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Osteoporosis

Background

Osteoporosis, a chronic progressive disease of multifactorial etiology (see Etiology), is the most common metabolic bone disease in the United States. It has been most frequently recognized in elderly white women, although it does occur in both sexes, all races, and all age groups.

This disease is considered a "silent thief" that generally does not become clinically apparent until a fracture occurs (see Clinical Presentation). Screening at-risk populations is, therefore, essential (see Workup).

Osteoporosis can affect almost the entire skeleton. It is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility.[1] The disease often does not become clinically apparent until a fracture occurs.

Osteoporosis represents an increasingly serious problem in the United States and around the world. Many individuals, male and female, experience pain, disability, and diminished quality of life as a result of having this condition. The economic burden the disease imposes is already considerable and will only grow as the population ages.[2]

Despite the adverse effects of osteoporosis, it is a condition that is often overlooked and undertreated, in large part because it is so often clinically silent before manifesting in the form of fracture. For example, a Gallup survey performed by the National Osteoporosis Foundation revealed that 75% of all women aged 45-75 years have never discussed osteoporosis with their physicians. Failure to identify at-risk patients, to educate them, and to implement preventive measures may lead to tragic consequences.

Medical care includes calcium, vitamin D, and antiosteoporotic medication such as bisphosphonates and parathyroid hormone. Antiresorptive agents currently available for osteoporosis treatment include bisphosphonates, the selective estrogen-receptor modulator (SERM) raloxifene, calcitonin, and denosumab. One anabolic agent, teriparatide (see

Medication), is available as well. Surgical care includes vertebroplasty and kyphoplasty. (See Treatment and Management.)

Osteoporosis is a preventable disease that can result in devastating physical, psychosocial, and economic consequences. Prevention and recognition of the secondary causes of osteoporosis are first-line measures to lessen the impact of the disease (see the images below). Osteoporosis of the spine. Observe the considerable reduction in overall vertebral bone density and note the lateral wedge fracture of L2. Osteoporosis of the spine. Note the lateral wedge fracture in L3 and the central burst fracture in L5. The patient had suffered a recent fall.

For more information, see Pediatric Osteoporosis, as well as Osteoporosis in Solid Organ Transplantation, Utility of Bone Markers in Osteoporosis, and Nonoperative Treatment of Osteoporotic Compression Fractures. Anatomy

Cortical and trabecular (cancellous) bone differ in architecture but are similar in molecular composition. Bone consists of cells and an extracellular matrix with mineralized and nonmineralized components. The composition and architecture of the extracellular matrix is what imparts mechanical properties to bone. Bone strength is determined by collagenous proteins (tensile strength) and mineralized osteoid (compressive strength).[3] The greater the concentration of calcium, the greater the compressive strength. Pathophysiology

Osteoporosis is a condition in which bone mass is low and microarchitectural deterioration of bone tissue occurs, leading to bone fragility and an increased risk of fracture. It results from hereditary and environmental factors that affect both bone mass and bone quality.

Traditionally, osteoporosis was described as type I (postmenopausal) or type II (senile). Postmenopausal osteoporosis (PMO) is primarily due to estrogen deficiency; senile osteoporosis is primarily due to an aging skeleton and calcium deficiency. However, it is increasingly recognized that multiple pathogenetic mechanisms interact in the development of the

osteoporotic state, regardless of age. Understanding the pathogenesis of osteoporosis starts with knowing how bone formation and remodeling occur. Normal bone formation and remodeling

Homeostasis of bone, a living tissue, is maintained by osteoclasts, which are responsible for bone resorption, and osteoblasts, which are responsible for bone formation. Osteoblasts are derived from mesenchymal stem cells, whereas osteoclasts are derived from hematopoietic precursors. The 2 types of cells are dependent on each other for production. In fact, the development of osteoclasts from hematopoietic precursors cannot be accomplished unless mesenchymal cells are present.

Mesenchymal cells with the potential to become osteoblasts also have the potential to become fibroblasts, chondrocytes, adipocytes, or muscle cells. This potential for differentiation allows the osteoblast to secrete the same cytokines and colony-stimulating factors produced by fibroblasts.

Hematopoietic granulocyte-macrophage colony-forming units (CFUs) produce osteoclasts and give rise to monocytes and macrophages. As such, the osteoclasts produce the same cytokines that monocytes produce. Interleukin (IL)-6 is produced, in part, by osteoblasts that stimulate osteoclastic activity. This phenomenon is one proposed mechanism for certain diseases that exhibit increased bone resorption. Two examples of diseases that result in osteoporosis by this mechanism are multiple myeloma and rheumatoid arthritis.

Bone is continually remodeled throughout life because bones sustain recurring microtrauma. Bone remodeling occurs at discrete sites within the skeleton and proceeds in an orderly fashion. Bone resorption is always followed by bone formation, a phenomenon referred to as coupling. In osteoporosis, this coupling mechanism is thought to be unable to keep up with the constant microtrauma to trabecular bone. In adults, approximately 25% of trabecular bone is resorbed and replaced every year, compared with only 3% of cortical bone.

Osteocytes, which are terminally differentiated osteoblasts embedded in mineralized bone, direct the timing and location of remodeling. Osteoblasts not only secrete and mineralize osteoid but also appear to control the bone resorption carried out by osteoclasts. Osteoclasts require weeks to

resorb bone, whereas osteoblasts need months to produce new bone. Therefore, any process that increases the rate of bone remodeling results in net bone loss over time.[4]

Furthermore, in periods of rapid remodeling (eg, after menopause), bone is at an increased risk for fracture because the newly produced bone is less densely mineralized, the resorption sites are temporarily unfilled, and the isomerization and maturation of collagen is impaired.[5]

Molecular biologists have begun to elucidate the mechanisms of bone remodeling. For example, it is now understood that the receptor activator of nuclear factor-kappa B ligand (RANKL)/receptor activator of nuclear factor-kappa B (RANK)/osteoprotegerin (OPG) system is the final common pathway for bone resorption.

Osteoblasts and activated T cells in the bone marrow produce the RANKL cytokine. RANKL binds to the RANK receptor expressed by osteoclasts and osteoclast precursors to promote osteoclast differentiation. Osteoprotegerin is a soluble decoy receptor that inhibits RANKRANKL by binding and sequestering RANKL.

Bone mass peaks by the third decade of life and slowly decreases afterward. The failure to attain optimal bone strength by this point is one factor that contributes to osteoporosis. Therefore, nutrition and physical activity are important during growth and development. Nevertheless, hereditary factors play the principal role in determining an individual's peak bone strength. In fact, genetics account for up to 80% of the variance in peak bone mass between individuals.[6] Alterations in bone formation and resorption

The hallmark of osteoporosis is a reduction in skeletal mass caused by an imbalance between bone resorption and bone formation. Under physiologic conditions, bone formation and resorption are in a fair balance. A change in eitherthat is, increased bone resorption or decreased bone formationmay result in osteoporosis.

Osteoporosis can be caused both by a failure to build bone and reach peak bone mass as a young adult and by bone loss later in life. Accelerated bone loss can occur in perimenopausal women and elderly men and women and can occur secondary to various disease states and medications.

Loss of gonadal function and aging are the 2 most important factors contributing to the development of osteoporosis. Studies have shown that bone loss in women accelerates rapidly in the first years after menopause. The lack of gonadal hormones is thought to up-regulate osteoclast progenitor cells.

Estrogen deficiency not only accelerates bone loss in postmenopausal women but also plays a role in bone loss in men. Estrogen deficiency can lead to excessive bone resorption accompanied by inadequate bone formation. Osteoblasts, osteocytes, and osteoclasts all express estrogen receptors. In addition, estrogen affects bones indirectly through cytokines and local growth factors. The estrogen-replete state may enhance osteoclast apoptosis via increased production of transforming growth factor (TGF)-beta.

In the absence of estrogen, T cells promote osteoclast recruitment, differentiation, and prolonged survival via IL-1, IL-6, and tumor necrosis factor (TNF)-alpha. A murine study, in which either the mice's ovaries were removed or sham operations were performed, found that IL-6 and granulocyte-macrophage CFU levels were much higher in the ovariectomized mice.[7] This finding provided evidence that estrogen inhibits IL-6 secretion, and IL-6 contributes to the recruitment of osteoclasts from the monocyte cell line, thus contributing to osteoporosis.

IL-1 has also been shown to be involved in the production of osteoclasts. The production of IL-1 is increased in bone marrow mononuclear cells from ovariectomized rats. Administering IL-1 receptor antagonist to these animals prevents the late stages of bone loss induced by the loss of ovarian function, but it does not prevent the early stages of bone loss. The increase in the IL-1 in the bone marrow does not appear to be a triggered event, but is a result of removal of the inhibitory effect of sex steroids on IL-6 and other genes directly regulated by sex steroids.

T cells also inhibit osteoblast differentiation and activity and cause premature apoptosis of osteoblasts through cytokines such as IL-7. Finally, estrogen deficiency sensitizes bone to the effects of parathyroid hormone (PTH; see below).

In contrast to postmenopausal bone loss, which is associated with excessive osteoclast activity, the bone loss that accompanies aging is associated with a progressive decline in the supply of

osteoblasts in proportion to the demand. This demand is ultimately determined by the frequency with which new multicellular units are created and new cycles of remodeling are initiated.

After the third decade of life, bone resorption exceeds bone formation and leads to osteopenia and, in severe situations, osteoporosis. Women lose 30-40% of their cortical bone and 50% of their trabecular bone over their lifetime, as opposed to men, who lose 15-20% of their cortical bone and 25-30% of trabecular bone.

Calcium, vitamin D, and PTH help maintain bone homeostasis. Insufficient dietary calcium or impaired intestinal absorption of calcium due to aging or disease can lead to secondary hyperparathyroidism. PTH is secreted in response to low serum calcium levels. It increases calcium resorption from bone, decreases renal calcium excretion, and increases renal production of 1,25-dihydroxyvitamin D (1,25[OH]2 D)an active hormonal form of vitamin D that optimizes calcium and phosphorus absorption, inhibits PTH synthesis, and plays a minor role in bone resorption.

Vitamin D deficiency can result in secondary hyperparathyroidism via decreased intestinal calcium absorption. Interestingly, the effects of PTH and 1,25[OH]2 D on bone are mediated via binding to osteoblasts and stimulating the RANKL/RANK pathway. Osteoclasts do not have receptors for PTH or 1,25[OH]2 D.[3]

Endocrinologic conditions or medications that lead to bone loss (eg, glucocorticoids) can cause osteoporosis. Corticosteroids inhibit osteoblast function and enhance osteoblast apoptosis.[8] Polymorphisms of IL-1, IL-6 and TNF-alpha, as well as their receptors, have been found to influence bone mass.

Other factors implicated in the pathogenesis of osteoporosis include polymorphisms in the vitamin D receptor; alterations in insulin-like growth factor-1, bone morphogenic protein, prostaglandin E2, nitrous oxide, and leukotrienes; collagen abnormalities; and leptin-related adrenergic signaling.[4]

Osteoporotic fractures represent the clinical significance of these derangements in bone. They can result both from low-energy trauma, such as falls from a sitting or standing position, and

from high-energy trauma, such as a pedestrian struck in a motor vehicle accident. Fragility fractures, which occur secondary to low-energy trauma, are characteristic of osteoporosis.

Fractures occur when bones fall under excess stress. Nearly all hip fractures are related to falls.[9] The frequency and direction of falls can influence the likelihood and severity of fractures. The risk of falling may be amplified by neuromuscular impairment due to vitamin D deficiency with secondary hyperparathyroidism or corticosteroids.

Vertebral bodies are composed primarily of cancellous bone with interconnected horizontal and vertical trabeculae (see Anatomy). Osteoporosis not only reduces bone mass in vertebrae but also decreases interconnectivity in their internal scaffolding.[3] Therefore, minor loads can lead to vertebral compression fractures.

An understanding of the biomechanics of bone provides greater appreciation as to why bone may be susceptible to an increased risk of fracture. When vertical loads are placed on bone, such as tibial and femoral metaphyses and vertebral bodies, a substantial amount of bony strength is derived from the horizontal trabecular cross-bracing system. This system of horizontal crossbracing trabeculae assists in supporting the vertical elements, thus limiting lateral bowing and fractures that may occur with vertical loading.

Disruption of such trabecular connections is known to occur preferentially in patients with osteoporosis, particularly in postmenopausal women, making females more at risk than males for vertebral compression fractures.

Rosen and Tenenhouse studied the unsupported trabeculae and their susceptibility to fracture within each vertebral body and found an extraordinarily high prevalence of trabecular fracture callus sites within vertebral bodies examined at autopsy, typically 200-450 healing or healed fractures per vertebral body.[10] These horizontal trabecular fractures are asymptomatic, and their accumulation reflects the impact of lost trabecular bone and greatly weakens the cancellous structure of the vertebral body.

The reason for preferential osteoclastic severance of horizontal trabeculae is unknown. Some authors have attributed this phenomenon to overaggressive osteoclastic resorption.

Osteoporosis may be confused with osteomalacia. The normal human skeleton is composed of a mineral component, calcium hydroxyapatite (60%), and organic material, mainly collagen (40%). In osteoporosis, the bones are porous and brittle, while in osteomalacia the bones are soft. This difference in bone consistency is related to the mineral-to-organic material ratio. In osteoporosis, the mineral-to-collagen ratio is within the reference range, whereas in osteomalacia, the proportion of mineral composition is reduced relative to organic mineral content. WHO definition of osteoporosis

Bone mineral density (BMD) in a patient is related to peak bone mass and, subsequently, bone loss. The World Health Organization (WHO) has established the following definitions of osteoporosis based on BMD measurements in white women: Normal - BMD within 1 standard deviation (SD) of the mean bone density for young adult women (T-score at -1 and above) Low bone mass (osteopenia) - BMD between 1-2.5 SD below the mean for young adult women (T-score between -1 and -2.5) Osteoporosis - BMD 2.5 SD or more below the normal mean for young adult females (T-score at or below -2.5) Severe or "established" osteoporosis - BMD 2.5 SD or more below the normal mean for young adult females (T-score at or below -2.5) in a patient who has already experienced 1 or more fractures

The WHO definition applies to postmenopausal women and men aged 50 years or older. Although these definitions are necessary to establish the prevalence of osteoporosis, they should not be used as the sole determinant of treatment decisions. This diagnostic classification should not be applied to premenopausal women, men younger than 50 years, or children.

Whereas the T-score is the bone density compared with the BMD of control subjects who are at their peak BMD, the Z-score reflects a bone density compared with that of patients matched for age and sex.[11, 12, 13, 14]

Z-scores should be used in premenopausal women, men younger than 50 years, and children. Zscores adjusted for ethnicity or race should be used, with Z-scores of -2.0 or lower defined as "below the expected range for age" and those above -2.0 being "within the expected range for age." The diagnosis of osteoporosis in these groups should not be based on densitometric criteria alone. Etiology

Osteoporosis has been divided into several classifications according to etiology and localization in the skeleton. Osteoporosis is initially divided into localized and generalized categories. These 2 main categories are classified further into primary and secondary osteoporosis. Postmenopausal osteoporosis (PMO) is primarily due to estrogen deficiency; senile osteoporosis is primarily due to an aging skeleton and calcium deficiency. Primary osteoporosis

Primary osteoporosis occurs in patients in whom a secondary cause of osteoporosis cannot be identified, including juvenile and idiopathic osteoporosis. Idiopathic osteoporosis can be further subdivided into postmenopausal (type I) and age-associated or senile (type II) osteoporosis, as follows: Juvenile osteoporosis usually occurs in children or young adults of both sexes. These patients have normal gonadal function. The age of onset usually is 8-14 years. The hallmark characteristic of juvenile osteoporosis is abrupt bone pain and/or a fracture following trauma. Type I osteoporosis (postmenopausal osteoporosis) occurs in women aged 50-65 years. This type of osteoporosis is characterized by a phase of accelerated bone loss. This bone loss occurs primarily from trabecular bone. In this phase, fractures of the distal forearm and vertebral bodies are common. Type II osteoporosis (age-associated or senile) occurs in women and men older than 70 years. This form of osteoporosis represents bone loss associated with aging. Fractures occur in cortical and trabecular bone. In addition to wrist and vertebral fractures, hip fractures are often seen in patients with type II osteoporosis. Secondary osteoporosis

Secondary osteoporosis occurs when an underlying disease, deficiency, or drug causes osteoporosis. Up to one third of postmenopausal women, as well as many men and premenopausal women, have a coexisting cause of bone loss.[15, 16]

Genetic (congenital) causes of osteoporosis include the following: Cystic fibrosis Ehlers-Danlos syndrome Glycogen storage disease Gaucher disease Hemochromatosis Homocystinuria Hypophosphatasia Idiopathic hypercalciuria Marfan syndrome Menkes steely hair syndrome Osteogenesis imperfecta Porphyria Riley-Day syndrome Hypogonadal states (see below)

Hypogonadal states that can cause osteoporosis include the following: Androgen insensitivity Anorexia nervosa/bulimia nervosa Female athlete triad Hyperprolactinemia Panhypopituitarism

Premature menopause Turner syndrome Klinefelter syndrome

Endocrine disorders that can cause osteoporosis include the following[17] : Acromegaly Adrenal insufficiency Cushing syndrome Estrogen deficiency Diabetes mellitus Hyperparathyroidism Hyperthyroidism Hypogonadism Pregnancy Prolactinoma

Deficiency states that can cause osteoporosis include the following: Calcium deficiency Magnesium deficiency Protein deficiency Vitamin D deficiency[17, 18] Bariatric surgery Celiac disease Gastrectomy Malabsorption

Malnutrition Parenteral nutrition Primary biliary cirrhosis

Inflammatory diseases that can cause osteoporosis include the following: Inflammatory bowel disease Ankylosing spondylitis Rheumatoid arthritis Systemic lupus erythematosus

Hematologic and neoplastic disorders that can cause osteoporosis include the following: Hemochromatosis Hemophilia Leukemia Lymphoma Multiple myeloma Sickle cell anemia Systemic mastocytosis Thalassemia Metastatic disease

Medications known to cause or accelerate bone loss include the following: Anticonvulsants - Phenytoin, barbiturates, carbamazepine (these agents are associated with treatment-induced vitamin D deficiency) Antipsychotic drugs

Antiretroviral drugs Aromatase inhibitors - Exemestane, anastrozole Chemotherapeutic/transplant drugs - Cyclosporine, tacrolimus, platinum compounds, cyclophosphamide, ifosfamide, methotrexate Furosemide Glucocorticoids and corticotropin[19] - Prednisone (5 mg/d for 3 mo)[20] Heparin (long-term) Hormonal/endocrine therapies - Gonadotropin-releasing hormone (GnRH) agonists, luteinizing hormone-releasing hormone (LHRH) analogs, depomedroxyprogesterone, excessive thyroid supplementation Lithium Methotrexate Selective serotonin reuptake inhibitors Thyroxine (excessive)

Miscellaneous causes of osteoporosis include the following: Alcoholism Amyloidosis Chronic metabolic acidosis Congestive heart failure Depression Emphysema Chronic or end-stage renal disease Chronic liver disease HIV disease/AIDS Idiopathic calciuria

Idiopathic scoliosis Immobility Multiple sclerosis Ochronosis Organ transplantation Pregnancy/lactation Sarcoidosis Weightlessness Risk factors

Risk factors for osteoporosis, such as advanced age and reduced bone mineral density (BMD), have been established by virtue of their direct and strong relationship to the incidence of fractures; however, many other factors have been considered risk factors based on their relationship to BMD as a surrogate indicator of osteoporosis. Risk factors for osteoporosis include the following[21, 22, 23] : Advanced age (50 years or older) Female sex White or Asian ethnicity Genetic factors, such as a family history of osteoporosis Thin build or small stature (eg, body weight less than 127 pounds) Amenorrhea Late menarche Early menopause Postmenopausal state Physical inactivity or immobilization[24] Use of drugs - Anticonvulsants, systemic steroids, thyroid supplements, heparin, chemotherapeutic agents, insulin

Alcohol and tobacco use Androgen[25] or estrogen deficiency Calcium deficiency

A study by Cummings et al in evaluated 9516 white women aged 65 years for an average of 4.1 years and found an indirect relationship between the number of risk factors and bone density values.[26] The study also identified factors that did not increase the risk of fracture, including hair color, number of children breastfed, prior smoking history, or use of short-acting benzodiazepines.

One very interesting finding of this study was that dietary intake of calcium was not correlated to the risk of hip fracture; however, the authors of the study did agree with other experts that dietary calcium would only help if the patient was calcium deficient.

A longitudinal and prospective cohort study, including a subcohort, evaluated the effect of dietary calcium on fracture incidence and osteoporosis in 61,433 women. The results found that low vitamin D intake was associated with a more pronounced rate of fracture in the first quintile. The risk of fractures of any type, or of osteoporosis, was not further reduced in the highest quintile of calcium intake but was associated with a higher rate of hip fracture. The study concludes that gradual increases in dietary calcium intake did not further reduce fracture risk or osteoporosis in women.[27]

One study sought to determine if the femoral neck BMD score and the World Health Organization Fracture Risk Algorithm (FRAX) score are associated with hip and nonspine fracture risk in older adults with type 2 diabetes mellitus (DM). Using data from 3 prospective observational studies, statistics from self-reported incidence of fractures in 9449 women and 7436 men in the United States were analyzed. The results found that participants with type 2 DM had a higher fracture risk and T score than those without type 2 DM, concluding that the femoral neck BMD T score and FRAX score were associated with higher hip and nonspine fracture risk in older adult patients with type 2 DM.[28] Epidemiology United States statistics

According to the National Osteoporosis Foundation (NOF), 10 million Americans have osteoporosis. Another 34 million have low bone mass, which leaves them at increased risk for osteoporosis.[29] Each year in the United States, 1.5 million osteoporotic fractures occur. Of these, 700,000 occur in the spine, 300,000 occur in the hip, and 200,000 occur in the wrist. The remainder of fractures occur at other sites in the body.

Most studies assessing the prevalence and incidence of osteoporosis use the rate of fracture as a marker for the presence of this disorder, although BMD also relates to risk of disease and fracture. The risk of new vertebral fractures increases by a factor of 2-2.4 for each SD decrease of BMD measurement. Women and men with metabolic disorders associated with secondary osteoporosis have a 2- to 3-fold higher risk of hip and vertebral fractures (see the images below). Normal femoral anatomy. Stable intertrochanteric fracture of the femur International statistics

Osteoporosis is by far the most common metabolic bone disease in the world and is estimated to affect over 200 million people worldwide.[30] An estimated 75 million people in Europe, the United States, and Japan have osteoporosis.[31] One in 3 women older than 50 years will eventually experience osteoporotic fractures, as will 1 in 5 men.[32] By 2050, the worldwide incidence of hip fracture is projected to increase by 240% in women and 310% in men.[33] Age distribution for osteoporosis

Risk for osteoporosis increases with age, as BMD declines. Senile osteoporosis is most common in persons aged 70 years or older. Secondary osteoporosis, however, can occur in persons of any age. Although bone loss in women begins slowly, it speeds up around the time of menopause, typically at about or after age 50 years. The frequency of postmenopausal osteoporosis is highest in women aged 50-70 years.

The number of osteoporotic fractures increases with age. Wrist fractures typically occur first, when individuals are aged approximately 50-59 years.

Vertebral fractures occur more often in the seventh decade of life. Jensen et al studied Danish women aged 70 years and found a 21% prevalence of vertebral fractures.[34] Melton et al reported that 27% of women in their study had evidence of vertebral fractures by age 65 years.[35]

Hip fractures occur more often in the eighth decade of life; 90% of such fractures occur in persons aged 50 years or older.[36] Sex distribution for osteoporosis

Women are at a significantly higher risk for osteoporosis. In primary osteoporosis, the female-tomale ratio is 5:1. Men have a higher prevalence of secondary osteoporosis, with an estimated 4560% being a consequence of hypogonadism, alcoholism, or glucocorticoid excess.[19] Only 3540% of osteoporosis diagnosed in men is considered primary in nature. Overall, osteoporosis has a female-to-male ratio of 4:1.[29]

Fifty percent of all women and 25% of all men older than 50 years experience an osteoporosisrelated fracture in their lifetime. Eighty percent of hip fractures occur in women.[36] Women have a 2-fold increase in the number of fractures resulting from nontraumatic causes, compared with men of the same age. Racial differences in incidence

Osteoporosis can occur in persons of all races and ethnicities. In general, however, whites (especially of northern European descent) and Asians are at increased risk.

In particular, non-Hispanic white women and Asian women are at higher risk for osteoporosis. An estimated one half of all hip fractures will occur in Asia in the next century. Twenty percent of non-Hispanic white and Asian women aged 50 years or older are estimated to have osteoporosis, and 52% have low bone mass. Ten percent of Hispanic women aged 50 years or older are estimated to have osteoporosis, and 49% have low bone mass. Five percent of nonHispanic black women older than 50 years are estimated to have osteoporosis, and 35% have low bone mass.

Seven percent of non-Hispanic white and Asian men aged 50 years or older have osteoporosis, and 35% have low bone mass. Four percent of non-Hispanic black men aged 50 years or older have osteoporosis, and 19% have low bone mass. Three percent of Hispanic men aged 50 years or older have osteoporosis, and 23% have low bone mass.[37, 38, 39]

Melton et al reported that the prevalence of hip fractures is higher in white populations, regardless of geographic location.[40] Another study indicated that the incidence of hip fractures was lower among African Americans in the United States and South Africa compared to agematched white populations within the same continent. A study of Japanese American women in Hawaii found a 5% incidence of vertebral fractures each year among individuals aged 80 years. Prognosis

The prognosis for osteoporosis is good if bone loss is detected in the early phases and proper intervention is undertaken. Patients can increase BMD and decrease fracture risk with the appropriate antiosteoporotic medication. In addition, patients can decrease their risk of falls by participating in a multifaceted approach that includes rehabilitation and environmental modifications, among others. Worsening of medical status can be prevented by providing appropriate pain management and, if indicated, orthotic devices. Effect of fractures on prognosis

Many individuals experience morbidity associated with the pain, disability, and diminished quality of life caused by osteoporosis-related fractures. According to a 2004 Surgeon General's report, osteoporosis and other bone diseases are responsible for about 1.5 million fractures per year. Osteoporosis-related fractures result in annual direct care expenditures of $12.2-$17.9 billion (in 2002 dollars).[41] In 2005, over 2 million osteoporosis-related fractures occurred in the United States.[42]

Osteoporosis is the leading cause of fractures in the elderly. Women aged 50 years have a 40% lifetime fracture rate as a result of osteoporosis. Osteoporosis is associated with 80% of all the fractures in people aged 50 years or older.

If full recovery is not achieved, osteoporotic fractures may lead to chronic pain, disability, and, in some cases, death. This is particularly true of vertebral and hip fractures.

Vertebral compression fractures (see the images below) are associated with increased morbidity and mortality rates. In addition, the impact of vertebral fractures increases as they increase in number. As posture worsens and kyphosis progresses, patients experience difficulty with balance, back pain, respiratory compromise, and an increased risk of pneumonia. Overall function declines, and patients may lose their ability to live independently. Osteoporosis. Lateral radiograph demonstrates multiple osteoporotic vertebral compression fractures. Kyphoplasty has been performed at one level. Osteoporosis. Lateral radiograph of the patient seen in previous image following kyphoplasty performed at 3 additional levels.

In one study, Cooper et al found that vertebral fractures increased the 5-year risk of mortality by 15%.[43] In a subsequent study, Kado et al[44] demonstrated that women with one or more fractures had a 1.23-fold increased age-adjusted mortality rate, while women with 5 or more vertebral fractures had a 2.3-fold increased age-adjusted mortality rate.

Furthermore, mortality rate was correlated with number of vertebral fractures, with 19 per 1000 woman-years in women with no fracture and 44 per 1000 woman-years in women with 5 or more fractures. Vertebral fractures were related to risk of subsequent cancer and pulmonary death, and severe kyphosis was further correlated with pulmonary deaths.

Only one third of people with radiographic vertebral fractures are diagnosed clinically.[45] Symptoms of vertebral fracture may include back pain, height loss, and disabling kyphosis. Compression deformities can lead to restrictive lung disease, abdominal pain, and early satiety.

More than 250,000 hip fractures are attributed to osteoporosis each year.[26] Like vertebral fractures, they are associated with significantly increased morbidity and mortality rates in men and women. In the year following hip fracture, excess mortality rates can be as high as 20%.[43, 46] Men have higher mortality rates following hip fracture than do women.

Patients with hip fractures incur decreased independence and a diminished quality of life. Of all patients with hip fracture, approximately 20% require long-term nursing care.[29] Among

women who sustain a hip fracture, 50% spend time in a nursing home while recovering. Approximately 50% of previously independent individuals become partially dependent, and one third become completely dependent.[47] Only one third of patients return to their prefracture level of function.[48]

Secondary complications of hip fractures include nosocomial infections and pulmonary thromboembolism.

Patients who have sustained one osteoporotic fracture are at increased risk for developing additional osteoporotic fractures.[49] For example, the presence of at least one vertebral fracture results in a 5-fold increased risk of developing another vertebral fracture. One in 5 postmenopausal women with a new vertebral fracture incurs another vertebral fracture within one year.[50]

Patients with previous hip fracture have a 2-fold[51] to 10-fold increased risk of sustaining a second hip fracture. In addition, patients with ankle, knee, olecranon, and lumbar spine fractures have a 1.5-, 3.5-, 4.1-, and 4.8-fold increased risk of subsequent hip fracture, respectively. WHO fracture-risk algorithm

The World Health Organization fracture-risk algorithm (www.shef.ac.uk/FRAX/) was developed to calculate the 10-year probability of a hip fracture and the 10-year probability of any major osteoporotic fracture (defined as clinical spine, hip, forearm, or humerus fracture) in a given patient. These calculations account for femoral neck bone mineral density (BMD) and other clinical risk factors, as follows[52] : Age Sex Personal history of fracture Low body mass index Use of oral glucocorticoid therapy Secondary osteoporosis (ie, coexistence of rheumatoid arthritis)

Parental history of hip fracture Current smoking status Alcohol intake (3 or more drinks per day)

The National Osteoporosis Foundation (NOF) recommends osteoporosis treatment in patients with low bone mass in whom a US-adapted WHO 10-year probability of a hip fracture is 3% or more or in whom the risk for a major osteoporosis-related fracture is 20% or more.[29]

Algorithms such as the FRAX algorithm are useful in identifying patients with low bone mass (T-scores in the osteopenic range) who are most likely to benefit from treatment. A study by Leslie et al demonstrated the effects of including a patient's 10-year fracture risk along with DXA results in Manitoba, Canada.[53] The authors found an overall reduction in dispensation of osteoporosis medications as more women were reclassified into lower fracture risk categories. Patient Education

Patient education is paramount in the treatment of osteoporosis. Many patients are unaware of the serious consequences of osteoporosis, including increased morbidity and mortality, and only become concerned when osteoporosis manifests in the form of fracture; accordingly, it is important to educate them regarding these consequences. Early prevention and treatment are essential in the appropriate management of osteoporosis.

The focus of patient education is on the prevention of osteoporosis. Prevention has 2 components, behavior modification and pharmacologic interventions. Appropriate preventive measures may include adequate calcium and vitamin D intake, exercise, cessation of smoking, and moderation of alcohol consumption.

Patients should be educated about the risk factors for osteoporosis, with a special emphasis on family history and the effects of menopause. Patients also need to be educated about the benefits of calcium and vitamin D supplements. All postmenopausal women should be offered bone densitometry, and they should understand the benefits of bone density monitoring. Society at large also should be educated about the benefits of exercise with regard to osteoporosis.

For patient education resources, see the following: Osteoporosis and Bone Health Center Eating Disorders Center Esophagus, Stomach, and Intestine Center Women's Health Center Osteoporosis Anorexia Nervosa Inflammatory Bowel Disease Menopause Hormone Replacement and Osteoporosis

History

Osteoporosis is typically asymptomatic until a fracture occurs. Patients who have not sustained a fracture often do not report symptoms that would alert the clinician to suspect a diagnosis of osteoporosis. This disease is a "silent thief" that generally does not become clinically apparent until a fracture occurs. Screening at-risk populations is, therefore, essential.

Multiple risk factors exist for osteoporosis. The National Osteoporosis Foundation (NOF) has categorized these risk factors into 2 categories: nonmodifiable and modifiable. Nonmodifiable risk factors include personal history of fracture as an adult, history of fracture in a first-degree relative, white race, advanced age, female sex, dementia, and poor health/fragility.

Potentially modifiable risk factors include current cigarette smoking, low body weight (< 127 lb), estrogen deficiency such as that caused by early menopause (age < 45 y) or bilateral ovariectomy and prolonged premenopausal amenorrhea (>1 y), low lifelong calcium intake, alcoholism,[54] impaired eyesight despite adequate correction, recurrent falls, inadequate physical activity, and poor health or frailty.

A thorough history should be obtained to screen for and identify the presence of known risk factors for osteoporosis and osteoporotic fracture. Specifically, the history should focus on the following[55] : Age (>50 years), sex (female), and race (white or Asian) Family history of osteoporosis, particularly maternal history of fractures Reproductive factors, especially regarding early menopause and estrogen replacement therapy Postmenopausal women are at high risk, as are women who have undergone hysterectomy and oophorectomy Hypogonadal states - Men with hypogonadism secondary to any genetic or other conditions are at higher risk Smoking - Smokers are at higher risk Alcohol consumption Low levels of physical activity - Immobility increases the risk[24] ; spinal cord injury and stroke cause physical impairment and are common causes of immobility Strenuous exercise (such as occurs in marathon runners) that results in amenorrhea Calcium and vitamin D intake History of low-trauma "fragility" fracture in patients aged 40 years or older - A fragility fracture is defined as a fracture due to trauma that would not normally cause fracture (a force equal to or less than that resulting from a fall from standing height) Signs of vertebral fracture (see below) Coexisting medical conditions associated with bone loss (see Etiology) Medications associated with bone loss (see Etiology) Risk factors for falls in older patients - These include poor balance, orthostatic hypotension, weakness of the lower extremity muscles and deconditioning, use of medications with sedative effects, poor vision or hearing, and cognitive impairment

Patients with acute insufficiency fractures may report a history of minimal or no trauma resulting in pain. They may report a fall from a standing or sitting position. Patients with compression fractures resulting in thoracic kyphosis may report iliocostal friction with associated abdominal

protrusion, decreased tolerance for oral intake, and breathing difficulties. Patients with hip, pelvic, or sacral fractures may report pain that is worsened with weightbearing.

Patients who have sustained a vertebral compression fracture may note progressive kyphosis with loss of height. They may also present with an episode of acute back pain after bending, lifting, or coughing. It should be noted, however, that two thirds of vertebral fractures are asymptomatic.

With respect to those vertebral fractures that are painful, typical subjective information may include the following: The episode of acute pain may follow a fall or minor trauma Pain is localized to a specific, identifiable, vertebral level in the midthoracic to lower thoracic or upper lumbar spine The pain is described variably as sharp, nagging, or dull; movement may exacerbate pain. In some cases, pain radiates to the abdomen Pain is often accompanied by paravertebral muscle spasms exacerbated by activity and decreased by lying supine Patients often remain motionless in bed because of fear of causing an exacerbation of pain Acute pain usually resolves after 4-6 weeks. In the setting of multiple fractures with severe kyphosis, the pain may become chronic

Patients who have sustained a hip fracture may experience the following: Patients may have pain in the groin, posterior buttock, anterior thigh, medial thigh, and/or medial knee during weightbearing or attempted weightbearing of the involved extremity Diminished hip range of motion (ROM) is reported, particularly internal rotation and flexion Patients may have external rotation of the involved hip while in the resting position

Patients with osteoporosis may report lactose intolerance and celiac sprue. Celiac sprue has been shown to be associated with osteoporosis in approximately 5% of cases.

Physical Examination

Patients with suspected osteoporosis should undergo a comprehensive physical examination. The physical examination should begin with an inspection of the patient. Height measurement with a stadiometer at each visit is useful. Examination of active and passive range of motion (ROM) assists in determining whether spine, hip, wrist, or other osseous pathology may be present. A thorough neurologic examination is essential to rule out spinal cord and/or peripheral nerve compromise.

The examination may elicit pain, or the patient may be pain free. Thoracic kyphosis may be present secondary to vertebral compression fractures, a dowager hump, and a history of loss of height. Patients may have an associated scoliosis.

Areas of concern include the following: A history of loss of height Low body weight (body mass index < 19 kg/m2) Signs that might indicate existing osteoporosis (eg, kyphosis or dowager's hump, point tenderness over a vertebrae or other suspected fracture site) Signs suggestive of secondary osteoporosis Signs in older patients that may indicate increased fall risk (eg, difficulty with balance or gait, orthostatic hypotension, lower-extremity weakness, poor vision or hearing, cognitive impairment) Signs of fracture

Patients with vertebral compression fractures may demonstrate a thoracic kyphosis with an exaggerated cervical lordosis (dowager's hump). This is followed by a loss of lumbar lordosis. After each episode of vertebral compression fracture and progressive kyphosis, the patient's height may decrease by 2-3 cm.

Patients with acute vertebral fractures may have point tenderness over the involved vertebrae. Palpation of the spinous processes often does not aid the examiner in localizing point tenderness, but percussion may be helpful in acute or subacute vertebral compression fractures.

Patients with hip fractures may have severe pain with ambulation. A flexion in abduction and external rotation (faber) hip joint test may reveal limited ROM with end-range pain. Patients with hip fractures may show decreased weightbearing on the fractured side or an antalgic gait pattern.

Patients with pubic and sacral fractures may report marked pain with ambulation and tenderness to palpation, percussion, or both. Furthermore, patients with sacral fractures may have pain with physical examination techniques used to assess the sacroiliac joint, such as the faber, Gaenslen, or squish test.

Fractures in other parts of the body, including the distal radius and humerus, are typically painful and result in limited range of motion of the involved joint. Signs of collagen defects

Patients with osteoporosis may have physical findings consistent with subtle collagen defects. These include a short fifth digit, dentinogenesis imperfecta, hyperlaxity, hearing loss, pes planus, bunions, and blue sclerae. Balance difficulties

Patients with osteoporosis are known to have decreased balance, possibly secondary to differences in balance control strategies and sway amplitude. Patients may have difficulty performing tandem gait and performing single limb stance. Poor balance may be noted particularly in patients with severe kyphosis resulting from vertebral compression fractures because their altered center of gravity makes ambulation with a stable base of support difficult for them.[56]

Fractures are the most common and serious complication of osteoporosis. Patients with osteoporosis are at high risk for recurrent fractures of the hips, vertebrae, ribs, and wrists.[26]

Complications

Vertebral compression fractures often occur with minimal stress, such as coughing, lifting, or bending. The vertebrae of the middle and lower thoracic spine and upper lumbar spine are involved most frequently. In many patients, vertebral fracture can occur slowly and without symptoms.

Hip fractures are the most devastating and occur most commonly at the femoral neck and intertrochanteric regions. Hip fractures are associated with falls. The likelihood of sustaining a hip fracture during a fall is related to the direction of the fall. Fractures are more likely to occur in falls to the side; less subcutaneous tissue is available to dissipate the impact. Secondary complications of hip fractures include nosocomial infections and pulmonary thromboembolism.

Fractures can cause further complications, including chronic pain from vertebral compression fractures and increased morbidity and mortality secondary to vertebral compression fractures and hip fractures. Patients with multiple fractures have significant pain, which leads to functional decline and a poor quality of life (QOL).[57] They are also at risk for all the complications of immobility, including deep vein thrombosis (DVT) and pressure ulcers. Respiratory compromise can occur in patients with multiple vertebral fractures that result in severe kyphosis.

Patients with osteoporosis develop spinal deformities and a dowager's hump, and they may lose 1-2 inches of height by their seventh decade of life. These patients can lose their self-esteem and are at increased risk for depression.

Diagnostic Considerations

The differential diagnosis of osteoporosis is very extensive and includes all the secondary causes. When dealing with reduced bone density, always rule out the other possible causes of symptoms before treating the patient for osteoporosis. Many patients have a coexisting cause of bone loss. This should be investigated and treated.

The differential diagnosis of an atraumatic compression fracture may include osteomalacia, tumor, osteonecrosis, infection, and other bone-softening metabolic disorders. Metastatic bone disease should always be ruled out when one is treating multiple fractures.

Osteoporosis may be confused with osteomalacia, but in osteoporosis, the bones are porous and brittle, while in osteomalacia the bones are soft. This difference in bone consistency is related to the mineral-to-organic material ratio. In osteoporosis, the mineral-to-collagen ratio is within the reference range, whereas in osteomalacia, the proportion of mineral composition is reduced relative to organic mineral content.

The presence of a fracture often is not only a marker for decreased bone mass but also potentially a symptom of failing health in general and 1 or more primary disorders in particular. Failure to diagnose and/or make appropriate referrals may create potential legal issues.

Other conditions to be considered include the following: Homocystinuria Leukemia Lymphoma Mastocytosis Metastases (bony and other) Pathologic fractures secondary to bone metastases from cancer Pediatric osteogenesis imperfecta Renal osteodystrophy Scurvy Sickle cell anemia Differentials Hyperparathyroidism Multiple Myeloma

Osteomalacia and Renal Osteodystrophy Paget Disease

Approach Considerations

Workup consists of appropriate laboratory studies to establish baseline values and look for potential secondary causes of osteoporosis, along with measurement of bone mineral density (BMD) to assess bone loss and estimate the risk of fracture. Bone biopsy may be indicated in specific situations. Lab Studies

The following laboratory studies are used to establish baseline conditions or to exclude secondary causes of osteoporosis: Complete blood count (CBC) Serum chemistries, including calcium, phosphate, creatinine, liver function tests, electrolytes Thyroid-stimulating hormone (TSH) level 25-Hydroxyvitamin D level

Calcium levels can reflect underlying disease states. Severe hypercalcemia may reflect underlying malignancy or hyperparathyroidism. In addition, hypocalcemia can contribute to osteoporosis. Levels of serum calcium, phosphate, and alkaline phosphatase are usually normal in persons with primary osteoporosis, although alkaline phosphatase levels may be elevated for several months after a fracture. Alkaline phosphatase, calcium, phosphate, and 25(OH) vitamin D levels may be obtained to assist in the diagnosis of osteomalacia.

Thyroid dysfunction has been associated with osteoporosis and should, therefore, be ruled out.[58]

Inadequate vitamin D levels can predispose persons to osteoporosis.

Other laboratory studies used to evaluate for secondary causes include the following: Twenty-four-hour urine calcium to assess for hypercalciuria Intact PTH level Thyrotropin (if on thyroid replacement) level Testosterone and gonadotropin levels Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) value Urinary free cortisol and tests for adrenal hypersecretion Serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) Antigliadin and antiendomysial antibodies for celiac disease Serum tryptase, urine N-methylhistamine for mastocytosis Bone marrow biopsy if a hematologic disorder is suspected

Twenty-four-hour urinary calcium levels help to rule out benign familial hypocalciuric hypercalcemia (FHH), in which urinary calcium levels are low.

An intact PTH level is essential in ruling out hyperparathyroidism. An elevated PTH level may be present in benign familial hypocalciuric hypercalcemia (FHH).

Experts are divided on whether to include thyrotropin testing, regardless of a history of thyroid disease or replacement; however, one study showed reduced femoral neck bone mineral density (BMD) in women with subclinical hypothyroidism and hyperthyroidism. In younger men with low bone densities, a testosterone profile and gonadotropin value should be obtained.

Some practitioners include ESR and CRP values in the workup, although their utility in this setting has not been proven in an evidence-based manner.

SPEP and UPEP are used to exclude the presence of multiple myeloma. SPEP may be performed to rule out plasma cell dyscrasias.

Specialized laboratory testing is guided by clinical suspicion or initial screening test results. A history of loose stools with anemia should raise the possibility of celiac sprue, which has been associated with approximately 5% of osteoporosis cases.

Patients with anemia, particularly those older than 60 years, should also be evaluated for multiple myeloma with a serum and urine protein electrophoresis. Cushing syndrome is not common but, when present, leads to rapidly progressive osteoporosis; a urine free cortisol value or overnight dexamethasone suppression testing should be ordered if Cushing syndrome is suspected. Serum iron and ferritin values are helpful if malabsorption or hemochromatosis is suspected.

An important study by Tannenbaum[59] evaluated 173 healthy women (ages 46-87 y) for secondary causes of osteoporosis and found that 55 (32%) had a previously undiagnosed disorder of bone or mineral metabolism. Given that occult disorders are so common among patients with osteoporosis, minimal laboratory screening is indicated in all patients who present with decreased bone mass. Biochemical Markers of Bone Turnover

Biochemical markers of bone turnover reflect bone formation or bone resorption. These markers (both formation and resorption) may be elevated in high-bone-turnover states (eg, early postmenopausal osteoporosis) and may be useful in some patients for monitoring early response to therapy.

Currently available serum markers of bone formation (osteoblast products) include the following: Bone-specific alkaline phosphatase (BSAP) Osteocalcin (OC) Carboxyterminal propeptide of type I collagen (PICP) Aminoterminal propeptide of type I collagen (PINP)

Currently available urinary markers of bone resorption (osteoclast products) include the following: Hydroxyproline Free and total pyridinolines (Pyd) Free and total deoxypyridinolines (Dpd) N-telopeptide of collagen cross-links (NTx) C-telopeptide of collagen cross-links (CTx)

Currently available serum markers of bone resorption include the following: Cross-linked C-telopeptide of type I collagen (ICTP) Tartrate-resistant acid phosphatase NTx CTx

Of the aforementioned tests, the ones most commonly used in clinical practice are BSAP, OC, urinary NTx, and serum CTx.

BSAP can be mildly elevated in patients with fractures. In addition, patients with hyperparathyroidism, Paget disease, or osteomalacia can have elevations of BSAP. Serum OC levels, if high, indicate a high-turnover type of osteoporosis.[60] Elevation of urinary NTx (>40 nmol bone collagen equivalent per mmol urinary creatine) indicates a high turnover state. NTx levels may also be used to monitor responses to antiosteoporotic treatments.

Significant controversy exists regarding the use of these biochemical markers, and concerns have been raised about intra-assay and interassay variability. At the primary author's institution, a urine NTx value normalized to creatinine excretion from the second urination of the day is used primarily to identify osteopenic patients in a high-turnover state who would benefit from therapy

and to monitor the response to therapy in all patients. However, further study is needed to determine the clinical utility of these markers in osteoporosis management. Plain Radiography

Plain radiography is recommended to assess overall skeletal integrity. In particular, in the workup for osteoporosis, plain radiography may be indicated if a fracture is already suspected or if patients have lost more than 1.5 inches of height.

Obtain radiographs of the affected area in symptomatic patients. Lateral spine radiography can be performed in asymptomatic patients in whom a vertebral fracture is suspected, in those with height loss in the absence of other symptoms, or in those with pain in the thoracic or upper lumbar spine. A scoliosis series is useful for detecting occult vertebral fractures.

Radiographic findings can suggest the presence of osteopenia, or bone loss, although they cannot be used to diagnose osteoporosis. Using the second metacarpal or the metaphysis of a long bone, the sum of the cortical width should be at least equal to the medullary width. Osteopenia is suggested by a sum that is less than the medullary width. Radiographs may also show fractures or other conditions such as osteoarthritis, disc disease, or spondylolisthesis.

Plain radiography is not as accurate as BMD testing. Because osteoporosis predominantly affects trabecular rather than cortical bone, radiography does not reveal osteoporotic changes until they affect the cortical bone. Cortical bone is not affected by osteoporosis until more than 30% bone loss has occurred. Approximately 30-80% of bone mineral must be lost before radiographic lucency becomes apparent on radiographs.[61] Thus, plain radiography is an insensitive tool for diagnosing osteoporosis. Dual-Energy X-Ray Absorptiometry

Several large prospective studies have shown that BMD measurements of the distal and proximal femur and the vertebral bodies can predict the development of the major types of osteoporotic fractures. BMD has been shown to be the best indicator of fracture risk. According to the National Osteoporosis Foundation (NOF), evaluating BMD on a periodic basis is the best way to monitor bone mass and future fracture risk.[62, 63]

The NOF and the International Society for Clinical Densitometry (ISCD) recommend that BMD be measured in the following patients: Women aged 65 years and older and men aged 70 years or older, regardless of clinical risk factors Younger postmenopausal women and men aged 50-70 years with clinical risk factors for fracture Women in menopausal transition with a specific risk factor associated with increased risk for fracture (ie, low body weight, prior low-trauma fracture, use of a high-risk medication) Adults with fragility fractures Adults who have a condition (eg, rheumatoid arthritis) or who take a medication (eg, glucocorticoids, 5 mg of prednisone daily for 3 mo) associated with low bone mass or bone loss Anyone being considered for pharmacologic therapy for osteoporosis Anyone being treated for osteoporosis (to monitor treatment effect) Anyone not receiving therapy in whom evidence of bone loss would lead to treatment

The US Preventive Services Task Force (USPSTF) has issued updated recommendations on screening for osteoporosis.[64] The USPSTF recommends measuring BMD in the following patients: Women aged 65 years and older without previous known fractures or secondary causes of osteoporosis Women younger than 65 years whose 10-year fracture risk is equal to or greater than that of a 65-year-old white woman without additional risk factors

These recommendations do not contradict the NOF recommendations for screening in women. However, in contradiction to the NOF recommendation, the USPSTF makes no recommendation for screening men without risk factors. For men without previous known fractures or secondary causes of osteoporosis, current evidence is insufficient to assess the balance of benefits and harms of screening.

Imaging options include densitometry, single-photon absorptiometry (SPA), dual-photon absorptiometry (DPA), dual-energy x-ray absorptiometry (DEXA), quantitative computed tomography (QCT) scanning, magnetic resonance imaging (MRI), bone scanning, and singlephoton emission CT (SPECT) scanning. The sensitivity, examination time, cost, and radiation exposure of the different imaging techniques differ greatly (see the table below).

Table. Comparison of Densitometry (Open Table in a new window) Single-Photon Absorptiometry Dual-Photon Absorptiometry Dual-Energy X-Ray Absorptiometry Quantitative Computed Tomography Time 5-15 min Cost $50-150 20-30 min $150-300 5-10 min $100-200 10-30 min $150-300

Sites Scanned Radius, forearm,

calcaneus

Spine, hip (anteroposterior) Spine (lateral), hip,

radius

Spine (lateral), hip,

radius

Out of all these imaging options, DEXA is currently the criterion standard for the evaluation of BMD.[62, 65] It is not as sensitive as QCT scanning for detecting early trabecular bone loss, but it provides rapid scanning times, lower costs, and greater precision. It is done on an outpatient basis,[63] and there are no special requirements (eg, dye injection) for performing it. Radiation exposure is kept to a minimum.

DEXA is used to calculate BMD at the lumbar spine, hip, and proximal femur. Densitometric spine imaging can be performed at the time of DEXA scanning to detect vertebral fractures. Vertebral fracture assessment (VFA) is not available with all DEXA machines. When available, VFA should be considered when the results may influence clinical management of the patient.[66] Peripheral DEXA is used to measure BMD at the wrist; it may be most useful in identifying patients at very low fracture risk who require no further workup.

First-generation DEXA scanners measured spinal BMD in just the anteroposterior view. This resulted in measurements of not only the trabecular-rich vertebral bodies but also the corticalrich spinal elements. New-generation scanners are capable of measuring spinal BMD in the lateral view, thus eliminating measurement of the cortical-rich structures. This improvement results in more accurate measurements of trabecular BMD and greater sensitivity for detecting osteoporosis.

Although measurement or BMD at any site can be used to assess overall fracture risk, measurement at a particular site is the best predictor of fracture risk at that site. Whenever possible, the same technologist should perform subsequent measurements on the same patient using the same machine. This method can be used in both adults and children. Factors that may

result in a falsely high BMD determination include spinal fractures, osteophytosis, and extraspinal (eg, aortic) calcification.

Bone density data from a DXA are reported as T-scores and Z-scores. The T-score is the value compared to control subjects who are at their peak BMD, whereas the Z-score reflects a value compared to patients matched for age and sex.[11, 12, 13, 14]

World Health Organization (WHO) criteria define a normal T-score value as within 1 standard deviation (SD) of the mean BMD value in a healthy young adult. Values lying farther from the mean are stratified as follows: T-score of -1 to -2.5 SD indicates osteopenia T-score of less than -2.5 SD indicates osteoporosis T-score of less than -2.5 SD with fragility fracture(s) indicates severe osteoporosis

For each SD reduction in BMD, the relative fracture risk is increased 1.5-3 times.

This diagnostic classification should not be applied to premenopausal women, men younger than 50 years, or children. Instead, Z-scores adjusted for ethnicity or race should be used, with values of -2.0 SD or lower defined as "below the expected range for age" and those above -2.0 SD being "within the expected range for age." The diagnosis of osteoporosis in these groups should not be based on densitometric criteria alone. Single- and Dual-Photon Absorptiometry

SPA of the proximal forearm provides precision and offers low radiation exposure, but it is relatively insensitive for detecting early-stage osteoporosis because it measures cortical rather than trabecular bone. DPA can measure BMD in the spine and proximal femur, but its use is limited by poor reproducibility, prolonged scanning times, and artifacts caused by vascular calcifications. Quantitative Computed Tomography Scanning

QCT scanning is another method employed to measure spinal BMD. It measures BMD as a true volume density in g/cm3, which is not influenced by bone size. This technique can be used in both adults and children but assesses BMD only at the spine. QCT scanning of the spine is the most sensitive method for diagnosing osteoporosis because it measures trabecular bone within the vertebral body.

QCT scanning may be useful in identifying fractures. It can be used to identify not only the fracture line but also areas of callus formation and sclerosis, consistent with healing fracture. It may also be used for evaluation of metastatic bone disease.

Compared with DEXA scanning, QCT is more expensive, has relatively poor reproducibility, and requires a higher radiation dose. In addition, it is subject to possible interference by osteophytes. It is not an ideal technique when repeated measurements are needed to detect small changes in BMD. Consequently, QCT scanning is seldom used now. Ultrasonography

Quantitative ultrasonography of the calcaneus is a low-cost portable screening tool. It has the advantage of not involving radiation, but it is not as accurate as other imaging methods. Ultrasonography cannot be used for monitoring skeletal changes over time, nor can it be used to monitor the response to treatment, because of its lack of precision. Magnetic Resonance Imaging

MRI may be useful in identifying fractures. Using fat suppression sequences, marrow edema consistent with fracture may be noted as areas of hypointensity on T1-weighted images in association with corresponding areas of hyperintensity on T2-weighted images. MRI is a very sensitive modality and is believed by some to be the first diagnostic imaging method of choice in the detection of acute fractures, such as sacral fractures.

MRI can be used to discriminate between acute and chronic fractures of the vertebrae and occult stress fractures of the proximal femur. These osteoporotic fractures demonstrate characteristic changes in the bone marrow that distinguish them from other uninvolved parts of the skeleton and the adjacent vertebrae.

MRI can be useful in the assessment of metabolic bone disease. Bone Scanning

Bone scanning assesses the function and tissue metabolism of organs by using a radionuclide (technetium-99m) that emits radiation in proportion to its attachment to a target structure. It is a nonspecific modality, but it is very sensitive for detecting bony abnormalities because an increase in osteoblastic activity (as seen in compression fractures) results in an increase of the radionuclide tracer concentration.

Images may be obtained in 3 phases of the bone scanning process. These phases are the immediate-flow study, the immediate static blood pool study, and the delayed static study. Acute fractures are visible in all phases of bone scanning and may remain beyond the reference range for up to 2 years. Single-Photon Emission CT Scanning

SPECT scanning represents a tomographic (CT-like) bone imaging technique that offers better image contrast and more accurate lesion localization than planar bone scanning. It increases the sensitivity and specificity of bone scanning for detection of lumbar spine lesions by 20-50% over planar techniques.

SPECT scanning is helpful when accurate localization of skeletal lesions within large and/or anatomically complex bony structures is required. This localization is possible because SPECT can visualize bony structures that would overlap on planar images (eg, separating vertebral body, facet and pars interarticularis lesions). Biopsy

Undecalcified iliac bone biopsy with double tetracycline labeling is rarely necessary but may be considered when no cause for osteoporosis is apparent, therapy is not eliciting a response, or osteomalacia is suspected. Bone biopsy can help to exclude underlying pathologic conditions such as multiple myeloma, which may be responsible for presumed osteoporotic fracture.

Typically, iliac crest biopsy is performed either in the minor procedure suite or in the operating room.

Tetracycline double labeling is a process used to calculate data on bone turnover. In this procedure, patients are given tetracycline, which binds to newly formed bone. This appears on biopsy samples as linear fluorescence. A second dose of tetracycline is given 11-14 days after the first dose; this appears on a biopsy sample as a second line of fluorescence. The distance between the 2 fluorescent labels can be measured to calculate the amount of bone formed during that interval.

One may also perform a vertebral body bone biopsy when performing a therapeutic procedure such as kyphoplasty (see images below) or vertebroplasty for fixation of a vertebral compression fracture. Osteoporosis. Lateral radiograph demonstrates multiple osteoporotic vertebral compression fractures. Kyphoplasty has been performed at one level. Osteoporosis. Lateral radiograph of the patient seen in previous image following kyphoplasty performed at 3 additional levels. Histologic Findings

Although bone biopsy is rarely needed to rule out neoplasms and other metabolic bone diseases, it is sometimes used to quantitate bone loss, using quantitative histomorphometric techniques. Histologic examination of osteoporotic bone may reveal generalized thinning of trabeculae and irregular perforation of trabeculae, reflecting unbalanced osteoclast-mediated bone resorption.[36] WHO Definition of Osteoporosis

Bone mineral density (BMD) in a patient is related to peak bone mass and, subsequently, bone loss. The World Health Organization (WHO) has established the following definitions of osteoporosis based on BMD measurements in white women: Normal - BMD within 1 standard deviation (SD) of the mean bone density for young adult women (T-score at -1 and above)

Low bone mass (osteopenia) - BMD between 1-2.5 SD below the mean for young adult women (T-score between -1 and -2.5) Osteoporosis - BMD 2.5 SD or more below the normal mean for young adult females (T-score at or below -2.5) Severe or "established" osteoporosis - BMD 2.5 SD or more below the normal mean for young adult females (T-score at or below -2.5) in a patient who has already experienced 1 or more fractures

The WHO definition applies to postmenopausal women and men aged 50 years or older. Although these definitions are necessary to establish the prevalence of osteoporosis, they should not be used as the sole determinant of treatment decisions. This diagnostic classification should not be applied to premenopausal women, men younger than 50 years, or children.

Whereas the T-score is the bone density compared with the BMD of control subjects who are at their peak BMD, the Z-score reflects a bone density compared with that of patients matched for age and sex.[11, 12, 13, 14]

Z-scores should be used in premenopausal women, men younger than 50 years, and children. Zscores adjusted for ethnicity or race should be used, with Z-scores of -2.0 or lower defined as "below the expected range for age" and those above -2.0 being "within the expected range for age." The diagnosis of osteoporosis in these groups should not be based on densitometric criteria alone.

Approach Considerations

Medical care includes the administration of adequate calcium, vitamin D, and antiosteoporotic medication such as bisphosphonates[67] and parathyroid hormone (PTH). In addition, potentially treatable underlying causes of osteoporosis such as hyperparathyroidism and hyperthyroidism should be ruled out or treated if detected.

Surgical care includes vertebroplasty and kyphoplasty. Vertebroplasty and kyphoplasty are minimally invasive spine procedures used for the management of painful osteoporotic vertebral compression fractures.

A 2008 literature review suggested that the use of "reminders plus education targeted to physicians and patients" can lead to increased bone mineral density (BMD) testing and greater use of osteoporosis medications.[68] In addition, a physician reminder in conjunction with a patient risk assessment strategy apparently can result in a reduction in patient fractures and an increase in osteoporosis therapy. The authors concluded that multicomponent tools aimed at doctors and patients may support clinical decision making in the management of osteoporosis.

A 2009 study indicated that the use of a case manager for the treatment of patients with hip fractures can, in comparison with a more commonly employed care strategy, can lead to more frequent use of appropriate osteoporosis treatment and may result in fewer fractures, increased life expectancy, and significant health-care cost savings.[2] Medical Care

Currently, no treatment can completely reverse established osteoporosis. Early intervention can prevent osteoporosis in most people. For patients with established osteoporosis, medical intervention can halt its progression. If secondary osteoporosis is present, treatment for the primary disorder should be provided.

Patients identified as at risk for osteoporosis (including children and adolescents) should undergo preventive measures, including adequate calcium intake, vitamin D intake, and exercise. Counsel patients to avoid tobacco use. Identify and treat alcoholism.

Protective measures should be taken in patients who must take glucocorticoids for other medical conditions. These include using the minimum effective dose, discontinuing the drug as soon as possible, and supplementing with calcium and vitamin D.

The National Osteoporosis Foundation (NOF) recommends that pharmacologic therapy should be reserved for postmenopausal women and men aged 50 years or older who present with the following: A hip or vertebral fracture (Vertebral fracture may clinical or morphometric [ie, identified on a radiograph alone].) Other prior fractures and low bone mass (T-score between -1.0 and -2.5 at the femoral neck, total hip, or spine) T-score less than -2.5 at the femoral neck, total hip, or spine after appropriate evaluation to exclude secondary causes Low bone mass (T-score between -1.0 and -2.5 at the femoral neck, total hip, or spine) and secondary causes associated with high risk of fracture (eg, glucocorticoid use or total immobilization) Low bone mass (T-score between -1.0 and -2.5 at the femoral neck, total hip, or spine) and (1) 10-year probability of hip fracture of 3% or more or (2) a 10-year probability of any major osteoporosis-related fracture of 20% or more based on the US-adapted World Health Organization (WHO) algorithm[52]

The American College of Physicians has reviewed the evidence and has proposed guidelines for pharmacologic treatments of osteoporosis.[69]

The agents currently available for osteoporosis treatment include bisphosphonates, the selective estrogen-receptor modulator (SERM) raloxifene, calcitonin, denosumab, and one anabolic agent, teriparatide (human recombinant PTH 1-34).[19, 70, 71] All therapies should be given with calcium and vitamin D supplementation.

These medications may be classified into 2 primary categories. The first includes medications that help to stimulate bone formation, such as vitamin D and bisphosphonates. The second includes medications that reduce bone resorption, such as estrogen, bisphosphonates, calcitonin, calcium, and vitamin D.[72]

Guidelines from the American Association of Clinical Endocrinologists (AACE), published in 2010, include the following recommendations for choosing drugs to treat osteoporosis[73] :

First-line agents - Alendronate, risedronate, zoledronic acid, denosumab Second-line agent - Ibandronate Second- or third-line agent - Raloxifene Last-line agent - Calcitonin Treatment for patients with very high fracture risk or in whom bisphosphonate therapy has failed - Teriparatide

The AACE guidelines advise against the use of combination therapy. Calcium and vitamin D supplementation

The goal of the current recommendations for daily calcium intake is to ensure that individuals maintain an adequate calcium balance. In 1994, the National Institutes of Health recommended the following daily calcium intake: Birth to age 6 months - 400 mg/d Age 6 months to 1 year - 600 mg/d Age 1 to 10 years - 800-1200 mg/d Age 11 to 24 years - 1200-1500 mg/d Age 25 to 50 years - 1000 mg/d Age 51 to 64 years - 1000 mg/d Age 51 years and older (only women not on hormone replacement therapy [HRT]) - 1500 mg/d Age 65 years and older - 1500 mg/d Pregnant or lactating women - 1200-1500 mg/d

Current recommendations from the National Osteoporosis Foundation for daily calcium intake are as follows: Age 1 to 3 years - 500 mg/d Age 4 to 8 years - 800 mg/d

Age 9 to 18 years - 1300 mg /d Age 19 to 49 years - 1000 mg/d Age 50 years and older - 1200 mg/d Pregnant and breastfeeding women age 18 years and younger - 1300 mg/d Pregnant and breastfeeding women age 19 years and older - 1000 mg/d

Vitamin D is increasingly being recognized as a key element in overall bone health and muscle function. The minimum daily requirement in patients with osteoporosis is 800 IU of vitamin D3, or cholecalciferol. Many patients require more, continuously or for a short period, to be considered vitamin D replete, defined as a serum 25-hydroxyvitamin D level of 32 ng/mL.

Several large studies have demonstrated that supplementation with a combination of calcium and vitamin D can reduce fracture risk.[74]

A meta-analysis of 12 double-blind, randomized, controlled trials of nonvertebral fractures and 8 randomized controlled trials of hip fractures comparing oral vitamin D (with or without calcium) with either calcium alone or placebo showed that nonvertebral fracture prevention with vitamin D is dose-dependent, and a higher dose reduced fractures by at least 20% in individuals aged 65 years or older.[75]

An additional meta-analysis concluded that vitamin D alone is not effective in preventing fractures, although, when administered with calcium, hip fractures and total fractures (and possibly vertebral fractures) were reduced.[76] The conclusions were based on 7 large studies that were randomized with at least one intervention arm in which vitamin D was given and included analysis of fractures as an outcome and at least 1000 participants.

More information is needed regarding risks associated with long-term calcium supplementation. Bolland et al conducted a meta-analysis of patients taking calcium supplements (without coadministered vitamin D) and association with cardiovascular risks. An increased risk for myocardial infarction was associated with patients taking calcium supplements.[77] This increased risk has not been associated with dietary calcium intake.

Bisphosphonates

Bisphosphonates are the most commonly used agents for osteoporosis. They have been employed for both treatment and prevention. (See Prevention of Osteoporosis.) Oral and intravenous (IV) options are available.

Alendronate has been shown to increase spinal and hip mineral density in postmenopausal women. Well-conducted controlled clinical trials using alendronate sodium indicate that treatment reduces the rate of fracture at the spine, hip, and wrist by 50% in patients with osteoporosis. The treatment dose of alendronate is 70 mg/wk, to be taken sitting upright with a large glass of water at least 30 minutes before eating in the morning. The results of a populationbased, national registerbased, open cohort study of 38,088 patients suggest that elderly patients who use proton pump inhibitors in conjunction with alendronate have a dose-dependent loss of protection against hip fracture.[78]

Other oral bisphosphonates include risedronate, given weekly or monthly, and ibandronate, given orally once a month. Risedronate reduced vertebral fractures by 41% and nonvertebral fractures by 39% over 3 years. Ibandronate has not shown efficacy in nonvertebral fractures in the clinical trials.

Intravenous bisphosphonates are excellent choices for patients intolerant of oral bisphosphonates or in those in whom adherence is an issue. Ibandronate is available as an intravenous formulation that is given every 3 months. Zoledronic acid is the most potent bisphosphonate available. It increases BMD at the spine by 4.3-5.1% and the hip by 3.1-3.5% compared with placebo. It reduces the incidence of spine fractures by 70%, hip fractures by 41%, and nonvertebral fractures by 25% over 3 years. Zoledronic acid is once-yearly intravenous infusion approved for the treatment of postmenopausal osteoporosis.[79]

Over time, bisphosphonate therapy decreases bone turnover and, at very high levels in animals, decreases bone strength and resilience. Some limited reports, including that by Odvina et al, describe patients on long-term bisphosphonate therapy developing transverse stress fractures; biopsy specimens of these individuals have suggested extremely low turnover states.[80]

Therefore, while the bisphosphonates are outstanding in their efficacy, bone turnover markers should be monitored; if these become profoundly suppressed, the patient should be taken off the bisphosphonates and given a rest period until he or she can return to therapeutic levels (Ntelopeptide of collagen cross-links [NTx], 20-40).

The limited trial data available on long-term treatment with bisphosphonates has raised questions about the optimal length of treatment with these medications.[81] This issue has become more important given newly recognized complications of bisphosphonate use, including osteonecrosis of the jaw and atypical (subtrochanteric or femoral shaft) femur fractures.

Some studies have sought to clarify the true risks of complications in patients receiving bisphosphonates. A Canadian study by Park-Willie et al found the estimated absolute risk of a subtrochanteric or femoral shaft fracture among 52,595 women with at least 5 years of bisphosphonate therapy to be low (0.13% during the subsequent year and 0.22% within 2 years).[82] Overall, a patients risk of fracture can be used to help guide length of treatment. Patients at high risk may be continued on bisphosphonates after 5 years; however, in some patients, especially those with a lower risk of fracture, bisphosphonate treatment may be stopped.[83]

The AACE recommends that clinicians consider a drug holiday after 4-5 years of bisphosphonate treatment, if osteoporosis is mild; if fracture risk is high, a drug holiday of 1-2 years may be considered after 10 years of treatment.[73] BMD and bone turnover markers should be monitored during the drug holiday, and treatment should be restarted if density declines substantially, bone turnover markers increase, or a fracture occurs.[73] Raloxifene

SERMs are considered to provide the beneficial effects of estrogen without the potentially adverse outcomes. Raloxifene, a SERM first studied for breast cancer prevention, decreases bone resorption through actions on estrogen receptors. It has been shown to prevent bone loss, and data in females with osteoporosis have demonstrated that raloxifene causes a 35% reduction in the risk of vertebral fractures. It has also been shown to reduce the prevalence of invasive breast cancer.

Raloxifene may be most useful in younger postmenopausal women without severe osteoporosis. It has been shown to increase the incidence of deep vein thrombosis and hot flashes. In 601 postmenopausal women who had daily therapy with raloxifene, BMD was increased, serum concentrations of total low-density lipoprotein cholesterol were lowered, and the endometrium was not stimulated.

Pooled mortality data from large clinical trials of raloxifene (60 mg/d) were analyzed by Grady et al in 2010. When compared with placebo, all-cause mortality was 10% lower among older postmenopausal women receiving raloxifene. The primary reduction was in noncardiovascular, noncancer deaths.[84] Teriparatide

Teriparatide (human recombinant PTH 1-34) is the only available anabolic agent for the treatment of osteoporosis. When PTH is given continuously, it is associated with increased osteoclastic and osteoblastic turnover, leading to a net loss of bone. However, in an intermittent subcutaneous administration of 20 mcg/d, PTH has been demonstrated to lead to a very active anabolic phase, with bone mass increasing up to 13% over 2 years in the spine and to a lesser degree within the hip.[85, 86, 87]

Indications for PTH in men and women are a bone density decline while on bisphosphonate therapy, bone density stabilization while on extremely low-level bisphosphonate therapy, a fracture occurring while on bisphosphonate therapy, or a very low initial bone turnover rate for which an anabolic effect is clearly warranted. Teriparatide should be considered in younger and older postmenopausal women with severe osteoporosis.

Most studies with PTH have been performed on women. The medication decreases the risk of vertebral and nonvertebral fractures to the same extent as bisphosphonates. Teriparatide is given for a maximum of 2 years, after which time the gains in BMD achieved with PTH are secure and can even be augmented with bisphosphonate therapy, otherwise the BMD slowly deteriorates to pretreatment levels.[88]

According to Finkelstein et al in 2003, initial studies using a combination of concurrent PTH and bisphosphonate therapy showed decreased benefit compared with therapy with either agent

alone; therefore, the general recommendation is that these drugs be given separately and in sequence.[89]

A 2005 study by Cosman and colleagues challenged this conclusion by giving 3-month-on, 3month-off pulses of teriparatide while the subjects were on weekly alendronate; BMD in the spine increased above that of the alendronate-only arm.[90] This pulsed regimen appears to take advantage of the 3- to 4-month so-called anabolic window, in which the markers of bone formation rise more quickly than the markers of bone resorption.

Studies by Deal et al and Ste-Marie et al on women have shown that the concurrent use of estrogen or raloxifene can enhance the bone-forming effects of teriparatide.[91, 92] Data on the use of PTH in men are much more limited, but they appear to have relatively comparable efficacy.

Bouxsein et al retrospectively analyzed data from the Fracture Prevention Trial and the Multiple Outcomes of Raloxifene Evaluation trial for the risk of new vertebral fractures adjacent to existing vertebral fractures in postmenopausal osteoporotic women in patients on teriparatide or raloxifene and found that teriparatide reduced fracture risk to a greater extent than raloxifene.[93]

In this study, 1226 untreated postmenopausal women had 1 or more vertebral fractures at baseline. During the 2-year follow-up, 196 (16%) had a total of 292 new vertebral fractures; 47% of fractures were adjacent to a previously existing fracture. Teriparatide reduced the risk of any new, new adjacent, and new nonadjacent vertebral fractures by 72%, 75%, and 70%, respectively, compared with placebo, whereas raloxifene reduced the risk by 54%, 54%, and 53%, respectively, compared with placebo. Calcitonin

Calcitonin is a hormone that decreases osteoclast activity, thereby impeding postmenopausal bone loss. It is delivered as a single daily intranasal spray that provides 200 U of the drug. The drug can be delivered subcutaneously, but this route is rarely used.

Results from a single controlled clinical trial indicate that calcitonin may decrease osteoporotic vertebral fractures by approximately 30%. In the first 2 years, calcitonin has been found to increase spinal BMD by approximately 2%. Calcitonin also has an analgesic property that makes it ideally suited for the treatment of acute vertebral fractures.

Calcitonin is an option for patients who are not candidates for other available osteoporosis treatments. Denosumab

Denosumab is a humanized monoclonal antibody directed against receptor activator of nuclear factor-kappa B ligand (RANKL), which is a key mediator of the resorptive phase of bone remodeling.[92] It decreases bone resorption by inhibiting osteoclast activity. Denosumab was approved by the US Food and Drug Administration (FDA) in June 2010. It has been studied in cancer patients and in patients with postmenopausal osteoporosis.[94, 95] It is indicated for patients with postmenopausal osteoporosis at high risk for fracture.

In patients with multiple myeloma or bone metastases from breast cancer, a single subcutaneous dose of denosumab decreases bone turnover markers within 1 day, and this effect is sustained through 84 days at the higher doses used in one study. Denosumab was shown to increase BMD and decrease bone resorption in postmenopausal women with osteoporosis over a 12-month period.

In a randomized placebo-controlled trial of 7868 women aged 60-90 years with osteoporosis who received either denosumab 60 mg SC or placebo every 6 months for 36 months, Cummings et al found that denosumab decreased the risk of vertebral, nonvertebral, and hip fractures in women with osteoporosis.[96]

Smith et al reported a reduction in incident vertebral fractures when denosumab was used in 734 men receiving androgen-deprivation therapy for prostate cancer compared with placebo.[97] In this study, denosumab significantly increased lumbar spine, hip, femoral neck, and radial BMD.

Because the overactivity of RANKL is a major factor in bone loss in patients with autoimmune and inflammatory disorders, such as ulcerative colitis, denosumab may become first-line therapy for these patients. Hormone replacement therapy

Hormone replacement therapy (HRT) was once considered a first-line therapy for the prevention and treatment of osteoporosis in women. Although HRT is not currently recommended for the treatment of osteoporosis, it is important to mention because many osteoporosis patients in a typical practice still use it for controlling postmenopausal symptoms.

Data from the Women's Health Initiative confirmed that HRT can reduce fractures.[98] However, the results of the Women's Health Initiative were distressing with respect to the adverse outcomes associated with combined estrogen and progesterone therapy (eg, risks for breast cancer, myocardial infarction, stroke, and venous thromboembolic events) and estrogen alone (eg, risks for stroke and venous thromboembolic events). Strontium ranelate

Evidence indicates that strontium ranelate (available in Europe) reduces the risk of fracture.[99, 100] Strontium is not approved for the treatment of osteoporosis in the United States. Other medical treatments

Based on preliminary data that suggest women on nitrates have higher BMDs and lower fracture risk, Jamal et al conducted a randomized placebo-controlled trial of women who applied daily nitroglycerin ointment for 24 months.[101] The nitroglycerin ointment increased BMD and decreased bone resorption, although headaches were a limiting factor for many patients. Other nitrate preparations may be better tolerated and could show efficacy for fracture risk reduction. Surgical Care

The goals of surgical treatment of osteoporotic fractures include rapid mobilization and return to normal function and activities. Traditional operative management of vertebral compression fractures is uncommon and is usually reserved for gross spinal deformity or for threatened or existing neurologic impairment.

Operative interventions include anterior and posterior decompression and stabilization with placement of such internal fixation devices as screws, plates, cages, or rods. Bone grafting is routinely performed to achieve bony union. The failure rate of spinal arthrodesis is significant because achieving adequate fixation of hardware in osteoporotic bone is difficult. Moreover, patients who are elderly have a reduced osteogenic potential.

Vertebroplasty and balloon kyphoplasty are indicated in patients with incapacitating and persistent severe focal back pain related to vertebral collapse. At the primary author's institution, vertebroplasty is used for lesions above T8 and kyphoplasty is used for the remainder. Vertebroplasty

Percutaneous vertebroplasty (PVP) with polymethylmethacrylate (PMMA) was developed in 1984. PMMA is the principal component of bone cements used for rapid stable fixation of implants, such as metal and plastic prosthetics placed in living bone during orthopedic procedures. PMMA is used in PVP to fortify a collapsed vertebral body and stabilize the vertebral column.

The first indication for this treatment was aggressive vertebral angiomas. PVP with PMMA was then used for other lesions that weakened the vertebral body, such as malignant tumors. PVP is one therapeutic alternative for the treatment of pain associated with compression fractures.

The procedure involves percutaneous injection of PMMA into a fractured vertebral body, either through a transpedicular or an extrapedicular route (see the image below). This procedure can be performed on an outpatient basis under local or general anesthesia with fluoroscopic assistance. Percutaneous vertebroplasty, transpedicular approach.

Because this is a continuous insertion into an unprepared bed, a venographic injection is often used to ensure that the needle is not directly aligned with an exiting vein. After verification of appropriate placement, 1-4 mL of a specially prepared PMMA-containing enhanced radiographic visualization material is then inserted directly with a syringe. One or more levels of the spine can be treated in a single setting.

One drawback of PVP with PMMA is that, although the bone cement is injected under pressure, the procedure does not have the potential to correct compression deformities. In addition, extravasation of the cement into the epidural space is a potential complication of this method.

Jensen et al studied age-related or steroid-induced osteoporotic vertebrae with partial compression fractures in patients who underwent PVP with PMMA.[102] A total of 48 vertebrae in 30 patients were injected, and 90% of the patients described marked improvement of pain within 1 week of treatment. All the patients who experienced pain relief noted increased mobility and decreased need for narcotics. The patients were tracked for an average of 9 months, and the rate of long-term pain relief was reported to be approximately 80%. Whether this pain relief was related to mechanical stabilization of the spine or was secondary to neurotoxic effects of PMMA remains to be determined.

In general, initial studies report good results.[103] However, success with vertebroplasty may be limited by the lack of significant height restoration and the high rate of cement extravasation. Kyphoplasty

The second therapeutic alternative for vertebral compression fractures is balloon kyphoplasty, which has been used since the mid 1990s. Kyphoplasty is similar to vertebroplasty, but a few key differences exist.[104]

Kyphoplasty involves the insertion of an inflatable balloon tamp into the vertebral body under fluoroscopic guidance. An extrapedicular approach is used in the midthoracic region, while a pedicular route may be used in the thoracolumbar or lumbar spine. The balloon is instilled with radiographic contrast material at pressures up to 360 pounds per square inch, which compacts the cancellous bone and re-expands the vertebral body, thus reducing the fracture.

The balloon is then removed, thereby creating a cavity. PMMA is infiltrated into the cavity, stabilizing the vertebral body and restoring vertebral body height. Because the cement is injected into the cavity under lower pressure than is used in PVP, the risk of cement extravasation is reduced (see the images below).

In kyphoplasty, a KyphX inflatable bone tamp is percutaneously advanced into the collapsed vertebral body (A). It is then inflated, (B) elevating the depressed endplate, creating a central cavity, and compacting the remaining trabeculae to the periphery. Once the balloon tamp is deflated and withdrawn, the cavity (C) is filled under low pressure with a viscous preparation of methylmethacrylate (D). Reduction in kyphotic angulation after kyphoplasty. Osteoporosis. Lateral radiograph demonstrates multiple osteoporotic vertebral compression fractures. Kyphoplasty has been performed at one level. Osteoporosis. Lateral radiograph of the patient seen in previous image following kyphoplasty performed at 3 additional levels.

This procedure has been successful both in reducing the amount of kyphosis and in restoring vertebral body height. It also has successfully reduced pain. Studies have shown kyphoplasty to be a safe and minimally invasive spine procedure that results in improved function in elderly patients, allowing them to participate in increased activities, with resulting improvements in independence and quality of life. Dietary Measures

Adequate calcium and vitamin D intake are important in persons of any age, particularly in childhood as the bones are maturing. Patients who ingest inadequate amounts of vitamin D and calcium should receive oral supplementation.

A diet that includes adequate vitamin D and calcium is essential. Recommendations for patients with osteoporosis include daily dosages of 400-800 IU of vitamin D and 1200-1500 mg of calcium.

Premenopausal women and men younger than 50 years without risk factors for osteoporosis should receive a total of 1000 mg of calcium daily. Postmenopausal women, men older than 50 years, and other persons at risk for osteoporosis should receive a total of 1200-1500 mg of calcium daily. Good sources of calcium include dairy products, sardines, nuts, sunflower seeds, tofu, vegetables such as turnip greens, and fortified food such as orange juice. See the National Osteoporosis Foundation Web site for further calcium recommendations.

Adults younger than 50 years should receive 400-800 IU of vitamin D3 daily. All adults older than 50 years should receive 800-1000 IU of vitamin D3 daily. Good sources of vitamin D include eggs, liver, butter, fatty fish, and fortified food such as milk and orange juice. See the National Osteoporosis Foundation Web site for further vitamin D recommendations.

A meta-analysis of 12 double-blind, randomized, controlled trials (RCTs) for nonvertebral fractures and 8 RCTs for hip fractures that compared oral vitamin D (with or without calcium) with either calcium alone or placebo found that nonvertebral fracture prevention with vitamin D was dose dependent and that a higher dose reduced fractures by at least 20% for individuals aged 65 years or older.[75]

The following conditions can interfere with nutrition: Alcohol intake - Excessive alcohol intake can interfere with calcium balance by increasing PTH production and by inhibiting the enzymes that convert inactive vitamin D to its active form; in addition, alcohol can result in hormonal deficiencies and can increase the tendency for falls Anorexia nervosa - Poor nutritional states, such as in anorexia nervosa, an eating disorder,[105] have been strongly associated with bone loss; nutritional and endocrine factors contribute to bone loss (in particular, low estrogen states, which result from low body weight, result in significant bone loss) Physical Therapy and Exercise

The first goal of rehabilitation in osteoporosis patients is to control pain if a fracture has occurred. Spinal compression fractures can be extremely painful and can cause short- and longterm morbidity. Oral analgesics on a regular schedule can be implemented. Pain-relieving modalities such as moist hot packs and transcutaneous electrical nerve stimulation should also be considered. During this period, monitoring the patient carefully for signs of constipation, urinary retention, and respiratory depression, which can occur with the use of narcotic analgesics, is essential.

A comfortable mechanical support for the spine and, in some cases, a thoracic orthosis, may need to be prescribed. The primary reason for the application of a thoracic orthosis is to limit motion in the spine. The length of time a patient should wear a rigid spinal orthosis is undetermined.

What is well known is that immobilization contributes to bone demineralization. During the early mobilization period, deep breathing exercises, pectoral and intercostal strengthening, and back conservation techniques need to be implemented.

Physical therapy then focuses on improving a patient's strength, flexibility, posture, and balance in order to prevent falls and maximize his/her physical function.[106, 107] Postural retraining is key in this population. Spinal BMD is directly correlated with the strength of the back extensors; therefore, maintaining and strengthening the back extensors should be emphasized.[108] Sinaki and others found that strengthening the back extensor muscles reduced kyphosis and decreased the risk of sustaining vertebral compression fractures.[109, 110]

As soon as the course of therapy allows, weightbearing exercises should be initiated. Regular weight-bearing exercises are essential for the maintenance of bone mass[24] and should be encouraged in all patients, including children and adolescents (in order to strengthen the skeleton during the maturation process). Exercise also improves agility and balance, thereby reducing the risk of falls.

Aerobic low-impact exercises, such as walking and bicycling, generally are recommended. During these activities, ensure the patient maintains an upright spinal alignment. In 1984, Sinaki and Mikkelsen showed that exercises that place flexion forces on the vertebrae tend to cause an increase in the number of vertebral fractures in patients.[108]

In postmenopausal women, impact exercises can increase BMD in the hip and spine. Chien et al examined the efficacy of a 24-week aerobic exercise program consisting of treadmill walking followed by stepping exercises in osteopenic postmenopausal women aged 48-65 years. Women who exercised had increased bone mineral density in L2-L4 and the femoral neck, as well as improved quadriceps strength, muscular endurance, and peak exercise oxygen consumption (VO2 max), while values in the control group declined.[111]

Also, Snow et al found increased BMD of the femoral neck, trochanter, and total hip in 18 postmenopausal women (average age 64 y), who wore weighted vests and participated in jumping exercises 3 times per week for 32 weeks of the year over 5 years.[112]

Although swimming is not a weightbearing exercise that will improve BMD, it does provide chest expansion, spinal extension, and low-impact cardiopulmonary fitness. Isometric exercises should also be used to strengthen abdominal muscles, aiding in the prevention of a kyphosis.

Proper therapy for osteoporosis includes 3-5 sessions per week of weight-bearing exercises, such as walking or jogging, with each session lasting 45-60 minutes. The patient should be instructed in a home exercise program that incorporates the necessary elements for improving his/her posture and overall physical fitness.

The physical therapist must address balance training, because fall prevention is important in eliminating the complication of fracture. Improving one's balance can significantly lower the risk of falling. Balance training incorporates the strengthening of various parts of the body (eg, trunk, legs), proprioception, and vestibular input. Several different exercises have been shown to be beneficial in patients with osteoporosis.[113, 114, 115, 116]

Tai Chi Chuan and specific physical therapy programs have been shown to be particularly effective in improving balance and reducing falls. Wolf et al monitored 200 elderly community dwellers who received Tai Chi and computerized balance training. After a 15-week intervention, the authors documented decreased fear of falling responses. In addition, Tai Chi was shown to reduce the risk of multiple falls by 47.5%.[117]

Campbell et al monitored 233 elderly community dwellers randomized to an individually tailored physical therapy program in the home compared with usual care and an equal number of social visits. The authors found that after one year, the mean rate of falls was lower in the exercise group than the control group (0.87 versus 1.34, respectively). In addition, after 6 months, subjects in the exercise group had improved balance.

Other types of exercise training programs may also positively impact balance and strength. Carter et al demonstrated that osteoporotic women aged 65-75 years who underwent a 10-week community-based physical activity intervention program improved their static balance, dynamic balance, and knee extension strength, although they did not benefit from a significant reduction in fall risk factors.[118] Occupational Therapy

Training in the performance of activities of daily living (ADLs) and in the proper use of adaptive equipment are essential to the prevention of future falls.[107] Home modification focuses on reducing the risk of falling by installing handrails and grab bars in hallways, stairs, and bathrooms. The use of a shower chair, tub bench, and adaptive bathing devices also can be beneficial. The application of nonskid tape to steps (indoors and outdoors), as well as the removal of throw rugs, greatly improves home safety. Prevention of Osteoporosis

Primary prevention of osteoporosis starts in childhood. Patients require adequate calcium intake, vitamin D intake, and weight-bearing exercise. Beyond this, prevention of osteoporosis has 2 components, behavior modification and pharmacologic interventions.

The National Osteoporosis Foundation (NOF) specified that the following behaviors should be modified to reduce the risk of developing osteoporosis: cigarette smoking; physical inactivity; and intake of alcohol, caffeine, sodium, animal protein, and calcium.[119, 120] Patients should be counseled on smoking cessation and moderated alcohol intake. Patients who have disorders or who take medications that can cause or accelerate bone loss should receive calcium and vitamin D supplementation and, in some cases, pharmacologic treatment.[121]

Pharmacologic prevention methods include calcium supplementation and administration of raloxifene or bisphosphonates (alendronate or risedronate). Raloxifene and bisphosphonates should be considered as first-line agents for the prevention of osteoporosis.[122]

When alendronate or risedronate is used for prevention, the recommended dosage is the equivalent of 5 mg/d. In a study by Hosking et al, doses of 2.5 mg and 5 mg of alendronate were evaluated in postmenopausal women who did not have osteoporosis.[123] They found that the women who received placebo lost BMD at all measured sites, whereas the women treated with 5 mg/d of alendronate had a mean increase in BMD of 3.5% 0.2% at the lumbar spine, 1.9% 0.1% at the hip, and 0.7% 0.1% for the total body.

In 2010, the American College of Rheumatology published revised recommendations for the prevention and treatment of glucocorticoid-induced osteoporosis. Recommendations included the

categorization of patients by fracture risk (using the FRAX score) and initiation of treatment in appropriate patients including alendronate, risedronate, zoledronic acid, and teriparatide (in those patients at highest risk).[124]

Estrogen-progestin therapy is no longer considered a first-line approach for the treatment of osteoporosis in postmenopausal women, because it is associated with an increased risk for breast cancer, stroke, venous thromboembolism, and perhaps coronary disease. Estrogen is now only recommended if patients are also seeking relief of postmenopausal symptoms.

Regular monitoring may be helpful. Periodic bone densitometry helps in diagnosing osteoporosis in the early phase and aids in preventing fractures. According to the NOF, evaluating BMD on a periodic basis is the best way to monitor bone density and future fracture risk.[63] Bone density checks are recommended every 2 years in postmenopausal women. Regular weight-bearing exercises and back extensor strengthening help to delay bone loss. Consultations

For a patient with osteoporosis in the diagnostic and therapeutic phases, the most important consultation is with a rheumatologist or an endocrinologist. These specialists are helpful in the diagnosis of osteoporosis; they can aid in the obtainment of the proper laboratory tests and imaging studies needed to rule out causes of secondary osteoporosis. In patients with uncontrolled pain that does not respond to conventional therapies, an invasive pain specialist may be consulted for proper interventional procedures.

A rheumatologist may also provide useful assistance with management and determination of underlying etiologies in complex cases.

Consultations can include discussions of nonmedical/nonpharmacologic management of osteoporosis.[125, 126] Consult an orthopedist to assist with fracture management. Consultation with a spine surgeon is appropriate for patients with intractable, severe, function-limiting symptomatology that has not been relieved by noninterventional techniques. Consultation with a nonsurgical spine specialist is appropriate for a patient who is not a surgical candidate or whose symptoms persist despite surgical fixation. Long-Term Monitoring

Dual-energy x-ray absorptiometry (DEXA) should be repeated every 2-3 years if the baseline test results are normal. DEXA should be performed every 1-2 years in patients who are undergoing osteoporosis treatment.

The USPSTF 2011 recommendations, however, state that evidence is lacking about optimal intervals for repeated screening.[64]

Orthotics are used to decrease the flexion forces to prevent the worsening of kyphosis and to reduce the pressure on the fracture site in the acute phase of disease.[127, 128] Common orthotics used include the following: Thoracolumbosacral orthosis (TLSO) Cruciform anterior spinal hyperextension (CASH) brace Jewett brace

Medication Summary

Antiresorptive agents, including bisphosphonates, the selective estrogen-receptor modulator (SERM) raloxifene, calcitonin, denosumab, and one anabolic agent, teriparatide, are currently available for osteoporosis treatment. All therapies should be given with calcium and vitamin D supplementation. The American College of Physicians has reviewed the evidence and proposed guidelines for pharmacologic treatments of osteoporosis. (See Treatment.) Bisphosphonate Derivative Class Summary

Bisphosphonates are stable analogues of inorganic pyrophosphate. Bisphosphonates have a high affinity for hydroxyapatite crystals, and by binding at sites of active bone resorption, these agents can inhibit osteoclastic resorption. All oral bisphosphonates have a poor absorption and a bioavailability of less than 5%. Bone uptake is 20-80%, with the remainder being rapidly excreted through the kidney.[129]

Bisphosphonates are approved in the United States for the prevention and treatment of postmenopausal osteoporosis, osteoporosis in males, and steroid-induced osteoporosis. View full drug information Alendronate sodium (Fosamax); alendronate sodium/cholecalciferol (Fosamax Plus D)

Alendronate increases bone mineral density (BMD) at the spine by 8% and the hip by 3.5%. It reduces the incidence of vertebral fractures by 47% and nonvertebral fractures by 50% over 3 y. Alendronate is approved for treatment and prevention of postmenopausal osteoporosis, male osteoporosis, and steroid-induced osteoporosis. A tab is available with 2800 or 5600 IU of vitamin D3. Alendronate is also available in an oral (PO) solution taken weekly. View full drug information Risedronate sodium (Actonel); risedronate sodium with calcium carbonate (Actonel with calcium)

Risedronate increases BMD at the spine by 5.4% and the hip by 1.6%. It reduces vertebral fractures by 41% and nonvertebral fractures by 39% over 3 y. It is approved for treatment and prevention of postmenopausal osteoporosis, male osteoporosis, and steroid-induced osteoporosis. View full drug information Ibandronate sodium (Boniva)

Ibandronate increases BMD at the spine by 5.7-6.5% and the hip by 2.4-2.8%. It reduces vertebral fractures by 50% with intermittent (nondaily) dosing over 3 y; it has no effects on reduction of nonvertebral fractures. Ibandronate is approved for postmenopausal osteoporosis. View full drug information Zoledronic acid (Reclast)

Zoledronic acid is the most potent bisphosphonate available. It increases BMD at the spine by 4.3-5.1% and the hip by 3.1-3.5% compared with placebo. It reduces the incidence of spine fractures by 70%, hip fractures by 41%, and nonvertebral fractures by 25% over 3 y. Zoledronic acid is approved for the treatment of postmenopausal osteoporosis. Endocrine and Metabolic Agents Class Summary

Peptide hormones that modulate osteoclast and/or osteoblast function have been shown to be effective in the treatment of osteoporosis. View full drug information Teriparatide (Forteo)

Teriparatide is recombinant human PTH 1-34, which has identical sequence to the 34 N-terminal amino acids (the biologically active region) of 84-amino acid human PTH. This anabolic agent acts as endogenous PTH, thus regulating calcium and phosphate metabolism in bone and kidneys. It works primarily to stimulate new bone by increasing number and activity of osteoblasts (bone-forming cells).

Additional physiological actions include regulation of bone metabolism, renal tubular reabsorption of calcium and phosphate, and intestinal calcium absorption. Teriparatide increases BMD at the lumbar spine by 9-13% and the hip by 3-6% compared with placebo. When given intermittently, PTH increases bone remodeling with the net effect of increased bone mass and improved skeletal microarchitecture. (This is in contrast to continuous exposure to PTH, which increases bone resorption with a net effect of decreased trabecular bone volume). PTH promotes new bone formation, leading to increased BMD. It reduces the risk of spine fractures by 65% and nonspinal fractures by 54% in patients after an average of 18 mo of therapy. Teriparatide is approved for men or women at high risk of fracture due to primary or hypogonadal osteoporosis or postmenopausal osteoporosis, respectively.[19] View full drug information

Calcitonin (Miacalcin, Fortical)

Calcitonin is a peptide hormone used to treat and prevent osteoporosis in patients in whom bisphosphonates and estrogen are contraindicated or not tolerated. It inhibits osteoclastic bone resorption. It also has some analgesic effects in patients with fractures. Although no research data support the idea that the use of intranasal calcitonin reduces the incidence of fractures, studies do show an increase in BMD with the use of calcitonin. Calcitonin increases BMD at the lumbar spine by 1-1.5%. It reduces the incidence of spine fracture by 33% in group receiving 200 IU/d. It is available in parenteral and intranasal forms; however, the intranasal form is more convenient and better tolerated. Diminution of benefit may occur after 20 months with the parenteral form. Selective Estrogen Receptor Modulator Class Summary

Selective estrogen receptor modulators (SERMs) affect some of the receptors stimulated by estrogen but can selectively act as antagonist or agonist, depending on the organ system. Like estrogen, these are antiresorptive agents. However, because of their selective receptormodulating property, they provide the beneficial effects of estrogens without the adverse effects. View full drug information Raloxifene (Evista)

Raloxifene increases BMD at the spine and the hip. It reduces the incidence of spine fractures by 30-55% over 3 y. Raloxifene is approved for the prevention and treatment of postmenopausal osteoporosis. It is most suitable in women < 70 y at moderate risk for osteoporosis who have infrequent vasomotor symptoms of menopause (eg, hot flashes) and who are at moderate-to-high risk for breast cancer. Biologic and Immunological Agents Class Summary

Monoclonal antibodies that prevent the formation of osteoclasts, which, in turn, leads to a decrease in bone formation and increase bone mass, have been shown to be effective in the treatment of osteoporosis. View full drug information Denosumab (Prolia)

This agent is a monoclonal antibody that binds to the receptor activator of nuclear factor-kappa B ligand (RANKL), a transmembrane or soluble protein essential for the formation, function, and survival of osteoclasts, the cells responsible for bone resorption. It is indicated for the prevention of fracture in postmenopausal women with osteoporosis and high fracture risk (ie, history of osteoporotic fracture, failed other treatments). Vitamins and Calcium Salts Class Summary

Calcium and vitamin D are essential in order to increase bone density. Vitamin D repletion is essential for calcium absorption. Calcium supplements are used to increase calcium levels.[72] Calcium citrate and vitamin D (Citracal-D)

Calcium supplementation in patients at young ages has been proven to lower the incidence of fractures. View full drug information Calcium carbonate (Oystercal, Caltrate)

Calcium carbonate is commonly found on the market. Calcium citrate is better absorbed than calcium carbonate, especially in patients taking antacids or proton pump inhibitors.

Estrogen Derivatives Class Summary

Estrogen derivatives are approved for the prevention of osteoporosis and relief of menopauseassociated vasomotor symptoms and vulvovaginal atrophy. They are used to increase serum estrogen levels, which, in turn, decreases the rate of bone resorption.[130] The lowest effective dose at the shortest duration necessary should be used. The FDA recommends that other approved nonestrogen treatments should be considered first for osteoporosis prevention. View full drug information Conjugated estrogens (Premarin)

This agent contains a mixture of estrogens obtained exclusively from natural sources, occurring as the sodium salts of water-soluble estrogen sulfates blended to represent the average composition of material derived from pregnant mares' urine. It is a mixture of sodium estrone sulfate and sodium equilin sulfate. It contains, as concomitant components, sodium sulfate conjugates, 17-alpha-dihydroequilenin, 17-alpha-estradiol, and 17-beta-dihydroequilenin.

Conjugated estrogens restore estrogen levels to concentrations that induce negative feedback at gonadotrophic regulatory centers, which in turn reduces release of gonadotropins from pituitary. They increase synthesis of DNA, RNA, and many proteins in target tissues.

Multiple aspects of menopause respond to estrogen replacement therapy, including vasomotor symptoms and atrophic vaginitis. Such therapy also reduces bone resorption and may increase osteoblast activity.

In the past, estrogen replacement was considered a primary therapy for the prevention of postmenopausal osteoporosis. Estrogen had the additional advantages of controlling menopausal symptoms and, presumptively, of preventing or delaying cardiovascular disease. However, data from the Women's Health Initiative (WHI) revealed that estrogen-progestin therapy does not reduce the risk of coronary heart disease; it was instead found to increase the risk of breast

cancer, stroke, and venous thromboembolic events.

As such, routinely prescribing conjugated estrogens to premenopausal women is not recommended. This medication should be used in postmenopausal women who are incontinent and who have had a hysterectomy. For postmenopausal women with an intact uterus, cautiously recommend a short-term, low dose of Premarin, with frequent monitoring. Other antiresorptive agents are now the drugs of choice and are prescribed more frequently for the prevention and treatment of osteoporosis in postmenopausal women. View full drug information Estradiol (Estrace, Vivelle, Climara, Estraderm, Alora)

Estradiol restores estrogen levels to concentrations that induce negative feedback at gonadotropic regulatory centers; this, in turn, reduces the release of gonadotropins from the pituitary. Estradiol increases the synthesis of DNA, RNA, and many proteins in target tissues; it also inhibits osteoclastic activity and delays bone loss. In addition, evidence suggests a reduced incidence of fractures. View full drug information Ethinyl estradiol and norethindrone (Femhrt)

Ethinyl estradiol with norethindrone is used to treat moderate-to-severe vasomotor symptoms and to prevent osteoporosis associated with menopause. View full drug information Conjugated estrogens/medroxyprogesterone acetate (Prempro, Premphase)

The combination of conjugated estrogens and medroxyprogesterone reduces bone resorption and retards or halts postmenopausal bone loss.