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FIGURE 53.3
Schematic of effects in tubular bones.
FIGURE 53.4
How bisphosphonates improve skeletal outcomes.
(2) reduced cortical porosity; (3) reduced endosteal
bone resorption, leading to increased cortical thickness
and (4) reduced resorption of trabecular material at the
metaphyses with accompanying widening (undertu-
bulation) of the ends of long bones. In addition there
is restoration of vertebral architecture accompanied by
end plate thickening - the trabecular bone in the center
of the vertebrae is not restored. Essentially, the balance
of resorption and formation is altered in favor of forma-
tion at a whole tissue level, resulting in increased bone
mass and improved architecture. The additional reduc-
tion in bone pain allows for increased mechanical stim-
ulation of bone, furthering favoring anabolism.
Stopping bisphosphonates before growth ceases
results in degradation of the newly formed bone at the
metaphyses and can create a “stress riser” at the inter-
face between treated and untreated areas. It is unclear
at present whether there are additional effects of
bisphosphonates at the level of mechanical sensing in
bone tissue that further favors bone anabolism.
Statins, which also inhibit the mevalonate pathway,
can also inhibit bone resorption
in vitro
, but not sig-
nificantly
in vivo
, probably reflecting their preferential
uptake by liver rather than bone.
The acute phase reaction seen in patients exposed for
the first time to a nitrogen-containing bisphosphonate
may be due to the upstream accumulation of isopentyl
pyrophosphate acting on γδ-T cells to cause cytokine
release.
18
There may also be direct effects of bisphosphonates on
bone-forming lineage cells; in contrast to their pro-apop-
totic effect in osteoclasts, bisphosphonates appear to pro-
tect both osteoblasts and osteocytes from the apoptosis
resulting from glucocorticoid exposure in experimental
model systems both
in vivo
and
in vitro
. In the setting of
the osteocytes and their canalicular network, bisphospho-
nates promote the opening of connexin CX43 hemichan-
nels; the downstream consequences of this are to activate
both extracellular signal-regulated kinases, leading to
inhibition apoptosis. Interestingly these actions are inde-
pendent of any osteoclastic effects since bisphosphonates
without anti-resorptive potency still exhibit this anti-
apoptotic effect
in vitro
.
19
The extent to which this effect is
influenced by the mineral binding affinity of the bisphos-
phonate and the influence that it has on maintaining or
increasing bone mass in therapeutic settings is unclear.
The effects of bisphosphonates on the skeleton (
Figure
53.4
) are monitored biochemically, by changes in bone
mineral density (BMD) and occasionally radiologically
in growing animals or children. The biochemical moni-
toring provides an insight into the effects of bisphos-
phonates on bone remodeling, with an initial fall in the
resorptive markers (such as urinary NTx or serum CTx)
followed by a smaller reduction in bone formation.
Differences between individual bisphosphonates can be
demonstrated in pharmacokinetic-pharmacodynamic
studies in terms of the degree of the reduction of bone
remodeling, but it is unclear how such differences trans-
late into anti-fracture efficacy.14
14
The typical increase of
3-5% in lumbar spine areal bone mineral density is dis-
proportionately small compared to the reduction in frac-
ture risk of around 50% for vertebral fracture.
The duration of effects of bisphosphonates on the
skeleton can be quite prolonged, but there may be
important differences among them. For example, the
effects of risedronate wear off within a few months of
stopping treatment, whereas the effects of a single infu-
sion of zoledronate can last for several years.
SA
FETY OF BISPHOSPHONAT
ES
Bisphosphonates are one of the most well-stud-
ied groups of medications. The overall safety profile
of bisphosphonates is good, thanks mainly to their
