DƯỢC LÍ Goodman & Gilman's The Pharmacological Basis of Therapeutics 12th, 2010

Pyrophosphate Bisphosphonate Medronate
O O
O R 1 O
O H O
O P O P O O P C P O O P C P
O
1295
OH
OH
OH
R 2
OH
OH
H
OH
O
Etidronate Clodronate Tiludronate
O CH 3 O
O Cl O
Cl
P C P O O P C P O
OH
OH OH
OH
Cl
OH
O
O
P
OH
S O
C P
OH OH
O
CHAPTER 44
O
Pamidrone
O
P
OH O
C P
OH CH 2 OH
CH 2 NH 2
Risedronate
Alendronate
Bisphosphonates concentrate at sites of active remodeling.
Because they are highly negatively charged, bisphosphonates
are membrane impermeable but are incorporated into the
bone matrix by fluid-phase endocytosis (Stenbeck and Horton,
2000). Bisphosphonates remain in the matrix until the bone is
remodeled and then are released in the acid environment of the
resorption lacunae beneath the osteoclast as the overlying mineral
matrix is dissolved. The importance of this process for the
antiresorptive effect of bisphosphonates is evidenced by the fact
that calcitonin blocks the antiresorptive action.
Although bisphosphonates prevent hydroxyapatite dissolution,
their antiresorptive action is due to direct inhibitory effects on
osteoclasts rather than strictly physiochemical effects. The antiresorptive
activity apparently involves two primary mechanisms:
osteoclast apoptosis and inhibition of components of the cholesterol
biosynthetic pathway.
The current model is that apoptosis accounts for the antiresorptive
effect of first-generation bisphosphonates, whereas the
inhibitory action of aminobisphosphonates proceeds through the
O
O
O
P
N
O
O
P
OH O
C P
OH CH 2 OH
OH O
C P
OH CH 2 OH
O
O
CH 2 CH 2 NH 2
O
O
Ibandronate
Zoledronate
O
P
O
P
N
OH O
C P
OH CH 2 OH
H
CH 2 N (CH 2 ) 4 CH 3
OH O
C P
OH CH 2 OH
Figure 44–11. Structures of pyrophosphate and bisphosphonates. The substituents (R 1
and R 2
) on the central carbon of the bisphosphonate
parent structure are shown in blue.
N
CH 3
O
O
latter mechanism. Consistent with this view, the antiresorptive effect
of aminobisphosphonates such as alendronate and risedronate, but
not of clodronate or etidronate, persists when apoptosis is suppressed
(Halasy-Nagy et al., 2001). First-generation bisphosphonates are
metabolized into a nonhydrolyzable ATP analog (AppCCl 2
p) that
accumulates within osteoclasts and induces apoptosis (Rogers,
2003). In contrast, the aminobisphosphonates such as alendronate
and ibandronate directly inhibit multiple steps in the pathway from
mevalonate to cholesterol and isoprenoid lipids, such as geranylgeranyl
diphosphate, that are required for the prenylation of proteins
that are important for osteoclast function. The potency of aminobisphosphonates
for inhibiting farnesyl synthase correlates directly with
their antiresorptive activity (Dunford et al., 2001).
Available Bisphosphonates
Several bisphosphonates are available in the U.S. (Figure 44–11).
Etidronate sodium (DIDRONEL) is used for treatment of Paget’s disease
and may be used parenterally to treat hypercalcemia. Because
etidronate is the only bisphosphonate that inhibits mineralization, it
AGENTS AFFECTING MINERAL ION HOMEOSTASIS AND BONE TURNOVER