Osteoporosis is defined as a progressive systemic skeletal
disorder characterized by low bone mineral density (BMD),
deterioration of the microarchitecture of bone tissue, and
susceptibility to fracture. A recent consensus conference defined
osteoporosis as "a skeletal disorder characterized by compromised
bone strength predisposing to an increased risk of fracture."
In 1994 The World Health Organization (WHO) proposed a clinical
definition of osteoporosis based on measurements of BMD. According
to the WHO definition, a patient is osteoporotic based on a BMD
measurement that is 2.5 standard deviations (SDs) below typical peak
bone mass of young healthy white women. This measurement of standard
deviation from peak mass is called the T score.
Assigning the T score permits the early detection of
osteoporosis, and thus, lowers the risk of either hip or spine
fractures. However, the use of T scores at different sites and with
different techniques has been controversial because intersite and
intermodality correlation has been poor. The WHO had not established
standards for osteoporosis in men, children, and persons of ethnic
groups.
Types of osteoporosis
Osteoporosis can be subdivided into 3 types: (1) involutional, or
primary, osteoporosis in which no underlying cause can be
identified; (2) secondary osteoporosis in which the underlying cause
(eg, steroid use) is known; and (3) rare forms of the disease, such
as juvenile, pregnancy-related, and postpartum osteoporosis.
Involutional osteoporosis develops from excessive age-related
bone loss. Most consider that this phenotype is an excessive
expression of normal age-related changes in bone.
Risk factors
Age and menopause are the 2 main determinants in osteoporosis.
Other risk factors include a family and/or personal history of
fracture, estrogen deficiency, alcoholism, and a sedentary
lifestyle.
Complications and costs
Typically, osteoporotic fractures affect the vertebral body,
distal radius, and proximal femur. Osteoporotic fractures happen as
a consequence of minimal injury. A major complication is a fracture
of the femoral neck. About 20-30% of patients who have a femur neck
fracture die in the year following the fracture. Half of the
survivors remain disabled to some degree.
Osteoporosis causes considerable economic and social costs and
increased morbidity and mortality rates as a result of bone
fragility and fractures. Direct financial expenditures for the
management of osteoporotic fractures are estimated to be $10-15
billion annually.
Pathophysiology:
Pathogenesis
The pathogenesis of osteoporosis is multifactorial. Two types of
osteoporosis can be distinguished in aging women: (1) postmenopausal
osteoporosis and (2) age-related osteoporosis.
Postmenopausal osteoporosis affects women who are postmenopausal
but younger than 70 years. These women are said to have type I, or
postmenopausal, osteoporosis if excessive bone loss that meets WHO
criteria occurs within 15-20 years after menopause. Type I
osteoporosis is characterized by increased bone resorption due to
osteoclastic activity and is generally believed to be related to
estrogen deficiency. Vertebral crush fractures and fractures of the
distal radius (Colles fractures) are the main complications.
Age-related osteoporosis, also called senile or type II
osteoporosis, occurs when there is excessive bone loss manifested
after age 70 years in both women and men. Type II osteoporosis
results from normal aging and is associated with a steady, 1-2% loss
of cortical and trabecular bone mass each year. Age-related bone
loss begins at age 35-40 years when the balance shifts to favor
resorption and the skeleton begins to lose bone mass. Hip and
vertebral fractures are most common in this type of osteoporosis.
Risk factors for osteoporotic fractures
Risk factors for osteoporotic fractures include female sex,
advanced age, low calcium intake, genetic factors, smoking, alcohol
abuse, low BMD, low body weight, recurrent falls, personal history
of fracture, race or ethnic background, and inadequate physical
activity.
Female sex
Menopause occurs approximately at age 51-52 years (range, 42-60
y). Following menopause, levels of circulating estradiol and estrone
significantly decrease by around 25% and 75%, respectively.
There is controversy regarding the basic mechanisms underlying
the induction of high bone turnover after menopause. Several
theories stand out. Direct action of estradiol on osteoclasts has
been shown only for avian osteoclasts, but this mechanism remains a
clear favorite. Bone resorption is the unique function of the
osteoclast. In the avian model, estradiol decreases the development
and activity of osteoclasts and increases the activity of
osteoblasts directly. Estrogen deficiency induces increased
generation and activity of osteoclasts, which perforate bone
trabeculae, reducing their strength and increasing fracture risk.
The life span of functional osteoclasts and thus the amount of bone
that osteoclasts resorbed may also be enhanced following estrogen
deficiency.
Estrogen may affect osteoclast function by promoting apoptosis.
It has been shown that 17beta-estradiol promotes apoptosis of murine
osteoclasts in vitro and in vivo by 2-3 times. This suggests that
estrogen may prevent excessive bone loss before and after the
menopause by limiting the life span of osteoclasts.
Recently, estrogen has also been shown to regulate secretion of
osteoprotegerin, an inhibitor of osteoclast differentiation.
Most of the estriol present in the circulation after menopause
represents the extraendocrine conversion of androgen precursors in
muscle and adipose tissue to estriol. This conversion in adipose
tissue may explain why obese patients are relatively protected
against osteoporosis and fractures compared with asthenic
individuals.
Women undergoing early menopause or oophorectomy have accelerated
bone loss and a higher incidence of fractures. Amenorrhea also
predisposes women to osteoporosis. Those experiencing early
menopause usually have prolonged periods of oligomenorrhea, a trait
that has a strong genetic predisposition. Thus, these patients have
repeat periods of increased bone loss and low bone mass.
Early and late estrogen deficiency probably affects bone mass by
means of different mechanisms. Early estrogen deficiency, ie, that
occurring before age 25 years when patients attain peak bone mass,
probably affects bone maturation and formation during bone modeling.
This leads to a thinner and a more slender skeleton. Early estrogen
deficiency occurs in Turner syndrome, hyperprolactinemic amenorrhea,
and amenorrhea among athletes. By contrast, normal menopause and
late estrogen deficiency (eg, that following oophorectomy) induces a
state of accelerated bone loss from increased osteon activation
frequency. Recent work has also demonstrated increased cellular
sensitivity to parathormone (PTH) in patients with osteoporosis.
Advanced age
Bone mass peaks at age 25 years. Thereafter, the bone mass in
both sexes remains stable until age 45-55 years, when accelerated
bone loss ensues in women and a more gradual loss commences in men.
The accelerated bone loss in women causes the loss of 25-30% of
skeletal mass over 5-10 years, followed by a slower phase with
stable loss rates of 0.5-1% per year. Males do not have an
accelerated bone loss, but rather, a stable loss rate.
Recent studies suggest that both sexes undergo a late phase of
accelerated bone loss in old age. The mechanisms by which bone loss
occurs after age 35 years are poorly understood, but several factors
related to age-dependent changes in skeletal and calcium homeostasis
have been implicated; these include estrogen deficiency, reduced
osteoprotegerin levels, reduced calcium and vitamin D intake,
impaired calcium and vitamin D absorption, increased interleukin-1
and interleukin-6 levels, tumor necrosis factor-alpha, increased
bone resorption and turnover, impaired osteoblast function,
decreased insulin-like growth factor secretion, decreased
transforming growth factor–beta secretion, and reduced core-binding
factor–1 levels.
Recent work has shown that in both males and females the effects
of estrogen deficiency on the rate of bone loss last throughout life
in both sexes. In males, the bone loss rate with increasing age is
also related to circulating estradiol levels.
Low calcium intake
Calcium is an essential mineral in maintaining nerve function,
muscle function, and bone mineralization, and it is involved in the
control of several intracellular processes. Physiologically, several
hormonal systems work to maintain calcium homeostasis. Vitamin D is
essential for the absorption of calcium from the gut. Calcium is
then transported via the blood to bone, where it is incorporated in
the bone matrix during calcification. During periods of calcium
deficiency from decreased intake or decreased absorption, bone acts
as a buffer, maintaining a constant level of calcium in the blood.
Calcium can be removed from bone either through transport over
the osteocyte-lining cell system, which is responsible for the rapid
regulation of serum calcium, or via the liberation from the bone
matrix through osteoclastic resorption. Calcium loss also occurs
through the gut, kidney, and skin. The kidney plays an important
role in calcium homeostasis by affecting PTH levels.
Adequate calcium intake is important to maintain normal calcium
homeostasis and to protect the bones from excessive calcium loss. If
calcium intake is low, mechanisms that increase secretion of PTH are
brought into play, resulting in a high-turnover state and possible
negative effects on bone mass. The minimum calcium intake necessary
to maintain skeletal health is difficult to define. Nutrition may
affect peak bone mass.
Matkovic et al compared incidence of femoral neck fractures in
people living in 2 geographically and dietetically separated valleys
in the area formerly known as Yugoslavia. They found a reduced
incidence of femoral neck fractures among individuals living in the
valley with the higher calcium intake. The difference is probably
attributable to differences in peak bone mass.
The impact that calcium has on developing and maintaining bone
mass varies throughout life. To reduce the risk of osteoporosis,
calcium intake should be highest during adolescence, pregnancy, and
old age.
Genetic factors
About 60% of a person's peak bone mass is genetically determined.
A woman whose mother has osteoporosis is more likely to have the
condition. The remaining 40% of one's peak bone mass is attributed
to dietary factors, physical activity, medication use, and
lifestyle.
Smoking
Smoking is an important risk factor for osteoporosis. Several
epidemiologic studies and a recent meta-analysis showed a
significant impact of smoking on bone mass, especially in older age
groups. However, 2 large-scale European studies did not show any
significant effect on osteoporotic fractures.
Smokers are known to experience menopause earlier than nonsmokers,
and because they are slimmer than nonsmokers, they have reduced
extraendocrine production of estrogens, as in adipose tissue.
Smokers may also have increased metabolic clearance rate of
estrogens. In addition, smoking may directly inhibit osteoblast
function.
Alcohol
Previous or present alcoholism is a risk factor for the
development of osteoporosis. Moreover, inebriation increases the
risk of falls and thus potentiates fractures. Alcohol affects
osteoblast proliferation in vitro and reduces matrix protein
synthesis in vivo. It exerts a direct toxic effect on other bone
cells as well. Even so, 2 large European studies showed no
significant effect of moderate alcohol consumption on osteoporotic
fracture risk in women.
Hormones
Bone remodeling is responsible for the replacement of old bone
with new. This process initiated by osteoclastic activity
responsible for the resorption of old bone. Bone resorption lasts
for 20-40 days and is followed by osteoblast formation of
unmineralized bone matrix, which subsequently mineralizes over the
next 100-150 days. Under physiologic conditions, homeostasis occurs
between bone resorption and bone formation. However, during
pathologic conditions, negative bone balance may occur.
Occasionally, positive balance can lead to the overproduction of
bone.
Calcium homeostasis is maintained through a complex interaction
between the parathyroid glands, skin, gut, and kidneys. In this
process, serum calcium levels are maintained within a narrow
physiologic range. Normally, a negative feedback loop involving PTH
and 1,25-dihydroxy vitamin D-3, or 1,25-(OH)2D3,
maintains body calcium levels despite large variations in the influx
and efflux of calcium from the body. A negative feedback loop also
exists between serum calcium and PTH to inhibit secretion of the
latter.
Renal parenchymal disease causes low levels of 1,25-(OH)2D3
resulting in compensatory hyperparathyroidism, which increases bone
resorption and bone turnover. While bone loss in early menopause is
mainly related to decreased endogenous estrogen production, bone
loss after age 65 years involves mechanisms more closely related to
disturbance of calcium homeostasis due to reduced vitamin D and
calcium intake.
With aging, calcium intake is reduced. Production of active
vitamin D in the skin is also decreased resulting in decreased
absorption of consumed calcium. Reduced calcium absorption may cause
secondary hyperparathyroidism, which in turn accelerates bone loss
through increased osteoclast activity and hence bone turnover.
Impaired osteoblast function, however, causes accelerated bone
loss. Like fibroblasts, osteoblasts undergo cellular aging with
increasing age. As a result, collagen matrix synthesis and secretion
of other osteotropic factors decrease. This leads to lower rates of
bone formation in the elderly. The main difference between
osteoporotic women and non-osteoporotic women is defective bone
formation. Osteoporotic women without fractures have significantly
thinner bone structural units compared with age-matched controls.
Genetic and hormonal factors besides aging may also contribute to
osteoblastic insufficiency.
Estrogens increase serum levels of 1,25-(OH)2D3. In
osteoporotic women, calcium absorption increases with calcitriol
supplementation. This effect has been considered one of the indirect
effects of estradiol, and it may explain the beneficial role of
estrogen supplementation in the prophylaxis against osteoporotic
fractures.
Low body weight
Body weight and rates of hip fracture are inversely related. In
the Framingham study, the relative risk of fracture was 0.63 in
individuals who were 114-123% overweight and 0.33 in individuals
more than 138% overweight. Obesity appears to protect the skeleton
in several ways: by increased the production of estrone in fatty
tissue, by improving vitamin D storage in fatty tissues, by exerting
a cushioning effect in association with falls, and by creating a
larger skeleton as a result of increased weight bearing.
Recurrent falls
Both falls and reduced skeletal resistance are important
determinants of fracture risk. The risk of falls increases
exponentially after age 40 years and is greater in women than in
men. Most falls that lead to fractures, especially age-related
fractures, occur from a standing height or shorter distance. Most
age-related fractures are associated with slips, trips, and drop
attacks. Such falls cause the majority of fractures of the distal
radius and a substantial proportion of hip fractures. Falls down
stairs are the major cause of vertebral fractures associated with
spinal cord injuries. Naturally, falls from heights are an important
but less common cause of fractures.
Preventing falls is important prophylaxis against osteoporotic
fractures. Predisposing factors, such as postural hypotension or
drowsiness due to drug use, should be detected and treated. If
necessary, patients should receive physiotherapy and walking aids to
improve their balance and righting reflexes.
Personal history of fracture
Lindsay and colleagues determined the incidence of recurrent
vertebral fractures in women receiving placebo in 4 large, 3-year
clinical trials to evaluate the efficacy of bisphosphonates for
treatment of postmenopausal osteoporosis. The cumulative incidence
of new vertebral fractures in the first year was 6.6%. Among women
who had an incident vertebral fracture, the incidence of another
vertebral fracture in the subsequent year was 19.2%. The presence of
a vertebral fracture at study baseline was associated with an
increased risk of another fracture.
Racial differences in peak BMD partly may account for racial
differences in the incidence of osteoporosis and fractures.
Populations of African origin have higher bone mass and lower rates
of fractures, as compared with white populations. BMD is greater in
adult blacks than in whites. Also, prepubertal BMD in the hip,
trochanter, and femoral neck is higher in black males than in white
males. Reduced thickness of the femoral neck and shaft cortex, a
wider intertrochanteric region, and a longer hip-axis length are
thought to contribute to the higher incidence of hip fracture among
white women. In comparison, women of African origin on average have
thicker cortical bone in the hip, a shorter hip-axis length, and
smaller intertrochanteric widths.
Although Asian women have lower bone mass than that of Caucasian
women, they have a lower rate of hip fractures. Several postulates
have been forwarded to explain this discrepancy, including a shorter
hip-axis length in the Asian women, higher activity levels in
childhood, and, the cultural practice of taking care of the elderly,
and the practice in which women are not allowed to leave their beds
(which reduces the opportunity for falling). Hispanic women tend to
have bone density equivalent to that of white women, but they have
one half as many fractures. This probably related to cultural
differences or possible may be related to the microarchitecture of
the bone itself.
There are major differences between BMD values in European
population samples, which, with variations in anthropometric
variables, have the potential to contribute substantially to
variations in rates of osteoporotic fracture risk. The highest rates
are in Scandinavian countries, likely secondary to reduced sun
exposure and hence less vitamin D formation.
Physical activity is essential for bone remodeling. The skeleton
needs continuous physical stimulation to maintain healthy bones,
otherwise bone loss ensues.
Osteoblast activity is sensitive to mechanical stresses.
Experiments of repetitive physical stress on bone have shown
profound increases in bone formation in stressed bone. Significant
bone loss occurs from immobilization or during space flight. Studies
have shown that physically active women have a higher bone mineral
content than women who are less active. Antigravity exercises, such
as dancing or running, seem to be more effective than swimming in
maintaining BMD. In vertebrae, the preferential loss of horizontal
trabeculae leads to compensatory thickening of vertical trabeculae.
The correction of tooth alignment exploits physical stress to create
changes in bone remodeling in the jaw.
The steady decrease in general physical activity in the
population is probably one of the factors responsible for the
increasing prevalence of osteoporosis over the last 10 years.
Several studies in perimenopausal women have shown increases in bone
mass between 5-7% over a 3-year period following the institution of
an exercise regimen compared with sedentary controls. Therefore, a
reasonable amount of physical activity throughout life may protect
individuals against bone loss.
It is unlikely that physical activity alone can offset the 30-40%
loss of bone occurring after menopause. In fact, a meta-analysis of
all controlled clinical trials showed no significant effects of
physical activity on bone mass. Further, long-term clinical trials
have shown no fracture protection from exercise. To the contrary,
one study showed an increased fracture risk in a population of older
women who walked for exercise.
Prolonged heavy exercise may have deleterious effects on bone
mass. Extremely high levels of physical activity in young women may
produce hypothalamic amenorrhea and hence estrogen deficiency.
Data suggest that hypogonadism is but one determinant of male
osteoporosis. In recent publications about male osteoporosis, only
12% of men had low s-testosterone levels. Other research has shown
that male estrogen deficiency may also be an important cause of male
osteoporosis. Low bone mass in men may be related to aromatase
deficiency, which normally converts testosterone to estradiol.
Currently, there is no agreed-upon standard intervention
threshold for BMD. A universally accepted threshold depends not only
on the interpretation of individual results but also on agreement
among manufacturers to use a single normal range. The WHO has made
some progress by defining osteoporosis with BMD measurements.
According to WHO definitions, women with bone mineral content or BMD
more than 2.5 SDs below the mean for healthy young white women are
osteoporotic. Though simple, this definition has several
limitations: It does not account for age, and it cannot be applied
to men. Furthermore this measurement is not universally applicable
among various techniques of measuring bone mass.
Age is of critical importance. For example, if the WHO BMD-based
definition is applied to women older than 80 years, 70% are in the
osteoporotic group. Most osteoporosis specialists would be hesitant
to treat 70% of women the women in this age group for osteoporosis.
This problem may be overcome by expressing the result in terms of
the age-matched normal value also known as a Z-score. This approach
is consistent with the convention of expressing the relative risk of
future fracture; that is, results are expressed as SDs above or
below the age-matched normal range or Z score.
Another drawback of using T scores is the fact the overall
prevalence of osteoporosis is higher if sites other than the hip are
measured. This suggests that osteoporosis occurs nonuniformly
throughout the skeleton. Therefore we should be measuring the site
of most clinical concern to estimate the risk of fracture.
Generally, current and future fracture risks are expressed by
using a combination of the WHO definition of osteoporosis and a Z
score.
The skeleton is made up of 2 types of bone: 80% is cortical bone,
and about 20% is trabecular bone. The cortical bone is compact in
appearance and makes up the external layer of bones. Cortical bone
predominates in the shafts of the long bones and in bones of the
appendicular skeleton. Trabecular bone forms a trusslike framework
within the medullary cavity of the bones. They are most prominent
where high degrees of compressive stress exist and so are very
prominent in the vertebral bodies, pelvis, and ends of long bones.
The ratio of trabecular to cortical bone varies considerably in
different in different skeletal sites and at different locations in
the same bone. Trabecular bone has a higher surface-to-volume ratio
than cortical bone and is thus potentially more sensitive to
alterations in the rate of bone turnover, a process that occurs on
the surface of bone.
Despite their seemingly static appearance, bones are
physiologically active and undergo a continuous process of
resorption and formation in discrete bone-remodeling units. About
10% of adult skeleton is remodeled each year. Remodeling with a
daily turnover of up to 1 g of calcium continues even after the
skeleton has fully matured. This turnover prevents fatigue damage
and is important for calcium homeostasis. Bone loss results from an
imbalance between bone resorption and bone formation.
Bone remodeling consists of 2 phases. The resorption phase to
remove old, dead, damaged, or underutilized bone is followed by a
formation phase that produces new bone. Involved in the remodeling
process are the cells of the bones: osteocytes, osteoblasts, and
osteoclasts. The osteocytes and osteoblasts are both uninucleated
cells of mesenchymal origin. In adults, osteoblasts are found most
abundantly along bone-forming surfaces. They have receptors for PTH
and an abundance of ribosomes involved in the synthesis of collagen
propeptides. These areas are also rich in collagenases, plasminogen
activator, and alkaline phosphatase. The serum level of bone
alkaline phosphatase mirrors new bone formation, whatever the
stimulus. Osteocytes are osteoblasts that become incorporated into
the bone matrix.
Osteoclasts are multinucleated cells found along the cortical
endosteal surface and trabeculae in the Howship lacunae where
mineralized bone is being actively resorbed. In women with
established osteoporosis, the total body bone mineral content is
typically as at least 30% lower than in healthy control subjects.
If the present estimates of the cancellous bone mass are correct,
a loss of one half the bone mass of cancellous bone yields a deficit
of only 10% of total bone mass. Thus, loss of cortical bone should
account for the majority of the bone loss in osteoporosis.
Unfortunately, lack of correlation between bone density measurements
at different skeletal sites in the same individual means that a
measurement at one site is not predictive of bone density at another
site. Because the strength of bone is related to its mineral
density, the risk of fracture can be predicted only by measuring
bone density at that particular site.
Symptoms of osteoporosis indicate advanced disease. Fractures of
the hip, spine, and wrist are most common. Kyphosis (dowager's hump)
results from collapse of several vertebral bodies. Skeletal back
pain may also be a symptom. Radiographs may show osteopenia. This
finding indicates that at least 30% of the bone mass has been lost.
Differential diagnoses
Endocrinologic diseases
Endocrinologic diseases include the following:
- Hypogonadism in men and women
- Cushing syndrome
- Corticosteroid-induced osteoporosis
- Hyperthyroidism
- Severe primary hyperparathyroidism
In patients with acromegaly, the effects of growth-hormone excess
on bone mass are controversial. Some studies show increased bone
mass, and some studies show reduced bone mass. The latter findings
may reflect accompanying hypogonadism, a frequent finding in
acromegaly. However, the data about bone mass and fractures in
diabetes, acromegaly and endometriosis are conflicting.
A rare form of osteoporosis occurs during pregnancy or shortly
after delivery. The presentation usually includes severe back pain
and multiple vertebral fractures. About 70% of cases occur in first
pregnancies, and recurrences are unusual. Most cases resolve
spontaneously, and bone mass increases after the termination of
breastfeeding. In many women, bone mass normalizes after 3 years.
Only a small number of patients are disabled for months or years.
Patients with osteoporosis of pregnancy are at increased risk for
postmenopausal osteoporosis.
Osteoporosis occurring late in pregnancy may be related to poor
diet or calcium and vitamin D deficiency, whereas cases occurring
during lactation seem to be related to excessive secretion of PTH-related
peptide, which is responsible for calcium transport in the breast
and for the mobilization of calcium from bone to milk.
Nutritional deficiencies
Nutritional deficiencies affect the skeleton by impairing the
supply of calcium and vitamin D, leading to secondary
hyperparathyroidism and osteomalacia. Such deficiencies can occur
after gastric resection and in patients with short-bowel syndrome.
In those with anorexia nervosa, nutritional deficiency is
exacerbated by amenorrhea.
Immobilization
Immobilization, either temporary or from permanent neurological
deficit may cause bone loss from disuse.
Medication use
Long-term corticosteroid use constitutes the most common form of
secondary osteoporosis in both men and women. Corticosteroids cause
impaired osteoblast function and changes in calcium homeostasis,
which lead to accelerated bone loss and fracture. In patients
treated with prednisolone doses exceeding 7.5 mg/d for more than 6
months, the prevalence of vertebral fracture is 30-50%.
Agonists of gonadotropin-releasing hormone reduce circulating
estrogen levels and thereby cause excessive bone loss. In
premenopausal women, tamoxifen and Raloxifene interfere with the
binding of estradiol to nuclear receptors and thereby impair the
cellular action of the hormone.
In vitro experiments have shown that heparin reduces osteoblastic
activity and decreases osteoblast adhesion to matrix proteins.
Long-term treatment with heparin is a known cause of osteoporosis.
Both aluminum and lithium interfere with intracellular signaling,
and aluminum also impairs osteoblast function and causes
osteomalacia. Antiepileptic drugs, especially phenytoin, have been
shown to interfere with vitamin D metabolism and to increase the
risk of osteoporotic fractures.
Juvenile osteoporosis
This type of osteoporosis affects children and is therefore
unlikely to be confused with Involutional osteoporosis. Juvenile
osteoporosis is characterized by the occurrence of primarily
vertebral and metaphyseal fractures that lead to back pain and
difficulty in walking. In most publications, boys are predominantly
affected, but most children recover fully.
The causes of secondary osteoporosis differ between men and
women. The relative contribution of secondary causes in men amount
to 50-65% of clinical cases compared with 20-30% in women.
Alcoholism and malignancies are more prevalent secondary causes in
men.
Preferred Examination:
Methods for BMD measurement
BMD is determined by measuring the amount of bone mineral
(calcium hydroxyapatite) per unit volume of bone tissue. X-rays or
gamma rays are often used to quantify BMD. In quantitative terms,
BMD is the amount of calcium hydroxyapatite, or Ca10(PO4)6(OH)2,
per unit volume of bone tissue examined.
Common methods conventional radiography, quantitative CT (QCT),
single-photon absorptiometry (SPA), dual-photon absorptiometry (DPA),
quantitative ultrasonography (QUS), and dual-energy X-ray
absorptiometry (DEXA).
Bone-density measurements can be performed by using X-ray
methods, such as DEXA, QCT, and ultrasonic methods. The most
accurate way to diagnosis osteoporosis is by measuring bone mass.
DEXA scans can be used to detect small changes in bone mass by
comparing the patient's bone density to that of healthy adults (T
score) and to age-matched adults (Z score).
A number of methods have been developed for the in vivo
determination of bone density in patients at risk of osteoporosis.
Two of the most frequently used methods are based on measuring the
attenuation of a beam of electromagnetic radiation or ultrasound
when it passes through the bone. Ultrasonic measurement of velocity
through the bone has also been used to determine bone density.
Currently, DEXA is the most accurate and recommended method for
BMD measurement. It is a sensitive technique and can detect changes
in bone density only 6-12 months after a previous measurement is
obtained. Density measurements of the spine or hip are used. The
procedure takes approximately 20-30 minutes. The radiation exposure
is low at approximately 2.5 mrem.
Bone biopsy may be useful in unusual forms of osteoporosis, such
as osteoporosis in young adults. Biopsy provides information about
the rate of bone turnover and the presence of secondary forms of
osteoporosis, such as myeloma and systemic mastocytosis. Patients
with a high turnover usually respond better to antiresorptive drugs
than other treatments. Bone turnover can also be evaluated by
estimating certain biochemical markers, such as osteocalcin and
deoxypyridinoline. Biochemical markers can be more useful than bone
density for monitoring treatment, as changes in bone density may not
be detected for 2 years.
Recommendations for BMD testing
The National Osteoporosis Foundation recommends bone density
testing for the following groups: women aged 65 or older,
postmenopausal women younger than 65 years who have at least 1
additional risk factor, all postmenopausal women with a new
fracture, and all women who have used estrogen replacement therapy
for several years.
The National Osteoporosis Society Advisory Committee in the UK
recommends bone density measurements for the following groups:
menopausal woman in whom the decision to use HRT could be affected
by other results; those with osteopenia (or low bone density), as
reported by a radiologist examining spinal radiographs; patients
taking prednisolone (more than 5 mg/d for more than 6 mo); patients
with disease known to cause osteoporosis; and select patients in
whom the response to treatment should be monitored.
Limitations of Techniques: Plain radiography is
widely available but not preferred because it is not suitable for
the early detection of osteoporosis. Changes on plain radiographs
can be seen only after an approximately 30% of the bone is lost.
However, plain radiographs are useful to rule out osteoporotic
fractures and other pathology, such as myeloma. Radiation exposure
for an average radiograph is approximately 50 mrem.
Osteoporototic femur
X-RAY
Findings:
Radiographic study
Conventional radiographs are relatively insensitive for
demonstrating osteoporosis. At least 30% of the bone mass must be
lost before it is recognized. At this stage, the radiographic
changes of generalized osteoporosis are more prominent in the axial
skeleton than elsewhere.
In the spine, the accentuated primary trabecular pattern produces
a vertically striated appearance in the vertebral bodies. Likewise,
the loss of trabecular mass causes accentuation of the cortical
outline, which is described as picture framing of the
vertebral bodies. The vertebral bodies may develop a biconcave shape
or compression fractures. In tubular bones, the loss of trabecular
bone may cause the metaphyses to appear radiolucent. Pathologic
fractures may occur at multiple sites.
In the tubular bones, bone resorption may be distinguished in 3
sites: endosteal envelope, intracortical [haversian] envelope, and
periosteal envelope. These changes are best depicted with
magnification radiography and quantitated with radiogrametry.
Other radiographic manifestations of osteoporosis include the
following:
- Involvement of the lower dorsal and lumbar spine, proximal
humerus, femoral neck, and ribs (These sites are most commonly
affected.)
-
-
- Increased radiolucency of bones
- Decreased number and increased thickness of trabeculae
- Cortical thinning
- Juxta-articular osteopenia with trabecular prominence
- Bone bars (reinforcement lines)
- Insufficiency fractures
- Vertebral wedge fractures, fish vertebrae, Schmorl nodes, and
decreased heights of vertebrae and accentuation of the cortical
outlines (also called picture framing)
-
- Absence of osteophytes
- Compression deformities associated with protrusion of
intervertebral disks and prominence of end plates
- Vertical vertebral striations due to marked thinning of the
transverse trabeculae with relative prominence of vertical
trabeculae.
Singh index
Plain radiographs of trabecular bone show a distinct pattern.
Osteoporosis results in characteristic changes in this pattern and
distinctive differences in the appearance of healthy bone and
osteoporotic bone. To underline the usefulness of this pattern in
osteoporosis, the Singh Index grading system was devised in the
1960s by using radiographs of the proximal femur. The Singh index is
used to assess patterns of trabecular loss. Although of historical
interest, it is no longer used in the United States.
Radiographic absorptiometry
Absorptiometry is a semiquantitative method of determining BMD.
Radiographic absorptiometry is used for peripheral body sites with
little overlying soft tissue, such as the hand. The extremity is
radiographed simultaneously with an aluminum step wedge, and a
densitometer is subsequently used to compare the density of the
bones with that of the step wedge. Computer-assisted analysis of
paired images obtained at slightly different exposures has led to
more accurate results.
SPA study
SPA was established in 1963 for the bone densitometric evaluation
of the appendicular skeleton. SPA uses a single-energy source of
gamma rays (iodine 125; photon energy, 27.3 keV) or Am-241 (60 keV)
to produce a collimated pencil beam, which is tracked across the
measurement site. The half-life of 125I is approximately
60 days, resulting in a useful life of around 6 months. The
transmitted photons are counted by using a sodium iodide
crystal/photomultiplier for each point along the track.
Because of the low photon flux and energy source, the technique
is usually applied to a peripheral skeletal site, such as the
forearm and, less commonly, the heel. The forearm chosen is the
nondependent arm. To allow correction for soft tissues, the forearm
must be placed in a water bath. The mean photon count through the
water bath without the interposed limb is used as a baseline value.
A reduction in the photon count below this baseline is assumed to be
due to the bone. Muscles of the forearm have attenuation effect
similar to that of water. The effects of a varying muscle mass are
thus eliminated by the water bath.
SXA study
SXA is the X-ray–based equivalent of SPA and uses a filtered
X-ray spectrum (55 KeV, 300 mA) with
k-edge filtration and solid-state detectors. As with SPA, the arm to
be measured must be placed in a water bath to allow correction for
the overlying soft tissues The source and counter move together over
the body part being examined, creating an image.
The X-ray–based equivalent of this method, SXA, has been used
only with the radius and calcaneus. The area of interest is
positioned in tissue-equivalent material to produce uniform
soft-tissue uptake that can then be subtracted from the image for
the calculation of bone density. The distal radius is the most
sensitive region for measuring bone density in most disease
processes because this site reflects the high turnover of trabecular
bone.
The difference in photon absorption between bone and soft tissue
allows the calculation of the total bone mineral content in the
scanning path. Bone mineral content is expressed as grams of bone
mineral per square centimeter imaged.
DPA study
DPA is an extension of the SPA principle that was developed to
compensate for errors in SPA bone-mass measurements due to the
varying composition and thickness of surrounding soft tissues. This
deficiency of SPA was overcome by using 2 distinct photon energies,
usually gadolinium 153. Photons of different energy are
differentially attenuated by bone and soft tissues. Therefore, their
absorption by bone, and hence bone density, can be calculated by
measuring the percentage of each transmitted beam and then by
applying simple simultaneous equations. The source of photons is
153Ga, which emits photons of 2 discrete energies (44 and
100 keV). The scanning approach is similar to that of SPA.
DEXA study
DEXA is very much like DPA except that the radionuclide source is
replaced by an X-ray source. The spectrum is heavily filtered with
different filters, giving a spectrum with 2 narrow distributions of
photons that simulate the spectrum from the radionuclide source.
This technique eliminates the need to constantly subtract the
soft-tissue thickness as in single-photon measurements; therefore,
DEXA permits measurement of the spine and hip.
A deficiency of this method, in the conventional AP projection of
the spine, is that the posterior elements, which consist of cortical
bone, are included in the result. The mechanical strength of the
vertebrae is mainly dependent on the amount of trabecular bone in
the vertebral body. Despite this drawback, the low radiation dose,
speed of examination, and low cost have made it popular as a
clinical screen for osteoporosis.
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A T-SCORE is the number of standard deviations the bone mineral
density measurement is above or below the YOUNG-NORMAL MEAN bone
mineral density.
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A Z-SCORE is the number of standard deviations the measurement is
above or below the AGE-MATCHED MEAN bone mineral density.
The T- and Z-scores were developed because of variation in BMD
measurement technology among different manufacturers. Therefore, the
BMD results are expressed as standard deviations from a comparison
to the referent mean.
Copyright Osteoporosis International (Used with
permission) (1)
T-scores are commonly used to define osteoporosis/osteopenia.
A BMD more than 2.5 standard deviations below the mean for a young
healthy adult white woman identifies 30 percent of all
postmenopausal women as having osteoporosis; half of these women
will already have had a fracture. The hip T-score is the site used
in clinical decisions.
Z-score is less commonly used but may be helpful in
identifying persons who should undergo a work-up for secondary
causes of osteoporosis. A Z-score changes over time in relation
to the T-score.
The following shows how one might interconvert T- and Z-scores.
Converting T-score to Z-score at the hip:
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Age 50: T = Z - 0.37
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Age 60: T = Z - 1.01
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Age 70: T = Z - 1.56
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Age 80: T = Z - 2.11
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Age 90: T = Z - 2.52
Degree of Confidence:
Radiographic study
The Singh Index grading system has always been considered too
variable for diagnosis or epidemiologic studies. However, recent
advances in image processing techniques have shown its promise as a
method that can overcome the limitations of observer grading.
Despite the growing body of evidence that such techniques may be
useful, results so far are inconclusive but near to providing a tool
for the study of osteoporosis.
SPA study
Although both SPA and DPA were widely used and although provide
valuable research data, the radionuclide source is a disadvantage.
The energy source is subject to decay and must be replaced
regularly. The low photon flux can cause the scanning times to be
long (up to 40 min), and spatial resolution tends to be poor. SPA
machines repeatedly scanned in a single line and were limited
(because of the physics of their operating principle) to measuring
bone sites that could be either immersed in water or embedded in
material with absorption properties equivalent to soft tissue (to
simulate homogenous overlying soft tissues).
SXA study
The equipment is relatively compact and mobile, and scanning
usually takes about 5 minutes with the forearm in a standard
position. The accuracy of is 3%, and the precision is better than 1%
in the distal forearm. The radiation dose is less than 0.1
mSv. More recently a new SXA scanner (Osteoanalyser
SXA 300; Dove Medical Systems/Noreland Medical Systems, Newbury
Park, Calif) has been introduced for the measurement of BMD in the
heel, where scanning is completed in 2 minutes with a precision
better than 1%.
Rectilinear scanning is performed in the distal (87% cortical
bone) and ultradistal forearm (65% trabecular bone). Results are
expressed as BMD or as bone mineral content in grams per square
centimeter.
DPA study
DPA represents an improvement over SPA in that it allows the
direct measurement vertebral or femoral bone density. DPA eliminates
the need for a constant soft-tissue thickness across the scanning
path (allowing its use in areas such as the spine and femur). DPA
can be used to quantify changes in patients with metabolic bone
disease or in those undergoing treatment with drugs that alter bone
mineral content.
The desirable characteristics of DPA include its capability in
assessing vertebral, proximal femoral, or total body bone content;
its independence from effects of marrow fat and other soft tissue;
and its relatively low radiation dose. However, it is more expensive
than other techniques, it has a longer scanning time, and it is not
as widely available as SPA.
DEXA study
DEXA overcomes many of the problems of DPA in that it is
inexpensive and has high accuracy, precision, and resolution. DEXA
has a number of advantages over DPA, including a precision of 1% or
less (vs 2-5%), a radiation dose of less than 2 mrem (vs 10-20 mrem),
and an examination time of less than 5 minutes (vs 20-30 min).
Because of its precision, DEXA is well suited to making serial
measurements to monitor the effect of treatment. At present, DEXA is
the most precise method for measuring BMD.
False Positives/Negatives: Conventional
radiography is insensitive for diagnosing osteoporosis. At least 30%
of the bone mass must be lost before it is recognized.
The precision error (coefficient of variation) is 1% for SPA. The
precision error is affected not only by the measurement of technique
but also subject characteristics. Precision error tends to increase
in an elderly or osteoporotic population due to factors such as
greater difficulty in repositioning and lower mean BMD.
SXA cannot separate trabecular and cortical bone components. The
precision of this method is around 1-2%, and the accuracy is ±2-4%.
With DPA, the error of precision and accuracy is 2-3%. The
precision of DEXA is 2 -6%, and the accuracy is about ±5%. One
unavoidable source of error in the dual-photon technique is the fat
distribution in the path of the radiation beam. It is possible to
correct for an evenly distributed fat layer across the scanning
path, but an uneven distribution introduces error into the
measurements. DEXA has some limitations, including artifacts such as
degenerative disk disease and osteophytosis in the older spine that
can cause a false elevation of BMD.
