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Bisphosphonates In The Management of OP
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Category: Practitioners
Dr Stan Lipschitz
NOF Council Member and Physician in Private Practice, Rosebank, Johannesburg
Osteoporosis can be defined as a reduction in bone mass with an alteration
in bone microarchitecture that results in an increased susceptibility
to fractures. The commonest osteoporotic fractures occur in the forearm,
vertebral body (back bone) and hip but fractures of the humerus (upper
arm), tibia (leg), pelvis and ribs are also common. The lifetime risk
of symptomatic fracture for a 50-year-old woman is estimated at around
15% for the forearm, 15% for the vertebrae and 15% for the hip with a
cumulative lifetime risk of around 35-40%. The corresponding figures for
a 50-year-old man are 2%, 2% and 5% respectively. The absolute number
of osteoporotic fractures is however rising because of the ageing of the
population and improvement in life expectancy. Excess mortality during
the year following a hip fracture is estimated at around 20% and up to
50% of patients with a hip fracture remain permanently disabled. Vertebral
fractures may lead to chronic back pain with loss of height and restricted
mobility.
In most cases, bone loss occurs as a result of increased bone destruction
(resorption) relative to bone formation. Both bone resorption and formation
occur continuously in the skeleton as part of normal skeletal function,
and during this process packets of bone are being destroyed and rebuilt,
a process called remodeling. Osteoclasts resorb bone. With estrogen deficiency,
(as occurs in the postmenopausal state) and in some other conditions osteoclastic
number and activity increases and results in bone loss. A rational strategy
to treat and to prevent osteoporosis is therefore to inhibit the osteoclast
activity. Bisphosphonates are most effective inhibitors of osteoclastic
bone resorption.
Bisphosphonates are analogues of naturally occurring pyrophosphate, but
contain a carbon instead of an oxygen atom (P-C-P instead of P-O-P). Substitutions
on the carbon yield a large family of different compounds with different
properties determined by these side chains. Examples of different bisphosphonates
include Etidronate (Didronel), Pamidronate (Aredia), Alendronate (Fosamax),
Clodronate, Olpadronate, Ibandronate, Risedronate and Tiludronate. The
potency of these compounds in inhibition of osteoclastic activity differs
by as much as 10 000 fold depending on the structure. As a class however
they are characterized by their ability to inhibit bone resorption and
all have similar absorption, distribution and elimination.
Bisphosphonates are generally poorly absorbed from the gastrointestinal
tract. Once absorbed, bisphosphonates disappear rapidly from the circulation
as they are taken readily up by bone and the remainder is excreted through
the kidneys. This skeletal uptake is one of the most desirable features
of bisphosphonates since it concentrates the drug in the target organ.
Bisphosphonates bind to the bone mineral hydroxy appetite and the capacity
of bone for bisphosphonates is extremely large. Uptake of bisphosphonates
in the skeleton is not homogeneous. Bisphosphonates bind preferentially
to areas of the skeleton that are actively remodeling. After deposition
in bone, bisphosphonates are liberated again only when the bone is resorbed
(by osteoclasts). The half life of bisphosphonates in bone is therefore
extremely long, approximately 10 years in humans.
Although bisphosphonates are similar, their antiresorptive effects differ
markedly. For example at any given dose Alendronate is approximately 700
times more potent than Etidronate at decreasing bone resorption.
MODE OF ACTION OF BISPHOSPHONATES
Bisphosphonates reduce bone turnover by decreasing the number of sites
at which bone remodeling is initiated. Thus fewer packets of bone are
being resorbed and reformed thus countering the negative effects of estrogen
deficiency and other diseases that activate bone resorption. Treatment
thus results in the maintenance of both the amount of bone and bone structure.
Studies on Alendronate have shown preferential localization of Alendronate
on bone resorption surfaces within 4 hours after administration. Alendronate
is noted inside osteoclasts within 12 hours after administration.
CLINICAL USE OF BISPHOSPHONATES IN THE TREATMENT OF OSTEOPOROSIS
Osteoporosis treatment aims to prevent bone loss at clinically important
sites in order to reduce the risk of fractures in patients with underlying
low bone mass. The effectiveness of treatment can be measured in several
ways. The simplest measurement is the effect on bone mineral density.
The effect on bone turnover can be assessed by measuring bone breakdown
products (bone markers). The most useful measurement however is the effect
on fracture reduction. Finally the effects on bone quality can be measured
by doing bone biopsies and examining these sections under the microscope.
EFFECTS ON BONE MINERAL DENSITY
A large variety of clinical trials have been done with several bisphosphonates.
The earliest studies were done with Etidronate administered in a cyclical
(intermittent) fashion. The larger of these Etidronate studies involved
423 women and showed a significant increase in spine bone density of 4-5%
within 2 years compared with a non-significant rise of less than 1.5%
in patients given calcium only. At the femur a much smaller increase of
1.44 - 2.65 % in bone mass was noted with this compound. Significant increases
of around 10% in spine bone density have been seen after 2 years of treatment
with intravenous Pamidronate. Significant increases in bone density have
similarly been observed with the bisphosphonates Clodronate and Ibandronate.
5 mg of Risedronate results in an increase in bone mineral density from
baseline at the lumbar spine by 5.4%, and at the femur by between 1.6
and 3.3%. The optimal dosage of Alendronate 10 mg per day results in an
increase in spine bone density by 8.8% compared with placebo and an increase
by 5.9 - 7.8% in bone mineral density at the hip when compared with placebo
or calcium. Alendronate thus induced highly significant and clinically
meaningful increases in bone density at all skeletal sites. Over 96% of
patients treated with the 10 mg dosage had an increase in bone density
relative to baseline. In general the increases in bone density are most
rapid during the first 6-12 months but continue through the years thereafter.
With Alendronate continued increases in bone mineral density has been
observed through 3 and 4 years of treatment.
EFFECT OF BISPHOSPHONATES ON BONE QUALITY
Questions have been raised about possible adverse effects of bisphosphonates
on bone quality. In early trials using Etidronate continuously, problems
with mineralisation (calcification) of bone were noted after prolonged
treatment. The use however of Etidronate intermittently has not resulted
in this problem. Alendronate and Risedronate studies have now clearly
demonstrated that the bone formed during treatment with these bisphosphonates
is of normal quality and no problems with mineralisation or micro structural
damage occur following prolonged usage.
EFFECT OF BISPHOSPHONATES ON FRACTURE INCIDENCE
The ultimate aim of any treatment in patients with osteoporosis is reduction
of risk of fracture. In the 2 year study of cyclical Etidronate the incidence
of new vertebral fractures was reduced by 53%. The largest and most significant
figures on fractures have been obtained using Alendronate. The incidence
and risk of sustaining at least one vertebral fracture, two or more such
fractures, or a painful vertebral fracture have been studied. The use
of Alendronate will reduce the risk of sustaining at least one vertebral
fracture by 47%, reduce the risk of sustaining two or more vertebral fractures
by 90% and reduce the risk of sustaining a painful vertebral fracture
by 55%. Alendronate has also been shown to result in a 48% reduction in
wrist (or forearm) fractures and a 51% risk reduction in the risk of hip
fractures.
This is the first time for any treatment used for osteoporosis that a
prospective clinically controlled trial demonstrated the capacity of a
drug to reduce the incidence of hip fractures in a free living population
of women. Since hip fractures are associated with the greatest suffering
and cost resulting from osteoporosis this halving of risk of hip fracture
is extremely beneficial.
The use of Risedronate 5 mg over 3 years results in a significant 41%
reduction in the risk of new vertebral fractures.
USE OF BISPHOSPHONATES IN CORTISONE INDUCED AND MALE OSTEOPOROSIS
In addition to their role in the management of postmenopausal osteoporosis,
bisphosphonates may also be extremely useful in the treatment of corticosteroid
induced and male osteoporosis. Corticosteroid use is a major cause of
secondary osteoporosis and fractures in men and women. Steroid therapy
is associated with poor absorption of calcium, increased urinary excretion
of calcium, decrease in sex hormone levels, increased osteoclastic bone
resorption and decreased osteoblastic bone formation. This may result
in extremely rapid bone loss in particular during the first 6-12 months
of steroid therapy. The use of oral Pamidronate, cyclical Etidronate,
and oral Alendronate has been shown to prevent bone loss in patients starting
steroid therapy and significantly increase spine bone mineral density
when used in patients long after initiation of steroid therapy. The studies
of Alendronate in steroid induced osteoporosis included 141 men and 336
women aged 70-79 who were expected to remain on significant doses of oral
cortisone. There were significant increases in bone density in both the
men and women who received Alendronate. After 42 weeks of treatment 10
mg of Alendronate compared to Placebo resulted in a 3.37% increase in
bone mass at lumbar spine, and a 2.1 - 3.25% increase in bone mass at
femur.
Osteoporosis in men has in general been poorly studied. Osteoporotic fractures
in men are associated with a marked degree of disability and death, even
exceeding that seen in women. For example in one 5-year study of 4311
men and women aged 60 years and older, 37% of the men who experienced
a hip fractured died within one year of the event compared to 20% of the
women. The corresponding death rates following clinically diagnosed spine
fractures were 32% and 12 % for men and women respectively.
In a 2-year placebo controlled study of 241 men aged 31-87 years treatment
with Alendronate resulted in significant increases in bone density at
the spine and hip compared to those seen with placebo. At the spine the
men treated with Alendronate experienced a 7.1% increase in bone density
versus a 1.8% increase in the placebo group. At the femoral neck the men
treated with Alendronate experienced a 2.5% increase in bone density versus
a 0.1% decrease in bone density with placebo. This study also found that
height loss was 3 times greater in the placebo group (2.38 mm) than in
the men treatment with Alendronate (0.58 mm). The incidence of spinal
fractures in men treated with Alendronate was 62% less than those treated
with placebo. In addition those spinal fractures resulting in sufficient
pain to cause the patient to visit a Doctor occurred 78% less frequently
in men treated with Alendronate than in those who received placebo.
CAN BISPHOSPHONATES BE USED AS COMBINATION THERAPY?
In general it is recommended to use a single antiresorptive agent in the
management of osteoporosis. In certain patients however e.g. those with
extremely severe disease or those who fail to respond to a single agent,
combination therapy may be necessary. Adding Alendronate to patients who
have been on long term hormone replacement therapy results in an increase
of spine density by 2-3%. Whether this is of any benefit in further fracture
reduction has not been established.
TOLERABILITY
The most common adverse events with oral bisphosphonates are gastrointestinal
disturbances including abdominal discomfort, pain and diarrhoea. In general
Alendronate is extremely well tolerated and the overall safety profile
of Alendronate 5-20 mg is remarkably similar to that of placebo. In early
marketed use some cases of esophageal irritation, oesophagitis and even
esophageal ulcers were reported. Post marketing surveillance however suggested
that in 61% of reported cases of oesophagitis, patients had not complied
with the recommended instructions of administration. The rate of such
reports has since declined despite the much more widespread use of Alendronate,
suggesting increased awareness and compliance with dosing instructions.
Alendronate should be taken before breakfast with at least 250 ml of water
and the patient should then remain upright and not eat for at least 1⁄2
an hour. The patient should not lie down until after their first food
of the day.
CONCLUSIONS
The primary objective of treating osteoporosis is to substantially reduce
risk of fractures. Bisphosphonates are therefore an extremely important
group of drugs for the treatment of osteoporosis because they inhibit
bone resorption, increase bone density and therefore decrease risk of
fractures. Alendronate is currently the most extensively investigated
treatment for osteoporosis and is the only agent that has been shown in
large controlled trials to increase bone density at the forearm, spine
and hip and decrease the incidence of fractures at each of these sites.
Early results with Risedronate look promising in terms of reduction of
spine and hip fractures.
Given that treatment for osteoporosis should be long term, compliance
and tolerability are important. The side effect profile of bisphosphonates
is similar to that of placebo. In clinical practice oesophagitis has rarely
been reported and in most cases seems to be related to inappropriate administration.
Published on 2005-06-08