Denosumab showed biological efficacy against osteolysis after total hip replacement in a proof-of-concept trial. "Denosumab is already a well-established licensed drug for the indications of osteoporosis and metastatic bone lesions in cancer, and has been shown to be effective in reducing erosions in inflammatory arthritis," Dr. Mark JM Wilkinson of the University of Sheffield, UK, told Reuters Health by email. "Here we tested the drug in the setting of osteolysis after hip replacement, a condition that currently has no effective non-surgical treatment." "We demonstrate the biological concept that the drug is 90% effective in reducing osteoclast numbers within these osteolytic lesions," he said. "The drug does not currently have licensing authorization for this indication," he noted. "Our next step would be to confirm that this biological efficacy translates into a clinically measurable benefit by reducing symptoms and re-operation rates in a phase 3 clinical trial, subject to attracting the necessary clinical trial funding." As reported in The Lancet Rheumatology, Dr. Wilkinson and colleagues conducted a phase-2 randomized, placebo-controlled, proof-of-concept study of patients scheduled for revision surgery for symptomatic osteolysis. The primary outcome was the between-group difference in osteoclast number per mm of bone surface of biopsies taken from the osteolytic membrane-bone interface at surgery eight weeks after the intervention. Twenty-four patients were randomly assigned to subcutaneous denosumab (60 mg single-dose) or placebo. Patients had a mean age of 72; 60% of denosumab patients were men, as were 83% of those on placebo. There were 83% fewer osteoclasts at the osteolysis membrane-bone interface in the denosumab group: median 0.05 per mm versus 0.30 mm for placebo. Further, the length of the osteoclast surface was 87% shorter (0.14% vs. 1.04%); the length of the eroded surface was 72% shorter (0.22% vs. 0.78%); the osteoblast number was 90% fewer (0.04 per mm vs. 0.41 per mm); and the length of the osteoblast surface was 91% shorter (0.05% vs. 0.53%). Thirteen patients were included in the safety analysis. "No life-threatening or disabling adverse events, or deaths were recorded," the authors state. Dr. Hannu Aro of the University of Turku and Turku University Hospital, author of a related editorial, called the study "good news." He noted by email that osteolysis is caused by wear particles, and is "a frequent complication of conventional polyethylene bearing surfaces. Current material options are more wear-resistant but the problem still exists." "Current surgical guidelines remain controversial and overshadowed by unexpectedly high rates of surgical complications," he told Reuters Health. "If the implant is still well fixed, the clinician and the patient are faced with difficult decisions in timing revision surgery." "The molecular approach of denosumab treatment—inhibition of osteoclast differentiation and activity via blockade of RANK ligand—hits the core pathological mechanism of wear-induced osteolysis," he said. Like Dr. Wilkinson, he pointed to randomized clinical trials as the next step. "The obvious main goal is the prevention of disease progression in patients with stable well-fixed implants," he affirmed. "Potentially, denosumab could also be applied to improve the success of surgical curettage and bone grafting." "As an ideal target," he added, "denosumab could control osteolytic lesions in patients with age-related low bone mineral density and in patients with advanced rheumatoid arthritis, who poorly tolerate revision surgery due to inherent skeletal fragility." "As a limitation, the lesions may reappear after cessation of the medication," he noted. "The potential, albeit rare, adverse events of using denosumab in arthroplasty patients include osteonecrosis of the jaw and atypical femur fractures, even in the periprosthetic region." The study was funded by Amgen. The authors received a grant from Amgen to conduct the study. —Marilynn Larkin Source
