Osteoporosis: Therapies
researched and written by the ProjectAWARE group, 2001
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The optimal goal for the treatment of osteoporosis, especially
for patients who already have advanced bone loss, is to increase
bone mass and bone strength to levels seen in average young women
and men so as to prevent all osteoporotic fractures. Indeed, with
the rapid aging of the population, there is an urgent need for a
cure, not merely the management of osteoporosis. This goal is not
attainable with present pharmacotherapies.5
The pharmacotherapies currently approved by the Food and
Drug Administration for the treatment of osteoporosis—estrogen,
raloxifene, alendronate, risedronate and calcitonin—are
antiresorptive
agents that work by slowing the rate of bone remodeling.
Thereby, they slow or retard bone loss. None of these
agents is capable of rebuilding bone. The small but
variable increases in bone mineral density (BMD) in
patients treated with antiresorptive agents are not
due to bone rebuilding. Instead, they are the result
of contraction of the remodeling space and more complete
secondary mineralization.5
During and following menopause, estrogen administration
(ERT) is important, not only in slowing bone loss, but
also significantly decreasing hip and vertebral fractures.
However, neither estrogen nor increased bone density
is likely to reduce fracture risk once there is substantial
trabecular
bone loss.9, 13, 38
Observational studies have indicated a significant hip
fracture reduction in women who maintain hormone replacement
therapy (HRT); still trials with fractures as the endpoint
are scarce. HRT trials have shown decreased risk of
vertebral fractures, but there have been no trials of
estrogen with hip fracture as the primary outcome.33
Trials have shown that physical activity is necessary
for bone building and maintenance through adulthood.
Complete bed rest and microgravity
have devastating effects on bone. Exercise intervention
has had the most effect during skeletal growth and in
very inactive adults. Improved muscular strength and
balance may be very significant in fracture-risk reduction,
and trials in older adults have successfully used various
forms of exercise to reduce falls. High-impact exercise
(weight training) stimulates accrual of bone mineral
content in the skeleton. Lower impact exercises, such
as walking, have beneficial effects on other aspects
of health and function, although their effects on bone
density have been minimal.33
There is an urgent need for randomized clinical trials
of combination therapy, which includes pharmacologic,
dietary supplement, and lifestyle interventions (including
muscle strengthening, balance, and management of multiple
drug use, smoking cessation, psychological counseling,
and dietary interventions).33
Current Therapies
Estrogen and HRT
Estrogen replacement therapy (ERT) can improve bone density
measurements in osteoporotic women20, but
does not eliminate risk of fractures. It was originally
thought that estrogens only restrain the osteoclasts.
Now we know that estrone stimulates the development
of the osteoblasts
(as well as myoblasts, which form muscle tissue).14
However, once estrogen administration ceases, the rate
of bone mineral density decline returns to that of untreated
women during the immediate postmenopausal period.10
The effective dose of conjugated estrogens has been found
to be as low as 0.3 mg/day.11 However, most
studies have found a dose of 0.625 mg to be more widely
effective. Other forms of oral estrogen seem to be equally
efficacious and, because the action is directly upon
the target tissue, route of administration does not
seem to matter.21
Treatment intervals, routes of administration, and dosages
have varied among the many favorably reported studies.
On average, it takes from 5-10 years of ERT before a
significant difference in fracture incidence can be
demonstrated.10
An improvement in bone density can be demonstrated after
as short a therapy interval as 6 months.11
However, to be effective in controlling osteoporosis,
ERT must be taken for at least 15 years from the last
menses until roughly the age of 70 or longer.33
Hormone replacement therapy (HRT) is an established approach
for osteoporosis treatment and prevention. Many short-term
studies and some longer term studies with bone density
as the primary outcome have shown significant efficacy.33
Data demonstrating the beneficial effect of hormone replacement
for women with osteoporosis is strong. Forthcoming results
from the WHI (Women's Health Initiative) are expected
to validate smaller studies that have demonstrated fracture
reduction for patients taking replacement therapy. In
addition, the association between HRT and breast cancer
is clear and must be carefully considered, especially
in high-risk patients.12
While combined hormone replacement therapy (HRT) offers
"undeniable and significant reduction in osteoporosis,
the synthetic progesterone (progestin)
used in HRT carries with it another set of risks." 23
Micronized progesterone
is the preferred progestogen
until new information points to another choice.12
Diet, exercise, and lifestyle factors offer identical
benefits without the risks.23
Young women with osteopenia should not be frightened,
but should be concerned enough to discuss estrogen with
their physician so that they do not develop osteoporosis
in the future. Elderly women with osteopenia are above
average for their age and don't require more than activity
and a good calcium intake (although even in the elderly
estrogen will make the bones even stronger and will
have other benefits).6
Unfortunately, hormone replacement is often not quite
as simple as just replacing one hormone, as is sometimes
implied by proponents. Nor is bone density a simple
matter of hormone replacement.47
The real difficulty is to find the desirable levels of
the hormones estrogen, progesterone and testosterone
required, and this can to some extent be gauged by doing
serial salivary hormone levels when using hormone replacements,
taking into account the levels of the three hormones
as well as their relative levels. Many practitioners
have found that by adequately restoring and balancing
these three hormone levels, bone densities do increase
significantly over a period of two years, during which
time overall well-being also increases.47
Bisphosphonates
Randomized placebo-controlled trials of cyclic etidronate,
alendronate, and risedronate analyzed by a systematic
review and meta-analysis have revealed that all of these
bisphosphonates increase bone density at the spine and
hip in a dose-dependent manner. They consistently reduce
the risk of vertebral fractures by 30 to 50 percent.
Alendronate and risedronate reduce the risk of subsequent
nonvertebral fractures in women with osteoporosis and
adults with glucocorticoid-induced
osteoporosis. There is uncertainty about the effect
of antiresorptive therapy in reducing nonvertebral fracture
in women without osteoporosis.33
With bisphosphonates, there is a one-time increase in
the bone density (it's like cashing in your life savings
all at once). As with estrogen, if the bisphosphonate
medication is stopped, bone density will decrease again.
If it is not stopped, bone density reaches a plateau.
The bisphosphonates get deposited in the bone and will
accumulate for years. Maybe they will continue to prevent
bone loss for 30 years without loss of bone strength.
We don't have any data longer than 5 years for alendronate.
It is possible that many years of accumulated medicine
would weaken the ability of the bone to repair damage.6
Etidronate (Didronel), in doses that are now considered
too high, was first used over 20 years ago to treat
patients with osteoporosis. They developed osteomalacia
(calcium deficiency in bone). These results discouraged
studies until a decade later, when investigators began
to focus on cyclical regimens for treatment of osteoporosis.6
Alendronate (Fosamax), a second generation bisphosphonate,
is 1,000 times as potent as etidronate in blocking bone
resorption. It is deposited in the bone and has a very
long half-life (greater than 10 years). Several studies
have convincingly showed improvement in bone density
at the spine and the hip after 2 to 4 years of treatment.
Most of the increase happens in the first year. The
effective dose for increasing bone density has been
found to be 5 or 10 mg/day, however, new evidence shows
35mg once a week is effective. The Fracture Intervention
Trial (FIT) documented significant fracture reduction
at 2 years with the 5mg/day dose.6
Risedronate (Actonel) was recently approved for treatment
of osteoporosis. The results appear similar to alendronate.
Risedronate significantly reduces the risk of hip fracture
among elderly women with confirmed osteoporosis but
not among elderly women selected primarily on the basis
of risk factors other than low bone mineral density.26
There are conflicting data about whether more gastrointestinal
side effects are seen with alendronate than with risedronate.
At this time, this newer bisphosphonate does not seem
to provide any definite advantage to alendronate for
the treatment of osteoporosis, other than possibly price.6
One researcher puts it this way: "Risedronate prevents
fractures - sometimes." In a large hip-fracture endpoint
trial, the rate of hip fractures was reduced in postmenopausal
women younger than 80 who had established osteoporosis
or who were at very high risk. In women older than 80,
however, who did not have bone density measurements,
there was no reduction in rate of hip fracture. The
reasons are not yet clear, but it could be due to the
more overwhelming impact of falls.6
Estrogen improves the bone density better than new drugs
such as alendronate (Fosamax) and calcitonin (Miacalcin).
The long-term safety of alendronate is unknown, so it
is not wise to use it for prevention unless there are
other strong risk factors. In fact, the recent large
FIT study showed that in those with osteopenia, the
percentage of women who developed new fractures after
4.5 years was 10% in women taking placebo and 11% in
women taking alendronate. The trabecular bone becomes
more brittle, and is thus more prone to fracture, as
the bone replacement is non-organic and cannot grow.6
There is no evidence that using a combination of estrogen
and bisphosphonates helps to prevent osteoporotic fractures,
but it does add to the expense and potential toxicity.
Another option for the 50-70 year old woman with osteopenia
who can't take estrogen due to breast cancer is to wait
a few years (just use calcium and exercise) until there
is more information about the new estrogen-like medications
that may suppress breast cancer.6
Calcitonin
Calcitonin is a naturally occurring hormone that acts
directly on osteoclasts (via receptors on the cell surface
for calcitonin), and bone biopsies from patients treated
with the drug show no effects on mineralization. It
has a short half-life. In one study, calcitonin given
as a subcutaneous injection showed significant improvements
in bone density, however, there was a high incidence
of side effects, including pain at the injection site,
flushing and nausea, which limited the use of the drug.6
Calcitonin is now available as a nasal spray, which has
made it much more tolerable for patients. The studies
using this drug have not included as many subjects as
the studies of bisphosphonates, but available data does
show increases in bone density. However, the increases
are not as great as with the bisphosphonates, and the
bone formation rate is not as depressed. This natural
hormone has been in clinical use for many years with
a good safety profile. Minor adverse effects such as
nasal irritation are seen in a small number of patients.
Calcitonin does not reduce the serum calcium levels
below normal in patients with postmenopausal osteoporosis
but has been shown to reduce magnesium levels in some
cases.6
Salmon calcitonin has demonstrated positive effects on
bone density at the lumbar spine, but this effect is
less clear at the hip. Other than a recently completed
randomized controlled trial of nasal calcitonin, no
analysis of fracture risk is available. The PROOF study
revealed a significant reduction in vertebral fracture
risk at a 200 IU dose but not at a 100 IU or 400 IU
dose. The absence of dose response, a 60 percent dropout
rate, and the lack of strong supporting data from bone
density and markers decrease confidence in the fracture
risk data from this trial.33
Calcitonin is a safe alternative to estrogen in women
who cannot or will not take estrogen. There are no data
about effectiveness of adding calcitonin to estrogen.6
SERMs (Selective Estrogen Receptor
Modulators)
Estrogen has effects on many different tissues. These
effects are mediated by intracellular estrogen receptors.
The estrogen receptors are complex, and after binding
with estrogen the receptor changes configuration. These
conformational changes are different in different tissues,
and analogs of estrogen can inhibit the final estrogen
effect in some tissue but not others.6
In postmenopausal women, estrogen improves bone mass and
serum
lipid concentrations, effects that are beneficial.
Estrogen also causes endometrial
hypertrophy and vaginal bleeding, which are undesirable
side effects, and it stimulates breast tissue, which
may account for the increase in breast cancer seen after
long-term use.6
The development of selective estrogen receptor modulators
(SERMs) has been an important new thrust in osteoporosis
research. The goal of these agents is to maximize the
beneficial effect of estrogen on bone and to minimize
or antagonize the deleterious effects on the breast
and endometrium.
Tamoxifen, used in the treatment and prevention of breast
cancer, can maintain bone mass in postmenopausal women,
however, effects on fracture are unclear. Raloxifene,
a SERM approved by the FDA for the treatment and prevention
of osteoporosis, has been shown to reduce the risks
of vertebral fracture by 36 percent in large clinical
trials.33
Tamoxifen, the first available SERM, was used as adjunct
therapy in women with breast cancer; however, tamoxifen's
protective effect on breast cancer appears to wear off
after five years. Increased bone density was noted in
these women. Tamoxifen also stimulates the endometrium.
In women with an intact uterus, progesterone therapy
would be needed to protect against endometrial carcinoma,
but the progesterone has been found to stimulate breast
tissue which could lead to recurrence of cancer.6
Raloxifene (Evista) has recently been approved for prevention
of osteoporosis. This SERM has protective effects on
the breast, and it decreases the LDL cholesterol (although
it does not increase the HDL cholesterol). There is
no stimulation of the endometrium. Bone density shows
small increases, which are less than seen with estrogen.
Raloxifene potentially could be useful in prevention
of osteoporosis, but the skeletal effects do not appear
to be strong enough to use it as a first choice in treatment
of established disease.6
Injection of polymethylmethacrylate
bone cement (vertebroplasty and kyphoplasty)
Due to the challenges of reconstruction of osteoporotic
bone, open surgical management is reserved only for
those rare cases that involve neurologic deficits or
an unstable spine. Recently, there has been increased
interest in two "minimally invasive" procedures for
management of acute vertebral fractures, vertebroplasty
and kyphoplasty, which involve the injection of polymethylmethacrylate
bone cement into the fractured vertebra.
Anecdotal reports with both techniques claim frequent
acute pain relief; however, neither technique has been
subjected to a controlled trial to demonstrate the benefits
over traditional medical management. Furthermore, the
long-term effect of one or more reinforced rigid vertebrae
on the risk of fracture of adjacent vertebrae is unknown
for both of these procedures.33
New and Experimental Therapies
Hip protection pads
Nonpharmacologic interventions directed at preventing
falls and reducing their effect on fractures have been
promising. These include studies to improve strength
and balance in the elderly, as well as using hip protectors
to absorb or deflect the impact of a fall.33
A large new study published in the New England Journal
of Medicine has shown that hip protectors prevent falls.17
This study was community-based and involved 1801 frail
elderly patients. Those assigned to the hip protector
group had half as many fractures. Of 1034 falls, only
4 hip fractures occurred while patients were wearing
the protectors. The brand of the hip protector used
in this study was KPH Hip Protector, from Helsinki,
Finland.6
Hip protection pads prevent osteoporotic hip fracture
in elderly women as long as they are wearing the pads
and are now available in the US under the brand name
"SafeHip".6
Growth Hormone
Growth hormone has been studied as a method of increasing
bone density in elderly persons. The results are mixed.
Biochemical markers of bone formation and resorption
increase, and in some cases bone density increases modestly.
Side effects are seen, however, which limit potential
use.6
Patients with adult-onset pituitary deficiency may have
osteoporosis. These patients also have hypogonadism,
which is known to decrease bone density. In these cases
growth hormone may improve bone density beyond that
seen with sex hormone replacement. Adults who had childhood
onset growth hormone deficiency do not necessarily have
osteoporosis. They have short stature, but the volumetric
density of the bone is normal. Thus, the physiological
role of growth hormone in maintaining adult bone density
is uncertain.6
Parathyroid Hormone
Parathyroid hormone (PTH) looks promising as a treatment
for osteoporosis. PTH peptides are the most promising
of the anabolic
agents, but are still in clinical trials33.
Several studies have been done which show substantial
increases in spinal bone density with PTH injections.
The bone density of the hip also increases, and data
shows reduction in fracture rates. These studies which
show benefit were all done in combination with estrogen,
which seems to protect the cortical bone from the ill
effects of PTH, although there might still be a little
increase in the cortical porosity.6
The role of PTH in control of bone mass is perplexing.
PTH stimulates osteoblastic activity, especially on
trabecular surfaces. In some cases this effect predominates
over the increased resorption, and osteosclerosis
results. Patients with either primary or secondary hyperparathyroidism
have increased bone density of the spine, but decreased
cortical bone mass. Iliac crest bone biopsies show increased
trabecular bone volume but cortical thickening. Patients
with osteoporosis treated with PTH show increases at
the spine but decreases at cortical sites. Recent studies
using a combination of PTH and estrogen in postmenopausal
women have shown increased bone density at both the
spine and the hip.6
Whether PTH will be used as direct therapy, or whether
one of the cytokines
released by PTH-stimulated stromal
cells or preosteoblasts will emerge as the treatment
of choice, is unknown. For now, the antiresorptive agents
continue to be the mainstay of drug therapy for osteoporosis.12
There is a critical need to develop and assess anabolic
agents that stimulate bone formation.33
Progesterone
Many medical practitioners do not differentiate between
progesterone
and progestin,
both of which fall into the category of progestogens.
The terms 'progesterone' and 'progestin' are often incorrectly
used interchangeably by both practitioners and scientists.
Studies involving natural progesterone are scarce. In
this document 'progesterone' will mean 'natural progesterone',
and 'progestin' will mean 'synthetic progesterone'.
Experimental, epidemiological, and clinical data has indicated
progesterone is active in bone metabolism. Critical
analysis of the reviewed data indicate that progesterone
meets the necessary criteria to play a causal role in
mineral metabolism. This review provides the preliminary
basis for further molecular, genetic, experimental,
and clinical investigation of the role(s) of progesterone
in bone
remodeling.37
Despite the fact that many articles and even some books
advocate progestin as an alternate to estrogen for building
bone, several studies have concluded that progestin
does not result in any additional benefits to the bone
in women who are taking estrogen, either premenopausal36,
16, 1 or postmenopausal 25, 6
The only currently accepted/proven reason to take progestins
is to protect the uterus from cancer. The form commonly
given in the USA is a progestin called medroxyprogesterone
(Provera), which can be given in cyclical or daily doses.
Both cyclical and daily dosing have been shown to result
in a risk of endometrial cancer that is lower than in
women taking "unopposed" estrogen, although after many
years there may still be a slight risk. A new form has
recently been approved, micronized progesterone (Prometrium)
also called natural progesterone. This comes in 100
mg tablets, and can be used cyclically at 200 mg/day
for 12 days a month or 100 mg/day daily. It may also
be compounded by compounding pharmacies as an oral capsule
or transdermal application.6
In one random clinical trial, progestin did cause increased
bone density at some skeletal sites in comparison to
placebo, but it did not add to estrogen therapy and
was definitely not as beneficial as estrogen. In young
women taking injectable medroxyprogesterone acetate
(Depo-provera)* for contraception, the bone density
is lower than in control women. This is a situation
where the high progestin clearly is NOT beneficial.
It has been shown that Depo-provera is associated with
lower bone density, especially in young women.6
* Medroxyprogesterone acetate (Depo-provera)
is a progestin (synthetic progestogen), not natural
progesterone.
New information suggests that progestins may increase
the risk of breast cancer and may make the breast tissue
denser. Given these facts, it is not clear what to recommend,
and there are few studies on natural progesterone. Certainly
breast cancer is much worse than endometrial cancer.
A hysterectomy almost always cures endometrial cancer.
Some physicians have recommended progestins for 2 weeks
every 6 months, which causes withdrawal bleeding and
no problems in a small study of 150 women. Willett (JAMA,
2000; 283:534) says "This approach seems logical, but
direct evidence is lacking." 6
In postmenopausal women initiating hormone replacement
therapy (HRT), dydrogesterone (a progestin) does not
contribute to the beneficial effects of HRT on the skeleton,
and in fact it may reduce the beneficial effects of
estrogen on bone resorption.43
The findings, which contradict some previous research,
come from a UK study led by Dr. Jonathan H. Tobias of
the Bristol Royal Infirmary in the UK. In a double-blind
protocol, his team randomized 26 women to receive 2
mg estradiol daily or 2 mg estradiol plus 10 mg dydrogesterone
daily for 8 weeks.43
When given alone, estrogen appeared to be associated with
significantly higher osteocalcin levels (a marker of
bone formation) and significantly reduced urinary deoxypyridinoline
excretion (a marker of bone resorption) compared with
combination therapy, the researchers report in the March
issue of the Journal of Clinical Endocrinology and
Metabolism.43
Tibolone, and Conjugated estrogens
and Norgestrel
Doctor's Guide reviews the outcome of a recent study as
reported in Menopause 2000;7:327–333
"Two Regimens May Prevent Osteoporosis: Tibolone as well
as conjugated oestrogens, plus sequential Norgestrel
significantly increase bone mineral density and should
prevent osteoporosis in postmenopausal women, a new
study confirms."
During the study, 50 women volunteered not to receive
treatment, 32 women received tibolone and 31 received
conjugated estrogens plus sequential norgestrel. The
authors measured bone mineral density at baseline as
well as after 48 and 96 weeks using dual photon absorptiometry.
After 96 weeks, women who received either tibolone or
conjugated estrogens plus sequential norgestrel showed
increased bone mineral density at all sites. The control
group showed reduced bone mineral density compared to
baseline.
The authors concluded that both tibolone and conjugated
estrogens plus sequential norgestrel significantly increase
bone mineral density in postmenopausal women. On the
other hand, bone mineral density declines in postmenopausal
women who opt not to be treated. The findings confirm
that both tibolone and conjugated estrogens plus sequential
norgestrel should prevent osteoporosis.48
Thiazide
Several large, prospective epidemiological studies in
elderly men and women have shown that thiazide use is
associated with a reduced risk of hip fracture. Several
possible mechanisms could explain this association.
Thiazides act directly on the distal nephron to enhance
calcium reabsorption. In men with hypercalciuria,
thiazides lower urine calcium and lead to positive calcium
balance. Thiazides may also reduce osteoclastic activity,
possibly by inhibiting carbonic anhydrase.6
One randomized study of treatment of systolic hypertension
included bone mass as a secondary endpoint in a subset
of patients. The subjects who took thiazide had increased
bone mass, whereas those on other forms of antihypertensive
medication showed decreases in bone mass. The effect
of thiazides on bone density in patients with normal
blood pressure has not been studied, but a randomized
trial is underway.6
Sodium Fluoride
From the 1950s through the 1980s, sodium fluoride, an
anabolic agent, was widely advocated as a treatment
that reduced fractures and improved radiographic defects.
One of the strongest proponents of this therapy was
the Mayo Clinic in Rochester, Minnesota. In the 1980s,
the National Institutes of Health funded 2 prospective,
controlled trials of fluoride therapy in postmenopausal
women. Trials were conducted at the Mayo Clinic and
the Henry Ford Hospital in Detroit.12
In these studies, fluoride treatment was found to increase
bone density values but did not reduce the rate of fractures.
On the contrary, the treated subjects experienced more
fractures, especially in the lower extremities, than
the placebo groups. The increased bone density values
were explained by the fact that the substitution of
fluoride in the hydroxyapatite crystal produces a denser
crystal called fluoroapatite. The surprising results
from these trials rang a death knell for fluoride therapy
in the United States, at least for daily doses of 75
mg or more.12
Another study found that fluoride definitely increased
the bone formation rate as well as the bone density,
however, osteomalacia still resulted. In a large well-designed
randomized, blinded clinical trial, women who used fluoride
for four years had increased fracture rates compared
to placebo controls. The bone density of the spine increased
by 32%, but the hip did not show increased density and
the rate of hip fractures was nearly three times as
high in the fluoride group. After this study was published,
investigators wondered if even lower doses of fluoride
might reduce fracture risk. A relatively small study
of low-dose, slow-release fluoride has suggested a reduction
in fracture risk, but many of the subjects had not taken
the fluoride for more than two years. There was no osteomalacia
seen in those subjects who had bone biopsies. However,
another group measured the mechanical strength of bone
in patients receiving low dose fluoride for five years,
and found it was significantly more fragile than bone
from control patients.6
At this time fluoride cannot be recommended for clinical
use, but because it is one of the few medications that
can enhance osteoblast activity, it deserves further
research.6
References 
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