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Osteoporosis

Introduction

Osteoporosis remains a serious health problem for society. It is estimated that 36 million Americans, both men and women, suffer from the disorder, which is responsible for a high risk for serious fractures especially of the spine, hip and wrist. It is an insidious disease, sometimes referred to as the silent thief, as it slowly drains away bone mass, usually remaining undiagnosed until a fracture occurs. Many factors are responsible for the development of osteoporosis. Although it can affect any age group and either sex, the vast majority of clinically significant cases of osteoporosis occur in postmenopausal women.

Osteoporosis is responsible for 1.5 million fractures annually, resulting in acute and chronic disability and death and an annual cost of treatment estimated at $17 billion. 1 in 2 women and 1 on 4 men over the age of 50 will suffer a vertebral fracture. As the population ages, the prevalence of the diagnosis is predicted to rise. Other factors promoting this increase include the increased public awareness of osteoporosis and the improvement in diagnostic techniques and therapy.

The Pathophysiology Of Osteoporosis

The pathophysiology of osteoporosis is dependent on the relative activity of bone-forming osteoblasts and bone-destructive osteoclasts. There is growing evidence that this ratio is genetically based and determines the bone mass of the individual. Bone mass peaks at about age 30 following which bone breakdown outpaces formation and bone density declines since the volume of bone remains about the same.

After a transient period of stability ending at about age 40 in both sexes, a slow phase of bone loss begins. There is some difference between cortical and trabecular bone in the rate of bone loss. Over their lifetime, women lose about 35% of their cortical bone, which is found predominantly in the shafts of the long bones. Trabecular bone is concentrated in the vertebrae, in the pelvis and other flat bones, and in the ends of long bones. With its greater surface area, trabecular bone is metabolically much more active than is cortical bone, and consequently bone loss occurs at a higher rate, averaging about 50% over the lifetime of a woman. Men lose about two-thirds of these amounts.

The initial rate of cortical bone loss is about 0.3 to 0.5 percent per year and increases with age until it slows or ceases late in life. In postmenopausal women, an accelerated phase of cortical bone loss is superimposed on this pattern. The rate increases to 2 to 3% annually and then the rate decreases to the original bone loss rate after 8 to 10 years.

Data concerning the rate and pattern of decrease of trabecular bone loss are controversial, and some of the studies have demonstrated an accelerated phase of bone loss following natural menopause. Several conclusions, however, can be drawn from the studies that have been performed. The pattern of trabecular bone loss differs from that of cortical bone loss in several ways. In both sexes, the onset of trabecular bone loss occurs at least a decade earlier than the onset of cortical bone loss. In women, the extent of pre-menopausal trabecular bone loss is much greater than the extent of cortical bone loss. Additionally, the rate of accelerated postmenopausal phase of trabecular bone loss may have an initial rate that is greater than that for cortical bone loss, but a duration that is shorter.

Bone formation and bone resorption do not occur randomly throughout the skeleton. Rather, they follow a programmed sequence at discrete foci called bone-remodeling units (BMU). At the beginning of each remodeling cycle, osteoclasts appear on a previously inactive surface and, over a period of about two weeks, construct a tunnel in cortical bone or a lacuna in trabecular bone. Osteoblasts then take control and fill in the resorption cavities over a period of three to four months, creating a new bone structural unit.

The rate of bone turnover is determined mainly by the frequency of activation of new BMUs. Bone loss indicates an uncoupling of the phases of bone remodeling, with a relative or absolute increase in resorption over formation. Two basic abnormalities may be responsible for the uncoupling phenomenon: first, osteoclasts may function in their normal fashion, but osteoblasts fail to fill their resorption cavities. This impairment of bone formation is the usual mechanism responsible for osteoporosis during the slow, age-dependent phase of bone loss. Second, the accelerated phase of bone loss that occurs in postmenopausal women is usually associated with osteoclastic overactivity that overwhelms osteoblastic performance even though the latter may continue at a normal or even increased level of activity. The end result of either of these uncoupling mechanisms is the same bone loss.

As knowledge of the cellular and metabolic events in the normal bone remodeling process has accumulated over the last decade, attention has focused on the basic structural constituents of bone and in the control mechanisms likely responsible for normal bone remodeling. The organic matrix of bone contains several protein families, including collagen, proteoglycans, and glycoproteins, all of which may be modified by events such as phosphorylation and sulfation. By mechanisms not yet fully understood, bone matrix attracts calcium, which combines with phosphorus, oxygen, hydrogen and other elements to form crystals. These crystals, primarily of calcium phosphate, are responsible for the density and hardness of bone. Ninety-nine percent of the body’s calcium resides in bone; the other one percent is found in blood and extracellular fluids where it plays an important role in transmembrane transport of ions and in muscle contraction. The body’s sole source of calcium is dietary. It is absorbed from the small intestine with the help of Vitamin D.

A number of hormones play key roles in the determination of bone density. These include not only the androgenic and estrogenic sex hormones, but the hormones secreted by the parathyroid’s, thyroid, adrenals, as well as insulin-like growth factor I (somatomedin C), and pituitary growth hormone. In many cases, the exact mechanisms whereby these hormones exert their influences are unknown and remain the subject of extensive study. Extensive research is also ongoing on the potential role of cytokines and growth factors that may be responsible for stimulating osteoclastic bone resorption or osteoblastic senescence. The major mediators under study include interleukins 1 and 6, tumor necrosis factor (TNF), lymphotoxin, prostaglandins of the E type, leukotrienes, lipopolysaccharide, transforming growth factor-J, and the colony-stimulating factors (CSFs). At least twelve local regulators of growth, produced by bone, cartilage or marrow matrix, have been identified. However, until such basic influences can be elucidated the prevention and management of osteoporosis must depend on clinically relevant parameters.

One of the most significant advances in bone biology in the past decade has been the identification of the receptor activator of nuclear factor-kappa B (RANK) and its ligand (RANKL) as key regulators of bone turnover. RANKL, a member of the tumor necrosis superfamily, is secreted by osteoblasts in response to a variety of hormonal and cytokine signals known to be important to bone metabolism, and is the principal regulator of the differentiation and activity of osteoclasts. RANKL signaling is mediated by its receptor ( (RANK) on osteoclasts. The binding of RANKL to RANK is inhibited by sequestration to a soluble dummy receptor – osteoprotagerin (OPG). OPG is cosecreted by osteoblasts and serves to modulate the effective levels of RANKL. As expected, animal models confirm that RANKL excess shifts that balance of bone metabolism in the direction of catabolism and causes osteopenia, and conversely that absence of RANKL increases bone density. RANKL inhibition offers the therapeutic possibility of treating osteoporosis. Several Phase 2 studies have verified this. Early studies also indicate that the fully human monoclonal antibody, denosumab (formerly known as AMG 162), an immunoglobulin G2 antibody to RANKL, acts as a surrogate of OPG and specifically blocks RANKL binding to RANK. These results suggest the use of a new class of antiresorptive drugs for the treatment of osteoporosis based on the inhibition of RANKL.

Non-Modifiable Risk Factors For Osteoporosis

Any factor that disrupts the orderly function of the bone remodeling units, thereby producing an osteoclastic/osteoblastic imbalance, is a potential risk factor for osteoporosis. These have been divided into those risk factors that are non-modifiable, that is, those over which there is little or no control, and those that are modifiable, that is, those that are amenable to preventive measures and/or therapeutic correction.

Risk Factors for Osteoporosis

Genetics

There is increasing evidence that genetic factors play important direct and indirect roles in the pathogenesis of osteoporosis. Genetic traits such as a light skin and small body frame have been consistently described as risk factors for the development of osteoporosis. Peak bone mass as well as skeletal structure and metabolic activity have been shown to be genetically determined. Twin and family studies suggest that up to 85% of the variance in mineral density is genetically determined. Smith et al found that monozygotic twins had a significantly greater concordance for bone density of the radius than did dizygotic twins. Molecular genetic studies have identified several candidate genes, which may be involved in this process. The most promising gene candidate identified thus far is the collagen type I alpha gene, which affects recognition of a site for calcium deposition. Considerable attention has also been given to the role of a vitamin D receptor gene, but the findings have been inconsistent. It appears unlikely that a single gene will contribute more than a small percentage in the variation in a multi-factorial disease such as osteoporosis.

Age and Age-Related Factors

Age is by far the most important empirical determination of bone mass. If the age of an apparently healthy woman is known, the bone density of her lumbar spine or femoral neck can be predicted with a standard deviation of only about 10%. The decrease in bone density with age reflects the aggregate effects of several processes. Although these processes occur universally, variations in their magnitude may account, in part, for individual differences in bone loss.

The aging processes responsible for decreased bone mass and osteoporosis include the previously mentioned increase in osteoclastic activity and decreased osteoblastic activity resulting in an imbalance in the bone remodeling unit. Calcium absorption decreases with age in both sexes, especially after the age of 70, and serum levels of the active metabolite of vitamin D decrease by about 50% with aging. Additionally, serum levels of immunoreactive parathyroid hormone (iTPH) increase with age, possibly in response to decreased calcium absorption, thereby producing a compensatory increase in bone remodeling units, an increase in bone turnover, and an increase in bone loss. In fact, surgically produced hypoparathyroidism may result in increased lumbar spine density even in the very elderly. Calcitonin, a potent anti-resorptive agent produced by the thyroid gland, may contribute to the normal balance between bone formation and bone resorption. Calcitonin deficiency has been reported in age-related osteoporosis.

Gender

In addition to the effect of aging on bone density, other risk factors contribute to the development of osteoporosis. The most significant of these is menopause and the accompanying loss of estrogen in women. Women who have undergone oophorectomy in young adulthood have lower bone density in later life than their peers. Surgical menopause accelerates bone loss in both the appendicular and axial skeleton. In most cases, the bone-protective action of androgens is preserved in men, although in some elderly men and in men with overt hypogonadism, the decline in gonadal function is often associated with vertebral fractures. Estrogen receptor sites have been identified on bone and there is good evidence that estrogen has a favorable influence on bone growth and development despite recent concerns regarding the use of postmenopausal hormonal replacement therapy (in the prevention and therapy of cardiovascular disorders as well as their possible influence on the development of breast cancer).

Menopause, however, appears to be only one of several causes for the high prevalence of osteoporosis in women compared to men. Riggs et al found that vertebral bone loss began well before menopause. The sex difference in prevalence of osteoporosis may have a genetic basis. Seeman et al reported that the daughters of women with hip fractures secondary to osteoporosis had reduced femoral neck bone density – a finding not present in sons or daughters of women without osteoporosis. Dietary factors and differences in physical activity patterns between men and women may also play a role in the gender difference in osteoporosis prevalence.

Ethnicity

African-Americans have more bone mass and greater bone density throughout their skeletons than do Caucasians, and African-American women suffer fewer fractures than do Caucasian women. In fact, black women are only half as likely to suffer a hip fracture as are white and Asian women. Investigators measuring the spinal bone density of black and white prepubertal girls, found little difference until puberty. In girls age 7 through 12, bone density at various skeletal sites was greater in black children than in white, and at puberty, black girls had a 34% increase in bone density compared with an increase of 11% in white girls. It has been suggested that differences in spinal bone density between black and white women may stem from hormonal and metabolic differences during adolescence. These racial differences are probably of genetic origin and await the results of further studies.

Modifiable Risk Factors for Osteoporosis

Diet and Nutrition

Osteoporosis, is not a sudden event: the disease is a continuum. The former Surgeon General, C. Everett Koop, describes osteoporosis as a pediatric disease. An adequate intake of calcium and vitamin D, especially during childhood and adolescence is essential for the development and maintenance of good bone health. Guidelines for the dosage of calcium have been established (see ), indicating a daily need of 1200 to 1300 mg of calcium and 400 to 800 units of Vitamin D. Many women, especially those in the postmenopausal years are on a much lower daily dose of both components. More than half of adolescents in this country consume less than 500 mg of calcium daily, although the recommended dose during the growth spurt is 1200 mg daily. Since peak bone mass in women is attained between the ages of 17 and 20, poor calcium intake results in a reduced peak bone mass, lower bone mass throughout life, and fractures later in life.

Table 1: Recommended Daily Allowances (RDAs) for Calcium

Certain foods, especially dairy products, are naturally high in calcium. Many processed foods such as bread, juices, and cereal are “calcium fortified”. Milk is a reliable source because it contains vitamin D and lactose, which enhance the body’s ability to absorb and utilize calcium. There is an increase in the prevalence of lactase deficiency in osteoporotic patients compared to age-related non-osteoporotic subjects, and lactase supplementation may be necessary in these individuals.

Other nutritional factors seem to be less important. A high protein diet increases the urinary excretion of calcium primarily because acid radicals decrease renal tubular resorption. This may increase the amount of dietary calcium required to maintain balance. Although long term administration of phosphate can produce osteoporosis in laboratory animals, variations in phosphate intake over a wide range do not affect calcium balance in perimenopausal women. Serum levels of the active metabolite of vitamin D (25-OH-D) decline moderately with aging. However, because of the nutritional fortification of food, deficiency of vitamin D is probably not a major risk factor for osteoporosis in the United States, except in certain elderly housebound persons with inadequate dietary intake. Even a relatively short exposure to sunlight of 15 to 30 minutes can effect a significant increase in skin-generated vitamin D. Eating disorders such as bulimia and anorexia nervosa can contribute to osteoporosis. A triad of eating disorders, amenorrhea and osteoporosis, termed the female athletes’ triad has been described.

Lifestyle

A sedentary lifestyle and lack of exercise are frequently cited as risk factors for the development of osteoporosis. Prolonged immobility results in osteoporosis; people who are bedridden can lose up to 1% of their trabecular bone per week and astronauts can lose that much bone while weightless in space. Several controlled trials have provided evidence that regular exercise can maintain or even increase bone mass in postmenopausal women.

Paganini-Hill and coworkers evaluated 8,600 postmenopausal women and 5,049 men residing in a southern California retirement community for risk factors for hip fracture. Incidence rates were twice as high in women as in men, but in both sexes the rates nearly doubled every five years between 70 and 90 years of age. Active exercise was strongly negatively associated with hip fracture risk in both sexes. The age-adjusted relative risk was 0.6 and 0.5 for females and males, respectively, for one or more hours of exercise per day compared with less than a half-hour of exercise. The age-adjusted relative risk estimate did not change materially in multivariate analysis when adjusted simultaneously for age, body mass, smoking, and in women, for age at menarche or number of children. The study also confirmed previous reports that a high body mass index is associated with a significant reduction in hip fracture risk for females.

A Danish study of women aged 50 to 73 with previous wrist fractures found that women who engaged in carefully prescribed aerobic and isometric exercises for one hour twice weekly increased the mineral content of their lumbar spine by 3.5 percent. The control group who performed no exercise experienced a 2.7 percent drop in bone mineral density.Others have reported increments of 1 to 3% over an exercise period of two years, but at the same time, pointing out that these effects are small compared to the 5%-10% differential in mass theoretically required to decrease fracture rates by 25%-50%. he presence of a high bone mass in athletes, compared to more sedentary individuals, has been cited as supportive evidence of the value of exercise. Risk Factors For Osteoporosis

Any factor that disrupts the orderly function of the bone remodeling units, thereby producing an osteoclastic/osteoblastic imbalance, is a potential risk factor for osteoporosis. These have been divided into those risk factors that are non-modifiable, that is, those over which there is little or no control, and those that are modifiable, that is, those that are amenable to preventive measures and/or therapeutic correction.

Non-Modifiable Risk Factors for Osteoporosis

Genetics

There is increasing evidence that genetic factors play important direct and indirect roles in the pathogenesis of osteoporosis. Genetic traits such as a light skin and small body frame have been consistently described as risk factors for the development of osteoporosis.11,12 Peak bone mass as well as skeletal structure and metabolic activity have been shown to be genetically determined. Twin and family studies suggest that up to 85% of the variance in mineral density is genetically determined. Smith et al13 found that monozygotic twins had a significantly greater concordance for bone density of the radius than did dizygotic twins. Molecular genetic studies have identified several candidate genes, which may be involved in this process.14-16 The most promising gene candidate identified thus far is the collagen type I alpha gene, which affects recognition of a site for calcium deposition.17 Considerable attention has also been given to the role of a vitamin D receptor gene, but the findings have been inconsistent.18,19 It appears unlikely that a single gene will contribute more than a small percentage in the variation in a multi-factorial disease such as osteoporosis.

Age and Age-Related Factors

Age is by far the most important empirical determination of bone mass. If the age of an apparently healthy woman is known, the bone density of her lumbar spine or femoral neck can be predicted with a standard deviation of only about 10%.20 The decrease in bone density with age reflects the aggregate effects of several processes. Although these processes occur universally, variations in their magnitude may account, in part, for individual differences in bone loss.

The aging processes responsible for decreased bone mass and osteoporosis include the previously mentioned increase in osteoclastic activity and decreased osteoblastic activity resulting in an imbalance in the bone remodeling unit. Calcium absorption decreases with age in both sexes, especially after the age of 70, and serum levels of the active metabolite of vitamin D decrease by about 50% with aging.21 Additionally, serum levels of immunoreactive parathyroid hormone (iTPH) increase with age, possibly in response to decreased calcium absorption, thereby producing a compensatory increase in bone remodeling units, an increase in bone turnover, and an increase in bone loss.22 In fact, surgically produced hypoparathyroidism may result in increased lumbar spine density even in the very elderly.23 Calcitonin, a potent anti-resorptive agent produced by the thyroid gland, may contribute to the normal balance between bone formation and bone resorption. Calcitonin deficiency has been reported in age-related osteoporosis.24

Gender

In addition to the effect of aging on bone density, other risk factors contribute to the development of osteoporosis. The most significant of these is menopause and the accompanying loss of estrogen in women. Women who have undergone oophorectomy in young adulthood have lower bone density in later life than their peers. Surgical menopause accelerates bone loss in both the appendicular and axial skeleton.24 In most cases, the bone-protective action of androgens is preserved in men, although in some elderly men and in men with overt hypogonadism, the decline in gonadal function is often associated with vertebral fractures. Estrogen receptor sites have been identified on bone and there is good evidence that estrogen has a favorable influence on bone growth and development despite recent concerns regarding the use of postmenopausal hormonal replacement therapy (in the prevention and therapy of cardiovascular disorders as well as their possible influence on the development of breast cancer).

Menopause, however, appears to be only one of several causes for the high prevalence of osteoporosis in women compared to men. Riggs et al25 found that vertebral bone loss began well before menopause. The sex difference in prevalence of osteoporosis may have a genetic basis. Seeman et al16 reported that the daughters of women with hip fractures secondary to osteoporosis had reduced femoral neck bone density – a finding not present in sons or daughters of women without osteoporosis. Dietary factors and differences in physical activity patterns between men and women may also play a role in the gender difference in osteoporosis prevalence.

Ethnicity

African-Americans have more bone mass and greater bone density throughout their skeletons than do Caucasians, and African-American women suffer fewer fractures than do Caucasian women. In fact, black women are only half as likely to suffer a hip fracture as are white and Asian women. Investigators measuring the spinal bone density of black and white prepubertal girls, found little difference until puberty. In girls age 7 through 12, bone density at various skeletal sites was greater in black children than in white, and at puberty, black girls had a 34% increase in bone density compared with an increase of 11% in white girls.26 It has been suggested that differences in spinal bone density between black and white women may stem from hormonal and metabolic differences during adolescence.27,28 These racial differences are probably of genetic origin and await the results of further studies.

Modifiable Risk Factors for Osteoporosis

Diet and Nutrition

Osteoporosis, is not a sudden event: the disease is a continuum. The former Surgeon General, C. Everett Koop, describes osteoporosis as a pediatric disease. An adequate intake of calcium and vitamin D, especially during childhood and adolescence is essential for the development and maintenance of good bone health. Guidelines for the dosage of calcium have been established (see ), indicating a daily need of 1200 to 1300 mg of calcium and 400 to 800 units of Vitamin D. Many women, especially those in the postmenopausal years are on a much lower daily dose of both components.11 More than half of adolescents in this country consume less than 500 mg of calcium daily, although the recommended dose during the growth spurt is 1200 mg daily. Since peak bone mass in women is attained between the ages of 17 and 20, poor calcium intake results in a reduced peak bone mass, lower bone mass throughout life, and fractures later in life.29

Table 1: Recommended Daily Allowances (RDAs) for Calcium Age

Milligrams

0-6 months 400 6 months to 1 year 600 1-10 years 800 11-24 years 1200 25-onward (men) 800 25-50 (women) 1500 51 onward (women) 1200 Breast feeding 1200

Certain foods, especially dairy products, are naturally high in calcium. Many processed foods such as bread, juices, and cereal are “calcium fortified”. Milk is a reliable source because it contains vitamin D and lactose, which enhance the body’s ability to absorb and utilize calcium. There is an increase in the prevalence of lactase deficiency in osteoporotic patients compared to age-related non-osteoporotic subjects30, and lactase supplementation may be necessary in these individuals.

Other nutritional factors seem to be less important. A high protein diet increases the urinary excretion of calcium primarily because acid radicals decrease renal tubular resorption. This may increase the amount of dietary calcium required to maintain balance. Although long term administration of phosphate can produce osteoporosis in laboratory animals, variations in phosphate intake over a wide range do not affect calcium balance in perimenopausal women. Serum levels of the active metabolite of vitamin D (25-OH-D) decline moderately with aging. However, because of the nutritional fortification of food, deficiency of vitamin D is probably not a major risk factor for osteoporosis in the United States, except in certain elderly housebound persons with inadequate dietary intake. Even a relatively short exposure to sunlight of 15 to 30 minutes can effect a significant increase in skin-generated vitamin D. Eating disorders such as bulimia and anorexia nervosa can contribute to osteoporosis. A triad of eating disorders, amenorrhea and osteoporosis, termed the female athletes’ triad has been described31.

Lifestyle

A sedentary lifestyle and lack of exercise are frequently cited as risk factors for the development of osteoporosis. Prolonged immobility results in osteoporosis; people who are bedridden can lose up to 1% of their trabecular bone per week and astronauts can lose that much bone while weightless in space.32 Several controlled trials have provided evidence that regular exercise can maintain or even increase bone mass in postmenopausal women.33,34

Paganini-Hill and coworkers35 evaluated 8,600 postmenopausal women and 5,049 men residing in a southern California retirement community for risk factors for hip fracture. Incidence rates were twice as high in women as in men, but in both sexes the rates nearly doubled every five years between 70 and 90 years of age. Active exercise was strongly negatively associated with hip fracture risk in both sexes. The age-adjusted relative risk was 0.6 and 0.5 for females and males, respectively, for one or more hours of exercise per day compared with less than a half-hour of exercise. The age-adjusted relative risk estimate did not change materially in multivariate analysis when adjusted simultaneously for age, body mass, smoking, and in women, for age at menarche or number of children. The study also confirmed previous reports that a high body mass index is associated with a significant reduction in hip fracture risk for females.

A Danish study of women aged 50 to 73 with previous wrist fractures found that women who engaged in carefully prescribed aerobic and isometric exercises for one hour twice weekly increased the mineral content of their lumbar spine by 3.5 percent. The control group who performed no exercise experienced a 2.7 percent drop in bone mineral density.36 Others have reported increments of 1 to 3% over an exercise period of two years, but at the same time, pointing out that these effects are small compared to the 5%-10% differential in mass theoretically required to decrease fracture rates by 25%-50%.37 The presence of a high bone mass in athletes, compared to more sedentary individuals, has been cited as supportive evidence of the value of exercise.38

Chronic alcoholism can aggravate age-related osteoporosis leading to severe bone loss. Alcoholism is associated with decreased bone formation, possibly because of a direct effect of ethanol on osteoblast function.39,40 Other possible causes of bone loss in alcoholics include poor diet, mal-absorption of calcium due to vitamin D deficiency, and alcohol-related liver disease. Several studies have identified smoking as a risk factor for osteoporosis.35, 41

Other risk factors for osteoporosis include current tobacco use and body weight less than 127 pounds.

The Effects of Concomitant Diseases

Certain diseases and surgical procedures may be associated with the development of osteoporosis. The most common conditions in this group are early oophorectomy in women, hypogonadism in men, subtotal gastrectomy, hyperthyroidism, hyperparathyroidism, diabetes mellitus, and chronic obstructive pulmonary disease, conditions that interfere with normally protective nutritional and metabolic processes. These associations may occur in as many as 20% of women and 40% of men presenting with vertebral or hip fractures.5 The term “secondary osteoporosis” has been used to designate this type of osteoporosis as opposed to “primary osteoporosis” used to designate the more common and inexorable process that occurs with advancing age.

In contrast, obesity is protective against bone loss, possibly acting to increase skeletal loading stress, or by increasing the resistance of bone to parathyroid hormone, increasing active vitamin D metabolites, or by increasing the peripheral conversion of androgens to estrogens.42,43

The Effects of Medications

Glucocorticoids can cause both trabecular and cortical bone loss by repressing the generation of new osteoblasts and inhibiting their ability to reform new bone. Steroids also increase the amount of calcium excreted in the urine and reduce the intestinal absorption of calcium. The mobilization of calcium by steroids occurs rapidly but stabilizes in time although steroid takers remain in a negative calcium balance. Both spontaneous and drug-induced Cushing’s syndrome are notorious for their effect on bone loss.

Other medications that may accelerate bone loss include phenytoin and other anticonvulsants, chronic lithium therapy, chemotherapeutic agents, tetracycline, long-acting benzodiazepines, cyclosporine A, and thyroid supplements.44 On the other hand, thiazide diuretics have been reported as protective against bone loss.45

Other possible causes of bone loss in alcoholics include poor diet, mal-absorption of calcium due to vitamin D deficiency, and alcohol-related liver disease. Several studies have identified smoking as a risk factor for osteoporosis.

The Effects of Concomitant Diseases

Certain diseases and surgical procedures may be associated with the development of osteoporosis. The most common conditions in this group are early oophorectomy in women, hypogonadism in men, subtotal gastrectomy, hyperthyroidism, hyperparathyroidism, diabetes mellitus, and chronic obstructive pulmonary disease, conditions that interfere with normally protective nutritional and metabolic processes. These associations may occur in as many as 20% of women and 40% of men presenting with vertebral or hip fractures. The term “secondary osteoporosis” has been used to designate this type of osteoporosis as opposed to “primary osteoporosis” used to designate the more common and inexorable process that occurs with advancing age.

In contrast, obesity is protective against bone loss, possibly acting to increase skeletal loading stress, or by increasing the resistance of bone to parathyroid hormone, increasing active vitamin D metabolites, or by increasing the peripheral conversion of androgens to estrogens. The Effects of Medications

Glucocorticoids can cause both trabecular and cortical bone loss by repressing the generation of new osteoblasts and inhibiting their ability to reform new bone. Steroids also increase the amount of calcium excreted in the urine and reduce the intestinal absorption of calcium. The mobilization of calcium by steroids occurs rapidly but stabilizes in time although steroid takers remain in a negative calcium balance. Both spontaneous and drug-induced Cushing’s syndrome are notorious for their effect on bone loss.

Other medications that may accelerate bone loss include phenytoin and other anticonvulsants, chronic lithium therapy, chemotherapeutic agents, tetracycline, long-acting benzodiazepines, cyclosporine A, and thyroid supplements. On the other hand, thiazide diuretics have been reported as protective against bone loss.

The Diagnosis of Osteoporosis

Although there are no pathogonmic physical findings for osteoporosis, there are certain features that are suggestive of the diagnosis. Most osteoporotic patients are postmenopausal women, but it is important to recognize that the disease also occurs in men. Osteoporotic patients tend to be thin, with most females weighing less than 127 pounds, but the physical examination and routine laboratory studies are usually non-contributory.

Unfortunately, most diagnoses of osteoporosis are made following the occurrence of a fracture or at the suggestion of the radiologist during the course of a radiographic examination. Bone mineral density (BMD) is the most reliable diagnostic criterion of osteoporosis and the best predictor of osteoporotic fracture. Clinical risk factors for osteoporosis are poor predictors of actual bone mass. Two techniques are available for the measurement of bone density. Dual-energy x-ray absorptiometry (DEXA) is accurate, reproducible, relatively inexpensive, and involves low radiation exposure. Quantitative computed tomography (CT) using single-energy scanning is an alternate, but less efficient technique.

Routine roentgen studies cannot detect osteoporosis unless it’s advanced, but other radiological methods can. The FDA has approved several kinds of devices that use various methods to evaluate BMD at many different skeletal sites. Dual-energy X-ray absorptiometry (DXA, formerly DEXA) is considered the “gold standard”. Two X-ray beams with different energy levels are aimed at the patient’s bones. When soft tissue absorption is subtracted out, BMD can be determined from the absorption by bone by each beam. DXA is currently the most widely used and thoroughly studied BMD technology. The technique is non-invasive and pain-free and is responsible for miniscule irradiation exposure. The same instrument should be used for the individual patient as variations have been reported in the results from different machines. The staff should be trained in the procedure. Different states have different licensure and certification requirements. BMD is commonly expressed as a T-score, the standard deviation variance of the result compared to a reference population of untreated postmenopausal women with demographics similar to that of the patient.

Furthermore, osteoporosis is common, has a lifetime risk of fracture of greater than 40%, and is treatable. The cost per quality-adjusted life-year of using bone density measurements to decide on estrogen therapy is about $25,500, a cost comparable to treating diastolic hypertension.

In a study of the 8-year probability of a nonspine fracture, Hui et al found that the initial bone mass in the radius was an excellent predictor of fracture risk. Women with a bone density of 0.6 g/cm2 had an 80% risk of having a fracture during the 4.2 years of subsequent follow-up. Those with a bone density of 0.6 to 0.8 g/cm2 had an 18% risk of fracture and those with a bone density 0.8 g/cm2 had 5% risk. The presence of preexisting or prevalent fractures significantly increases the risk of subsequent fractures. Other studies are confirmatory of the above findings.

The total fracture risk is determined by bone mass; the rate of bone loss, especially at menopause; pre-existing and prevalent fractures; clinical risk factors for osteoporosis; and the risk of falls and other trauma.

About 90% of hip fractures in elderly persons result from falls Dargent-Molina and coworkers followed 7,575 women who were 75 years of age or older for a period of 1.9 years. During this period 154 women sustained a hip fracture, an annual rate of 1%. In an age-adjusted multivariate analysis, four independent fall-related risk factors predicted hip fracture: a slower gait speed (RR, 1.4), difficulty in performing a tandem walk (RR, 1.2), reduced visual acuity (RR, 2.0), and small calf circumference (RR, 1.5). The relative risk associated with decreased bone mineral density was 1.8 per SD below the mean for age.

Over 9500 white women age 65 or over have been enrolled in the ongoing Study of Osteoporotic Fractures centered in San Francisco. In a 4.1 year follow-up, there have been 192 hip fractures, a rate of 0.5% per year. The lower prevalence in this study compared to that of Dargent-Molina et al is probably related to the lower age of the patients enrolled. In the San Francisco study, falls were associated with an inability to rise from a chair without using arms, fewer hours on feet, and poor self-rated health. Calcaneal bone density and osteoporotic risk factors were evaluated in the enrollees. The data indicated that risk factors increased the risk of hip fracture independent of bone mass.

Biochemical Markers

Although the biochemical markers of bone formation and resorption are frequently referred to as markers of “bone turnover”, it is important to recognize the existence of the two types of markers. In the case of osteoporosis, the interest is high in bone resorption. Although a large amount of research effort has been directed toward biochemical markers during the last two decades, relatively little of clinical importance has been forthcoming. Table 2 lists the biochemical markers of bone resorption that have been identified.

Table 2: Biochemical Markers of Bone Resorption

None of these biochemical markers can be considered diagnostic for osteoporosis. Any disorder characterized by bone resorption will manifest elevations, including Paget’s disease, hyperparathyroidism, hyperthyroidism, Cushing’s disease, corticosteroid therapy, immunosuppressive therapy, hypercalcemia of malignancy and bony metastases. The markers serve best as an indicator of response to therapy, although significant drops in levels may not be seen for 3 to 6 months. A comparative study of three commonly used markers- NTX (Osteomark®), CTX (Osteometer®), and PYD (Pyridinoline) revealed minor differences between them, with PYD demonstrating analytical precision and accuracy equal or superior to NTX and CTX.

The Treatment of Osteoporosis

The treatment of osteoporosis has undergone significant improvements over the past two decades. The role of calcium and vitamin D has been better defined; a multitude of biphosphatases have been developed; and progress with has taken place.

General Measures in Childhood, Adolescence, and Early Adulthood

Achieving a peak bone mass as high as possible is paramount as a potential deterrent to the development of osteoporosis and osteoporotic fractures. Since peak bone mass in women is achieved by late adolescence or early adulthood, that is, from age 17 to 21, intervention during childhood and adolescence may be important, especially in those with identifiable risk factors.

Calcium and Vitamin D: The development of healthy bones requires an adequate intake of calcium and vitamin D to provide the substrate for increased bone mass. It is now recognized that many children and adolescents, particularly females, are deficient in calcium and this deficiency is an important precursor for the development of subsequent osteoporosis. Guidelines for age-related dosages of calcium have been established and if the diet is inadequate, supplementary calcium can be administered to provide an intake of 1200 to 1300 mg daily.

DAILY CALCIUM REQUIREMENTS

postmenopausal women randomly received 1000 mg of elemental calcium as calcium carbonate with 400 IU of vitamin D daily, or a placebo. The average follow-up was 7 years. BMD measured in the hip was 1.06% higher in the treatment group than in the placebo group (p<0,01). There was no significant difference between the two groups in number of hip fractures.

Exercise

Several studies suggest that exercise in prepubertal children has positive effects on bone density. It is uncertain whether these benefits are sustained into adulthood without the benefit of a continuing exercise program, although studies of retired athletes suggest that this may occur. In contrast, exercise after puberty appears to have less of a beneficial effect. A bone-strengthening exercise program should include aerobic and weight-bearing activities such as dancing, walking, stair climbing, and jogging. These are more likely to produce positive bone-strengthening results than are non-weight-bearing activities such swimming and cycling.

Calcium

A calcium intake of less than 800 mg a day is inadequate for the prepubertal child and adolescent. Supplemental calcium should be employed to raise the daily intake to 1200 – 1500 mg. Dietary calcium supplementation has a small positive effect on bone, mainly in prepubertal children. The effect is relatively small when compared with growth-related increases in bone density, and is lost when supplementation stops. Extremely low intakes of calcium may have irreversible effects on bone mass. Bone mass may be lost in childhood and early adulthood if normal body weight is not maintained; the effect may be due to gonadal dysfunction.

Lifestyle

In addition to regular exercise, avoidance of a sedentary lifestyle, and an adequate calcium intake, the lifestyle during childhood, adolescence, and early adulthood should include the avoidance of smoking and excessive alcohol intake. Concomitant disease states such as diabetes mellitus, cystic fibrosis, and malabsorption defects should be treated. Medications that increase bone loss such as corticosteroids, phenytoin, and benzodiazepines should be avoided, if possible, or, if deemed essential, should be carefully monitored for appropriate dosage.

General Therapeutic Measures in the Adult

The same general principles that apply to the treatment of children apply as well to the treatment of osteoporosis in adults.

Exercise

A number of well-controlled studies have demonstrated the hazards of a sedentary lifestyle and the benefits of an exercise program in both the prevention and treatment of osteoporosis.

Lifestyle

Avoidance of tobacco and excessive alcohol has been demonstrated to decrease the tendency toward bone loss. Comparative studies comparing non-smokers with smokers and heavy alcohol intake to none or moderate intake, have demonstrated that both of these agents act as bone toxins.

Concomitant Diseases

Diseases such as hyperthyroidism, hyperparathyroidism, diabetes mellitus, and malabsorption states, which are known to increase bone loss, should be controlled.

Concomitant Medications

Medications such as corticosteroids, anticonvulsants, thyroid hormone, lithium, and benzodia-zepines should be carefully monitored and, if necessary, maintained at the lowest effective dosages.

Prevention of Falls

It is well known that in most cases osteoporosis does not become manifest until the occurrence of a fall or other traumatic event results in an osteoporotic fracture. It is essential, therefore, that patients with known osteoporosis or those with a strong likelihood for the disease because of the presence of risk factors, should receive instructions on measures to be taken for the prevention of falls. Households, hospital and convalescent, nursing and retirement facilities should provide and participate in these instructions as well as providing safety devices (handrails, etc) for the prevention of falls.

Specific Therapeutic Measures In The Adult

Calcium and vitamin D

Long-term high calcium intake in postmenopausal women appears to prevent or reduce bone loss, resulting in a 1% to 3% difference in bone density compared with untreated individuals. Calcium has received FDA approval for the treatment of osteoporosis. Dawson-Hughes and co-workers found significant increases in bone density and a significant decrease in non-vertebral fractures in men and women who received 500 mg/day of supplemental calcium, plus 700 international units of Vitamin D per day over a 3-year period compared to a group who received placebo. Shikari et al compared the effects of 1 alpha-hydroxy vitamin D3 (n=57) with placebo (n=56) in 113 osteoporotic women over a period of 2 years. The group that received 1 alpha D3 had significant increases in bone density and decreases in new fractures while the group that received placebo experienced a decrease in bone density.

Although other studies report a poor correlation between calcium intake and bone density and insignificant decreases in bone loss with calcium supplementation, it is the consensus that calcium supplementation should be included as part of the therapeutic regimen for osteoporosis. At the recommended dosage of 800 to 1500 mg/day, calcium supplementation is safe except for those individuals with calcium nephrolithiasis or hypercalcemia.

Estrogen replacement therapy (ERT)

Numerous studies document the value of estrogen replacement therapy (ERT) in the treatment of postmenopausal osteoporosis. The data indicate that ERT is effective not only for prevention of bone loss, but for increasing bone density by about 5%. ERT has been shown to reduce the relative risk of fractures by about 50%. If treatment is stopped, the relative risk for hip fracture at age 80 rises to 0.8. In women with very low bone density, estrogen therapy should be continued lifelong.

Grady et al have recently reported a detailed meta-analysis of all English language literature studies on the effects of estrogen and estrogen plus progestin therapy on osteoporosis, coronary artery disease, and stroke. Of 11 studies of estrogen therapy in the prevention of hip fractures, all but 1 reported a reduction in the risk for hip fractures among estrogen users as compared with non-users. The pooled estimate of the relative risk for hip fractures comparing ever-users of estrogen with non-users was 0.75. In his recent review of the hormonal treatment of postmenopausal women, Belchetz64 emphasizes the need for treatment of at least 5 years duration to obtain substantive benefits in terms of decreasing the risk of fracture. Benefits appear to increase proportionately with the duration of estrogen therapy. Estrogen has received FDA approval for the treatment of osteoporosis.

Hormone replacement therapy has other benefits in postmenopausal women. It relieves urogenital symptoms and the evidence favors a reduction in the incidence of cardiovascular disease. The potential risk of estrogen causing breast cancer appears small, but women with an intact uterus are advised to use estrogen plus a progestin such as methylprogesterone acetate (MPA) norethindrone. The recommended dose of oral estrogen for the prevention and treatment of osteoporosis in women who have had hysterectomies is 0.625 mg/day, and for women who have not had hysterectomies, 0.625 mg/day plus a progestin orally. Included among the plain estrogen preparations are Ortho-est® (McNeil) and Premarin® (Wyeth-Ayerst). Products combining estrogen and a progestin include Prempro® (Wyeth-Ayerst), containing 0.625 mg of estradiol and 22.5 mg MPA, and Activella® (Pharmacia), containing 1 mg of estradiol and 0.5 mg of norethindrone. The recent (April, 2000) FDA approval of Activella for the prevention of osteoporosis was based on the results of two randomized, placebo-controlled, two-year clinical trials involving 462 postmenopausal women in the United States and Europe. The studies found Activella® to be effective in preventing bone loss in postmenopausal women compared to the placebo group based on bone density measurement in various sites, including the lumbar spine and total hip.

Calcitonin

Calcitonin, a polypeptide hormone secreted by the thyroid gland, is a powerful inhibitor of osteoclastic bone resorption. It acts directly on osteoclasts, which have calcitonin receptors. Calcitonin has been found effective in reducing bone loss in women with established osteoporosis, and may also produce small increases in bone mass, particularly in the first few years after menopause. Calcitonin (calcitonin-salmon Miocalcin®, Sandoz, Calcimar®, Rhone-Poulenc-Rorer) has been approved by the FDA for the treatment of postmenopausal osteoporosis and may be administered by subcutaneous or intramuscular injection at an initial dose of 100 IU every other day or by intranasal spray in doses of 200 IU/day. It is well tolerated. Phase I/II studies are currently underway to develop an orally effective calcitonin preparation.

Biphosphonates (also frequently referred to as bisphosphonates)

The biphosphonates (BP) are chemically stable analogues of inorganic pyrophosphate and are resistant to breakdown by enzymatic hydrolysis. BPs inhibit bone resorption by being selectively taken up and absorbed to mineral surfaces in bone, where they interfere with the action of the bone resorptive activities of the osteoclasts. Dosage varies from one pill daily to one pill monthly. Some preparations are available combined with calcium and vitamin D. All claim to produce an increase in BMD and a reduction in fractures. Side effects are uncommon even after long-term use.

The first biphosphonate approved by the FDA was etidronate (Didronel®, Proctor & Gamble). However, etidronate was approved only for use in Paget’s disease and for the prevention of heterotopic ossification occurring after hip replacement and spinal cord injury. Etidronate is not approved for the prevention of osteoporosis. A second generation preparation, Alendronate (Fosamax, Merck) has FDA approval for use in the prevention of postmenopausal osteoporosis.

Alendronate is 1,000 times more potent as an osteoclast inhibitor when compared with etidronate. Alendronate has been shown to increase lumbar spine bone density by 8.8% at 36 months, and by 5.9% at 36 months as compared with placebo. The fracture reduction in the spine was 48% at 3 years. Hip fractures were reduced by 51% and radial fractures by 44% Similarly beneficial results have been reported by others.

The recommended dose of alendronate is 10 mg/day, but doses of 2.5 and 5 mg/day have also been demonstrated as significantly better than placebo. Adverse events are mild and differed little from placebo in controlled studies.

Along with etidronate (Didronel) and alendronate (Fosamax), many other BPs are available on the market including:

  • clodronate (Clastoban®, Lytos®, Bonefos®, Ostec®)
  • ibandroate (Bondronat®, Boniva®)
  • panildronate (Aredia®)
  • zoledronate (Zometa®)
  • risedronate (Actonel®)

Selective estrogen receptor modulators (SERMs)

These are compounds that bind with estrogen receptors and exhibit estrogen activity in some tissues and anti-estrogen action in other tissues. Although SERMs may not be closely related chemically to those produced endogenously, they are frequently referred to as “designer estrogens”.

The search for a designer estrogen that would mimic estrogen’s beneficial effects on bone mass led to the discovery and eventual FDA approval of raloxifene (Evista®, Eli Lilly) in December 1997, for the prevention of postmenopausal osteoporosis. Chemically, raloxifene is 2-aryl-benzothioprene-1. Raloxifene (Evista®) is a nonsteroidal SERM whose favorable action on bone turnover mimics that of estrogen, reducing the elevated bone turnover seen in postmenopausal women. It is devoid of any adverse effects on the breast or endometrium and has received FDA approval for the treatment of osteoporosis in postmenopausal women. There is evidence from both animal and human studies that SERMs may have beneficial biological effects in men. Other SERMs include Tamoxiphene (Nolvadex®), approved for the treatment of breast cancer, and Clomiphene (Clomid®, Serophene®), approved for the induction of ovulation. Raloxifene is taken orally in doses of 60 mg once or twice daily and is well tolerated.

Forteo (teriparatide) Forteo is a genetically engineered fragment of parathyroid hormone (PTH). The drug has potent anabolic action stimulating the PTH receptor on osteoblasts and decreasing osteoclastic activity. It is the first in a new class of drugs called bone formation agents that work primarily to stimulate osteoblastic activity and new bone formation as indicated by increases in BMD (in comparison with a placebo). It produces an increase in bone turnover and reduces the relative risk of vertebral and non-vertebral fractures. It is administered parenterally once a day. The FDA’s approval of Forteo was based on 24 clinical trials involving more than 2,800 postmenopausal women and men with osteoporosis and who were at a high risk for fractures. The development of osteogenic sarcoma in a few rats receiving Forteo was not believed to be relevant in humans. Research with other derivatives of PTH is continuing.

Other therapies

Sodium fluoride has been reported to dramatically increasing spine bone density, but with a substantial loss of cortical bone from the radius and no decrease in fracture rate. A combination of slow-release fluoride and calcium is reported to have increased spinal bone density and decrease vertebral fracture rates. There is a possibility that fluoride may transfer bone from cortical to vertebral sites and further investigation is warranted.

Combinations of therapies may be helpful in preventing postmenopausal bone loss. Calcium plus estrogen replacement therapy and exercise plus estrogen have been reported as more efficacious than either therapy alone.

A look into the future

Both patient and physician can look forward to a continuation of intense research on the basic and clinical aspects of osteoporosis. These efforts will be carried out at the Federal level (National Institutes of Health, National Institute of Arthritis, Musculoskeletal and Skin Diseases), as well as by the pharmaceutical industry and consumer support groups.

The inherited predisposition to osteoporosis has prompted research on the identification of the genes involved both in normal bone development as well as in osteoporosis. The evidence suggests that the inheritance pattern is polygenic in nature. Several pharmaceutical companies are involved in developing gene transcription-based drugs.

Efforts are also being directed at the development of agents that block the protein kinase enzyme that signals osteoclast-induced bone degeneration. Another approach has been the development of recombinant human protein compounds that will supplement the action of inherent morphogenic proteins related to growth factor. Similarly, studies are ongoing to determine the possible role of mesenchymal stem cells in the regeneration of diseased tissues. Investigation is also ongoing on the possible role of immune factors in the development of osteoporosis.

Additionally, new technologies are emerging to measure bone quality as well as mineral density. Techniques include variations of micro-computed tomography or magnetic resonance imaging (MRI). Ultrasound technology is emerging as an alternative to bone densitometry, and studies are also underway to develop blood and urine tests that may be used to screen for osteoporosis.

Conclusions

The foundation of osteoporosis management consists of effective prevention techniques that maximize bone density, minimize bone loss, (especially during menopause), and reduce the risk of falls. This mandates early intervention to ensure that calcium and vitamin D intake and exercise levels are adequate during childhood and adolescence and maintained at satisfactory levels throughout life. The combination of clinical risk factors and determination of bone density provides a reliable diagnostic methodology for osteoporosis. Calcium supplementation, exercise, estrogen replacement therapy, calcitonin, biphosphonates, and selective estrogen replacement modulators, either alone or in combinations, are effective in combating bone loss and reducing the risk of fracture.

In the past two decades, increasing public and professional awareness of the serious health hazard imposed by osteoporosis has been combined with marked improvements in the diagnosis and treatment of osteoporosis. With intensive research continuing, especially in the fields of parathyroid derivatives and anti-RANKL antibodies, further improvement in patient care can be anticipated.


+1
  • Photo_user_blank_big

    cmellor2

    almost 7 years ago

    6 comments

    good information

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