Pharmacotherapy A Pathophysiologic Approach, 9th Ed.

73. Osteoporosis and Other Metabolic Bone Diseases

Mary Beth O’Connell and Jill S. Borchert


KEY CONCEPTS

 Images Osteoporosis is a public health epidemic that affects all ages, genders, races, and ethnicities. Lifestyle behaviors, diseases, and medications should be reviewed to identify risk factors for developing osteoporosis and osteoporotic fractures. Healthcare practitioners should identify and resolve reversible risks. Patients with early onset or severe osteoporosis should be evaluated for secondary causes of bone loss.

 Images Bone physiology and pathophysiology are complex, involving many different cell lines, pathways, and biofeedback systems. As these processes become more delineated, opportunities for additional drug targets exist creating new classes of investigational agents.

 Images An adult’s 10-year probability of developing an osteoporotic fracture can be estimated with the World Health Organization fracture risk assessment (FRAX) tool. Central bone densitometry can determine bone mass, predict fracture risk, and influence patient and provider treatment decisions. Portable equipment can be used for osteoporosis screening in the community to determine the need for further testing.

 Images All people throughout their life spans should incorporate a bone-healthy lifestyle, which emphasizes regular exercise, nutritious diet, tobacco avoidance, minimal alcohol use, and fall prevention to prevent and treat osteoporosis.

 Images Treatment should be considered for men or women older than age 50 years who have a hip or vertebral fracture, T-score ≤ –2.5 at the femoral neck or spine or those who have low bone mass (T-score between –1.0 and –2.5) at the femoral neck or spine and a 10-year probability of major osteoporotic fracture of ≥20% or hip fracture of ≥3% based on FRAX.

 Images The recommended dietary allowance for calcium in American adults is 1,000 to 1,200 mg of elemental calcium daily with diet as the preferred source. Supplements are only added when diet is insufficient.

 Images The recommended dietary allowance for vitamin D for American adults is 600 units and for older adults 800 units daily, with some organizations and guidelines recommending higher doses of at least 800 to 1000 units daily. The daily target is achieved through sun exposure, fortified foods, and supplements. Vitamin D insufficiency, usually defined as 25-hydroxy vitamin D concentrations of <30 ng/mL (<75 nmol/L), is common in Americans.

 Images Alendronate, risedronate, zoledronic acid, and denosumab decrease vertebral, hip, and nonvertebral fractures and are considered first-line osteoporosis treatments. Ibandronate and raloxifene are alternatives, and calcitonin is a last-line agent. Teriparatide is reserved for severe osteoporosis or for those intolerant to other medications.

 Images Adherence with osteoporosis medications is frequently suboptimal, and poor adherence is associated with less fracture prevention. Healthcare providers have an important role in prevention and treatment of osteoporosis by assessing medication administration and adherence and by providing additional medication and disease education.

 Images Patients taking long-term oral glucocorticoids and certain chemotherapeutic agents need to be identified and started on a bone-healthy lifestyle and usually should receive a bisphosphonate, denosumab, or teriparatide therapy to prevent or treat drug-induced osteoporosis.


Images Osteoporosis is a bone disorder characterized by low bone density, impaired bone architecture, and compromised bone strength that predisposes a person to increased fracture risk.1 Osteoporosis is a major public health threat, especially with 55% of the Americans 50 years of age and older expected to have this disease.2 In the United States, 8 million women and 2 million men are estimated to have osteoporosis. The at-risk population is also large, with low bone density (osteopenia) estimates of 34 million Americans2 and 37% to 50% of white women.1

Attention to bone health is needed in people of all ages. The development of osteoporosis and osteoporotic fractures is multifactorial, beginning at birth with genetics and then throughout life as a result of health behaviors that influence bone growth and maintenance, skeletal factors that lead to compromised bone strength, and nonskeletal factors that lead to falls (Fig. 73–1). Therefore all healthcare providers should educate everyone about prevention, especially providing encouragement to practice a bone-healthy lifestyle, monitor bone health in patients at risk, and provide optimal treatment for patients with osteoporosis.

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FIGURE 73-1 Etiology of osteoporosis and osteoporotic fractures.

EPIDEMIOLOGY

Images Low bone density, osteoporosis, and osteoporotic fractures are very common and affect all ethnic groups. Low bone density is estimated to occur in 52% of white and Asian, 49% of Hispanic, and 35% of black women age 50 and older.2 Osteoporosis affects 20% of white and Asian, 10% of Hispanic, and 5% of black women age 50 and older. Disease prevalence greatly increases with age; from 4% in women 50 to 59 years of age to 44% to 52% in women 80 years of age and older.1 White and Hispanic women have the highest fragility fracture (those occurring after falls from no more than a standing height and with minimal or no trauma) rate followed by Native American, African American, and Asian women when the data are adjusted for weight, bone mineral density (BMD), and other factors. Approximately 20% to 27% of men aged 50 years and older have low bone density rising to 49% in men 80 years and older.3 Osteoporosis prevalence in non-Hispanic white men is 4% to 5%, non-Hispanic black men is 3%, and Hispanic men is 2%. Osteoporosis prevalence rises to 17% in men 80 years and older. Although osteoporosis is a common finding in older adults with fractures, up to 50% of fragility fractures occur in patients with normal or low bone mass.1

Fragility wrist and vertebral fractures are common throughout adulthood, and hip fractures are more common in older adults. Fracture incidence has been estimated at 2 million (71% in women, 29% in men) in 2005, with an estimated total medical cost of $17 billion.4 Fractures in women accounted for 75% of the costs and in older adults 87% of the costs. Hip fractures represented 72% of these costs. Forecasting predicts 3 million fractures at a cost of $25 billion in 2025. The incidences of hip fracture and associated mortality are decreasing for both genders,5 with the hypothesis related to better efforts at osteoporosis prevention (e.g., bone-healthy lifestyle) and use of bisphosphonates. In a woman’s lifetime, she has a 17% likelihood of a hip fracture, 15.6% likelihood of a vertebral fracture, and 16% likelihood of a forearm fracture.1 In a man’s lifetime, osteoporotic fracture risk is 13% to 30%. However, rates in the United States remain higher than those in other countries, and comorbidities are increasing,5 suggesting a need for continued focus on bone health.

ETIOLOGY

Images Figure 73–1 depicts a model describing the etiology of osteoporosis and fractures. Table 73–11,69 lists risk factors for osteoporosis, and Tables 73–21,6,8,1013 and 73-310,14,15 list secondary causes of this condition.

TABLE 73-1 Risk Factors for Osteoporosis and Osteoporotic Fractures

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TABLE 73-2 Select Medical Conditions Associated with Osteoporosis in Children and Adults

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TABLE 73-3 Selected Medications Associated with Increased Bone Loss and/or Fracture Risk

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Low Bone Density

BMD is a major predictor of fracture risk. Every standard deviation decrease in BMD in women represents a 10% to 12% decrease in bone mass and a 1.5- to 2.6-fold increase in fracture risk.2 Low BMD can occur as a result of failure to reach a normal peak bone mass or bone loss. Bone loss occurs when bone resorption exceeds bone formation, usually from high bone turnover; when the number or depth of bone resorption sites greatly exceeds the rate and ability of osteoblasts to form new bone. Women and men begin to lose a small amount of bone mass starting in the third to fourth decade of life as a consequence of a slight reduction in bone formation.16 During perimenopause and menopause, bone loss occurs predominantly due to increases in bone resorption secondary to estrogen deficiency. Older adults steadily lose bone mass as a consequence of an accelerated rate of bone remodeling combined with reduced bone formation.

The major risk factors (see Tables 73–173-2, and 73-3) influencing bone loss are hormonal status, exercise, aging, nutrition, lifestyle, disease states, medications, and some genetic influences. Nonhormonal risk factors are similar between women and men.

Impaired Bone Quality

In addition to BMD, the strength of bone is highly affected by the quality of the bone’s composition and its structure.16 For example, besides decreasing bone mass, accelerated bone turnover can also impair bone quality and the structural integrity of bone by increasing the quantity of immature bone that is not yet adequately mineralized. In men, the bone loss that results from thinning of trabeculae with aging is less damaging to the quality and strength of bone structure than bone loss in women where damage to trabecular crosslinks is seen. Bone quality assessment is important because changes in bone quality affect bone strength much more than bone mass changes. Future osteoporosis diagnostic testing will assess both bone quality and density.

Falls

Although up to 50% of vertebral fractures can occur spontaneously with minimal to no trauma, most wrist fractures and greater than 90% of hip fractures result from a fall from standing height or less.2 One-third to one-half of all older adults fall each year, and 50% fall more than once. Up to 5% of all falls will result in a fracture. According to 2006 statistics, 2.1 million older adults were treated in the emergency department and 600,000 hospitalized for fall-related injuries, incurring costs of about $20 billion.17 Close to 17,000 older adults died in 2006 due to a fall-related injury.18

PATHOPHYSIOLOGY

Bone Physiology

The skeleton has two types of bone.19 Cortical bone makes up the majority of the skeleton (80%) and is found mostly in the long bones (e.g., forearm and hip). Trabecular bone is found mostly in the vertebrae and ends of long bones. This bone type is 10 times more metabolically active compared with cortical bone due to a much higher bone turnover rate because of its large surface area and honeycomb-like shape.

Bone is made of collagen and mineral components.19 The collagen component gives bone its flexibility and energy-absorbing capability. The mineral component gives bone its stiffness and strength. The correct balance of these substances is needed for bone to adequately accommodate stress and strain and resist fractures. Imbalances can impair bone quality and lead to reduced bone strength.

Bone strength reflects the integration of bone mass and bone quality (composition and microarchitecture).19 Bone mass increases rapidly throughout childhood and adolescence. Peak bone mass is attained by age 18 to 21 years.6,20 Peak bone mass is highly dependent on genetic factors that account for approximately 60% to 80% of the variability.8 The remaining 20% to 40% is influenced by modifiable factors such as nutritional intake (e.g., calcium, vitamin D, and protein), exercise, adverse lifestyle practices (e.g., smoking), hormonal status, and certain diseases and medications. Optimizing peak bone mass is important for preventing osteoporosis. The higher the peak bone mass, the more bone one can lose before being at an increased fracture risk. As the microarchitecture of bone deteriorates, the bone strength greatly decreases. Women loose more bone structure than men.6

Images Bone remodeling is a dynamic process that occurs continuously throughout life Figure 73–2A–C.19,2126 One to two million tiny sections of bone are in the process of remodeling at any given time. Many cytokines, growth factors, and hormones influence each remodeling step. The complete physiology of bone remodeling is not fully known but appears to begin with signals from lining cells or osteocytes (bone communication cells) that are triggered by stress, microfractures, biofeedback systems responsive to cytokines and growth factors, and potentially certain diseases and medications (see Fig. 73–2B, step 1). A major stimulus for hematopoietic stem cell (monocyte–macrophage lineage) differentiation to become mature osteoclasts (bone-resorbing cells) is the receptor activator of nuclear factor kappa B ligand (RANKL), which is emitted from the osteoblast (bone-forming cells) in step 2. Interleukin 1 and 6, colony-stimulating factor, parathyroid hormone (PTH), parathyroid hormone-related protein (PTHrP), 1,25(OH) vitamin D, tissue growth factor-β (TGF-β), prostaglandin E2 (PGE2), and tumor necrosis factor-α(TNF-α) stimulate RANKL release whereas estrogen, calcitonin, and estrogen agonists antagonists (EAAs) inhibit RANKL release. The RANKL then binds to its receptor, receptor activator of nuclear factor-κB (RANK), on the surface of osteoclast precursors initiating differentiation. The RANKL also stimulates mature osteoclast activation and bone adherence via αvβ3 integrins to resorb bone (step 3). This step is influenced by TGF-β, insulin-like growth factor-1 and 2 (IGF), platelet derived growth factor (PDGF), bone morphometric protein (BMP), and fibroblast growth factor (FGF). After bone attachment, the osteoclasts secrete proteinases, such as cathepsin K, collagenase, gelatinase, tartrate-resistant acid phosphate (TRAP), and matrix metalloproteases, and hydrogen ions to dissolve the mineralized bone. The hydrogen ion production is under src kinase control, which needs to be bound to other compounds such as Cbl, Fak, and phosphatidylinositol 3′-kinase (Pl3K).

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FIGURE 73-2 Bone remodeling cycle.19,2126 A. Overview of remodeling process: step 1, initiation; steps 2 and 3, resorption; step 4, reversal; step 5, formation; and step 6, quiescence.

B. Molecular level detail of major pathways during bone resorption steps 2 and 3, which also showcase drug targets for approved and investigational agents. (Ca+, calcium ion; Cbl, a ubiquitin ligase; FAK, focal adhesion kinase; H+, hydrogen ion; M-CSF, macrophage colony-stimulating factor; Mg+, magnesium ion; NCP, noncollagenous protein; NF-κB, nuclear factor kappa B; OPG, osteoprotegerin; Pl3K, phosphatidylinositol 3′-kinase; Phos, phosphorus; PTH, parathyroid hormone; RANK, receptor activator of nuclear factor-κB; RANKL, receptor activator of nuclear factor-κB ligand; src, tyrosine-protein kinase; TRAF-6, tumor necrosis factor receptor associated factor 6; Trap, tartrate-resistant acid phosphate.) C. Molecular level detail of major pathways during bone formation steps 4 and 5, which also showcase drug targets for approved and investigational agents. (BMP, bone morphogenetic protein; DKK-1, Dickkoff-1; FZD, frizzled element; GSK-3β, glycogen synthase kinase-3β; LRP5/6, lipoprotein receptor-related protein 5 or 6; PPAR-γ, peroxisome proliferator-activated receptor-γ; PTH, parathyroid hormone; PTHrP, parathyroid hormone-related protein; runX2, runt-related transcription factor; sFRP, secreted frizzled related protein; Wnt, wingless tail ligand.)

After bone is resorbed and a cavity is created, osteoclasts produce ephrinB2 that adheres to ephB4 receptors on osteoblasts and along with additional cytokines and growth factors elicit osteoblast differentiation from mesenchymal stem cells, maturation and activity (step 4). PTH and PTHrP also directly increase osteoblast differentiation and activity. Osteoblast differentiation can be inhibited by leptin and peroxisome proliferator-activated receptor-γ (PPAR-γ), which direct mesenchymal cell maturation to adipocytes instead of osteoblasts. Mature osteoblasts produce osteoprotegerin (OPG) that binds to RANKL, thereby stopping bone resorption.

Bone formation occurs over two phases (see Fig. 73–2C).2225 First the wingless tail ligand (Wnt) binds to low-density lipoprotein receptor–related protein 5 or 6 (LRP5/6) and a frizzled element (FZD). Wnt function is also influenced by PTH and PTHrP, which fit into the same receptor. Next LRP5/6 binds to axin, which then cannot bind to glycogen synthase kinase-3β (GSK-3β), thus preventing degradation of β-catenin (step 5). β-catenin then enters the nucleus and signals target genes to create proteins to fill the resorption cavity with osteoid. Growth hormone and IGF-1 also increase bone collagen production. The second phase is the mineralization of bone with calcium, magnesium and phosphorus to give it strength.

Once the cavity is mineralized, bone formation can be stopped by at least three processes. Sclerostin, predominantly secreted from osteocytes, and/or Dickkoff-1 (DKK-1) can bind to LRP5/6 or secreted frizzled related proteins (sFRP) can bind to Wnt to prevent Wnt signaling. Axin can then bind to GSK-3β, which then can cause β-catenin degradation, osteoblast apoptosis, and the end of osteoblastic activity (step 6). The mature osteoblasts can become lining cells or osteocytes. Recent discoveries have found osteocytes to be very biologically active producing OPG to stop resorption and sclerostin and DKK-1, to stop bone formation, with ongoing research to determine the triggers for this cell.25 Quiescence is the phase when bone is at rest until another remodeling cycle is initiated.

Estrogen has many positive effects on the bone remodeling process, with most of its actions helping to maintain a normal bone resorption rate.21 Estrogen suppresses the proliferation and differentiation of osteoclasts and increases osteoclast apoptosis. Estrogen decreases the production of several cytokines that are potent stimulators of osteoclasts, including interleukins (ILs) 1 and 6, TNF-α, and macrophage colony-stimulating factor (M-CSF), and increases TGF-α, which increases osteoclast apoptosis. Estrogen also decreases the production of RANKL, increases the production of OPG and TGF-α, which reduce osteoclastogenesis. Osteoclast apoptosis increases by activating Fas/FasL signaling.

Testosterone’s role in bone health is becoming more apparent with recent identification of some direct effects on bone resorption and osteoblasts.21 Most of testosterone’s bone effects relate to its metabolism to estradiol and the above bone effects of estrogens. Testosterone can also increase OPG production, which will inhibit bone resorption. Increased osteoblast proliferation and differentiation are direct effects. These effects might be from increasing TGF-β, TGF mRNA, FGF, and IGF-2, and decreasing IL-6.

Vitamin D, Parathyroid Hormone, and Calcium

Vitamin D and PTH work together to maintain calcium homeostasis. The most abundant source of vitamin D is the endogenous production from skin exposure to ultraviolet B light. The sun’s ultraviolet B light converts 7-dehydrocholesterol in the skin to cholecalciferol (vitamin D3). Dietary vitamin D sources and supplements include cholecalciferol and ergocalciferol (vitamin D2). Subsequent conversion of cholecalciferol and ergocalciferol to 25-hydroxyvitamin D [25(OH) vitamin D] (calcidiol) occurs in the liver, and then PTH stimulates conversion of 25(OH) vitamin D via 25(OH) vitamin D-1α-hydroxylase (cytochrome P450 [CYP]27B1) to its final active form, 1α,25-dihydroxyvitamin D (calcitriol), in the kidney. Calcitriol binds to the intestinal vitamin D receptor (VDR) and then increases calcium-binding proteins calmodulin and calbindin. As a result, calcium and phosphorous intestinal absorption is increased. The feedback system is completed with CYP27B1 activity inhibited by adequate calcium and phosphorus, and FGF-23. Vitamin D receptors and CYP27B1 are also found in many tissues, such as bone, intestine, brain, breast, colon, heart, stomach, pancreas, lymphocytes, skin, and gonads. Vitamin D is increasingly recognized as contributing to many nonbone benefits, and those may relate to the presence of these conversion capabilities and receptors throughout the body.

Calcium absorption under normal conditions is approximately 30% to 40%, decreasing to 10% to 15% with low vitamin D concentrations. Calcium absorption is thus lower in winter and is reported higher in obesity. Calcium absorption is predominantly an active rate-limited process in the duodenum and jejunum, which is controlled by many hormones such as 1,25 dihydroxyvitamin D and estrogen and TRPV6, which is under genomic control and responsive to dietary calcium intake. A calcium transporter (calmodulin or calbindin) is required to bring calcium from the gut into the tissue wall and then across the enterocyte. Calcium is extruded into the circulation via Ca2+adenosine triphosphatase (ATPase) and the sodium/calcium exchanger (NCX), high energy steps. Another absorption method is paracellular passive diffusion throughout the intestine, which counts for less than 15% of absorbed calcium, is not rate limited, and possibility is sensitive to 1,25 dihydroxyvitamin D as well. Solvent drag plays a minor role in calcium absorption.

When the calcium-sensing receptor (CaSR) on parathyroid cells senses low serum calcium, PTH production increases. PTH then increases calcitriol production and calcium reabsorption by the kidney. Calcium absorption increases as 25(OH) vitamin D concentrations increase until 29 to 32 ng/mL (72 to 80 nmol/L) when the effect plateaus; this observation provides the rationale for the cutoff point for vitamin D sufficiency being around 30 ng/mL (75 nmol/L). Sometimes the increased fractional calcium absorption is insufficient to maintain normal serum calcium, and thus bone resorption is needed for correction. Together, PTH and calcitriol increase RANKL and osteoclast activity, thereby releasing calcium from bone to restore calcium homeostasis.

Osteoporosis pathophysiology depends on sex, age, diet, genetics, and presence of secondary causes.

Postmenopausal Osteoporosis

Estrogen deficiency causes significant bone density loss and compromises bone architecture. Estrogen deficiency increases proliferation, differentiation, and activation of new osteoclasts and prolongs survival of mature osteoclasts.21Interleukins, prostaglandin E2, TNF-α, and interferon γ also increase resulting in more RANKL and less OPG. Loss of estrogen also increases calcium excretion and decreases calcium gut absorption through decreases in TRPV6 activity and 1,25 dihydroxy vitamin D binding proteins.27 The results of this deficiency can also be seen in other settings such as anorexia nervosa and during lactation, and with medications such as prolonged depot medroxyprogesterone acetate implants, aromatase inhibitors and gonadotropin releasing hormone agonists.14,21

During menopause, trabecular bone is most susceptible, leading to vertebral and wrist fractures. Accelerated bone loss begins during perimenopause and continues for 3 to 4 years after menopause from bone resorption exceeding formation.1,20 During this time annual bone loss can be as high as 2%, with total BMD loss due to menopause approximately 6% to 7%.1,20 The number of remodeling sites increases, and resorption pits are deeper and inadequately filled by normal osteoblastic function.

Male Osteoporosis

Male bone also decreases with decreased testosterone.3,6,21,28,29 Men do not undergo a period of accelerated bone resorption similar to menopause, but slowly decreasing testosterone concentrations with aging and or conditions or medications causing hypogonadism cause bone loss. Although the major effect of low testosterone is the loss of metabolism to estradiol, some direct positive bone effects are loss as well. Men are at a lower risk for developing osteoporosis and osteoporotic fractures because of larger bone size, greater peak bone mass, increase in bone width with aging, fewer falls, and shorter life expectancy. However, mortality rate after a fracture is greater for men than women.

The etiology of male osteoporosis tends to be multifactorial (see Tables 73–2 and 73-3). Most common risk factors for men are smoking, low body weight, weight loss, age, long-term glucocorticoid use, androgen deprivation therapy, and low testosterone concentrations.3

Age-Related Osteoporosis

Age-related osteoporosis occurs in older adults because of accelerated bone turnover rate and reduced osteoblast bone formation.30 These bone changes result from hormone,31 calcium,27 and vitamin D27deficiencies and/or changes in their absorption and metabolism, decreased production or function of cytokines or other bone biochemicals, increases in redox status and free radical formation, increases in adipocytes, telomere shortening, and less exercise. Approximately 0.5% BMD is loss each year after age 60 years.8 Fracture risk for a given BMD value increases with aging. Hip fracture risk rises dramatically in older adults as a consequence of the cumulative loss of cortical and trabecular bone and an increased risk for falls. Aging is associated with muscle changes as well, resulting in weakness, balance instability, and greater likelihood of falls.31

Secondary Causes of Osteoporosis

Images Osteoporosis often has secondary causes (see Tables 73–2 and 73-3).1,6,8,1015 Symptoms, initial screening laboratory test results, medication profile review, and or an elevated Z-score from a dual-energy absorptiometry (DXA) test can suggest a secondary cause could be present, warranting more comprehensive workups.

CLINICAL PRESENTATION

Osteoporosis is diagnosed by BMD measurement or presence of a fragility fracture. Many vertebral fractures are asymptomatic, with patients sometimes attributing mild lower back pain to “old age.” Some fractures present with moderate-to-severe back pain that radiates down the leg after a new vertebral fracture. The pain usually subsides significantly after 2 to 4 weeks; however, residual chronic lower back pain can persist. Multiple vertebral fractures decrease height and sometimes curve the spine (kyphosis or lordosis) with or without significant back pain. Patients who have experienced a nonvertebral fracture frequently present with severe pain, swelling, and reduced function and mobility at the fracture site.


CLINICAL PRESENTATION

General

    • Many patients are unaware they have osteoporosis until testing for a fracture.

    • Fractures can occur after bending, lifting, or falling, or independent of any activity.

Symptoms

    • Frequently asymptomatic

    • Pain

    • Immobility

    • Depression, fear, and low self-esteem from physical limitations and deformities

Signs

    • Shortened stature (>1.5-inch [3.81-cm] loss), kyphosis, or lordosis

    • Atraumatic vertebral, hip, wrist, or forearm fracture

Laboratory Tests

    • Routine tests: complete blood count, metabolic profile, creatinine, calcium, phosphorous, electrolytes, alkaline phosphatase, albumin, 25(OH) vitamin D, thyroid-stimulating hormone, total testosterone (for men), and 24-hour urine concentrations of calcium and creatinine. Twenty-four hour urine concentrations of phosphorous and protein are sometimes assessed.

    • Bone turnover markers (e.g., urinary or serum NTX, serum CTX, serum P1NP) are sometimes used, especially to determine if high bone turnover exists.

    • Additional testing if the patient’s history, physical examination, or initial laboratory and or diagnostic tests suggest a specific secondary cause (e.g., intact parathyroid hormone, free testosterone, serum protein electrophoresis, serum parathyroid, celiac panel).

Other Diagnostic Tests

    • Spine and hip bone-density measurement using central dual-energy x-ray absorptiometry (DXA)

    • Vertebral fracture assessment (VFA) with DXA technology

    • Radiograph ordered for other reasons that shows low bone density

    • Radiograph to confirm fracture

    • Balance and mobility tests

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CTX, C-terminal crosslinking telopeptide of type 1 collagen; NTX, N-terminal crosslinking telopeptide of type 1 collagen; P1NP, procollagen type 1 N-terminal propeptide.

From references 1, 6, 8, 10, 20, 37, and 38.

Consequences of Osteoporosis

A fragility fracture is defined as one that occurs as a result of a fall from standing height or less or with minimal to no trauma, sometimes referred to as atraumatic fracture. Fractures of the vertebrae, hip, forearm, or humerus are considered major osteoporotic fractures. Fractures of the face, skull, fingers, and toes are typically not considered osteoporosis-related. Osteoporotic fractures can lead to increased morbidity and mortality and decreased quality of life. Depression is common because of fear, pain, loss of self-esteem from physical deformity, and loss of independence and mobility.

Symptomatic vertebral fractures can cause significant pain, physical deformity, and adverse health consequences. Patients with severe kyphosis can experience respiratory problems as a result of compression of the thoracic region and gastrointestinal complications, such as poor nutrition, from intraabdominal compression. Women and men who suffer a symptomatic vertebral fracture have a lower survival rate compared with those without a fracture history.7

Wrist fractures occur more commonly in younger postmenopausal women and are frequently a result of a fall on an outstretched hand. Negative outcomes include prolonged pain and weakness, and decreased instrumental, (advanced) activities of daily living (such as cooking and shopping).

Hip fractures are associated with the greatest increase in morbidity and mortality. In 2007, hip fractures resulted in approximately 281,000 hospital admissions in those age 65 and older.32 After a hip fracture, only 50% of patients regain their ability to perform basic activities of daily living, while 20% become nonambulatory.33 Of patients age 50 and over, almost one-quarter die within 1 year either from complications of the hip fracture or other comorbid disease processes.2 Men have a twofold higher 1-year mortality rate after hip fracture than women.

Once a low-trauma fracture has occurred, the risk for subsequent fractures goes up exponentially. Peri- or post-menopausal women with a history of fracture have double the risk of a subsequent fracture compared to women without a fracture history.1 In older women with two or more vertebral fractures, the risk of a new fracture is 12-fold higher, than for subjects who did not have baseline fractures.

PATIENT ASSESSMENT

Bone pain, postural changes (i.e., kyphosis), and loss of height are simple useful physical examination findings. A height loss greater than 1.5 inches (3.8 cm) from the tallest mature height is considered significant and warrants further investigation.34,35 Height should be routinely measured using a wall-mounted stadiometer. Proper technique is essential; height is frequently measured incorrectly.36 A spine radiograph can be obtained to confirm the presence of vertebral fractures. Low bone density or osteopenia reported on routine radiographs is a sign of significant bone loss and requires further evaluation for osteoporosis. In addition to physical examination and laboratory studies (see Clinical Presentation),1,6,8,10,20,37,38 patients can be assessed with risk factor assessments, osteoporosis questionnaires, peripheral and central DXA or ultrasonography, and bone turnover biomarkers.5

Risk Factor Assessment

The aim of an initial osteoporosis risk assessment (see Table 73–1) is to identify those patients who are at highest risk for low bone density and who would benefit from further evaluation. Many risk factors for osteoporosis have been identified and are similar for both sexes. The majority of risk factors are predictors of either low BMD (e.g., female sex, ethnicity) or an increased fracture and fall risk (e.g., cognitive impairment, previous falls). The most important risk factors are those associated with fracture risk independent of BMD and fall risk. These major risk factors, in combination with BMD, are used to determine which patients are at greatest risk for fracturing and would benefit most from pharmacologic intervention.

Images A fracture prediction model used for treatment risk stratification was developed for the World Health Organization (WHO).9,39 The WHO model for the United States uses the following risk factors: age, race/ethnicity, sex, previous fragility fracture, parent history of hip fracture, body mass index, glucocorticoid use (current or past use for 3 or more months of prednisolone 5 mg daily or equivalent doses of other glucocorticoids), current smoking, alcohol use of three or more drinks per day, rheumatoid arthritis, and select secondary causes with femoral neck BMD data optional to predict an individual’s percent probability of fracturing in the next 10 years. The WHO fracture risk assessment (FRAX) tool can be used to help predict fracture risk in patients who do not have access to DXA. The FRAX model should not be used to predict fracture risk in patients already on therapy for osteoporosis although under investigation. Some risk factors for fracture are not accommodated in the FRAX model.9 For example, falls are a risk factor for fracture, but at this time researchers are unable to quantify the risk to add it to the model. Therefore, clinicians should use the FRAX model but also continue to assess all risk factors in an osteoporosis risk assessment.

Screening Using Peripheral Bone Mineral Density Devices

Peripheral bone density devices that use DXA (pDXA) or quantitative ultrasonography are helpful as screening tools to determine which patients require further evaluation with central DXA or for decision making if central DXA testing is not available.34,35 pDXA of the forearm, heel, and finger uses a low amount of radiation and requires personnel with special training. Heel quantitative ultrasonography uses sound waves without radiation or need for special training. Heel ultrasonography has better fracture predictive value than pDXA. The specific peripheral T-score threshold for referral is not universally defined and varies by device. These tests should not be used for diagnosis or for monitoring response to therapy.

Because peripheral devices are considerably less expensive than central DXA, easy to use, portable, fast (<5 minutes), and can predict general fracture risk, they are very popular for screening patients at health fairs, community pharmacies, and clinics. No guidelines specifically address screenings, but it is reasonable to limit use to postmenopausal women and men 65 years and older for whom results are predictive of future fracture risk.7,35 Healthy premenopausal women generally should not be screened. Patients already identified as being at high risk for osteoporosis based on risk factors, fragility fracture, or secondary causes for osteoporosis should not be screened but rather referred to a physician for central DXA testing.

Central Dual-Energy X-ray Absorptiometry

Images BMD measurements at the hip or spine (or radius if these bones cannot be scanned) can be used to assess fracture risk, establish the diagnosis and severity of osteoporosis, and sometimes confirm osteoporosis as causative for low-trauma fractures.1,68,35 Central DXA is considered the gold standard for measuring BMD because of its high precision, short scan times, low radiation dose (comparable to the average daily dose from natural background), and stable calibration. Measurement of lumbar spine, proximal femur, and total hip BMD is recommended with the lowest BMD value used for diagnosis. Newer methods, such as micromagnetic resonance imaging, are undergoing investigation to provide measurements of bone quality in addition to bone density.

Several consensus guidelines or position statements are consistent in recommending central BMD testing for all women aged 65 years or older, men aged 70 years or older, postmenopausal women younger than 65 years of age and men 50 to 69 years old with risk factors for fracture, and patients with an identified secondary cause for bone loss. The United States Preventive Services Task Force agrees with respect to women 65 years and older, but for women between 50 to 65 years old, the task force recommends getting a DXA only for those women with a FRAX major osteoporotic fracture score ≥9.3%.40They feel data are inadequate to make recommendations for men. Patients with a fragility fracture do not need a DXA for an osteoporosis diagnosis, but the results are helpful for determining disease severity and as a baseline for monitoring therapy effects. The DXA results can help patients make decisions about the need for lifestyle changes and prescription osteoporosis medications. In the absence of a suspected or known secondary cause for osteoporosis or a history of a low-trauma fracture, central BMD testing is not recommended for children, premenopausal women, or men younger than 50 years of age.

A central DXA BMD report provides the actual bone density value, T-score, and Z-score.34,35 The actual bone density value (g/cm2) is most useful for serial monitoring of therapy response, which is typically performed 1 to 2 years after medication initiation. The T-score is used for diagnosis and is a comparison of the patient’s measured BMD to the mean BMD of a healthy, young (20- to 29-year-old), sex-matched white reference population; no adjustments for race or ethnicity. The T-score is the number of standard deviations from the mean of the reference population. The Z-score is similar but compares the patient’s BMD to the mean BMD for a healthy sex- and age-matched population. Patient-reported race or ethnicity should be used for the Z-score if available. A Z-score value of ≤ –2.0 is sometimes helpful in determining whether a secondary cause for osteoporosis is present and is used for diagnosis in children, premenopausal women, and men younger than 50 years of age. Followup monitoring for patients identified with normal or low bone density has not been clearly defined, but one study has suggested a recall period of 15 years for those with T-scores > –1.49, 5 years for T-scores between –1.50 and –1.99, and 1 year for T-score between –2.00 and –2.49.41

Using the spine DXA image, an assessment of morphometric vertebral fractures, the vertebral fracture assessment (VFA), can be calculated.1,35 Each vertebra is assessed for compression (wedge, biconcave, and crush) and described as normal or mild (20% to 25%), moderate (25% to 40%), or severe (>40%) compression. This result becomes important for treatment decisions in patients with low bone mass. VFA is recommended in women >70 years old and in men >80 years old.6,7,35 They further recommend testing in younger postmenopausal women and men with low bone mass (T-score –1.5 or below) or specific risk factors, such as loss of height.

Laboratory Tests

Laboratory testing (see Clinical Presentation) is used to identify secondary causes of bone loss.1,6,10,20 If a preliminary investigation indicates a possible secondary cause, additional testing related to that specific secondary cause will be conducted.

Serum 25(OH) vitamin D is the best indicator of total body vitamin D status.1,42,43 The cutpoints for normal, insufficiency, and deficiency are controversial.43,44 Osteomalacia or severe vitamin D deficiency, which is discussed later in this chapter, can occur at concentrations less than 10 ng/mL (25 nmol/L).


Clinical Controversy…

The Institute of Medicine (IOM) defines 20 ng/mL (50 nmol/L; 1 ng/mL = 2.5 nmol/L) as the cutpoint for normal 25(OH) vitamin D,44,45 below which would be considered a deficiency. However, some experts and guidelines advocate for a goal 25(OH) vitamin D concentration of 30 to 60 ng/mL (75 to 150 nmol/L) or 30 to 100 ng/mL (75 to 250 nmol/L), with concentrations between 20 and 29 ng/mL (50 to 72 nmol/L) considered insufficient and those less than 20 ng/mL (50 nmol/L) considered deficiency.1,68,43 Guideline recommendations are based on data that suggest serum 25(OH) vitamin D concentrations necessary to maximize intestinal calcium absorption are ≥32 ng/mL (80 nmol/L), minimize secondary hyperparathyroidism are 28 to 45 ng/mL (70 to 112 nmol/L), and reduce fracture risk are 28 ng/mL (70 nmol/L) or greater, with some of these studies disputed or interpreted differently by others.44

Because vitamin D assays are fairly expensive and large inter-laboratory assay variability exists, routine vitamin D screening cannot be recommended at this time. However, a 25(OH) vitamin D concentration should be considered in anyone at higher risk for low vitamin D (e.g., older adults, patients who are obese or who have minimal sun exposure, insufficient vitamin D intake, dark-pigmented skin, or certain medical conditions especially liver and kidney disease, or are on medications known to affect vitamin D metabolism), and patients with low bone density, history of a low-trauma fracture or frequent falls, or history of unexplained muscle weakness and/or bone pain.42

Bone Turnover Markers

Increased concentrations of bone resorption markers (≥2 standard deviations above the premenopausal range) have been shown in some studies to predict fracture risk; however, results have been inconsistent.38 Bone turnover markers are commonly used in clinical trials and have documented responses to therapy and predictive of fracture prevention in some but not all studies.

Clinical utility is less since analytical and patient variability (within patient variability 26% to 43%) limit interpretation and accuracy. Circadian variability, seasonal variations, food intake, and recent exercise can all affect results. Although not diagnostic, these tests might be helpful in identifying accelerated bone turnover and increased fracture risk; however, most of these data are derived from osteoporosis studies in women. Bone turnover markers could be used to monitor therapy effects. Response to therapy can be measured as early as 2 to 3 months, but their utility is less for zoledronic acid and denosumab.1,6,37

Urine and serum bone turnover markers are either enzymes or proteins produced during bone formation or breakdown.1,6,37 Bone-specific alkaline phosphatase, osteocalcin, and procollagen type 1 propeptides (P1NP) are examples of bone formation markers. Hydroxypyridinium crosslinks of collagen pyridinoline and deoxypyridinoline, C-terminal crosslinking telopeptide of type 1 collagen (CTX), and N-terminal crosslinking telopeptide of type 1 collagen (NTX) are examples of bone resorption markers. CTX and P1NP, newer tests that are more accurate, are becoming the preferred tests. For serum markers, fasting morning samples should be obtained with repeat tests done at the same facility with the same assay.

DIAGNOSIS OF OSTEOPOROSIS

The diagnosis of osteoporosis is based on a low-trauma fracture or central hip and/or spine DXA using WHO T-score thresholds. Low bone mass (which is the preferred term) or osteopenia is a T-score between –1 and –2.5, and osteoporosis is a T-score at or below –2.5.1,68,34,35 Although these definitions are based on data from postmenopausal white women, they are also applied to perimenopausal women, men age 50 years and older, and adults from different races and ethnicities. The diagnosis of osteoporosis in children, premenopausal women, and men younger than 50 years of age should be based on a Z-score at or below –2.0 in combination with other risk factors or fracture.34,35 Children are not given a diagnosis of osteoporosis; “low BMD for chronological age” is the preferred term.34

PREVENTION AND TREATMENT

Osteoporosis

The foundation for osteoporosis prevention and treatment is a bone healthy lifestyle beginning at birth and continuing throughout life. Supplements and medications are used when lifestyle habits are suboptimal and/or osteoporosis has developed.


Desired Outcomes

The primary goal of osteoporosis care should be prevention. Optimizing skeletal development and peak bone mass accrual in childhood, adolescence, and early adulthood will ultimately reduce the future incidence of osteoporosis. Once low bone mass or osteoporosis develops, the objective is to stabilize or improve bone mass and strength and prevent fractures. In patients who have already suffered osteoporotic fractures, reducing pain and deformity, improving functional capacity, improving quality of life, and reducing future falls and fractures are the main goals.

General Approach to Prevention and Treatment

Images Images A bone-healthy lifestyle should begin at birth and continue throughout life. Insuring adequate intakes of calcium and vitamin D along with other bone-healthy lifestyle practices are the first steps in prevention and treatment. Recent guidelines and position statements recommend considering prescription therapy in any postmenopausal woman or man age 50 years and older presenting with one of the following scenarios: a hip or vertebral fracture; T-score of –2.5 or lower at the femoral neck, total hip or spine; or low bone mass (T-score between –1.0 and –2.5 at the femoral neck or spine) with a 10-year probability of hip fracture of 3% or more, or a 10-year probability of any major osteoporosis-related fracture of 20% or more.1,68 Figure 73–3 provides an osteoporosis management algorithm for postmenopausal women and men 50 years and older that incorporates both nonpharmacologic and pharmacologic approaches.

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FIGURE 73-3 Algorithm for the management of osteoporosis in postmenopausal women and men aged 50 and older.1,68 (BMD, bone mineral density; DXA, dual-energy x-ray absorptiometry; FRAX, WHO absolute fracture risk assessment tool; WHO, World Health Organization.)

Nonpharmacologic Therapy

Images Nonpharmacologic therapy, referred to as a bone-healthy lifestyle, includes proper nutrition, moderation of alcohol intake, smoking cessation, exercise, and fall prevention. A bone healthy lifestyle that is employed early in life will help to optimize peak bone mass and if continued throughout life, it will minimize bone loss over time. Not only does a bone healthy lifestyle target BMD, but it also contributes to decreasing the risk of falls and fragility fractures.

Diet

Overall, a diet well balanced in nutrients and minerals and limited in salt, alcohol, caffeine, and excessive protein is important for bone health.1,6,46 Certain nutrients are emerging to have direct and indirect effects on bone.26,46,47Being thin or having anorexia nervosa are well known to decrease bone mass. In the past, obesity was thought protective because of increased estrogen production and stimulating bone remodeling due to weight bearing; however, emerging literature suggests leptin and adipose have negative impacts on bone health.26,48

Calcium Images Data clearly indicate that adequate calcium intake is necessary for the development of bone mass during growth and for its maintenance throughout life.2,55 Adequate calcium intake is an essential component of all osteoporosis prevention and treatment strategies. Table 73–468,45 summarizes the recommended intakes for calcium based on age.27 This value represents the amount needed for 97.5% of the population; higher amounts might be needed when concomitant diseases and medications negatively affect calcium homeostasis. Using calcium-containing foods, which also contain other essential nutrients, is the preferred method to achieve daily calcium requirements. Milk and other dairy products have the highest amount of calcium per serving and are available in low-fat options.27 Some food sources are absorbed well but have low elemental calcium content (e.g., broccoli). Carbohydrates, fat, and lactose increase calcium absorption whereas fiber, wheat bran, phytates (e.g., beans), oxylates (e.g., spinach, rhubarb), high-protein diets, caffeine, and smoking decrease absorption. To get the same amount of calcium in one 8-ounce (~240 mL) glass of milk, one would need to eat 2.25 cups (~530 mL) of cooked broccoli or 8 cups (~1900 mL) of cooked spinach.

TABLE 73-4 Recommended Dietary Allowances and Upper Limits of Calcium and Vitamin D

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People should be encouraged to evaluate their food and beverage intake to determine if they are receiving adequate intakes. To calculate the amount of calcium in a serving of food, consumers can add a zero to the percentage of the daily value listed on food labels. For example, a serving of milk (8 oz. [~240 mL]) has 30% of the daily value of calcium. This translates to 300 mg calcium per serving.

Approximately 25% of the U.S. population has some level of lactose intolerance, with the incidence in Asian (80%) and African American (50%) populations being much higher than in whites (10%).57Lactose-intolerant patients have several options, including products containing lactase (Lactaid), lactose-reduced milk, lactose-free milk, calcium-fortified soy milk, certain aged cheeses, or yogurt with active cultures along with other nondairy calcium-fortified products (e.g., orange juice, breakfast cereals, and energy bars).

Vitamin D Images Table 73–4 lists the recommended adequate intakes for Vitamin D.45 The three main sources of vitamin D are sunlight (cholecalciferol, vitamin D3), diet, and supplements.42,43 Vitamin D3comes from oily fish, eggs, and fortified dairy products. Vitamin D2 comes from fungi and eggs. Websites can be used to identify the few foods high in vitamin D.61 To calculate the amount of vitamin D in a serving of food, multiply the percent daily value of vitamin D listed on the food label by 4 (e.g., 20% vitamin D = 80 units).

Inadequate concentrations of vitamin D are common in all age groups, especially in older adults and individuals who are malnourished or obese, live in an institution (e.g., nursing home), or live in more northern latitudes. Low vitamin D concentrations result from insufficient intake, dietary fat malabsorption, decreased sun exposure, decreased skin production, or decreased liver and renal metabolism. Endogenous synthesis of vitamin D can be decreased by factors that affect exposure to or decrease skin penetration of ultraviolet B light. Sunscreen use, full body coverage with clothing (e.g., women wearing veiled, full-length dresses), and darkly pigmented skin can all cause a decrease in vitamin D production. Seasonal variations in vitamin D concentrations are also seen with nadirs in late winter and peaks in late summer. Because few foods are naturally high or fortified with vitamin D, most people, especially older adults, require supplementation.

Other Nutrients and Minerals Vitamin K is a cofactor for carboxylation (activation) of proteins, such as osteocalcin, which are involved in bone formation.1,13 Vitamin K deficiency can contribute to bone loss and increase fracture risk. Although some vitamin K supplement studies in osteoporosis reported reduced bone loss and fracture risk, data are conflicting and insufficient to recommend routine supplementation. Patients on warfarin should either use calcium products without vitamin K or use supplements with vitamin K consistently after discussion with their healthcare provider. Insufficient to no data exist for routinely using or supplementing other nutrients and minerals such as potassium, boron, magnesium, and vitamins B, C, and E.1,13 Nutrition research continues to identify more foods that improve bone health, potentially by inhibiting oxidative stress’s negative impacts on bone remodeling, increasing BMP and Wnt signaling to increase bone formation, and altering the conversion of mesenchymal cells via PPAR-γ from adipocytes to osteoblasts.26

Isoflavones Isoflavone phytoestrogens are plant-derived compounds that possess weak estrogenic agonist and antagonist effects throughout the body.49 The most common source for isoflavones is dietary soy products. Genistein is the most abundant and biologically active isoflavone in soybeans. Isoflavones are also available as a supplement or part of a calcium combination product. The evidence supporting a positive bone benefit from isoflavone (soy protein or supplements) intake is conflicting1,49; however, meta-analyses of randomized placebo-controlled studies have found foods and supplements with at least 75 mg isoflavones increased spine, but not hip, BMD when compared with placebo.50 Isoflavones from soy foods appear safe, but more information is needed, especially in women with breast cancer and regarding use from supplements.

Alcohol Images Excessive, but not moderate, alcohol consumption is associated with an increased risk for osteoporosis or fractures.1,26 Alcohol increases bone resorption by increasing RANKL and decreases bone formation by inhibiting Wnt signaling pathway and increasing oxidative stress that results in osteoblast apoptosis. Patients with alcohol problems might also have poor nutrition and have balance impairments resulting in more falls and fractures. Alcohol consumption should not exceed one drink per day for women1 and two drinks per day for men.6

Caffeine Images Although results are conflicting, excessive caffeine consumption is associated with increased calcium excretion, increased rates of bone loss, and a modestly increased risk for fracture.46 Ideally, caffeine consumption should be limited to two servings or less per day. For those with greater intakes, the increased calcium excretion might be compensated by an additional 40 mg calcium intake for each cup of caffeine-containing beverage.

Smoking

Images Counseling patients of all ages on smoking cessation can help to optimize peak bone mass, minimize bone loss, and ultimately reduce fracture risk.51 Cigarette smoking is an independent risk factor for osteoporosis and is associated with up to an 80% increased relative risk for hip fracture.2 The effect is dose and duration dependent. The negative bone effects resulting from poor nutrition and/or lower 25(OH) vitamin D concentrations are associated with reduced intestinal calcium absorption, an increase in bone resorption from a decrease in production and increase in metabolism of estradiol, increase in RANKL and decrease in OPG, decrease in osteoblasts and bone formation secondary to increase in cortisol and dehydroepiandrosterone sulfate (DHEA-S), and impairment of osteoid production and mineralization. The detrimental effects of smoking on neuromuscular function and balance may contribute to an increased risk of falls.

Exercise

Images Physical activity or exercise is an important nonpharmacologic approach to preventing osteoporotic fractures. Exercise can decrease the risk of falls and fractures by stabilizing bone density and improving muscle strength, coordination, balance, and mobility.2 Physical activity is especially important early in life as lack of exercise during growth can lead to suboptimal loading/straining, decreased stimulation of bone deposition, and a subsequently reduced peak bone mass. All patients who are medically fit should be encouraged to perform a moderate-intensity weight-bearing activity (e.g., walking, jogging, golf, stair climbing) daily and a resistance activity (e.g., weight machines, free weights, or elastic bands) at all ages.7 For men, guidelines specifically suggest those at risk of osteoporosis participate in weight-bearing activities three to four times weekly for 30 to 40 minutes per session.6

Fall Prevention

Images Risk of falling increases with advanced age predominantly as a result of balance, gait, and mobility problems, poor vision, reduced muscle strength, impaired cognition, multiple medical conditions (e.g., arrhythmias, postural hypotension, Alzheimer’s dementia, Parkinson disease), and polypharmacy.52 Psychoactive medications such as benzodiazepines, antidepressants, antipsychotics, sedative–hypnotics, and opioids have been strongly associated with falls.

The ability to adapt to falls also decreases with aging. Older adults are more likely to sustain a hip or pelvic fracture because they tend to fall backward or sideways instead of forward.33

Because of the link between falls and fractures, all older adults should be asked whether they have experienced a fall within the last year and about difficulties with walking or balance. Older adults who experience an acute fall requiring medical treatment or those who report or are observed with difficulty with balance or walking should have a multifactorial fall risks assessment and potentially an intervention program.46,52 Multi- versus single-intervention programs have greater effects on decreasing falls, fractures, other injuries, and nursing home and hospital admissions.

Patients should be educated on personal and home safety options to decrease falls.7,52 Websites provide great patient education materials with solutions for commonly observed safety problems.32,53,54Medication profiles should also be reviewed for any unnecessary medications that can affect cognition and balance and potentially increase fall risk. Consideration should be given to replacing high-risk medications with safer alternatives. Vitamin D supplementation has been associated with reduced falls.42,43,52 Maintenance of a regular individualized exercise program, such as tai chi, should be recommended to improve body strength, balance, and agility.

Other recommendations include resolving vision, low blood pressure, heart rate and rhythm, and foot problems and using proper footwear.

External hip protectors are specialized undergarments designed to pad the area surrounding the hip, decreasing the force of impact from a sideways fall. Conflicting results and poor adherence limit their use.1,46

Pharmacologic Therapy

Because nonpharmacologic interventions alone are frequently insufficient to prevent or treat osteoporosis, medication therapy is often necessary. Table 73–51,8,5558 describes fracture and BMD effects, Table 73–6 describes dosing of osteoporosis medications and Table 73–7 outlines adverse effects and monitoring. These medications should always be combined with a bone-healthy lifestyle.

TABLE 73-5 Fracture and Bone Mineral Density Effects of Osteoporosis Medications from Pivotal Fracture Trialsa in Postmenopausal Women

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TABLE 73-6 Dosing of Medications Used in Prevention and Treatment of Osteoporosis

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TABLE 73-7 Monitoring of Medications Used in Prevention and Treatment of Osteoporosis

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Medication

Drug Treatments of First Choice

Images Combined with adequate calcium and vitamin D intakes, alendronate, risedronate, zoledronic acid or denosumab are the prescription medication of choice based on evidence of reduced risk of hip and vertebral fractures.1,7,58,59Ibandronate, teriparatide, or raloxifene are alternatives, and calcitonin is last-line therapy. Duration of bisphosphonate therapy has not been defined, but safety data exist for periods of 10 to 13 years (see below Clinical Controversy). Short-term (18 to 24 months) teriparatide is usually reserved for severe osteoporosis and then followed by bisphosphonate therapy. The algorithm (see Fig. 73–3) helps determine for whom medication therapy should be used. Osteoporosis prescription medications in children, pre- and perimenopausal women, and men younger than 50 years old are controversial and undergoing further investigation.

Published Guidelines and Treatment Protocols

The 2013 National Osteoporosis Foundation’s clinician’s guide,7 the 2010 North American Menopause Society’s position statement,1 the American Association of Clinical Endocrinologists’ guidelines for women8 and men,6 and the Agency for Healthcare Research and Quality58 provide guidance on osteoporosis prevention and treatment strategies. Applying the National Osteoporosis Foundation’s guidelines to a large clinical database, researchers found that approximately 72% of women ≥65 years old and 93% of women ≥75 years old would be eligible for treatment.60 Even with guidelines and algorithms, many patients are not being evaluated or receiving appropriate osteoporosis therapy, even after a hip fracture.61

Drug Class Information

Antiresorptive Therapies

Antiresorptive therapies include calcium, vitamin D, bisphosphonates, estrogen agonists antagonists (known previously as selective estrogen receptor modulators or SERMs), calcitonin, denosumab, estrogen, and testosterone.

Calcium Supplementation Images Calcium imbalance can result from inadequate dietary intake, decreased fractional calcium absorption, or enhanced calcium excretion. Adequate calcium intake (see Table 73–4) is considered a foundation for osteoporosis prevention and treatment and should be combined with vitamin D and osteoporosis medications when needed.45,58 Supplemental calcium intake will be needed in the majority of adults with or at risk for osteoporosis because the average U.S. adult diet contains only 590 to 730 mg calcium per day.1,62 The amount of the supplement needed is the difference between an individual’s dietary consumption and the recommended dietary allowance.

Efficacy Calcium increases BMD, but its BMD effects are less than other antiresorptive and formation osteoporosis medications.27,58,63 Almost all trials and observational studies showed the children and adults with the higher calcium intakes had greater increases or maintenance of BMD compared to BMD losses with placebo. Calcium’s independent role in fracture prevention is less clear. Fracture prevention is only documented with concomitant vitamin D therapy, and some studies were also confounded by poor patient adherence. While there may be insufficient evidence to assess the effect of calcium alone on fractures, it is important to note that clinical trials for the antiosteoporosis medications included adequate calcium intake through supplementation as a part of the study design.

Adverse Events Calcium’s most common adverse reaction, constipation, can first be treated with increased water intake, dietary fiber, and exercise. If still unresolved, smaller and more frequent administration or a lower total daily dose can be tried. Calcium carbonate can create gas and cause stomach upset, which might resolve with calcium citrate, a product with fewer GI side effects.

The upper tolerable limit for calcium ranges from 2,000 to 3,000 mg/day depending on age.45 Calcium supplementation rarely causes kidney stones.27 Some patients with a history of kidney stones can still ingest adequate amounts of calcium depending on the type of stones and/or will require increased fluid intake and decreased salt intake with their calcium supplementation.64 Observational data also suggest that calcium supplementation may be linked to a small increased risk of myocardial infarction in women.6567 After this chapter was prepared, a similar study demonstrated a similar effect in men and another study provided additional data for women (see Addendum at the end of the text). Because calcium supplements are not without adverse effects and risks, clinicians should encourage dietary calcium and ensure that patients are not getting more than they need.

Drug Interactions Because calcium carbonate requires acid for absorption, drugs such as the proton pump inhibitors may decrease absorption from the carbonate product. Fiber laxatives may decrease the absorption of calcium if given concomitantly. Further, calcium may decrease the oral absorption of some drugs including iron, tetracyclines, quinolones, bisphosphonates, and thyroid supplements.

Administration Most children and adults of all race and ethnic backgrounds do not ingest sufficient dietary calcium and therefore require supplements. To ensure adequate calcium absorption, 25(OH) vitamin D concentrations should be maintained in the normal range (30 to 60 ng/mL [75 to 150 nmol/L]).1,6 Because fractional calcium absorption is dose limited, maximum single doses of 500 to 600 mg or less of elemental calcium are recommended. Because peaks in serum calcium levels after supplementation are hypothesized as a reason for negative cardiovascular effects, limiting doses to 250 mg given more frequently has been proposed.68 Calcium carbonate is the salt of choice as it contains the highest amount of elemental calcium (40%) and is the least expensive. Calcium carbonate should be taken with meals to enhance absorption in an acidic environment. Calcium citrate absorption (21% calcium) is acid-independent and need not be administered with meals. Although tricalcium phosphate contains 38% calcium, calcium-phosphate complexes could limit overall calcium absorption. This product might be helpful in patients with hypophosphatemia that cannot be resolved with increased dietary intake. Disintegration and dissolution rates vary significantly between products and lots. Products labeled “USP Verified” for “United States Pharmacopeia,” which guarantees the identity, strength, purity, and quality of the product, or products from a reputable company should be recommended when possible. Products from unrefined oyster shell or coral calcium should not be recommended because of concerns for high concentrations of lead and other heavy metals. Some calcium products come in alternative dosage forms (e.g., chews, dissolvable tablet, liquid), which can be beneficial for select patients (e.g., swallowing problems). For all products, encourage patients to read the labeling carefully as multiple tablets per day may be needed to obtain adequate calcium intake, especially with noncarbonate salts.

Some commercial calcium supplements contain other nutrients associated with bone physiology such as magnesium, vitamin K and “natural estrogens” or isoflavones. Minimal BMD and no fracture data exist for these combination products.1,8 These products are also more expensive. Combining too many vitamins and supplements might lead to upper-tolerable nutrient limits being exceeded and a concern for toxicities. Further studies are needed before these combination products can be recommended for osteoporosis.

Vitamin D Supplementation Images Vitamin D intake is critical for the prevention and treatment of osteoporosis because it maximizes intestinal calcium absorption. Given its safety, low cost, and other benefits of vitamin D, no patient should have an inadequate intake (see Table 73–4).43,45

Efficacy Data show that higher dose vitamin D supplementation (≥700 units) is needed for fracture and fall prevention. In one meta-analysis, higher doses of vitamin D (>400 units daily) decreased nonvertebral and hip fractures by approximately 20%.58,69 A more recent meta-analysis found a fracture benefit only in those patients adherent to at least 800 units daily.70 Megadose studies (>300,000 units/year) demonstrated an increased fracture rate, and these doses should be avoided.42 Most studies and a meta-analysis support vitamin D decreasing falls.42,43,52

Drug Interactions Some drugs may induce vitamin D metabolism, including rifampin and some anticonvulsants such as phenytoin, barbiturates, valproic acid, and carbamazepine. Vitamin D absorption may be decreased by cholestyramine, colestipol, orlistat, and mineral oil. Vitamin D may enhance the absorption of aluminum; aluminum-containing products should be avoided to prevent aluminum toxicity.

Administration Vitamin D can be taken as a single agent or combination product (see Table 73–4 for daily requirements and guideline recommendations).68,43,45 Several experts believe higher doses (i.e., up to 2,000 units of vitamin D daily) should be recommended to achieve concentrations of at least 30 ng/mL, especially in certain populations.42,43 This dose is within the safe upper limit of vitamin D (4,000 units per day).45 The American Association of Clinical Endocrinologists (AACE) guidelines do not recommend a dose, but state supplements should be used to ensure a 25(OH) vitamin D concentration of ≥30 ng/mL.

Although some data support slight differences between vitamin D3 and D2 absorption (D3/D2 absorption ratio 1.14 (confidence interval [CI] 1.0 to 1.29)),71 guidelines suggest either agent for prevention and treatment of vitamin D deficiency.43 Based on a meta-analysis, vitamin D3 was more efficient than vitamin D2 at raising 25(OH) vitamin D concentrations, and produced greater BMD changes with bolus dosing but not with lower maintenance doses.72The differences could be related to greater metabolism of vitamin D2 to inactive metabolites. Usual supplementation is with daily nonprescription cholecalciferol products. The relationship between vitamin D3 dose and the increase in 25(OH) vitamin D concentration varies from 40 units to increase the concentration by 0.8 ng/mL73 to 100 units1 to increase the concentration by 0.6 ng/mL71 to 1 ng/mL,43 with higher vitamin D doses needed to raise concentrations in obese patients.73 Higher-dose prescription ergocalciferol regimens administered weekly, monthly, or quarterly can be used for replacement and maintenance therapy. More than one multivitamin or large doses of cod liver oil daily are no longer advocated because of the risk of hypervitaminosis A,13 which can increase bone loss. Because the half-life of vitamin D is about 1 month, approximately 3 months of therapy are required before a new steady state is achieved, and a repeat 25(OH) vitamin D concentration can be obtained.

Individuals with deficient concentrations of vitamin D are at risk for osteomalacia. Their management is discussed in Other Metabolic Bone Diseases later in the chapter. In patients who are pregnant or obese, have a concomitant disorder (e.g., celiac disease, cystic fibrosis, or Crohn’s disease), or take a concomitant medication (e.g., anticonvulsants, glucocorticoids, antifungals, AIDS medications) affecting vitamin D absorption, higher doses and more frequent monitoring are required.43 In patients with severe hepatic or renal disease, the activated form of vitamin D (calcitriol) might be needed; however, newer research suggests adequate amounts of 25(OH) vitamin D are also important for total body health creating a need for both cholecalciferol and calcitriol coadministration.74

Bisphosphonates Images Alendronate, risedronate, and IV zoledronic acid are FDA indicated for postmenopausal, male, and glucocorticoid-induced osteoporosis. IV and oral ibandronate and some specialized oral formulations of other bisphosphonates are indicated only for postmenopausal osteoporosis.

Pharmacology Bisphosphonates mimic pyrophosphate, an endogenous bone resorption inhibitor. Bisphosphonate antiresorptive activity results from blocking prenylation and inhibiting guanosine triphosphatase-signaling proteins, which lead to decreased osteoclast maturation, number, recruitment, bone adhesion, and life span. Their various R2 side chains produce different bone binding, persistence, and affinities; however, the resulting clinical significances are not known.

Pharmacokinetics Oral bisphosphonates’ bioavailability is <1%; and is further decreased by concomitant food and beverages.75,76 All bisphosphonates become incorporated into bone, giving them long biologic half-lives of up to 10 years. Absorbed bisphosphonates are renally eliminated and elimination decreases linearly with decreasing renal function.

Within 24 hours of an IV administration, approximately 40% of alendronate and zoledronic acid is excreted, whereas approximately 50% to 65% of risedronate and ibandronate is excreted, which coincides with alendronate and zoledronic acid having greater bone absorption, longer bone retention times (less desorption), and more reattachment after bone release.

Efficacy Of the antiresorptive agents, bisphosphonates consistently provide some of the higher fracture risk reductions and BMD increases (see Table 73–5).1,6,7,58,77,78 Fracture clinical trial data only exist for daily oral bisphosphonate and annual IV therapy, not weekly, monthly, or quarterly regimens. Fracture reductions are demonstrated as early as 6 months, with the greatest fracture reduction seen in patients with lower initial BMD and in those with the greatest BMD changes with therapy. Hip fracture reduction was not seen with daily oral ibandronate. The hip fracture incidence in the placebo group was low, suggesting the study might have been underpowered; the lack of hip fracture reduction data with ibandronate is reflected in evidence-based therapy recommendations (see Fig. 73–3). Although comparative fracture prevention trials do not exist, no differences between oral bisphosphonates and fractures were found based on claims data.79 Annual IV zoledronic acid has documented both secondary fracture prevention and a decrease in mortality in the treated group.56 Zoledronic acid has also been documented to decrease bone loss and fractures for patients receiving certain chemotherapy.1,14 Combination therapy is not recommended.80

BMD increases with bisphosphonates are dose dependent and greatest in the first 6 to 12 months of therapy. Small increases continue over time at the lumbar spine, but plateau after 2 to 5 years at the hip. Weekly alendronate, weekly and monthly risedronate, and monthly oral and quarterly IV ibandronate therapy produce equivalent BMD changes to their respective daily regimens. Weekly alendronate therapy increases BMD more than weekly risedronate therapy;81 however, no evidence indicates that this difference would equate to greater fracture efficacy. Weekly alendronate and monthly ibandronate produced similar BMD effects.82 After discontinuation, the increased BMD is sustained for a prolonged period of time that varies depending on the bisphosphonate used.1

The BMD increases with alendronate, risedronate, zoledronic acid, and oral ibandronate in men are similar to those in postmenopausal women.6,83 Because of a lack of fracture data from pivotal trials in men, bisphosphonates are only FDA indicated to increase BMD, not to reduce fracture risk in men. Pooled analysis of risedronate studies and one open-label risedronate study document fracture prevention in men, and alendronate has been shown to decrease radiographic but not clinical vertebral fractures in men.6,29

Adverse Events If oral bisphosphonates are prescribed correctly and the patient takes them correctly, they are well-tolerated (see Table 73–7).84 Patients who have serious GI conditions (abnormalities of the esophagus that delay emptying, such as stricture), or who are pregnant should not take bisphosphonates. Although oral bisphosphonates are to be avoided in patients with creatinine clearances less than 30 to 35 mL/min (0.50 to 0.58 mL/s), some experts suggest (not zoledronic acid) can be used in select patients with decreased renal function (see Clinical Controversy and Chap. 29, Chronic Kidney Disease).

Weekly and monthly therapies have similar common but less serious GI effects (perforation, ulceration, GI bleeding) than daily therapy.8,84 The GI event rates were not increased with concomitant nonsteroidal antiinflammatory medication use. If GI adverse events occur, switching to a different bisphosphonate might resolve the problem. Patients should be encouraged to discuss GI complaints with a healthcare provider. IV ibandronate and zoledronic acid can be used for patients with GI contraindications or intolerances to oral bisphosphonates. Other common bisphosphonate adverse effects include injection reactions and musculoskeletal pain. If severe musculoskeletal pain occurs, the medication can be discontinued temporarily or permanently. Acute phase reactions (e.g., fever, flulike symptoms, myalgias, arthralgias) are typically associated with IV administration, but rarely have been reported with weekly or monthly oral bisphosphonates. This reaction usually diminishes with subsequent administration.

Rare adverse effects include osteonecrosis of the jaw and subtrochanteric femoral (atypical) fractures.84 Osteonecrosis of the jaw (ONJ) occurs more commonly in patients with cancer, chemotherapy, radiation, and/or glucocorticoid therapy receiving higher-dose IV bisphosphonate therapy. In osteoporosis treatment, about 1 in 100,000 patients might develop ONJ. When possible, major dental work should be completed before bisphosphonate initiation. For patients already on therapy, some practitioners withhold bisphosphonate therapy during and after major dental procedures, but no data exist to support any beneficial effect of such practice. To date, no causal relationship has been identified between atypical femoral shaft fractures and bisphosphonates. Since some patients with atypical fracture experience prodromal thigh or hip pain, any such pain should be evaluated. For patients with rare and unusual bone fractures while on long-term bisphosphonates, a metabolic bone disease workup should be conducted.

Drug Interactions Because of poor bioavailability, oral bisphosphonates should not be administered at the same time as other medications. The administration instructions described below should be followed.

Dosing and Administration Before bisphosphonates are used, especially before IV administration, the patient’s serum calcium concentrations must be normal (see Table 73–6). A dental examination with major dental work completed before initiation is also suggested.6 Because bioavailability is very poor for bisphosphonates and to minimize GI side effects, each oral tablet should be taken with at least 6 ounces of plain water (not coffee, juice, mineral water, or milk) at least 30 (60 for ibandronate) minutes before consuming any food, supplements (including calcium and vitamin D), or medications. For patients with swallowing difficulties (e.g., after stroke, tube feeding), a buffered, strawberry-flavored effervescent tablet marketed as Binosto, which is dissolved in 4 ounces of room-temperature water, could be used. This formulation has the same food restrictions as traditional oral tablets. Of note, delayed-release risedronate is administered immediately following breakfast with at least 4 ounces of plain water. The patient should also remain upright (i.e., either sitting or standing) for at least 30 minutes after alendronate and risedronate and 1 hour after ibandronate administration. A patient who misses a weekly dose can take it the next day. If more than 1 day has lapsed, that dose is skipped until the next scheduled ingestion. If a patient misses a monthly dose, it can be taken up to 7 days before the next administration.

The IV products need to be administered by a healthcare provider. The quarterly ibandronate injection comes as a prefilled syringe (3 mg/mL) kit with a butterfly needle. The injection is given IV over 15 to 30 seconds. The injection can also be diluted with dextrose 5% in water or normal saline and used with a syringe pump. Once-yearly or every 2-year administration of zoledronic acid should be infused over at least 15 minutes with a pump. Acetaminophen or ibuprofen can be given to decrease acute phase reactions.

Images Although these medications are effective, adherence to daily therapy is poor and results in decreased effectiveness.85 Once-monthly therapy does not always improve adherence. While dosing frequency is a common barrier to adherence, adverse effects (e.g., GI complaints) and concerns about adverse effects remain important predictors of adherence and persistence. Even after a hip fracture, bisphosphonate persistence is suboptimal.58,85 To help overcome the barriers associated with dosing frequency, IV ibandronate and zoledronic acid could be used as replacements if cost is not an issue. Weekly alendronate plus vitamin D can potentially help to ensure better adherence with vitamin D intake, but at an increased cost over generic alendronate.


Clinical Controversy…

The ideal duration of bisphosphonate therapy is not yet known. Because bisphosphonates are deposited into the bone and continue to suppress bone turnover after discontinuation, some clinicians recommend a “drug holiday.”8,59,86

Data from studies with a drug holiday after therapy with risedronate for 3 years or alendronate for 5 years show a continued fracture benefit after therapy is discontinued. However, continued treatment with alendronate reduced the risk of new vertebral fracture compared with a drug holiday, and the risk of nonvertebral fracture was reduced in patients with T-scores of –2.5 or below.59 Based on pharmacology and study results, drug holidays after 5 years of alendronate with reinitiation of therapy in 1 to 2 years, after 5 years of risedronate with reinitiation in 1 year, and after 3 years for zoledronic acid with reinitiation in 2 to 3 years have been proposed.86

Another recommendation is based on fracture risk: mild, no need for reinitiation; moderate, reinitiate in 2 to 3 years (depending on bisphosphonate); severe, reinitiate in 1 to 2 years with the same or different medication.59

Questions remain regarding which patients a drug holiday might be appropriate, the optimal duration of therapy before a drug holiday, and the length of the drug holiday.

Denosumab Images Denosumab is FDA approved for treatment of osteoporosis in women and men at high risk for fracture. It is also approved to increase bone mass in men receiving androgen-deprivation therapy for nonmetastatic prostate cancer and in women receiving adjuvant aromatase inhibitor therapy for breast cancer who are at high risk for fracture.

Pharmacology Denosumab is a fully human monoclonal antibody that binds to RANKL, blocking its ability to bind to its RANK receptor on the surface of osteoclast precursor cells and mature osteoclasts. Denosumab inhibits osteoclastogenesis and increases osteoclast apoptosis.

Pharmacokinetics Following subcutaneous injection, the concentration of denosumab peaks in approximately 10 days and slowly declines over a period of 4 to 5 months.87 The half-life is approximately 25 days. The drug does not accumulate with repeated dosing at 6-month intervals. No dosage adjustment is necessary in renal impairment; however, hypocalcemia is more common in severe renal impairment. There are currently no studies in hepatic impairment.

Efficacy Over 3 years, denosumab significantly decreased vertebral fractures, nonvertebral fractures, and hip fractures in postmenopausal women with low bone density (see Table 73–5).1,8,58,87 The BMD effects are at least similar to weekly alendronate and can increase BMD in patients with prior alendronate therapy. In men receiving androgen-deprivation therapy, denosumab improved BMD and decreased new vertebral fractures without significant changes in nonvertebral or clinical vertebral fractures. While significant increases in BMD have been demonstrated over 2 years in women with nonmetastatic breast cancer on adjuvant aromatase inhibitor therapy, no fracture data are available.88 Activity appears to dissipate upon medication discontinuation.87

Adverse Events In trials lasting up to 8 years, denosumab was generally well tolerated.87 Dermatologic reactions not specific to the injection site such as dermatitis, eczema, and rashes were more common than with placebo (see Table 73–7).

Rare, serious adverse effects have included bone turnover suppression and serious infections including skin infections. If any signs of skin infection such as cellulitis appear, patients should be advised to seek medical attention. Because osteonecrosis of the jaw has been reported, major dental work should be completed before use when possible. As with the bisphosphonates, atypical fractures have been reported with this antiresorptive and prodromal pain should be evaluated. Hypocalcemia may occur; adequate calcium and vitamin D supplementation should be ensured and any existing hypocalcemia corrected before therapy initiation. Severe hypocalcemia is more common in patients with underlying kidney dysfunction.

Drug Interactions No drug–drug interactions have been identified with denosumab.

Dosing and Administration Denosumab is administered subcutaneously by a healthcare professional in the upper arm, upper thigh, or abdomen (see Table 73–6). The product is available as a refrigerated prefilled pen or single-use vial that can be stored at room temperature for up to 14 days before administration.

Mixed Estrogen Agonists Antagonists Images Raloxifene is a second-generation mixed EAA approved for prevention and treatment of postmenopausal osteoporosis and for reducing the risk of invasive breast cancer in postmenopausal women with and without osteoporosis. At the time this chapter was prepared, bazedoxifene was a third-generation EAA under FDA review for prevention of postmenopausal osteoporosis and menopausal symptoms.

Pharmacology EAAs have estrogenic agonist actions in bone and antagonist actions in breast and uterine tissue.89,90 Bazedoxifene has been combined with conjugated equine estrogens to create a new medication class called the tissue selective estrogen complexes; if approved by FDA, these agents will maximize effects on bone, minimize adverse effects, and eliminate the need for progestogens.55

Pharmacokinetics Food has a nonsignificant effect on absorption, which is approximately 2% for raloxifene91 and 6% for bazedoxifene.89 Raloxifene is 95% protein bound. Half-life of raloxifene is 28 hours and of bazedoxifene is 30 hours. EAAs are predominantly eliminated via glucuronidation.

Efficacy Raloxifene and bazedoxifene decrease vertebral but not nonvertebral fractures and increase spine and hip BMD, but to a lesser extent than bisphosphonates (see Table 73–5).1,8,58,89 Raloxifene’s vertebral fracture prevention is greater in women without previous fracture. Bazedoxifene’s BMD increases are greater, but fracture prevention is similar to raloxifene.56,89,90 Bazedoxifene with conjugated estrogens produced significantly greater increases in spine and hip BMD than raloxifene and placebo;55 however, fracture data are not yet available. Raloxifene 7- and 8-year data8 and bazedoxifene 5-year data57 support long-term effects and safety in postmenopausal women. After raloxifene discontinuation, the medication effect is lost, with bone loss returning to age- or disease-related rates. Raloxifene’s breast cancer prevention benefits might influence its selection for a subset of women at risk for or with osteoporosis and breast cancer.

Raloxifene and bazedoxifene cause some positive lipid effects (decreased total and low-density lipoprotein cholesterol, neutral to increased high-density lipoprotein cholesterol); however, triglycerides can increase slightly.55 No benefit on cardiovascular disease was demonstrated in the RUTH (Raloxifene Use for the Heart) or MORE-CORE (Multiple Outcomes with Raloxifene study and its continuation) trials; however, when these trials are combined, the raloxifene group had a 10% lower mortality rate due to changes in noncardiovascular and noncancer deaths.92

Adverse Events Tolerability is similar with both EAAs (see Table 73–7).89 Hot flushes are common (<28%).90 EAAs rarely cause endometrial bleeding; rare but minor vaginal thickenings were seen more frequently with raloxifene than with bazedoxifene.89 Leg cramps and muscle spasms are common (<17%).90 Thromboembolic events are uncommon (<1%) but can be fatal. In large trials, no change in overall death, cardiovascular death, or overall stroke incidence was seen; however, a slight increase in fatal stroke (0.7/1,000 women year difference) was documented, resulting in a medication warning for raloxifene.1,90 Further analysis documented this event in only those with a Framingham stroke risk score ≥13.1

Drug Interactions Because of raloxifene’s highly protein-bound nature (95%), it can interact with other highly protein-bound medications such as warfarin. Monitoring of both medications is suggested.91Cholestyramine can decrease raloxifene absorption. No interactions to date with bazedoxifene.

Dosing and Administration Images Although once-daily administration is easy (see Table 73–6), adherence and persistence problems exist. Minimal data suggest that dosage adjustments in renal failure are not needed. For severe liver failure, these medications should be used with caution or avoided. EAAs are contraindicated for women with an active or past history of venous thromboembolic disease. Therapy should be stopped if a patient anticipates extended immobility. Women at high risk for a stroke (e.g., Framingham stroke risk score ≥13)1 or coronary events and those with known coronary artery disease, peripheral vascular disease, atrial fibrillation, or a prior history of cerebrovascular events might not be good candidates for this medication.

Calcitonin Images Calcitonin is FDA approved for osteoporosis treatment for women who are at least 5 years past menopause. Because efficacy is less robust than the other antiresorptive therapies, calcitonin is reserved as last-line treatment.

Pharmacology Calcitonin is an endogenous hormone released from the thyroid gland when serum calcium is elevated. The prescription product contains salmon calcitonin, which is more potent and longer lasting than the mammalian form.

Pharmacokinetics Availability is 3% to 5% with nasal administration.93 Half-life is 18 minutes. Intermittent nasal regimens and an oral product are being explored.

Efficacy Only vertebral fractures have been documented to decrease with intranasal calcitonin therapy (see Table 73–5).1,8,58 Calcitonin does not consistently affect hip BMD and does not decrease hip fracture risk. Data for use in men have not been published.

Calcitonin might provide some pain relief to some patients with acute vertebral fractures.1

Adverse Events Adverse events are listed in Table 73–7.

Drug Interactions Lithium doses might need reduction.93

Dosing and Administration Images Some patients do not like to administer medications in their nose (see Table 73–6). In clinical trials, a high drop-out rate exists with calcitonin. Subcutaneous administration with 100 units daily is available but rarely used because of more adverse effects and costs.1 If the nasal product is used for vertebral fracture pain, calcitonin should be prescribed for short-term (4 weeks) treatment and should not be used in place of other more effective and less expensive analgesics nor should it preclude the use of more appropriate osteoporosis therapy.

Estrogen Therapy Estrogens are FDA indicated for prevention of osteoporosis for women at significant risk and for whom other osteoporosis medications cannot be used.1,8

Pharmacology Exogenous estrogens provide similar effects as endogenous estrogens. Even though the Women’s Health Initiative trials only assessed one dose of conjugated equine estrogens, most clinicians extrapolate the results to all postmenopausal estrogen therapies until data indicate otherwise.

Efficacy Hormone therapy (HT)—estrogen with or without a progestogen—significantly decreases fracture risk (see Table 73–5).1,8,58 Increases in BMD are less than those with bisphosphonates, denosumab, or teriparatide, but greater than those with raloxifene and calcitonin. Oral and transdermal estrogens at equivalent doses and continuous or cyclic HT regimens have similar BMD effects. Effect on BMD is dose dependent, with some benefit seen with lower estrogen doses; however, fracture risk reduction has not been demonstrated with the lower doses. When HT is discontinued, bone loss accelerates and fracture protection is lost.

Adverse Events and Drug Interactions A complete discussion of adverse events for all estrogen products can be found in Chapter 65, Hormone Therapy in Women.

Dosing and Administration The lowest effective HT dose that prevents and controls menopausal symptoms is used and discontinued as soon as possible. A complete discussion of administration and precautions for all estrogen products can be found in Chapter 65, Hormone Therapy in Women.

Testosterone Decreased testosterone concentrations are seen with certain gonadal diseases, eating disorders, glucocorticoid therapy, oophorectomy, menopause, and andropause. Although it is not FDA indicated for osteoporosis, the male osteoporosis guideline recommends testosterone alone for men with testosterone concentrations <200 ng/dL (6.9 nmol/L) if low fracture risk and in combination with an osteoporosis medication if fracture risk is high.6 For men on testosterone maintenance therapy, an antiosteoporosis medication can be added when risk for osteoporotic fracture is or becomes high. Women with low libido might also be prescribed methyltestosterone.94 This medication is not solely prescribed for osteoporosis.

Pharmacology Testosterone is converted to estradiol, which decreases bone resorption in men and women.

Efficacy Testosterone has increased BMD in men with low testosterone concentrations, but has no effect if testosterone concentrations are normal.6 No fracture data are available. Adding alendronate to testosterone therapy in hypogonadal men improved BMD benefits. A few small studies of methyltestosterone in women demonstrated small increases in BMD, but again there are no fracture data.94

Adverse Events and Drug Interactions Further discussion of adverse events for testosterone products for men can be found in Chapter 66, Erectile Dysfunction.

Dosing and Administration Testosterone from gels can be transferred to other people from skin and clothing contacts. Patients need to be educated to decrease exposure to partners and children, especially monitoring for virilization adverse effects in children.

Anabolic Therapies

Teriparatide Images Teriparatide is FDA indicated for treatment of postmenopausal women who are at high risk for fracture, for increase of BMD in men with idiopathic or hypogonadal osteoporosis who are at high risk for fracture, for men or women intolerant to other osteoporosis medications, and for patients with glucocorticoid-induced osteoporosis. Patients who have a history of osteoporotic fracture, multiple risk factors for fracture, very low bone density (e.g., T-score < –3.5), or who have failed previous bisphosphonate therapy could be candidates for PTH therapy.

Pharmacology Teriparatide is a recombinant product representing the first 34 amino acids in human PTH. Teriparatide increases bone formation, the bone remodeling rate, and osteoblast number and activity. Its actions result from activation of Wnt signaling, induction of runt-related transcription factor (runX2), increased IGF-1 production, and inhibition of osteoblast apoptosis and sclerostin.24 Both bone mass and architecture are improved. Different PTH analogs (e.g., human PTH 1–31) and parathyroid hormone-related protein are being investigated.24,25 Full PTH (1–84) is marketed in Europe.1

Pharmacokinetics Bioavailability is 95%.95 The peptide is cleared through hepatic and extrahepatic pathways, with a half-life of 60 minutes. No pharmacokinetic changes are noted with decreasing renal function. No studies have been done in hepatic impairment. Oral, intranasal transdermal, microneedle patch, and implantable microchip PTH formulations, and once-weekly subcutaneous teriparatide are being investigated.24,25,96,97

Efficacy Teriparatide reduces vertebral and nonvertebral fracture risk in postmenopausal women (see Table 73–5);1,8,58 however, no fracture data are available in men or for patients taking glucocorticoids. Lumbar spine BMD increases are greater than other osteoporosis medications. Although wrist BMD is decreased, wrist fractures are not increased. Discontinuation of teriparatide therapy results in a decrease in BMD, which can be alleviated with subsequent antiresorptive therapy.

Because of concern over osteosarcoma, the agent is currently approved for use up to 2 years. Using a second course of teriparatide is controversial.1 Some advocate no second course.111 One study found that a second course of teriparatide increased BMD but not to the extent with the first course.112

Adverse Events Transient hypercalcemia rarely occurs with teriparatide (see Table 73–7). Because of an increased incidence of osteosarcoma in rats, teriparatide contains a box warning against use in patients at increased baseline risk for osteosarcoma (e.g., Paget’s bone disease, unexplained elevations of alkaline phosphatase, pediatric patients, young adults with open epiphyses, or patients with prior radiation therapy involving the skeleton).95

Drug Interactions An increased calcium concentration could be a concern if on digoxin therapy.95

Dosing and Administration Teriparatide is commercially available as a prefilled “pen” delivery device (see Table 73–6). The pen must be kept refrigerated and can be used immediately after removing from the refrigerator. The daily subcutaneous injection is delivered to the thigh or abdominal area with site rotation. The administration of the first dose should take place with the patient either sitting or lying down in case orthostatic hypotension occurs. The pen must be discarded 28 days after the initial injection. The patient should be reeducated on correct use with each pen refill. Suboptimal adherence decreases efficacy, which might be resolved in the future with newer PTH formulations and less frequent administrations. Besides the conditions listed above, teriparatide should not be used in patients with hypercalcemia, metabolic bone diseases other than osteoporosis, metastatic or skeletal cancers, or premenopausal women of child-bearing potential. Teriparatide should not be used in men with previous radiation therapy.6

Teriparatide is the most expensive osteoporosis therapy. Prior authorization may be required. Special arrangements need to be made when patients travel, especially on airplanes.

Combination Therapy

Combinations of different classes of osteoporosis medications have been explored but are not recommended at this time.8,80,98 Combining two antiresorptive agents (e.g., a bisphosphonate with HT or raloxifene) has demonstrated small additive effects on BMD but with concern that the dual suppression of bone turnover could decrease bone strength. When PTH is combined with raloxifene, zoledronic acid, or HT, greater increases or no additive effects in BMD occurred; however, a blunting of the BMD effect has been seen when PTH was combined with alendronate. Antiresorptive therapy combined with cyclical anabolic therapy has been studied for increased patient convenience and lower cost over daily PTH therapy. Combining alendronate with cyclical PTH (3 months on and 3 months off) has produced similar BMD increases to PTH alone. Recently, the combination denosumab and teriparatide for 12 months was demonstrated to increase BMD at the hip and spine more than monotherapy with either drug.99Fracture outcomes from combination therapies are not available. Because no clear benefit with combination therapy exists and such therapy is associated with increased cost and the potential for more adverse effects and nonadherence, combination therapy is not recommended.

Investigational Therapies

Images Besides the aforementioned investigational products, additional new classes of medications are beginning to show promise in phase II and III studies.22,24,25 Investigational antiresorptive agents inhibit bone matrix degradation (cathepsin K inhibitors, e.g., odanacatib) or block osteoclast activation (c-src kinase inhibitor, e.g., saracatinib). Anabolic therapies under investigation include subcutaneously administered neutralizing antibodies against sclerostin, (e.g., romosozumab), and DKK-1, which endogenously inhibit osteoblast differentiation and bone formation. Calcilytic drugs stimulate PTH release via antagonism of CaSR by mimicking hypocalcemia. These drugs have the advantage of being given orally while PTH must be administered subcutaneously. However, calcilytic drugs developed to date have a narrow therapeutic index.

Strontium ranelate and tibolone are approved in Europe, and the latter agent is approved in Canada. Most likely, these two medications will not be marketed in the United States.

Vertebroplasty and Kyphoplasty

The use of vertebroplasty and kyphoplasty are controversial in light of randomized controlled trials that suggest at the most short-term but not long-term benefits or cost effectiveness.46,100 During the procedure, cement is injected into fractured vertebra(e) for patients with debilitating pain 6 to 52 weeks after fracture. In some studies, the procedure stabilized the damaged vertebrae, reduced pain, and decreased opioid intake; the effects are sometimes similar to sham interventions and standard patient care. Long-term adverse outcomes are a concern, including cement leakage into the spinal column (10%), which although frequently asymptomatic can result in nerve damage, and vertebral fracturing around the cement.

SPECIAL POPULATIONS

Osteoporosis is a particular threat in some subgroups because of age, genetic abnormalities, diseases, and medications.

Children

Although rare, osteoporosis in children and adolescents can lead to significant pain, deformity, and chronic disability. Secondary causes are the main contributors to osteoporosis in children (see Tables 73–2and 73-3),12,101 but genetic disorders and idiopathic juvenile osteoporosis can be the origin of bone disease.

The diagnosis and treatment of osteoporosis in children and adolescents is challenging.12,101 No guidelines or consensus recommendations exist. The International Society for Clinical Densitometry’s official position is that the diagnosis of osteoporosis in children (<20 years of age) requires the presence of a clinically significant fracture history (long bone fracture of the lower extremity, vertebral compression fracture, or two or more long bone fractures of the upper extremities) in combination with low bone mass.34 Low bone mass is defined as a Z-score below a –2.0 (adjusted for body size and ethnicity/race) using central DXA of the spine or total body.

After correcting any underlying causes and instituting a bone-healthy lifestyle, pharmacologic treatment should be considered for children with low bone mass and fragility fractures.12,101 Several small studies, mostly evaluating the IV bisphosphonate pamidronate or oral alendronate, have demonstrated increases in BMD. No studies have demonstrated fracture efficacy in this population. The optimal medication, dose, and duration of therapy are unknown, and more safety data are needed. A major concern with bisphosphonates is their effect on longitudinal bone growth and modeling; however, fracture healing, skeletal growth and maturation, or the appearance of growth plates do not appear to be impaired. Teriparatide cannot be used in children as it has a box warning indicating an increased risk for osteosarcoma.

Premenopausal Women

Clinically significant bone loss and fractures in healthy premenopausal women are rare.102,103 Approximately 15% of healthy premenopausal women will have low BMD as a normal variation of peak bone mass. Low peak bone mass is a major risk factor for postmenopausal osteoporosis and fractures but thus far is not a predictor of an increased risk for fractures in the premenopausal years. This might be a result of better bone architecture contributing to better bone strength in younger women.

Routine bone density screening and testing are not cost effective and should not be performed in healthy premenopausal women. No evidence supports that identifying low bone density in healthy premenopausal women results in improved bone-healthy lifestyle practices nor does any evidence exist to support that pharmacologic treatment will reduce future fracture risk.

Most premenopausal women with osteoporosis (Z-score < –2.0) or a history of fragility fracture have an identifiable secondary cause (see Tables 73–2 and 73-3). Therefore, premenopausal women presenting with a history of low-trauma fracture or with a suspected secondary cause for osteoporosis should undergo central DXA testing; if BMD is low, the patient should be considered for pharmacologic therapy. Women with an unidentified cause for osteoporosis and no history of fracture should be treated with a bone-healthy lifestyle and watchful waiting. Therapy may also be considered for premenopausal women experiencing bone loss from cancer chemotherapy or glucocorticoids.

Pharmacologic therapy for osteoporosis should be used with caution in premenopausal women as efficacy and safety have not been adequately demonstrated. Select agents are only FDA-approved for premenopausal women on glucocorticoids. The pregnancy categories are outlined in Table 73–7. Notably, raloxifene and denosumab are in pregnancy category X.

Bisphosphonates are incorporated into the bone matrix and slowly released over time. A theoretical concern is a risk for fetal harm with pregnancies that occur during and after therapy has been stopped. While limited case reports have documented healthy infants after bisphosphonate use, more safety data are needed.

The Older Adult

Osteoporosis and adverse fracture outcomes increase with age.39 Age is an independent risk factor for osteoporosis and osteoporotic fractures, with the prevalence increasing dramatically with age. The number of older adults with osteoporosis is on the rise, yet the condition is underdiagnosed and undertreated in this population. A challenge is determining the correct screening for nursing home residents; FRAX® slightly overestimated whereas ultrasound underestimated the true osteoporosis incidence in one trial.104 In another study, 80% of older adults did not receive osteoporosis medication after a fracture.105 Universal screening of older women with alendronate therapy prescribed only for those with osteoporosis was found to be cost effective, with more cost savings generated with greater age.106

Older adults should practice a bone-healthy lifestyle, ingest adequate calcium and vitamin D,33,45,107 and implement measures to prevent falls.46,52 Exercise might be difficult in older adults due to osteoarthritis, and or limited by underlying cardiac and respiratory diseases. However, walking and resistance exercise with low weights can stimulate bone remodeling. Lactose intolerance and hypercholesterolemia increases with aging. Dairy products might not be ingested as frequently, increasing the need for calcium supplements. Limited sun exposure due to frailty and institutional residence can increase the need for vitamin D for bone and muscle health.42,43 Encouraging older adults to do a home safety evaluation for falls can assist with fracture prevention. Multidisciplinary fall prevention programs with multiple interventions generally have greater impact on fall prevention.52 Many fall prevention materials are available without cost on the Internet.32,53,54

Although efficacy and safety data are limited in the oldest older adults,33,107 evidence consistently shows that those at highest risk for fracture could benefit most from pharmacologic therapy.108 When deciding whether or not to use prescription medications in older adults, the following factors need to be taken into consideration: remaining life span, ability to take and afford medications, cognitive function, GI disorders, polypharmacy, desire to avoid additional medications, and regimen complexity. Oral bisphosphonate administration is difficult in older adults who are bed bound, have difficulties swallowing, have fluid restrictions for cardiovascular or kidney diseases, or forget to drink adequate amounts of fluid or stay upright for the given time. Osteoporosis medications can put an older adult into the Medicare Part D medication insurance plan “donut hole,”109 the segment during which the older adult pays most of the medication expenses out of pocket. During this time, older adults might need to make decisions on which medications to continue if finances are an issue. This gap in Part D medication coverage is closing gradually under the Affordable Care Act and is scheduled to be eliminated by 2020.

Chronic Kidney Disease

A bone healthy lifestyle is still required in patients with chronic kidney disease (CKD; glomerular filtration rate [GFR] <60 mL/min/1.73 m2 [1 mL/s/1.73 m2]). Vitamin D deficiency exists in 70% of patients with CKD stage 3 (GFR 30 to 59 mL/min [0.5 to 0.99 mL/s]) and 83% of patients with CKD stage 4 (GFR 15 to 29 mL/min [0.25 to 0.49 mL/s]) disease warranting 25(OH) vitamin D monitoring and replacement when needed.74 Adequate 25(OH) vitamin D concentrations should be achieved in end-stage renal disease (CKD5 – GFR <15 mL/min [<0.25 mL/s] and CKD5D – dialysis) patients as well; however, the data are not yet strong.

Renal osteodystrophy describes a constellation of metabolic bone disorders that develop in patients with stage 4 and 5 CKD as a consequence of intrinsic kidney damage. Bone biopsy might be necessary to differentiate the different types of renal osteodystrophy from osteoporosis in this population. Antiresorptive therapies would be appropriate for the management of osteoporosis; however, they are contraindicated in patients with osteomalacia or adynamic bone and might be ineffective for osteitis fibrosa cystica. In patients with osteoporosis and a creatinine clearance (CLcr) greater than 30 mL/min (0.50 mL/s), routine management can be used (see Fig. 73–3).110 For patients with osteoporosis and a CLcr less than 30 or 35 mL/min (0.50 or 0.58 mL/s), oral bisphosphonates are not recommended because of potential drug accumulation. Zoledronic acid is contraindicated in patients with CLcr <35 mL/min (0.5 mL/s). Raloxifene has been used in patients with CLcr <45 mL/min (0.75 mL/s). Denosumab is not renally eliminated and might be useful, however, additional research is required for confirmation.


Clinical Controversy…

Although bisphosphonates are not indicated in stage 4 chronic kidney disease (CKD4), some experts suggest the oral agents or IV ibandronate could be used if the CKD4 is due to aging and not a different pathophysiology.110 Oral bisphosphonates appear safe and efficacious in the low numbers of patients studied with creatinine clearance (CLcr) as low as 15 mL/min (0.25 mL/s). Some experts recommend decreasing the bisphosphonate dose by 50% or extending the dosing interval, and using the agent for less than 3 years.

DRUG-INDUCED DISEASE

Glucocorticoid-Induced Osteoporosis

Images Current and prior glucocorticoid use is the most common cause of drug-induced osteoporosis.14,111,112 Approximately 30% to 50% of patients taking chronic oral glucocorticoids will experience a fracture. The relative risk for a vertebral or hip fracture is 5.2 and 2.3 respectively for prednisone doses ≥7.5 mg daily or equivalent.14 Fracture risk is not increased for patients receiving glucocorticoids for adrenal insufficiency.113 Although this is a well-documented risk, many patients receiving glucocorticoids are not evaluated and/or treated for glucocorticoid-induced osteoporosis (GIO).114

Bone losses with glucocorticoids are rapid, with the greatest decrease occurring in the first 6 to 12 months of therapy.111,112 Oral doses as low as 2.5 mg prednisone or equivalent daily have been associated with fractures. GIO has also been associated with inhaled glucocorticoids, although most data suggest no major bone effects.

The pathophysiology of glucocorticoid bone loss is multifactorial. Glucocorticoids decrease bone formation through decreased proliferation and differentiation, and enhanced apoptosis of osteoblasts. They can interfere with the bone’s natural repair mechanism through increased apoptosis of osteocytes, the bone’s communication cells. Glucocorticoids increase bone resorption by increasing RANKL and decreasing OPG. They can reduce estrogen and testosterone concentrations. A negative calcium balance is created from decreased calcium absorption and increased urinary calcium excretion via alterations in calcium transporters.27 Risk is greater in patients with a polymorph in the glucocorticoid receptor gene and in older adults partly because of an increase in 11β-hydroxysteroid dehydrogenase 1 that activates the glucocorticoid.112 The underlying disease requiring this medication sometimes also contributes negatively to bone metabolism.

FRAX® and DXA can be used for BMD evaluation.111 Based on FRAX® estimates of the 10-year risk of major osteoporotic fracture, patients are risk stratified; low <10%, medium 10% to 20%, high >20%. Because FRAX®does not account for specific dose, duration of therapy, or accumulation of dose, the FRAX® score should be multiplied by various corrections based on patient age to prevent over- and under-estimations.113 Patients are also classified as high risk if DXA T-score ≤ –2.5 or a history of fragility fracture. A baseline central DXA is recommended before glucocorticoid initiation. Because of the rapid loss of bone that can occur with oral glucocorticoid therapy, central DXA can be repeated yearly thereafter or more often if needed. A vertebral fracture assessment for patients with significant height loss or pain consistent with a vertebral fracture or spine radiography is suggested at baseline and for those already receiving ≥5 mg prednisone or equivalent.

All patients using glucocorticoids should practice a bone-healthy lifestyle (described above) and minimize glucocorticoid exposure when possible.111 All patients starting or receiving glucocorticoid therapy (any dose or duration) should ingest 1,200 to 1,500 mg elemental calcium and 800 to 1,200 units of vitamin D daily or more to achieve therapeutic 25(OH) vitamin D concentrations. Minimizing fall risk is important. Counseling should occur for all patients using this medication for more than 3 months regardless of dose. Glucocorticoids should be used at the lowest dose and for the shortest duration possible.

Current GIO guidelines divide recommendations for prescription medication use by fracture risk, age, menopause and childbearing status, glucocorticoid dose and duration, and fragility fracture (Tables 73–8and 73-9).111,112,115Alendronate and risedronate decrease bone loss and vertebral fractures. IV zoledronic acid and teriparatide produce greater and quicker decreases in bone loss than do oral bisphosphonates. In an observational followup study of patients on glucocorticoids treated with up to 18 months of teriparatide for patients on glucocorticoids, fracture risk was decreased.116 These agents have FDA indications for prednisone doses ≥7.5 mg daily (bisphosphonates) or at high risk for fracture (teriparatide); this differs from the guideline recommendations. Denosumab is being investigated for GIO and in theory should provide benefit. Recommendations exist for therapy in premenopausal and younger men (<50 years old) if they have already experienced a fragility fracture, but, because of insufficient data, no recommendations provide guidance in those without fracture. Osteoporosis doses and directions for use are the same for postmenopausal and male osteoporosis.

TABLE 73-8 Therapy to Prevent or Treat Glucocorticoid-Induced Osteoporosis in Postmenopausal Women and Men > 50 Years Old

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TABLE 73-9 Therapy to Prevent or Treat Glucocorticoid-Induced Osteoporosis in Premenopausal Women and Men <50 Years Old with a Fragility Fracture

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Because glucocorticoids can cause hypogonadism, this condition is frequently evaluated in premenopausal women and men. Although the guidelines no longer include hormone therapy,111 sometimes this therapy will be prescribed for the symptoms of hypogonadism.115 While not specifically for osteoporosis treatment, some positive bone effects could occur.

CANCER TREATMENT–RELATED BONE LOSS

Images Several important risk factors for osteoporosis are found more commonly in patients with cancer.117 Prostate cancer and breast cancer are the most commonly diagnosed cancers among men and women, respectively. In these patients, antiandrogen and antiestrogen therapies increase the risk of osteoporosis. Premature menopause and related ovarian failure induced by chemotherapy may also lead to bone loss. Glucocorticoids used as antiemetic therapy, as a premedication for certain chemotherapies, and in treatment regimens for hematologic malignancies increase bone loss. The need for GIO preventive therapy should be considered if glucocorticoid therapy is planned for 3 months or more.

In addition to the screening recommendations set forth by the National Osteoporosis Foundation (NOF), a baseline DXA is recommended for women taking aromatase inhibitors.118 Further, the National Comprehensive Cancer Network recommends testing men on androgen-deprivation therapy.117 When using FRAX® to predict fracture risk, premature menopause and hypogonadism are considered factors contributing to secondary osteoporosis in the risk model. If the fracture risk exceeds the treatment threshold, appropriate therapy should be considered.

For a patient with a history of cancer or active malignancy, individual characteristics will help to guide treatment selection.117 Some agents have been specifically evaluated for skeletal-related events or for the prevention of cancer therapy–induced bone loss. Data suggest a potential role for bisphosphonates in decreasing recurrence of early stage breast cancer. In women, bisphosphonates have been shown to reduce bone loss associated with chemotherapy-related ovarian failure and ovarian suppression with gonadotropin-releasing hormone and aromatase inhibitors. Raloxifene decreases the risk of invasive breast cancer in high-risk women.

In men with prostate cancer, recommendations include use of denosumab, zoledronic acid, or alendronate.119 Denosumab is specifically indicated for androgen deprivation-induced bone loss in men with prostate cancer and aromatase inhibitor-induced bone loss in women with breast cancer based on bone mineral density outcomes in these patients.120

Because of the risk of osteosarcoma, teriparatide is contraindicated in patients with prior radiation to the skeleton.117 In all patients with a history of malignancy, clinicians should take a careful history of prior radiation before selecting the most appropriate treatment option.

PERSONALIZED PHARMACOTHERAPY

Bone physiology and pathophysiology are under many genomic and genetic influences. Isolating one or a few genes for correction will unlikely resolve the epidemic of osteoporosis.

Hereditary is important since family history, especially of a hip fracture in a parent, is a strong risk factor for osteoporosis development, and twin studies have suggested that 50% to 85% of variability is due to genetics.1,121,122 As of early 2013, 62 loci have been identified that influence BMD and 14 loci for fracture risk, ranging from impacts on bone resorption (RANKL, osteoprotegerin) to formation (Wnt, LRP5, sclerostin).

Calcium, vitamin D, and estrogen receptors are also under genetic influence. Genetic modulation is in its infancy for osteoporosis prevention and treatment but might lead to new medications.

EVALUATION OF THERAPEUTIC OUTCOMES

Images Assessment of adherence and tolerability of medication should be performed at each visit. Having a patient repeat back instructions for medication administration will help identify administration problems and enable timely correction. Assessment of fracture, back pain, and height loss can help identify worsening osteoporosis.

To evaluate efficacy, a central DXA BMD measurement can be obtained 1 to 2 years after initiating a medication to monitor response. To minimize test variability, BMD testing should be performed on the same DXA machine. A statistical change must be greater than the least significant change for that specific piece of equipment. Since BMD continues to decrease with aging, no change from baseline can be an acceptable response. Because changes in BMD do not entirely explain changes in fracture risk, many experts believe that decisions on whether or not to continue a particular therapy should not be based solely on BMD response. Central DXAs are then repeated thereafter every 1 to 2 years until BMD is stable, at which time the interval for reassessment could be expanded. In patients with conditions associated with higher rates of bone loss (e.g., glucocorticoid use), more frequent monitoring might be warranted.

Bone turnover markers have been used to determine response as well as use of an osteoporosis prescription medication.6,8,37,38 The patient either provides a first or second morning voiding urine sample or has blood drawn after an overnight fast to measure the markers 3 to 6 months after therapy initiation. The results are compared with baseline values. To be clinically relevant, changes again need to be greater than the least significant change for that test; beyond that no specific guidelines for interpretation exist. No consensus on result interpretation and high test variability exists, and thus these tests are not yet considered routine.

Osteoporosis Services

Images Currently not all patients are being adequately screened, tested, and treated according to guidelines nor educated about prevention via a bone-healthy lifestyle.61 All healthcare providers play an important role in screening and monitoring for osteoporosis.78,123 Community pharmacies and groups can offer health fairs with osteoporosis screenings using ultrasonography and/or FRAX® to identify postmenopausal women and older adult men at risk and then make appropriate referrals for DXA assessment. Healthcare providers can increase bone-healthy lifestyle changes, ensure correct medication use, and resolve medication adverse events. This practice has been financially sustainable in the community pharmacy setting124 and as part of a patient-centered medical home.125

Because adherence is strongly linked to fracture prevention,58 all healthcare providers should identify and resolve barriers to optimal medication adherence. Some pharmacists are beginning to administer denosumab in community pharmacies to improve adherence and ease of administration. Databases can also be used to ensure that all patients with a low-trauma fracture either have a DXA conducted or osteoporosis medication started. Everyone can work together as interprofessional teams to ensure that health systems and providers meet all quality assurance indicators for optimal patient osteoporosis prevention and treatment.

OTHER METABOLIC BONE DISORDERS

Because of increased interest in bone diseases and newer medications, better therapies are being explored and developed for other bone diseases.

Osteomalacia

Osteomalacia, meaning “soft bones,” is a condition seen in adults in which the bone is significantly undermineralized. Rickets is the childhood equivalent of osteomalacia. The most common cause of osteomalacia is severe, prolonged vitamin D deficiency. Disorders that cause hypophosphatemia and, rarely, medications such as long-term anticonvulsant therapy can also cause osteomalacia.50

Patients with osteomalacia present with pathologic fractures and/or deep bone pain, proximal muscle weakness, or no obvious symptoms but low BMD. Patients with osteomalacia will have an extremely low 25(OH) vitamin D concentration (<10 ng/mL [<25 nmol/L]) and might have an elevated bone-specific alkaline phosphate, hypophosphatemia and hypocalcemia. The treatment of osteomalacia caused by vitamin D deficiency is high-dose vitamin D replacement therapy. Prescription oral ergocalciferol 50,000 units once to twice weekly for at least 8 weeks is a regimen that is frequently used to raise vitamin D concentrations into the sufficient range. Other high-dose oral and intramuscular vitamin D regimens have also been used. Once 25(OH) vitamin D concentrations are greater than 30 ng/mL (75 nmol/L), chronic maintenance vitamin D therapy can be instituted. Oral ergocalciferol 50,000 units once or twice a month or nonprescription cholecalciferol of 1,000 to 2,000 units once daily are reasonable maintenance options.

CONCLUSION

Osteoporosis prevention begins at birth and continues throughout life by practicing a bone-healthy lifestyle (adequate calcium and vitamin D intake, exercise, no smoking, minimal alcohol use, and fall prevention). Generally osteoporosis occurs in postmenopausal women and older men; however, the disease can occur in all ages as a result of secondary causes such as genetics, diseases, and medications. Central bone densitometry (i.e., DXA) can be used for screening, diagnosis, and monitoring, and the fracture risk assessment tool (i.e., FRAX) can be used for screening and to assist in identifying patients at high risk for fracture requiring treatment.

Alendronate, risedronate, zoledronic acid, and denosumab are first-line therapies since these drugs have been demonstrated to decrease hip, nonvertebral, and vertebral fractures. Teriparatide is the only medication that can build bone; however, cost and subcutaneous administration limit its use. Although medications decrease fracture risk, prescribing of osteoporosis medications and patient adherence to such therapy is suboptimal, leading to less fracture prevention. All healthcare providers need to be actively involved in osteoporosis education, counseling, and prevention across the life span and then attentive to treatment and medication adherence to prevent osteoporotic fractures in patients with osteoporosis. Many diseases and medications can cause secondary osteoporosis. Healthcare providers need to be proactive to achieve better disease control, adjust medications when possible to decrease risk, and prescribe osteoporosis medications when appropriate.

ADDENDUM

As discussed in the adverse effects portion of the Calcium Supplementation section, the link between calcium intake and increased risk of cardiovascular disease and mortality continues to be evaluated.

In a large, prospective, 12-year cohort study following dietary and supplemental calcium intake, the risk of death from heart disease was increased by supplemental calcium (>1,000 mg/d) intake in men but not in women.126 This effect was not observed from dietary calcium or lower intake of supplements.

Increased overall and cardiovascular mortality was demonstrated in a prospective cohort study of women consuming 1,400 mg or more of calcium daily through diet and/or supplements.127 There was an increased risk of all-cause mortality, cardiovascular disease mortality, and ischemic heart disease mortality. The risk of all-cause mortality was more pronounced in those who used supplements in addition to a high dietary calcium intake.

While data are conflicting, these studies nonetheless reinforce that clinicians should not promote calcium supplements in patients already consuming adequate dietary amount of this element.

Recent denosumab data documented BMD continues to increase after eight years of therapy with similar side effect profile to the four year data.128

ABBREVIATIONS

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