Bisphosphonates (BPs) used as inhibitors of bone resorption all contain two phosphonate
groups attached to a single carbon atom, forming a "P-C-P" structure. The bisphosphonates
are therefore stable analogues of naturally occuring pyrophosphate-containing compounds,
which now helps to explain their intracellular as well as their extracellular modes
of action. Bisphosphonates adsorb to bone mineral and inhibit bone resorption. The
mode of action of bisphosphonates was originally ascribed to physico-chemical effects
on hydroxyapatite crystals, but it has gradually become clear that cellular effects
must also be involved. The marked structure-activity relationships observed among
more complex compounds indicate that the pharmacophore required for maximal activity
not only depends upon the bisphosphonate moiety but also on key features, e.g., nitrogen
substitution in alkyl or heterocyclic side chains. Several bisphosphonates (e.g.,
etidronate, clodronate, pamidronate, alendronate, tiludronate, risedronate, and ibandronate)
are established as effective treatments in clinical disorders such as Paget's disease
of bone, myeloma, and bone metastases. Bisphosphonates are also now well established
as successful antiresorptive agents for the prevention and treatment of osteoporosis.
In particular, etidronate and alendronate are approved as therapies in many countries,
and both can increase bone mass and produce a reduction in fracture rates to approximately
half of control rates at the spine, hip, and other sites in postmenopausal women.
In addition to inhibition of osteoclasts, the ability of bisphosphonates to reduce
the activation frequency and birth rates of new bone remodeling units, and possibly
to enhance osteon mineralisation, may also contribute to the reduction in fractures.
The clinical pharmacology of bisphosphonates is characterized by low intestinal absorption,
but highly selective localization and retention in bone. Significant side effects
are minimal. Current issues with bisphosphonates include the introduction of new compounds,
the choice of therapeutic regimen (e.g., the use of intermittent dosing rather than
continuous), intravenous vs. oral therapy, the optimal duration of therapy, the combination
with other drugs, and extension of their use to other conditions, including steroid-associated
osteoporosis, male osteoporosis, arthritis, and osteopenic disorders in childhood.
Bisphosphonates inhibit bone resorption by being selectively taken up and adsorbed
to mineral surfaces in bone, where they interfere with the action of osteoclasts.
It is likely that bisphosphonates are internalized by osteoclasts and interfere with
specific biochemical processes and induce apoptosis. The molecular mechanisms by which
these effects are brought about are becoming clearer. Recent studies show that bisphosphonates
can be classified into at least two groups with different modes of action. Bisphosphonates
that closely resemble pyrophosphate (such as clodronate and etidronate) can be metabolically
incorporated into nonhydrolysable analogues of ATP that may inhibit ATP-dependent
intracellular enzymes. The more potent, nitrogen-containing bisphosphonates (such
as pamidronate, alendronate, risedronate, and ibandronate) are not metabolized in
this way but can inhibit enzymes of the mevalonate pathway, thereby preventing the
biosynthesis of isoprenoid compounds that are essential for the posttranslational
modification of small GTPases. The inhibition of protein prenylation and the disruption
of the function of these key regulatory proteins explains the loss of osteoclast activity
and induction of apoptosis. These different modes of action might account for subtle
differences between compounds in terms of their clinical effects. In conclusion, bisphosphonates
are now established as an important class of drugs for the treatment of bone diseases,
and their mode of action is being unravelled. As a result, their full therapeutic
potential is gradual