Is tartrate-resistant acid phosphatase 5b a potent bio-marker for late stage aseptic implant loosening?

PURPOSE: Aseptic loosening is a serious complication after total joint arthroplasty. Plain radiography, along with clinical signs of prosthesis loosening, is the technique of first choice to evaluate loosening of joint replacements. Nevertheless, radiographical signs of osteolysis may not be apparent until progressed stages of loosening. Thus the search for alternative diagnostic methods is of great importance. The purpose of the present study was to evaluate the potential diagnostic significance of TRAP 5b, Osteocalcin, CrossLaps and Bone ALP for aseptic loosening of total joint replacements. METHODS: Thirty-seven patients (25 women, 12 men, mean age 65 years, age range 54-76 years) treated with revision surgery due to clinically and radiologically confirmed late aseptic prosthesis loosening were examined prospectively. Serum levels of TRAP 5b, Osteocalcin, CrossLaps and Bone ALP were compared with a matched control group (n = 39). RESULTS: We found a significant decrease in TRAP 5B level in patients with aseptic loosening. Bone ALP and Osteocalcin as markers of osteoblast activity, and CrossLaps as another resorption marker did not allow any prediction of bone remodeling in this late phase of loosening. CONCLUSION: In the "late" phase of aseptic joint replacement loosening, no increase of TRAP 5b and therefore no increase of osteoclast number and activity was measurable. Thus, in this situation an anti-osteolytic therapy with a bisphosphonate or denosumab would not gain any further benefit.

Efficacy of delayed thromboprophylaxis with dabigatran: pooled analysis.

INTRODUCTION: Oral thromboprophylaxis with dabigatran etexilate should be initiated as a half dose 1 to 4h after major orthopaedic surgery. However, a delay in dosing could occur for clinical or logistical reasons. A post hoc analysis was carried out to determine if patients with delayed dosing received adequate anticoagulation. PATIENTS AND METHODS: The RE-MODEL™ and RE-NOVATE® trials compared 220 mg and 150 mg dabigatran etexilate with 40 mg enoxaparin. Pooled data for major venous thromboembolism (VTE) and VTE-related mortality (efficacy outcome) and major bleeding events (MBE), MBE/clinically relevant bleeding events, and all bleeding events (safety outcomes) were analysed. Results in patients with dosing delayed more than 4h postsurgery were compared with those of patients without a delay. RESULTS: Onset of treatment was delayed in 724 (13.3%) of 5425 patients. Efficacy of 220 mg dabigatran etexilate was similar in patients without delayed dosing, patients with a delay and patients with a delay until the day after surgery. Rates of efficacy outcome were higher in patients on 150 mg dabigatran etexilate, but more than 80% of these patients were undertreated based on age or renal clearance status. Some differences in bleeding events were seen among patient groups by treatment arm. CONCLUSION: Dabigatran etexilate thromboprophylaxis should be initiated 1 to 4h postsurgery. Results from our post-hoc analysis indicate that no loss of efficacy appears to occur if initiation of dabigatran etexilate 220 mg needs to be delayed.

Thromboprophylaxis in patients older than 75 years or with moderate renal impairment undergoing knee or hip replacement surgery [corrected].

PURPOSE: Prospective, double-blind studies in orthopaedic patients have been conducted using the direct thrombin inhibitor dabigatran etexilate (hereafter referred to as dabigatran), with two doses investigated and approved for adults (220 mg and 150 mg once daily) to prevent venous thromboembolism (VTE). The European Medicines Agency decided that in major joint orthopaedic surgery, the lower dose should be used in elderly patients (aged over 75 years) and those with reduced renal function (creatinine clearance between 30 and 50 ml/min). Our objective was to understand the efficacy and bleeding data for the lower dose in this subpopulation. METHODS: We extracted and analysed data from the elderly or from moderately renally impaired patients (n 632 of = 5,539) from the orthopaedic clinical development programme of dabigatran. RESULTS: Dabigatran 150 mg once daily was as effective as the standard European enoxaparin regimen, with numerically fewer major bleeding events. Rates of major VTE were 4.3% vs 6.4% of patients, respectively. Major bleeding events occurred in four (1.3%) vs 11 (3.3%), which shows a trend towards lower bleeding with dabigatran 150 mg [odds ratio (OR) 0.40; 95% confidence interval (CI) 0.13-1.25; p = 0.110]. Mean volume of blood loss was 395 vs 417 ml, and transfused units were 2.4 vs 2.5, respectively. Other safety parameters, including the incidence of wound infections and complications, were similar for 150 mg once daily dabigatran and enoxaparin. CONCLUSION: For patients at higher risk of bleeding, dabigatran 150 mg once daily is as effective as enoxaparin following major orthopaedic surgery and is associated with a favourable bleeding rate.

Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II*). A randomised, double-blind, non-inferiority trial.

This trial compared the efficacy and safety of oral dabigatran, a direct thrombin inhibitor, versus subcutaneous enoxaparin for extended thromboprophylaxis in patients undergoing total hip arthroplasty. A total of 2,055 patients were randomised to 28-35 days treatment with oral dabigatran, 220 mg once-daily, starting with a half-dose 1-4 hours after surgery, or subcutaneous enoxaparin 40 mg once-daily, starting the evening before surgery. The primary efficacy outcome was a composite of total venous thromboembolism [VTE] (venographic or symptomatic) and death from all-causes. The main secondary composite outcome was major VTE (proximal deep-vein thrombosis or non-fatal pulmonary embolism) plus VTE-related death. The main safety outcome was major bleeding. In total, 2,013 were treated, of whom 1,577 operated patients were included in the primary efficacy analysis. The primary efficacy outcome occurred in 7.7% of the dabigatran group versus 8.8% of the enoxaparin group, risk difference (RD) -1.1% (95%CI -3.8 to 1.6%); p<0.0001 for the pre-specified non-inferiority margin. Major VTE plus VTE-related death occurred in 2.2% of the dabigatran group versus 4.2% of the enoxaparin group, RD -1.9% (-3.6% to -0.2%); p=0.03. Major bleeding occurred in 1.4% of the dabigatran group and 0.9% of the enoxaparin group (p=0.40). The incidence of adverse events, including liver enzyme elevations and cardiac events, during treatment was similar between the groups. Extended prophylaxis with oral dabigatran 220 mg once-daily was as effective as subcutaneous enoxaparin 40 mg once-daily in reducing the risk of VTE after total hip arthroplasty, and superior to enoxaparin for reducing the risk of major VTE. The risk of bleeding and safety profiles were similar.

Total joint replacement in HIV positive patients.

BACKGROUND: Recent HIV therapies have improved life expectancy in HIV positive patients. For the purpose of the following retrospective investigation, we analyzed the results of total joint replacement in HIV positive patients. This study exemplifies orthopaedic treatment options and perioperative problems in HIV positive patients. Our population included a high proportion of hemophilic patients. DESIGN AND METHODS: Between 1988 and 2000, we performed 55 endoprosthetic procedures (20 total hip replacements (THR), 33 total knee replacements (TKR), two shoulder replacements) in 41 patients suffering form HIV. Thirty patients are afflicted with hemophilia, seven patients were intravenous drug addicts. The mean follow-up was 81 months (2-14) years. Patients were seen annually; either the Harris Hip Score or the Knee Society Rating System was applied. RESULTS: The following septic complications were observed: a mycotic abscess of both hips 5/10 months after bilateral THR, two early infections following coxitis in patients with intravenous drug abuse, and one further case of septic loosening after 15 months in one patient after THR. Furthermore, one aseptic loosening of a THR after 14 months in a hemophilic patient was seen. After TKR, two early infections in patients with intravenous drug addiction were seen. The total complication rate was 12.7%. A coherency between the infection rate and the CD4+ count was not seen. DISCUSSION: An analysis of the results shows that the complications occurred in patients living under difficult social circumstances. Whereas total joint replacement in hemophilic patients with or without HIV seems to be a fairly safe procedure concerning the postoperative infection rate, intravenous drug abuse increases the risk. Functional outcome does not differ from an HIV negative population both in the TKR and THR groups.

Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial.

BACKGROUND: After hip replacement surgery, prophylaxis following discharge from hospital is recommended to reduce the risk of venous thromboembolism. Our aim was to assess the oral, direct thrombin inhibitor dabigatran etexilate for such prophylaxis. METHODS: In this double-blind study, we randomised 3494 patients undergoing total hip replacement to treatment for 28-35 days with dabigatran etexilate 220 mg (n=1157) or 150 mg (1174) once daily, starting with a half-dose 1-4 h after surgery, or subcutaneous enoxaparin 40 mg once daily (1162), starting the evening before surgery. The primary efficacy outcome was the composite of total venous thromboembolism (venographic or symptomatic) and death from all causes during treatment. On the basis of the absolute difference in rates of venous thromboembolism with enoxaparin versus placebo, the non-inferiority margin for the difference in rates of thromboembolism was defined as 7.7%. Efficacy analyses were done by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00168818. FINDINGS: Median treatment duration was 33 days. 880 patients in the dabigatran etexilate 220 mg group, 874 in the dabigatran etexilate 150 mg group, and 897 in the enoxaparin group were available for the primary efficacy outcome analysis; the main reasons for exclusion in all three groups were the lack of adequate venographic data. The primary efficacy outcome occurred in 60 (6.7%) of 897 individuals in the enoxaparin group versus 53 (6.0%) of 880 patients in the dabigatran etexilate 220 mg group (absolute difference -0.7%, 95% CI -2.9 to 1.6%) and 75 (8.6%) of 874 people in the 150 mg group (1.9%, -0.6 to 4.4%). Both doses were thus non-inferior to enoxaparin. There was no significant difference in major bleeding rates with either dose of dabigatran etexilate compared with enoxaparin (p=0.44 for 220 mg, p=0.60 for 150 mg). The frequency of increases in liver enzyme concentrations and of acute coronary events during the study did not differ significantly between the groups. INTERPRETATION: Oral dabigatran etexilate was as effective as enoxaparin in reducing the risk of venous thromboembolism after total hip replacement surgery, with a similar safety profile.

Tartrate-resistant acid phosphatase 5b (TRAP 5b) as a marker of osteoclast activity in the early phase after cementless total hip replacement.

BACKGROUND: After total hip replacement, increased bone metabolism is seen. A local periprosthetic osteopenia can be measured by dual-energy X-ray absorptiometry (DXA), but it is still unkown whether biochemical markers can be used to monitor the local remodeling at an earlier stage. PATIENTS AND METHODS: In this prospective study we compared the biochemical markers tartrate-resistant acid phosphatase 5b (TRAP 5b), bone ALP, osteocalcin and CrossLaps with periprosthetic DXA in 17 consecutive patients after uncemented total hip replacement. RESULTS: We found a highly significant early increase in TRAP 5b after 2 weeks and 6 weeks, which was followed by a densitometrically detectable decrease in bone mineral density after 26 weeks, especially in periprosthetic section Gruen zone 7. Bone ALP and osteocalcin levels as markers of osteoblast activity, and also Cross-Laps as a further marker of osteoclast activity, did not appear to allow any significant prediction of local bone remodeling. DISCUSSION: Our findings show that TRAP 5b is a sensitive parameter for monitoring of osteoclast activity after cementless total hip replacement, and may predict local osteopenia.

Preventative ibandronate treatment has the most beneficial effect on the microstructure of bone in experimental tumor osteolysis.

We investigated the effect of ibandronate on three-dimensional (3-D) microstructure and bone mass in experimentally induced tumor osteolysis. Walker carcinosarcoma cells were implanted into the left femur of female rats that received 26-day ibandronate pretreatment followed by continued therapy or ibandronate posttreatment only. A tumor-only group received isotonic saline. At endpoint, excised femurs were scanned using microcomputed tomography (microCT) to assess bone volume density, bone mineral content, trabecular number/thickness, and separation for cortical plus trabecular bone or trabecular bone alone. Compared with the nonimplanted right femur, bone volume and surface density and trabecular number and thickness were reduced in the distal left femur following tumor cell implantation. microCT analysis revealed greater cortical and trabecular bone mineral content in the preventative and interventional (pre-post tumor) ibandronate group, and the interventional (post-tumor) ibandronate group, versus the tumor-only group. Bone volume density was significantly higher in pre-post and post-tumor groups compared to the tumor-only group. After preventative and interventional ibandronate, bone volume density and trabecular thickness were 13% and 60% greater, respectively, than in the post-tumor treatment group. 3-D microCT images confirmed microstructural changes. We conclude that combined interventional and preventative ibandronate preserves bone strength and integrity more than intervention alone.

Evaluation of tartrate-resistant acid phosphatase (TRACP) 5b as bone resorption marker in irradiated bone metastases.

BACKGROUND: The aim of our study was to evaluate if the determination of the active isoform 5b of tartrate-resistant acid phosphatase (TRACP 5b) provides the possibility to monitor the effect of local radiotherapy in bone metastases and if TRACP 5b will predict further osseous progression. MATERIALS AND METHODS: In 48 breast cancer patients with bone metastases, patients' characteristics, diagnostic imaging and laboratory investigation, tumor- and therapy-related parameters were registered at the beginning and the end of radiotherapy, as well as 6 and 12 weeks afterwards. TRACP 5b activity was measured using a solid phase immunofixed enzyme activity assay with the monoclonal antibody O1A. RESULTS: During follow-up, progression in another part of the skeleton was diagnosed in 31 patients (65%). There was a significant decrease of TRACP 5b in patients without progression in non-irradiated regions, whereas in progressive disease, TRACP 5b levels remained stable with a slightly increasing tendency (p < 0.007). In patients with < or =3 metastases, all TRACP 5b values were significantly lower than the values of those with >3 metastases (p = 0.01). CONCLUSION: In patients without further osseous progression, TRACP 5b is able to monitor the effectiveness of local radiotherapy. The estimation of sensitivity and specificity based on each TRACP 5b value demonstrates that the ability to discriminate between those patients with or without osseous progression increases with time.

Tartrate-resistant acid phosphatase 5b as serum marker of bone metabolism in cancer patients.

BACKGROUND: The serum marker tartrate-resistant acid phosphatase isoform 5b (TRACP 5b) is considered a specific parameter of osteoclast activity and a useful marker of bone resorption. Regarding the utility of TRACP 5b in bone metastases, this review aims to draw clinically relevant conclusions. MATERIALS AND METHODS: The available literature data regarding the laboratory methods, the characteristics of TRACP 5b and the clinical data, as well as our own results about TRACP 5b in cancer patients has been reviewed. RESULTS: In contrast to enzymatic assays, two new assays based on a monoclonal antibody and on heparin-induced inhibition of TRACP 5a, respectively, demonstrated low biological and analytical variabilities in healthy subjects as well as in patients with osteoporosis. Up to now, only a few studies have evaluated the utility of TRACP 5b in cancer patients with bone metastases. In these studies, the sensitivity of TRACP 5b was higher compared to other markers. Furthermore, TRACP 5b activity correlates with the response to the treatment of bone metastases. CONCLUSION: Although the clinical data available are promising, the results are still preliminary. In addition to further evaluation of the analytical method, more studies in cancer patients are needed to establish TRACP 5b in the diagnostic procedure and in the therapy monitoring of bone metastases.