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In Depth Tutorials and Information
FIGURE 53.1
Structure of some bisphosphonates (from ref.
5
).
single carbon atom with two carbons (P-C-C-P) or a sin-
gle nitrogen (P-N-P) prevents their activity.
8
The avid-
ity of binding to crystalline hydroxyapatite depends on
the phosphonate groups and both the R1 and R2 side
chains. R1 can be H, Cl or OH and the binding affinity
tends to be higher for OH than for H. The R2 side chain
also has a considerable influence on the avidity with
which the drug binds to bone, with zoledronate being
among the most strongly bound of all the nitrogen-con-
taining compounds and risedronate among the least of
the commonly used treatments for osteoporosis. As a
group, the nitrogen-containing compounds tend to bind
more strongly than the non-nitrogen compounds.
6
The selectivity of bisphosphonates for bone, with pref-
erential uptake to exposed mineral surfaces, is key to
both their safety and efficacy. When the bone surface is
resorbed through osteoclastic activity, the bisphosphonate
molecules are endocytosed along with other resorption
products into the osteoclast.
14
The cell thus most exposed
to “free” bisphosphonate is the mature osteoclast.
Bisphosphonate that is removed from bone by osteo-
clastic activity can be excreted or taken up again by
bone. It is not clear how long bisphosphonates, once
administered, will stay in the skeleton. Published data
suggest that pamidronate can linger for at least 10
years, since it can be detected in the urine several years
after administration ceased.
15
Bisphosphonates are excreted unchanged in the
urine, and a very small amount appears in bile. Renal
excretion depends on renal function; patients with renal
insufficiency or failure need to have their dose adjusted
downwards to reflect this.
14
Renal toxicity has been
reported in animal studies, and also in patients, when
bisphosphonates are administered rapidly in high
doses.
The general class effect of bisphosphonates is to
inhibit osteoclastic bone resorption either by reducing
osteoclastic activity or by causing osteoclast apopto-
sis, although additional effects have been demonstrated
on osteoclast recruitment and differentiation.
3
The pas-
sage of bisphosphonates through the basal membrane of
actively resorbing osteoclasts into intracellular vesicles
has been confirmed by studies of both radio- and luo-
rescently labeled compounds.
16
Following adsorption in
