Bisphosphonates and PTH for Preventing Fractures - Skeletal Aging and Osteoporosis: Biomechanics and Mechanobiology - page 150

Fig. 1 Agents that act
primarily by reducing bone
loss are classified as anti-
catabolic while those that act
by altering bone valance in
favor of formation, or cause
direct apposition to bone
surfaces, are anabolic
2 The Mechanism of Action of Bisphosphonates
Bisphosphonates work by suppressing activation of osteoclasts and inducing their
apoptosis by interfering with the mevalonate pathway [ 1 , 10 ]. Upon liberation
from the bone surface in the low pH environment of resorption lacunae, BPs are
taken up by the osteoclast through the ruffled boarder via fluid-phase endocy-
tosis. Once in the cell, BPs inhibit both FPPS (farnesyl diphosphonate synthase)
and GGPPS (geranylgeranyl diphosphate synthase), blocking prenylation of
small GTPases such as Ras, Rho, Rac and Rap as well as cell survival signaling
pathways. Inhibiting the interaction of these GTPases with the cell membrane
down-regulates signaling through the Akt and ERK 1/2 signaling pathways,
causing the release of cytochrome c, and eventually the activation of caspases.
BPs also acts by perturbing the cell cycle of osteoclasts, inhibiting cell growth
by inducing cell cycle arrest in the S-phase. The cellular effects of BPs are
largely confined to osteoclasts, as these are the cells most often subjected to the
highest concentrations of drug in vivo. Recently, the clinical observation of an
acute phase reaction following intravenous BP treatment led to the discovery that
other cells (gamma delta T cells in the case of the acute phase reaction, but also
macrophages) can be adversely affected in vivo by BPs if they see sufficient
concentrations [ 11 - 14 ]. This emphasizes the point that BPs do not specifically
target osteoclasts, and any cell that sees sufficiently high concentrations is likely
to have disrupted function.
By suppressing the initiation of osteoclast activity, BPs reduce the number of
active bone multicellular units (BMUs) and the erosion pits that do form are not as
large. In untreated individuals there normally exists a net negative bone balance
within each BMU meaning a small amount of bone loss occurs at the BMU-level
with each remodeling cycle. In post-menopausal women, there is an increase in
bone remodeling sites, and also a larger net bone loss within each BMU—together
these are responsible for the accelerated bone loss during the post-menopausal
years. Although some differences exist in the degree to which activation frequency
(the variable assessed histologically to determine the degree of remodeling) is
suppressed, BP-induced suppression usually exceeds 70% in cancellous bone,
assessed in iliac crest biopsies. This suppression of remodeling significantly