Denosumab may reduce need for revision hip arthroplasty due to osteolysis

Results of a small phase II, single-centre study have suggested that denosumab may be able to reduce the number of osteolysis-induced revision total hip arthroplasty surgeries.

“For decades scientists have been looking for a therapy that will help to protect vulnerable areas of bone and prevent revision surgery which not only has huge cost implications … but also causes pain and reduces mobility for patients,” said lead investigator Professor Mark Wilkinson from the University of Sheffield, Sheffield, UK.

“This study is a significant breakthrough as we’ve demonstrated there is a drug, already available and successful in the treatment of osteoporosis, which has the potential to prevent up to half of all revised replacement surgeries which are caused by osteolysis,” he said.

Participants were 24 patients aged ≥30 years scheduled for revision surgery at Sheffield Teaching Hospitals NHS Foundation Trust in Sheffield, UK, due to symptomatic osteolysis of the femur or pelvis following total hip arthroplasty surgery. They were randomized 1:1 to receive a single 60 mg dose of subcutaneous denosumab or placebo. Due to surgery cancellation for two patients, 22 patients (10 in the denosumab group) were included in the analysis (mean age 72 years, 73 percent male).

Biopsies were taken from the osteolytic membrane–bone interface at surgery 8 weeks post-injection. Patients who received denosumab had 83 percent fewer osteoclasts* per mm of osteolytic membrane at the osteolytic membrane–bone interface than those who received placebo (median 0.05 vs 0.30 per mm; p=0.011). [Lancet Rheumatol 2021;doi:10.1016/S2665-9913(20)30394-5]

The length of osteoclast surface was shorter in the denosumab than placebo group (87 percent shorter; 0.14 percent vs 1.04 percent; p=0.0089), as was the length of the eroded surface (72 percent shorter; 0.22 percent vs 0.78 percent; p=0.015) and length of the osteoblast surface (91 percent shorter; 0.05 percent vs 0.53 percent; p=0.015). There were also 90 percent fewer osteoblasts in the denosumab than placebo group (0.04 vs 0.41 per mm; p=0.017).

The quiescent surface, the most affected surface in both groups, was 2 percent longer in the denosumab than placebo group (99.4 percent vs 97.8 percent; p=0.0041).

There was no between-group difference pertaining to immunocytochemistry for cell proliferation (Ki67) and apoptosis (Caspase-3) or the amount of osteolysis membrane–bone surface interface identified (p>0.05 for all).

Serum and urinary biomarkers of bone resorption declined sharply in the denosumab but not the placebo group (between-group absolute difference p<0.0003 for all biomarkers). Levels of the bone formation marker N-terminal propeptide of type-I procollagen (PINP) reduced by 56 percent in the denosumab group, with no significant change in the placebo group.

Four patients in the denosumab group experienced seven adverse events (AEs), including one severe AE. Five patients in the placebo group experienced 10 AEs including three severe AEs. Two incidents of arthralgia, one in each group, were deemed possibly study drug related. There were no treatment-related serious AEs or deaths.

Reduced need for revision surgery

“[P]rosthesis wear-induced osteolysis leading to loosening remains the most frequent reason for revision surgery to a total hip arthroplasty across Europe, Australia, New Zealand, and Canada,” said the authors.

“Revision surgery is an extensive procedure and carries much higher risks of infection and other complications compared to first time surgery, and the recovery period is longer and more painful,” noted Wilkinson. At present, there are no alternatives for surgery in this setting, the authors added.

“It is very clear from our bone biopsies and bone imaging that the injection stops the bone absorbing the micro-plastic particles from the replacement joint and therefore could prevent the bone from being eaten away and the need for revision surgery,” Wilkinson continued.

“Using the antibody therapy denosumab to prevent the need for a second hip replacement could have a huge impact on thousands of patients who currently undergo revision surgery every year. This is particularly good news for younger patients and those with higher activity levels who tend to wear away the plastic part of the implant quicker,” he said.

“These data provide the biological evidence base necessary to justify phase III trials in participants with earlier-stage disease to test for clinical efficacy in reducing rates of disease progression and the need for revision surgery,” the authors said. These studies would need to assess the outcomes in patients with less advanced lesions as well as the role of multiple doses of denosumab.