Effect of Denosumab on Osteolytic Lesion Activity after Total Hip Arthroplasty: A Single-Centre, Randomised, Double-Blind, Placebo-Controlled, Proof-of-Concept Study

Background: Osteolysis causes recurrent pain and disability after total hip arthroplasty (THA) for which the only established treatment is revision surgery. In this proof-of-concept study we aimed to investigate the efficacy of the human monoclonal antibody denosumab on osteolytic lesion activity in patients undergoing revision surgery for osteolysis after THA. Methods: We did a phase 2, randomised, double-blind, placebo-controlled trial at a single centre in the UK. Eligible patients aged 30 years or older and scheduled for revision surgery for symptomatic, radiologically-confirmed osteolysis were randomised (1:1) to receive either denosumab 60mg or placebo subcutaneously eight weeks prior to operation. The primary outcome was osteoclast number per millimetre of bone surface of biopsies taken from the osteolytic membrane-bone interface at surgery, measured by quantitative histomorphometry. Secondary outcome measures included other static histomorphometric indices and systemic bone turnover markers. Adverse events and patient-reported clinical outcomes were recorded as safety endpoints. Findings: 24 participants were enrolled between December 19, 2012 and June 24, 2018. 2 had their revision surgery cancelled, leaving 22 (92%) for analysis. There were 83% fewer osteoclasts at the osteolysis membrane-bone interface (0∙05 vs. 0∙30/mm, p=0∙011), 87% lower osteoclast surface (0∙14 vs. 1∙04%, p=0∙009), and 72% lower eroded surface (0∙22 vs. 0∙78%, p=0∙015) in those receiving denosumab versus the placebo. Osteoblast number and osteoblast surface were 90% (0∙04 vs. 0∙41/mm, p=0∙017) and 91% (0∙05 vs. 0∙53%, p=0∙015) lower, respectively. At surgery, serum biochemical markers of bone turnover were also more than 50% reduced in those receiving denosumab (p<0∙001). The adverse event rate and patient-reported outcomes were similar between groups. Interpretation: This is the first clinical trial of a non-surgical therapy for inflammatory osteolysis that indicates biological efficacy. These findings justify clinical trials using pain and revision as endpoints.   Trial Registration: The trial is registered with the EU Clinical Trials Register (EudraCT2011-000541-20), and has clinical trial authorisation from the MHRA (21304/0239/001-0001). Funding Statement: This study was funded by Amgen. Declaration of Interests: RE declares grants from Alexion, Amgen, IDS, Roche, Nittobo, and personal fees from Amgen, IDS, Roche, GSK Nutrition, Mereo, Sandoz, Nittobo, AbbVie, Samsung, Haoma Medica, Elsevier, CL Bio, FNIH, Viking, UCSF, Biocon and Lyramid outside the submitted work. All other authors declare no competing interest. Ethics Approval Statement: Ethical approval for the trial was provided by NRES Committee Yorkshire & The Humber – Leeds West (REC reference 11/YH/0252). We obtained written, informed consent from all participants.