|
Osteoporosis: Therapies
researched and written by the ProjectAWARE group, 2001
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
| NOTE: When you click on
a word in blue, a definition of the term will open in a new window. |
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. Results from the WHI (Women's Health Initiative)
have validated smaller studies that 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
| |
|
Clarification:
The
terms "progesterone" and "progestin" are often
used interchangeably. Many medical practitioners and scientists
do not differentiate between progesterone and progestin, both of
which fall into the category of progestogens. However, there are
differences both in chemical structure and effect. For clarity and
accuracy, ProjectAWARE feels it’s important to distinguish
these differences. Therefore, throughout this site, "progesterone"
means the endogenous hormone produced in the ovaries; "natural
progesterone" refers to bio-identical hormone products known
as micronized progesterone or natural micronized progesterone; and
"progestin" refers to any of the synthetic progestogens
with altered chemical structures that have progesterone-like actions
in the uterus.
|
| |
|
|
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.
Another form has been approved, micronized progesterone (Prometrium) also
called natural progesterone. This comes in 100 mg tablets, and can be
used cyclically at 200mg/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
Next: Improving
& Maintaining Bone Health 
|
