Sarcopenia prevalence and incidence in older men - a MrOs Sweden study.

INTRODUCTION: The European Working Group on Sarcopenia in Older People (EWGSOP) published a revised definition of sarcopenia in 2018. There are few incidence studies of sarcopenia following the latest definition. OBJECTIVE: To study prevalence, incidence proportion and incidence rate of sarcopenia in a simple random sample of older Swedish men using the EWGSOP2 definition. METHODS: Men aged 69-81 were invited to participate in the Osteoporotic Fractures in Men (MrOs) Sweden study. Of 2,004 included participants, 1,266 participants (mean age 75.1, SD 3.1 years) completed baseline and 5-year follow-up measurements. We assessed muscle strength by measuring grip strength and chair stands test, lean mass by dual energy X-ray absorptiometry and physical performance by gait speed at baseline and follow-up. Sarcopenia prevalence and incidence were calculated according to the EWGSOP2 definition. RESULTS: Sarcopenia prevalence increased from 5.6% at baseline to 12.0% at follow-up. During the mean 5.2-year follow-up period, 9.1% developed sarcopenia (incidence proportion), corresponding to an incidence rate of 1.8 per 100 person-years at risk while 39.4% of the participants with sarcopenia at baseline participating in follow-up reversed to no longer having confirmed sarcopenia at 5-year follow-up. CONCLUSION: The prevalence of sarcopenia defined along EWGSOP2 criteria doubled within 5 years in older men, and more than a third of the study participants with sarcopenia at baseline did not have sarcopenia at follow-up. We conclude that sarcopenia is not a static condition.

Continuous periprosthetic bone loss but preserved stability for a collum femoris-preserving stem: follow-up of a prospective cohort study of 21 patients with dualenergy X-ray absorptiometry and radiostereometric analysis with minimum 8 years of follow-up.

Background and purpose - We previously described a decrease in bone mineral density (BMD) in the calcar region 2 years after insertion of the collum femoris-preserving (CFP) stem, but the implants were stable. Now we have examined the long-term changes in periprosthetic BMD and stability of the CFP stem. Patients and methods - We conducted a minimum 8-year follow-up of 21 patients from our original investigation. We examined periprosthetic BMD by dual-energy X-ray absorptiometry (DEXA) and implant stability by radiostereometric analysis (RSA). Results - Between 2 and 8 years 1 stem was revised due to aseptic loosening. Between 2 and 8 years we found a 14% (95% confidence interval [CI] 9-19) reduction in BMD in Gruen zone 6 and 17% (CI 6-28) in Gruen zone 7. From baseline the reduction in BMD was 30% (CI 23-36) in Gruen zone 6, 39% (CI 31-47) in Gruen zone 7, and 19% (CI 14-23) in Gruen zone 2. Between 2 and 8 years, RSA (n = 17) showed a mean translation along the stem axis of 0.02mm (CI -0.02 to 0.06) and a mean rotation around the stem axis of 0.08° (CI -0.26 to 0.41). From baseline mean subsidence was 0.07 mm (CI -0.16 to 0.03) and mean rotation around the stem axis was 0.23° (CI -0.23 to 0.68) at 8 years. Interpretation - There was continuous loss of proximomedial BMD at 8 years while the CFP stem remained stable. Proximal periprosthetic bone loss cannot be prevented by this stem.

Denosumab prevents acetabular bone loss around an uncemented cup: analysis of secondary outcomes in a randomized controlled trial.

BACKGROUND AND PURPOSE: Uncemented total hip arthroplasty (THA) is associated with periprosthetic bone loss. In a secondary outcome analysis from a randomized controlled trial, we studied whether denosumab can prevent loss of acetabular periprosthetic bone mineral density (pBMD) in patients who received a trabecular metal cup during uncemented THA. PATIENTS AND METHODS: 64 patients (aged 35-65 years) with unilateral osteoarthritis of the hip were randomized to 2 subcutaneous injections with denosumab or placebo, given 1-3 days post-surgery and 6 months post-surgery. Acetabular pBMD was measured in 5 regions of interest (ROIs) by dual-energy X-ray absorptiometry. Serum markers for bone metabolism were analyzed. Periprosthetic osteoblastic activity, measured as standardized uptake values (SUVs) by [18F] positron emission tomography/computed tomography, was evaluated in 32 of the 64 study patients. RESULTS: After 12 months, patients treated with denosumab had higher pBMD compared with the placebo-treated patients in 4 of 5 ROIs and in sum of ROIs 1-5. After 24 months, the effect on pBMD for patients treated with denosumab declined. Serum markers declined pronouncedly up to 12 months in patients treated with denosumab, but rebounded above baseline levels after 24 months. Patients treated with denosumab had statistically significantly lower SUVs in all ROIs, except ROI 5, after 6 months. INTERPRETATION: Based on this exploratory analysis of secondary endpoints the application of denosumab seems associated with preserved acetabular pBMD, reduced bone metabolism and attenuated periprosthetic osteoblastic activity. However, given the known rebound affects after discontinuation of denosumab treatment, these effects cannot be expected to persist. If prolonged treatment or shift to other regimes would be beneficial to reduce the risk of cup loosening is yet to be investigated.

Do dual-mobility cups cemented into porous tantalum shells reduce the risk of dislocation after revision surgery?

Background and purpose - Dual-mobility cups (DMCs) reduce the risk of dislocation and porous tantalum (TM) shells show favorable osseointegration after acetabular revision surgery, yet the combination of these implants has not been studied. We hypothesized that (1) cementing a DMC into a TM shell decreases the risk of dislocation; (2) DMCs cemented into TM shells are not at greater risk of re-revision; (3) liberation of tantalum ions is marginal after use of this combined technique. Patients and methods - We investigated the outcome in 184 hips (184 patients) after acetabular revision surgery with TM shells, fitted either with DMCs (n = 69), or with standard poly-ethylene (PE) liners (n = 115). Chart follow-up was complete for all patients, and the occurrence of dislocations and re-revisions was recorded. 20 were deceased, 50 were unable to attend follow-up, leaving 114 for assessment of hip function after 4.9 (0.5-8.9) years, radiographs were obtained in 99, and tantalum concentrations in 84 patients. Results - 1 patient with a DMC had a dislocation, whereas 14 patients with PE liners experienced at least 1 dislocation. 11 of 15 re-revisions in the PE group were necessitated by dislocations, whereas none of the 2 re-revisions in the DMC group was performed for this reason. Hence, dislocation-free survival after 4 years was 99% (95% CI 96-100) in the DMC group, whereas it was 88% (CI 82-94, p = 0.01) in the PE group. We found no radiographic signs of implant failure in any patient. Mean tantalum concentrations were 0.1 µl/L (CI 0.05-0.2) in the DMC group and 0.1 µg/L (CI 0.05-0.2) in the PE group. Interpretation - Cementing DMCs into TM shells reduces the risk of dislocation after acetabular revision surgery without jeopardizing overall cup survival, and without enhancing tantalum release.

Global miRNA expression and correlation with mRNA levels in primary human bone cells.

MicroRNAs (miRNAs) are important post-transcriptional regulators that have recently introduced an additional level of intricacy to our understanding of gene regulation. The aim of this study was to investigate miRNA-mRNA interactions that may be relevant for bone metabolism by assessing correlations and interindividual variability in miRNA levels as well as global correlations between miRNA and mRNA levels in a large cohort of primary human osteoblasts (HOBs) obtained during orthopedic surgery in otherwise healthy individuals. We identified differential expression (DE) of 24 miRNAs, and found 9 miRNAs exhibiting DE between males and females. We identified hsa-miR-29b, hsa-miR-30c2, and hsa-miR-125b and their target genes as important modulators of bone metabolism. Further, we used an integrated analysis of global miRNA-mRNA correlations, mRNA-expression profiling, DE, bioinformatics analysis, and functional studies to identify novel target genes for miRNAs with the potential to regulate osteoblast differentiation and extracellular matrix production. Functional studies by overexpression and knockdown of miRNAs showed that, the differentially expressed miRNAs hsa-miR-29b, hsa-miR-30c2, and hsa-miR-125b target genes highly relevant to bone metabolism, e.g., collagen, type I, α1 (COL1A1), osteonectin (SPARC), Runt-related transcription factor 2 (RUNX2), osteocalcin (BGLAP), and frizzled-related protein (FRZB). These miRNAs orchestrate the activities of key regulators of osteoblast differentiation and extracellular matrix proteins by their convergent action on target genes and pathways to control the skeletal gene expression.

Are porous tantalum cups superior to conventional reinforcement rings?

Background and purpose - Porous tantalum cups have been introduced as an alternative to various reinforcement rings in revision hip surgery. We hypothesized that porous tantalum cups would be superior to Müller acetabular roof reinforcement rings (MARRs) in revision hip surgery with re-revision for aseptic loosening as the primary outcome measure. Patients and methods - 207 hips operated with either a porous tantalum cup (TM cup, n = 111) or a MARR (n = 96) at index procedure were identified in our local arthroplasty register. Acetabular defects were classified according to Paprosky. There were 96 men and 111 women with a median age of 71 (35-95) years, presenting acetabular defect size type I in 39 cases, IIA in 22, IIB in 27, IIC in 43, IIIA in 32, and IIIB in 37 cases. Analysis of medical records identified all patients with subsequent re-revision and reasons for re-revisions. Kaplan-Meier survival functions were used to estimate implant survival. Results - With re-revision for aseptic loosening as the endpoint, the 6-year unadjusted cumulative survival was 97% (95% CI: 94-100) for TM cups and 96% (CI: 92-100) for MARR (p = 0.6). Using re-revision for any reason as the endpoint, 6-year survival was 87% (CI: 81-94) for TM cups and 95% (CI: 90-99) for MARR (p = 0.06). The main reason for re-revision in the TM group was dislocation (n = 10), followed by loosening (n = 3), whereas the main reason for re-revision in the MARR group was aseptic loosening (n = 8). Duration of the index procedure and perioperative blood loss were lower in the TM group. Interpretation - Both TM and MARR lead to good 6-year results in acetabular revision surgery. The methods differ in their respective failure mechanisms. We conclude that TM cups are a valuable treatment option in acetabular revision surgery, but the reasons underlying dislocations after the use of TM cups must be analyzed further.

International and ethnic variability of falls in older men.

AIMS: Fallers and especially recurrent fallers are at high risk for injuries. The aim of this study was to evaluate fall epidemiology in older men with special attention to the influence of age, ethnicity and country of residence. METHODS: 10,998 men aged 65 years or above recruited in Hong Kong, the United States (US) and Sweden were evaluated in a cross-sectional retrospective study design. Self-reported falls and fractures for the preceding 12 months were registered through questionnaires. Group comparisons were done by chi-square test or logistic regression. RESULTS: The proportion of fallers among the total population was 16.5% in ages 65-69, 24.8% in ages 80-84 and 43.2% in ages above 90 (P <0.001). The corresponding proportions of recurrent fallers in the same age groups were 6.3%, 10.1% and 18.2%, respectively (P <0.001), and fallers with fractures 1.0%, 2.3% and 9.1%, respectively (P <0.001). The proportion of fallers was highest in the US, intermediate in Sweden and lowest in Hong Kong (in most age groups P <0.05). The proportion of fallers among white men in the US was higher than in white men in Sweden (all comparable age groups P <0.01) but there were no differences in the proportion of fallers in US men with different ethnicity. CONCLUSIONS: The proportion of fallers in older men is different in different countries, and data in this study corroborate with the view that society of residence influences fall prevalence more than ethnicity.

Global analysis of the impact of environmental perturbation on cis-regulation of gene expression.

Genetic variants altering cis-regulation of normal gene expression (cis-eQTLs) have been extensively mapped in human cells and tissues, but the extent by which controlled, environmental perturbation influences cis-eQTLs is unclear. We carried out large-scale induction experiments using primary human bone cells derived from unrelated donors of Swedish origin treated with 18 different stimuli (7 treatments and 2 controls, each assessed at 2 time points). The treatments with the largest impact on the transcriptome, verified on two independent expression arrays, included BMP-2 (t = 2h), dexamethasone (DEX) (t = 24 h), and PGE2 (t = 24 h). Using these treatments and control, we performed expression profiling for 18,144 RefSeq transcripts on biological replicates of the complete study cohort of 113 individuals (n(total) = 782) and combined it with genome-wide SNP-genotyping data in order to map treatment-specific cis-eQTLs (defined as SNPs located within the gene ± 250 kb). We found that 93% of cis-eQTLs at 1% FDR were observed in at least one additional treatment, and in fact, on average, only 1.4% of the cis-eQTLs were considered as treatment-specific at high confidence. The relative invariability of cis-regulation following perturbation was reiterated independently by genome-wide allelic expression tests where only a small proportion of variance could be attributed to treatment. Treatment-specific cis-regulatory effects were, however, 2- to 6-fold more abundant among differently expressed genes upon treatment. We further followed-up and validated the DEX-specific cis-regulation of the MYO6 and TNC loci and found top cis-regulatory variants located 180 kb and 250 kb upstream of the transcription start sites, respectively. Our results suggest that, as opposed to tissue-specificity of cis-eQTLs, the interactions between cellular environment and cis-variants are relatively rare (∼1.5%), but that detection of such specific interactions can be achieved by a combination of functional genomic approaches as described here.

A prospective cohort study on the short collum femoris-preserving (CFP) stem using RSA and DXA. Primary stability but no prevention of proximal bone loss in 27 patients followed for 2 years.

BACKGROUND AND PURPOSE: Short femoral stems have been introduced in total hip arthroplasty in order to save proximal bone stock. We hypothesized that a short stem preserves periprosthetic bone mineral density (BMD) and provides good primary stability. METHODS: We carried out a prospective cohort study of 30 patients receiving the collum femoris-preserving (CFP) stem. Preoperative total hip BMD and postoperative periprosthetic BMD in Gruen zones 1-7 were investigated by dual-energy x-ray absorptiometry (DXA), stem migration was analyzed by radiostereometric analysis (RSA), and the Harris hip score (HHS) was determined. RESULTS: 2 patients were excluded intraoperatively and 1 patient was revised due to a deep infection, leaving 27 patients for analysis. The mean HHS increased from 49 (24-79) preoperatively to 99 (92-100) after 2 years. DXA after 1 year showed substantial loss of BMD in Gruen zone 7 (-31%), zone 6 (-19%), and zone 2 (-13%, p < 0.001) compared to baseline BMD determined immediately postoperatively. The bone loss in these regions did not recover after 2 years, whereas the more moderate bone loss in Gruen zones 1, 3, and 5 partially recovered. There was a correlation between low preoperative total hip BMD and a higher amount of bone loss in Gruen zones 2, 6 and 7. RSA showed minor micromotion of the stem: mean subsidence was 0.13 (95% CI: -0.28 to 0.01) mm and mean rotation around the longitudinal axis was 0.01º (95% CI: -0.1 to 0.39) after 2 years. INTERPRETATION: We conclude that substantial loss in proximal periprosthetic BMD cannot be prevented by the use of a novel type of short, curved stem, and forces appear to be transmitted distally. However, the stems showed very small migration-a characteristic of stable uncemented implants.

Population genomics in a disease targeted primary cell model.

The common genetic variants associated with complex traits typically lie in noncoding DNA and may alter gene regulation in a cell type-specific manner. Consequently, the choice of tissue or cell model in the dissection of disease associations is important. We carried out an expression quantitative trait loci (eQTL) study of primary human osteoblasts (HOb) derived from 95 unrelated donors of Swedish origin, each represented by two independently derived primary lines to provide biological replication. We combined our data with publicly available information from a genome-wide association study (GWAS) of bone mineral density (BMD). The top 2000 BMD-associated SNPs (P < approximately 10(-3)) were tested for cis-association of gene expression in HObs and in lymphoblastoid cell lines (LCLs) using publicly available data and showed that HObs have a significantly greater enrichment (threefold) of converging cis-eQTLs as compared to LCLs. The top 10 BMD loci with SNPs showing strong cis-effects on gene expression in HObs (P = 6 x 10(-10) - 7 x 10(-16)) were selected for further validation using a staged design in two cohorts of Caucasian male subjects. All 10 variants were tested in the Swedish MrOS Cohort (n = 3014), providing evidence for two novel BMD loci (SRR and MSH3). These variants were then tested in the Rotterdam Study (n = 2090), yielding converging evidence for BMD association at the 17p13.3 SRR locus (P(combined) = 5.6 x 10(-5)). The cis-regulatory effect was further fine-mapped to the proximal promoter of the SRR gene (rs3744270, r(2) = 0.5, P = 2.6 x 10(-15)). Our results suggest that primary cells relevant to disease phenotypes complement traditional approaches for prioritization and validation of GWAS hits for follow-up studies.

Inferior physical performance test results of 10,998 men in the MrOS Study is associated with high fracture risk.

BACKGROUND: most fractures are preceded by falls. OBJECTIVE: the aim of this study was to determine whether tests of physical performance are associated with fractures. SUBJECTS: a total of 10,998 men aged 65 years or above were recruited. METHODS: questionnaires evaluated falls sustained 12 months before administration of the grip strength test, the timed stand test, the six-metre walk test and the twenty-centimetre narrow walk test. Means with 95% confidence interval (95% CI) are reported. P < 0.05 is a statistically significant difference. RESULTS: fallers with a fracture performed worse than non-fallers on all tests (all P < 0.001). Fallers with a fracture performed worse than fallers with no fractures both on the right-hand-grip strength test and on the six-metre walk test (P < 0.001). A score below -2 standard deviations in the right-hand-grip strength test was associated with an odds ratio of 3.9 (95% CI: 2.1-7.4) for having had a fall with a fracture compared with having had no fall and with an odds ratio of 2.6 (95% CI: 1.3-5.2) for having had a fall with a fracture compared with having had a fall with no fracture. CONCLUSION: the right-hand-grip strength test and the six-metre walk test performed by old men help discriminate fallers with a fracture from both fallers with no fracture and non-fallers.

Inferior physical performance tests in 10,998 men in the MrOS study is associated with recurrent falls.

BACKGROUND: recurrent fallers are at especially high risk for injuries. OBJECTIVE: to study whether tests of physical performance are associated with recurrent falls. SUBJECTS: a total of 10,998 men aged 65 years or above. METHODS: questionnaires evaluated falls sustained 12 months preceding testing of grip strength, timed stand, 6-m walk and 20-cm narrow walk test. Means with 95% confidence interval (95% CI) are reported. P < 0.01 is a statistically significant difference. RESULTS: in comparison to both occasional fallers and non-fallers, recurrent fallers performed more poorly on all the physical ability tests (all P < 0.001). A score below -2 standard deviations (SDs) in the right-hand grip strength test was associated with an odds ratio of 2.4 (95% CI 1.7, 3.4) for having had recurrent falls compared with having had no fall and of 2.0 (95% CI 1.3, 3.4) for having had recurrent falls compared with having had an occasional fall. CONCLUSION: low performance in physical ability tests are in elderly men associated with recurrent falls.

Tissue effect on genetic control of transcript isoform variation.

Current genome-wide association studies (GWAS) are moving towards the use of large cohorts of primary cell lines to study a disease of interest and to assign biological relevance to the genetic signals identified. Here, we use a panel of human osteoblasts (HObs) to carry out a transcriptomic survey, similar to recent studies in lymphoblastoid cell lines (LCLs). The distinct nature of HObs and LCLs is reflected by the preferential grouping of cell type-specific genes within biologically and functionally relevant pathways unique to each tissue type. We performed cis-association analysis with SNP genotypes to identify genetic variations of transcript isoforms, and our analysis indicates that differential expression of transcript isoforms in HObs is also partly controlled by cis-regulatory genetic variants. These isoforms are regulated by genetic variants in both a tissue-specific and tissue-independent fashion, and these associations have been confirmed by RT-PCR validation. Our study suggests that multiple transcript isoforms are often present in both tissues and that genetic control may affect the relative expression of one isoform to another, rather than having an all-or-none effect. Examination of the top SNPs from a GWAS of bone mineral density show overlap with probeset associations observed in this study. The top hit corresponding to the FAM118A gene was tested for association studies in two additional clinical studies, revealing a novel transcript isoform variant. Our approach to examining transcriptome variation in multiple tissue types is useful for detecting the proportion of genetic variation common to different cell types and for the identification of cell-specific isoform variants that may be functionally relevant, an important follow-up step for GWAS.

The effects of different weight-bearing regimes on press-fit cup stability: a randomised study with five years of follow-up using radiostereometry.

PURPOSE: There is little evidence to support immediate weight bearing after uncemented total hip arthroplasty (THA). METHODS: Thirty-seven patients with unilateral osteoarthritis of the hip received a press-fit cup. Cup stability was assessed with radiostereometry (RSA) over five years. Patients were randomised to immediate full weight bearing, or partial weight bearing for three months. RESULTS: At five years, we found no difference in micro-motion as assessed with radiostereometry. Numerically, there was more proximal translation and increased inclination with immediate weight bearing, but these values barely exceeded the precision limit for the method. Pooled data for the two groups revealed translations of 0.1-0.3 mm and rotations of 0.2-0.3° over the five year follow-up period. CONCLUSIONS: We found no adverse effects of immediate weight bearing after THA in relation to stability of these press-fit cups. Early mobilisation might have other advantages.

Prevalence of primary hyperparathyroidism and impact on bone mineral density in elderly men: MrOs Sweden.

BACKGROUND: Age and sex are of importance in the development of primary hyperparathyroidism (PHPT), and the disease is most common in postmenopausal women. Skeletal complications are well known at an advanced stage of PHPT, although the impact on bone mineral density (BMD) is evident in patients with mild disease. This study examines the prevalence of PHPT in elderly men and its impact on BMD. METHODS: Calcium homeostasis and BMD, measured by dual X-ray absorptiometry, were evaluated in 3014 men ages 69 to 81 years in the MrOS-Sweden cohort. Individuals with a low glomerular filtration rate (<21 ml/min/1.73 m2) and vitamin D deficiency (<50 nmol/l) were excluded. Among the remaining subjects, PHPT was assumed in subjects with above-normal albumin-adjusted serum (s)-calcium and plasma intact parathyroid hormone (p-iPTH) levels (PHPT group). BMD was compared between the PHPT group and men without PHPT. Subjects with inappropriately elevated iPTH (IEP group), based on both s-calcium (2.34 mmol/l) and iPTH (4.24 pmol/l) levels being above the median level, were compared to the rest of the cohort. RESULTS: The prevalence of PHPT was estimated to be 0.73%. The mean BMD in the total hip and femoral neck was lower in the PHPT group than in the PHPT controls. Significantly lower BMD (p<0.05) was seen in the IEP group (total hip and lumbar spine). CONCLUSIONS: Elderly men appear to have a lower prevalence of PHPT than women at the same age. The impact of disturbed calcium homeostasis on BMD was also evident in this population group.

Periprosthetic bone mineral density and fixation of the uncemented CLS stem related to different weight bearing regimes: A randomized study using DXA and RSA in 38 patients followed for 5 years.

BACKGROUND AND PURPOSE: There is no consensus on the best rehabilitation regime after uncemented total hip arthroplasty. Theoretically, bone ingrowth into the implant should benefit from initial partial weight bearing. We investigated whether the degree of postoperative weight bearing influences the periprosthetic bone mineral density (BMD) and/or the stability of the CLS stem. PATIENTS AND METHODS: 38 patients received an uncemented CLS stem and were randomized to either unrestricted postoperative weight bearing or to partial weight bearing for 3 months. Periprosthetic BMD was measured in the 7 Gruen zones with DXA and the stability of the femoral stem was assessed by radiostereometric analysis (RSA) after surgery and at 3, 12, 24, and 60 months. RESULTS: Periprosthetic BMD was not influenced by the type of postoperative weight bearing. BMD was reduced by 8-15% in all Gruen zones at 3 months. Restoration toward initial BMD was observed in all zones except in zone 7 (calcar region), where BMD was reduced by 22% at 5 years. Immediate weight bearing after surgery had no influence on the stability of the CLS stem, as assessed by RSA. INTERPRETATION: Immediate full weight bearing after uncemented total hip arthroplasty is safe. There is no difference in the periprosthetic BMD or in stability of the stem as measured by RSA compared to partial weight bearing for 3 months. BMD is reduced by more than 20% in the calcar region around a CLS stem after 5 years.

Safety of Use of Tantalum in Total Hip Arthroplasty.

BACKGROUND: Tantalum implants have been used in >500,000 orthopaedic patients. Although the risks of metallosis and aseptic lymphocyte-dominated vasculitis-associated lesions (ALVAL) after total hip arthroplasty (THA) are being debated, we are not aware of any studies investigating the liberation of tantalum ions and their potential effects on the immune system. We evaluated whether tantalum concentrations are elevated after THA with acetabular tantalum implants and assessed potential alterations in T-cell subpopulations. METHODS: After a mean follow-up of 4 years (range, 0.5 to 8.9 years) of 144 patients who had undergone THA, blood samples were analyzed regarding blood tantalum concentrations, total white blood-cell counts, and lymphocyte subsets in 3 groups of patients: those treated with non-tantalum primary THA ("primary non-tantalum," n = 30), those treated with primary THA with a tantalum cup ("primary tantalum," n = 30), and those who underwent revision surgery with a tantalum shell ("revision tantalum," n = 84). Blood donors served as controls for immunological parameters (n = 59). Correlations between tantalum concentrations and human leukocyte antigen (HLA)-DR T cells were calculated, radiographic signs of implant loosening were assessed, and the Harris hip score (HHS) was used to evaluate hip function. RESULTS: The median tantalum concentration was similar to the detection limit both in the primary non-tantalum group (0.05 µg/L, 95% confidence interval [CI] = 0.05 to 0.05 µg/L) and in the primary tantalum group (0.051 µg/L, 95% CI = 0.050 to 0.055 µg/L), and it was 0.091 µg/L (95% CI = 0.083 to 0.112 µg/L) in the revision tantalum group (p < 0.0001 in the group-wise comparison with both primary non-tantalum and primary tantalum). We found a weak negative correlation of higher tantalum concentration with the concentration of HLA-DR/CD8 T cells (r = -0.22, 95% CI = -0.35 to -0.05, p = 0.01) but no correlation of tantalum concentration with the concentration of HLA-DR/CD4 T cells (r = -0.11, 95% CI = -0.27 to 0.06, p = 0.24). The values for all lymphocyte subgroups were within normal ranges. No implants were deemed loose. The median HHS was good to excellent. CONCLUSIONS: Exposure to stable tantalum cups is associated with low blood concentrations of tantalum. Signs of T-cell activation typical of ALVAL seem to be lacking. LEVEL OF EVIDENCE: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

Denosumab Prevents Early Periprosthetic Bone Loss After Uncemented Total Hip Arthroplasty: Results from a Randomized Placebo-Controlled Clinical Trial.

Implant loosening is the most common indication for revision surgery after total hip arthroplasty (THA). Although bone resorption around the implants plays a pivotal role in the pathophysiology of loosening, it is unknown whether potent early inhibition of osteoclasts could mitigate this process and thus reduce the need for revision surgery. We performed a randomized, double-blind, placebo-controlled phase 2 trial in 64 patients aged 35 to 65 years with unilateral osteoarthritis of the hip. They underwent surgery with an uncemented THA and were randomized to either two subcutaneous doses of denosumab (n = 32) or placebo (n = 32) given 1 to 3 days and 6 months after surgery. Patients were followed for 24 months. Primary outcome was periprosthetic bone mineral density (BMD) of the hip at 12 months as measured by dual-energy X-ray absorptiometry (DXA). In addition, [18 F] sodium fluoride positron emission tomography/CT (F-PET) was performed in half of the patients for analysis of periprosthetic standardized uptake value (SUV). Analyses were made according to intention-to-treat principles. The trial was registered at ClinicalTrials.gov 2011-001481-18, NCT01630941. Denosumab potently inhibited early periprosthetic bone loss. After 12 months, BMD in the denosumab group was 32% (95% confidence interval [CI] 22-44) higher in Gruen zone 7 and 11% (95% CI 8-15) higher in zones 1 to 7. After 24 months, the difference in BMD between groups had decreased to 15% (95% CI 4-27) in zone 7 and 4% (95% CI 0-8) in zones 1 to 7. In both groups, SUV increased after surgery, but the increase was less pronounced in the denosumab group. Biochemical markers of bone metabolism decreased in the denosumab group in the first 12 months, but a rebound effect with marker concentrations above baseline was observed after 24 months. Denosumab potently prevents early periprosthetic bone loss after uncemented THA; however, the effect diminishes after discontinuation of treatment. Further research is needed to determine whether this bone loss will prove to be of clinical importance and, if so, whether the positive effect observed in this study could be preserved by either prolonged treatment with denosumab or additional antiresorptive treatment. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.

Heterozygosity for a coding SNP in COL1A2 confers a lower BMD and an increased stroke risk.

Genetic variation plays an important role in osteoporosis and a prime candidate gene is Collagen alpha2(I) (COL1A2). A coding polymorphism (rs42524) in COL1A2 has previously been associated with intracranial aneurysms. Here the effects of this polymorphism have been studied in relation to bone mineral density (BMD) and prevalences of stroke and myocardial infarction (MI). rs42524 was genotyped in elderly men (n = 2004) from the Swedish MrOS cohort. Genotypes were analysed for association to BMD and certain health parameters. Significant associations (overall P < 0.05), were observed between rs42524 genotype and BMD at several skeletal sites. Surprisingly, the heterozygote genotype class exhibited lower BMD than either homozygote group. When subjects were classified as heterozygotes or homozygotes, the heterozygous genotype was found to confer a lower BMD at total hip, femoral neck and trochanter Furthermore, the heterozygote genotype had an increased risk of stroke and MI, with population Attributable Risks being 0.12 and 0.08, respectively.

Systematic assessment of the human osteoblast transcriptome in resting and induced primary cells.

Osteoblasts are key players in bone remodeling. The accessibility of human primary osteoblast-like cells (HObs) from bone explants makes them a lucrative model for studying molecular physiology of bone turnover, for discovering novel anabolic therapeutics, and for mesenchymal cell biology in general. Relatively little is known about resting and dynamic expression profiles of HObs, and to date no studies have been conducted to systematically assess the osteoblast transcriptome. The aim of this study was to characterize HObs and investigate signaling cascades and gene networks with genomewide expression profiling in resting and bone morphogenic protein (BMP)-2- and dexamethasone-induced cells. In addition, we compared HOb gene expression with publicly available samples from the Gene Expression Omnibus. Our data show a vast number of genes and networks expressed predominantly in HObs compared with closely related cells such as fibroblasts or chondrocytes. For instance, genes in the insulin-like growth factor (IGF) signaling pathway were enriched in HObs (P = 0.003) and included the binding proteins (IGFBP-1, -2, -5) and IGF-II and its receptor. Another HOb-specific expression pattern included leptin and its receptor (P < 10(-8)). Furthermore, after stimulation of HObs with BMP-2 or dexamethasone, the expression of several interesting genes and pathways was observed. For instance, our data support the role of peripheral leptin signaling in bone cell function. In conclusion, we provide the landscape of tissue-specific and dynamic gene expression in HObs. This resource will allow utilization of osteoblasts as a model to study specific gene networks and gene families related to human bone physiology and diseases.