Osteoporosis

Practice Essentials
Osteoporosis is the most common metabolic bone disease in the United States and can result in devastating physical, psychosocial, and economic consequences. It is often overlooked and undertreated, however, in large part because it is so often clinically silent before manifesting in the form of fracture.

Essential update: New osteoporosis diagnosis and management guidelines

In June 2013, the National Osteoporosis Guideline Group (NOGG) updated its guidelines on the diagnosis and management of osteoporosis in postmenopausal women and men at least 50 years of age in the United Kingdom. Recommendations include the following[1, 2] : Pharmacotherapies shown to lower the risk for vertebral fracture (and for hip fracture in some cases) include bisphosphonates, denosumab, parathyroid hormone peptides, raloxifene, and strontium ranelate Generic alendronate is usually first-line treatment because of its broad spectrum of anti-fracture efficacy and low cost Ibandronate, risedronate, zoledronic acid, denosumab, raloxifene, or strontium ranelate may be appropriate therapy if alendronate is contraindicated or poorly tolerated Because of their high cost, parathyroid hormone peptides should be used only for patients at very high risk, especially for vertebral fractures Postmenopausal women may benefit from calcitriol, etidronate, and hormone replacement therapy Treatments for men at increased fracture risk include alendronate, risedronate, zoledronic acid, and teriparatide Patients at increased risk for fracture should start alendronate or other bone-protective treatment at the onset of glucocorticoid therapy For postmenopausal women, pharmacotherapy for prevention and treatment of glucocorticoid-induced osteoporosis includes alendronate, etidronate, and risedronate; treatment options for both sexes are teriparatide and zoledronic acid Calcium and vitamin D supplementation is widely recommended for older persons who are housebound or live in residential or nursing homes and is often recommended as an adjunct to other treatments for osteoporosis Potential adverse cardiovascular effects of calcium supplementation are controversial, but it may be prudent to increase dietary calcium intake and use vitamin D alone rather than using both calcium and vitamin D supplementation Withdrawal of bisphosphonate treatment is associated with decreases in BMD and bone turnover after 2-3 years for alendronate and 1-2 years for ibandronate and risedronate Continuation of bisphosphonates without the need for further evaluation is recommended for high-risk individuals; when bisphosphonates are continued, treatment review, including renal function evaluation, is needed every 5 years If bisphosphonates are discontinued, fracture risk should be reevaluated after every new fracture, or after 2 years if no new fracture occurs After 3 years of zoledronic acid treatment, the benefits on BMD density persist for at least another 3 years after discontinuation; most patients should stop treatment after 3 years, and their physician should review the need for continuation of therapy 3 years later Persons with a previous vertebral fracture or a pretreatment hip BMD T-score of 2.5 SD or less may be at increased risk for vertebral fracture if zoledronic acid is discontinued

Signs and symptoms

Osteoporosis generally does not become clinically apparent until a fracture occurs. Two thirds of vertebral fractures are painless. Typical findings in patients with painful vertebral fractures 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:

Pain in the groin, posterior buttock, anterior thigh, medial thigh, and/or medial knee during weightbearing or attempted weight-bearing of the involved extremity Diminished hip range of motion (ROM), particularly internal rotation and flexion External rotation of the involved hip while in the resting position On physical examination, patients with vertebral compression fractures may demonstrate the following: With acute vertebral fractures, point tenderness over the involved vertebra Thoracic kyphosis with an exaggerated cervical lordosis (dowager hump) Subsequent loss of lumbar lordosis A decrease in height of 2-3 cm after each vertebral compression fracture and progressive kyphosis Patients with hip fractures may demonstrate the following: Limited ROM with end-range pain on a FABER (flexion in abduction and external rotation) hip joint test Decreased weight-bearing on the fractured side or an antalgic gait pattern Patients with pubic and sacral fractures may have the following: Marked pain with ambulation Tenderness to palpation, percussion, or both With sacral fractures, pain with physical examination techniques used to assess the sacroiliac joint (eg, FABER, Gaenslen, or squish test) Balance difficulties may be evident, especially in patients with an altered center of gravity from severe kyphosis.[3] Patients may have difficulty performing tandem gait and performing single limb stance. See Clinical Presentation for more detail.

Diagnosis
Baseline laboratory studies include the following: Complete blood count: May reveal anemia or raise suspicion of alcoholism Serum chemistry levels: Usually normal in persons with primary osteoporosis Serum iron and ferritin levels: Helpful when malabsorption or hemochromatosis is suspected Liver function tests: Elevations may indicate alcoholism Thyroid-stimulating hormone level: Thyroid dysfunction has been associated with osteoporosis 25-Hydroxyvitamin D level: Vitamin D insufficiency can predispose to osteoporosis Bone mineral density (BMD) measurement is recommended in the following patients [4, 5] : Women aged 65 years or 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 associated with low bone mass or bone loss (eg, rheumatoid arthritis) Adults who take a medication associated with low bone mass or bone loss (eg, glucocorticoids, 5 mg of prednisone daily for 3 mo)

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 Dual-energy x-ray absorptiometry (DXA) is currently the criterion standard for the evaluation of BMD. [5, 6] Peripheral DXA 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. DXA provides the patients T-score, which is the BMD value compared with that of control subjects who are at their peak BMD.[7, 8, 9, 10] 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[9] :

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 DXA also provides the patients Z-score, which reflects a value compared with that of persons matched for age and sex. Z-scores adjusted for ethnicity or race should be used in the following patients: Premenopausal women Men younger than 50 years Children Z-score values of 2.0 SD or lower are defined as "below the expected range for age" and those above 2.0 SD as "within the expected range for age." The diagnosis of osteoporosis in these groups should not be based on densitometric criteria alone. Quantitative calcaneal ultrasonography offers the following benefits [11] :

As effective as DXA at predicting femoral neck, hip, and spine fractures Lower cost than DXA More portability than DXA No exposure to ionizing radiation However, no diagnostic criteria based on quantitative ultrasonography or a combination of quantitative ultrasonography and DXA have been defined. Plain radiography features and recommendations are as follows:

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; a scoliosis series is useful for detecting occult vertebral fractures Radiographic findings can suggest the presence of osteopenia, or bone loss, but cannot be used to diagnose osteoporosis Radiographs may also show other conditions, such as osteoarthritis, disk disease, or spondylolisthesis See Workup for more detail.

Management
Lifestyle modification for prevention of osteoporotic fractures includes the following [12] : Increasing weight-bearing and muscle-strengthening exercise Ensuring optimum calcium and vitamin D intake as an adjunct to active antifracture therapy 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[4] : A hip or vertebral fracture (vertebral fractures may be clinical or morphometric [ie, identified on a radiograph alone]) T-score of 2.5 or less at the femoral neck or spine after appropriate evaluation to exclude secondary causes

Low bone mass (T-score between 1.0 and 2.5 at the femoral neck or spine) and a 10-year probability of a hip fracture of 3% or greater or a 10-year probability of a major osteoporosis-related fracture of 20% or greater based on the US-adapted World Health Organization algorithm Guidelines from the American Association of Clinical Endocrinologists include the following recommendations for choosing drugs to treat osteoporosis[13] : 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 Medical care also includes the identification and treatment of potentially treatable underlying causes of osteoporosis such as hyperparathyroidism and hyperthyroidism. Surgical care includes vertebroplasty and kyphoplasty, which are minimally invasive spine procedures used for the management of painful osteoporotic vertebral compression fractures. See Treatment and Medication for more detail.

Image library

Osteoporosis of the spine. Observe the considerable reduction in overall vertebral bone density and note the lateral wedge fracture of L2.

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. Screening at-risk populations is essential (see Workup). Osteoporosis is a systemic skeletal disease characterized by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility. [14] The disease often does not become clinically apparent until a fracture occurs (see the following image).

Osteoporosis. Lateral radiograph demonstrates multiple osteoporotic vertebral compression fractures. Kyphoplasty has been performed at one level.

Osteoporosis represents an increasingly serious health and economic problem in the United States and around the world.[15] Many individuals, male and female, experience pain, disability, and diminished quality of life as a result of having this condition. 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 86% of all women aged 45-75 years had never discussed osteoporosis with their physicians, and more than 80% were unaware that osteoporosis is directly responsible for disabling hip fractures. [16] 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 antiresorptive agents such as 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). 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 firstline measures to lessen the impact of this condition (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.

WHO definition of osteoporosis

Bone mineral density (BMD) in a patient is related to peak bone mass and, subsequently, bone loss. Whereas the T-score is the patients 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.[7, 8, 9, 10] The World Health Organizations (WHO) definitions of osteoporosis based on BMD measurements in white women are summarized in Table 1, below.[9, 10] For each standard deviation (SD) reduction in BMD, the relative fracture risk is increased 1.5-3 times. 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. Table 1. WHO Definition of Osteoporosis Based on BMD Measurements by DXA(Open Table in a new window)
Definition Normal Low bone mass (osteopenia) Osteoporosis Severe or established osteoporosis Bone Mass Density Measurement BMD within 1 SD of the mean bone density for young adult women BMD 12.5 SD below the mean for young-adult women BMD 2.5 SD below the normal mean for young-adult women BMD 2.5 SD below the normal mean for young-adult women in a patient who has already experienced 1 fractures T-Score T-score 1 T-score between 1 and 2.5 T-score 2.5 T-score 2.5 (with fragility fracture[s])

Sources :

(1) World Health Organization (WHO). WHO scientific group on the assessment of osteoporosis at primary health care level: summary meeting report. Available at: http://www.who.int/chp/topics/Osteoporosis.pdf. Accessed February 6, 2012.[17]

(2) Kanis JA. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis: synopsis of a WHO report. WHO Study Group. Osteoporos Int. Nov 1994;4(6):368-81.[10]

(3) Czerwinski E, Badurski JE, Marcinowska-Suchowierska E, Osieleniec J. Current understanding of osteoporosis according to the position of the World Health Organization (WHO) and International Osteoporosis Foundation. Ortop Traumatol Rehabil. Jul-Aug 2007;9(4):337-56.[9]

BMD = bone mass density; DXA = dual x-ray absorptiometry; SD = standard deviation; T-score = a measurement expressed in SD units from a given mean that is equal to a patient's BMD measured by DXA minus the value in a young healthy person, divided by the SD measurement in the population.[18]

Z-scores should be used in premenopausal women, men younger than 50 years, and children. Z-scores 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 with Z-scores above 2.0 being defined as "within the expected range for age." The diagnosis of osteoporosis in these groups should not be based on densitometric criteria alone. For more information, see Pediatric Osteoporosis, as well as Osteoporosis in Solid Organ Transplantation, Bone Markers in Osteoporosis, and Nonoperative Treatment of Osteoporotic Compression Fractures.

Pathophysiology
It is increasingly being recognized that multiple pathogenetic mechanisms interact in the development of the osteoporotic state. Understanding the pathogenesis of osteoporosis starts with knowing how bone formation and remodeling occur.

Normal bone formation and remodeling

Bone is continually remodeled throughout our lives in response to microtrauma. Bone remodeling occurs at discrete sites within the skeleton and proceeds in an orderly fashion, and bone resorption is always followed by bone formation, a phenomenon referred to as coupling. Dense cortical bone and spongy trabecular or cancellous bone differ in their architecture but are similar in molecular composition. Both types of bone have 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).[19] The greater the concentration of calcium, the greater the compressive strength. In adults, approximately 25% of trabecular bone is resorbed and replaced each year, compared with only 3% of cortical bone. Osteoclasts, derived from mesenchymal cells, are responsible for bone resorption, whereas osteoblasts, from hematopoietic precursors, are responsible for bone formation (see the images below). The 2 types of cells are dependent on each other for production and linked in the process of bone remodeling. Osteoblasts not only secrete and mineralize osteoid but also appear to control the bone resorption carried out by osteoclasts. Osteocytes, which are terminally differentiated osteoblasts embedded in mineralized bone, direct the timing and location of bone remodeling. In osteoporosis, the coupling mechanism between osteoclasts and osteoblasts is thought to be unable to keep up with the constant microtrauma to trabecular bone. 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.[20]

This image depicts bone remodeling with osteoclasts resorbing one side of a bony

trabecula and osteoblasts depositing new bone on the other side. Osteoclast, with bone below it. This image shows typical distinguishing characteristics of an osteoclast: a large cell with multiple nuclei and a

"foamy" cytosol. In this image, several osteoblasts display a prominent Golgi apparatus and are actively synthesizing osteoid. Two osteocytes can also be seen.

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 are impaired. [21] The receptor activator of nuclear factor-kappa B ligand (RANKL)/receptor activator of nuclear factorkappa 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 RANK expressed by osteoclasts and osteoclast precursors to promote osteoclast differentiation. Osteoprotegerin is a soluble decoy receptor that inhibits RANK-RANKL by binding and sequestering RANKL. Bone mass peaks around the third decade of life and slowly decreases afterward. A failure to attain optimal bone strength by this point is one factor that contributes to osteoporosis, which explains why some young postmenopausal women have low bone mineral density (BMD) and why some others have 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. [12, 22]

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 be affected by hormonal status, as occurs in perimenopausal women; can impact elderly men and women; and can be secondary to various disease states and medications.

Aging and loss of gonadal function 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 leads to increased expression of RANKL by osteoblasts and decreased release of OPG; increased RANKL results in recruitment of higher numbers of preosteoclasts as well as increased activity, vigor, and lifespan of mature osteoclasts. Estrogen deficiency 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.[23] This finding provided evidence that estrogen inhibits IL-6 secretion and that 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, rather, 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). Aging 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 deficiency 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 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.[19] Osteoporotic fractures 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. [24] 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. Osteoporosis not only reduces bone mass in vertebrae but also decreases interconnectivity in their internal scaffolding.[19]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 cross-bracing 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 (see the images below).

Osteoporosis is defined as a loss of bone mass below the threshold of fracture. This slide (methylmethacrylate embedded and stained with Masson's trichrome) demonstrates the loss of connected trabecular

bone. The bone loss of osteoporosis can be severe enough to create separate bone "buttons" with no connection to the surrounding bone. This easily leads to insufficiency 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.[25]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 versus osteomalacia 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, whereas 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. Additional factors and conditions Endocrinologic conditions or medications that lead to bone loss (eg, glucocorticoids) can cause osteoporosis. Corticosteroids inhibit osteoblast function and enhance osteoblast apoptosis.[26] 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.[20]

Epigenetics
Prenatal and postnatal factors contribute to adult bone mass. In one study, the health of the mother in pregnancy, the infants birth weight, and the childs weight at age 1 year were predictive of adult bone mass in the seventh decade for men and women.[27] It is postulated that growth in the first year of life programs growth hormone that is maintained into the seventh decade.[28] Larger babies and rapid growth in the first year of life predicted increased bone mass in adults aged 65-75 years.

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, and these 2 main categories are further 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
Patients are said to have primary osteoporosis when 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 described in Table 2, below. Table 2. Types of Primary Osteoporosis (Open Table in a new window)
Type of Primary Osteoporosis Juvenile osteoporosis Characteristics

Usually occurs in children or young adults of both sexes Normal gonadal function Age of onset: usually 8-14 years Hallmark characteristic: abrupt bone pain and/or a fracture following trauma

Idiopathic osteoporosis

Postmenopausal osteoporosis (type I osteoporosis)

Occurs in women aged 50-65 years Characterized by a phase of accelerated bone loss, primarily from trabecular bone Fractures of the distal forearm and vertebral bodies common

Age-associated or senile osteoporosis (type II osteoporosis)

Occurs in women and men older than 70 years Represents bone loss associated with aging Fractures occur in cortical and trabecular bone Wrist, vertebral, and hip fractures often seen in patients with type II osteoporosis

Secondary osteoporosis
Secondary osteoporosis occurs when an underlying disease, deficiency, or drug causes osteoporosis (see Table 3, below). Up to one third of postmenopausal women, as well as many men and premenopausal women, have a coexisting cause of bone loss,[29, 30] of which renal hypercalciuria is one of the most important secondary causes of osteoporosis and treatable with thiazide diuretics. [31] Table 3. Causes of Secondary Osteoporosis in Adults (Open Table in a new window)
Cause Genetic/congenital Examples

Renal hypercalciuria one of the most important secondary causes of osteoporosis; can be treated with thiazide diuretics Cystic fibrosis Ehlers-Danlos syndrome Glycogen storage disease Gaucher disease Marfan syndrome Menkes steely hair syndrome Riley-Day syndrome Osteogenesis imperfecta Hemochromatosis Homocystinuria Hypophosphatasia Idiopathic hypercalciuria Porphyria Hypogonadal states Androgen insensitivity Anorexia nervosa/bulimia nervosa Female athlete triad Hyperprolactinemia Panhypopituitarism Premature menopause Turner syndrome Klinefelter syndrome Cushing syndrome Diabetes mellitus Acromegaly Adrenal insufficiency Estrogen deficiency Hyperparathyroidism Hyperthyroidism Hypogonadism Pregnancy Prolactinoma Calcium deficiency Magnesium deficiency Protein deficiency Vitamin D deficiency[32, 33] Bariatric surgery

Hypogonadal states

Endocrine disorders[32]

Deficiency states


Inflammatory diseases

Celiac disease Gastrectomy Malabsorption Malnutrition Parenteral nutrition Primary biliary cirrhosis Inflammatory bowel disease Ankylosing spondylitis Rheumatoid arthritis Systemic lupus erythematosus Hemochromatosis Hemophilia Leukemia Lymphoma Multiple myeloma Sickle cell anemia Systemic mastocytosis Thalassemia Metastatic disease 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, high-dose methotrexate[34] Furosemide Glucocorticoids and corticotropin[35] : prednisone (5 mg/day for 3 mo)[36] Heparin (long term) Hormonal/endocrine therapies: gonadotropin-releasing hormone (GnRH) agonists, luteinizing hormone-releasing hormone (LHRH) analogues, depomedroxyprogesterone, excessive thyroxine Lithium Selective serotonin reuptake inhibitors (SSRIs) Alcoholism Amyloidosis Chronic metabolic acidosis Congestive heart failure Depression Emphysema Chronic or end-stage renal disease Chronic liver disease HIV/AIDS Idiopathic scoliosis Immobility Multiple sclerosis Ochronosis Organ transplantation Pregnancy/lactation Sarcoidosis Weightlessness

Hematologic and neoplastic disorders

Medications

Miscellaneous

Sources:

(1) American Association of Clinical Endocrinologists medical guidelines for clinical practice for the prevention and treatment of postmenopausal osteoporosis: 2001 edition, with selected updates for 2003. Endocr Pract. Nov-Dec 2003;9(6):544-64.[29]

(2) Kelman A, Lane NE. The management of secondary osteoporosis. Best Pract Res Clin Rheumatol. Dec 2005;19(6):1021-37.[30]

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[37, 38, 39] : Advanced age (50 years) 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 lb) Amenorrhea Late menarche Early menopause Postmenopausal state Physical inactivity or immobilization[40] Use of drugs: anticonvulsants, systemic steroids, thyroid supplements, heparin, chemotherapeutic agents, insulin Alcohol and tobacco use Androgen[41] or estrogen deficiency Calcium deficiency Dowager hump A potentially useful mnemonic for osteoporotic risk factors is OSTEOPOROSIS, as follows: L O w calcium intake S eizure meds (anticonvulsants) T hin build E thanol intake Hyp O gonadism P revious fracture Thyr O id excess R ace (white, Asian) O ther relatives with osteoporosis S teroids I nactivity S moking A study by Cummings et al 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. [42] 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. An interesting finding of this study was that dietary intake of calcium was not correlated with 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.

Epidemiology

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. [4] In the United States, 1.5 million osteoporotic fractures occur each year. Of these, 700,000 are spinal fractures; 300,000 are hip fractures; and 200,000 are wrist fractures. 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 standard deviation (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. Globally, osteoporosis is by far the most common metabolic bone disease, and it is estimated to affect over 200 million people worldwide.[43] An estimated 75 million people in Europe, the United States, and Japan have osteoporosis.[44]Approximately 1 in 2 women and 1 in 5 men older than 50 years will eventually experience osteoporotic fractures.[4] By 2050, the worldwide incidence of hip fracture is projected to increase by 240% in women and 310% in men.[45]

Age demographics
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.[46] Melton et al reported that 27% of women in their study had evidence of vertebral fractures by age 65 years. [47] Ninety percent of hip fractures occur in persons aged 50 years or older, occurring most often in the eighth decade of life.[48]

Sex demographics
Women are at a significantly higher risk for osteoporosis. According to the NOF, of the estimated 10 million Americans who have osteoporosis, 80% are women.[4]Men have a higher prevalence of secondary osteoporosis, with an estimated 45-60% of cases being a consequence of hypogonadism, alcoholism, or glucocorticoid excess.[35] Only 35-40% of osteoporosis diagnosed in men is considered primary in nature. Overall, osteoporosis has a female-to-male ratio of 4:1.[49] Fifty percent of all women and 25% of all men older than 50 years experience one or more osteoporosisrelated fracture in their lifetime. Eighty percent of hip fractures occur in women. [48] Women have a 2-fold increase in the number of fractures resulting from nontraumatic causes, as compared with men of the same age.

Racial demographics
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. In the most recent government census, 178 million Chinese were over age 60 years in 2009, a number that the United Nations estimates may reach 437 millionone-third of the populationby 2050.[50] These numbers suggest that approximately 50% of all hip fractures will occur in Asia in the next century.

Table 4, below, summarizes some osteoporosis prevalence statistics among racial/ethnic groups. Note that this disease is underrecognized and undertreated in white and black women. [49] Relative to other racial/ethnic groups, the risk of developing osteoporosis is increasing fastest among Hispanic women. [49] Table 4. Prevalence of Osteoporosis Among Racial and Ethnic Groups (Open Table in a new window)
Race/Ethnicity Non-Hispanic white; Asian Sex (age 50 y) Women Men Non-Hispanic black Women Men Hispanic Women Men % Estimated to have osteoporosis 20 7 5 4 10 3 % Estimated to have low bone mass 52 35
*

19 49 23

Source: National Osteoporosis Foundation. Fast facts. Available at: http://www.nof.org/node/40. Accessed: February 16, 2012.[49]

Low bone density is present in an additional 35% of black women, increasing their risk of developing osteoporosis.

Melton et al reported that the prevalence of hip fractures is higher in white populations, regardless of geographic location.[51] Another study indicated that, in the United States and South Africa, the incidence of hip fractures was lower in black persons than in age-matched white persons. Cauley et al found that the absolute fracture incidence across bone mineral density (BMD) distribution was 30-40% lower in black women than in white women. This lower fracture risk was independent of BMD and other risk factors.[52]

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 anti-osteoporotic medication. In addition, patients can decrease their risk of falls by participating in a multifaceted approach that includes rehabilitation and environmental modifications. 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 billion to $17.9 billion. [53] In 2005, over 2 million osteoporosis-related fractures occurred in the United States.[54] Osteoporosis is the leading cause of fractures in the elderly. Women aged 50 years have about a 50% 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 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 the 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%.[55] In a subsequent study, Kado et al[56] demonstrated that women with one or more fractures had a 1.23-fold increased age-adjusted mortality rate and that 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 womanyears in women with no fracture, versus 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. [57] 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. Hip fractures More than 250,000 hip fractures are attributed to osteoporosis each year.[42] 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%. [55, 58] 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.[4] 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. [59] Only one third of patients return to their prefracture level of function.[60] Secondary complications of hip fractures include nosocomial infections and pulmonary thromboembolism. Additional fractures Patients who have sustained one osteoporotic fracture are at increased risk for developing additional osteoporotic fractures.[44] 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.[61] Patients with previous hip fracture have a 2-fold[62] 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 (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 [63] : 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.[4] Note that osteoporosis is, by definition, present in those with a fragility fracture, irrespective of their T-score. 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.[64] The authors found an overall reduction in dispensation of osteoporosis medications as more women were reclassified into lower fracture risk categories. One study sought to determine if the femoral neck BMD score and 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 Tscore and FRAX score were associated with higher hip and nonvertebral fracture risk in older adult patients with type 2 DM.[65]

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 (see the image below). 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.

Stable intertrochanteric fracture of the femur.

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).[66] They are also at risk for the complications associated with 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.

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, as well as strategies to prevent falls in the elderly (see Primary Care Relevant Interventions to Prevent Falling in Older Adults: A Systematic Evidence Review for the US Preventive Services Task Force [USPSTF]). All postmenopausal women older than 65 years should be offered bone densitometry, as well as some younger women and men. These patients 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 information, see the Osteoporosis Center, Digestive Disorders Center, and Women's Health Center, as well as Osteoporosis, Anorexia Nervosa, Inflammatory Bowel Disease, and Menopause.

History
Keep in mind that osteoporosis occurs in many people who have no factors, or just a few risk factors, for this condition. Often, patients who have not sustained a fracture do not report symptoms that would alert the clinician to suspect a diagnosis of osteoporosis; thus, this disease is a "silent thief" that generally does not become clinically apparent until a fracture occurs. Screening at-risk populations is, therefore, essential; unfortunately, many women are not receiving proper screening or treatment for osteoporosis, which, in turn, may result in improper management of this disease and its related complications.[67] For example, the existence of a disorder in a patient known to cause secondary osteoporosis such as rheumatoid arthritis, celiac disease, or Crohn diseaseshould increase a clinicians suspicion that osteoporosis may be present and that screening may be indicated. 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 years) or bilateral ovariectomy and prolonged premenopausal amenorrhea (>1 year); low lifelong calcium intake; alcoholism [68] ; impaired eyesight despite adequate correction; recurrent falls; inadequate physical activity; and poor health or frailty.

Assessment of fracture risk

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 [69, 70] : Age (>50 years), sex (female), and race (white or Asian) [69] ; the US Preventive Services Task Force (USPSTF) recommendations include screening for osteoporosis in women aged 65 years or older and in younger women with a fracture risk that is the same or greater than that of a 65-year-old white woman who has no additional risk factors[70] 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[69] ; the USPSTF notes that there is insufficient current evidence to assess the risk versus benefit of screening for osteoporosis in men[70] Smoking: smokers are at higher risk Alcohol consumption Low levels of physical activity: immobility increases the risk [40] ; spinal cord injury and stroke cause physical impairment and are common causes of immobility Strenuous exercise that results in amenorrhea (such as that which occurs in marathon runners) 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 Medications associated with bone loss 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 FRAX tool

Although the USPSTF did not find any studies that assessed effects of the use of risk prediction instruments on patient outcomes, either alone or in combination with bone measurement tests, there are many validated instruments for predicting the risk for low bone mineral density (BMD) in postmenopausal women; few of these, however, have been validated for use in men.[70] The Fracture Risk Assessment (FRAX) tool, accessible to healthcare providers and patients, is a validated instrument used to estimate 10-year risks for fractures, including those for black, Asian, and Hispanic women.[63] A 65-year-old white woman with no other risk factors has a 9.3% 10-year risk for any osteoporotic fracture. Generally, estimated fracture risks in nonwhite women are lower than those for white women of the same age. White women between the ages of 50 and 64 years with 10-year fracture risks based on specific risk factors include the following persons[70] : A 50-year-old current smoker with a body mass index (BMI) less than 21 kg/m 2, daily alcohol use, and parental fracture history A 55-year-old woman with a parental fracture history A 60-year-old woman with a BMI less than 21 kg/m2 and daily alcohol use A 60-year-old current smoker with daily alcohol use

Differentiating fracture types by history

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 weight-bearing. 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 weight-bearing or attempted weight-bearing 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 may be 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/m 2) Signs that might indicate existing osteoporosis (eg, kyphosis or dowager 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) A 10-year longitudinal study assessed the Timed Up and Go (TUG) test performance (a validated predictor of falling) and hip areal BMD (aBMD). Using data from 1126 women (mean age, 75 years), the study noted that risks of nonvertebral fracture and hip fracture were significantly higher among those who had slow TUG test performance and normal hip BMD or both slow TUG test performance and low hip BMD. These results suggest that the TUG test is an independent risk factor for incident nonvertebral fracture; this inexpensive physical assessment may be beneficial in screening patients with increased risk of fracture.[71]

Signs of fracture
Patients with vertebral compression fractures may demonstrate a thoracic kyphosis with an exaggerated cervical lordosis (dowager 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 faber (ie, flexion in abduction and external rotation) hip joint test may reveal limited ROM with end-range pain. Patients with hip fractures may show decreased weight-bearing 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.[3]

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. [42]

Screening in Men
Although routinely screening men for osteoporosis is not as widespread a practice as that of screening in women, the US Preventive Services Task Force (USPSTF) indicates that using bone measurement tests in men may not only help to detect this disease but also prevent its associated burden of fractures and fracture-related illness.[11] In weighing the risk versus benefit of screening men, clinicians should consider that osteoporosis is a preventable condition and that the potential harm in screening is likely to be small and mostly due to cost, such as that required to increase the number of dual-energy x-ray absorptiometry (DXA) scanners available for screening.[11] In addition, assuming that the risk versus benefit of therapy for osteoporosis is similar for men and women, the men who are most likely to benefit from screening would be those with a 10-year risk for osteoporotic fracture that is equal to or greater than that for 65-year-old white women who have no additional risk factors.[11] It is important to note, however, that there is insufficient current evidence for assessing the risk versus benefit of screening for osteoporosis in men. The American College of Physicians (ACP) has similar recommendations for screening of osteoporosis in men, including periodic evaluation of risk factors in older men before age 65 years (particularly men who do not choose to be screened) and obtaining dual x-ray absorptiometry (DXA) for men at increased risk for the disease who are candidates for drug therapy.[72] Risk factors for osteoporosis in men include the following[72] : Age older than 70 years Low body weight (body mass index [BMI] < 20 to 25 kg/m 2) Greater than 10% weight loss (relative to the usual young or adult weight or weight loss in recent years) Physical inactivity Corticosteroid use Androgen deprivation therapy Previous fragility fracture As with the USPSTF, the ACP recommends further research is needed to assess osteoporosis screening tests in men to determine whether risk factors for osteoporosis in women also apply to men. [72]

Diagnostic Considerations
The differential diagnosis of osteoporosis is very extensive. 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. 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 ratio of mineral to organic material. 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. Often, the presence of a fracture is not only a marker for decreased bone mass but also potentially a symptom of failing health in general and one 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: Leukemia

Lymphoma Metastases (bony and other) Pathologic fractures secondary to bone metastases from cancer Pediatric osteogenesis imperfecta Renal osteodystrophy

Differential Diagnoses
Homocystinuria/Homocysteinemia Hyperparathyroidism Mastocytosis Multiple Myeloma Osteomalacia and Renal Osteodystrophy Paget Disease Scurvy Sickle Cell Anemia

Approach Considerations
Workup consists of appropriate laboratory studies to establish baseline values and to 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. Imaging options include densitometry, single-photon absorptiometry (SPA), dual-photon absorptiometry (DPA), dual-energy x-ray absorptiometry (DXA), quantitative computed tomography (QCT) scanning, magnetic resonance imaging (MRI), bone scanning, and single-photon emission computed tomography (SPECT) scanning. The sensitivity, examination time, cost, and radiation exposure of the different imaging techniques differ greatly (see Table 5, below). Table 5. Comparison of Densitometry Techniques and Cost-Effectiveness (Open Table in a new window)
Single-photon absorptiometry Time Cost Sites scanned 5-15 min $50-150 Radius, forearm, Dual-photon absorptiometry 20-30 min $150-300 Spine, hip (anteroposterior) Dual-energy x-ray absorptiometry 5-10 min $100-200 Spine (lateral), hip, Quantitative computed tomography 10-30 min $150-300 Spine (lateral), hip,

calcaneus

radius

radius

Source: Nayak S, Roberts MS, Greenspan SL. Cost-effectiveness of different screening strategies for osteoporosis in postmenopausal women. Ann Intern Med. Dec 6 2011;155(11):751-61.[73]

DXA of the hip and lumbar spine and quantitative calcaneal ultrasonography are the 2 most common bone measurement tests used to screen for osteoporosis [11] ; DXA quantifies bone loss, and quantitative calcaneal ultrasonography evaluates bone properties.[74] Conventional radiography is used for the qualitative and semiquantitative evaluation of osteoporosis, whereas morphometry assesses the presence of fractures.[74] In the United States, current diagnostic and treatment criteria for osteoporosis are based solely on QCT hip and DXA spine or hip T-score measurements,[75, 76]despite quantitative calcaneal ultrasonography being as effective as DXA at predicting femoral neck, hip, and spine fractures with lower cost, more

portability, and no exposure to ionizing radiation.[11] No criteria based on quantitative ultrasonography or a combination of quantitative ultrasonography and DXA have been defined. For information on The American College of Radiology recommendations for evaluating the appropriateness of BMD measurement tests for osteoporosis in patients at risk of developing this condition, see ACR Appropriateness Criteria for osteoporosis and bone mineral density.

Children and adolescents

The official position of the International Society for Clinical Densitometry (ISCD) is that fracture prediction should primarily identify children at risk of clinically significant fractures (eg, fracture of lower -extremity long bones, vertebral compression fractures, or 2 or more upper-extremity long-bone fractures).[5]However, densitometric criteria alone should not be used to diagnose osteoporosis in children and adolescents. Rather, such a diagnosis in this population must be based on a low bone mineral content (BMC) or BMD in conjunction with a clinically significant fracture history. Fractures are considered clinically significant[5] if one or more of the following are present: Lower-extremity long-bone fracture Vertebral compression fracture 2 or more upper-extremity long-bone fractures Low BMC or BMD, defined as a BMC or areal BMD Z-score that is 2.0, adjusted for age, sex, and body size, as appropriate

Laboratory Studies
Laboratory studies are used to establish baseline conditions or to exclude secondary causes of osteoporosis. They are summarized in Tables 6 and 7, below. Table 6. Baseline Studies for Baseline Conditions in Osteoporosis (Open Table in a new window)
Baseline test Complete blood count (CBC) Disorder CBC results may reveal anemia, as in sickle cell disease (patients with anemia, particularly those older than 60 years, should also be evaluated for multiple myeloma), and may raise the suspicion for alcohol abuse (in conjunction with results from serum chemistry tests and liver function tests) Calcium levels can reflect underlying disease states (eg, severe hypercalcemia may reflect underlying malignancy or hyperparathyroidism; hypocalcemia can contribute to osteoporosis)

Serum chemistry levels

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

Levels of serum calcium, phosphate, alkaline phosphatase, and 25(OH) vitamin D may be obtained to assess osteomalacia

Creatinine levels may decrease with increasing parathyroid hormone (PTH) levels or may be elevated in patients with multiple myeloma

Creatinine levels are also used to estimate creatinine clearance, which may indicate reduced renal function in elderly patients

Magnesium is very important in calcium homeostasis [77] ; decreased levels of magnesium may affect calcium absorption and metabolism

Serum iron and ferritin levels

These tests are helpful when malabsorption or hemochromatosis are suspected

Liver function tests

Increased levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), gamma-glutamyl transferase (GGT), bilirubin, and alkaline phosphatase may indicate alcohol abuse Thyroid dysfunction has been associated with osteoporosis and should therefore be ruled out [78]

Thyroid-stimulating hormone (TSH) level 25-Hydroxyvitamin D level

This test assesses for vitamin D insufficiency; inadequate vitamin D levels can predispose persons to osteoporosis

An important study by Tannenbaum evaluated 173 healthy women (ages 46-87 years) for secondary causes of osteoporosis and found that 55 (32%) had a previously undiagnosed disorder of bone or mineral metabolism.[79] Given that occult disorders are so common in patients with osteoporosis, minimal laboratory screening is indicated in all patients who present with decreased bone mass. Table 7. Tests for Secondary Causes of Osteoporosis (Open Table in a new window)
Tests for Secondary Causes of Osteoporosis 24-Hour urine calcium level Disorder

This study assesses for hypercalciuria to help rule out benign familial hypocalciuric hypercalcemia (FHH), in which urinary calcium levels are low An intact PTH result is essential in ruling out hyperparathyroidism; an elevated PTH level may be present in benign 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[78] These tests may help evaluate a sex hormone deficiency as a secondary cause of osteoporosis

Parathyroid hormone (PTH) level Thyrotropin level (if on thyroid replacement)

Testosterone and gonadotropin levels in younger men with low bone densities Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) levels Urinary free cortisol level and tests for adrenal hypersecretion

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 These tests are used to exclude Cushing syndrome, which, although uncommon, can lead to rapidly progressive osteoporosis when the condition is present; a urine free cortisol value or overnight dexamethasone suppression test should be ordered in suspected cases These are used to identify multiple myeloma

Serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) Antigliadin and antiendomysial antibodies Serum tryptase and urine Nmethylhistamine Bone marrow biopsy

These tests can help identify celiac disease These tests help identify mastocytosis and are used to exclude the presence of multiple myeloma; serum tryptase may be performed to rule out plasma cell dyscrasias This study is obtained when a hematologic disorder is suspected

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) (also available as a serum marker) C-telopeptide of collagen cross-links (CTx) (also available as a serum marker) Currently available serum markers of bone resorption include cross-linked C-telopeptide of type I collagen (ICTP) and tartrate-resistant acid phosphatase, as well as NTx and CTx. Of all the biochemical markers of bone turnover mentioned above, 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 highturnover type of osteoporosis.[80]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 anti-osteoporotic 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. For more information, see the Medscape Reference article Bone Markers in Osteoporosis.

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 (see the following image).

Asymmetric loss in vertebral body height, without evidence of an acute fracture, can develop in patients with osteoporosis. These patients become progressively kyphotic (as shown) over time, and the characteristic hunched-over posture of severe osteoporosis develops eventually.

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 (see the following images). A scoliosis series is useful for detecting occult vertebral fractures.

Severe osteoporosis. This radiograph shows multiple vertebral crush fractures. Source: Government

of Western Australia Department of Health. This radiograph of the spine shows a lateral wedge fracture of L3 (yellow asterisk) and compression fracture of L5 (red asterisk) in an osteoporotic patient who suffered a recent fall. More detailed imaging, usually with computed tomography (CT) scanning, is often needed to better evaluate compression fractures and to determine the urgency of surgical interventions.

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 cortical width should be at least equal to the medullary width. Osteopenia is suggested by a cortical width that is less than the medullary width. Radiographs may also show fractures or other conditions, such as osteoarthritis, disk disease, or spondylolisthesis. Plain radiography is not as accurate as BMD testing. Because osteoporosis predominantly affects trabecular bone 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% of bone loss has occurred. Approximately 30-80% of bone mineral must be lost before radiographic lucency becomes apparent on radiographs.[81] Thus, plain radiography is an insensitive tool for diagnosing osteoporosis.

Dual-Energy X-Ray Absorptiometry (DXA)

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.[4, 6] DXA is currently the criterion standard for the evaluation of BMD.[5, 6] Compared with other screening tools (eg, calcaneal quantitative ultrasonography, the Simple Calculated Osteoporosis Risk Estimation [SCORE]), DXA has been found to be efficacious and cost-effective.[73] DXA is not as sensitive as quantitative computed tomography (QCT) scanning for detecting early trabecular bone loss, but it provides comparable costs,[73] it is done on an outpatient basis,[4] and there are no special requirements for performing it. Also, radiation exposure is kept to a minimum.

DXA is used to calculate BMD at the lumbar spine, hip, and proximal femur (see the images below). Densitometric spine imaging can be performed at the time of DXA scanning to detect vertebral fractures. Vertebral fracture assessment (VFA) is not available with all DXA machines. When available, VFA should be considered when the results may influence clinical management of the patient. [82] Peripheral DXA 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.

Example of a dual energy x-ray absorption (DXA) scan. This image is of the left hip bone.

Source: Government of Western Australia Department of Health. Example of a dual energy xray absorption (DXA) scan. This image is of the lumbar spine. Source: Government of Western Australia Department of Health.

Although measurement of 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 that of control subjects who are at their peak BMD, whereas the Z-score reflects a value compared to that of patients matched for age and sex.[7, 8, 9, 10]

NOF, ISCD, and USPSTF recommendations

The NOF and the International Society for Clinical Densitometry (ISCD)recommend that BMD be measured in the following patients[4, 5] : Women aged 65 years or 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 associated with low bone mass or bone loss (eg, rheumatoid arthritis)

Adults who take a medication associated with low bone mass or bone loss (eg, glucocorticoids, 5 mg of prednisone daily for 3 mo) 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.[11] 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-yearold 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.

WHO T-score and Z-score criteria

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[9] : 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. Of note, about half of osteoporotic fractures occur in women with a T-score greater than 2.5, and the other half occur in those with a T-score lower than 2.5, the WHOs cutoff for DXA-based diagnosis of osteoporosis. 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.

International Society of Clinical Densitometry (ISCD) positions

The following are the official positions of the ISCD on peripheral DXA (pDXA) [5] : pDXA can be used in postmenopausal women for fracture risk assessment (vertebral and global fragility fracture risk), although its vertebral fracture predictive ability is weaker than central DXA and heel quantitative ultrasonography (QUS); evidence for use in men is insufficient The World Health Organization (WHO) diagnostic classification can be applied only to the one-third (33%) radius region of interest measured by pDXA devices utilizing a validated young-adult reference database pDXA devices should be independently validated for fracture risk prediction by prospective trials or by demonstration of equivalence to a clinically validated device Bone density measurements from different pDXA devices cannot be directly compared If central DXA cannot be done, radius pDXA measurements can be used to identify patients in whom pharmacologic treatment should be initiated; the fracture probability, based on both devise-specific thresholds and clinical risk factors, should be high in those patients Radius pDXA plus clinical risk factors can also be used to identify patients at very low fracture probability in which no further diagnostic testing is necessary pDXA cannot be used to monitor the effects of osteoporosis treatments

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.

Computed Tomography
Abdominal CT
Abdominal CT scans performed for other indications can be used to screen for osteoporosis, according to a cross-sectional study of 1867 adults who underwent both CT and DXA scanning within 6 months of each other over a 10-year period.[83, 84] Of 119 patients whose scans showed evidence of osteoporotic vertebral compression fractures, 62 (52.1%) had normal BMD on DXA scans. Attenuation values for CT scans were significantly (P < .001) lower at all vertebral levels in patients with DXA results showing evidence of osteoporosis. A CT-attenuation threshold of 160 HU or less at the L1 level was associated with 90% sensitivity, and a threshold of 110 HU was associated with greater than 90% specificity for distinguishing between osteoporosis, osteopenia, and normal BMD.[83, 84] Positive predictive values for osteoporosis were 68% or higher at L1 CT-attenuation thresholds less than 100 HU, and negative predictive values at thresholds above 200 HU were 99%.

Quantitative CT
QCT is another method employed to measure spinal BMD. At the spine, 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. QCT scanning of the spine is the most sensitive method for diagnosing osteoporosis, because it measures trabecular bone within the vertebral body. At the hip, QCT produces DXA-equivalent T-scores and BMD measures in g/cm2.[75, 76] 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 DXA scanning, QCT has a comparable cost[73] and precision.[75, 85, 86, 87] In addition, like DXA, no dye injection should be used.[88] QCT is a very sensitive technique when repeated measurements are needed to detect small changes in BMD, and modern 3-dimensional QCT acquisition has a scan time less than 10 seconds for the lumbar spine or proximal femur.[89] However, QCT requires a higher radiation dose, and there is no interference by osteophytes.[90] Nonetheless, QCT scanning is less commonly used than DXA; based on Medicare data, about 5% of all BMD assessments are done with QCT scanning. Smaller, rural hospitals may favor QCT scanning, as they often already have a CT scanner for trauma cases and may not be able to afford a DXA machine as well.

International Society of Clinical Densitometry positions

The following are the official positions of the International Society of Clinical Densitometry (ISCD) on QCT of the lumbar spine[5] : QCT of the spine can be used to predict vertebral fractures in postmenopausal women; but there is insufficient evidence to recommend spine QCT for spinal fracture prediction in men or hip fracture prediction in both women and men Because T-scores by QCT are not equivalent to T-scores based on DXA, the World Health Organization (WHO) diagnostic classification of osteoporosis cannot be used If central DXA measurements cannot be obtained, QCT of the spine along with consideration of clinical risk factors can be used to identify patients appropriate for pharmacologic treatment QCT of the spine can be used to monitor age-, disease- and treatment-related BMD changes via trabecular BMD of the lumbar spine

The following are the official positions of the ISCD on peripheral QCT (pQCT) of the radius[5] : pQCT of the forearm at the ultra-distal radius cannot be used for fracture risk assessment of the spine, but it does predict hip fragility fractures in postmenopausal women There is insufficient evidence to recommend pQCT for fracture risk prediction in men As with QCT of the spine, pQCT of the radius cannot be used to diagnose osteoporosis based on the WHO diagnostic classification As with QCT of the spine, pQCT of the radius along with clinical risk factors can be used to initiate pharmacologic treatment if central DXA cannot be obtained pQCT measurements of the trabecular and total BMD of the ultra-distal radius can be used to monitor age-related BMD changes

Single-photon emission CT
Single-photon emission computed tomography (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).

Ultrasonography
Quantitative ultrasonography (QUS) 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.

International Society of Clinical Densitometry positions

The following are the official positions of the ISCD on QUS: Bone density measurements from QUS devices should be independently validated; measurements by different devices cannot be directly compared The heel is the only validated skeletal site for the clinical use of QUS in osteoporosis management Validated calcaneal QUS devices can be used in postmenopausal women to predict hip, vertebral, and global fracture risk and in men older than 65 years to predict hip and all nonvertebral fractures The World Health Organization (WHO) diagnostic classification cannot be applied to T-scores from QUS measurements If central DXA cannot be obtained, calcaneal QUS in combination with clinical risk factors can be used to identify patients in whom pharmacologic treatment should be initiated Calcaneal QUS plus clinical risk factors can also be used to identify patients at very low fracture probability in whom no further diagnostic testing is necessary QUS cannot be used to monitor the skeletal effects of treatments for osteoporosis

Magnetic Resonance Imaging

Magnetic resonance imaging (MRI) may be useful in identifying fractures and in the assessment of metabolic bone disease. 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 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.

Bone Scanning
Bone scanning assesses the function and tissue metabolism of organs by using a radionuclide (technetium-99m [99m Tc]) that emits radiation in proportion to its attachment to a target structure. This technique detects an increase in osteoblastic activity (as seen in compression fractures). Images may be obtained in 3 phases of the bone scanning process (immediate-flow study, immediate static blood pool study, and 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.

Biopsy and Histologic Features

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, which may potentially indicate that too little bone formation or too much bone resorption is the cause of osteoporosis in a patient. Tetracycline labeling may also help clinicians to test potential therapy (ie, did the treatment slow bone resorption, increase bone formation, or both?) and study other metabolic bone responses. One may also perform a vertebral body bone biopsy when performing a therapeutic procedure such as kyphoplasty (see the images below) or vertebroplasty for fixation of a vertebral compression fracture.

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). Osteoporosis. Lateral radiograph demonstrates multiple osteoporotic vertebral compression fractures. Kyphoplasty has been performed at

one level.

Osteoporosis. Lateral radiograph of the patient seen in the previous image following

kyphoplasty performed at 3 additional levels. transpedicular approach.

Percutaneous vertebroplasty,

Histologic examination of osteoporotic bone may reveal generalized thinning of trabeculae and irregular perforation of trabeculae, reflecting unbalanced osteoclast-mediated bone resorption.[48] The following are histologic specimens from patients with osteoporosis.

Osteoporosis is defined as a loss of bone mass below the threshold of fracture. This slide (methylmethacrylate embedded and stained with Masson's trichrome) demonstrates the loss of connected trabecular

bone. The bone loss of osteoporosis can be severe enough to create separate bone "buttons" with no connection to the surrounding bone. This easily leads to insufficiency fractures.

Inactive osteoporosis is the most common form and manifests itself without active

osteoid formation.

Osteoporosis that is active contains osteoid seams (red here in

the Masson's trichrome).

Woven bone arising directly from surrounding

mesenchymal tissue. This image depicts bone remodeling with osteoclasts resorbing one side of a bony trabecula and osteoblasts depositing new bone on the other side.

Osteoclast, with bone below it. This image shows typical distinguishing characteristics of an osteoclast: a large cell with multiple nuclei and a "foamy" cytosol.

In this image, several osteoblasts display a prominent Golgi apparatus and are actively synthesizing osteoid. Two osteocytes can also be seen.

Approach Considerations
According to a clinical practice guideline by the American College of Physicians, because of the significant disability, morbidity, mortality, and expenses associated with osteoporotic fractures,[72] treatment is aimed at fracture prevention and includes modification of general lifestyle factors, such as increasing weight-bearing and muscle-strengthening exercise, which have been linked to fractures in epidemiologic studies and ensuring optimum calcium and vitamin D intake as adjunct to active antifracture therapy.[12] Medical care includes the administration of adequate calcium, vitamin D, and anti-osteoporotic medication such as bisphosphonates,[82] parathyroid hormone (PTH), raloxifene, and estrogen.[11] 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.[91] 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 lead to more frequent use of appropriate osteoporosis treatment and may result in fewer fractures, increased life expectancy, and significant health-care cost savings.[15] 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 long-term 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.

Pharmacologic Therapy

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. Therapy should be individualized based on each patients clinical scenario, with the risks and benefit s of treatment discussed between the clinician and patient.[11, 92] Patients identified as at risk for osteoporosis (including children and adolescents) should undergo preventive measures, including adequate calcium intake, vitamin D intake, and exercise. It is recommended to counsel patients to avoid tobacco and excessive alcohol use. 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.

Expert recommendations
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 [4] : A hip or vertebral fracture (vertebral fractures may be clinical or morphometric [ie, identified on a radiograph alone]) T-score of -2.5 or less at the femoral neck or spine after appropriate evaluation to exclude secondary causes Low bone mass (T-score between -1.0 and -2.5 at the femoral neck or spine) and a 10-year probability of a hip fracture of 3% or greater or a 10-year probability of a major osteoporosis-related fracture of 20% or greater based on the US-adapted WHO algorithm The American College of Physicians has reviewed the evidence and has proposed guidelines for pharmacologic treatments of osteoporosis.[72] The agents currently available for osteoporosis treatment include bisphosphonates, the selective estrogen-receptor modulator (SERM) raloxifene, calcitonin, denosumab, and an anabolic agent, teriparatide (human recombinant PTH [1-34]).[35, 93, 94] All therapies should be given with calcium and vitamin D supplementation. Guidelines from the American Association of Clinical Endocrinologists (AACE), published in 2010, include the following recommendations for choosing drugs to treat osteoporosis [13] : 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 There are no studies that have shown that combination therapy with 2 or more agents have a greater effect on fracture reduction than single therapy. The AACE guidelines advise against the use of combination therapy, until the effect of combination therapy on fracture is better understood.

Bisphosphonates
Bisphosphonates are the most commonly used agents for osteoporosis. They have been employed for both treatment and prevention. Oral and intravenous options are available. Alendronate (Fosamax) is approved for the treatment of osteoporosis in men, in postmenopausal women, and in patients with glucocorticoid-induced osteoporosis. It has been shown to increase spinal and hip mineral density in postmenopausal women. Well-conducted controlled clinical trials indicate that alendronate 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. Alendronate is also available in combination with cholecalciferol (vitamin D3). The combination alendronate/vitamin D3 (Fosamax Plus D) is indicated for the treatment of osteoporosis in men to increase bone mass.

The results of a population-based, national registerbased, open cohort study of 38,088 patients suggest that elderly patients who use proton pump inhibitors in conjunction with alendronate have a dosedependent loss of protection against hip fracture.[95] Other oral bisphosphonates include risedronate (Actonel) or risedronate delayed-release (Atelvia), given daily, weekly, or monthly. It is also available as a combination product with calcium as risedronate/calcium carbonate (Actonel with Calcium). Risedronate reduced vertebral fractures by 41% and nonvertebral fractures by 39% over 3 years. Ibandronate (Boniva) is another bisphosphonate that can be given orally once a month. Intravenous bisphosphonates are excellent choices for patients intolerant of oral bisphosphonates or for those in whom adherence is an issue. Ibandronate is also available as an intravenous formulation that is given every 3 months. Ibandronate has not shown efficacy in nonvertebral fractures in clinical trials. Zoledronic acid Zoledronic acid (Reclast) 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%, as compared with placebo. Over 3 years, it reduces the incidence of spine fractures by 70%, hip fractures by 41%, and nonvertebral fractures by 25%. A similar effect on vertebral fractures has been shown in men. A 2012 randomized, 2-year trial of men with osteoporosis found once-yearly zoledronic acid infusions significantly decreased the risk of new morphometric vertebral fractures by 67%.[96] Zoledronic acid is a once-yearly intravenous infusion approved for the treatment of osteoporosis in men, in postmenopausal women, and in patients with glucocorticoid-induced osteoporosis.[97] A randomized, placebo-controlled, double-blind trial suggested that a once-yearly 5-mg dose of IV zoledronic acid increases bone mass in men within 90 days of hip fracture repair; similar increases were noted in women.[98] In September 2011, the FDA updated the prescribing information for zoledronic acid (Reclast) to provide improved information regarding the risk of kidney failure. Acute renal failure requiring dialysis and fatal outcomes have been reported to the FDA following the use of zoledronic acid. It is contraindicated with moderate to severe renal impairment (ie, CrCl < 35 mL/min) or in patients with evidence of acute renal impairment. Other risks for renal impairment include coadministration of zoledronic acid with nephrotoxic or diuretic medications, severe dehydration before or after administration, or advanced age. [99] Bisphosphonates and bone turnover 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. [100] Therefore, although the bisphosphonates are outstanding in their efficacy, bone turnover markers should be monitored. If these markers become profoundly suppressed, the patient should be taken off the bisphosphonates and given a rest period until return to therapeutic levels (N-telopeptide of collagen cross-links [NTx], 20-40). Treatment interval and complications with bisphosphonate therapy The limited trial data available regarding long-term treatment with bisphosphonates has raised questions about the optimal length of treatment with these medications.[101] 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 (see the images below).

Normal femoral anatomy.

Stable intertrochanteric fracture of the femur.

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 to be low in 52,595 women with at least 5 years of bisphosphonate therapy (0.13% during the subsequent year and 0.22% within 2 years).[102] 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.[103] The AACE recommends that if osteoporosis is mild, clinicians should consider a drug holiday after 4-5 years of bisphosphonate treatment; if fracture risk is high, a drug holiday of 1-2 years may be considered after 10 years of treatment.[13] 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.[13]

Selective estrogen receptor modulator

Selective estrogen receptor modulators (SERMs) are considered to provide the beneficial effects of estrogen without the potentially adverse outcomes. Raloxifene (Evista) is indicated for the treatment and prevention of osteoporosis in postmenopausal women. The usual dose is 60 mg given orally daily. It can also be given in combination with calcium and vitamin D. It is the first SERM studied for breast cancer prevention, and it 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 lowdensity lipoprotein cholesterol were lowered, and the endometrium was not stimulated. Pooled mortality data from large clinical trials of raloxifene (60 mg/day) were analyzed by Grady et al in 2010. When compared with placebo, all-cause mortality was 10% lower in older postmenopausal women receiving raloxifene. The primary reduction was in noncardiovascular, noncancer deaths. [104]

Parathyroid hormone
Teriparatide (Forteo) is a human recombinant parathyroid hormone (1-34) (PTH [1-34]) and is the only available anabolic agent for the treatment of osteoporosis. It is indicated for the treatment of women with postmenopausal osteoporosis who are at high risk of fracture, who have been intolerant of previous osteoporosis therapy, or in whom osteoporosis treatment has failed, as well as to increase bone mass. It is indicated in men with idiopathic or hypogonadal osteoporosis who are at high risk of fracture, who have been intolerant of previous osteoporosis therapy, or in whom osteoporosis therapy has failed. Teriparatide is also approved for the treatment of patients with glucocorticoid-induced osteoporosis. Before treatment with teriparatide, levels of serum calcium, PTH, and 25(OH)D need to be monitored.

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/day, 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 in the hip.[105, 106, 107] 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. [108] According to Finkelstein et al, 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.[109] A study by Cosman and colleagues challenged this conclusion by giving 3-month-on, 3-month-off pulses of teriparatide while the patients were on weekly alendronate; BMD in the spine increased above that of the alendronate-only arm.[110] This pulsed regimen appears to take advantage of the 3- to 4-month socalled 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.[111, 112] Data on the use of PTH in men are much more limited, but they appear to have relatively comparable efficacy. In a retrospective analysis of the data from the Fracture Prevention Trial and the Multiple Outcomes of Raloxifene Evaluation trial, Bouxsein et al found that teriparatide reduced fracture risk to a greater extent than raloxifene in postmenopausal osteoporotic women. Compared with placebo, teriparatide reduced the risk of any new fractures by 72%, new adjacent fractures by 75%, and new nonadjacent vertebral fractures by 70%. Raloxifene reduced the risks by 54%, 54%, and 53%, respectively. [113] A study performed by the Austrian group using PTH 1-84 to treat pelvic fractures clearly demonstrated that the anabolic agent used in osteoporosis also has the ability to both increase the rate of union and enhance the speed of the process. Using CT evaluation of the fracture site, the authors not only proved their primary goal of improved fracture healing but also noted a significant decrease of pain and improved function over the placebo arm. This clinical study supports the extensive animal data that predicted a clear role for PTH in fracture repair.[114] In a randomized, controlled trial, 94 postmenopausal women with weak bones who took teriparatide and denosumab in combination had increased bone-mineral density (BMD) after 12 months.[115, 116] The women were randomized to receive 20 g teriparatide per day or 60 mg denosumab every 6 months, or both for 12 months. They also took supplemental calcium and vitamin D. The 12-month changes in posterioranterior lumbar spine, femoral-neck, and total-hip BMD in the combination-therapy group (9.1%, 4.2% and 4.9%, respectively) were greater than than those in the groups receiving only teriparatide (6.2%, 0.8% and 0.7%, respectively) or only densumab (5.5%, 2.1% and 2.5%, respectively). [116]

Calcitonin
Calcitonin-salmon (Fortical, Miacalcin) is a hormone that decreases osteoclast activity, thereby impeding postmenopausal bone loss. It is indicated for the treatment of women who are more than 5 years post menopause and have low bone mass relative to healthy premenopausal women. Calcitonin-salmon should be reserved for patients who refuse or cannot tolerate estrogens or in whom estrogens are contraindicated. It is recommended in conjunction with adequate calcium and vitamin D intake to prevent

the progressive loss of bone mass. It is available as an injection and as an intranasal spray. The intranasal spray is delivered as a single daily spray that provides 200 IU 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 bone mineral density (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. Common side effects of nasally administered calcitonin include nasal discomfort, rhinitis, irritation of nasal mucosa, and occasional epistaxis. Nausea, local inflammatory reactions at the injection site, sweating, and flushing are side effects noted with parenteral use.

Denosumab
Denosumab (Prolia) is a humanized monoclonal antibody directed against the receptor activator of the nuclear factor-kappa B ligand (RANKL), which is a key mediator of the resorptive phase of bone remodeling.[112] It decreases bone resorption by inhibiting osteoclast activity. Denosumab was approved by the US Food and Drug Administration in June 2010. It has been studied in cancer patients and in patients with postmenopausal osteoporosis.[117, 118] It is indicated to increase bone mass in men[119] and postmenopausal women with osteoporosis who are at high risk of fracture (defined as a history of osteoporotic fracture), have multiple risk factors for fracture, are intolerant to other available osteoporosis therapies, or in whom osteoporosis therapies have failed. In postmenopausal women with osteoporosis, denosumab reduces the incidence of vertebral, nonvertebral, and hip fractures. Denosumab also increases bone mass in men at high risk for fracture who are receiving androgen deprivation therapy for nonmetastatic prostate cancer. In these patients, denosumab also reduces the incidence of vertebral fractures. It is also used to increase bone mass in women at high risk for fracture receiving adjuvant aromatase inhibitor therapy for breast cancer. Approved dosage is 60 mg given subcutaneously every 6 months. 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 higher doses. Denosumab has been 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, denosumab decreased the risk of vertebral, nonvertebral, and hip fractures.[120] Smith et al reported a reduction in incident vertebral fractures when denosumab was used in 734 men receiving androgen-deprivation therapy for prostate cancer.[121] 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.[122] In a randomized, controlled trial, 94 postmenopausal women with weak bones who took teriparatide and denosumab in combination had increased bone-mineral density (BMD) after 12 months.[115, 116] The women were randomized to receive 20 g teriparatide per day or 60 mg denosumab every 6 months, or both for 12 months. They also took supplemental calcium and vitamin D. Denosumab in combination with teriparatide has been shown to increase BMD more than either drug alone.[115, 116] In a randomized, controlled trial consisting of 94 postmenopausal women with weak bones, 12-month changes in posterior-anterior lumbar spine, femoral-neck, and total-hip BMD in the

combination-therapy group (9.1%, 4.2% and 4.9%, respectively) were greater than than those in the groups receiving only teriparatide 20 g per day (6.2%, 0.8% and 0.7%, respectively) or only densumab 60 mg denosumab every 6 months(5.5%, 2.1% and 2.5%, respectively).[116] Supplemental calcium and vitamin D was also provided.

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. [123] 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).

Other agents
Strontium ranelate is approved for the treatment of osteoporosis in some countries in Europe. It reduces the risk of both spine and nonvertebral fractures.[124, 125]Strontium is not approved for the treatment of osteoporosis in the United States. 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.[126] 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.

Vertebroplasty and Kyphoplasty

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 (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 the 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. For more information, see the Medscape Reference article Percutaneous Vertebroplasty and Kyphoplasty.

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. Recommendations for patients with osteoporosis include daily dosages of 12001500 mg of calcium and 400-800 IU of vitamin D. Adequate calcium intake is essential in the prevention and treatment of osteoporosis. 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 daily calcium intake of 1200 mg. 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 Website 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 Website for further vitamin D recommendations. A meta-analysis of 12 double-blind, randomized, controlled trials for nonvertebral fractures and 8 trials for hip fractures 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. [127] However, a longitudinal and prospective cohort study concluded that gradual increases in dietary calcium intake did not further reduce fracture risk or osteoporosis in women.[128] Alcohol and anorexia nervosa can interfere with nutrition. 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. Poor nutritional states, such as in anorexia nervosa,[129] 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.

Calcium and vitamin D supplementation

Calcium The goal of the current recommendations for daily calcium intake is to ensure that individuals maintain an adequate calcium balance. Current recommendations from the American Association of Clinical Endocrinologists (AACE) for daily calcium intake are as follows [13] : Age 0-6 months: 200 mg/day Age 6-12 months: 260 mg/day Age 1-3 years: 700 mg/day Age 4-8 years: 1000 mg/day Age 9-18 years: 1300 mg /day Age 19-50 years: 1000 mg/day Age 50 years and older: 1200 mg/day Pregnant and breastfeeding women age 18 years and younger: 1300 mg/day Pregnant and breastfeeding women age 19 years and older: 1000 mg/day Commonly used calcium supplements include calcium carbonate and calcium citrate. Calcium carbonate is generally less expensive and is recommended as a first choice option. Calcium carbonate has better absorption with food, as opposed to calcium citrate, which is better absorbed in the fasting state. Also, fewer tablets are needed with calcium carbonate than with calcium citrate. Vitamin D Vitamin D is increasingly being recognized as a key element in overall bone health and muscle function. It plays a significant role in bone health, calcium absorption, balance (eg, reduction in risk of falls), [130] and muscle performance. The minimum daily requirement in patients with osteoporosis is 800 IU of vitamin D3, or cholecalciferol. Many patients require higher levels (continuously or for a short period) to be considered vitamin D replete, which is defined as a serum 25-hydroxyvitamin D level of 32 ng/mL. Vitamin D is available as ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Vitamin D is metabolized to active metabolites. These metabolites promote the active absorption of calcium and phosphorus by the small intestine, elevating serum calcium and phosphate levels sufficiently to permit bone mineralization. Calcium and vitamin D studies

Several large studies have demonstrated that supplementation with a combination of calcium and vitamin D can reduce fracture risk.[131] A meta-analysis showed that nonvertebral fracture prevention with vitamin D is dose-dependent and that a higher dose reduced fractures by at least 20% in individuals aged 65 years or older.[127] Another 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.[132] 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 found that an increased risk for myocardial infarction was associated with calcium supplements.[133] This increased risk has not been associated with dietary calcium intake.

Physical and Occupational Therapy

Physical therapy
Physical therapy focuses on improving a patient's strength, flexibility, posture, and balance to prevent falls and maximize physical function.[134, 135] Postural retraining is key in this population. Spinal bone mineral density (BMD) is directly correlated with the strength of the back extensors; therefore, maintaining and strengthening the back extensors should be emphasized.[136] In studies by Sinaki and colleagues, strengthening the back extensor muscles reduced kyphosis and decreased the risk of sustaining vertebral compression fractures.[137, 138] As soon as the course of therapy allows, weight-bearing exercises should be initiated. Regular weightbearing exercises are essential for the maintenance of bone mass [40] and should be encouraged in all patients, including children and adolescents (to strengthen the skeleton during the maturation process). Exercise also improves agility and balance, thereby reducing the risk of falls.

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.[135] 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.

Exercise
Aerobic low-impact exercises, such as walking and bicycling, generally are recommended. During these activities, ensure that the patient maintains an upright spinal alignment. 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.[136] 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 homeexercise program that incorporates the necessary elements for improving posture and overall physical fitness. 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), whereas values in the control group declined.[139]

Snow et al found increased BMD of the femoral neck, trochanter, and total hip in 18 postmenopausal women (average age, 64 years) who wore weighted vests and participated in jumping exercises 3 times per week for 32 weeks a year for 5 years.[140] The results of a Cochrane Database of Systematic Reviews study found that exercise may help prevent bone loss and fractures in postmenopausal women. The most effective type of exercise on BMD for the neck of the femur was found to be nonweight-bearing, high-force exercise, such as lower limb resistance strength training; combination exercise programs were most effective for BMD at the spine.[141] Although swimming is not a weight-bearing 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. 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.[142, 143, 144, 145] 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%.[146] 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 in the control group (0.87 vs 1.34, respectively). In addition, after 6 months, persons 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. [147]

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.[4] Patients should be counseled on smoking cessation and moderated alcohol intake. Patients who have disorders or take medications that can cause or accelerate bone loss should receive calcium and vitamin D supplementation and, in some cases, pharmacologic treatment.[148] 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.[149] 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.[150] 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).[151] 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. [4] Bone density checks are recommended every 2 years in postmenopausal women. Regular weight-bearing exercises and back extensor strengthening help 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 can help obtain 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. [152, 153] 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 (DXA) should be repeated every 2-3 years if the baseline test results are normal. DXA should be performed every 1-2 years in patients who are undergoing osteoporosis treatment. The USPSTF 2011 recommendations, however, state that evidence is lacking regarding optimal intervals for repeated screening, as well as regarding whether a woman with normal BMD requires repeated screening.[11] A minimum of 2 years may be needed to reliably measure a change in BMD; however, longer intervals may be necessary to improve fracture risk prediction. According to a study funded by the National Institutes of Health, osteoporosis will develop in less than 10% of older, postmenopausal women during rescreening intervals of approximately 15 years for women with normal BMD or mild osteopenia; during rescreening intervals of approximately 5 years for women with moderate osteopenia; and during rescreening intervals of approximately 1 year for women with advanced osteopenia. [154] 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.[155, 156] Common orthotics used include the following: Thoracolumbosacral orthosis (TLSO) Cruciform anterior spinal hyperextension (CASH) brace Jewett brace

Medication Summary
Antiresorptive agents decrease bone resorption, including bisphosphonates, the selective estrogen-receptor modulator (SERM) raloxifene, calcitonin, and denosumab. In addition, there are anabolic steroids that promote bone formation in patients with osteoporosis, such as teriparatide. All therapies should be given with calcium and vitamin D supplementation.

Calcium Metabolism Modifiers

Class Summary
Calcium metabolism modifiers such as 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 poor absorption and have a bioavailability of less than 5%. Bone uptake is 20-80%, with the remainder being rapidly excreted through the kidneys.[157] Bisphosphonates are approved in the United States for the prevention and treatment of postmenopausal osteoporosis, osteoporosis in males, and glucocorticoid-induced osteoporosis. Their major pharmacologic action is the inhibition of bone resorption. View full drug information

Alendronate (Fosamax); alendronate sodium/cholecalciferol (Fosamax Plus D)

Alendronate inhibits osteoclast activity and bone resorption. By binding to calcium salts, alendronate blocks the transformation of calcium phosphate into hydroxyapatite and inhibits the formation, aggregation, and dissolution of hydroxyapatite crystals in bone. 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 years. Alendronate is approved for the treatment and prevention of postmenopausal osteoporosis, male osteoporosis, and glucocorticoid-induced osteoporosis. View full drug information

Risedronate (Actonel, Atelvia)

Risedronate is a potent antiresorptive agent that does not affect bone mineralization. The inclusion of an amino group within the heterocyclic ring makes risedronate one of the most potent antiresorptive bisphosphonates. As with other bisphosphonates, risedronate inhibits osteoclast formation and activity. 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 years. It is approved for the treatment and prevention of postmenopausal osteoporosis, male osteoporosis, and glucocorticoid-induced osteoporosis. View full drug information

Calcitonin salmon (Miacalcin, Fortical)

Calcitonin is used for the treatment of postmenopausal osteoporosis in women more than 5 years post menopause with low bone mass relative to healthy premenopausal females. Calcitoninsalmon injection should be reserved for patients who refuse or cannot tolerate estrogens or in whom estrogens are contraindicated. Use of calcitonin-salmon injection is recommended in conjunction with adequate calcium and vitamin D intake to prevent the progressive loss of bone mass. It inhibits osteoclastic bone resorption and 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 groups receiving 200 IU/day. It is available in parenteral and intranasal forms; however, the intranasal form is more convenient and better tolerated. View full drug information

Ibandronate (Boniva)

Ibandronate increases BMD and reduces the incidence of vertebral fractures. 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 years; it has no effects on reduction of nonvertebral fractures. Ibandronate is approved for the treatment and prevention of postmenopausal osteoporosis. It is available as a 150-mg oral tablet and intravenous solution. View full drug information

Zoledronic acid (Reclast)

Zoledronic acid inhibits bone resorption by altering osteoclast activity and by inhibiting normal endogenous, as well as tumor induced, mediators of bone degradation. Like other bisphosphonates, zoledronic acid binds to hydroxyapatite crystals in mineralized bone matrix. The binding to calcium phosphates slows the dissolution of hydroxyapatite crystals, as well as inhibits the formation and aggregation of these crystals. It increases BMD at the spine by 4.35.1% and at the hip by 3.1-3.5%, as 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 approved for the treatment and prevention of postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, osteoporosis in men, and Paget disease of bone. It is contraindicated in patients with severe renal failure.

Parathyroid Hormone Analogues

Class Summary
Parathyroid hormone (PTH) is the primary regulator of calcium and phosphate metabolism in bone and kidneys. Teriparatide is a recombinant amino terminal fragment of PTH composed of the first 34 amino acids of PTH, which produce most of its chief biologic effects. 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.[35]

Selective Estrogen Receptor Modulator

Class Summary
Selective estrogen receptor modulators (SERMs) affect some of the receptors stimulated by estrogen but can selectively act as an 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)
The biological actions of raloxifene are largely mediated through binding to estrogen receptors, which results in activation of estrogenic pathways in some tissues (agonism) and blockade of estrogenic pathways in others (antagonism). Raloxifene increases BMD at the spine and the hip. It reduces the incidence of spine fractures by 30-55% over 3 years. Raloxifene is approved for the

prevention and treatment of postmenopausal osteoporosis in women. It is available as 60 mg tablets that are given orally daily. Adverse reactions commonly seen include hot flashes, leg cramps, peripheral edema, flu syndrome, arthralgia, and sweating.

Monoclonal Antibodies, Endocrine

Class Summary
Monoclonal antibodies such as denosumab (Prolia) inhibit osteoclast formation, decrease bone resorption, increase BMD, and reduce the risk of fracture. View full drug information

Denosumab (Prolia)
Denosumab 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, which are the cells that are responsible for bone resorption. It is indicated to increase bone mass in men and postmenopausal women with osteoporosis at high risk for fracture. It is also indicated for men at high risk for fracture who are receiving androgen deprivation therapy for nonmetastatic prostate cancer. The general dosage is 60 mg every 6 months as an SC injection in the upper arm, upper thigh, or abdomen. Patients should be instructed to take 1000 mg of calcium daily and at least 400 IU of vitamin D daily.

Calcium Salts
Class Summary
Calcium and vitamin D are essential to increase bone density. Vitamin D repletion is essential for calcium absorption. Calcium supplements are used to increase calcium levels. [158] Adequate calcium intake is essential to attain peak bone mass and for continued maintenance of bone health. View full drug information

Calcium citrate (Cal-Citrate, Cal-Cee, Cal-C-Caps)

Calcium is the primary component of skeletal tissue, providing structural integrity and support for individual growth. Bone undergoes constant remodeling and turnover. A combination of supplemental calcium and vitamin D can potentially lower the incidence of fractures. Calcium citrate is absorbed equally well when taken with or without food. View full drug information

Calcium carbonate (Caltrate 600, Calcarb 600, Oysco 500, Super Calcium 600, Tums Ultra)
Calcium intake is essential in the prevention and treatment of osteoporosis. Calcium carbonate is generally more inexpensive and requires fewer tablets. Because of its dependence on stomach acid for absorption, calcium carbonate is absorbed most efficiently when taken with food.

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 the serum estrogen level, which, in turn, decreases the rate of bone resorption. [159] The lowest effective dose at the shortest duration necessary should be used. Estrogen therapy reduces bone resorption and retards or halts postmenopausal bone loss. Estrogen therapy is no longer a first-line approach for the treatment of osteoporosis in postmenopausal women because of increased risk of breast cancer, stroke, venous thromboembolism, and coronary disease. The FDA recommends that other approved nonestrogen treatments be considered first for osteoporosis prevention. View full drug information

Conjugated estrogens (Premarin)

Conjugated estrogens (Premarin)

Estrogens can directly affect bone mass through estrogen receptors in bone, reducing bone turnover and bone loss. Estrogens can also indirectly increase intestinal calcium absorption and renal calcium conservation and, therefore, improve calcium balance. When prescribing solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for women at significant risk of osteoporosis and for whom nonestrogen medications need to be carefully considered. View full drug information

Estradiol (Estrace, Estraderm, Menostar, Vivelle-Dot, 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

Estropipate
Estropipate is indicated for the prevention of osteoporosis. The results of a double-blind, placebocontrolled 2-year study have shown that treatment with 1 tablet of estropipate, 0.75 mg daily for 25 days (of a 31-day cycle per month), prevents vertebral bone mass loss in postmenopausal women. When estrogen therapy is discontinued, bone mass declines at a rate comparable to that of the immediate postmenopausal period. There is no evidence that estrogen replacement therapy restores bone mass to premenopausal levels.

Vitamins, Fat-Soluble
Class Summary
Vitamin D is a fat-soluble sterol compound that includes ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). It can be obtained from food and produced by skin when exposed to sunlight of sufficient intensity. When activated in the liver and then the kidney, vitamin D promotes calcium absorption and bone mass. Vitamin D replacement also increases muscle strength and lowers the risk of falling. View full drug information

Vitamin D (Calciferol, Drisdol)

Vitamin D refers to both ergocalciferol (D2) and cholecalciferol (D3). Following exposure to UV light, 7-dehydrocholesterol (provitamin D3) is converted to cholecalciferol, which is then converted by the liver to calcifediol and then again by the kidney to calcitriol. Vitamin D is available in various forms, including tablets, oral liquid, and capsules. It is commonly coadministered with calcium supplements in patients with osteoporosis.

Estrogens/Progestins
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 the serum estrogen level, which, in turn, decreases the rate of bone resorption. [159] The lowest effective dose at the shortest duration necessary should be used. Estrogen therapy reduces bone resorption and retards or halts postmenopausal bone loss. Estrogen therapy is no longer a first-line approach for the treatment of osteoporosis in postmenopausal women because of increased risk of breast cancer, stroke, venous thromboembolism, and coronary disease. The FDA recommends that other approved nonestrogen treatments be considered first for osteoporosis prevention. View full drug information

Norethindrone/ethinylestradiol (Femhrt)

Ethinyl estradiol with norethindrone is used to prevent osteoporosis associated with menopause. When prescribing it solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for women at significant risk of osteoporosis. View full drug information

Estradiol/norethindrone acetate (Activella, Mimvey, CombiPatch)

Ethinyl estradiol with norethindrone is used to prevent osteoporosis associated with menopause. When prescribing it solely for the prevention of postmenopausal osteoporosis, therapy should be considered only for women at significant risk of osteoporosis.

Estrogens/Progestins-HRT
Class Summary
The combination of conjugated estrogens and medroxyprogesterone reduces bone resorption and retards or halts postmenopausal bone loss. 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. View full drug information

Estradiol/levonorgestrel (Climara Pro)

Estradiol/levonorgestrel transdermal system releases both estradiol and levonorgestrel continuously upon application to skin. It is approved for the prevention of postmenopausal osteoporosis. View full drug information

Estradiol/norgestimate (Prefest)
Estradiol/norgestimate is approved for the prevention of postmenopausal osteoporosis. It is available as a combination of estradiol 1 mg/norgestimate 0.09 mg.