Update on osteoporosis drugs
> Update on osteoporosis drugs
on osteoporosis drugs
(This article was first printed
in the August, 2004 issue of the Harvard
Women's Health Watch. For more information
or to order, please go to http://health.harvard.edu/women.)
Research is suggesting
new ways to prevent the worst consequence
of osteoporosis: broken bones.
The loss of bone strength
through osteoporosis, as many people know,
increases the risk of fractures. In the United
States, a 50-year-old woman has a 40%-50% lifetime
chance of having a broken bone due to osteoporosis.
The most common fracture sites are the spine,
hip, and wrist. Men, too, can have such fractures,
but women are far more vulnerable because they
lose bone at an accelerated rate during the
first several years following menopause. Their
bones are also less dense to begin with. However,
many additional factors influence the development
of osteoporosis, including age, genes, race,
level of physical activity, and estrogen status.
There are various treatments
available for osteoporosis, and those that
are preventive are particularly important.
Mainstays in reducing osteoporosis and fracture
risk include regular weight-bearing exercise,
adequate calcium and vitamin D, quitting smoking,
good nutrition, and fall prevention. But women
who already have osteoporosis or are at high
risk for it may need to take medications as
Researchers have gained considerable
insight into what constitutes bone strength
and the biological pathways that affect it.
As a result, we can expect to see new and better
uses of current drug therapies, most of which
reduce fracture risk by curbing bone loss,
and the development and approval of new drugs,
particularly ones that work by building bone.
bone mineral density
bone strength in a variety of ways.
For example, bone quality includes
bone mineralization, microarchitecture,
and rate of turnover, among other
factors. The best known way to characterize
bone strength is bone mineral density
(BMD). We cannot measure bone quality,
so calculating BMD with low-dose
x-rays (dual-energy x-ray absorptiometry,
or DXA) is the best way of assessing
fracture risk in postmenopausal women.
Most official guidelines suggest
that women ages 65 and over should
receive DXA screening (women at high
risk for osteoporosis should begin
at age 60). Keep in mind that a BMD
score is only one of several predictors
of fracture risk. Others include
age, low weight, family history of
hip fracture, and personal history
of broken bones after age 50.
beyond bone mass
Clinicians rely on measurements
of bone mineral density (BMD) - sometimes referred
to as bone quantity or bone mass - to diagnose
osteoporosis, determine who should be treated,
and monitor therapy. But the main problem with
osteoporosis is fracture, not low bone mass.
Studies of postmenopausal
women show a relationship between low bone
mass and future fracture risk, but BMD isn't
the whole story. For one thing, women with
similar BMD scores can have very different
levels of fracture risk. For example, an 80-year-old
with a low BMD score has a greater risk of
bone fracture than a 60-year-old with the same
score. Also, half of all fractures occur in
people who don't have osteoporosis (as defined
by BMD measurements). Furthermore, in some
osteoporosis drug trials, improvements in BMD
haven't always led to reductions in fracture
According to some experts,
currently available drugs that reduce fractures
may do so not because they improve BMD, but
through other effects on bone. Scientists are
looking at several such biomechanical contributors
to bone strength and fracture resistance. A
major focus of their work is bone quality,
a term that encompasses the bone's thickness,
interior structure (microarchitecture), cumulative
damage, mineralization, and rate of turnover.
Researchers have also identified genes and
gene products, growth factors, and hormones
that influence bone quality and may be targets
of future therapies.
turnover: Tear down, build up
undergoes a process called remodeling,
or bone turnover. It involves two
distinct stages: bone resorption
(breakdown) and bone formation. Calcium
is stored in bone. When it's needed
in the body, bone cells called osteoclasts
attach to the bone surface and break
it down, leaving cavities in the
bone (A). Bone-forming cells called
osteoblasts move in and release collagen
and other proteins into these cavities
(B) and stimulate bone mineralization.
The osteoblasts then join with calcium
and other substances to form new
bone material (matrix) to replace
what was lost (C). Osteoblasts that
remain part of the matrix are called
Bone loss occurs with age
because the normal process of remodeling, or
bone turnover (see illustration above), removes
more bone than it replaces. (Earlier in life,
the reverse is true.) Bone resorption takes
less time than bone formation - resorption
at a particular bone site takes about two weeks;
formation takes three months or more - so there's
also a shortfall of bone at what are called
remodeling spaces. Normally, this is of little
consequence, but if the remodeling cycle is
out of balance, bone turnover can result in
major bone loss. High bone turnover is believed
to increase fracture risk.
Most approved osteoporosis
drugs are antiresorptive - that is, they slow
the destructive phase of bone turnover (resorption).
This slows bone loss and helps fill in the
remodeling spaces. All antiresorptive agents
reduce the risk of vertebral (spinal) fractures,
and they all reduce markers of bone turnover.
(These markers are substances in the blood
and urine that reflect the activity of the
bone cells involved in breakdown and formation.)
include bisphosphonates, estrogen, selective
estrogen receptor modulators (SERMs), and calcitonin
(se e the medications chart, below). The bisphosphonates
alendronate and risedronate are often the first
drugs recommended for treating postmenopausal
osteoporosis. They reduce nonvertebral fractures
(at the hip or wrist, for example) as well
as vertebral fractures, and when taken properly
have few side effects. Raloxifene, the only
SERM currently approved for osteoporosis, reduces
spine fractures about as effectively as bisphosphonates.
Researchers are investigating its effects on
hip and non-spine fractures.
Antiresorptives produce modest
increases in bone density. Research on alendronate
suggests that such increases may be due, in
part, to mineralization of old bone. Mineral
content contributes to bone strength, but too
much mineralization can make bones brittle.
Data suggest that bisphosphonates are safe
taken for up to 10 years, but longer-term studies
are needed to clarify their cumulative effects
There's also a need for fracture-reduction
trials that compare antiresorptive agents directly
with one another - and with exercise, calcium
and vitamin D supplementation, and other nondrug
interventions. A trial comparing raloxifene
to alendronate is under way in postmenopausal
women with BMD-defined osteoporosis.
for osteoporosis prevention or treatment
agents (slow bone remodeling, increase
. alendronate (Fosamax)
. risedronate (Actonel)
. ibandronate (Boniva)
and treatment. Alendronate and risedronate
reduce the risk of vertebral, hip,
and wrist fractures by 40%-50%. Ibandronate
reduces vertebral fractures, possibly
by as much as 50%.
tolerated when taken properly, but
may cause nausea, heartburn, or esophageal
or stomach irritation. Alendronate
and risedronate are available in a
once-weekly dosage, which may help
reduce side effects.
interfere with cells that break down
bone (osteoclasts). Taken first thing
in the morning with a full glass of
water at least 30 minutes before eating
anything. Ibandronate will not be available
until a once-monthly formulation is
estrogen receptor modulators (SERMs)
. raloxifene (Evista)
and treatment. Reduces vertebral fractures
side effects include hot flashes, leg
cramps, and blood clots.
bone density, but not at the same rate
as bisphosphonates. May reduce breast
cancer risk. Lowers LDL (bad) cholesterol.
. Various agents,
including Premarin, Prempro, Estrace,
Estraderm, and Climara
only. Reduces vertebral and hip fractures
by 34%.** Preventive effects are most
evident when HT is started as close
to menopause as possible.
(estrogen) increases the risk of stroke
and uterine cancer. Premarin plus a
progestin (Prempro) increases the risk
of heart attack, stroke, blood clots,
and breast cancer.
slows bone remodeling. Low-dose (0.3
mg) Premarin plus calcium has been
shown to protect bone mass. Can increase
HDL (good) cholesterol. Raises triglycerides,
a marker for heart disease risk.
. calcitonin (Miacalcin)
only. Modest reduction in risk of vertebral
fractures. Not widely used.
effects include stomach upset and flushing.
Miacalcin nasal spray can cause runny
nose and respiratory symptoms.
as an injection or nasal spray. May
relieve pain associated with bone fractures.
agent (builds new bone)
. teriparatide (Forteo)
only. May double the rate of bone formation.
Reduces vertebral fractures by 65%-70%
and cuts the risk of nonvertebral fractures
by about 50%.
PTH-treated rats developed a form of
bone cancer, there is no evidence of
this risk in humans.
be taken as an injection. Because effects
appear to wane and long-term safety
data are lacking, PTH should not be
prescribed for more than about two
years. Treatment costs about $7,000
* Fracture data
is derived from individual studies,
not from head-to-head trials of osteoporosis
** In women without
osteoporosis participating in the Women's
Health Initiative trials of Premarin
(estrogen only) and Prempro (combined
estrogen and progestin).
+ Etidronate (Didronel),
pamidronate (Aredia), and zolendronic
acid (Zometa) are bisphosphonates that
are FDA-approved for treating bone
problems related to cancer or Paget's
disease. They may be used off-label
to treat osteoporosis. Pamidronate
and zolendronic acid are given intravenously.
better bone: What's new?
Antiresorptives do not build
bone beyond what is produced to help fill the
remodeling spaces. Bone-building (anabolic)
drugs, on the other hand, stimulate bone formation
by increasing the activity of the cells known
as osteoblasts. The only such medication approved
for treating osteoporosis is teriparatide (Forteo),
a form of human parathyroid hormone (PTH).
The drug comes as a daily injection, which
can be self-administered.
PTH produces larger increases
in BMD than antiresorptives do. It also improves
bone microarchitecture (see photo below). However,
it is prescribed for no more than about two
years because its long-term safety and efficacy
are unknown. Most experts recommend that antiresorptive
drugs be stopped during PTH therapy and restarted
after the course of PTH is complete.
At a scientific meeting sponsored
by the American Society of Bone and Mineral
Research, the National Institutes of Health,
and several other organizations, researchers
and clinicians discussed anabolic drugs and
other potential advances in preventing fractures,
including the following:
Strontium ranelate. Strontium
ranelate is a compound that incorporates the
element strontium, which is found in trace
amounts throughout the skeleton. Results from
Phase III trials conducted by French researchers
suggest that strontium ranelate may reduce
vertebral fractures about as well as bisphosphonates.
The drug is believed to work by decreasing
animal, and observational studies have suggested
that statins (drugs that lower cholesterol)
may be useful in preventing fractures. However,
clinical trials have shown no consistent effect
on bone mass or fracture rate. Some researchers
think that higher doses than those used to
lower blood lipids are required. For now, statins
are not an appropriate osteoporosis treatment.
More vitamin D. New
research indicates that to improve bone strength
and reduce hip fractures, we need more vitamin
D than the currently recommended level of 400
IU. The experts suggest getting 800-1,000 IU
of vitamin D per day.
Oscillating plate. Experiments
in animals and humans suggest that standing
on a special, gently oscillating mechanical
plate for 10-20 minutes per day can reduce
bone loss and possibly stimulate bone formation.
This could be a boon to people who may be too
frail or incapacitated to exercise.
of parathyroid hormone (PTH) on bone
These scanning electron
microscopy pictures show bone biopsies
taken from a 64-year-old woman, before
(A) and after (B) PTH treatment.
Improvements can be seen in interior
structure (microarchitecture) and
outer (cortical) thickness.
Reproduced from Journal
of Bone and Mineral Research (Oct.
2001), Vol. 16, No. 10, pp. 1846-1853
with permission of the American
Society for Bone and Mineral Research