Introduction
Background
Definition of osteoporosis
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 if the patient's BMD 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 has not established standards for determining osteoporosis in men, children, and persons of ethnic groups.1,2
Involutional osteoporosis. Note the lateral wedge fracture of L3 and a central burst fracture of L5. The patient had a recent fall.
Involutional osteoporosis. Insufficiency fractures of the sacrum and the pubic rami are seen on an isotopic bone scan as a characteristic H, or Honda, sign (arrows), which appears as intense radiopharmaceutical uptake at the fracture sites.
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.3,4 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.5,6
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.7,8
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 lifespan of functional osteoclasts and thus the amount of bone that osteoclasts resorb 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 menopause by limiting the lifespan of osteoclasts.
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. Studies have 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, after which there occurs a slower phase, with stable loss rates of 0.5-1% per year. Males do not have an accelerated rate of 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 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 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 in maintaining normal calcium homeostasis and in protecting 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 the incidence of femoral neck fractures in people living in 2 geographically and dietetically separated valleys in the area formerly known as Yugoslavia.9 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 is an important risk factor for osteoporosis. Several epidemiologic studies and a recent meta-analysis showed that smoking has a significant impact 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, such as occurs in adipose tissue. In addition, the metabolic clearance rate of estrogens may be increased in smokers, and 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 is 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)2 D3, 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)2 D3, resulting in compensatory hyperparathyroidism, which increases bone resorption and bone turnover. Whereas 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 nonosteoporotic women is defective bone formation. Osteoporotic women without fractures have significantly thinner bone structural units compared with age-matched control subjects. Genetic and hormonal factors besides aging may also contribute to osteoblastic insufficiency.
Estrogens increase serum levels of 1,25-(OH)2 D3. 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 increasing 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 that evaluated the efficacy of bisphosphonates for the treatment of postmenopausal osteoporosis.10 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.
Race or ethnic backgroundRacial 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, 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 is probably related to cultural differences, or it may possibly be 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.
Inadequate physical activity
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 past 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.
Involutional osteoporosis in men
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.
Interpretation and normal ranges of BMD
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 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, to estimate the risk of fracture, measurements should be made at the site of most clinical concern.
Generally, current and future fracture risks are expressed by using a combination of the WHO definition of osteoporosis and a Z score (see Images below and Images 1-4 in Multimedia).
Involutional osteoporosis. T and Z scores in an 80-year-old woman.
Involutional osteoporosis. T and Z scores in an 80-year-old woman.
Involutional osteoporosis. T and Z scores in an 80-year-old woman.
Involutional osteoporosis. T and Z scores in an 80-year-old woman.
Frequency
United States
In the United States, 10 million individuals have osteoporosis, and an additional 18 million have low bone mass, which places them at risk for this disorder. According to the 1995 estimates from the National Osteoporosis Foundation, osteoporosis-related fractures resulted in more than 400,000 hospital admissions, 2.5 million physicians visits, and about 180,000 nursing home admissions.
The lifetime fracture risk in white women is 18% for hip fracture, 16% for spine fracture, and 16% for wrist fractures, as compared with 6%, 5% and 3%, respectively, for white men. One half of all white women in the United States will have a fracture caused by osteoporosis sometime during their life. More than one half of all women and about one third of men will have an osteoporotic fracture during their lifetime.
International
Involutional osteoporosis is a major health problem in developed countries, affecting approximately 100 million people worldwide. Osteoporotic fractures occur in one third of the female population older than 65 years.
Epidemiologic studies of the social and economic impact of osteoporosis in Europe show that osteoporosis develops in 11-12% of the population and that 40% of women aged 70 years and 50% of women aged 75 years or older had osteoporotic fractures. The epidemiologic importance of osteoporosis is considerable: Some 40% of women aged 50 years are at risk for at least 1 osteoporotic fracture during their lifetime. The frequency of those fractures is constantly increasing, mainly because the population is aging. In 1990, 1.7 million patients worldwide had a hip fracture; the majority were older than 50 years.
One in eight men and women older than 50 years have evidence of vertebral deformity.
In the United Kingdom, the management of a hip fracture costs £4000-5000. In 1997, the annual acute hospital cost was approximately £325 million.
Mortality/Morbidity
Involutional osteoporosis is a significant cause of morbidity and mortality worldwide, leading to fractures of the hip, spine, and wrist.11 See also Complications in Clinical details below.
- The incidence of osteoporotic hip fracture in white women is 1 in 6. The frequency of hip fractures increases exponentially with age, particularly after age 70 years. About 20-30% of patients with hip fractures die within a year of their fracture. The risk of death in women with hip fracture is approximately 2-4 times greater in the year after hip fracture than in women without hip fracture.
- In addition to hip fracture, men also experience painful and debilitating fractures of the spine, wrist, and other bones from osteoporosis. Several studies have shown that the mortality rate from fractures is higher in men than in women. Men account for one third of the annual incidence of hip fractures; one third of these men do not survive longer than 1 year.
- Fractures of the wrist cause less mortality and morbidity, but the consequences are substantial for the patients. About 20% of patients with wrist fracture may be hospitalized. Potential complications of wrist fractures include secondary arthritis, chronic pain, limitation of motion, and physical deformity. Morbidity may also be related to associated injures, including those of the median and ulnar nerves and the radial and ulnar arteries.
Race
In people of African descent, rates of fractures are lower than those in white populations. Although Asian women have lower bone mass than white women, they have a lower rate of hip fractures. Hispanic women also have half as many fractures as white women despite similar peak bone masses.
- There are substantial geographic differences in the prevalence of vertebral deformities in Europe, with a range of 6-20%. The highest rates occur in Scandinavian countries.
- The incidence of osteoporotic fractures is lower in Japanese individuals than in whites.
Sex
Involutional osteoporosis predominantly affects postmenopausal women, but both sexes can be affected.
- Bone loss is greater in women than in men because the rate of loss significantly increases after menopause.
- In women and men, respectively, the rates of femoral fractures are 17.5% and 6.0%, the rates of vertebral fractures are 15.6% and 5.0%, and the rates of distal forearm fractures are 16.0% and 2.5%.
- The life expectancy of women with femoral fractures is reduced by 12-15%.
Age
Approximately 7% of all women aged 35-40 years and 33% of women older than 65 years have involutional osteoporosis.
- The projected growth of the elderly population will cause the number of hip fractures, in particular, to increase dramatically because the incidence of hip fractures increases exponentially with age, particularly after age 70 years.
- See also the Frequency section above.
Anatomy
The human skeleton is dynamic. Besides functioning as a framework for the muscular system, it provides protection for the internal organs and serves as both the body's major hematopoietic organ and as the mineral reservoir where 98% of the body's calcium is stored.
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 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. In the resorption phase, old, dead, damaged, or underutilized bone is removed. This is followed by a formation phase, in which new bone is produced. The remodeling process involves 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 actively resorbed. In women with established osteoporosis, the total body bone mineral content is typically 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.
Presentation
Signs and symptoms
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.12,13,14,15
Complications
Vertebral fracture, a well-recognized complication of osteoporosis, is the most common osteoporotic fracture. Less than one third of these fractures are clinically identified. Regardless of whether they are symptomatic or are identified on imaging, vertebral fractures are associated with increased mortality and morbidity rates.16,17 Complications include back pain and decreased mobility, with consequent days of bed rest. Compression fractures of the vertebrae vary in degree from mild wedges to complete compression.
Disfiguring kyphosis (dowager's hump) is usually related to multiple wedge fractures of the dorsal vertebrae. Abdominal protrusion, which occurs as a consequence of kyphosis, is an unrecognized aspect of osteoporosis. Height loss occurring as a consequence of vertebral fractures is one of the most distressing aspects of osteoporosis to many women.
Decreased pulmonary capacity is a known complication of kyphosis; if severe, this may lead to shortness of breath and pulmonary symptoms of restrictive lung disease. Also, the incidence of esophagitis is increased in patients with kyphosis because of changes in the abdominal cavity. Once vertebral fractures occur, the process may be relentless, with ongoing further vertebral fractures and height loss despite correction of BMD.
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 breast-feeding. 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.18
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 neurologic 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 at 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; 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. 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 include conventional radiography, quantitative CT (QCT), single-photon absorptiometry (SPA), dual-photon absorptiometry (DPA), quantitative ultrasonography (QUS), and dual-energy X-ray absorptiometry (DEXA).19,20,21
Bone-density measurements can be performed by using X-ray methods, such as DEXA, QCT, and ultrasonic methods. The most accurate way to diagnose 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 for 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.22,23,24,25,26,27,28,29,30,31,32,33,34,35
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 to 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.36,37
Recommendations for BMD testing
The National Osteoporosis Foundation recommends bone density testing for the following groups: women aged 65 years 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 women 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 is not preferred because it is not suitable for the early detection of osteoporosis. Changes on plain radiographs can be seen only after 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.
Bone-density measurements are not an effective method to monitor the response to treatment because changes in bone density may not be detected for up to 2 years. Radiation techniques to measure BMD, such as single-photon absorptiometry and DPA, have several limitations. The most important limitation is posed by the inhomogeneity of soft tissues because different components have their own attenuation coefficients. Fat has the lowest attenuation and is generally unevenly distributed in the region of BMD measurement; therefore, it has a variable affect on the accuracy of the measurement. The accuracy of density and attenuation coefficients for the bone mineral and soft-tissue components are also uncertain, though this limitation can partly be overcome with direct DPA and DXA measurement.
The accuracy of photon absorptiometry has been estimated to be 4-8% for SPA and 4-6% for DXA. However, the accuracy can be as low as 11% and is worse for lateral projections, as compared with anteroposterior (AP) projections.
SPA is used to measure forearm bone density, and it may not provide an accurate assessment of bone density of spine or hip. The procedure takes about half an hour. Radiation exposure from SPA is approximately 5 mrem. DPA is used to measure the density of the spine or hip. The precision of DPA is acceptable for diagnosing osteoporosis but insufficient for detecting changes in individual patients. Radiation exposure from DPA is approximately 5 mrem.
Soft-tissue inhomogeneity affects the accuracy of QCT. The content of yellow marrow in the vertebrae may have a significant effect on the accuracy of BMD measurements. Machine-related artifacts, such as beam hardening, might also affect its accuracy. Overall, the value of single-energy methods is in the range of 5-15%. With 2 effective beam energies, this changes to 3-10%, but at the cost of poor precision. The precision and accuracy of QCT is good, but the radiation involved is relatively high (approximately 200-300 mrem). Therefore, QCT is not a preferred technique when other methods are available.
Ultrasound transmission is attenuated by the thickness and composition of tissues within and surrounding the bone. In trabecular bone, fatty marrow in the intertrabecular spaces influences both broadband ultrasound attenuation (BUA) and velocity. Measurements are determined by means of ultrasonography of the heel. Osteoporosis Australia's Consensus Statement states that this type of measurement of bone strength lacks acceptable measurement precision and long-term stability to be recommended for use in the diagnosis of osteoporosis. If such ultrasound measurements show low bone density, the patient should be referred for DEXA because of its high accuracy and precision.
Differential Diagnoses
Other Problems to Be Considered
See Differential diagnoses in the Clinical details section above.
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Further Reading
Keywords
primary osteoporosis, secondary osteoporosis, postmenopausal osteoporosis, juvenile osteoporosis, pregnancy-related osteoporosis, postpartum osteoporosis, bone mineral density, BMD, T score, type 1 osteoporosis, type II osteoporosis
