The Journal of Bone and Joint Surgery (American) 83:1057-1061 (2001)
© 2001 The Journal of Bone and Joint Surgery, Inc.
Oral Pentoxifylline Inhibits Release of Tumor Necrosis Factor-Alpha from Human Peripheral Blood Monocytes
A Potential Treatment for Aseptic Loosening of Total Joint Components
Paul F. Pollice, MD,
Randy N. Rosier, MD, PhD,
R. John Looney, MD,
J. Edward Puzas, PhD,
Edward M. Schwarz, PhD and
Regis J. O’Keefe, MD, PhD
Investigation performed at the University of Rochester Medical
Center, Rochester, New York
Paul F. Pollice, MD
Randy N. Rosier, MD, PhD
R. John Looney, MD
J. Edward Puzas, PhD
Edward M. Schwarz, PhD
Regis J. O’Keefe, MD, PhD
Department of Orthopaedics (P.F.P., R.N.R., J.E.P., E.M.S., and
R.J.O’K.), Box 665, and Department of Medicine (R.J.L.),
University of Rochester Medical Center, 601 Elmwood Avenue, Rochester,
NY 14642. E-mail address for R.J. O’Keefe: regis_okeefe{at}urmc.rochester.edu
One or more of the authors may receive benefits for personal
or professional use from a commercial party related directly or
indirectly to the subject of this article. Two of the authors hold
a United States patent for the use of phosphodiesterase inhibitors
to prevent inflammatory bone resorption. There are no current commercial
interests and there have been no discussions or relationships with
commercial parties concerning this. P.F. Pollice was awarded a 2000
American Orthopaedic Association/Zimmer Resident Travel
Award for this work. The work was supported by Public Health
Service Awards AR46545 (R.J.O’K.) and AR44220 (R.J.O’K.) from
the National Institutes of Health.
Background: Pentoxifylline (Trental) is a methylxanthine-derivative
drug that has been used for more than twenty years in the treatment
of peripheral vascular disease. Pentoxifylline is also a potent
inhibitor of tumor necrosis factor-alpha (TNF- )
secretion, both in vitro and in vivo, and
has demonstrated efficacy in the treatment of certain animal and
human inflammatory diseases. Pentoxifylline has a potential therapeutic
role in the treatment of aseptic loosening of total joint replacement
components because it inhibits TNF- secretion by
particle-stimulated human peripheral blood monocytes. The purpose
of our study was to determine whether the particle-stimulated secretion of
TNF- by peripheral blood monocytes was inhibited
in volunteers who had received pentoxifylline orally.
Methods: Human peripheral blood monocytes were harvested
from eight healthy volunteers and were exposed to three different
concentrations of titanium particles or to 500 ng/mL of
lipopolysaccharide as a positive control. The same volunteers were then
given pentoxifylline (400 mg, five times per day) for seven days.
Their peripheral blood monocytes were again isolated and exposed
to experimental conditions, and the TNF- levels were
measured.
Results: The peripheral blood monocytes from all
eight volunteers showed a significant reduction in TNF-
release following oral treatment with pentoxifylline. This reduction
was observed at exposures of 107 and
106 titanium particles/mL and
in the lipopolysaccharide-treated group, but not at 105 particles/mL.
Conclusions: To our knowledge, this is the first
study to demonstrate the ability of an oral drug to decrease the release
of TNF- from human peripheral blood monocytes exposed ex
vivo to particle debris. TNF- is involved
in the pathogenesis of osteolysis and subsequent loosening of total
joint arthroplasty components. The ability to suppress the release
of TNF- in patients with a total joint replacement
may help to control osteolysis and to reduce the development of aseptic
loosening. This effect could increase implant longevity and decrease
the need for revision arthroplasty.
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