Impact and Pathogenesis of Osteoporosis
Anita Chopra, MD, FACP

Dr. Chopra is Associate Professor of Medicine and Director, Center for Aging, University of Medicine and Dentistry of New Jersey, School of Osteopathic Medicine, Stratford, NJ. Address for correspondence: Anita Chopra, MD, FACP, UMDNJ-School of Osteopathic Medicine, 42 East Laurel Rd, Suite 3200, Stratford, NJ 08084.

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Osteoporosis is a major health problem. It is a skeletal disorder characterized by low bone mass and increased susceptibility to fractures. In the United States, osteoporosis accounts for 1.5 million fractures annually. Forty percent of Caucasian women will experience an osteoporotic fracture during their lifetime. The consequences of osteoporosis include decreased functional independence and increased morbidity and mortality. Osteoporosis is a multifactorial disease. It can result pathogenetically from inadequate peak bone mass, excessive bone resorption or impaired bone formation, and be influenced by genetic, hormonal, and environmental factors. The relative importance of these factors may differ among patients and is not fully understood. Nevertheless, improved understanding of specific pathogenetic mechanisms is critical in developing an optimal approach to diagnosis, prevention, and treatment of this devastating disease. (Annals of Long-Term Care: Clinical Care and Aging 2002;10[3]:27-33)

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O steoporosis is a systemic skeletal disorder characterized by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fractures.1 The World Health Organization operationally defines osteoporosis based on measurement of bone mineral density (BMD) (Table I). A woman is classified as osteoporotic if her BMD is at least 2.5 standard deviation (SD) below the mean for young Caucasian adult women. 2 Osteopenia is defined as BMD values between 1.0 SD and 2.5 SD below the mean for young Caucasian adult women. It is unclear how to apply this diagnostic criterion to men, or across ethnic and racial groups. Osteoporosis does not only mean low BMD, but also bone fragility; therefore, the limitations of BMD measurements are slowly being recognized.

Osteopenia is a broader term and is often referred to as the appearance of decreased bone mineral content on radiography. Osteopenia more appropriately refers to a phase in the continuum of decreased bone mass leading to increased susceptibility to fractures. By the time the diagnosis of osteopenia is made radiographically, significant bone loss has already occurred. The most common cause of osteopenia is osteoporosis; however, it also encompasses osteomalacia, which is characterized by reduced mineralization of bone matrix. Osteoporosis is a major health problem in the United States (Table II). Currently, it is estimated that between four and six million postmenopausal women have osteoporosis and an additional 13 to 17 million women have low bone mass or osteopenia, which increases their risk of osteoporosis and fractures. 3 Clinical interest in osteoporosis is related to fractures and the associated physical, psychosocial, and financial consequences. Osteoporosis accounts for 1.5 million fractures annually in the United States. 4 Vertebral fractures account for 47% of osteoporotic fractures, and hip fractures and distal forearm (colles’) fractures each account for 17% of osteoporotic fractures. 4 Approximately, 37,500 people die each year as a result of complications related to osteoporotic fractures. In 1995, osteoporosis was responsible for more than 44 million patient-days in nursing homes and an estimated $13.8 billion in annual health care expenditures. 5 Based on the estimated increase in the aging population, hip fracture costs in the year 2050 are expected to reach $131.5 billion. 6 A majority of these estimated costs are due to inpatient care and do not incorporate indirect costs, which are expected to be considerable.

The incidence of fracture is high in persons with osteoporosis and increases with age. The rate of hip fracture is two to three times higher in women than men. The probability of developing a hip fracture during one’s lifetime is 14% for Caucasian women and 5% to 6% for Caucasian men (Table III). The risk for African Americans is much lower. Osteoporotic fractures, particularly vertebral fractures, can be associated with chronic disabling pain. Approximately 20% of patients with hip fractures die in the year following their fracture. Nearly one-third of patients with hip fractures are discharged to nursing homes within the year following their hip fracture, and only one-third fully regain their prefracture level of independence. 7 Osteoporosis in men has also started to receive attention. One in eight men older than 50 has osteoporosis. Presently, more than two million men in the United States are affected by osteoporosis and another three million are at risk for the disease. For men age 85 and older, 85% of hip fractures can be attributed to osteoporosis. 8

There is a common misconception that osteoporosis is always the result of accelerated bone loss. Bone loss commonly occurs as women and men age. However, an individual who does not reach optimal peak bone mass during childhood and adolescence may develop osteoporosis without the occurrence of accelerated bone loss. The two major determinants of osteoporosis are peak bone mass and rate of bone loss, which are influenced by genetic and environmental factors. Other risk factors for low bone density are advanced age, female gender, Caucasian race, low weight and low body mass index, a family history of fracture, prior fracture, and smoking. 7 Although the combination of preexisting fractures and low bone mass predict future fracture risk, clinical risk factors related to falls also serve as important predictors of fractures.9.10 Fracture risk has been consistently associated with a history of falls, low physical functioning, such as slow gait speed and decreased quadriceps strength, impaired cognition, limited vision, and the presence of environmental hazards.10 Thus, it is important to draw a distinction between risk factors that affect bone metabolism and risk factors for fracture. The risk factors for osteoporosis can be broadly divided into those that can not be altered—such as genetics, age, and race—and those that can be modified, such as nutrition, lifestyle, calcium intake, physical activity, and smoking (Table IV).

Bone Physiology There are two types of bone—cortical and trabecular bone. Cortical bone, the compact layer, forms the outer shell of bone and accounts for approximately 80% of the skeleton. Cortical bone predominates in the shafts of the long bones. Trabecular bone, also known as the spongy or cancellous bone, constitutes the remaining 20% of the skeleton and is concentrated in the vertebrae, ends of the long bones, pelvis, and flat bones. The trabecular bone is much more sensitive to metabolic influences; therefore, conditions that produce rapid bone loss tend to affect trabecular bone more quickly than cortical bone. The skeleton is a dynamic tissue that actively remodels by a coupled process of bone resorption followed by bone formation. Bone remodeling continues throughout life. At the beginning of each remodeling cycle, osteoclasts appear and over several weeks reabsorb a portion of cortical or trabecular bone. The osteoclasts are then replaced by osteoblasts, which over three to four months fill the resorption space with new bone. 11 The osteoblasts synthesize the bone matrix, whereas the osteoclasts remove or resorb the bone. During remodeling, resorption usually precedes formation. These events are called the Activation-Resorption-Formation sequence. Bone remodeling is influenced by circulating hormones including estrogen, testosterone, parathyroid hormone (PTH), and 1,25- dihydroxyvitamin D; local humeral factors such as interleukin-1 (IL-1), interleukin-6 (IL-6), transforming growth factor (TGF), and tumor necrosis factor (TNF); and the impact of mechanical forces on the skelton. There is increasing research into the relationship of osteoblast differentiation and other cell lineages. 12,13 Deeper understanding of the molecular basis of bone remodeling will hopefully provide new insights into the management of osteoporosis. New bone formation exceeds bone resorption during childhood and early adulthood, leading to a net increase in the bone mass. By about age 30, peak bone mass is achieved, with 80% to 90% of the peak bone mass being deposited during skeletal growth. In healthy adults, the resorption and formation phases are highly coupled and the bone mass is maintained. Decreased bone mass and changes in structure that predispose a person to fragility fractures can occur by three mechanisms. The first of these mechanisms is a failure to achieve peak bone mass during skeletal growth. Although approximately 80% of the peak bone mass is genetically determined, 20% is modulated by environmental factors, such as nutrition, hormones, and mechanical loading. 14 Poor nutrition, limited activity, and delayed puberty may impair the ability to achieve optimal peak bone mass. The amount of bone developed during childhood and adolescence determines how much bone can be lost before a critical low bone mass is reached. 15 Excessive bone resorption leading to decreased bone mass and strength is the second mechanism to produce osteoporosis. Estrogen deficiency is associated with increased bone resorption. Finally, relative impairment of bone formation is critical in the pathogenesis of osteoporosis. In osteoporosis, there is a decrease in the capacity of osteoblasts to form new bone, even though the absolute rates of bone resorption in adolescents who are gaining bone mass are higher than those rates found in patients with osteoporosis.

Pathogenetic Mechanisms in Osteoporosis Pathogenetic mechanisms in osteoporosis include genetics, lifestyle variables, hormonal factors, and local factors. These mechanisms will be discussed in detail below and are shown in Table V.

Genetics

Genetic factors play an important role in defining the height of acquisition of peak bone mass. The incidence of osteoporotic fractures differs greatly among racial and ethnic groups; for example, Caucasian and Asian women are at greater risk for these fractures. Daughters of mothers with osteoporosis have been shown to have significantly lower peak bone mass.15 Monozygotic twins have BMDs that are more similar than those of dizygotic twins. 14 Specific genes, such as the vitamin D receptor gene, the estrogen receptor gene, and the PTH-related peptide receptor gene, may determine bone mass, bone turnover, and bone loss.16

Lifestyle Variables Nutrition. An adequate intake of calcium and vitamin D and good general nutrition can help optimize peak bone mass, slow bone loss, and decrease the risk of fracture. Conversely, calcium and vitamin D deficiency may increase the risk of osteoporosis. Vitamin D deficiency is a problem in institutionalized elderly people. The major effect of vitamin D is to enhance intestinal calcium absorption, but additional effects on osteoblast function and PTH secretion may also be important. A review of studies published since 1998 by Heaney 17 related to calcium intake revealed that 26 studies reported an association of calcium intake in some way to bone mass, bone loss, or fracture; 16 studies found no such link. Calcium supplements have been observed to be more effective in women with low baseline calcium and a high mean age, and in those who show clinical evidence of osteoporosis. 18

Exercise. Physical activity early in life contributes to higher peak bone mass, with resistance and high-impact exercise perhaps exerting the most benefit. The role of physical activity during the middle years of life has numerous health benefits, but there are few studies of the effect of exercise on BMD. 19

Hormonal Factors Sex Hormones . Sex steroids secreted during puberty substantially increase BMD and peak bone mass. The loss of endogenous estrogen production associated with menopause leads to increased bone resorption by increasing osteoclastic activity. Estrogen deficiency may contribute substantially to the continuous bone loss of aging men; 20 it also results in impaired calcium absorption and decreased tubular reabsorbtion of calcium. The resulting negative calcium balance can be compensated by an increase in dietary calcium. If this increase does not occur, secondary hyperparathyroidism develops, which increases bone resorption. Testosterone deficiency may also play a role in the pathogenesis of osteoporosis. Testosterone can have direct anabolic effects on bone and is a precursor of estrogen.

Parathyroid Hormone. The decreased absorption of calcium from the intestine that occurs with aging leads to an increase in PTH levels. This secondary hyperparathyroidism increases bone turnover and may lead to increased bone resorption through increased osteoclastic activity. The ability of calcium and vitamin D supplementation to decrease fracture risk is probably related to reduction of PTH levels. PTH is undergoing consideration as a potential treatment of bone loss, 21 because when given intermittently, it may result in an increase in bone mass.

Calcitonin. Calcitonin is secreted by C cells or parafollicular cells in the thyroid gland. Calcitonin inhibits bone resorption by a direct action on the osteoclasts. The exact relationship of calcitonin to the development of osteoporosis is unclear.

Growth Hormone and Insulin-Like Growth Factor. Growth hormone and insulin-like growth factor 1 (IGF-1), which are maximally secreted during puberty, play a role in the acquisition and maintenance of bone mass. Age-related decreases occur in growth hormone secretion and in the levels of IGF-1 and its major binding protein. Insulin-like growth factor can stimulate both resorption and formation of bone, but its major long-term effect is to increase bone formation. 22

Glucocorticoids. Bone cells have glucocorticoid receptors. Excess corticosteroids activity results in inhibition of osteoblasts and a decrease in calcium absorption with secondary hyperparathyroidism. Glucocorticoids are a major cause of secondary osteoporosis, but it is possible that glucocorticoid excess associated with chronic disease, depression, and stress may contribute to pathogenesis in primary cases as well.23

Local Factors

Bone remodeling is affected by the impact of mechanical forces at specific sites on the skelton. Therefore, local factors must play a role in bone formation and resorption. A number of these factors have been identified, including cytokines, such as IL-1ýand IL-6, TNF, and growth factors, such as TGFß, IGF-1, and fibro- blast growth factor, that are produced locally by bone cells. These local factors include both stimulators and inhibitors of bone resorption and formation and are influenced by systemic hormones. It is quite possible that the interaction of local and systemic factors may be critical in the pathogenesis of osteoporosis. 24

Types of Osteoporosis Traditionally, the term “primary osteoporosis” is used when the causative medical conditions are absent, and the term “secondary osteoporosis” is used when these conditions are present. Primary osteoporosis is more common and can be divided into type I, where the bone loss mainly involves the trabecular bone and is related to postmenopausal loss of ovarian function; and type II, where bone loss involves cortical bone and is thought to be associated with age.

Primary Osteoporosis

Bone loss occurs in both sexes. During a woman’s lifetime, she will lose about 35% of her cortical bone and 50% of her trabecular bone, whereas a man will lose about two-thirds as much.25 A biphasic pattern of bone loss has been identified for both cortical and trabecular bone. A prolonged slow phase occurs in both sexes and a transient rapid phase occurs in women after menopause. 26 In this group, the rate of bone loss is quite rapid and can range from 3% to 7% per year for up to seven years as a result of estrogen deficiency. In later life, bone loss continues at a slower rate of 1% to 2% per year. The decrease in bone density with age is thought to be secondary to an increase in PTH secretion resulting from decreased gastrointestinal absorption of calcium and decreased osteoblastic function. 26

Secondary Osteoporosis

Men are more likely to have a secondary cause of osteoporosis than women. In men, most cases are due to disease or drug therapy, but in 30% to 45% of affected individuals no cause can be found.27 Common conditions associated with osteoporosis include hypogonadism (in men), hyperthyroidism, hyperparathyroidism, chronic renal disease, malabsorption, rheumatoid arthritis, Cushing’s syndrome, and multiple myeloma. The use of medications, such as glucocorticoids, anticonvulsants, heparin, and thyroid supplements, can also cause bone loss. Glucocorticoid use is the most common secondary risk factor for osteoporosis. As many as 90% of patients treated with corticosteroids have glucocorticoid-related bone loss and a greater risk of fracture. 28 A daily prednisone dose greater than 7.5 mg results in significant trabecular bone loss. Accelerated bone loss occurs in the first one to two months of therapy, followed by a reduced rate of bone loss.23

Summary Osteoporosis is a major health problem that occurs primarily in postmenopausal women but can affect either sex, especially in later life. It is characterized by decreased bone mass and changes in structure that predispose one to fragility fractures. Fractures secondary to osteoporosis vastly increase morbidity and mortality. Although much remains to be learned, significant strides have been made in understanding how bone cell activity is regulated physiologically. Osteoporosis is a complex disease and the pathogenetic mechanisms are heterogeneous. Better identification of specific pathogenetic mechanisms will help in the development of more precise methods for prevention and therapy.

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Annals of Long-Term Care - ISSN: 1524-7929 - Volume 10 - Issue 03 - March 2002