LE Magazine September 2002
Page 3 of 4
Osteoporosis—Bisphosphonates
Bisphosphonates: safety and efficacy
in the treatment and prevention of osteoporosis.
Osteoporosis affects more than 28 million Americans. With
the advent of accessible and affordable diagnostic studies,
awareness and recognition of this disease by patients and
clinicians are growing. Osteoporotic fractures of the spine
and hip are costly and associated with significant morbidity
and mortality. Over the past decade, a surge of new
antiosteoporotic drugs have been labeled or are awaiting
labeling by the U.S. Food and Drug Administration. One class
of agents used to treat osteoporosis is the bisphosphonates,
which inhibit bone resorption, cause an increase in bone
mineral density and reduce the risk of future fractures caused
by aging, estrogen deficiency and corticosteroid use. Overall,
bisphosphonates have been shown to have a strong safety and
tolerability profile.
Am Fam Physician 2000 May
1;61(9):2731-6
Bisphosphonates: preclinical aspects
and use in osteoporosis.
Bisphosphonates are synthetic compounds characterized by a
P-C-P bond. They have a strong affinity to calcium phosphates
and hence to bone mineral. In vitro they inhibit both
formation and dissolution of the latter. Many of the
bisphosphonates inhibit bone resorption, the newest compounds
being 10,000 times more active than etidronate, the first
bisphosphonate described. The antiresorbing effect is cell
mediated, partly by a direct action on the osteoclasts, partly
through the osteoblasts, which produce an inhibitor of
osteoclastic recruitment. When given in large amounts, some
bisphosphonates can also inhibit normal and ectopic
mineralization through a physical-chemical inhibition of
crystal growth. In the growing rat the inhibition of
resorption is accompanied by an increase in intestinal
absorption and an increased balance of calcium.
Bisphosphonates also prevent various types of experimental
osteoporosis, such as after immobilization, ovariectomy,
orchidectomy, administration of corticosteroids or low calcium
diet. The P-C-P bond of the bisphosphonates is completely
resistant to enzymatic hydrolysis. The bisphosphonates studied
up to now, such as etidronate, clodronate, pamidronate, and
alendronate, are absorbed, stored and excreted unaltered. The
intestinal absorption of the bisphosphonates is low, between
1% or less and 10% of the amount ingested. The newer
bisphosphonates are at the lower end of the scale. The
absorption diminishes when the compounds are given with food,
especially in the presence of calcium. Bisphosphonates are
rapidly cleared from plasma, 20% to 80% being deposited in
bone and the remainder excreted in the urine. In bone, they
deposit at sites of mineralization as well as under the
osteoclasts. In contrast to plasma, the half-life in bone is
very long, partially as long as the half-life of the bone in
which they are deposited. In humans, bisphosphonates are used
successfully in diseases with increased bone turnover, such as
Paget’s disease, tumoural bone disease, as well as in
osteoporosis. Various bisphosphonates, such as alendronate,
clodronate, etidronate, ibandronate, pamidronate and
tiludronate, have been investigated in osteoporosis. All
inhibit bone loss in postmenopausal women and increase bone
mass. Furthermore, bisphosphonates are also effective in
preventing bone loss both in corticosteroid-treated and in
immobilized patients. The effect on the rate of fractures has
recently been proven for alendronate. In humans, the adverse
effects depend upon the compound and the amount given. For
etidronate, practically the only adverse effect is an
inhibition of mineralization. The aminoderivatives induce for
a period of two to three days a syndrome with pyrexia, which
shows a similitude with an acute phase reaction. The more
potent compounds can induce gastrointestinal disturbances,
sometimes oesophagitis, when given orally. Bisphosphonates are
an important addition to the therapeutic possibilities in the
prevention and treatment of osteoporosis.
Ann Med 1997 Feb;29(1):55-62
Osteoporosis - evidence based
therapy.
Osteoporosis therapy has been controversially discussed in
the past. In the meantime, several therapeutic options to
prevent fractures are available for this disease. With respect
to proven fracture benefit, however, the quality of evidence
from randomized and controlled clinical trials varies
substantially among therapies. From systematic research the
best external evidence is available for a supplementation with
calcium and vitamin D and a therapy with the bisphosphonates
alendronate or risedronate, as well as the SERM raloxifene.
For other therapeutic agents like fluorides, vitamin D
metabolites, calcitonin and etidronate the quality of evidence
is much lower. So far, there is no evidence for other
pharmaceutical therapies. Hip protectors are effective in the
prevention of hip fractures.
Z Gastroenterol 2002 Apr;40 Suppl
1:57-61
Bisphosphonate therapy in
osteoporosis. Inhibition of trabecular perforation by
aminobisphosphonate.
After many years of experience with bisophosphonates in the
treatment of “tumor osteopathy” and Paget’s
disease, these substances have now also been approved for use
in the treatment of osteoporosis. Owing to their high affinity
for calcium hydroxyapatite, the bisphosphonates are deposited
in the bony surface, and the aminobisphosphonates exert their
effect at the site of active resorption via direct inhibition
of active osteoclasts. As a result of this inhibition of the
osteoclastic bone resorption, trabecular perforation is
reduced and during the course of bone remodelling by the
activity of the osteoblasts, boneformation occurs. In addition
to an increase in bone density, both etidronate and
alendronate have been shown to inhibit vertebral fractures in
patients with osteoporosis. In addition, in patients with
preexisting fractures, alendronate is able, at the same time,
to lower the incidence of fractures of the femoral neck. With
proper administration, the associated occasional
gastrointestinal side effects can be avoided. The introduction
of bisphosphonates into the treatment of osteoporosis is
definitely an enrichment of the therapeutic spectrum in
conjunction with the basic treatment comprising calcium,
vitamin D, diet and physical measures.
Fortschr Med 1997 Oct
20;115(29):37-42
Bisphosphonates: from the laboratory
to the clinic and back again.
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
occurring 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 mineralization, 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
post-translational 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 unraveled. As a result,
their full therapeutic potential is gradual.
Bone 1999 Jul;25(1):97-106
Continuous therapy with pamidronate, a
potent bisphosphonate, in postmenopausal osteoporosis.
There is a need for effective and acceptable therapies for
postmenopausal osteoporosis. The bisphosphonates show promise
in this role, but the effects of the potent bisphosphonates in
established osteoporosis have not yet been reported. We
performed a 2-yr, randomized, double blind, placebo-controlled
trial of pamidronate (150 mg/day) in 48 postmenopausal
osteoporotic women. Bone mineral density of the total body,
lumbar spine and proximal femur was measured every six months
by dual energy x-ray absorptiometry. Bone mineral density
increased progressively in the total body (1.9 +/- 0.7%; P
< 0.01), lumbar spine (7.0 +/- 1.0%; P < 0.0001), and
femoral trochanter (5.4 +/- 1.3%; P < 0.001) in subjects
receiving pamidronate, but did not change significantly in
those receiving placebo. There were significant decreases in
bone density at both the femoral neck (P < 0.02) and
Ward’s triangle (P < 0.01) in subjects taking placebo,
which did not occur in the pamidronate group. The differences
between the treatment groups were significant at all sites
(0.0001 < P < 0.05) except Ward’s triangle.
Vertebral fracture rates were 13/100 patient yr in the
pamidronate group and 24/100 patient yr in those receiving
placebo (P = 0.07), and there was a nonsignificant trend
toward height loss being less in those receiving pamidronate
(P = 0.16). It is concluded that pamidronate is an effective
therapy in postmenopausal osteoporosis.
J Clin Endocrinol Metab 1994
Dec;79(6):1595-9
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