade IV (Mason classification), a radial head prosthesis can be the optimal compromise between bone saving and recovering the “terrible triad”.

A commercially available design of radial head prosthesis such as Antea (Adler Ortho, Milan, Italy) is characterized by flexibility in selecting the best matching size for patients and induced osteointegration thanks to the Ti-Por^® radial stem realized by 3D printing with laser technique (Figure 1). As demonstrated, Ti-Por^® push-out resistance increased 45% between 8 −12 weeks after implantation, hence confirming the ideal bone-osteointegration. Additional features of Antea are: bipolarity, modularity, TiN coating, radiolucency, hypoallergenic, 10° self-aligning.

The osteointegration is of paramount importance for radius, in fact the literature is unfortunately reporting several clinical cases for which the fracture of the prosthesis happened after bone-resorption. Even if related to an uncommon activity, the combination of mechanical resistance provided by the prosthesis and the stabilization due to the osteointegration should cover also accidental movements.

Based upon Lacheta et al. (2019), after axial compression-load until radii failure, all native specimens survived a compression-load of 500N, while the failure happened for a mean compression force of 2560N.

The aim of this research study was to test the mechanical resistance of a radial head prosthesis obtained by 3D printing. In detail, a finite element analysis (FEA) was used to understand the mechanical resistance of the core of the prosthesis and the potential bone fracture induced in the radius with simulated bone- resorption (Figure 2a). The critical level was estimated at the height for which the thickness of the core is the minimum (Figure 2b).

Considered boundary conditions:

- Full-length prosthesis plus radius out of the cement block equal to 60mm (Figure 2a);

Figure 3 shows the results in terms of maximum stress on the core of the prosthesis and the risk of fracture (Schileo et al., 2008).

According to the obtained results, the radial head prosthesis shows promising mechanical resistance despite of the simulated bone-resorption for all applied loads except for 2560N. The estimated mechanical limit for the material in use is 200MPa. The risk of fracture is in agreement with the experimental findings (Lacheta et al. (2019)), in fact bone starts to fail for the minimum reported failure load, but only for osteoporotic conditions.

The presented FEA aimed at investigating the behavior of a femoral head prostheses made by 3D printing with simulated bone-resorption. The prosthesis shows to be a skilled solution even during accidental loads.

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