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Osteoporosis
is epidemic in the United States, presently affecting more than 20 million
individuals ~ The increase in osteoporotic fractures in the developed world is
partly due to an increase in the elderly population, but not totally. This is a
major global public health problem A comparison of bone densities in proximal
femur bones in specimens from a period of over 200 years suggested that women
lose more bone today, perhaps due to less physical activity and less parity.79
Other contributing factors include a dietary decrease in dairy products and an
earlier and greater loss of bone because of the impact of smoking. Osteoporosis
is characterized by microarchitectural deterioration of bone tissue, leading to
enhanced bone fragility and a consequent increase in the risk of fractures. The
skeleton consists of two bone types Cortical bone is responsible for 80% of
total bone, while trabecular bone, the bone of the spinal column, constitutes a
honeycomb structure providing greater surface area per unit volume The onset of
spinal bone loss begins in the 20s, but the overall change is small until
menopause. Bone density in the femur peaks in the mid to late 20s and begins to
decrease around age 30. In general, trabecular bone resorption and formation
occur four to eight times as fast as cortical bone. Beyond age 40, resorption
begins to exceed formation by about 0.5% per year. This adverse relationship
accelerates after menopause and up to 5% of trabecular bone and 1—1.5% of
total bone mass loss will occur per year after menopause. This accelerated loss
will continue for 10—15 years, after which bone loss is considerably
diminished but continues as the aging-related loss. For the first 20 years
following cessation of menses, menopause related bone loss results in a 50%
reduction in trabecular bone and a 30% reduction in cortical bone. The process
is slower in blacks. The
change in trabecular bone in postmenopausal women is attributed to estrogen
deficiency; 75% or more of the bone loss that occurs in women during the first
15 years after menopause is attributable to estrogen deficiency rather than to
aging itself. A study of the premenopausal daughters of women with osteoporosis
revealed a reduction in bone mass, suggesting either a genetic influence or the
sharing of a lifestyle which produces a relatively low peak bone mass. The
subsequent risk of fracture from osteoporosis will depend upon bone mass at the
time of menopause and the rate of bone loss following menopause. In general,
bone mass is increased in black and obese women and decreased in white, Asian,
thin and sedentary women. Vertebral bone is especially vulnerable, with a bone
density threshold for fracture only slightly below the lower limit of normal for
premenopausal women. It is no surprise that vertebral fractures account for 50%
of all fractures. Indeed 25% of individuals over 70 years of age show
radiographic evidence of these crush type fractures that lead to dorsal kyphosis
(dowager’s hump). The average non-treated postmenopausal white woman can
expect to shrink 2.5 inches (6.4 cm). Hip
fractures begin to occur in the 10—15 years following menopause such that by
age 90, 20% of all white women will have developed hip fractures, of which
one-sixth will be fatal within three months. Hip fractures alone occur in about
250,000 women per year in the U.S. with a mortality of 40,000 annually and an
associated cost of billions of dollars. In addition, the survivors are
frequently severely disabled and may become permanent invalids. Estrogen
therapy will stabilize the process of osteoporosis or prevent it from occurring.
The critical blood level of estradiol that is necessary to maintain bone is
40—5Opg/ml (150—l8Opmol/L). With estrogen therapy one can expect a 50—60%
decrease in fractures of the arm and hip, and when estrogen is supplemented with
calcium, an 80% reduction in vertebral compression fractures can be observed.
This reduction is seen primarily in patients who have taken estrogen for more
than 5 years. If bone loss can be delayed with estrogen therapy for 8 years,
fracture incidence can be reduced by 75%. The
positive impact of hormone therapy on bone has been demonstrated to take place
even in women over age 65. This is a strong argument in favor of treating very
old women who have never been on estrogen. Estrogen use between the ages of 65
and 74 has been documented to protect against fractures. However, protection
against fractures wanes with age, and long-term estrogen use is necessary to
reduce the risk of fracture after age 75. Studies have demonstrated that a dose of 0.625 mg of conjugated estrogens is necessary to preserve bone density. A lower dose of 0.3 mg daily of conjugated estrogens or 0.5 mg estradiol prevented loss of vertebral trabecular bone when combined with calcium supplementation (to achieve a total intake of 1,500 mg daily). A study of women randomized to treatment either with continuous transdermal delivery of estradiol 50 mg of oral estrogen demonstrated that both equally prevented postmenopausal bone loss. 5 The positive impact of estrogen increases with increasing dose; thus, whether fracture protection with either the lower oral dose regimens or via a transdermal route of administration is equal to the standard oral program awaits further epidemiologic study. Furthermore, some decrease in cardiovascular protection occurs with the use of lower doses of estrogen. The
precise mechanism of action for sex steroid protection of bones remains unknown,
however a growing body of knowledge indicates complex interactions at the
molecular level. Increased efficiency of calcium absorption (probably secondary
to estrogen induced enhancement of the availability of the active metabolite of
vitamin D,1,25-dihydroxyvitamin D) and a direct role for the estrogen receptors
in the osteoblasts are likely important factors Many estrogen-dependent growth
factors and cytokines are involved in bone remodeling. Estrogen modulates the
production of bone resorbing cytokines such as interleukin-1 and -6, bone
stimulating factors such as insulin-like growth factors I and IT, and
transforming growth factor. Estrogen also promotes the synthesis of calcitonin
(which inhibits bone resorption). Estrogen increases vitamin D receptors in
osteoblasts, and this may be a method by which estrogen modulates
1,25dihydroxyvitamin D activity in bone. While
progestational agents arc considered anti estrogenic, they have been known to
act independently, in a manner similar to estrogen, to reduce bone resorption
However, this effect may be limited to cortical bone. When added to estrogen,
progestins actually lead to a synergistic increase in bone formation associated
with a positive balance of calcium. The daily, continuous combination of
estrogen-progestin is equally efficacious in maintaining bone density as the
standard sequential regimens. There
has been considerable confusion over whether calcium supplementation by itself
can offer protection against postmenopausal osteoporosis This is partly due to
the fact that calcium studies have been performed in women who were in the very
early postmenopausal years, in the midst of the rapid loss of calcium associated
with estrogen deficiency Studies that involve women beyond this early stage of
the postmenopausal period definitely indicate a positive impact of calcium
supplementation. Calcium
absorption decreases with age and becomes significantly impaired after menopause
A positive calcium balance is mandatory to achieve adequate prevention against
osteoporosis Calcium supplementation (1,000 mg per day) reduces bone loss and
decreases fractures, especially in individuals with low daily intakes 05
However, estrogen acts to improve calcium absorption and makes it possible to
utilize effective supplemental calcium in lower doses In order to remain in zero
calcium balance, women on estrogen therapy require a total of 1,000 mg elemental
calcium per day. Since the average woman receives only 500 mg of calcium in her
diet, the minimal daily supplement equals an additional 500 mg Women not on
estrogen require a daily supplement of at least 1,000 mg calcium Even with the
commonly used therapeutic doses of calcium, nearly 40% of postmenopausal women
will have inefficient absorption. 08 Therefore estrogen improves calcium
absorption and makes it possible to utilize supplemental calcium in effective
doses without the side effects associated with higher doses (constipation and
flatulence) that diminish compliance Nevertheless, the calcium supplementation
should be administered in divided doses with meals. We must emphasize that
although calcium supplementation is important, it cannot provide the same degree
of protection against osteoporosis as that achieved by hormonal therapy. The
addition of vitamin D or its active metabolite in some studies has no impact on
the osteoporosis fracture rate and may cause hypercalcemia and renal stone
formation. However, elderly people
in nursing homes are usually deficient in vitamin D, and it is now recommended
that individuals over age 70 should add 800 units of vitamin D to calcium
supplementation. A large randomized trial in Finland has documented a reduced
rate of fractures in elderly women receiving supplementation of vitamin D (by an
annual intramuscular injection), and in France, supplementation of calcium and
vitamin D reduced the number of hip fractures by 43%. Because adequate vitamin D
depends upon cutaneous generation mediated by sun exposure, women who live in
cloudy areas during the winter months are relatively vitamin D deficient and
lose bone 113 Vitamin D supplementation is recommended for these women as well
but at a lower level, 400 units daily. If uncertain regarding vitamin D
supplementation, the serum level of the active metabolite, 1,25-dihydroxyvitamin
D, can be measured; the normal range is 19—57 mg/L (45—140 pmol/L). The
addition of fluoride, a potent stimulator of bone formation, does offer some
benefit but with a high rate of side effects (which may be greatly reduced with
slow release preparations) A further concern is that this therapy may lead to
more brittle bones subject to fracture. Calcitonin will act to prevent bone resorption and eventually might be used in patients for whom hormone therapy is contraindicated Given by injection in a dose of 100 IU daily to women early after menopause it has the same effectiveness as estrogen in conserving bone density.1 5 Studies with intranasal delivery of calcitonin (200 IU daily) suggest it may be similarly effective. Etidronate
disodium is an oral biphosphonate compound known to reduce bone resorption
through the inhibition of osteoclastic activity. In postmenopausal women with
osteoporosis randomized to intermittent cyclical etidronate (400 mg daily for 2
weeks followed by a 12-week drug free interval during which 1500 mg/day of
calcium is administered) or placebo, a significant increase in vertebral bone
mineral content and a significant decrease in fracture rate was observed in the
treatment group. Newer
biphosphonate are more active than etidronate Alendronate
given in various doses to postmenopausal women for only 6 weeks increased bone
density with a lack of side effects. Biphosphates may prove to be an effective addition to
osteoporotic prevention because they are well tolerated and have no discernible
side effects. However, unlike estrogens,
biphosphonates have no effect on
cardiovascular disease, hot flushes, or the atrophic changes seen in menopause.
At the present time further studies must be performed to evaluate the efficacy
and value of
biphosphonates for prevention of osteoporosis. Lifestyle
can have a beneficial effect on bone density. Physical activity (weight
bearing), as little as 30 minutes a day for 3 days a week, will increase the
mineral content of bone in older women. The exercise need not be extreme.
Walking 1.5 miles and ordinary calisthenics will suffice. The impact of exercise
on bone is significantly less; however, than that achieved by hormone therapy.
Women require the full combination of hormone therapy, calcium supplementation,
and exercise in order to fully minimize the risk of fractures. Adverse
habits such as cigarette smoking or excessive alcohol consumption are associated
with an increased risk of osteoporosis The lower blood levels of estrogen in
smokers have been correlated with an earlier menopause and a reduced bone
density, and therefore estrogen therapy will not totally counteract the
predisposition of smoking toward osteoporosis. The titration of estrogen dosage
with circulating blood estradiol levels in smokers makes clinical sense,
allowing the use of higher hormonal doses to maintain bone density Clinicians
should always remember that exposure to excessive thyroid and glucocorticoid
hormones is associated with osteoporosis and an increased rate of fractures. The
protection of estrogen is maintained only while women are maintained on the
hormone. In the 3 to 5 year period following loss of estrogen, whether after
menopause or after cessation of estrogen therapy, there is an accelerated loss
of bone. For the greatest impact on the risk of fractures, it is vital that
hormone therapy be initiated as close to the menopause as possible, and it must
be maintained long-term, if not life long. Patients
with osteoporosis or with a history of osteoporotic fracture should be treated
more vigorously. While hormone therapy will significantly increase bone mass,
agents such as fluoride, calcitonin and perhaps etidronate should also be
considered. Patients
with osteoporosis should be screened for other conditions that lead to
osteoporosis: 1.
Serum parathyroid hormone, calcium, phosphorus, and alkaline phosphatase;
for primary hyperparathyroidism. 2.
Renal function tests for secondary hyperparathyroidism with chronic renal
failure. 3
Blood count and smear, sedimentation rate, protein electrophoresis for multiple
myeloma, leukemia, or lymphoma. 4.
Thyroid function tests; for hyperthyroidism. 5.
Careful history and, when indicated, appropriate laboratory studies to
rule out hypercortisolism, alcohol abuse, and metastatic cancer. Measuring Bone Density There
is a 50—100% increase in fracture risk for each standard deviation decline in
bone mass. Measurement of lower bone mass in the hip is even more predictive; a
one standard deviation is associated with nearly a 3-fold increase in risk of
fracture. This impressive correlation between fracture risk and bone density has
raised the question whether it is of value to screen for osteoporosis. It is not
cost-effective to attempt to screen all postmenopausal women, especially since
hormonal treatment is advised for nearly all However, bone density measurements
are useful when an individual woman requires the information in order to make an
informed decision regarding hormone therapy. Indeed, better compliance with a
hormone program is correlated with patient’s knowledge of an increased risk of
fracture because smokers have lower estrogen levels on estrogen therapy, it
might he worthwhile to document the impact of treatment on bon density in order
to consider whether dosage is adequate. Patients who have receive long-term
corticosteroid or thyroxine treatment deserve bone mass assessment. There
are a percentage of postmenopausal women on hormone therapy (about 10—20%) who
continue to lose bone. It is likely that this reflects poor compliance, and
consideration should be given to an occasional measurement of bone density as an
effective method of assessment and to motivate compliance. Summary
of Reasons to Measure Bone Mass 1.
To help patients to make decisions regarding hormone therapy. 2.
To assess response to therapy in selected patients, e.g., smokers. 3.
To confirm the diagnosis and assess the severity of osteoporosis to aid
in treatment decisions. Standard
x-rays do not provide an early assessment of fracture risk; 30—40% of bone
must be lost before radiographic changes become apparent. Photon absorptiometry
measures the transmission of photons through bone. Single photon absorptiometry
uses an 125J source of energy or, more recently, miniature x-ray tubes. This
method measures bone density of the radius and the calcaneus. These measurements
correlate with vertebral bone density but not very accurately. Dual energy
absorptiometry employs photons from two energy sources Dual energy x-ray
absorptiometry (DEXA) provides good precision for all sites of osteoporotic
fractures Whole body scans by DEXA can measure total body calcium, lean body
mass, and fat mass Quantitative computed tomography for bone density
measurements can be performed on most commercial computed tomography (CT)
systems; however, radiation exposure is higher than with DEXA, and measurements
of the femur are not available. The most accurate information is provided by the
DEXA technique, measuring the three sites of greatest interest, the radius, the
hip, and the spine Serial measurements are usually at least one year apart. Prevention of Osteoporosis The risk of osteoporosis is significantly influenced by the amount of bone accumulation during growth and maturation, followed by the rate of bone loss thereafter The preventive health efforts of clinicians should be directed to those factors that influence accumulation and loss of bone throughout life 26 Improved calcium intake in adolescents results in significant increases in bone density and skeletal mass, providing protection against osteoporosis later in life 127 As always, counseling should be provided regarding diet, exercise, avoidance of smoking and alcohol abuse, and maintenance of normal menstrual function The primary care clinician should always keep in mind the necessity to monitor thyroid hormone dosage with periodic measurements of thyroid stimulating hormone (TSH). Postmenopausal women receiving long-term treatment with corticosteroids should be urged to use estrogen-progestin therapy and calcium supplementation. From:
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