Denosumab for treating periprosthetic osteolysis; study protocol for a randomized, double-blind, placebo-controlled trial.

BACKGROUND: Wear-induced osteolysis is the main factor in reducing the longevity of total hip arthroplasty (THA). The transmembrane Receptor Activator of Nuclear Factor κ B (RANK) and its corresponding ligand RANKL is an important regulator of osteoclast activity and bone resorption and is associated with osteolysis around implant. Inhibiting RANKL with denosumab is effective in vivo in preventing osteoporosis-related fractures. In vitro, osteoclasts can be blocked in animal models of osteolysis. We hypothesize that denosumab is effective in reducing wear-induced osteolysis around uncemented acetabular implants in THA. METHODS/DESIGN: A randomized, double-blind, placebo-controlled trial will be conducted. We will include 110 patients, 40-85 years of age, with a known osteolytic lesion around an uncemented acetabular component ≥7 years after the primary operation. The patients will be randomized in a 1:1 ratio to subcutaneous injections of 60 mg denosumab or placebo for a total of 6 doses with start on day one and every 6 months with last treatment at 30 months. The primary endpoint will be the change in volume of the osteolytic lesion at 3 years measured with three-dimensional computed tomography (3D-CT). Secondary endpoints include functional outcome scores, change in bone mineral density of the lumbar spine, serological markers of bone turnover and adverse events. DISCUSSION: In vitro results of both bisphosphonates and RANKL inhibitors have been promising, showing reduced osteolysis with treatment. This is, to our knowledge, the first clinical trial testing the efficacy of denosumab in reducing wear-induced osteolysis. The study is an academic, phase II trial from an independent center and is designed to demonstrate efficacy in reducing volume of osteolytic lesions around a total hip arthroplasty. TRIAL REGISTRATION: ClinicalTrials.gov (NCT02299817) 2014-11-20.

Ureaplasma urealyticum infection in total hip arthroplasty leading to revision.

We describe an infection with Ureaplasma urealyticum causing rapid loosening of a cemented total hip arthroplasty. When reviewing the literature we found that no such case has been reported previously. Taking intraoperative cultures for U urealyticum during revision surgery is not a standard procedure. In cases with rapid, presumed aseptic, loosening of a total hip arthroplasty, an infection with U urealyticum should be considered.

A randomized double-blind noninferiority trial, evaluating migration of a cemented vitamin E-stabilized highly crosslinked component compared with a standard polyethylene component in reverse hybrid total hip arthroplasty.

AIMS: Radiostereometric analysis (RSA) studies of vitamin E-doped, highly crosslinked polyethylene (VEPE) liners show low head penetration rates in cementless acetabular components. There is, however, currently no data on cemented VEPE acetabular components in total hip arthroplasty (THA). The aim of this study was to evaluate the safety of a new cemented VEPE component, compared with a conventional polyethylene (PE) component regarding migration, head penetration, and clinical results. PATIENTS AND METHODS: We enrolled 42 patients (21 male, 21 female) with osteoarthritis and a mean age of 67 years (sd 5), in a double-blinded, noninferiority, randomized controlled trial. The subjects were randomized in a 1:1 ratio to receive a reverse hybrid THA with a cemented component of either argon-gas gamma-sterilized PE component (controls) or VEPE, with identical geometry. The primary endpoint was proximal implant migration of the component at two years postoperatively measured with RSA. Secondary endpoints included total migration of the component, penetration of the femoral head into the component, and patient-reported outcome measurements. RESULTS: In total, 19 control implants and 18 implants in the VEPE group were analyzed for the primary endpoint. We found a continuous proximal migration of the component in the VEPE group that was significantly higher with a difference at two years of a mean 0.21 mm (95% confidence interval (CI) 0.05 to 0.37; p = 0.013). The total migration was also significantly higher in the VEPE group, but femoral head penetration was lower. We found no difference in clinical outcomes between the groups. CONCLUSION: At two years, this cemented VEPE component, although having a low head penetration and excellent clinical results, failed to meet noninferiority compared with the conventional implant by a proximal migration above the proposed safety threshold of RSA. The early proximal migration pattern of the VEPE component is a reason for continued monitoring, although a specific threshold for proximal migration and risk for later failure cannot be defined and needs further study. Cite this article: Bone Joint J 2019;101-B:1192-1198.

Aseptic loosening after total hip arthroplasty and the risk of cardiovascular disease: A nested case-control study.

BACKGROUND: Patients with surgically treated osteoarthritis of the hip have an increased risk of cardiovascular morbidity and mortality many years after the operation compared with controls. Our hypothesis is that this increased risk after total hip arthroplasty (THA) is mediated by development of periprosthetic osteolysis leading to aseptic loosening of the implant. METHODS: We conducted a nation-wide, nested, case-control study consisting of patients receiving a cemented THA due to osteoarthritis between the years 1992 and 2005. Our study population included a total of 14,430 subjects identified in the Swedish hip arthroplasty register and linked to the Swedish National Patient Register. The case group consisted of patients (n = 2,886) who underwent reoperation of the treated hip due to osteolysis or aseptic loosening at any time within five years after the index surgery. Each case was matched with four controls (n = 11,544) who had not undergone reoperation. The main outcomes were cardiovascular events i.e. myocardial infarction, heart failure and cerebral infarction according to ICD-codes and time to the first cardiovascular event during the exposure period. Outcomes were subgrouped into cardiac and cerebral events. We used regression models to calculate the incidence rates and adjusted our results for confounders. FINDINGS: Overall, 5.1% of patients had cardiac events, with slightly more overall cardiovascular events occurring in the control group (8.1% vs. 6.7%, odds ratio 0.8, 95% confidence interval (CI) 0.7 to 1.0). After adjusting for confounders, the case group had an increased relative risk of 1.3 (95% confidence interval (CI) 1.1 to 1.3) for total number of cardiovascular events. Similar effect sizes were observed for time to first event. INTERPRETATION: Patients with osteoarthritis who received THA and subsequently underwent a revision operation due to loosening had a higher relative risk of developing cardiovascular events than controls. Thus there is an association which could be explained by a common inflammatory disease pathway that requires further experimental research.

Migration and head penetration of Vitamin-E diffused cemented polyethylene cup compared to standard cemented cup in total hip arthroplasty: study protocol for a randomised, double-blind, controlled trial (E1 HIP).

INTRODUCTION: In vitro, Vitamin-E-diffused, highly cross-linked polyethylene (PE) has been shown to have superior wear resistance and improved mechanical properties when compared to those of standard highly cross-linked PE liners used in total hip arthroplasty (THA). The aim of the study is to evaluate the safety of a new cemented acetabular cup with Vitamin-E-doped PE regarding migration, head penetration and clinical results. METHODS AND ANALYSIS: In this single-centre, double-blinded, randomised controlled trial, we will include 50 patients with primary hip osteoarthritis scheduled for THA and randomise them in a 1:1 ratio to a cemented cup with either argon gas-sterilised PE (control group) or Vitamin-E-diffused PE (vitamin-e group). All patients and the assessor of the primary outcome will be blinded and the same uncemented stem will be used for all participants. The primary end point will be proximal migration of the cup at 2 years after surgery measured with radiostereometry. Secondary end points include proximal migration at other follow-ups, total migration, femoral head penetration, clinical outcome scores and hip-related complications. Patients will be followed up at 3 months and at 1, 2, 5 and 10 years postoperatively. RESULTS: Results will be analysed using 95% CIs for the effect size. A regression model will also be used to adjust for stratification factors. ETHICS AND DISSEMINATION: The ethical committee at Karolinska Institutet has approved the study. The first results from the study will be disseminated to the medical community via presentations and publications in relevant medical journals when the last patient included has been followed up for 2 years. TRIAL REGISTRATION NUMBER: NCT02254980.

Increased Long-Term Cardiovascular Risk After Total Hip Arthroplasty: A Nationwide Cohort Study.

Total hip arthroplasty is a common and important treatment for osteoarthritis patients. Long-term cardiovascular effects elicited by osteoarthritis or the implant itself remain unknown. The purpose of the present study was to determine if there is an increased risk of late cardiovascular mortality and morbidity after total hip arthroplasty surgery.A nationwide matched cohort study with data on 91,527 osteoarthritis patients operated on, obtained from the Swedish Hip Arthroplasty Register. A control cohort (n = 270,688) from the general Swedish population was matched 1:3 to each case by sex, age, and residence. Mean follow-up time was 10 years (range, 7-21).The exposure was presence of a hip replacement for more than 5 years. The primary outcome was cardiovascular mortality after 5 years. Secondary outcomes were total mortality and re-admissions due to cardiovascular events.During the first 5 to 9 years, the arthroplasty cohort had a lower cardiovascular mortality risk compared with the control cohort. However, the risk in the arthroplasty cohort increased over time and was higher than in controls after 8.8 years (95% confidence interval [CI] 7.0-10.5). Between 9 and 13 years postoperatively, the hazard ratio was 1.11 (95% CI 1.05-1.17). Arthroplasty patients were also more frequently admitted to hospital for cardiovascular reasons compared with controls, with a rate ratio of 1.08 (95% CI 1.06-1.11).Patients with surgically treated osteoarthritis of the hip have an increased risk of cardiovascular morbidity and mortality many years after the operation when compared with controls.