Developmental low-dose exposure to bisphenol A induces chronic inflammation, bone marrow fibrosis and reduces bone stiffness in female rat offspring only.

BACKGROUND: Developmental exposure to low doses of the endocrine disruptor bisphenol A (BPA) is known to alter bone tissue in young rodents, although how bone tissue is affected in aged animals is not well known. We have recently shown that low-dose developmental exposure to BPA increases procollagen type I N-terminal propeptide (P1NP) levels, a peptide formed during type 1 collagen synthesis, in plasma of 5-week-old female rat offspring while male offspring showed reduced bone size. OBJECTIVE: To analyze offspring bone phenotype at 52 weeks of age and clarify whether the BPA-induced increase in P1NP levels at 5 weeks is an early sign of bone marrow fibrosis development. METHODS: As in our 5-week study, pregnant Fischer 344 rats were exposed to BPA via drinking water corresponding to 0.5 µg/kg BW/day (BPA0.5), which is in the range of human daily exposure, or 50 µg/kg BW/day (BPA50) from gestational day 3.5 until postnatal day 22. Controls were given only vehicle. The offspring were sacrificed at 52 weeks of age. Bone effects were analyzed using peripheral quantitative and micro-computed tomography (microCT), 3-point bending test, plasma markers and histological examination. RESULTS: Compared to a smaller bone size at 5 weeks, at the age of 52 weeks, femur size in male offspring had been normalized in developmentally BPA-exposed rats. The 52-week-old female offspring showed, like the 5-week-old siblings, higher plasma P1NP levels compared to controls but no general increasing bone growth or strength. However, 2 out of 14 BPA-exposed female offspring bones developed extremely thick cortices later in life, discovered by systematic in vivo microCT scanning during the study. This was not observed in male offspring or in female controls. Biomechanical testing revealed that both doses of developmental BPA exposure reduced femur stiffness only in female offspring. In addition, histological analysis showed an increased number of fibrotic lesions only in the bone marrow of female rat offspring developmentally exposed to BPA. In line with this, plasma markers of inflammation, Tnf (in BPA0.5) and Timp1 (in BPA50) were increased exclusively in female offspring. CONCLUSIONS: Developmental BPA exposure at an environmentally relevant concentration resulted in female-specific effects on bone as well as on plasma biomarkers of collagen synthesis and inflammation. Even a dose approximately eight times lower than the current temporary EFSA human tolerable daily intake of 4 µg/kg BW/day, appeared to induce bone stiffness reduction, bone marrow fibrosis and chronic inflammation in female rat offspring later in life.

Bone remodeling of the proximal tibia after uncemented total knee arthroplasty: secondary endpoints analyzed from a randomized trial comparing monoblock and modular tibia trays-2 year follow-up of 53 cases.

Background and purpose - Bone remodeling as a response to bone trauma, postoperative immobilization, and device-related bone reactions can lead to loss of bone stock and increase the risk of periprosthetic fracture and aseptic loosening. This study investigates the adaptive bone remodeling of the proximal tibia after uncemented total knee arthroplasty (TKA). Patients and methods - We performed a 2-year follow up of 53 patients (mean age 62 (38-70) years, 27 of whom were men, who received an uncemented TKA in a randomized controlled trial with bone mineral density (BMD) as secondary endpoint. Patients were randomized to 2 groups of either monoblock (A) or modular (B) polyethylene design. The TKAs were performed using the uncemented Zimmer Nexgen trabecular metal. Measurements of BMD were done postoperatively and after 3, 6, 12, and 24 months. BMD was measured in 3 regions of interest (ROI). Results and interpretation - In group A statistically significant changes in BMD were seen after 24 months in both the medial and lateral ROI. BMD decreased medially by 15% (p = 0.004) and laterally by 13% (p = 0.01). In group B the BMD changes were limited and after 24 months returned to the preoperative values. The differences in BMD change between groups were statistically significant in both the medial (p = 0.03) and lateral (p = 0.02) ROI. In the distal ROI we found no significant change in BMD in either group. A significantly different bone remodeling pattern of the proximal tibia was seen in the 2 groups with a higher degree of bone loss in the knees that received the monoblock polyethylene design, indicating that the flexible monoblock implant design, previously shown to improve fixation, does not decrease the bone loss of the proximal tibia.

Bone Remodeling of the Distal Femur After Uncemented Total Knee Arthroplasty-A 2-Year Prospective DXA Study.

Loss of bone stock as a response to the bone trauma, immobilization, and stress shielding related to joint replacement surgery increases the risk of fracture of the distal femur after total knee arthroplasty. Previous studies of uncemented femoral components have reported very high levels of bone loss in the distal femur. This study investigates the adaptive bone remodeling of the distal femur after uncemented total knee arthroplasty. We performed a 2-year follow-up of 53 patients (mean age 61.5 [38-70] years, F/M = 27/26, body mass index 29.5) who because of osteoarthritis received an uncemented total knee arthroplasty. All patients received a NexGen CR-Flex Porous Femoral Component. Measurements of bone mineral density of the distal femur using dual-energy X-ray absorptiometry were performed postoperatively and after 3, 6, 12, and 24 months. Bone mineral density (g/cm2) was measured in 3 regions of interest in the periprosthetic bone of the distal femur. Repeated measures analysis of variance and Tukey post hoc test for bone mineral density changed over time (p < 0.05 were considered significant). In the distal femur, significant changes in bone mineral density were seen after 24 months of follow-up, and bone mineral density decreased by 23.6% in the anterior region behind the anterior flange of the prosthesis (p < 0.001), 10.1% in the posterior region (p < 0.001), and 5.5% in the most proximal region (p < 0.001). We found highly significant bone mineral change in the distal femur after uncemented total knee arthroplasty, most pronounced in the anterior region, where a decrease in bone mineral density of almost 25%, was seen. Taking the expected age-related decay in bone mineral density in this age group into consideration, the decrease was substantial and must be considered to predispose to periprosthetic fractures.

Low-dose developmental exposure to bisphenol A induces sex-specific effects in bone of Fischer 344 rat offspring.

BACKGROUND: Bisphenol A (BPA) is a component of polycarbonate plastics to which humans are regularly exposed at low levels, and an endocrine disruptor with effects on several hormonal systems. Bone is a sensitive hormone target tissue, and we have recently shown that in utero and lactational exposure to 25µg BPA/kg BW/day alters femoral geometry in rat offspring. OBJECTIVE: To investigate bone effects in rat offspring after developmental exposure to a BPA dose in the range of human daily exposure (0.1-1.5µg/kg BW/day) as well as a dose to corroborate previous findings. METHODS: Pregnant Fischer 344 rats were exposed to BPA via drinking water corresponding to 0.5µg/kg BW/day: [0.5], (n=21) or 50µg/kg BW/day: [50], (n = 16) from gestational day 3.5 until postnatal day 22, while controls were given only vehicle (n = 25). The offspring was sacrificed at 5 weeks of age. Bone effects were analyzed using peripheral quantitative computed tomography (pQCT), the 3-point bending test, plasma markers of bone turnover, and gene expression in cortical bone and bone marrow. RESULTS: Compared to controls, male offspring developmentally exposed to BPA had shorter femurs. pQCT analysis revealed effects in the [0.5] group, but not in the [50] group; BPA reduced both trabecular area (-3.9%, p < 0.01) and total cross sectional area (-4.1%, p < 0.01) of femurs in the [0.5] group, whereas no effects were seen on bone density. Conversely, bone length and size were not affected in female offspring. However, the procollagen type I N-terminal propeptide (P1NP), a peptide formed during type 1 collagen synthesis, was increased in plasma (42%: p < 0.01) in female offspring exposed to [0.5] of BPA, although collagen gene expression was not increased in bone. The biomechanical properties of the bones were not altered in either sex. Bone marrow mRNA expression was only affected in male offspring. CONCLUSIONS: Developmental low-dose exposure to BPA resulted in sex-specific bone effects in rat offspring. A dose approximately eight times lower than the current temporary EFSA human tolerable daily intake of 4µg/kg BW/day, reduced bone length and size in male rat offspring. Long-term studies are needed to clarify whether the increased plasma levels of P1NP in female offspring reflect development of fibrosis.

Low Preoperative BMD Is Related to High Migration of Tibia Components in Uncemented TKA-92 Patients in a Combined DEXA and RSA Study With 2-Year Follow-Up.

BACKGROUND: The fixation of uncemented tibia components in total knee arthroplasty may rely on the bone quality of the tibia; however, no previous studies have shown convincing objective proof of this. Component migration is relevant as it has been shown to predict aseptic loosening. METHODS: We performed 2-year follow-up of 92 patients who underwent total knee arthroplasty surgery with an uncemented tibia component. Bone mineral density (BMD; g/cm2) of the tibia host bone was measured preoperatively using dual energy X-ray absorptiometry. The proximal tibia was divided into 2 regions of interest (ROI) in the part of the tibia bone where the components were implanted. Radiostereometric analysis was performed postoperatively and after 3, 6, 12, and 24 months. The primary outcome was maximum total point motion (MTPM; mm). Regression analysis was performed to evaluate the relation between preoperative BMD and MTPM. RESULTS: We found low preoperative BMD in ROI1 to be significantly related to high MTPM at all follow-ups: after 3 months (R2 = 20%, PBMD = 0.017), 6 months (R2 = 29%, PBMD = 0.003), 12 months (R2 = 33%, PBMD = 0.001), and 24 months (R2 = 27%, PBMD = 0.001). We also found a significant relation for low BMD in ROI2 and high MTPM: 3 months (R2 = 19%, PBMD = 0.042), 6 months (R2 = 28%, PBMD = 0.04), 12 months (R2 = 32%, PBMD = 0.004), and 24 months (R2 = 24%, PBMD = 0.005). CONCLUSION: Low preoperative BMD in the tibia is related to high MTPM. Thus, high migration of uncemented tibia components is to be expected in patients with poor bone quality.

Changes in bone mineral density of the proximal tibia after uncemented total knee arthroplasty. A prospective randomized study.

PURPOSE: Regenerex is a novel porous titanium construct with a three-dimensional porous structure and biomechanical characteristics close to that of normal trabecular bone. The aim of this study was to evaluate the adaptive bone remodeling of the proximal tibia after uncemented total knee arthroplasty (TKA) using a tibial tray with this novel coating compared to a well-proven standard porous coated (PPS) tibial tray. MATERIALS: Sixty patients scheduled for TKA were randomized to receive either a Regenerex (n = 31) or a PPS tibial component (n = 29). Changes in bone mineral density (BMD) of the proximal tibia were measured at three, six, 12 and 24 months by dual-energy X-ray absorptiometry (DEXA). RESULTS: In the lateral region (ROI 3), a significant increase in BMD was seen in both groups at three, six, and 12 months after surgery. The relative increase at 12 months was 8.1 % (P = 0.007) for the PPS group and 6.5 % (P = 0.002) for the Regenerex group. Positive values were retained at 24 months in both groups. At 24 months BMD in the distal region below the central stem (ROI 1) had decreased in the PPS group by 3.4 % (P = 0.005) and in the Regenerex group by 2.4 % (P = 0.17). In the medial region (ROI 2) BMD remained unchanged at all follow-up evaluations in both groups. There were no significant differences between the two groups (P = 0.45) in any ROI at any follow-up evaluation. CONCLUSION: The significant increase in BMD of the lateral proximal tibia plateau with very limited changes medially and distally seen in both implants suggests that the novel porous titanium construct Regenerex and the PPS implant have a pronounced beneficial effect with regard to maintaining periprosthetic BMD in all regions of interest investigated.

Cementless metaphyseal sleeves without stem in revision total knee arthroplasty.

INTRODUCTION: Revision total knee arthroplasty with a cementless metaphyseal sleeve is suggested to be used without stem in revision total knee arthroplasty (rTKA). To the best of our knowledge, no papers investigating this have been published. The purpose of this study was to evaluate clinical outcome. METHOD: In this retrospective study, 71 patients operated with rTKA with sleeves without stem in the period 2009-2011 were identified; 63 were examined. All patients with the prosthesis still in place were invited to a medical examination including X-rays. American Knee Society Score (AKSS) and Oxford Knee Score (OKS) were used as primary clinical outcome scores. RESULTS: Mean number of revisions including the revision with sleeve was 1.7. AKSS increased significantly from 62.7 to 109.6; (p value <0.0001). The overall satisfaction was 2.5 on a four-stage scale, going from very satisfied to dissatisfied (range 1-4). The Anderson Orthopaedic Research Institute (AORI) classification showed 63 % of the tibias and 56 % of the femurs to be type 2B, whereas 19 % tibias and 5 % femurs were type 3. Review of the X-rays showed all prostheses fixed. Mean tibiofemoral alignment was 6.0° valgus, and 51 % were outside optimal alignment (2.4°-7.2°). Six patients were excluded from the study. CONCLUSIONS: We found that the prostheses were overall well fixed and patients' AKSS increased significantly. Many patients had pain conditions, both comorbid pain and pain that might be alignment-related, and adding a stem thus seems to be a good idea in terms of alignment. Level of evidence Level IV, case series without control group.

Monoblock versus modular polyethylene insert in uncemented total knee arthroplasty.

Background and purpose - Backside wear of the polyethylene insert in total knee arthroplasty (TKA) can produce clinically significant levels of polyethylene debris, which can lead to loosening of the tibial component. Loosening due to polyethylene debris could theoretically be reduced in tibial components of monoblock polyethylene design, as there is no backside wear. We investigated the effect of 2 different tibial component designs, monoblock and modular polyethylene, on migration of the tibial component in uncemented TKA. Patients and methods - In this randomized study, 53 patients (mean age 61 years), 32 in the monoblock group and 33 in the modular group, were followed for 2 years. Radiostereometric analysis (RSA) was done postoperatively after weight bearing and after 3, 6, 12, and 24 months. The primary endpoint of the study was comparison of the tibial component migration (expressed as maximum total point motion (MTPM)) of the 2 different implant designs. Results - We did not find any statistically significant difference in MTPM between the groups at 3 months (p = 0.2) or at 6 months (p = 0.1), but at 12 and 24 months of follow-up there was a significant difference in MTPM of 0.36 mm (p = 0.02) and 0.42 mm (p = 0.02) between groups, with the highest amount of migration (1.0 mm) in the modular group. The difference in continuous migration (MTPM from 12 and 24 months) between the groups was 0.096 mm (p = 0.5), and when comparing MTPM from 3-24 months, the difference between the groups was 0.23 mm (p = 0.07). Interpretation - In both study groups, we found the early migration pattern expected, with a relatively high initial amount of migration from operation to 3 months of follow-up, followed by stabilization of the implant with little migration thereafter. However, the modular implants had a statistically significantly higher degree of migration compared to the monoblock. We believe that the greater stiffness of the modular implants was the main reason for the difference in migration, but an initial creep in the polyethylene metal-back locking mechanism of the modular group could also be a possible explanation for the observed difference in migration between the 2 study groups.

Analgesic effect of perioperative escitalopram in high pain catastrophizing patients after total knee arthroplasty: a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Sufficient pain treatment remains a challenge after total knee arthroplasty (TKA), especially in high pain catastrophizing patients. Serotonergic signaling may be involved in pain processing, but the effect of selective serotonin reuptake inhibitors on well-defined postoperative pain has not previously been investigated. The authors hypothesized that perioperative escitalopram would reduce pain after TKA in high pain catastrophizing patients. METHODS: A total of 120 pain catastrophizing patients (selected using the pain catastrophizing scale as preoperative screening tool) scheduled for TKA were randomized in a double-blind manner to either 10 mg escitalopram or placebo daily from preanesthesia to postoperative day 6 in addition to a standardized analgesic regime. The primary outcome was pain upon ambulation 24 h after surgery. Secondary outcomes were overall pain during well-defined mobilizations and at rest from 2 to 48 h and from days 2 to 6, morphine equivalents, anxiety, depression, and side effects. RESULTS: Pain upon ambulation (mean [95% CI]) 24 h after surgery in the escitalopram versus placebo group was 58 (53 to 64) versus 64 (58 to 69), the mean difference being -5 (-13 to 3), P = 0.20. Overall pain upon ambulation and at rest from days 2 to 6 was lower in the escitalopram versus placebo group, as was depression score at day 6 (all P ≤ 0.01 in analyses uncorrected for multiple tests). Side effects were nonsignificant except for reduced tendency to sweat and prolonged sleep in the escitalopram group. No other between-group differences were observed. CONCLUSIONS: Escitalopram did not reduce pain upon ambulation 24 h after TKA in high pain catastrophizing patients. Future studies on optimal timing, dose, and duration of selective serotonin reuptake inhibitor treatment might be warranted.

Adamts1 is highly induced in rachitic bones of FGF23 transgenic mice and participates in degradation of non-mineralized bone matrix collagen.

Transgenic mice overexpressing fibroblast growth factor 23 (FGF23) in osteoblasts have a rachitic bone phenotype. These mice display hypomineralized bones, increased expression of osteoblast markers, but osteoclast numbers are unaltered or slightly reduced. Paradoxically, they show increased serum levels of the bone resorption marker CTX, a type I collagen degradation fragment. Here we analyzed a matrix metalloproteinase- (MMP-) like secreted protease, Adamts1, that has previously been associated with osteoblastic type I collagen breakdown in vitro. Bones from FGF23 transgenic (tg) mice displayed increased Adamts1 protein upon both immunohistological staining and Western blotting. We further found Adamts1 protein together with excessively degraded type I collagen in the non-mineralized bone fraction of FGF23 tg mice. A similar degradation pattern of type I collagen was noticed upon forced expression of Adamts1 in osteoblastic cells in vitro. Importantly, these Adamts1-expressing osteoblastic cells exhibited increased release of CTX fragments when cultured on demineralized bone discs. Together, these results demonstrate for the first time that Adamts1 can be highly induced in bone tissue and that this MMP-like protease can increase osteoblastic release of CTX fragments from non-mineralized bone. Thus, Adamts1 potentially contributes to the increased serum levels of CTX in rickets/osteomalacia.

Tibial Component Undersizing Is Related to High Degrees of Implant Migration Following Cementless Total Knee Arthroplasty: A Study of Radiostereometric Analysis Data for 111 Patients with 2-Year Follow-up.

Radiostereometric analysis (RSA) studies have shown that the continuous migration of tibial components is predictive of aseptic loosening following total knee arthroplasty (TKA). In the present study, we investigated whether accurate sizing and placement of tibial components are related to the degree of implant migration as measured with use of RSA. Methods: A total of 111 patients who underwent TKA surgery with a cementless tibial component were followed for a period of 2 years postoperatively, during which implant migration was assessed with use of RSA. RSA was performed within 7 days postoperatively and after 3, 6, 12, and 24 months. Postoperative radiographs were evaluated for component size and placement in the tibia. The evaluations were performed by experienced knee surgeons who were blinded to the migration data and clinical outcomes. A multivariable linear regression analysis was conducted. Results: Continuous implant migration (i.e., migration occurring between 12 and 24 months postoperatively) had a negative association with tibial component size (coefficient [B], -0.2; 95% confidence interval [CI], -0.33 to -0.08). Subsidence was associated with the absence of posterior cortical bone support (B, -0.7; 95% CI, -1.09 to -0.28), the absence of lateral cortical bone support (B, 0.8; 95% CI, 0.29 to 1.37), frontal-plane varus malalignment (B, 0.6; 95% CI, 0.12 to 1.16), and component undersizing (B, -0.4; 95% CI, -0.06 to -0.68). Posterior tilt was associated only with undersizing (B, 0.6; 95% CI, 0.27 to 1.11). Conclusions: Undersized cementless tibial components are at a higher risk for poor fixation with continuous migration following TKA. Therefore, a higher risk of aseptic loosening should be expected. Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

Microarray profiling of diaphyseal bone of rats suffering from hypervitaminosis A.

Vitamin A is the only known compound that produces spontaneous fractures in rats. In an effort to resolve the molecular mechanism behind this effect, we fed young male rats high doses of vitamin A and performed microarray analysis of diaphyseal bone with and without marrow after 1 week, i.e., just before the first fractures appeared. Of the differentially expressed genes in cortical bone, including marrow, 98% were upregulated. In contrast, hypervitaminotic cortical bone without marrow showed reduced expression of 37% of differentially expressed genes. Gene ontology (GO) analysis revealed that only samples containing bone marrow were associated with a GO term, which principally represented extracellular matrix. This is consistent with the histological findings of increased endosteal/marrow osteoblast number. Fourteen genes, including Cyp26b1, which is known to be upregulated by vitamin A, were selected and verified by real-time PCR. In addition, immunohistochemical staining of bone sections confirmed that the bone-specific molecule osteoadherin was upregulated. Further analysis of the major gene-expression changes revealed apparent augmented Wnt signaling in the sample containing bone marrow but reduced Wnt signaling in cortical bone. Moreover, induced expression of hypoxia-associated genes was found only in samples containing bone marrow. Together, these results highlight the importance of compartment-specific analysis of bone and corroborate previous observations of compartment-specific effects of vitamin A, with reduced activity in cortical bone but increased activity in the endosteal/marrow compartment. We specifically identify potential key osteoblast-, Wnt signaling-, and hypoxia-associated genes in the processes leading to spontaneous fractures.

Over-expression of Adamts1 in mice alters bone mineral density.

ADAMTS1, a secreted multifunctional metalloproteinase with disintegrin and thrombospondin motifs, is an early response gene of parathyroid hormone (PTH) in osteoblasts. Mice engineered to lack Adamts1 are smaller compared to wild-type (WT) mice and ADAMTS1 metalloproteinase activity has been shown to increase osteoblastic growth in collagen gels. However, there are no reports investigating the consequence of Adamts1 over-expression on bone tissue in vivo. Here, we analyze bones of female and male transgenic (TG) mice over-expressing mouse Adamts1 using peripheral quantitative computed tomography to evaluate its effect on bone shape and mineral density. Western blotting of protein extracts and immunohistochemistry of bone sections reveal increased presence of Adamts1 protein in TG bones compared to WT bones. Phenotypic analyses of femur show that female TG mice have reduced metaphyseal total density, trabecular bone mineral density and trabecular mineral content. In contrast, male TG mice which were without changes in the metaphysis showed increased total density and cortical density at the mid-diaphysis cortical site. Female TG mice showed no significant changes at the cortical site compared to WT mice. Furthermore, diaphyseal endosteal compartment was only affected in male TG mice. Along these lines, Adamts1 increased blood levels of PTH only in females whereas it reduced osteocalcin levels only in males. These results reveal that Adamts1 has an impact on bone mineral density and thus further confirm Adamts1 as a potent regulator of bone remodeling.

Effects of patient accessible electronic health records on nurses' work environment: a survey study on expectations in Sweden.

OBJECTIVES: The introduction of information and communication technology influences the work environment of large groups of employees in healthcare. In Sweden, a national healthcare service providing patient accessible electronic health records (PAEHR) has been deployed, and this paper investigates nurses' expected effects of this implementation. SETTING: Nurses associated with the Swedish Association of Health Professionals working in healthcare such as primary care, hospitals and midwives in Sweden. Before a full-scale national implementation of PAEHR, a web survey study was distributed nationally. The respondents represented all 21 Swedish regions. Questions included five-point Likert scale questions and open questions. PARTICIPANTS: A survey link was distributed via email to 8460 registered nurses, midwives and union representatives in Sweden. The response rate was 35.4% (2867 respondents: registered nurses 84%; midwives 6%; chief position 5%; in projects 2% and other 3%). Three reminders were sent out, all of them increasing the response rate. A majority of the respondents were female (89.9%), 8.4% male, whereas 1.7% did not indicate their gender. 31.4% were under 40 years old, 53.8% 40-59 and 13.7% over 60. RESULTS: Data were analysed using exploratory factor analysis with principal component analysis as the extraction method. The analysis revealed three distinct factors related to nurses' expectations of PAEHR: (1) PAEHR improves the quality of care, (2) PAEHR improves the quality of the work environment and (3) risk and fears concerning patients' well-being. Some interesting results include that more experienced nurses are more favourable to PAEHR. Our analysis also shows that the view of the nurse-patient relationship is an essential underlying factor related to positive or negative expectations. CONCLUSIONS: Results show that the expectations and perceptions of PAEHR vary depending on the nurse's view of who the electronic record belongs to. Younger nurses are somewhat more negative towards PAEHR than older nurses.

Mast cell chymase has a negative impact on human osteoblasts.

Mast cells have been linked to osteoporosis and bone fractures, and in a previous study we found that mice lacking a major mast cell protease, chymase, develop increased diaphyseal bone mass. These findings introduce the possibility that mast cell chymase can regulate bone formation, but the underlying mechanism(s) has not previously been investigated. Here we hypothesized that chymase might exert such effects through a direct negative impact on osteoblasts, i.e., the main bone-building cells. Indeed, we show that chymase has a distinct impact on human primary osteoblasts. Firstly, chymase was shown to have pronounced effects on the morphological features of osteoblasts, including extensive cell contraction and actin reorganization. Chymase also caused a profound reduction in the output of collagen from the osteoblasts, and was shown to degrade osteoblast-secreted fibronectin and to activate pro-matrix metallopeptidase-2 released by the osteoblasts. Further, chymase was shown to have a preferential impact on the gene expression, protein output and phosphorylation status of TGFß-associated signaling molecules. A transcriptomic analysis was conducted and revealed a significant effect of chymase on several genes of importance for bone metabolism, including a reduction in the expression of osteoprotegerin, which was confirmed at the protein level. Finally, we show that chymase interacts with human osteoblasts and is taken up by the cells. Altogether, the present findings provide a functional link between mast cell chymase and osteoblast function, and can form the basis for a further evaluation of chymase as a potential target for intervention in metabolic bone diseases.

Evaluation of different coatings of the tibial tray in uncemented total knee arthroplasty. A randomized controlled trial with 5 years follow-up with RSA and DEXA.

BACKGROUND: Regenerex® is a porous titanium construct with a 3D interconnecting pore structure and biomechanical characteristics close to that of normal trabecular bone. This study aimed to compare the Regenerex (VR) to the non-interconnecting pore structure Porous Plasma Spray (VP) on tibial implants for total knee arthroplasty (TKA) at 5 years. METHODS: We enrolled and randomized 61 patients (mean age = 63(49-71) years, Female/Male = 35/26) who were planned for an uncemented Vanguard TKA (Biomet, Warsaw, Indiana, USA) to receive either a VR or a VP coated tibial component (31/29). We performed radiostereometric analysis (RSA) and Dual Energy X-ray Absorptiometry (DEXA) postoperatively, and at three, six, 12, 24 and 60 months with measurements of migration. In total 55 patients attended the 5-year follow-up. RESULTS: One patient died and four were reoperated during the 60-months period; none due to aseptic loosening. All reoperations were in the VR-group. The mean (range) 60-months MTPM was 1.4 mm (0.5-3.7) for the VP-group and 1.8 mm (0.4-4.9) for the VR-group (p = 0.8). The 24 to 60-months mean (range) MTPM was -0.3 mm (-5 to 1.24) in the VP-group and 0.2 mm (-0.4 to 3.5) in the VR-group (p = 0.8). CONCLUSION: We did not find any statistically significant differences between the VP- and VR-group and both groups show recognizable migration. We will continue to follow the groups for years to come.

Bone remodeling and implant migration of uncemented femoral and cemented asymmetrical tibial components in total knee arthroplasty - DXA and RSA evaluation with 2-year follow up.

BACKGROUND: Aseptic loosening is one of the major reasons for late revision in total knee arthroplasty (TKA). The risk of aseptic loosening can be detected using radiostereometric analysis (RSA), whereby micromovements (migration) can be measured, and thus RSA is recommended in the phased introduction of orthopedic implants. Decrease in bone mineral density (BMD), as measured by dual-energy x ray absorptiometry (DXA), is related to the breaking strength of the bone, which is measured concurrently by RSA. The aim of the study was to evaluate bone remodeling and implant migration with cemented asymmetrical tibial and uncemented femoral components after TKA with a follow up period of 2 years. METHODS: This was a prospective longitudinal cohort study of 29 patients (number of female/male patients 17/12, mean age 65.2 years), received a hybrid Persona® TKA (Zimmer Biomet, Warsaw, IN, USA) consisting of a cemented tibial, an all-polyethylene patella, and uncemented trabecular metal femoral components. Follow up: preoperative, 1 week, and 3, 6, 12 and 24 months after surgery, and double examinations for RSA and DXA were performed at 12 months. RSA results were presented as maximal total point of motion (MTPM) and segmental motion (translation and rotation), and DXA results were presented as changes in BMD in different regions of interest (ROI). RESULTS: MTPM at 3, 6, 12, and 24 months was 0.65 mm, 0.84 mm, 0.92 mm, and 0.96 mm for the femoral component and 0.54 mm, 0.60 mm, 0.64 mm, and 0.68 mm, respectively, for the tibial component. The highest MTPM occurred within the first 3 months. Afterwards most of the curves flattened and stabilized. Between 12 and 24 months after surgery, 16% of femoral components had migrated by more than 0.10 mm and 15% of tibial components had migrated by more than 0.2 mm. Percentage change in BMD in each ROI for distal femur was as follows: ROI I 26.7%, ROI II 9.2% and ROI III 3.3%. BMD and at the proximal tibia: ROI I 8.2%, ROI II 8.6% and ROI III 7.0% after 2 years compared with 1 week postoperative results. There was no significant correlation between maximal percentwise change in BMD and MTPM after 2 years. CONCLUSION: Migration patterns and changes in BMD related to femoral components after TKA in our study correspond well with previous studies; we observed marginally greater migration with the tibial component.

Melphalan flufenamide inhibits osteoclastogenesis by suppressing proliferation of monocytes.

Myeloma bone disease is a major complication in multiple myeloma affecting quality of life and survival. It is characterized by increased activity of osteoclasts, bone resorbing cells. Myeloma microenvironment promotes excessive osteoclastogenesis, a process of production of osteoclasts from their precursors, monocytes. The effects of two anti-myeloma drugs, melphalan flufenamide (melflufen) and melphalan, on the activity and proliferation of osteoclasts and their progenitors, monocytes, were assessed in this study. In line with previous research, differentiation of monocytes was associated with increased expression of genes encoding DNA damage repair proteins. Hence monocytes were more sensitive to DNA damage-causing alkylating agents than their differentiated progeny, osteoclasts. In addition, differentiated progeny of monocytes showed increased gene expression of immune checkpoint ligands which may potentially create an immunosuppressive microenvironment. Melflufen was ten-fold more active than melphalan in inhibiting proliferation of osteoclast progenitors. Furthermore, melflufen was also superior to melphalan in inhibition of osteoclastogenesis and bone resorption. These results demonstrate that melflufen may exert beneficial effects in patients with multiple myeloma such as reducing bone resorption and immunosuppressive milieu by inhibiting osteoclastogenesis.

A small scale cell culture system to analyze mechanobiology using reporter gene constructs and polyurethane dishes.

Mechanical forces are translated into biochemical signals and contribute to cell differentiation and phenotype maintenance. Mesenchymal stem cells and their tissue-specific offspring, as osteoblasts and chondrocytes, cells of cardiovascular tissues and lung cells are sensitive to mechanical loading but molecules and mechanisms involved have to be unraveled. It is well established that cellular mechanotransduction is mediated e.g. by activation of the transcription factor SP1 and by kinase signaling cascades resulting in the activation of the AP1 complex. To investigate cellular mechanisms involved in mechanotransduction and to analyze substances, which modulate cellular mechanosensitivity reporter gene constructs, which can be transfected into cells of interest might be helpful. Suitable small-scale bioreactor systems and mechanosensitive reporter gene constructs are lacking. To analyze the molecular mechanisms of mechanotransduction and its crosstalk with biochemically induced signal transduction, AP1 and SP1 luciferase reporter gene constructs were cloned and transfected into various cell lines and primary cells. A newly developed bioreactor and small-scale 24-well polyurethane dishes were used to apply cyclic stretching to the transfected cells. 1 Hz cyclic stretching for 30 min in this system resulted in a significant stimulation of AP1 and SP1 mediated luciferase activity compared to unstimulated cells. In summary we describe a small-scale cell culture/bioreactor system capable of analyzing subcellular crosstalk mechanisms in mechanotransduction, mechanosensitivity of primary cells and of screening the activity of putative mechanosensitizers as new targets, e.g. for the treatment of bone loss caused by both disuse and signal transduction related alterations of mechanotransduction.

Surgical treatment of acute and chronic acromioclavicular dislocation Tossy type III and V using the Hook plate.

We treated 16 patients with acute and chronic acromioclavicular dislocations type III and V by open reduction and fixation using a Hook plate (AO). Plate removal was performed 7 months later on average (range 3 1/2 - 13). A clinical and radiological follow-up was performed after a mean time interval of 29 months (range, 11-40) from the date of plate removal. The L'Insalata scoring system was used to compare the function of the injured shoulder before operation and after removal of the hook plate. Constant's score was used to evaluate the operated shoulder after the removal of the hook plate. Complications were limited and the overall results were excellent.