Osteoporosis Update (Reference revised 2012)

Fleitz Continuing Education Jeana Fleitz, M.E.D., RT(R)(M) The X-Ray Lady 6511 Glenridge Park Place, Suite 6 Louisville, KY 40222 Telephone (502) 425-0651 Fax (502) 327-7921 Website www.x-raylady.com Email address xrayladyce@gmail.com Osteoporosis Update (Reference revised 2012) Approved for 2.5 Category A Continuing Education Credits American Society of Radiologic Technologists Course Approval Start Date 01/01/08 Course approval End Date 02/01/16 Florida Radiologic Technology Program Course Approval Start Date 07/02/07 Course Approval End Date 01/31/18 Provider # 3200615 Please call our office before course approval end date for renewal status. Please let us know if your mailing address or email address changes. Thank you. A Continuing Education Course for Radiographers

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Osteoporosis Update Approved for 2.5 Category A CE Credits Course Description This homestudy course titled Osteoporosis Update provides current information about osteoporosis and other bone loss diseases. After the introduction regarding health impacts of osteoporosis and other bone loss diseases, additional topics presented include: The magnitude of the problem. Skeletal anatomy and physiology. Causes of disease of bone. Medications & therapies causing osteoporosis. Renal osteodystrophy and osteoporosis. Gastrointestinal disorders and bone health. Malignancy and the skeleton. Demographics. Prevention and diet. Smoking and alcohol. Biochemical markers. Radiation safety Bone health. Bone metabolism. What is osteoporosis. Rickets and osteomalacia. Paget s disease and osteoporosis. Developmental skeletal disorders. Oral health and bone disease. Risk factors. Exercise, clothing, & fall proofing. Treatment & diagnosis. BMD technologies. Interpretation of results. Objectives: Upon completion of this homestudy course, the participant will: 1. Recognize that osteoporosis and other bone loss diseases are a major public health threat in the U.S. 2. Recall facts about bone anatomy and physiology. 3. Identify the process that occurs during osteoporosis. 4. Recognize risk factors for osteopenia and osteoporosis. 5. Identify medications and therapies that may cause bone loss. 6. Recall the guidelines for baseline BMD screening and for high-risk populations. 7. Select correct responses regarding recommended diet and lifestyle choices that contribute to bone health. 8. Discriminate between advantages and disadvantages of various medications used for bone loss disease. 9. Identify facts concerning bone mineral density equipment. 10. Recall basic radiation safety guidelines for bone densitometry measurements. 11. Select the correct responses concerning patient preparation for a BMD exam.

Osteoporosis Update (2010-2012) Introduction Osteoporosis and other bone loss diseases affect millions of people, from newborns to the elderly, resulting in pain, disability, and even death. Radiography has a significant role in the diagnosis and monitoring of bone loss diseases, and as such, radiographers should be familiar with one of the most common bone loss diseases, osteoporosis. In recognition of the importance of promoting bone health and preventing fractures, former President George W. Bush declared 2002-2011 as the Decade of the Bone and Joint. 1 With this designation, the U.S. has joined with other nations throughout the world in committing resources to accelerate progress in a variety of areas related to the musculoskeletal system, including bone disease and arthritis. 1 This course will provide information about the etiology, prevalence, characteristic symptoms, and current treatment protocols of osteoporosis. Since bone densitometry is a companion diagnostic tool to radiography in detecting and monitoring bone mineral density (BMD) in osteoporosis, a brief introduction to bone densitometry will also be provided. The term technologist will be used in this course when reference is made to the person who operates bone densitometry equipment. The Magnitude of the Problem The National Osteoporosis Foundation (NOF) estimates that more than 44 million Americans have osteoporosis, or 55% of the people 50 years of age or older. 2 In the United States (U.S.) today, 10 million people already have the disease, and almost 34 million more have low bone mass (osteopenia), placing them at increased risk for osteoporosis. 3,4 Osteoporosis is an under-diagnosed and silent condition that has financial, physical, and psychosocial consequences. The World Health Organization (WHO) Study Group defined osteoporosis (1994) as a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, resulting in an increase in bone fragility and susceptibility to fracture. 5 1

The impact of bone disease is more appropriately evaluated over a lifetime. 1 Approximately 1 in 2 women and 1 in 4 men over age 50 will have an osteoporosis related fracture in their remaining lifetime. While the lifetime risk for men and non-white women is less across all fracture types, it is significant for people in all ethnic backgrounds. 1 Typically, those with osteoporosis have no pain or indication of the disease process until they break a hip or wrist, or sustain spinal fracture(s) that may leave a dowager s hump or reduce their height by a few inches. A broken hip or crushed vertebrae may begin a downward spiral of lost mobility and illness, culminating in death. Fractures can have devastating consequences for both the individuals who suffer them and their family members. 1 For example, hip fractures are associated with increased risk of mortality. 1 The risk of mortality is 2.8 to 4 times greater among hip fracture patients during the first 3 months after the fracture, than it is among individuals of similar age who live in the community and do not suffer a fracture. 1 For those who do survive, these fractures often precipitate a decline in physical and mental health that dramatically impairs quality of life. 1 Nearly 1 in 5 hip fracture patients ends up in a nursing home, a living situation that a majority of participants in one study considered to be less favorable than death. 1 Many fracture victims become isolated and depressed as the fear of falls and additional fractures paralyzes them. 1 Spine fractures, which are not as easily diagnosed and treated as are fractures at other sites, can become a source of chronic pain as well as disfigurement. 1 Osteoporosis is the most important underlying cause of fractures in the elderly. 1 Osteoporosis is recognized as one of the most common and serious health problems facing the aging population in the U.S. The prevalence of osteoporosis and osteoporotic-related fractures is expected to increase significantly unless the bone health status of Americans is improved. 1 By 2010, roughly 52 million individuals over age 50 are expected to have osteoporosis, and another 40 million will have low bone mass. 1 By 2020, those figures are expected to jump to 14 million cases of osteoporosis and over 61 million cases of low bone mass. 1 These demographic changes could cause the number of hip fractures in the U.S. to double or triple by 2040. 1 Bone disease takes a significant financial toll on society and the individuals that suffer from it. The direct care expenditures (2005) for 2

osteoporotic fractures in the United States alone were responsible for 19 billion dollars in costs. 1 Experts predict that by 2025, these costs will rise to approximately 25 billion dollars. Factoring in both the direct and indirect costs for caring for other bone diseases, would likely add billions of additional dollars to this tab. 1 In the Surgeon General s report on bone health and osteoporosis, several challenges are posed concerning the bone health of Americans. One challenge addresses significant gaps between clinical knowledge and its application in practice. 1 This means that too little of what has been learned thus far about bone health has been applied in practice. 1 The report states that the biggest problem is lack of awareness of bone disease on the part of both the public and healthcare professionals. 1 Studies show that physicians frequently fail to diagnose and treat osteoporosis, even in elderly patients who have suffered a fracture. 1 Contributing to this lack of awareness is the fact that managed care organizations and other insurers that provide coverage to individuals under age 65 may not see the full impact of bone disease in their enrollees, since most will have moved on to Medicare by the time they suffer a fracture. 1 Commercial insurance providers may not pay sufficient attention to bone health, and to the preventive strategies available to and suitable for younger people. 1 Some of the most important barriers relate to men and racial and ethnic minorities. 8,9 For the poor (especially the low-income elderly population), individuals with disabilities, individuals living in rural areas, and other underserved populations, timely access to care is difficult to obtain. 1,9 Recognizing that bone health can have a significant impact on the overall health and well-being of Americans, the Public Health Service has already begun work on the issue. 1 In the Healthy People 2010 Public Health Service Report there are specific objectives that aim to reduce the number of individuals with osteoporosis or hip fractures, and that seek to promote greater amounts of calcium intake and physical activity. Additional information is also available from the Clinician s Guide to Prevention and Treatment of Osteoporosis developed and published by the National Osteoporosis Foundation. 3

Bone Health The bony skeleton serves a structural function, providing mobility, support, and protection for the body, as well as a reserve function, storing up essential minerals. 1 Many assume that the adult skeleton is an inert framework, a sort of stone-like foundation for the living flesh of our bodies. This assumption is false, however, since bone is living tissue, and from birth to death is in a constant state of flux. Bone health is difficult to maintain because the skeleton is simultaneously serving two different functions that are in competition with each other. 1 First, bone must be responsive to changes in mechanical loading or weight bearing activities, which require they have ample supplies of calcium and phosphorus. Yet when these elements are in short supply elsewhere, the regulating hormones take them out of the bone to serve vital functions in other body systems. 1 The skeleton can be compared to a bank where calcium or phosphorus is deposited and then later withdrawn in times of need. 1 Too many withdrawals weaken the bone, and can lead to the most common bone disorder, fractures. 1 The amount of bone and its architecture or shape are determined by the mechanical forces that act on the skeleton. 1 Both genes and the environment contribute to bone health. Genes generally determine elements of bone health like size and shape of the skeleton, and errors in signaling on the part of these genes can result in birth defects. 1 External factors, such as diet and physical activity, are critically important to bone health throughout life, and can be modified. 1 To respond to the dual roles of physically supporting the body and regulating the amounts of calcium and phosphorus within it, bone is constantly changing. Osteoporosis and many related bone diseases cause bones to become porous, gradually making them weaker and more brittle. 2 The word osteoporosis literally means porous bones. Skeletal Anatomy and Physiology Bone consists of approximately 25% organic substances and 75% inorganic substances, and is the supporting framework of the body. The major organic component of bone is collagen, a strong and flexible protein. Calcium and phosphate in the form of calcium phosphate crystals are the primary 4

inorganic substances found in bone. Together, the combination of organic and inorganic substances makes bone both flexible and able to withstand weightbearing stresses (Figure 1). Fig.1. Bone tissue (A) femur with distal end cut (B) Microscopic cross section of compact bone. Reprint permission from Scanlon VC, Sanders T. Essential of Anatomy & Physiology. Philadelphia, PA. FA Davis Company:1991:103. 5

Microscopically, bone consists of a mixture of connective tissue, blood vessels, specialized cells, and crystals of calcium and phosphate. The skeleton contains 99% of the body s total calcium, but being rich in calcium is not enough to make bones resistant to fracture. Bones can be dense yet brittle, lacking flexibility, which will cause them to break easily. The collagen protein content is crucial for maintaining flexibility. It is thought that the quality and quantity of collagen protein in bones may be more essential to preventing fractures than the calcium content. In addition to calcium, bones are a reservoir of numerous other minerals that the body requires for day-to-day function. The bones act as a bank for nutrients, with a constant flow of deposits and withdrawals. Calcium, phosphorus, sodium, magnesium, and collagen protein enter and leave bone during the resorption and remodeling process. Humans obtain these nutrients from the foods they ingest. Food is broken down in the stomach and duodenum, where nutrients are absorbed through the walls of the small intestine and enter the bloodstream. Once in the blood, calcium migrates to the bones, and is deposited and stored. Bone resorption takes place as needed, liberating calcium for necessary functions in the blood, muscles, nerves, and elsewhere. The kidneys excrete excess calcium that is not absorbed. Deposition of calcium in the bones is increased by the influence of gravity, which occurs when the human body is in motion, for example when walking. A sedentary lifestyle contributes to the loss of bone mass by preventing deposition of calcium, so that the process of mineral resorption slowly uses up the available bone mass. Bone is classified as a connective tissue and contains three basic parts: cells (osteocytes, osteoblasts, and osteoclasts), the matrix, and inorganic calcium salts. The two cell types relevant to osteoporosis and bone density measurements are osteoblasts and osteoclasts. These cells react to hormones, physical stress, and calcium blood levels, and bone repair demands. The osteoblasts, or bone-producing cells, produce the organic bone matrix components that later become mineralized through a process that is not well understood. The osteoclasts are responsible for bone remodeling and have large multinucleated cells that contain and secrete calcium-dissolving acids. Excessive bone breakdown by osteoclasts is an important cause of bone fragility, not only in osteoporosis but in other bone disease such as hyperparathyroidism, 6

Paget s disease, and fibrous dysplasia. 1 Inhibitors of osteoclastic bone breakdown have been developed to treat these disorders. The balance of the calcium moving in and out of bone forms the basis for bone remodeling (Figure 2). Fig.2. Bone Remodeling. (Reprint permission from Boning up on Osteoporosis: A Guide to Prevention and Treatment. National Osteoporosis Foundation (4/03)B107. Calcium in the blood moves into bone as osteoblasts make new bone, and returns into the blood when the osteoclasts break bone down. Osteoclasts are sensitive to blood calcium levels, and respond by increasing or decreasing activity levels. Other factors, whether physiological, environmental, or behavioral, can also alter the delicate balance between osteoblast and osteoclast equilibrium. Some of these factors include low estrogen and testosterone levels, calcium and vitamin D deficient diets, and a sedentary lifestyle. 7

There are two major bone classifications: cortical (compact) bone and trabecular (spongy) bone. Cortical bone consists of dense, tightly aligned lamellar osteons (tubules), and is found in locations where bone compresses in a limited number of directions. Cortical bone may be found in the skull and femur shafts. Cortical bone is organized into units called haversian systems, each containing osteocytes and an intracellular matrix arranged in circular layers around central haversian canals, (Figure 1). Trabecular bone has a honeycomb appearance, with a partitioned internal design, and weighs less than cortical bone, thus reducing skeletal weight. Trabecular bone is found in locations that receive either low mechanical stresses or multi-directional stresses. The femoral head, calcaneus, and spine are all examples of predominately trabecular bone. Trabecular bone is more metabolically active than cortical bone, and responds quickly to factors that affect the skeleton. The differentiation of bone as either cortical or trabecular is important in bone densitometry because certain diseases show a preference for one type of bone over another. Thus, the selection of the site or sites to be scanned for bone mineral density (BMD) is an important consideration in the diagnostic process, and is generally made by the requesting physician. The technologist should be knowledgeable about the differences between cortical and trabecular bone, and about how various disease conditions and drug therapies affect each type. In addition to describing skeletal bones as predominantly cortical or trabecular, there are three other ways to characterize skeletal sites: Weight-bearing or non weight bearing Axial or appendicular Central or peripheral Weight-bearing sites include the lower extremities, the cervical, thoracic, and lumbar spines, and the calcaneus, with all other bones being non weightbearing. The axial skeleton includes the skull, ribs, sternum, and spine; and the appendicular skeleton include the extremities. The thoracic and lumbar spines and the proximal femur are central skeletal sites. Peripheral skeletal sites are noncentral sites, and include the calaneus, tibia, and forearm. 8

The mature skeleton gradually increases in mass during early adult life. Peak bone mass is achieved between 30 and 35 years of age. Peak bone mass is affected by genetics, mechanical loading, and hormonal and nutritional levels, and is approximately 30% higher in men than in women. After reaching its peak, bone mass declines throughout life due to an imbalance in remodeling. In women, bone mass decreases rapidly for 3 to 7 years after menopause. Estrogen produced by the female ovaries, plus other hormones, regulate the absorption and release of calcium in the bones. After menopause, the ovaries no longer produce estrogen, and bone loss accelerates, finally slowing down at about age 65. Bone loss may also be accelerated by a variety of diseases and drugs, (Figure 3). In males, testosterone affects bone mass. 5,6 Recent research in the U.S. and Germany demonstrates that testosterone replacement therapy for men with deficient hormone levels has helped to increase both cortical and trabecular bone density. 7,8,10,11 Fig.3. Bone mass over the aging continuum. Retrieved from www.emedicinehealth.com on September 2, 2012. 9

As humans age, bone formation does not keep pace with bone loss. The rate of bone loss increases with advancing age. When the long-term rate of bone dissolution is greater than the rate of replacement, mineral content slowly decreases, and the bones become thin, brittle, and easily broken. 10 This cycle is called the process of destruction, or resorption, and renewal formation, known as remodeling. In the mature adult, approximately 25% of trabecular bone and about 3% of cortical bone is renewed on an annual basis. This cycle is called the process of destruction, or resorption, and renewal formation, known as remodeling. The remodeling cycle can be divided into the following stages: activation, resorption, reversal, formation, and quiescence or rest, (Figures 2 and 4). During the activation stage, osteoclasts begin to form on the surface of the bone. Resorption starts when the osteoclasts dissolve the mineral components of the bone and matrix, forming hollows in trabecular bone and cylindrical cavities in cortical bone. Reversal is a transition phase between resorption and formation when preosteoblasts appear in the holes formed by the osteoclasts. In the formation stage, a cement line, or bond, is formed that secures the new bone to the old. After formation, the bone returns to a resting state during quiescence. About 90% of bone surfaces are normally at rest. Resorption is more rapid than formation, and by age 40 the entire resorption stage may last one month, while the formation stage may take up to 3 months. 12 By age 65, the entire process of resorption and formation may take up to 5 months. 12 Modeling and remodeling continue throughout life, so that most of the adult skeleton is replaced about every 10 years. 1,12 Steps in Normal Bone Regeneration Osteoclasts attach to bone surface Osteoclasts resorb bone Osteoblasts enter cavity and build new bone Amount of bone formed is equal to bone resorbed so that bone mass/strength are maintained Steps in Abnormal Bone Regeneration Osteoclasts attach to bone surface Osteoclasts resorb more bone tissue and leave a deeper resorption cavity Osteoblasts build less bone than was resorbed Bone resorption exceeds bone formation, leading to a progressive decline in bone mass, weakening bones and increasing risk of fractures 10

Figure. 4. Steps in normal and abnormal bone regeneration. Bone Metabolism Alkaline phosphatase, which raises calcium and phosphate levels, is thought to play a role in bone mineralization. However, many factors influence the bone metabolism and remodeling process by direct action on the osteoblasts and osteoclasts. The most critical systemic hormones regulating bone growth include: Calcium-regulating hormones; Parathyroid hormone (PTH) Calcitriol (active vitamin D) Calcitonin Sex hormones; and, Estrogen Testosterone Other systemic hormones Growth hormone/insulin-like hormone growth factor Thyroid hormone Cortisol Four small glands adjacent to the thyroid gland produce parathyroid hormone (PTH). These glands control the level of calcium in the blood, and are sensitive to small changes in calcium concentration. PTH acts on the kidneys to conserve calcium and stimulate calcitriol production, which increases intestinal absorption of calcium. PTH also acts on the bone to increase movement of calcium from bone to blood. Excessive production of PTH, usually due to a small tumor of the parathyroid glands, is called hyperparathyroidism and can lead to bone loss. PTH stimulates bone formation as well as absorption. Recently discovered, a second hormone, parathyroid hormone-related protein (PTHrP), related to PTH, normally regulates cartilage and bone development in the fetus. 1 It has been found to be overproduced in individuals with certain types of cancer. PTHrP then acts like PTH, causing excessive bone breakdown and abnormally high blood calcium levels, a condition called hypercalcemia of malignancy. 1 11

Calcitriol, 1,25 dehydroxycholecalciferol, is a hormone formed in the liver and kidneys by the action of enzymes on from vitamin D. Calcitriol acts on many different tissues, but its most important action is to increase intestinal absorption of calcium and phosphorus. Vitamin D can be made in the skin through the action of ultraviolet light from the sun on cholesterol. Many people need vitamin D in their diet because they do not derive adequate levels of it from exposure to the sun. Vitamin D deficiency leads to a disease of defective mineralization called rickets in children and osteomalacia in adults. These conditions can cause bone pain, bowing and deformities of the legs, and fractures. Treatment with vitamin D can restore calcium supplies and reduce bone loss. Calcitonin is a calcium-regulating hormone produced by cells of the thyroid gland. Calcitonin is thought to be more important for maintaining bone development and normal blood calcium levels in early life. Excesses or deficiencies of calcitonin in adults do not cause problems in maintaining calcium concentration or the strength of bone. Calcitonin can be used as a drug for treating bone disease. Sex hormones, along with calcium-regulating hormones, are extremely important in regulating the growth of the skeleton and maintaining the mass and strength of bone. 12,13 Estrogen and testosterone have effects on bone in both men and women. 14,15 Estrogen acts on the osteoclasts and osteoblasts to inhibit bone breakdown at all stages of life. 14 Testosterone is important for skeletal growth because of its direct effects on bone, and its ability to stimulate muscle growth. 12,13 Growth hormone from the pituitary gland is also an important regulator of skeletal growth. It acts by stimulating the production of another hormone, called insulin-like growth factor (IGF-1), which is produced in large amounts in the liver and released into circulation. IGF-1 is produced locally in other tissues, particularly in bone, also under the control of growth hormone. Thyroid hormones increase the energy production of all body cells, including bone cells. Thyroid hormones increase the rates of both bone formation and resorption. Thyrotropin (TSH), the pituitary hormone that controls the thyroid gland, may also have a direct effect on bone. Cortisol, the major hormone of the adrenal gland, is a critical regulator of metabolism, and is important to the body s ability to respond to stress and injury. 12

Small amounts are necessary for normal bone development, but large amounts block bone growth. Synthetic forms of cortisol, called glucocorticoids, are used to treat many diseases such as asthma and arthritis. They can cause bone loss due to decreased bone formation and increased bone breakdown, both of which lead to a high risk of fracture. 1 What Causes Bone Diseases? Genetic abnormalities can produce weak, thin bones, or bones that are too dense. The disease osteogenesis imperfecta is triggered by abnormalities in the collagen molecule that cause the matrix to be weak, and this leads to multiple fractures. Osteopetrosis, another congenital disorder, causes the bones to become too dense because of failure in osteoclast formation and function. 1 Nutritional deficiencies, particularly of vitamin D, calcium, and phosphorus, can result in the formation of weak, poorly-mineralized bone. Many hormonal disorders can also affect the skeleton. Overactive parathyroid glands, or hyperparathyroidism, can cause excessive bone breakdown and increase the risk of fracture. Use of glucocorticoids as medication is a common cause of bone disease. Many bone disorders are local, affecting only a small region of the skeleton. Inflammation can lead to bone loss as well as certain bacterial infections. What is Osteoporosis The National Institutes of Health (NIH) defines osteoporosis as a skeletal disorder characterized by compromised bone strength, predisposing an individual to an increased risk of fracture. The NIH definition recognizes factors that prevent people from achieving optimal bone mass, as well as conditions that lead to bone loss later in life. The NIH also states that bone strength is a combination of bone density and bone quality, (Figure 5). 2 13

Fig.5. Osteoporotic bone versus normal bone. Reprint permission from Boning up on Osteoporosis A guide to prevention and treatment. National Osteoporosis Foundation 2009. The 2 types of osteoporosis characterized by etiology are known as primary and secondary osteoporosis. Primary osteoporosis is mainly a disease of the elderly, the result of the cumulative impact of bone loss and the deterioration of bone structure that occurs as people age. 1 Primary osteoporosis may also be referred to as Type I, or age-related, osteoporosis. Since postmenopausal women are at greater risk, the term postmenopausal osteoporosis may also be used. 1 Younger individuals (including children and young adults) rarely get primary osteoporosis, although it can occur; this type of osteoporosis is referred to as idiopathic osteoporosis, since in many cases the exact causes of the disease are not known. Idiopathic primary osteoporosis can affect both children and adolescents, although such an occurrence is quite rare. 1 Juvenile osteoporosis affects previously healthy children between the ages of 8 and 14. The condition may be 14

mild, causing only one or two collapsed bones in the spine, or it may be severe, affecting the entire spine. 1 Primary osteoporosis in children and adolescents occurs for reasons, which are still unknown. For example, bone loss occurs in adolescents with anorexia nervosa, an eating disorder. Although it is mainly girls who suffer from this condition, boys and men can also be affected. Many studies have shown an imbalanced state of bone turnover in young people with anorexia nervosa, with both decreased bone formation and increased bone resorption. Approximately 25% of patients with inflammatory bowel disease (IBD) are diagnosed with osteopenia as children. 16 This condition is controlled with minimal corticosteroid use, which has direct impacts on bone formation and remodeling. 17 There are many common pediatric disorders that can lead to low bone density and fractures. Female athlete triad Asthma Chronic liver and kidney disease Cystic fibrosis Deprivational rickets Diabetes, type II Endocrine disorders Neoplastic disease Neuromuscular diseases such as: spina bifida, cerebral palsy, paralysis, and muscular dystrophy Organ transplantation Rheumatic diseases Seizure disorders Sickle cell disease Several uncommon pediatric disorders that may lead to low bone density and fractures. 15

Chondrodysplasia Cushing syndrome Ehlers-Danlos syndrome Gaucher disease Hypophosphatasia Idiopathic juvenile osteoporosis Klinefelter and Turner syndromes Osteogenesis imperfecta Osteoporosis pseudoglioma syndrome Primary osteoporosis related to age is by far the most common form of the disease. 1,18 There are many different causes, but the bone loss that leads to the disease typically begins early in life, at a time when corrective action (such as changes in diet and physical activity) could potentially slow down its course. 1 While osteoporosis occurs in both sexes, the disease is two to three times more common in women. 19,20 This is partly due to the fact that women have two phases of age-related bone loss. The first, a rapid phase that begins at menopause and lasts 4-8 years, followed by a slower continuous phase that lasts throughout the rest of life. 1 Men go through only the slow, continuous phase. As a result, women typically lose more bone than do men. The rapid phase of bone loss alone results in losses of 5-10% of cortical bone and 20-30% of trabecular bone in women. The slow phase of bone loss results in losses of 20-25% of cortical and trabecular bone in both men and women, but over a longer period of time. 1 Although other factors such as genetics and nutrition contribute, both the rapid phase of bone loss in postmenopausal women and the slow phase of bone loss in aging women and men appear to be largely the result of estrogen deficiency. 1 For women, the rapid phase of bone loss is initiated by a dramatic decline in estrogen production by the ovaries at menopause. The loss of estrogen action on estrogen-receptors in bone results in large increases in bone resorption, as well as reduced bone formation. By contrast, the slower phase of bone loss is caused by a combination of factors. These factors include age-related impairment of bone formation, decreased calcium and vitamin D intake, 16

decreased physical activity, and the loss of estrogen s positive effects on calcium balance in the intestines and kidneys as well as bone. For aging men, sex steroid deficiency also appears to be a major factor in age-related osteoporosis. 1 Although testosterone is the major sex steroid in men, some of it is converted by the aromatase enzyme into estrogen. 1 Between 30-50% of elderly men are deficient in biologically active sex steroids. 1 Secondary, or Type II, osteoporosis is often referred to as senile osteoporosis, and occurs particularly in the seventh decade of life. Secondary osteoporosis is caused by decreased absorption of calcium from the intestines, as well as by a diminished secretion of calcitonin, a naturally produced non-sex hormone that is involved in calcium regulation and bone metabolism. 10 The type of osteoporosis that occurs in individuals as a consequence of some condition or medication use is also referred to as secondary osteoporosis. 21 Those with secondary osteoporosis typically experience greater levels of bone loss than would be expected for a normal individual of the same age, gender, and race. Examples of factors contributing to secondary osteoporosis includes various disorders of the endocrine glands, a sedentary lifestyle, malnutrition, iatrogenic or pharmacological related conditions, other illnesses of the liver and gastrointestinal tract, and cancer. Additional contributing factors and causes of secondary osteoporosis include those listed below. Dietary deficiencies: low calcium, low vitamin D, and anorexia Skeletal diseases: osteogenesis imperfecta and hypophosphatasia Medications: corticosteroids, thyroid drugs, heparin, and antiseizure drugs Sedentary lifestyle Spinal cord injury Alcohol and tobacco use Endocrine disorders, rheumatoid arthritis and connective tissue diseases Gastrointestinal tract disorders Renal disease Cancer Medications and Therapies That Can Cause Osteoporosis As mentioned previously, certain medications and therapies can cause osteoporosis. 19 Glucocorticoid-induced osteoporosis (GIO) is by far the most 17

common form of osteoporosis produced by drug treatment. 1 With the increased use of prednisone and other drugs that act like cortisol for the treatment of many inflammatory and autoimmune diseases, this form of bone loss has become a major clinical concern. 1 Glucocorticoids cause a profound reduction in bone formation and may, to a lesser extent, increase bone resorption, leading to loss of trabecular bone at the spine and hip. The most rapid bone loss occurs early in the course of treatment, and even small doses (equivalent to 2.5-7.5 mg prednisone per day) are associated with an increase in fractures. 1 Cyclosporine A and tacrolimus are widely used in conjunction with glucocorticoids to prevent rejection after organ transplantation, and high doses of these drugs are associated with a particularly severe form of osteoporosis. 1 Bone disease has also been reported among those taking several frequentlyprescribed anticonvulsant drugs, including diphenylhydantoin, phenobarbital, sodium valproate, and carbamazepine. 1 Methotrexate, a folate antagonist used to treat malignancies and (in lower doses) inflammatory diseases, such as rheumatoid arthritis, may also cause bone loss. Gonadotropin-releasing hormone agonists, which are used to treat endometriosis in women and prostate cancer in men, reduce both estrogen and testosterone levels, which may cause significant, bone loss and fragility fractures. 1 Rickets and Osteomalacia Rickets (which affects children) and osteomalacia (which affects adults) are relatively uncommon diseases in the U.S. 1 Generally both diseases can be prevented by ensuring adequate intake of vitamin D. 1 Rickets and osteomalacia are typically caused by a variety of environmental abnormalities, but can also be inherited as a result of mutations in the gene producing the enzyme that converts 25-hydroxy vitamin D to the active form, 1,25-dihydroxy vitamin D receptor. Since vitamin D is formed in the skin by sunlight, the most common cause of rickets or osteomalacia is reduced sun exposure, particularly in northern latitudes where the winter sun does not have the strength to form vitamin D in the skin. Individuals who are confined indoors, or who are housebound due to chronic ill health or frailty, are also at risk. 18

Renal Osteodystrophy and Osteoporosis Individuals with chronic renal disease are not only at risk of developing rickets and osteomalacia, they are also at risk of developing a complex bone disease known as renal osteodystrophy. 1 The condition is characterized by a stimulation of bone metabolism caused by an increase in parathyroid hormone, and a delay in bone mineralization initiated by decreased kidney production of 1,25-dihydroxy vitamin D. 1 Renal dialysis can significantly extend the life expectancy of patients with chronic renal failure, but it does not prevent further progression of the osteodystrophy. Paget s Disease and Osteoporosis Osteoporosis and Paget s are both metabolic bone diseases characterized by low bone density. 22 The majority of people affected by osteoporosis are women, while 60% of those affected by Paget s disease are men. 20 A notable difference between the two is that in Paget s disease the bones grow abnormally large in some areas but not others, due to excess numbers of overactive osteoclasts. While bone formation increases to compensate for the loss, the rapid production of new bone leads to a disorganized structure. The resulting bone is expanded in size, and associated with increased formation of blood vessels and connective tissue in the bone marrow. Affected bone becomes more susceptible to deformity or fracture. Paget s disease is a progressive, often crippling disorder of remodeling that commonly involves the spine, pelvis, legs, or skull (although any bone can be affected). 22 Depending on the location, the condition may not produce any clinical signs or symptoms, or it may be associated with bone pain, deformity, fracture, or osteoarthritis of the joints adjacent to the abnormal bone. 23,24 In very rare cases, probably occurring less than 1% of the time, the disease is complicated by the development of an osteosarcoma. If diagnosed early, its impact can be minimized. Although Paget s disease is the second most common bone disease after osteoporosis, many questions remain regarding its pathogenesis. 1 There is a strong familial predisposition for Paget s disease, but no single genetic abnormality has been identified that can explain all cases. 1,25 Paget s disease 19

can be transmitted across generations in an affected family; 15-40% of patients have a relative with the disorder. 1,26,27 Some studies have suggested that Paget s disease may result from a slow virus infection with measles; however, more research is needed before conclusive evidence can be made available. 1,28,29,30,31 Gastrointestinal Disorders and Bone Health Celiac disease, or sprue, is an inherited intestinal disorder in which gluten intolerance alters the body s ability to absorb calcium and other nutrients. 16 Gluten is a protein found in wheat, rye, farina, semolina and bulgar. Individuals with celiac disease often consume adequate amounts of calcium and vitamin D, but its absorption may be compromised. For this reason, low bone density is common in untreated and newly diagnosed cases of celiac disease. When foods containing gluten are eliminated from the diet, normal absorption from the intestines is restored. In some cases, the diagnosis of celiac disease is missed because the only symptom the person has is occasional diarrhea or failure to gain or maintain body weight. The amount of bone a person loses will depend on the age at diagnosis and the onset of treatment with a gluten-free diet. When celiac disease is diagnosed and treated in childhood, peak bone density may still be achieved. Even adults with celiac disease show improvement in bone density once they are treated with a gluten-free diet. Additionally, those with celiac disease should have optimal intake of vitamin D, participate in an exercise program, and avoid all products containing gluten. Diagnosis is usually made with a special antibody blood test, or by examining a piece of intestinal tissue removed in biopsy. Developmental Skeletal Disorders There are many genetic and developmental disorders that affect the skeleton, and the most common (and most important) of which is a group of inherited disorders referred to as osteogenesis imperfecta, or OI. 1,32 Osteogenesis imperfecta results from genetic defects or mutations that interfere with the body s production of type I collagen. 33 There are four main types of OI, which can be distinguished by their clinical signs and symptoms. 20

Most OI patients suffer from low bone mass, or osteopenia, and as a result suffer from recurrent fractures and skeletal deformities. 1 Type I OI is the most common form, and presents with the mildest symptoms. 34,35 The second mildest form of the disease is called Type IV, because it was the fourth type of OI to be discovered. Type IV produces mild to moderate bone deformity, and is associated with dental problems and hearing loss. A unique characteristic of patients with OI is that they sometimes have a blue, purple, or gray discoloration in the sclera. Type III OI is a more severe form of the disease, resulting in frequent fractures, short stature, hearing loss, and dental problems. Type II OI is the most severe form of the disease; sufferers typically experience numerous fractures and severe bone deformity, which generally leads to early death. 1 Malignancy and the Skeleton Many skeletal disorders are not inherited, but develop later in life as a result of a tumor in the bone. Bone tumors can originate in the bone (primary tumors), or maybe the result of metastasis from tumors originating elsewhere in the body. Primary bone tumors can be either benign or malignant. The most common benign bone tumor is osteochondroma, and the most common malignant ones are osteosarcoma and Ewing s sarcoma. 1 Metastatic bone tumors are often the result of breast or prostate cancer that has spread to bone. 1 Breast cancer metastases are usually osteolytic, while most prostate cancer metastases are osteoblastic. 1 Multiple myeloma, another type of cancer, is a malignancy of the plasma cells that produce antibodies. Bone-resorbing cytokines are also produced in acute and chronic leukemia. Patients with Burkitt s lymphoma and non-hodgkin s lymphoma have associated loss of bone mass and osteoporosis. Oral Health and Bone Disease The prevalence of oral bone loss is significant among adult populations worldwide, and it increases with age for both sexes. 1 The maxilla and mandible, like the rest of the skeleton, are comprised of both trabecular and cortical bone, and undergo formation and resorption throughout one s lifetime. 1 Significant oral 21

bone loss results in loss of tooth-anchoring support, such that a variety of prosthetic and peridontal procedures might later be necessary. 1 Demographics The current data on osteoporosis supports the concern that osteoporosis is increasing at an alarming rate in the U.S. Nearly 44 million Americans are affected by bone loss, of these, approximately 10 million already have the disease, and 34 million have low bone mass. 2 According to WHO, a woman s lifetime risk for an osteoporotic-related fracture may be as high as 1 in 2 women. 5 Osteoporosis does not affect everyone to the same degree. Women, especially older women, are much more likely to get the disease than are men. 1 According to both the WHO and NOF, a BMD of 2.5 standard deviations (SD) or more below that of a young normal adult (T-score at or below 2.5)) indicates osteoporosis. Individuals in this group who have already experienced one or more fractures are deemed to have severe or established osteoporosis. A BMD between 1.0 and 2.5 SD below that of a young normal adult (T-score between 1.0 and 2.5) is considered low bone mass or osteopenia. In data from the National Osteoporosis Risk Assessment (NORA) study (done on 149,524 white, postmenopausal women), researchers found that only 18% of the women who had fractures would have been treatment candidates if the intervention threshold had been set at 2.5 (T-score) or less. They concluded that this would have resulted in no intervention for 82% of the women who actually experienced a new fracture during the first year after BMD was measured. The researchers believe that this demonstrates the unmet need to identify those women, who are most likely to fracture, which might benefit from targeted drug intervention. 10 The public misconception that osteoporosis is a woman s disease is rampant. According to recent polls, men are more likely to reply, when asked about who gets osteoporosis, that only women are at risk of developing the disease. Researchers estimate that at least 10 million men are considered to have low bone mass and osteoporosis. 11 Demographic information about the significance of the aging U.S. population also indicates that of the number of men older than 70 will double between 1993 and 2050, thus increasing the potential number of cases of osteoporosis in males. 22