OTA 2006 Posters
Scientific Poster #95 Basic Science
Bone Healing and NSAIDS: Their Effect on Endochondral Ossification
Ippokratis Pountos, DO; Elena Jones; Dennis McGonagle, PhD;
Peter V. Giannoudis, MD; (all authors - a-AO Foundation Research
Grant)
Academic Department of Trauma & Orthopaedic Surgery, School of Medicine,
University of Leeds, United Kingdom
Purpose: Bone healing is initiated with the proliferation of progenitor
cells followed by endochondral ossification. Several drugs, especially nonsteroidal
anti-inflammatory drugs (NSAIDS) have been convicted to interfere with this
process. The purpose of this study was to elucidate the direct effect of
these drugs on bone healing and consequently on endochondral ossification.
Methods: Cancellous bone samples were obtained intraoperatively from
10 consecutive adult patients suffering from lower extremity fractures requiring
surgical intervention. There were 6 males and 4 females. The mean age was
43 years (range, 16 to 81). Mesenchymal stem cells (MSCs) were isolated
by enzymatic digestion. Cells were cultured in standard tissue culture conditions
and freely proliferated until passage (P2). Subsequently, cells were forced
to differentiate towards chondrogenic lineage. The drugs Diclophenac and
Ketorolac were added in the medium in concentrations similar to the level
in human circulation after administration. Comparison was performed with
a control group of untreated cells. After 3 weeks (21 days) of culture,
the pellets was removed and their content on sulphated glycosaminoglycans
(sGAG) was measured. Prostaglandin E2 (PGE-2) was also measured throughout
the course of differentiation. RT-PCR was performed on Cox-1 and Cox-2 expression
of the untreated cell. Finally, the morphologic appearance of the pellets
was studied.
Results: A decrease of sGAG content of pellets treated with Diclophenac
and Ketorolac by 39% and 51%, respectively, was noted. Diclophenac seems
to have a milder effect compared to Ketorolac. PGE-2 production was severely
decreased (30-fold) in the pellets treated with both drugs compared with
the untreated cells. RT-PCR revealed a threefold increase of Cox-2
expression during the first 3 days of chondrogenic differentiation and a
gradual decrease over the following days. Cox-1 was low throughout the chondrogenic
differentiation. The morphology of the treated chondrocytes and pellets'
size were altered.
Conclusion: The above findings indicate that NSAIDS have a negative
effect on the bone healing process, especially on endochondral ossification.
The pathway of this remains obscure but the decreased levels of PGE-2, in
association with cellular determination to upregulate Cox-2 expression and
production of PGE-2, seems to be an important factor.
If noted, the author indicates something of value received.
The codes are identified as a-research or institutional support; b-miscellaneous
funding; c-royalties; d-stock options; e-consultant or employee; n-no conflicts
disclosed, and *disclosure not available at time of printing.
·
The FDA has not cleared this drug and/or medical device for the use
described in this presentation (i.e., the drug or medical device is being
discussed for an "off label" use). · · FDA
information not available at time of printing.