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Practice of Geriatrics
Luis R. Navas, M.D., and Kenneth W. Lyles, M.D.
Epidemiology and Cost of Osteoporosis
Skeletal Function and Remodeling
Hormonal Control and Effects on the Skeleton and Minerals
Factors Associated with Bone Mass
Classification of Osteoporosis
Clinical Presentation
Diagnostic Approach and Differential Diagnosis
Management and Therapy of Osteoporosis
Prevention of Osteoporosis
Osteoporosis is a systemic skeletal disease characterized by a reduction in the amount of bone mass, microarchitectural impairment of bone tissue, and a subsequent increase in fractures. This disease is present in epidemic proportions in the United States, affecting between 20 and 25 million people. Because osteoporosis is characterized by a long latency period and a lack of symptoms, many patients’ first encounter with the disease is a skeletal fracture with minimal trauma. The resulting physical deformities can lead to functional impairments that may have a significant impact on quality of life, mobility, and mortality. The primary care physician should have a high level of suspicion for this disease because it is much easier to prevent bone loss than it is to manage the sequelae of skeletal fractures.
Life expectancy at birth has improved in the United States and is projected to increase to 82 years for women and 74.2 years for men by the year 2020. Furthermore, the older population (over age 65) is projected to reach 52 million people by the year 2020. Because osteoporotic fractures occur more commonly in people over 65 years old, the burden of this disease is expected to increase during the next few decades.1 It was estimated in 1990 that approximately 1.7 million hip fractures occurred throughout the world, and about 50% of these fractures occurred in North America, Europe, and Oceana.2 There are more than 1.5 million osteoporotic fractures annually in the United States, and these fractures are expected to increase in the next 50 years.3 The annual cost of care for osteoporosis in the United States is now approximately $10 to $20 billion, but within 50 years this cost may exceed $240 billion.4 In the United States 265,000 hip fractures occur each year, most of them in patients over the age of 70 years.3 There is a perception that money is being wasted on individuals who have a short life expectancy, but in fact, the cost of hip fracture treatment per quality-adjusted life year compares favorably with that for renal transplant or coronary artery bypass.5 By the age of 90, 32% of women (one in three) and 17% of men (one in six) will have suffered a hip fracture.3,6
Vertebral fractures are more common than hip fractures, and frequently patients may not seek medical attention for these. The lifetime risk of vertebral fractures for a woman aged 50 is estimated at 32%, whereas her lifetime risk of hip fracture is 15.6%.7 Although early work suggested that vertebral fractures were not clinically significant, several more recent studies have shown that vertebral compression fractures in older patients have a major impact on their physical, functional, and psychosocial status.8,9 Osteoporotic fractures at any site are associated with an approximate doubling of the risk of physical limitations and an even higher risk of functional limitations.2,9 Combining information about bone mass and prevalent (existing) fractures is a powerful means of predicting the occurrence of new vertebral fractures. A reduced initial bone mass of 2 standard deviations (SD) at a given age is associated with a fourfold to sixfold increase in the risk of new vertebral fracture. A single fracture at the baseline examination increases the risk for a new vertebral fracture fivefold. The presence of two or more fractures at baseline increases the risk twelvefold.10,11
Mortality in patients with osteoporosis is increased. Older women with low bone density have a significant increased risk of a nonfracture-related death within 3 years. For each standard deviation decrease in bone mineral density in the proximal radius there is a 1.19-fold increase in nontraumatic mortality.12 Also, it is well known that there is an increased risk of death after a hip fracture. The death rate within 1 year of hip fracture ranges from 12% to 24% and increases with age.2,13,14 The coexisting chronic diseases and frailty that are present in some older patients sustaining a hip fracture may be the cause of the increased mortality.2,13 Because of the excess morbidity and mortality suffered by patients with osteoporosis and the services needed by impaired patients after sustaining a skeletal fracture, early diagnosis and appropriate treatment are crucial to try to prevent the disease or slow its pathologic progression.
The skeleton has three distinct functions. First, it serves as a lightweight frame to which the muscles and tendons are attached, thus allowing movement and change of position. Second, it provides protection for important organs like the brain, spinal cord, heart, lungs, and bone marrow. Finally, the skeleton provides a reservoir of minerals and buffers (i.e., calcium, phosphorus, magnesium, sodium, and carbonate). When an excess amount of acid occurs in the diet of a patient with chronic acidosis, skeletal phosphate and carbonate can serve as buffers. Likewise, when dietary calcium is not sufficient, calcium will be resorbed from the skeleton. Because the metabolic function of the bone precedes its structural function, in states of calcium deficiency or chronic acidosis bone growth or remodeling (formation and resorption) is impaired.
The skeleton is formed of two type of bones: cancellous or trabecular bone and cortical bone. Cancellous bone is a series of trabeculae (plates) that form the meshwork in the vertebral body and at the end of the long bones. It represents 20% to 25% of the skeleton. The cortical bone is the compact bone that forms the outer shell of the bones. It provides most of the support for the body and represents 75% to 80% of the skeleton. Long bones such as the femur are at least 90% cortical bone. Trabecular bone is more sensitive to changes in bone remodeling than cortical bone because it has a greater surface-to-volume ratio.
The bones grow in two ways: longitudinal growth, which ceases with the closure of the epiphyses in the early twenties, and bone mass growth. The bone mass reaches a peak at about the age of 30 years. After a period of stabilization, when the rates of bone formation and bone resorption are in equilibrium, bone loss begins in both sexes. Over her lifetime a female loses approximately 35% of her cortical bone mass and 40% to 50% of her trabecular bone mass. Two rates of bone loss have been identified.3,15,16,17 and 18 First, slow loss, or “normal bone loss,” is a slow and gradual loss of both trabecular and cortical bone that affects males and females equally. Second, the so-called fast bone loss is a transient and more rapid phase of bone loss. This rapid phase of bone loss occurs in approximately 35% of early postmenopausal women and in some men who develop hypogonadism. At this time it cannot be predicted who will undergo such rapid bone loss. Local production of selected cytokines may mediate this effect. In women identified as “fast losers” at menopause, about 50% of bone mass has been lost within 12 years of menopause.16,17 The loss of bone that occurs during the menopause is a transient phase that usually lasts 5 to 8 years.
All areas of the skeleton undergo a complex remodeling process. In areas of increased skeletal loading, the remodeling process increases the bone mass, a phenomenon referred as Wolf’s law.3 The bone remodeling process is carried out by cellular units called the bone morphologic units in which osteoclasts, osteoblasts, and osteocytes are the cellular elements. The osteoclast, a multinuclear cell derived from granulocyte-macrophage colony-forming units, resorbs bone, forming a resorption cavity. Osteoblasts, derived from fibroblast colony-forming units in the bone marrow, fill the resorption cavity, depositing a protein collagen matrix called osteoid. Osteoblasts then mineralize the osteoid tissue over a period of 2 months. Twenty percent of osteoblasts become surrounded by calcified matrix and become osteocytes. The process of remodeling takes 100 to 150 days to complete, and about 5% of the bone mass is undergoing remodeling at any one time.
Recently, it has been proposed that interleukin-1 beta (IL-1b) and other cytokines such as tumor necrosis factor alpha and beta (TNFa and b) produced by osteoclasts in the bone morphologic unit stimulate the production of osteoclast precursor cells. The production of interleukin-6 (IL-6) and anexin II by osteoclasts also stimulates and promotes adhesion of circulating osteoclast precursor cells to the endothelium of the capillary supplying the bone morphologic unit.19
The process of bone formation and resorption in a young adult results in conservation of bone mass. Imbalance of these processes may result in bone loss when more bone resorption occurs than bone formation. Two histologic forms of bone loss have been described. High-turnover osteoporosis occurs when bone resorption is increased. The activity of both osteoclasts and osteoblasts is increased, but the osteoblasts fail to keep pace with the accelerated resorption, and the net result is a reduction in bone mass. As a result of the high turnover, the resorption cavities or lacunae in the bones become deeper. The second type of bone loss is the low-turnover type, which is more common in older patients. In this type, the function of the osteoclasts is normal, but the osteoblasts fail to refill the resorption cavities completely, causing a reduction in bone mass.
The three major hormones involved in the regulation of mineral metabolism (calcium and phosphate) in the skeleton are parathyroid hormone (PTH), calcitonin, and 1,25-dihydroxycholecalciferol (the active form of vitamin D).20 PTH is secreted by the parathyroid glands and regulates the serum ionized calcium level by directly increasing bone resorption and increasing reabsorption of calcium in the distal tubules of the kidneys. It also increases phosphate excretion in urine. PTH increases the conversion of 25-hydroxycholecalciferol to 1,25-dihydroxycholecalciferol in the renal tubule. Serum levels of PTH are increased with aging, probably in response to decreased gastrointestinal absorption of calcium and a reduction in the glomerular filtration rate.
Vitamin D is involved in the absorption of calcium and phosphate in the gastrointestinal system. Vitamin D3, or cholecalciferol, is produced in the skin from 7-dehydrocholesterol by the action of ultraviolet rays in sunlight. In the liver, the cholecalciferol is hydroxylated to 25-hydroxycholecalciferol or calcidiol. Calcidiol is converted in the proximal tubules of the kidney into the active metabolite 1,25-dihydroxycholecalciferol, or calcitriol. Calcitriol supplies adequate calcium and phosphate for mineralization by increasing calcium and phosphorus absorption by the intestine. In bone, calcitriol improves mineralization and probably stimulates osteoblastic activity. With aging, absorption of calcium and phosphate in the gastrointestinal tract is decreased, especially after age 70, and the serum level of calcitriol is decreased about 50%. The production of vitamin D in the skin is also reduced with age, particularly in institutionalized elderly patients. Several studies have shown evidence of a primary impairment in the renal production of calcitriol in elderly patients with osteoporosis.
Calcitonin is secreted by the C cells or parafollicular cells in the thyroid gland and acts to reduce the serum calcium concentration by inhibiting bone resorption. The relationship of calcitonin in mineral metabolism is not clear, and its role in osteoporosis is also unclear. Calcium metabolism and bones are affected by various other hormones. Long-term use of or excessive endogenous production of glucocorticoids causes bone loss by altering bone remodeling. Glucocorticoids increase bone resorption by osteoclasts and decrease bone formation by osteoblasts.21 Also, they reduce gastrointestinal calcium-phosphorus absorption by exerting a direct action on the intestine, and they increase renal calciumphosphorus excretion. The decreased absorption of calcium by the gut is reported to cause an increase in PTH secretion, causing a secondary hyperparathyroidism.22
Thyroid hormone is necessary for normal bone growth and turnover, but excess thyroid hormone may produce hypercalcemia (due to a direct stimulation of osteoclasts) and may lead to bone loss (osteoporosis) and hypercalciuria.
Insulin increases bone formation, and the Rotterdam study23 demonstrated that women with non-insulin-dependent diabetes mellitus have increased bone density and a lower frequency of nonvertebral fractures. This “protective effect” of insulin in diabetics may be explained by the period of hyperinsulinemia due to insulin resistance before the onset of the diabetes or by the strong binding effect of insulin on sex hormone binding globulin, which may lead to higher levels of free serum estradiol and testosterone during the hyperinsulinemia stage.
Growth hormone is required for growth of the skeleton. Somatomedins and insulin-like growth factor-1 (IGF-1) stimulate protein synthesis in bones. The sex steroids are also required for optimal bone mass and will be discussed subsequently.
Bone mass is the net result of the amount of bone formed minus the amount of bone lost. Genetics, race, sex, diet and nutrition, exercise, and the use of tobacco and alcohol are important factors in determining bone mass and bone turnover. In twin studies it has been shown that 60% to 80% of peak bone density is genetically determined.24,25 A positive family history of osteoporosis is a risk factor for osteoporosis. In blacks, osteoporosis is rare; whites, Eskimos, and Asians have a higher incidence of osteoporosis. Two factors may explain why blacks may have a low incidence of this disease. First, they have a greater initial bone mass, and second, they have slower bone remodeling rates. Females in general have a lower bone mass than males, and this may explain why women suffer more osteoporosis than men. White, Asian, and Eskimo women have a greater risk of developing osteoporosis than black or Hispanic women.
Nutrition may also play an important role in the development of osteoporosis. An acid-ash diet* may have a negative effect on bone mass. This diet generates a residue of approximately 100 mEq of acid daily. With a chronic acid load, the bones provide buffers (calcium and phosphorus) through increasing bone resorption. This chronic acid diet causes an excessive loss of calcium, which is manifested by hypercalciuria, and may play a role in the development of osteoporosis.27 There is some suggestion that the incidence of osteoporosis is lower in vegetarians, but appropriate long-term studies are required to verify this hypothesis.27
Diets high in phosphorus were formerly thought to have an adverse effect on bone mass. However, diets that contain the average daily phosphate intake of most Americans (800 to 2000 mg) are not harmful to the skeleton.3
In the United States, osteoporotic postmenopausal women have been shown to be in negative calcium balance, and most of these women fail to replace these calcium losses. Dietary calcium deficiency has been associated with lactose intolerance and low dietary calcium intake. A consideration that may contribute to the calcium deficiency seen in elderly patients is that they may lack the ability to absorb most of the calcium they ingest. Multiple studies have shown that calcium supplements produce a sustained reduction in the rate of loss of bone mass in postmenopausal women and may reduce the incidence of fractures. So the consensus is that calcium supplements are warranted in older women.3,28,29,30 and 31
Polymorphism of the vitamin D receptor gene allele (genotypes BB, Bb, and bb) has been suggested as a cause of a significant portion of the total genetic effect on peak bone, bone turnover, and rate of bone growth and bone loss.32 At this time, this effect is controversial, and studies are ongoing to resolve this dilemma. However, it has been found that elderly people with the BB and Bb genotypes were less responsive to calcium supplements for maintenance of bone density.33 The bb genotype is more common in the Japanese population, whereas the BB and Bb genotypes are more common among Caucasians.25 In the future, such polymorphisms could be an invaluable aid in selecting the optimal therapy for the prevention and treatment of osteoporosis.
Prolonged immobility is a cause of bone loss. Patients undergoing complete bedrest who experience prolonged absence of weight bearing can lose up to 1% of their bone mass per week. Resuming weight-bearing activity gradually restores the bone mass to normal. Exercise or physical activity such as walking is associated with an increase in bone mass. Obesity appears to protect against bone loss by increasing skeletal loading or by increasing the levels of estrogen.
Intake of a moderate amount of alcohol can have a positive effect on bone mass.34 However, the bone loss and fractures seen in some people who consume large amounts of alcohol is multifactorial. Alcohol in large amounts may have a direct toxic effect on osteoblasts and produces a low-turnover osteoporosis. It may also reduce the dietary protein intake, lower the calcium intake, and cause low testosterone levels, which can contribute to the development of osteoporosis.3,35 Heavy alcohol drinking can impair gait and predispose patients to falls, placing them at higher risk for fractures.
Cigarette smoking is a risk factor for bone loss and may have a secondary effect on ovarian function. Currently it is believed that smoking accelerates estrogen metabolism in the liver. Patients who smoke should be advised not to do so.
A number of conditions, diseases, and drugs have effects on the skeleton (Table 21-1). Conditions and diseases associated with osteoporosis are gastrectomy, castration, thyrotoxicosis (hyperthyroidism), hyperparathyroidism, rheumatoid arthritis, Cushing’s syndrome, and possibly diabetes mellitus. Chronic use of glucocorticoids, heparin, and anticonvulsants (e.g., phenytoin) can cause bone loss. Consumption of caffeine can cause mild renal calcium losses. Thiazide diuretics may have a protective role by causing renal calcium conservation.


Osteoporosis can result from multiple factors; however, clinical risk factors may help the clinician predict the bone mass of a patient. Increasing age (over 65 years), low body index, a history of maternal fracture, and smoking are associated clinically with low bone mass. On the other hand, a history of estrogen use, non-insulin-dependent diabetes, thiazide use, increased weight, greater muscle strength, later age at menopause, and greater height are associated with higher bone mass.36,37
The World Health Organization (WHO) defines low bone mass or low bone mass density as values that are from 1 to 2.5 SD below the normal mean values for young normal adults in the third or fourth decade of life; values below 2.5 SD are defined as osteoporosis.15
Osteoporosis has a variety of presentations. In general, it has been classified as primary or not associated with other diseases, and secondary or associated with inherited disorders or acquired pathologies. Primary osteoporosis can be divided into several types (see Table 21-1). Primary osteoporosis in most patients is classified as involutional osteoporosis, which has two subcategories. Type I or postmenopausal osteoporosis is found usually in women 15 to 20 years after the menopause. The incidence in women is six to eight times higher than that in men. It has been postulated that the cause of this osteoporosis is accelerated bone resorption. The increased bone turnover results in a secondary decrease in PTH secretion as well as a secondary reduction in the renal production of calcitriol. Patients present with trabecular bone loss with vertebral fractures or distal forearm fractures.
Type II, age-associated, or senile osteoporosis occurs in men or women over the age of 70; it has a female-to-male ratio of 2:1 or 3:1. The mechanisms of this bone mass loss are thought to be increased PTH secretion resulting from decreased gastrointestinal calcium absorption and decreased osteoblast function. Patients usually present with fractures of the hip or vertebrae, sites that contain cortical and trabecular bone, although fractures of the pelvis, ribs, and tibia can also occur. A great number of these fractures are the result of falls or trauma, which occur frequently in elderly patients.
There are other diseases and medications that are associated with reduced bone formation or accelerated bone loss. These secondary causes of osteoporosis are listed in Table 21-1. The use of some medications can affect the bones. Long-term use of glucocorticoids is a cause of osteoporosis. Two thirds of patients who receive doses of more than 10 mg of prednisone per day are at risk for bone loss and subsequent fractures. Dilantin used over the long term can cause low-turnover osteoporosis. Heparin therapy has also been associated with bone loss resulting from increased amounts of bone resorption. The use of thyroid hormone with significant long-term suppression of thyroid-stimulating hormone (TSH) levels is associated with low bone mass; however, an increase in skeletal fractures has not been demonstrated yet. Another cause of bone loss and subsequent fractures may be either a primary malignancy of the skeleton such as multiple myeloma or a metastatic cancer such as lung or breast carcinoma.
Although osteoporosis is a generalized disorder of the skeleton, it is generally a silent disease. There are few if any clinical manifestations until a fracture occurs. Vertebral compression fractures can occur with minimal trauma, such as bending, coughing, sitting down hard, or falling. In general, these fractures affect the lower thoracic and upper lumbar vertebrae. The usual symptom of a compression fracture is severe pain that the patient can localize to the area of the fracture. It may radiate to the abdomen or into the flanks, and occasionally an ileus can develop. Back movement, bending, coughing, straining to have a bowel movement, and sitting or standing for long periods of time may worsen the pain. The pain from a vertebral compression fracture generally lasts 4 to 8 weeks and then gradually subsides. The patient lies on the back or side in a fetal position. To move from a supine to a sitting or standing position, the patient must push up from a lateral position. By careful examination, it is possible to determine by percussion the spinous process affected because tenderness is elicited. Vertebral compression fractures can be associated with lost height. Occasionally in the presence of two or more vertebral compression fractures, the patient complains of intermittent back pain.
After the acute pain of the fracture subsides, recurrent back pain may be present, described by patients as back tiredness. This may represent new fractures or muscle spasm. The natural progression of the clinical problems can be variable. Frequently, there are several years between fracture episodes, and after the first fracture the patient may have several symptom-free years. The patient may develop a deformity of the back with an increase in the curve of the thoracic spine (kyphosis), commonly known as dowager’s hump. Flattening of the natural lumbar lordosis also occurs. More fractures of the thoracic and lumbar spine lead to relaxation of the abdominal muscles and angulation of the ribs, resulting in abdominal protrusion; such patients complain of early satiety. Ultimately, the ribs can come to rest on the iliac crests. In the severe forms of the disease the loss of the anterior lumbar curve leads to a hip tilt, hamstring contractures, permanent hip joint flexion, stiff ankles, and pronated feet, resulting in a unsteady gait.
Other fractures can occur in patients with osteoporosis. The clinical picture of the distal forearm or Colles’ fracture is that the patient falls and, in an attempt to lessen the impact of the fall, extends the wrist. After the fracture has been reduced and heals, the patient may have a decreased range of motion of the wrist. Hip fracture is the most devastating osteoporotic fracture of the elderly. Falls play a significant role in causing hip fractures. Risk factors that influence the mechanics of falling are the orientation of the fall (especially lateral falls), the amount of soft tissue padding over the hip, and the amount of bone mass. Fortunately, most falls do not result in injury, and only about 5% of falls lead to fractures.
Following a hip fracture community-dwelling elderly subjects experience a substantial decline in physical function. A prospective cohort study of community-living elderly who had a hip fracture showed that 86% of them could dress themselves independently at baseline, but only 49% could do so 6 months after the hip fracture. In the same study, 75% of the subjects could walk across the room independently, but only 15% could do so 6 months after the event.6 Premorbid physical and mental function prior to the fracture can predict this decline.
Because a diverse group of diseases can result in bone loss, the etiology of bone loss must be defined if at all possible before therapy is instituted. A history and physical examination are needed when osteoporosis is suspected. The history should include a family history of bone disease. A history of nephrolithiasis and a history of sexual development (in women this may include menarche, number of children, menopause, and hormone replacement therapy; in men it includes potency and libido) should be obtained. A pharmacologic history should focus on prior and current use of glucocorticoids, anticonvulsants, anticoagulants, and thyroid medications. Both tobacco use and alcohol consumption should be quantified. The review of systems should focus on symptoms of malignancy, Cushing’s disease, hyperthyroidism, and hyperparathyroidism. A history of skeletal fractures, bone pain, and height loss is also important. An attempt should be made to understand how the fracture or fractures impair the patient’s function. A history of back tiredness and back pain triggered by activities that involve bending, such as cooking, removing clothes from the washer and dryer, vacuuming, or pushing a lawn mower, can be a symptom of a vertebral compression fracture. The physical examination should include information about weight, height, size of thyroid gland, spine configuration, and range of motion of the spine in flexion, extension, and side bending. The gait should be noted as well as the ability to handle transfers and climbing and descending stairs. For patients who have had a prior hip fracture, leg length discrepancy should be assessed. With the patient in a supine position, both legs are measured, and the distance from the anterior iliac crest to the medial malleolus in each is compared.
All patients with osteoporosis should be evaluated at least once for treatable conditions; this evaluation should include a complete blood count, urinalysis, calcium, phosphorus, and alkaline phosphatase levels, liver function tests (SGOT, SGPT, bilirubin), thyroid panel (TSH, free T4), serum creatinine, and blood urea nitrogen (BUN). Further evaluation may be necessary in the presence of abnormal results—e.g., an elevated serum calcium level may be the result of an asymptomatic hyperparathyroidism. If gastrointestinal malabsorption or malnutrition is suspected, a 25-hydroxyvitamin D level should be measured. Bone mass density measurements are useful in the management of patients with osteoporosis. If the bone mass measurement is low, aggressive therapy may be indicated; if the measurement is within normal limits, prophylactic therapy and exercise can be prescribed. Further details about bone density measurements are discussed in the next section, on management and therapy.
Other diseases should be considered in the differential diagnosis of a patient with osteoporosis, including Paget’s disease, osteomalacia, and malignancies of various types. Paget’s disease of bone is a common disorder that affects 1% to 3% of people over the age of 60 years. The diagnosis is usually made on finding either an elevated serum alkaline phosphatase level or increased excretion of urine hydroxyproline. If Paget’s disease presents in the lytic phase it may be confused with osteoporosis, but a bone scan and radiographs can be used to make this diagnosis. Osteomalacia is a disorder in which the newly formed osteoid tissue fails to mineralize normally. Clinically, the disease may present with fractures, bone pain, and osteopenia on radiographs. The diagnosis of osteomalacia is complex, but the most common causes are vitamin D deficiency and phosphate depletion from antacids or renal phosphate wasting. Neoplasms of several types may cause osteopenia: leukemias, multiple myeloma, lymphoma, and carcinomatosis can result in bone loss, particularly in the vertebral column. Multiple myeloma is frequently present in the elderly and is evident by compression fractures, hypercalcemia, and renal failure.
Conventional radiographs can provide some information about the skeleton. At least 30% to 60% of bone mineral must be lost before osteopenia can be seen on radiographs. Radiographs are not useful as a measurement of bone mass. However, radiographs can give useful facts about the skeleton. In osteopenic vertebrae there is a loss of horizontal trabeculae, and the vertical trabeculae appear more prominent. The vertebral end-plate surfaces are accentuated. Biconcave depressions on the superior and inferior surfaces can result from expansion of the intervertebral disks into the vertebral body, giving a codfishlike appearance on radiographs. Osteoporosis does not cause erosion of the vertebral cortex; if this is present, neoplasm should be ruled out. When a compression fracture is seen on radiographs, the apex of the wedge fracture in the lumbar and thoracic vertebrae is usually anterior. Posterior wedging of a fracture suggests another disease process, such as Paget’s disease, osteomyelitis, or metastasic malignancy.
New methods have been developed to quantitate the amount of bone mass. These methods include single- and dual-energy photoabsorptiometry, dual-energy x-ray absorptiometry, quantitative computed tomography and neutron activation analysis, and quantitative ultrasound. Each method provides different information, and quality control in the measurement is essential. At present the most widely used method is dualenergy x-ray absorptiometry (DEXA), which measures the bone mass of the proximal femur, lumbar vertebral spine, and radius. These measurements of bone mass are useful clinically.
The Scientific Advisory Board of the National Osteoporosis Foundation38 has suggested five indications for measurements of bone mass: (1) in estrogen-deficient women, to diagnose significantly low bone mass to make decisions about therapy; (2) in patients with vertebral abnormalities or roentgenographic osteopenia, to diagnose spinal osteoporosis to make decisions about further diagnostic evaluation and therapy; (3) in patients receiving long-term glucocorticoid therapy, to diagnose low bone mass to adjust therapy; (4) in patients with asymptomatic primary hyperparathyroidism, to diagnose low bone mass to identify those at risk of severe skeletal disease who may be candidates for surgical intervention; and (5) in patients receiving therapy for osteoporosis, to determine the efficacy of the therapy. Bone mass measurements are not recommended for screening. They are valuable when they will determine the institution or withholding of therapy such as estrogen, bisphosphonates, or calcitonin.
Bone biopsy and histomorphometric studies are not commonly used but are useful techniques for determining the effects of experimental interventions on bone resorption and formation indices.
Therapy for a patient with an acute vertebral fracture consists of strong analgesics; narcotics and muscle relaxants may be necessary. Bed rest may be needed until the pain and coexisting muscle spasm subside but should be limited to prevent deconditioning. In some cases a back brace may be helpful in providing support and can aid in relieving the muscle spasm. During the period of bed rest the patient can be given literature about the disease and how to manage it. After the acute episode of pain has subsided, many patients are left with chronic lumbosacral pain that is due to muscle spasm. At this point, the patient should be referred to a physical therapist for instruction and practice in an exercise program. He or she is taught how to lift objects and how to function so that the chances of future fractures are reduced. Because osteoporosis is a chronic disease, therapy should be directed toward preventing further bone loss and teaching the patient strategies for management of the disease.
In patients with established osteoporosis, currently the Food and Drug Administration (FDA) has approved three drugs for its treatment: estrogen, alendronate, and calcitonin. These drugs act by decreasing bone resorption so that the rate of bone loss is decreased. Estrogen is believed to act in part by decreasing the production of local cytokines (IL-6), which increase osteoclastic bone resorption. Estrogen replacement therapy can be given as oral conjugated estrogens or estradiol, or by transdermal patch. For women with an intact uterus progesterone in low doses (2.5 or 5 mg of medroxyprogesterone acetate) daily or cyclic progesterone (5 to 10 mg for 10 to 12 days of the cycle) must be administered to prevent the development of endometrial hyperplasia or endometrial carcinoma. A daily dose of 0.625 mg of conjugated estrogens or 2 mg of estradiol generally is adequate to treat or prevent bone loss. Furthermore, this dose of estrogen reduces both vertebral and hip fractures by 50% if it is given for 10 years.
The problem with estrogen replacement therapy is patient compliance. Less than 30% of patients placed on replacement therapy are still taking it after 1 year.39,40 Many factors enter into the decision to start estrogen therapy, but even in a woman who begins therapy 20 years after menopause positive benefits have been shown. Estrogen decreases the incidence of vasomotor symptoms (hot flashes), vaginitis, urethritis, dyspareunia, urinary tract infections, and possibly depression. More than 30 epidemiologic studies indicate that postmenopausal estrogen use is associated with a 44% reduction in the risk of coronary heart disease.
The risks of estrogen therapy are an increase in endometrial hyperplasia and endometrial carcinoma and a possible increase in the risk of breast cancer. Patients receiving estrogens have more abnormal vaginal bleeding, which can lead to endometrial biopsy or dilation and curettage. The relation between estrogen therapy and breast cancer is far from clear. A number of earlier studies found no link between hormone replace therapy (HRT) and the risk of breast cancer.41,42,43 and 44 A more recent study showed an increased risk of breast cancer after 5 or more years of estrogen therapy.45,46 At the present time, the Women’s Health Initiative is under way to help determine the risk of breast cancer in postmenopausal women on HRT. Until that study is completed, patients should be informed about the current knowledge of the risks and benefits of HRT and allowed to choose for themselves whether or not to use therapy. In general, patients with hypertension should be monitored to make sure that HRT does not alter blood pressure control. The practitioner should also bear in mind that estrogens increase the incidence of gallstones.
Alendronate (Fosamax), an aminobisphosphonate, was approved by the FDA for the treatment of postmenopausal osteoporosis in 1995. Alendronate reduces bone resorption by decreasing osteoclast activity, causing a premature apoptosis (programmed cellular death) of osteoclasts.19 This drug increases bone mass in the spine and hip in 96% of patients who receive it. It is also associated with a 48% reduction in the rate of vertebral compression fractures.47 The major side effect of this drug is esophageal irritation, but more than 95% of people who received this drug in clinical trials had little difficulty with this side effect. Alendronate is poorly absorbed by the gastrointestinal tract, so the patient must take the medication while fasting and wait a minimum of 30 minutes before eating or drinking anything but water. Patients should not be recumbent after taking alendronate. For the treatment of osteoporosis 10 mg of alendronate daily is recommended. Adequate calcium intake of 800 to 1000 mg daily must also be ensured.
Calcitonin has also been approved for the treatment of postmenopausal osteoporosis. It prevents bone loss by inhibiting osteoclastic resorption. Because it can also prevent vertebral bone loss in postmenopausal women, it should be considered as an alternative in women who cannot take or refuse to take estrogen. Previously, only injectable calcitonin (Calcimar) was available, but the FDA approved the use of nasal salmon calcitonin (Miacalcin) in 1995. Nasal calcitonin used in doses of 200 units/day plus calcium supplements increased bone density in the lumbar spine. Calcitonin in the injectable or nasal form has some analgesic effect and can be used to treat the pain caused by vertebral compression fractures.
In addition to the therapies just described, calcium intake should be monitored. Postmenopausal women should have a daily intake of calcium of 1200 to 1500 mg/day. Treatment of elderly patients with vitamin D is effective in maintaining bone mass and may reduce the frequency of hip fractures.48,49 Vitamin D has a direct effect on bones. It stimulates the formation of osteoblasts, inhibits osteoclast progenitors, increases inherent bone strength, stimulates the formation of compact bone, and corrects the secondary hyperparathyroidism common in the elderly. Supplementation with 400 to 800 IU daily is sufficient.
Other agents can stimulate bone formation or increase existing bone mass and may reduce the chance of further fractures. Several drugs have been shown to have such properties, including thiazide diuretics, sodium fluoride, and human synthetic 1-34 parathyroid hormone fragments. These agents, particularly the latter two, must still be considered experimental therapies for osteoporosis. The thiazides in some studies have been associated with a decreased incidence of bone loss and osteoporotic fractures. Thiazides probably act by conserving renal calcium, thus reducing bone resorption. Trials are under way to determine if these agents reduce bone loss and prevent fractures.
Fluoride increases the number, activity, and lifespan of osteoblasts. In doses of 40 to 80 mg/day it can increase trabecular bone volume, but it has no effect on cortical bone. When given alone, fluoride causes the formation of abnormal bone, but this effect can be minimized by giving 800 to 1000 mg/day of calcium. Fluoride increases trabecular bone in about half of the patients, causes a minimal increase in another 25%, and has no effect in the remainder.50 The bone formed as a result of stimulation by fluoride is less strong than normal bone. There have been divergent results in studies of the incidence of osteoporotic fractures in patients treated with fluoride.50,51 A study using a slow-release form of sodium fluoride and calcium citrate administered for 4 years to postmenopausal women showed an increase in bone mass in the spine and hip.51 This drug also inhibited new vertebral compression fractures. Slow-release sodium fluoride is currently being considered by the FDA for approval as a therapy for postmenopausal osteoporosis. Fluoride has significant side effects: nausea and gastric irritation occur in most patients. About 10% of patients may develop lower extremity pain, which may result from stress fractures or tendonitis.
Exogenous testosterone has also been considered for the treatment of osteoporosis in women. There is one randomized study of the benefit of testosterone on bone density in women with osteoporosis.52 After 3 years it showed no change in bone density in those receiving estrogen alone, but a 2.5% increase in bone density was evident in those receiving combined therapy with estrogen and testosterone. Further studies are necessary to confirm whether the combination of testosterone and estrogen has a clinical role.
Osteoporosis is less common in men than in women, probably because men have a greater bone mass and do not experience an equivalent of menopause. Among men with osteoporosis, secondary causes are present in 26% to 72% of patients. The most common causes of secondary osteoporosis in men are exposure to high-dose glucocorticoids, hypogonadism, long-term heavy alcohol consumption, smoking, and hyperthyroidism. Also, age-related declines in testosterone, adrenal androgens, and insulin-like growth factor-1 may contribute to a reduction in bone formation and bone loss.53,54
Evaluation of men with osteoporosis should rule out secondary causes. Currently, we lack studies that identify effective therapies in men with osteoporosis; however, studies are under way to test the effects of calcium, vitamin D, testosterone, bisphosphonates, and calcitonin. Testosterone in men is an appropriate treatment in the presence of diagnosed hypogonadism and no history of prostate cancer. Testosterone is available as an intramuscular injection of a long-acting testosterone ester (testosterone cypionate or testosterone enanthate), and there are also two transdermal preparations of testosterone (Testoderm and Androderm). As replacement therapy, the suggested dosage for the injectable preparation is 50 to 400 mg every 2 to 4 weeks. Transdermal delivery through the scrotal skin (Testoderm) has the advantage of requiring only one patch per day but must be worn on the scrotum. Nonscrotal delivery (Androderm) may produce normal plasma concentrations of testosterone and its metabolites when two patches are applied to nonscrotal skin at bedtime. The most common adverse effects of the patch are skin irritation and contact dermatitis, which can lead some patients to stop using it.
A number of new drugs for the treatment and prevention of osteoporosis are under study. Some of them are bisphosphonates (i.e., risedronate and tiludronate), recombinant human parathyroid hormone (ALX1-11), estrogen agonist-antagonist (i.e., droloxifene), selective estrogen receptor modulator (raloxifene), and vitamin D2 analog, which is intended to improve intestinal absorption of calcium.
Prevention is the only intervention that is cost-effective for osteoporosis. The 1994 National Institutes of Health (NIH) Consensus Conference29 recommended increasing the calcium content of the diet to 1200 to 1500 mg/day for young adults and 1500 mg/day for older patients unless the patient has a history of hypercalcemia or hypercalciuria,. Calcium may be more bioavailable in dairy products than in green vegetables. Calcium therapy should be given to all patients with osteoporosis in three or four doses totaling 1000 to 1500 mg/day of elemental calcium. Once this treatment has been initiated, serum calcium levels should be monitored annually. Recent data have shown also that high calcium intakes are associated with a significantly decreased risk of fractures of the wrist and hip.28,55 Excessive calcium intake (more than 2000 mg/day) is to be avoided because it can cause hypercalcemia or the milk-alkali syndrome. Elderly subjects may experience difficulties with flatulence and constipation if calcium intakes exceed 1500 mg./day.
Physical exercise is another form of therapy for all patients, but the amount should be dictated by common sense. Prevention of falls and other trauma may be as beneficial as therapy aimed at preventing further bone loss. Cigarette smoking and heavy alcohol consumption should cease.
Use of estrogen appears to be the most effective therapy in preventing postmenopausal bone loss. Epidemiologic studies suggest that estrogen use can decrease fracture frequency in women. Estrogen should be initiated as soon as possible after the menopause or oophorectomy. It is unknown how long estrogens should be continued, but at least 10 years is advised; some authorities suggest administering them for life. In women who are currently postmenopausal the only FDA-approved therapy for the prevention of bone loss is estrogen; however, studies are under way to determine whether alendronate and calcitonin can be used to prevent postmenopausal osteoporosis. Hypogonadal young adults should be evaluated, and if the hypogonadism cannot be reversed, sex hormone replacement therapy should be initiated.

Shneider E, Guralnik J: The aging of America. JAMA 1990;263:2335–2340.

Barret-Connor E: The economic and human cost of osteoporotic fractures. Am J Med 1995;98(Suppl 2A):3–8.

Lyles K: Osteopenia: Osteoporosis and osteomalacia. Ambulatory Geriatric Care. St. Louis, Mosby-Year Book, in press, 1997.

Lindsay R: The burden of osteoporosis: Cost. Am J Med 1995;98(Suppl 2A):9–11.

Parker MJ, Myles JW, Anand JK, Drewett R: Cost-benefit analysis of hip fracture treatment. J Bone Joint Surg 1992;74b:261–264.

Marottoli RA, Berkman LF, Cooney LM: Decline in physical function following hip fracture. J Am Geriatr Soc 1992;40:861–866.

Cummings SR, Black DM, Ruben SM: Lifetime risks of hip, Colles’ or vertebral fracture and coronary heart disease among white postmenopausal women. Arch Intern Med 1989;149:2445–2448.

Lyles KW, Gold DT, Shipp KM, et al: Association of osteoporotic vertebral compression fractures with impaired functional status. Am J Med 1993;94:595–601.

Greendale GA, Barrett-Connor E, Ingles S, Haile R: Late physical and functional effects of osteoporotic fracture in women: The Rancho Bernardo study. J Am Geriatr Soc 1995;43:955–961.

Ross PD, Davis JW, Epstein RS, Wasnich RD: Preexisting fractures and bone mass predict vertebral fracture incidence in women. Ann Intern Med 1991;114:919–923.

Silman AJ: The patient with fracture: The risk of subsequent fractures. Am J Med 1995;98(Suppl 2A):12–16.

Browner WS, Seeley DG, Vogt TM, Cummings ST: Non-trauma mortality in elderly women with low mineral density. Lancet 1991;338:355–358.

Lu-Yao GL, Baron JA, Barrett JA, Fisher ES: Treatment and survival among elderly Americans with hip fractures: A population-based study. Am J Public Health 1994;84:1287–1291.

Ray WA, Griffin MR, Baugh DK: Mortality following hip fracture before and after implementation of the prospective payment system. Arch Intern Med 1990;150:2109–2114.

Riis BJ: The role of bone loss. Am J Med 1995;98(Suppl 2A):29–32.

Christiansen C: What should be done at the time of menopause? Am J Med 1995;98(Suppl 2A):56–59.

Christiansen C, Riis BJ, Rodbro P: Prediction of rapid bone loss in postmenopausal women. Lancet 1987;Vol. I.

Hansen MA, Overgaard K, Riis BJ, Christiansen C: Role of peak bone in postmenopausal osteoporosis: 12-year study. Br Med J 1991;303:961–964.

Parfitt AM, Mundy GR, Roodman GD, Hughes DE, Boyce BF: A new model for the regulation of bone resorption, with particular reference to the effects of bisphosphonates. J Bone Miner Res 1996;11:150–159.

Ganong WF (ed): Review of Medical Physiology. Norwalk, CT: Appleton & Lange, 1993.

Mitchell DR, Lyles KW: Glucocorticoid-induced osteoporosis: Mechanisms for bone loss; evaluation of strategies for prevention. J Gerontol 1990;45:153–158.

Prince RL, Dick I, Devine A, et al: The effects of menopause and age on calcitropic hormones: A cross-sectional study of 655 healthy women aged 35 to 90. J Bone Miner Res 1995;10:835–842.

Van Daele PL, Stolk RP, Burger H, et al: Bone density in non-insulin dependent diabetes mellitus. The Rotterdam Study. Ann Intern Med 1995;122:409–414.

Peacock M: Vitamin D receptor gene alleles and osteoporosis: A contrasting view (editorial). J. Bone Miner Res 1995;10:1294–1297.

Eisman JA: Vitamin D receptor gene alleles and osteoporosis: An affirmative view. (editorial). J. Bone Miner Res 1995;10:1289–1293.

Stedman’s Medical Dictionary, 25th ed. Baltimore, Williams & Wilkins, 1989.

Barzel US: The skeleton as an ion exchange system: Implications for the role of acid-base imbalance in the genesis of osteoporosis. J Bone Miner Res 1995;10:1431–1436.

Reid IR, Ames RW, Evans MC, et al: Long-term effects of calcium supplementation on bone loss and fractures in postmenopausal women: A randomized controlled trial. Am J Med 1995;98:331–335.

NIH Consensus Development Panel on Optimal Calcium Intake. JAMA 1994;272:1942–1948.

Cummings SR, Nervitt MC, Browner WS, et al: Risk factors for hip fractures in white women. N Engl J Med 1995;332:767–773.

Prince R, Devine A, Dick I, et al: The effects of calcium supplementation (milk powder or tablets) and exercise on bone density in postmenopausal women. J Bone Miner Res 1995;10:1068–1075.

Garnero P, Borel O, Sornay-Rendu E, Delmas PD: Vitamin D receptor gene polymorphisms do not predict bone turnover and bone mass in healthy premenopausal women. J Bone Miner Res 1995;10:1283–1288.

Ferrari S, Rissoli R, Chevalley D, Slosman D, Eisman JA, Bonjour J-P: Vitamin D receptor gene polymorphisms and change in lumbar spine bone mineral density. Lancet 1995;345:423–424.

Felson DT, Zhang Y, Hannan MT, Kannel WB, Kiel DP: Alcohol intake and bone mineral density in elderly men and women. The Framingham Study. Am J Epidemiol 1995;142:485–492.

Keck E, Bremer G, Franck H: Alcohol-induced osteopenia. Radiologe 1986;26:587–591.

Bauer DC, Browner WS, Cauley JA, et al: Factors associated with appendicular bone mass in older women. Ann Intern Med 1993;118:657–665.

Earnshaw SA, Hosking DJ. Clinical usefulness of risk factors for osteoporosis. Ann Rheum Dis 1996;55:338–339.

Jonston CC, Melton LJ, Lindsay R, Eddy D: Clinical indications for bone mass measurements. A report from the Scientific Advisory Board of the National Osteoporosis Foundation. J Bone Miner Res 1989;4(Suppl 2):1–28.

Nachtigall LE: Enhancing patient compliance with hormone replacement therapy at menopause. Obstet Gynecol 1990;75:77s–80s.

Genant HK, Baylink DJ, Gallagher JC: Estrogens in the prevention of osteoporosis in postmenopausal women. Am J Obstet Gynecol 1989;161:1842–1846.

Belchetz PE. Hormonal treatment of postmenopausal women. N Engl J Med 1994;330:1062–1071.

Henrich JE: The postmenopausal estrogen/breast cancer controversy. JAMA 1992;268:1900–1902.

Grady D, Rubin SM, Petitti DB, et al: Hormone therapy to prevent disease and prolong life in postmenopausal women. Ann Intern Med 1992;117:1016–1037.

Stanford JL, Weiss NS, Voigt LF, et al: Combined estrogen and progestin hormone replacement therapy in relation to risk of breast cancer in middle-age women. JAMA 1995;274:137–142.

Colditz GA, Hankinson SE, Hunter DJ, et al: The use of estrogens and progestins and the risk of breast cancer in postmenopausal women. N Engl J Med 1995;332:1589–1593.

Colditz GA, Stampfer MJ, Willett WC, et al: Prospective study of estrogen replacement therapy and risk of breast cancer in postmenopausal women. JAMA 1990;264:2648–2653.

Liberman U, Weiss S, Broll J, et al: Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 1995;333:1437–1443.

Ooms ME, Roos JC, Bezemer PD, et al: Prevention of bone loss by vitamin D supplementation in elderly women: A randomized double-blind trial. J Clin Endocrinol Metab 1995;80:1052–1058

Chapuy MC, Arlot ME, Delmas PD, Meunier PJ: Effect of calcium and cholecalciferol treatment for three years on hip fractures in elderly women. Br Med J 1994;308:1081–1082.

Riggs BI, Hodgson SF, O’Fallon WM, et al: Effect of fluoride treatment on the fracture rate in postmenopausal women with osteoporosis. N Engl J Med 1990;322:802–808.

Pak Ch, Sakhaee K, Adams-Huet B, et al: Treatment of postmenopausal osteoporosis with slow-release sodium fluoride. Ann Intern Med 1995;123:401–408.

Barlow Dh, Abdalla HI, Roberts AD, et al: Long-term hormone implant therapy: Hormonal and clinical effects. Obstet Gynecol 1986;67;321–325.

Kelepouris N, Harper KD, Gannon F, Kaplan FS, Haddad JG: Severe osteoporosis in men. Ann Intern Med 1995;123:452–460.

Seeman E: The dilemma of osteoporosis in men. Am J Med 1995;98(Suppl 2A):76–88.

Abelow BJ, Holford TR, Insogna KL: Cross-cultural association between dietary animal protein and hip fracture: A hypothesis. Calcif Tissue Int 1992;50:14–18.

* An acid-ash diet consists largely of meat, fish, eggs, and cereals with little fruit, vegetables, cheese, or milk; when catabolized, it leaves an acid load to be excreted in the urine.26



  1. Great article except for the failure to mention spine alignment and bone remodeling. Wolff’s law is a direct testament to the influence of abnormal loading resulting in abnormal spine remodeling due to abnormal alignment.

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