Among the
bisphosphonates, the
nitrogen-containing
bisphosphonates have much stronger anti-bone-resorptive activities than
bisphosphonates containing no
nitrogen, but
nitrogen-containing
bisphosphonates mostly have inflammatory side effects. Our previous murine-model experiments with a single intraperitoneal
bisphosphonate injection demonstrated that (i)
nitrogen-containing
bisphosphonates induce various inflammatory reactions via an IL-1-dependent mechanism, (ii)
alendronate (an
nitrogen-containing
bisphosphonate) produces a clear sclerotic line in the tibia that is easily detectable by radiography a few weeks later (tentatively called the
bisphosphonate line, a useful marker for the anti-bone-resorptive activities of
bisphosphonates), and (iii)
clodronate (a non-
nitrogen-containing
bisphosphonate) reduces the inflammatory reactions induced by
alendronate but does not reduce the
bisphosphonate line formation induced by
alendronate. We compared the effects of
clodronate,
aspirin and
dexamethasone on the inflammatory reactions induced by
alendronate (40 micromol/kg) (induction of the
histamine-forming
enzyme, accumulation of pleural exudate and
splenomegaly) and on the
bisphosphonate line formation induced by
alendronate (0.1 micromol/kg). The effects of
aspirin (833 micromol/kg) were weak. However, like
clodronate,
dexamethasone (10 micromol/kg, injected 5 min. after
alendronate), strongly inhibited the
alendronate-induced inflammatory reactions but did not reduce the
alendronate-induced
bisphosphonate line formation.
Alendronate produced normal
bisphosphonate lines in IL-1-deficient mice, too. These results suggest that
clodronate and/or
dexamethasone may be suitable for preventing or reducing the inflammatory side effects of
nitrogen-containing
bisphosphonates while preserving their powerful anti-bone-resorptive activities (although in practice the known side effects of
dexamethasone may limit its use), and that the anti-bone resorptive activities of
nitrogen-containing
bisphosphonates are not influenced by
IL-1.