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The effects of low molecular weight and standard heparin on calcium loss
from fetal rat calvaria
SG Shaughnessy, E Young, P Deschamps and J Hirsh
Department of Pathology, McMaster University, Hamilton, Ontario, Canada.
Osteoporosis is a well-recognized complication of long-term heparin use.
However, the mechanisms by which heparin can influence bone metabolism are
unclear. We report here that unfractionated heparin stimulates the process
of bone resorption and that the low molecular weight heparins (LMWHs),
enoxaparin, fragmin, logiparin, and ardeparin produce significantly less
calcium loss than unfractionated heparin. To assess calcium loss from bone,
we quantified the release of 45Ca into the culture medium of fetal rat
calvaria. 45Ca release was increased in a dose-dependent manner by the
addition of either unfractionated heparin or the LMWHs; but more than
50-fold higher LMWH concentrations were required to obtain an equivalent
effect to unfractionated heparin. Thus, at concentration > or = 2
micrograms/mL (0.35 anti-Xa units/mL), unfractionated heparin stimulated
45Ca release 1.53 +/- 0.06 fold. 45Ca release was increased to a similar
extent by the addition of either 10(- 7) mol/L parathyroid hormone (PTH) or
10(-6) mol/L 1,25 dihydroxyvitamin D3 (1,25 Vit D3). In contrast to
unfractionated heparin, LMWH concentrations > or = 100 micrograms/mL
(> or = 14.0 anti- Xa units/mL) were required before maximum isotope
release was observed. At concentrations well above therapeutic levels, the
LMWHs stimulated 45Ca release by only 1.25 /+- 0.01-fold. Heparins with
high and low antithrombin III affinities stimulated 45Ca release equally
well. Both size and sulfation were found to be major determinants of
heparin's ability to promote isotope release. Thus, the ability of defined
heparin fragments to stimulate 45Ca release correlated with their molecular
weight, and after N-desulfation the ability of heparin to induce isotope
release was greatly diminished. Dermatan sulfate had no effect on 45Ca
release. We conclude that size and sulfation are major determinants of
heparin's ability to promote bone resorption and that the risk of
heparin-induced osteoporosis may be reduced by the use of LMWH
preparations.
Volume 86,
Issue 4,
pp. 1368-1373,
08/15/1995
Copyright © 1995 by The American Society of Hematology
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