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

Olof Sköldenberg, Agata Rysinska, Thomas Eisler, Mats Salemyr, Henrik Bodén, Olle Muren, Olof Sköldenberg, Agata Rysinska, Thomas Eisler, Mats Salemyr, Henrik Bodén, Olle Muren

Abstract

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.

Keywords: Computed tomography; Denosumab; Osteolysis; Outcome; Randomized clinical trial; Total hip arthroplasty.

Figures

Fig. 1
Fig. 1
3D-CT = Three-dimensional volumetric computed tomography, DxV = DXA scan vertebrae L1-L4, Rad = Anterioposterior and lateral radiographs, Clin = clinical follow-up including Harris hip score, EQ-5D, Activity scores and Pain Numerical Rating Scale, Ser = serological markers of bone turnover markers, Sta = standard blood test, Adm = Administration of IMP/placebo, AE = AE/SAE assessment, Cal = S-Calcium

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