Prosthesis failure due to wear debris-induced
osteolysis remains a major clinical problem and the greatest limitation for total joint
arthroplasty. Based on our knowledge of osteoclast involvement in this process and the requirements of
receptor activator of NF-kappaB (RANK) signaling in osteoclastogenesis and
bone resorption, we investigated the efficacy of RANK blockade in preventing and ameliorating
titanium (Ti)-induced
osteolysis in a mouse calvaria model. Compared with placebo controls we found that all doses of
RANK:Fc above 1 mg/kg intraperitoneally (ip) per 48 h significantly inhibited osteoclastogenesis and
bone resorption in response to Ti implanted locally. Complete inhibition occurred
at 10 mg/kg ip per 48 h, yielding results that were statistically equivalent to data obtained with Ti-treated RANK-/- mice. We also evaluated the effects of a single injection of
RANK:Fc on day 5 on established
osteolysis and found that Ti-treated were still depleted for multinucleated
tartrate-resistant acid phosphatase-positive (TRAP+) cells 16 days later. More importantly, this osteoclast depletion did not affect bone formation because the bone lost from the
osteolysis on day 5 was restored by day 21. An assessment of the quantity and quality of the newly formed bone in these calvariae by
calcein labeling and infrared (IR) microscopy, respectively, showed no significant negative effect of
RANK:Fc treatment. These studies indicate that osteoclast depletion via RANK blockade is an effective method to prevent and reverse wear debris-induced
osteolysis without jeopardizing osteogenesis.