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MLO\u2010Y4\u2010osteocytes were mechanically stimulated for 1\u2009h by fluid shear stress using regimes simulating: (i) supraphysiological loading in the peri\u2010prosthetic interface (2.9\u2009\u00b1\u20092.9\u2009Pa, 1\u2009Hz, square wave); (ii) physiologic loading in the cortical bone (0.7\u2009\u00b1\u20090.7\u2009Pa, 5\u2009Hz, sinusoidal wave); and (iii) stress shielding. Cellular morphological parameters, membrane\u2010bound RANKL expression, gene expression influencing osteoclast differentiation, nitric oxide release and caspase 3\/7\u2010activity were determined. Either Mouse bone marrow cells were cultured on top of loaded osteocytes or osteocyte\u2010conditioned medium was added to bone marrow cells. Osteoclast differentiation was assessed after 6 days. We found that osteocytes subjected to supraphysiological loading showed similar morphology and caspase 3\/7\u2010activity compared to simulated physiological loading or stress shielding. Supraphysiological stimulation of osteocytes enhanced osteoclast differentiation by 1.9\u2010fold compared to physiological loading when cell\u2010to\u2010cell contact was permitted. In addition, it enhanced the number of osteoclasts using conditioned medium by 1.7\u2010fold, membrane\u2010bound RANKL by 3.3\u2010fold, and nitric oxide production by 3.2\u2010fold. The stimulatory effect of supraphysiological loading on membrane\u2010bound RANKL and nitric oxide production was higher than that achieved by stress shielding. In conclusion, the in vitro model developed recapitulated the catabolic biological situation in the peri\u2010prosthetic interface during instability that is associated with osteoclast differentiation and enhanced RANKL expression. The model thus provides a platform for pre\u2010clinical testing of pharmacological interventions with potential to stop instability\u2010induced bone implant loosening. \u00a9 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. 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