Loosening of orthopaedic implants is mediated by cytokines that
elicit bone resorption and are produced in response to phagocytosis
of implant-derived wear particles. This accelerated bone resorption
could be due to increased osteoclastic activity, survival, or differentiation.
Although a number of in vitro studies have shown
that wear particles increase osteoclastic activity, the increase
was less than twofold in all cases. The objective of the current
study was to test the hypothesis that wear particles stimulate bone
resorption by inducing osteoclast differentiation.
Conditioned media were prepared from murine marrow cells or human
peripheral blood monocytes incubated in the presence or absence
of titanium particles. The effects of conditioned media on osteoclast
differentiation were examined with use of a recently developed assay
in which osteoclast precursors are co-cultured with mesenchymal
The present study showed that titanium particles induced both
murine marrow cells and human peripheral blood monocytes to produce
factors that stimulated osteoclast differentiation. The mean increase
in osteoclast differentiation was 29.3 ± 9.4-fold.
The stimulation of osteoclast differentiation led to a parallel
increase in bone resorption. The amount of stimulation was regulated
in a dose-dependent manner by the concentration of both titanium
particles and conditioned media. The stimulation of osteoclast differentiation
required interactions between the cells and the particles themselves
and, therefore, was not due to metal ions, soluble contaminants
released from the particles, or submicrometer particles. In contrast,
conditioned media from control cells incubated in the absence of
titanium particles had no detectable effect on any of the examined
The present study showed that titanium particles stimulate in
vitro bone resorption primarily by inducing osteoclast differentiation.
In contrast, the titanium particles had only small effects on osteoclast
activity or survival.
The present study provides strong support for the hypothesis
that osteoclast differentiation is an important factor in the development
of aseptic loosening. The development of therapeutic interventions
to reduce osteoclast differentiation may be a useful approach for
improving the performance of orthopaedic implants.