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1483
CHAPTER
93Osteoporosis and Other Metabolic
Bone Diseases
MARY BETH O’CONNELL AND SHERYL F. VONDRACEK
KEY CONCEPTS
ᕡ Postmenopausal women, men older than age 65 years, and
those with potential disease- or drug-induced bone loss should
be assessed for osteoporosis. Patients with premature or se-
vere osteoporosis should be evaluated for secondary causes of
bone loss.
ᕢ Central bone densitometry can determine bone mass, predict
fracture risk, and influence patient and provider treatment de-
cisions. Portable equipment can be used for screening in the
community to determine the need for further testing.
ᕣ Vitamin D insufficiency and deficiency, which sometimes causes
osteomalacia, can be insidious and coexist with osteoporosis. A
serum 25(OH) vitamin D concentration should be obtained in
patients with decreased oral vitamin D intake, limited or no sun
exposure, or unexplained muscle weakness or pain.
ᕤ All people, regardless of age, should incorporate a bone-
healthy lifestyle beginning at birth, which emphasizes regular
exercise, nutritious diet, tobacco avoidance, minimal alcohol
use, and fall prevention to prevent and treat osteoporosis.
ᕥ The adequate intake for calcium in American adults is 1,000 to
1,500 mg of elemental calcium daily in divided doses from
diet or supplements. The adequate intake for American adults,
especially seniors, is 600 to 1,000 units of vitamin D daily from
mainly supplements, with some experts recommending even
higher doses.
ᕦ Bisphosphonates decrease vertebral, hip, and nonvertebral
fractures and are considered the drug of choice for osteoporo-
sis treatment.
ᕧ Raloxifene is an alternative treatment option to prevent verte-
bral fractures, particularly in women who cannot tolerate,
should not, or will not take bisphosphonates. Postmenopausal
women at high risk for breast cancer might choose this medi-
cation to obtain dual actions.
ᕨ Male osteoporosis is often secondary to specific diseases and
drugs and responds well to a bone-healthy lifestyle, bisphospho-
nate therapy, and in some cases, testosterone replacement.
ᕩ Patients taking chronic oral glucocorticoids (e.g., rheumatoid ar-
thritis, cystic fibrosis, transplantation, bowel disorders, cancer)
need to be identified and started on a bone-healthy lifestyle,
higher doses of calcium and vitamin D, and bisphosphonate
therapy to prevent or treat osteoporosis.
µ Patients with certain diseases such as gastrectomy, celiac dis-
ease, inflammatory bowel disease, and organ transplantation,
or taking medications known to influence vitamin D and/or
bone metabolism should be evaluated for disease and drug in-
duced osteopenia and osteoporosis.
Osteoporosis is a major public health threat for an estimated 44
million Americans, or 55% of the people 50 years of age and older.1
In the United States, 8 million women and 2 million men are
estimated to have the disease. Osteoporosis is defined as a “skeletal
disorder characterized by compromised bone strength predisposing
a person to an increased risk of fracture.”2
The development of
osteoporosis and osteoporotic fractures is multifactorial, beginning
with genetics and unhealthy bone lifestyles, along with other skeletal
factors, which lead to compromised bone strength, and nonskeletal
factors that lead to falls (Fig. 93–1). President Clinton declared 2002
to 2011 to be the Decade of the Bone and Joint. To coincide with this
initiative, the Surgeon General released a report in 2004 on Bone
Health and Osteoporosis, providing information, challenges, and
opportunities for change.3
Healthcare practitioners must take an
active role in educating people of all ages and healthcare providers on
healthy bone habits and osteoporosis treatment options.
EPIDEMIOLOGY
Osteopenia (low bone mass), osteoporosis, and osteoporotic fractures
are very common and affect all ethnic groups. Almost 34 million
Americans are estimated to have low bone mass (osteopenia),1
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SECTION 12
RHEUMATOLOGIC DISORDERS
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1484SECTION12RheumatologicDisorders
including 50% of Asian, 47% of Hispanic, 45% of Native American,
40% of white, and 28% of black women.4
Osteoporosis affects 12% of
Native American, 10% of Asian, 10% of Hispanic, 7% of white, and
4% of black women. 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.5,6
Fragility or low trauma wrist and vertebral
fractures are common throughout adulthood, whereas hip fractures
are more common in seniors. Fracture incidence was estimated to be
2 million (71% in women, 29% in men) in 2005, with an estimated
total medical cost of $17 billion.7
Fractures in women accounted for
75% of the costs and in seniors 87% of the costs. Hip fractures
represented 72% of these costs. Forecasting predicts 3 million frac-
tures at a cost of $25 billion in 2025. In a women’s lifetime, hip
fracture risk is 17% for whites, 14% for Hispanics, and 6% for African
Americans.5
In a man’s lifetime, hip fracture risk is 6% to 11%.8
BONE PHYSIOLOGY
Bone is made of collagen and mineral components. The collagen
component gives bone its flexibility and energy-absorbing capability.9
The mineral component gives bone its stiffness and strength. The
correct balance of these substances is needed for bone to adequately
accommodate to stress and strain and resist fractures. Imbalances can
impair bone quality and lead to reduced bone strength.
Bone strength reflects the integration of bone quality and bone
mineral density (bone mass). Bone mass increases rapidly through-
out childhood and adolescence. Ninety percent of peak bone mass is
attained by age 18 to 20 years, with small gains until approximately
age 30 years. Peak bone mass is highly dependent on genetic factors
that account for approximately 60% to 80% of the variability.5,10,11
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.
The skeleton is composed of mostly cortical bone (80%) with
some trabecular bone (20%), which varies by bone site. The forearm
is predominantly cortical bone (95%), the spine is predominantly
trabecular bone (66% to 75%), and the femoral neck of the hip and
wrist are mostly cortical bone (50% to 75%, respectively).12
Of note,
trabecular bone has a 5 to 10 times higher metabolic turnover rate
than cortical bone.
Bone remodeling is a dynamic process that occurs continuously
throughout life. One to two million tiny sections of bone are in the
process of remodeling at any given time. 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,
and potentially certain diseases and medications (Fig. 93–2, step
1).12,13
Many cytokines, growth factors, and hormones influence
each remodeling step. 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 osteo-
blast (bone-forming cells) in step 2. RANKL also stimulates mature
osteoclast activation and bone adherence via integrins to resorb
bone. Proteinases are secreted to resorb the protein matrix, and
hydrogen ions are secreted to dissolve the mineralized component
(step 3). After bone is resorbed and a cavity is created, additional
cytokines and growth factors are released that first mature osteo-
blasts from mesenchymal stem cells and then stimulate osteoblast
bone formation (step 4). Mature osteoblasts produce osteoproteg-
erin (OPG) that binds (step 4) to RANKL, thereby stopping bone
resorption.
Bone formation occurs over two phases. First, osteoblasts fill the
resorption cavity with osteoid and then mineralization occurs (step
5). Once bone formation is complete, mature osteoblasts undergo
FIGURE 93-1. Etiology of osteoporosis.
• Genetics
• Diet
• Lifestyle
• Hormonal status
• Disease states
• Medications
Aging Bone Loss Suboptimal
Peak Bone Mass
Skeletal Factor
Impaired Bone Quality
Skeletal Factor
Low Bone Density
Non-Skeletal Factors
(e.g., ↑ Fall Risk)
Low Trauma Fractures
(Severe Osteoporosis)
Reduced Bone Strengh
(Osteoporosis)
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1485
CHAPTER93OsteoporosisandOtherMetabolicBoneDiseases
apoptosis or become lining cells or osteocytes (step 6). Quiescence
is the phase when bone is at rest until another remodeling cycle is
initiated at that site.
Estrogen has many positive effects on the bone remodeling process,
with most of its actions helping to maintain a normal bone resorption
rate. Estrogen suppresses the proliferation and differentiation of
osteoclasts and increases osteoclast apoptosis. Estrogen decreases the
production of several cytokines that are potent stimulators of osteo-
clasts including interleukins 1 and 6, and tumor necrosis factor-α.
Estrogen also decreases the production of RANKL and increases the
production of OPG; both of which reduce osteoclastogenesis.14
VITAMIN D, PARATHYROID HORMONE,
AND CALCIUM
Vitamin D and parathyroid hormone (PTH) maintain calcium homeo-
stasis.15
The most abundant source of vitamin D is the endogenous
production from exposure to ultraviolet B light. The sun’s ultraviolet B
light converts 7-dehydrocholesterol in the skin to cholecalciferol (vita-
min D3). Maximal skin production occurs within 20 minutes for whites
and 60 to 120 minutes for blacks or darker-skin individuals.16
Dietary
vitamin D sources include cholecalciferol and ergocalciferol (vitamin
D2). Subsequent conversion of cholecalciferol and ergocalciferol to 25-
hydroxyvitamin D [25(OH) D] (calcidiol) occurs in the liver and then
PTH stimulates conversion of 25(OH) D via 25(OH) D-1α-hydroxy-
lase to its final active form, 1α,25-dihydroxyvitamin D (calcitriol), in
the kidney.15
Calcitriol binds to the intestinal vitamin D receptor and
then increases calcium binding protein. As a result, calcium and
phosphorous intestinal absorption is increased. Vitamin D receptors
are also found in many tissues, such as bone, intestine, brain, heart,
stomach, pancreas, lymphocytes, skin, and gonads.
Calcium absorption under normal conditions is approximately
30% to 40%, decreasing to 10% to 15% with low vitamin D concen-
trations.15
Calcium absorption is predominantly rate limited through
vitamin D controlled intestinal transport with less than 23% absorbed
through passive paracellular diffusion, which is not rate limited.17
Elevated PTH concentrations secondary to hypocalcemia increase
kidney calcitriol production and calcium reabsorption by the kidney.
PTH concentrations also increase when vitamin D concentration falls
below around 30 ng/mL, the minimum normal therapeutic vitamin
D concentration.18
Sometimes the increased fractional calcium
absorption is insufficient and thus bone resorption is needed.
Together, PTH and calcitriol increase osteoclast activity, thereby
releasing calcium from bone to restore calcium homeostasis.
ETIOLOGY
ᕡ Figure 93–1 depicts a model describing the etiology of osteopo-
rosis and fractures. Table 93–1 lists risk factors for osteoporosis and
Table 93–2 lists secondary causes.
FIGURE 93-2. Bone remodeling cycle.12,13
(1α,25(OH)D2, calcitriol/1,25(OH)2 vitamin D; BMP, bone morphogenetic protein; Ca, calcium; CSF,
colony-stimulating factors; EAA, estrogen agonist/antagonist; FGF, fibroblast growth factor; IGF, insulin-like growth factor; Il, interleukin; Mg,
magnesium; MMP, matrix metalloproteases; NCP, noncollagenous proteins; OPG, osteoprotegerin; PDGF, platelet-derived growth factor; PG,
prostaglandin; Phos, phosphorous; PTH, parathyroid hormone; PTHrP, parathyroid hormone-related protein; SERM, selective estrogen receptor
modulator; TGF, transforming growth factor; TNF, tumor necrosis factor; Trap, tartrate-resistant acid phosphate.)
Step 1: Initiation of Bone Remodeling
Step 3: Osteoclastic Bone Resorption
Step 5: Osteoblastic Bone Formation
Cathepsin K,
Trap
Type-1
Collagen
NCP Proteoglycan Mg++ Ca++ Phos
Mineralization
New Bone
Old Bone
Step 4: Reversal – Switch from Resorption to Formation
Step 6: Quiescence - Resting Bone
Step 2: Differentiation and Activation of Osteoclasts
Rank = RANKL receptor
= Rank Ligand (RANKL)
= Rank ligand (RANKL)
Osteoclast
precursor cell
Mature osteoclast
Rank = RANKL Receptor
OPG = Osteoprotegerin
Osteoclast
precursor cell
Mature osteoclast apoptosis
Mature
osteoblast
Bone Surface
Osteoblast
precursor cell
Bone Surface
Osteoblast
precursor cell
Stress and/or
microfractureOsteocytes = retired osteoblasts
Lining Cells = retired osteoblasts
Signal = release of various
cytokines & growth factors
collagenase, MMP,
gelatinase
H+
ATPase
Osteoid Deposition
II-1, II-6, CSF, PTH, 1,25(OH) D,
PThrP, TGF-β,PGE, TNFα
Inhibitors – estrogen, EAA, calcitonin
TGF-β, PDGF, IGF-I,
IGF-II BMP, FGF
αVβ3-integrin
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LOW BONE DENSITY
Bone mineral density (BMD) is a major predictor of fracture risk.19
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.5
Low BMD can occur as a result of failure to reach a
normal peak bone mass and/or bone loss.
Bone loss occurs when bone resorption exceeds bone formation,
usually from high bone turnover; when the number and/or depth of
bone resorption sites greatly exceed the rate and ability of osteo-
blasts 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.9
During
perimenopause and for up to 5 to 7 years after menopause, women
can experience an accelerated rate of bone loss because of the drop
in circulating estrogen and an increase in bone resorption. The rate
and duration of loss can vary greatly, with up to 3% to 5% of bone
density lost per year, and can differ depending on the skeletal site
measured. Seniors steadily lose bone mass at approximately 0.5% to
1% per year as a consequence of an accelerated rate of bone
remodeling combined with reduced bone formation.
The major factors (see Tables 93–1 and 93–2) influencing bone
losses are hormonal status, exercise, aging, nutrition, lifestyle, dis-
ease states, medications, and some genetic influences. Nonhor-
monal risk factors are similar between women and men.
IMPAIRED BONE QUALITY
In addition to BMD, the strength of bone is highly impacted by the
quality of the bone’s material properties and its structure.9
For
example, accelerated bone turnover can result in bone loss, but also
can impair bone quality and the structural integrity of bone by
increasing the quantity of immature bone that is not yet adequately
mineralized. Bone quality assessment is important because changes
in bone quality effect 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.20
One-third to one-half of all seniors fall each year with 50% falling
more than once. Up to 5% of all falls will result in a fracture. In
2003, more than 1.8 million seniors were treated in the emergency
department, and more than 400,000 were hospitalized for a fall-
related injury.
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., stroke, Alzheimer’s dementia, Parkinson’s disease), and poly-
pharmacy. Psychoactive medications such as benzodiazepines, anti-
depressants, antipsychotics, sedative hypnotics, and narcotics have
been strongly associated with falls. The ability to adapt to falls also
decreases with aging. Seniors are more likely to sustain a hip or pelvic
fracture because they tend to fall backwards or sideways instead of
forward.
PATHOPHYSIOLOGY
Osteoporosis pathophysiology depends on gender, age, and pres-
ence of secondary causes.
POSTMENOPAUSAL OSTEOPOROSIS
The accelerated bone loss during perimenopause and postmenopause
results from enhanced resorption mainly as a result of the loss in
ovarian hormone production, specifically estrogen. Estrogen defi-
ciency increases proliferation, differentiation, and activation of new
osteoclasts and prolongs survival of mature osteoclasts.14
The number
of remodeling sites increases and resorption pits are deeper and
inadequately filled by normal osteoblastic function. Significant bone
TABLE 93-1 Risk Factors for Osteoporosis and
Osteoporotic Fractures
Low bone mineral densitya
History of low trauma fracture as an adulta,b
Current cigarette smokinga,b
Low body weight or body mass indexa,b
Advanced agea
Alcohol in amounts >2 drinks/daya
Systemic glucocorticoid therapya
Female sex
Osteoporotic fracture in a first-degree relative (especially hip fracture)a,b
Secondary osteoporosis (especially rheumatoid arthritisa
)
Low calcium intake
Low physical activity
Poor health/frailty
Minimal sun exposure
Recent falls
Cognitive impairment
Estrogen deficiency before 45 years old
Impaired vision
a
Proposed factors included in World Health Organization fracture risk model.
b
Major risk factors per National Osteoporosis Foundation.
TABLE 93-2 Secondary Causes for Osteoporosis in Children
and Adults
Disease States Drugs
Primary or secondary ovarian failure Chronic systemic glucocorticoids
Testosterone deficiency Excessive thyroxine
Thyrotoxicosis Anticonvulsant therapy (e.g., phenytoin,
carbamazepine, phenobarbital, val-
proic acid)
Cushing’s syndrome
Growth hormone deficiency
Primary hyperparathyroidism Depot medroxyprogesterone acetate
(DMPA)Type 1 diabetes
Disorders of calcium balance Cytotoxic chemotherapy
Anorexia nervosa Cyclosporine
Chronic liver disease (e.g., primary bili-
ary cirrhosis)
Gonadotropin-releasinghormone(GnRH)
agonists or analogs (e.g., leuprolide)
Malabsorptive states Long-term unfractionated heparin
Inflammatory bowel disease Aromatase inhibitors
Crohn’s or celiac disease Highly-active antiretroviral therapy for
human immunodeficiency virus (e.g.,
zidovudine, nucleoside reverse tran-
scriptase inhibitors)
Gastrectomy or Billroth I
Rheumatoid arthritis
Ankylosing spondylitis
Osteogenesis imperfecta Long-term proton pump inhibitor therapy
Organ transplant Selective serotonin reuptake inhibitors
Chronic kidney disease
Malignancies (multiple myeloma,
lymphoma, leukemia)
Human immunodeficiency virus infection/
acquired immunodeficiency syndrome
Cystic fibrosis
Chronic obstructive pulmonary disease
Multiple sclerosis
Stroke/cerebrovascular accident
Turner’s syndrome
Down’s syndrome
Marfan’s syndrome
Klinefelter’s syndrome
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1487
density is lost and bone architecture is compromised. Trabecular
bone is most susceptible leading to vertebral and wrist fractures.
MALE OSTEOPOROSIS
Men are at a lower risk for developing osteoporosis and osteopo-
rotic fractures because of larger bone size, greater peak bone mass,
and fewer falls.21
Men also do not undergo a period of accelerated
bone resorption similar to menopause. However, men have a higher
mortality rate after fractures.
The etiology of male osteoporosis tends to be multifactorial with
secondary causes (see Table 93–2) and aging being the most common
contributing factors. In young and middle-age men, a secondary cause
for bone loss is usually identified, with hypogonadism being the most
common. Idiopathic osteoporosis (no known cause) can occur and is
probably a result of genetic factors that have yet to be determined.
AGE-RELATED OSTEOPOROSIS
Age-related osteoporosis occurs in seniors mainly as a result of
hormone, calcium, and vitamin D deficiencies leading to an acceler-
ated bone turnover rate in combination with reduced osteoblast
bone formation. Hip fracture risk rises dramatically in seniors as a
consequence of the cumulative loss of cortical and trabecular bone
and an increased risk for falls.
SECONDARY CAUSES OF OSTEOPOROSIS
ᕡ A secondary cause (see Table 93–2) is identified in more than half
of premenopausal and perimenopausal women, about one-third of
postmenopausal women, and more than two-thirds of men.22
The
two most common secondary causes for osteoporosis are vitamin D
deficiency and glucocorticoid therapy, which are discussed in Osteo-
malacia and Glucocorticoid-Induced Osteoporosis sections later. A
potential drug-induced cause of bone loss in premenopausal women
is depot medroxyprogesterone acetate (DMPA or Depo-Provera), a
long-acting progestin-only contraceptive injection. This drug con-
tains a “black box” warning based on data from several studies that
demonstrated significant bone loss or impaired bone mass accrual.23
Some women will recover some or all bone loss after discontinua-
tion, especially if the agent has been used for a short time. Although
more information is needed to fully understand the risks associated
with depot medroxyprogesterone acetate, more than 2 years’ use
warrants consideration of BMD testing using central dual-energy
x-ray absorptiometry (DXA).
CLINICAL PRESENTATION
Table 93–3 outlines the clinical presentation of osteoporosis.
Osteoporosis is diagnosed by BMD measurement or presence of a
low trauma fracture. Two-thirds of patients with a vertebral fracture
are asymptomatic or attribute mild lower back pain to “old age.” The
other third present with moderate to severe back pain that radiates
down their leg after a new vertebral fracture. The pain usually
subsides significantly after 2 to 4 weeks; however, residual chronic
lower back pain may 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.
CONSEQUENCES OF OSTEOPOROSIS
A fragility or low-trauma fracture is defined as one that occurs as a
result of a fall from standing height or less or with minimal to no
trauma. The most common osteoporosis-related fractures are those
of the vertebrae, proximal femur, and distal radius (wrist or Colles
fracture).24
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, physi-
cal deformity, and adverse health consequences. Patients with severe
kyphosis can experience respiratory problems as a result of compres-
sion 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 5-year
survival rate compared to those without a fracture history.
Wrist fractures occur more commonly in younger postmeno-
pausal women and are frequently a result of a fall on an outstretched
hand. Negative outcomes include prolonged pain and weakness,
and decreased advanced activities of daily living (such as cooking
and shopping).
Hip fractures are associated with the greatest increase in morbid-
ity and mortality. In 1999, hip fractures resulted in approximately
340,000 hospital admissions.25
After a hip fracture, only 33% to 40%
of patients regain their ability to perform basic activities of daily
living, while 20% become nonambulatory. Three to 4% of patients
die during the initial hospitalization for hip fracture, and 14% to
36% will die within 1 year either from complications of the hip
fracture or other comorbid disease processes. 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. In subjects with one clinical verte-
bral fracture, the chance of experiencing any new fracture was 2.8-
fold higher, and with two or more vertebral fractures it was 12-fold
higher, than for subjects who did not have baseline fractures.26
PATIENT ASSESSMENT
Bone pain, postural changes (i.e., kyphosis), and loss of height are
simple useful physical examination findings. Height loss greater than
TABLE 93-3 Clinical Presentation of Osteoporosis
General
• Many patients are unaware they have osteoporosis and only present after fracture
• Fractures can occur after bending, lifting, or falling, or independent of any activity
Symptoms
• Pain
• Immobility
• Depression, fear, and low self-esteem from physical limitations and deformities
• Two-thirds of vertebral fractures are asymptomatic
Signs
• Shortened stature (>1.5'' loss), kyphosis, or lordosis
• Vertebral, hip, wrist, or forearm fracture
• Low bone density on radiography
Laboratory tests
• Routine tests to detect a possible secondary cause: complete blood count, liver
function tests, creatinine, urea nitrogen, calcium, phosphorous, alkaline phos-
phatase, albumin, thyroid-stimulating hormone, free testosterone, 25(OH)
vitamin D, and 24-hour urine concentrations of calcium and phosphorous.
• Urine or serum biomarkers (e.g., NTX, osteocalcin) are sometimes used,
especially to determine if high bone turnover exists. Additional testing might
be necessary if the patient’s history, physical examination, or the initial
investigation suggests a specific secondary cause.
Other diagnostic tests
• Spine and hip bone-density measurement using DXA
• Radiograph to confirm vertebral fracture
DXA, dual-energy x-ray absorptiometry; NTX, N-terminal crosslinking telopeptide of type 1 collagen.
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1.5 inches from the tallest mature height is considered significant
and warrants further investigation. Height should be routinely meas-
ured using a wall-mounted stadiometer. A spine radiograph can
confirm vertebral fractures. Low bone density or osteopenia reported
on routine radiographs requires an evaluation for osteoporosis. In
addition to physical examination and laboratory studies (see Table
93–3), patients can be assessed with risk factor assessment, osteopo-
rosis questionnaires, peripheral and central DXA, and biomarkers.
RISK FACTOR ASSESSMENT
The aim of an initial fracture risk assessment (see Table 93–1) 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 gender, ethnicity) or an increased 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 patient will benefit most from pharmacologic
intervention. Current smoker, low body weight (<127 lb in post-
menopausal women), history of osteoporotic fracture in a first-
degree relative, and personal history of low-trauma fracture as an
adult are all considered major risk factors by the National Osteopo-
rosis Foundation.27
Other identified independent risk factors
include age, high bone turnover, low body mass index (<19 kg/m2
),
rheumatoid arthritis, and glucocorticoid use.
RISK ASSESSMENT TOOLS
Several clinical predication tools help clinicians determine who should
undergo BMD testing. The Osteoporosis Risk Assessment Instrument
(ORAI) decision tool for postmenopausal women is based on age
range, weight range, and current estrogen therapy, with high sensitiv-
ity (93%) but low specificity (61%). The Simple Calculated Osteopo-
rosis Risk Estimation (SCORE) decision tool, also for postmenopausal
women, assesses race, rheumatoid arthritis, use of estrogen therapy
(ever), number of osteoporotic fractures, age, and weight, with a
sensitivity and specificity similar to that of the Osteoporosis Risk
Assessment Instrument. Both the Osteoporosis Risk Assessment
Instrument and Simple Calculated Osteoporosis Risk Estimation per-
formed well when compared to other prediction rules.28,29
Other tools
are the Osteoporosis Self-Assessment Tool, Osteoporosis Self-Assess-
ment Tool for Asians, and the FRACTURE index.
A fracture prediction model is being developed by the World
Health Organization (WHO) to determine which patients would
benefit most from therapy, not to determine which patient should
undergo BMD testing.29
The WHO model uses the following risk
factors: age, previous fracture, family history of hip fracture, body
mass index, glucocorticoid use (ever), current smoking, alcohol use
>2 units/day, and rheumatoid arthritis with or without BMD to
predict an individual’s percent absolute probability of fracturing in
the next 10 years.
SCREENING USING PERIPHERAL BONE
MINERAL DENSITY DEVICES
ᕢ Peripheral bone density devices that utilize x-ray absorptiometry
or quantitative ultrasonometry are helpful as screening tools to
determine which patients require further evaluation with central
DXA. They should not be used for diagnosis or monitoring
response to therapy. Peripheral DXA of the forearm, heel, and finger
uses a low amount of radiation. Heel quantitative ultrasonometry
uses sound waves without radiation or need for specialty training.
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.30
No
guidelines specifically address who should undergo peripheral bone
density screening.31
However, the best population to screen is
younger postmenopausal women without major risk factors for
osteoporosis. A low peripheral BMD value for postmenopausal
women would warrant further testing. The specific T-score thresh-
old for referral is not universally defined and varies by device.31
Healthy premenopausal women and 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.
CLINICAL CONTROVERSY
The use of peripheral BMD screenings for older men and
perimenopausal women with risk factors for osteoporosis is
controversial. Data supporting fracture risk predication with
these devices are either lacking or not as robust in older men and
perimenopausal women. The T-score thresholds for referral in
these populations are unknown. In addition, many peripheral
devices do not have a male reference database. More data are
needed on the predictive value of peripheral screening devices in
these populations before routine use.
CENTRAL DUAL-ENERGY
X-RAY ABSORPTIOMETRY
ᕢ BMD measurements at the hip or spine can be used to assess
fracture risk, establish the diagnosis and severity of osteoporosis,
and sometimes confirm osteoporosis as causative for low-trauma
fractures. Central DXA is considered the gold standard for measur-
ing 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 both lumbar
spine and proximal femur or total hip BMD are 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.
ᕡ ᕢ Several consensus guidelines or position statements are
available that discuss which women should undergo central
DXA.5,27,32,33
Most are consistent in recommending central BMD
testing for all senior women aged 65 years or older, postmenopausal
women younger than 65 years of age with risk factors for fracture,
women with a low-trauma fracture, and women with an identified
secondary cause for bone loss. The United States Preventive Services
Task Force recommends screening all senior women and women 60
to 64 years of age who are at increased risk for osteoporotic frac-
tures.34
The International Society for Clinical Densitometry recom-
mends central BMD testing using a male database in all men older
than age 70 years, men with a history of a low-trauma fracture as an
adult, and men with an identified secondary cause for bone loss.35
Ethnic-specific reference databases are not recommended at this time.
In the absence of a suspected or known secondary cause for osteopo-
rosis or a history of a low trauma fracture, central BMD testing is not
recommended for premenopausal or perimenopausal women.
A central DXA BMD report provides the actual bone density
value, T-score, and Z-score. The actual bone density value (g/cm2
)
is most useful for serial monitoring of drug therapy response. The
T-score 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. The T-score is the number of standard devia-
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1489
tions from the mean of the reference population. The Z-score
compares the patient’s BMD to the mean BMD for a healthy, sex,
and age-matched white population and is usually low when second-
ary causes of osteoporosis are present.
LABORATORY TESTS
Laboratory testing (see Table 93–3) is used to identify secondary
causes of bone loss. If a preliminary investigation indicates a
possible secondary cause, additional testing might be needed.
ᕣ Serum 25(OH) D is the best indicator of total body vitamin D
status.15
Data suggest that serum 25(OH) D concentrations of at
least 30 ng/mL are necessary to maximize intestinal calcium absorp-
tion, minimize secondary hyperparathyroidism, and reduce fracture
risk.15,36
Osteomalacia can occur at concentrations less than 8 to 10
ng/mL.18
Although no consensus exists, a reasonable definition for
vitamin D deficiency can be considered a 25(OH) D concentration
of ≤10 ng/mL, insufficiency as a concentration between 11 and 29
ng/mL, and sufficiency as ≥30 ng/mL (1 ng/mL = 2.5 nmol/L).
Vitamin D insufficiency and deficiency are common in all age
groups, especially in seniors and individuals who are malnourished,
living in an institution (e.g., nursing home), or living in extreme
northern latitudes.15,18,36
Low vitamin D concentrations result from
insufficient intake, decreased sun exposure, decreased skin produc-
tion, or decreased liver and renal metabolism. Endogenous synthe-
sis of vitamin D can be decreased by factors that impact exposure to
or decrease skin penetration of ultraviolet B light. Sunscreen use,
full body coverage with clothing (e.g., women wearing veiled dress),
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 vitamin D assays are expensive and large interlab assay
variability exists, routine vitamin D screening cannot be recom-
mended.15
A 25(OH) D concentration should be considered in
anyone at high risk for vitamin D deficiency (e.g., seniors with
minimal sun exposure, insufficient intake, dark pigmented skin),
low bone density, history of a low-trauma fracture or frequent falls,
on medications known to affect vitamin metabolism, or with a
history of unexplained muscle and/or bone pain.15
BONE TURNOVER MARKERS
Urine and serum bone turnover markers are either enzymes or
proteins produced during bone formation or breakdown. Bone-
specific alkaline phosphatase, osteocalcin and procollagen type 1
propeptides are examples of bone formation markers. Hydroxypy-
ridinium crosslinks of collagen pyridinoline and deoxypyridinoline,
C-terminal crosslinking telopeptide of type 1 collagen and N-
terminal crosslinking telopeptide of type 1 collagen are examples of
bone resorption markers. Increased concentrations of bone resorp-
tion markers (≥2 standard deviations above the premenopausal
range) have been shown in some studies to predict fracture risk;
however, results have been inconsistent.19
Although not diagnostic,
these tests my be helpful in identifying accelerated bone turnover
and increased fracture risk or in monitoring response to therapy.
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.
Osteopenia or low bone mass is a T-score of –1 to –2.4 and
osteoporosis is a T-score at or below –2.5. Although these defini-
tions are based on data from postmenopausal white women, they
are applied to other racial/ethnic groups and senior men. The
International Society for Clinical Densitometry recommends the
presence of risk factors in addition to a low T-score before the
diagnosis of osteoporosis can be made in men ages 50 to 65 years.
PREVENTION AND TREATMENT
Osteoporosis
Osteoporosis prevention and treatment begins with a bone-healthy
lifestyle and uses nonprescription and prescription medications as
needed.
■ DESIRED OUTCOMES
The primary goal of osteoporosis management should be preven-
tion. Optimizing skeletal development and peak bone mass accrual
in childhood, adolescence, and early adulthood will ultimately
reduce the future incidence of osteoporosis. Once osteopenia 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 future falls and
fractures, improving functional capacity, reducing pain and defor-
mity, and improving quality of life are the main goals.
■ GENERAL APPROACH TO PREVENTION
AND TREATMENT
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. Prescription medication use for
osteopenia (T-score –1 to –2.4) remains controversial. The National
Osteoporosis Foundation recommends considering prescription
therapy in any postmenopausal woman with a T-score less than –2.0
or less than –1.5 if they have one or more major osteoporosis risk
factors.27
Prescription medications, with bisphosphonates being the
drug of choice, are recommended for men and women with osteo-
porosis (T-score of –2.5 or lower or presence of low-trauma
fracture). Figure 93–3 provides an osteoporosis management algo-
rithm that incorporates both nonpharmacologic and pharmaco-
logic approaches.
■ NONPHARMACOLOGIC THERAPY
Nonpharmacologic therapy, referred to as bone-healthy lifestyle
changes, includes diet, smoking cessation, exercise, fall prevention,
and hip protectors.
Diet
ᕤ Overall, a diet well balanced in nutrients and minerals is
important for bone health. In addition, limiting intakes of caffeine,
alcohol, sodium, cola, and other carbonated beverages.
Although results are conflicting, excessive caffeine consumption
is associated with increased calcium excretion, increased rates of
bone loss, and a modest increased risk for fracture.37
Ideally,
caffeine consumption should be limited to two servings or less per
day. Moderate caffeine intake (two to four servings per day) should
not be a concern if adequate calcium intake is achieved daily. For
excessive caffeine use, intake should be decreased. Alcohol con-
sumption in moderation is not associated with an increased risk for
osteoporosis or fractures. Excessive alcohol intake can increase risk
because of poor nutrition, impaired calcium and vitamin D metab-
olism, and an increased risk for falls. According to 2005 dietary
guidelines, alcohol consumption should not exceed one drink per
day for women and two drinks per day for men.38
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Sodium intake increases calcium excretion.39
In patients with low
intakes of calcium, excessive sodium intake can lead to increased bone
resorption and lower BMD. To minimize calcium loss secondary to
increased sodium intake, an individual can consume higher amounts of
daily calcium and potassium and decrease sodium intake to <2.4 g/day.
Consumption of cola beverages with or without caffeine is
associated with decreased BMD and increased fracture risk; how-
ever, data are conflicting.40
Caffeine and phosphoric acid content of
cola beverages might cause bone loss by altering calcium balance.
This effect is compounded by decreased milk consumption with a
consequent reduction in calcium intake and simultaneous increased
carbonated beverage intake in the United States.41
Calcium ᕤ ᕥ Data clearly indicate that adequate calcium intake
is necessary for the development of bone mass during growth and
for its maintenance throughout life. Adequate calcium intake is an
essential component of all osteoporosis prevention and treatment
strategies.
Table 93–4 summarizes the recommended adequate intakes for
calcium based on age. Achieving daily calcium requirements from
calcium-containing foods, which also contain other essential nutri-
ents, is preferred (Table 93–5). Some food sources are absorbed well
but have low elemental calcium content (e.g., broccoli), or contain
oxalic acid (e.g., spinach) or phytic acid (e.g., wheat bran) that bind
calcium within the food and decrease its absorption.42
Approximately
25% of the U.S. population has some level of lactose intolerance, with
the incidence in Asian (80%) and African American (50%) popula-
tions being much higher than in whites (10%).42
For lactose-intoler-
ant patients, lactose-reduced milk, lactose-free milk, yogurt with
active cultures or Lactaid, along with other nondairy calcium-fortified
products (e.g., orange juice, breakfast cereals, and energy bars) can be
recommended.
Vitamin D ᕤ ᕥ Table 93–4 lists the Institute of Medicine’s ade-
quate intakes for Vitamin D.43
The National Osteoporosis Foundation
guidelines recommend 800 to 1,000 units vitamin D daily for adults
age 50 years and older.27
Several experts believe at least 800 to 2,000
units of vitamin D daily are needed, especially in seniors.18
The three
main sources of vitamin D are sunlight, diet, and supplements.
Because few foods are naturally high or fortified with vitamin D (Table
93–6), most people, especially seniors, require supplementation.
Other Nutrients and Minerals Vitamin K is a cofactor for car-
boxylation (activation) of proteins, such as osteocalcin, which are
involved in bone formation.18,39,44
Several studies have demon-
strated that vitamin K deficiency can contribute to bone loss and an
increased risk for fractures.44
Data suggest that the current recom-
mended adequate intakes for vitamin K might be too low for
optimal bone health.44
More data are needed before recommending
routine supplementation.
Minimal to no data exist for other nutrients and minerals such as
boron and magnesium.45
Until more data are available, taking a
FIGURE 93-3. Algorithm for the management of osteoporosis in postmenopausal women (A) and men (B). (BMD, bone mineral density; DXA, dual-
energy x-ray absorptiometry, RA, rheumatoid arthritis.)
NO
T-score ≥ –1.0
YES
YES
A
T-score <–2.0 or
T-score –1.6 to –2.0 with ≥ 1
major risk factor for fracturea
T-score –1.1 to –2.0 without
any major risk factorsa
Presence of a low trauma fracture
(vertebrae, hip, wrist or forearm)
Patient’s characteristic:
• ≥ 65 years of age
• < 65 years of age with ≥ 1 major risk factor for fracturea
• Abnormal peripheral BMD test
• Radiographic evidence of osteopenia
• Medical conditions or medications known to increase the
risk for bone loss and fracture (e.g., RA)
• Bone-healthy lifestyleb
• Calcium 1,200 mg/day
• Vitamin D 800–1,000 units/day
• Drug Therapy:
• First-line: bisphosphonate
• Second-line: teriparatidec
• Third-line: raloxifene
• Fourth-line: intranasal calcitonin
Obtain baseline central BMD testing for
monitoring response to therapy.
Re-evaluate BMD in 1-2 years
Send for central DXA testing
a
Major risk factors: current smoker, low body weight, personal history of fracture as an adult (after age 45 years), history of low-trauma fracture in a first-degree relative and rheumatoid arthritis.
b
Bone-healthy lifestyle: smoking cessation, well-balanced diet, resistance exercise, and fall prevention for seniors.
c
Teriparatide can be considered a first-line option in patients with a T-score <−3.5.
• Calcium 1,000–1,200 mg/day
Re-evaluate BMD in 5 years or as
appropriate
• Drug therapy:
• First-line: bisphosphonate
• Second-line: teriparatidec or raloxifene
• Third-line: intranasal calcitonin
• Drug therapy to prevent bone
loss can be considered
Re-evaluate BMD in ≥ 2 years or
as appropriate
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1491
multivitamin once daily and consuming a healthy diet, following the
United States Department of Agriculture food pyramid recommen-
dations for daily fruit and vegetable intake, should provide an ade-
quate intake of these vitamin and minerals for general bone health.
Protein Dietary protein represents a key nutrient for bone health.46
High protein intakes (especially animal protein) were thought to be
detrimental to bone health by increasing urinary calcium excretion.
However, evidence suggests that low protein intakes increase osteopo-
rosis risk and that higher protein intakes are protective against bone
loss and fractures. The increased calciuria seen with higher intakes of
protein is more likely an indicator of an increased absorption of
dietary calcium rather than increased bone resorption as proposed.
Dietary Soy Isoflavone phytoestrogens are plant-derived com-
pounds that possess weak estrogenic agonist and antagonist effects.
The most common source for isoflavone is dietary soy products.
Genistein is the most abundant and biologically active isoflavone in
soybeans. The evidence supporting a positive bone benefit from soy
protein (isoflavone) intake is conflicting, with some positive data
with larger isoflavone intakes (76 mg daily).47
In the Chinese diet,
higher soy protein intake was significantly associated with a lower
risk of fractures, especially within 10 years of menopause and in
women taking at least 21 mg isoflavone per day.48
Since isoflavones
are safe, patients can be encouraged to increase their intake, but true
benefits on fracture are not clear.
Smoking Cessation
ᕤ Counseling patients of all ages on smoking cessation can help to
optimize peak bone mass, minimize bone loss, and ultimately
reduce fracture risk. Cigarette smoking is an independent risk factor
for osteoporosis and is associated with up to an 80% increased
relative risk for hip fracture.49
The effect is dose and duration
dependent. A decrease in sex hormone concentrations, reduced
intestinal calcium absorption, a direct toxic effect on osteoblasts,
and detrimental effects of smoking on neurovascular function have
been implicated for the negative bone effects.
Exercise
ᕤ Physical activity or exercise is an important nonpharmacologic
approach to preventing osteoporotic fractures. Exercise can decrease
FIGURE 93-3. (Continued)
NO
T-score ≥ –1.0
YES
YES
T-score <–2.5 or
T-score –2.0 to –2.4 with ≥ 1
major risk factor for fracturea
T-score –1.1 to –2.4 without
any major risk factorsa
Patient’s characteristics
• ≥ 70 years of age
• 50–70 years of age with multiple risk factors for fracturea
• Abnormal peripheral BMD test
• Radiographic evidence of osteopenia
• Medical conditions or medications known to increase the
risk for bone loss and fracture (e.g., RA)
Presence of a low trauma fracture
(vertebrae, hip, wrist or forearm)
• Bone-healthy lifestylec
• Drug Therapy:
• First-line: bisphosphonatee
• Second-line: teriparatidef
• Third-line: intranasal calcitoning
Obtain baseline BMD testing for
monitoring response to therapyb
Send for central DXA testingb
a
Major risk factors: current smoker, low body weight, personal history of fracture as an adult (after age 45 years), history of low-trauma fracture in a first-degree relative and rheumatoid arthritis.
b
Based on a normal male reference database.
c
Bone-healthy lifestyle: smoking cessation, well-balanced diet, resistance exercise, and fall prevention for seniors.
d
Examples of secondary causes include hypogonadism, rheumatoid arthritis, chronic obstructive pulmonary disease, systemic glucocorticoids.
e
Alendronate and risedronate are FDA-approved in men. Intravenous bisphosphonates are an option if patient cannot tolerate oral bisphosphonates or has significant adherence problems.
f
Teriparatide is FDA-approved for use in men and can be considered a first-line option in men with a T-score <–3.5.
g
Calcitonin is not FDA-approved for use in men.
Re-evaluate BMD in 5 years or as
appropriate
• Investigate for a secondary
cause and treat as appropriated
Re-evaluate BMD in ≥ 2 years or as
appropriate
• Investigate for a secondary cause and
treat as appropriated
• Drug therapy:
• First-line: alendronate or risedronatee
• Second-line: teriparatidef
• Third-line: intranasal calcitoning
B
TABLE 93-4 Calcium and Vitamin D Recommendations
Institute of Medicine Adequate Intake
Group and Ages
Elemental
Calcium (mg)a
Vitamin D
(units)a,b
Infants
Birth to 6 months 210 200
6–12 months 270 200
Children
1–3 years 500 200
4–8 years 800 200
9–13 years 1,300 200
Adolescents/young adults
14–18 years 1,300 200
Adults
19–30 years 1,000 200
31–50 years 1,000 200
51–70 years 1,200 400
>70 years 1,200 600
a
U.S. Institute of Medicine of the National Academy of Sciences recommends no more than 2500 mg/
day elemental calcium and 2000 units/day vitamin D.
b
Most experts believe the recommended Adequate Intakes for Vitamin D are too low.
www.PharmaDost.info

the risk of falls and fractures by improving muscle strength, coordina-
tion, balance, and mobility. 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) for at least
30 minutes most days of the week and a resistance activity (e.g.,
weight machines, free weights, or elastic bands) at least twice per week
for 20 to 30 minutes.3,27,38
Fall Prevention
ᕤ Because of the link between falls and fractures, homes should be
made safe and potentially harmful medications eliminated.3,5
Table
93–7 provides solutions for commonly observed personal and home
safety problems.50
Medication profiles should be reviewed for any
medications that can affect cognition and balance and potentially
increase fall risk and that are unneeded or can be replaced with a
safer alternative. Maintenance of a regular exercise program, such as
Tai Chi, should be recommended to improve body strength, balance,
and agility.
Hip Protectors
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.5,51
■ PHARMACOLOGIC THERAPY
Because nonpharmacologic interventions alone frequently are
insufficient to prevent or treat osteoporosis, drug therapy is often
necessary. Table 93–8 describes fracture and BMD effects and Table
93–9 describes important aspects of common osteoporosis medica-
tions. These medications should always be combined with a bone-
healthy lifestyle.
Drug Treatments of First Choice
Currently, bisphosphonates are the prescription drug of choice with
teriparatide, raloxifene, and calcitonin considered alternative agents.
Duration of bisphosphonate therapy has not been defined, but safety
data exist for periods of 7–10 years.52
Short-term (18 to 24 months)
teriparatide is used for severe osteoporosis and then followed by
bisphosphonate therapy. The algorithm (see Fig. 93–3) helps deter-
mine for whom drug therapy should be used. Osteoporosis prescrip-
TABLE 93-5 Elemental Calcium Content of Selected Foods
and Beverages
Foods/Beverages
Elemental Calcium
Content (mg)a
Milk (skim, low-fat, whole), 1 cup 276–309
Calcium-fortified soy milk, 1 cup 80–300
Calcium-fortified orange juice, 1 cup 300
Calcium-fortified cranberry juice, 1 cup 100
7UP Plus, 1 cup 100
Low-fat fruit yogurt, 1 cup 345
Frozen yogurt, 1 cup 180–240
Vanilla ice cream, 1 cup 176–200
Soft-serve vanilla ice cream, 1 cup 236
Swiss cheese, 1.5 oz. 336
Cheddar, mozzarella, or provolone cheese, 1.5 oz. 307–311
Ricotta cheese, 1
/2 cup 255–335
Cottage cheese, 4 oz. 78–100
Fortified breakfast cereals 236–1,043
Fortified instant oatmeal 99–110
Figs, dried, 10 270
Collard greens, cooked, 1
/2 cup 178
Broccoli, cooked, 1 cup 100–180
Soybeans, cooked, 1
/2 cup 88–130
Okra, cooked, 1
/2 cup 88
Bok choy, raw, 1 cup 160–250
Tofu, firm, 1
/2 cup 253
Almonds, 1 oz. 75
Salmon, canned with bones, 3 oz. 170–210
a
Food labels are based on a RDA of 1,000 mg/day; multiply percentage on package by 10 (e.g.,
product containing 30% calcium = 300 mg).
Data from www.health.gov/dietaryguidelines/dga2005/document/html/appendixB.htm.
TABLE 93-6 Vitamin D Content of Selected Foods and Beverages
Foods/Beverages Vitamin D (international units)a
Salmon, 3.5 oz 360
Mackerel, 3.5 oz 345
Tuna fish, canned in oil, 3 oz 200
Sardines, canned in oil, 1.75 oz 250
Cow’s milk (all forms), 1 cup 100
Vitamin D fortified orange juice 100
Ready-to-eat-cereal (fortified), 1 cup 40
Margarine, 1 tablespoon 60
Egg, 1 whole (or egg yolk) 20
Liver, beef, cooked, 3.5 oz 15
a
Food labels are based on a RDA of 400 units/day; multiply percentage on package by 4 (e.g., product
containing 20% vitamin D = 80 units).
Data from http://dietary-supplements.info.nih.gov/factsheets/vitamind.asp.
TABLE 93-7 Personal and Home Fall Prevention Strategies
Lighting
Place switches/lamps at room entrances and at the bottom and top of stairs
Put in brighter light bulbs
Use nightlights, 100- to 200-watt bulbs
Keep a flashlight with fresh batteries by the bed for night use
Floors
Keep home environment neat and tidy; always keep objects off the floor
Remove low-lying or difficult-to-see objects
Remove throw rugs or use rugs with a nonslip backing
Remove all loose electrical and telephone wires
Bathrooms
Install elevated toilet seats
Install grab bars in bathtubs or showers
Apply nonskid strips, rubber mats, or decals to shower or bathtub floor
Place nonskid mats on bathroom floor
Install a seat in the bathtub or shower
Stairways (inside and outside the home)
Install cylindrical handrails on both sides of the stairs
Do not leave objects lying on the stairs
Fix any uneven or broken steps
Apply nonskid treads to steps
Furniture
Replace low furniture with higher or thicker furniture
Provide chairs with armrest support
Storage
Keep frequently used items at waist level
Use “reach” device to obtain objects
Personal safety
Watch out for small pets or children in home or outdoors
Use handrails when going up or down stairs
Wear shoes that grip well (nonskid rubber soles)
Always look where you are going (be cautious of uneven surfaces or icy spots)
Clean up spills immediately so you do not slip
Rise slowly from a seated position
Visit ophthalmologist annually (ensure adequate vision correction)
Exercise regularly to improve strength, balance, and coordination
Modified from reference 50. Also available in Spanish and Chinese.
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1493
tion medications in children and pre- and perimenopausal women
are controversial and undergoing further investigation.
Published Guidelines and
Treatment Protocols
Osteoporosis diagnosis and treatment guidelines exist but none are
universally accepted. Two North American guidelines are evidence
based: the 2003 update of the American Association of Clinical
Endocrinologists evidence-based guidelines for prevention and
treatment of postmenopausal osteoporosis and the 2002 Canadian
osteoporosis guidelines for women, men, and special popula-
tions.33,53
The 2006 North American Menopause Society’s position
statement used both evidence and consensus to develop recommen-
dations on the management of postmenopausal osteoporosis.5
In
2003, the National Osteoporosis Foundation updated its consensus
guidelines for postmenopausal women.27
The National Institutes of
Health held an osteoporosis consensus conference in 2001 and
published the findings, recommendations, and research needs.2
Guidelines are being updated to reflect newer diagnostics (e.g.,
WHO fracture risk assessment), agents (e.g., teriparatide), and
monitoring (e.g., biomarkers, osteonecrosis of the jaw). Subspe-
cialty guidelines continue to be developed (e.g., osteoporosis and
gastrointestinal [GI] diseases, rheumatology and glucocorticoid-
induced osteoporosis). Based on these guidelines and newer infor-
mation, an algorithm reflecting current suggested practice is pre-
sented (see Fig. 93–3). Even with guidelines and algorithms, many
patients are neither being evaluated nor receiving appropriate
osteoporosis therapy.54
Antiresorptive
Antiresorptive therapies include calcium, vitamin D, bisphospho-
nates, estrogen agonists/antagonists (known previously as selective
estrogen receptor modulators or SERMs), and calcitonin.
Calcium Supplementation ᕥ Calcium imbalance can result
from inadequate dietary intake, decreased fractional calcium
absorption, or enhanced calcium excretion. Adequate calcium
intake (see Table 93–4) is considered the minimal standard for
osteoporosis prevention and treatment and should be combined
with vitamin D and osteoporosis medications when needed. Supple-
mental calcium intake (Table 93–10) will be needed in the majority
of people with or at risk for osteoporosis as survey data indicate that
the average U.S. diet contains only 600 mg calcium per day.42
Efficacy. Although calcium increases BMD, fracture prevention
is minimal. More than 150 studies have evaluated calcium’s effect
on BMD with almost all trials and observational studies showing
that higher calcium intake in children and adults produced greater
increases or maintenance of BMD compared to BMD losses with
placebo.17
Calcium’s BMD effects are less than other antiresorp-
tive and formation osteoporosis medications. If fracture preven-
tion was documented, concomitant vitamin D therapy was usually
given. Nonbone benefits of calcium intake include decreased
TABLE 93-8 Fracture and Bone Mineral Density Effects of FDA-Indicated Osteoporosis Medications in Postmenopausal Womena
Product
Vertebral Fracture Reduction Nonvertebral Fracture Reduction Hip Fracture Reduction
Lumbar
Spine BMD
Femoral
Neck BMD RefAbsolute Risk/Relative Risk Absolute Risk/Relative Risk Absolute Risk/Relative Risk
Bisphosphonates 5,58,59
Alendronate 1.7%–3.7%/44%–48% 1.5%–2.8%/12%–21% 0.2%–1.1%/21%–51% 8.8% 5.9%
Ibandronate (oral) 4.9%/38% NS NS 5.2% 4.1%
Risedronate 4%–11%/41%–65% 3.2%–5.1%/33%–39% 1.3%/40%b
4.3% 2.8%
Zoledronic acid (IV) 7.6%/70% 2.7%/25% 1.1%/41% 6.7% 5.1%
Raloxifene 2.2%–6.5%/30%–50% NS NS 2.6% 2.1% 5,58,68
Calcitonin 8%/33% NS NS 3% NS 5,58
Teriparatide 9.3%/65% 2.9%/53% NS 6%–14% 1.5%–3.5% 5,58,78
Estrogenc
NA/36%d
0.53%/29% 0.07%/35% 7.1% 1.8% 72
Estrogen with progestine
NA/35%d
0.47%/25% 0.05%/33% 7.6% 3.7% 71
BMD, bone mineral density; NA, not available; NS, not significant; Ref, reference.
a
Only the pivotal trials with daily oral or yearly intravenous therapy were powered for fracture evaluation. Fracture data not available for weekly, monthly, and quarterly oral bisphosphonate therapy. For estrogen
and estrogen/progestin, only the Women’s Health Initiative Trials were used.
b
Only seen in women 70 to 79 years old, not those ≥80 years old.
c
Conjugated equine estrogen 0.625 mg daily.
d
Only clinical vertebral fracture data given.
e
Conjugated equine estrogen 0.625 mg and medroxyprogesterone 2.5 mg daily.
TABLE 93-9 Medications Used to Prevent and Treat Osteoporosis
Drug Adult Dosage Pharmacokinetics Adverse Effects Drug Interactions
Calcium Adequate intake (Table 93–4) in
divided doses
Absorption––predominantly
active transport with some
passive diffusion, fractional
absorption 10%–60%, fecal
elimination for the unab-
sorbed and renal elimina-
tion for the absorbed
calcium
Constipation, gas, upset
stomach, rare kidney
stones
Carbonate salts––decreased absorption
with proton pump inhibitors
Decrease absorption of iron, tetracycline,
quinolones,bisphosphonates,phenytoin,
and fluoride when given concomitantly
Might antagonize verapamil
Might induce hypercalcemia with thiazide
diuretics
Fiber laxatives (variable), oxalates,
phytates, and sulfates can decrease cal-
cium absorption if given concomitantly
(continued)
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TABLE 93-9 Medications Used to Prevent and Treat Osteoporosis (continued)
Drug Adult Dosage Pharmacokinetics Adverse Effects Drug Interactions
D3 (cholecalciferol) Adequate intake (Table 93–4); if
malabsorption or multiple
anticonvulsants might require
higher doses (~ ≥4,000 or
more units daily)
Hepatic metabolism to
25(OH) vitamin D and then
renal metabolism to active
compound 1,25(OH)2 vita-
min D, other active and
inactive metabolites
Hypercalcemia, (weakness,
headache, somnolence,
nausea, cardiac rhythm
disturbance), hypercalci-
uria
Phenytoin, barbiturates, carbamazepine,
rifampin increase vitamin D metabo-
lism
D2 (ergocalciferol) For vitamin D deficiency, 50,000
units once weekly or once
monthly; dosed dependent on
serum calcium
Cholestyramine, colestipol, orlistat, or
mineral oil decrease vitamin D absorp-
tion
1,25(OH)2 vitamin D (cal-
citriol, Rocaltrol PO, Cal-
cijex IV)
0.25–0.5 mcg orally or 1–2 mcg/
mL intravenously daily for renal
osteodystrophy, hypoparathy-
roidism, and refractory rickets
Might induce hypercalcemia with thiazide
diuretics in hypoparathyroid patients
Oral bisphosphonates Poorly absorbed—<1%
decreasing to zero with food
or beverage intake—long
T1/2 (<10 years); renal elim-
ination (of absorbed) and
fecal elimination (unab-
sorbed)
Nausea; heartburn; GI pain,
irritation, perforation,
ulceration, and/or bleed-
ing; transient flu-like ill-
ness; muscle pains; black
box warning for rare
osteonecrosis of the jaw
Do not coadminister with any other med-
ication or supplements (including cal-
cium and vitamin D)
Alendronate (Fosamax,
Fosamax plus D)
5 mg daily, 35 mg weekly (pre-
vention)
10 mg daily, 70 mg tablet, 70
mg tablet with vitamin D
2,800 or 5,600 units, or 75 mL
liquid weekly (treatment)
Risedronate (Actonel) 5 mg daily, 35 mg weekly, 75
mg on two consecutive days
once monthly
150 mg monthly, 3 mg intrave-
nous quarterly
Intravenous bisphosphonates Muscle pains, transient flu-
like illness, redness or
swelling at injection site,
black-box warning for rare
osteonecrosis of the jaw
Ibandronate (Boniva) 5 mg intravenous infusion yearly
Zoledronic acida
(Reclast)
Mixed estrogen agonist/
antagonist
Hepatic metabolism Hot flushes, leg cramps,
venous thromboembo-
lism, peripheral edema,
rare cataracts and gallblad-
der disease; black box
warning for fatal stroke
None
Raloxifene (Evista) 60 mg daily
Calcitonin (Miacalcin) 200 units intranasal daily, alter-
nating nares every other day
Renal elimination Rhinitis, epistaxis None
3% nasal availability
Teriparatide (1–34 units,
Forteo)
20 mcg subcutaneously daily for
up to 2 years
95% bioavailability Pain at injection site, nau-
sea, dizziness, leg cramps,
rare increase in uric acid,
slightly increased calcium
None
Tmax ~30 minutes
T1/2 ~60 minutes
Hepatic metabolism
Testosterone products 10% gel absorption (5 mg
absorbed from 50 mg tes-
tosterone in 5 g of gel)
Weight gain, acne, hirsut-
ism, dyslipidemia, hepatic
consequences, gyneco-
mastia, priapism, prostate
disorders, testicular atro-
phy, sleep apnea, and
skin reactions with
patches
Transdermal patch
(Testoderm TTS, Andro-
derm, Testim)
5 mg patch applied to arm, back,
or thigh every evening
(patches 2.5, 4, 5, & 6 mg)a
Testoderm (R) with or
without adhesive)
6 mg applied to scrotal skin
every evening
Gel (AndroGel 1%,
Testim 1%)
5 gm gel applied to shoulder,
upper arm, or abdomen every
morning
Buccal system (Striant 30
mg)
Place one system in gum area
twice a day. Alternate sides of
mouth. Do not crush or swallow
Injection
Cypionate (100 or 200
mg/mL) or enanthate
(200 mg/mL) salt
200–300 mg IM every 2–3
weeks
Methyltestosterone (for
women)
1.25–2.5 mg with esterified
estrogen
GI, gastrointestinal; IM, intramuscular; Tmax, time to maximum concentration; T1/2, half life.
a
No abdomen patch placement for Testim; none of these patches can be applied to the genitals.
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1495
blood pressure, cholesterol, and colorectal cancer risk, the last
being controversial.17
Adverse Events/Precautions. 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 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.
Calcium rarely causes kidney stones. 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.
Administration. Most children and adults of all ethnic back-
grounds do not ingest sufficient (see Table 93–4) dietary calcium
(see Table 93–5) and require supplements (see Table 93–10).17,55
To insure adequate calcium absorption, 25(OH) D concentrations
should be maintained in the normal range. Because fractional
calcium absorption is dose-limited, maximum single doses of 600
mg or less of elemental calcium are recommended. Calcium car-
bonate is the salt of choice as it contains the highest amount of
elemental calcium and is the least expensive (see Table 93–10).
Calcium carbonate tablets should be taken with meals to enhance
absorption. Calcium citrate absorption is acid-independent and
need not be administered with meals. Although tricalcium phos-
phate contains 39% calcium, calcium-phosphate complexes could
limit overall calcium absorption compared to other products. This
product might be helpful in the 10% of seniors with hypophos-
phatemia 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, should be recommended. Oyster
shell (other than the OsCal brand) or coral calcium should not be
recommended because of concerns for high concentrations of lead
and other heavy metals. “Bone designer” nonprescription products
continue to be developed by combining calcium and vitamin D
with other nutrients, some of which are associated with bone
physiology (e.g., magnesium, manganese, boron, vitamin K).45
Minimal BMD and no fracture data exist for these combination
products. Because product labeling is confusing, patients might not
realize they need 4 to 6 tablets per day to obtain adequate calcium
intakes. 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.
Vitamin D Supplementation ᕥ Vitamin D intake is critical for
the prevention and treatment of osteoporosis because it maximizes
intestinal calcium absorption. Given the safety, low cost, and other
benefits of vitamin D, no patient should have an inadequate intake.
Efficacy. Two meta-analyses evaluated the efficacy of cholecal-
ciferol with or without calcium supplementation on fracture risk
and falls in seniors. Higher doses of vitamin D (700 to 800 units/
day) demonstrated a significant 26% relative risk reduction in hip
fractures, a 23% relative risk reduction in any nonvertebral
fracture, and a 22% relative risk reduction in falls.36,56
While
several studies have demonstrated a beneficial effect of vitamin D
on fractures and falls, not all studies have demonstrated a benefi-
cial effect.56
Conflicting results between studies are thought to be
a result of differences in vitamin D dosing, concomitant calcium
administration, adherence, and baseline vitamin D status of
subjects.
Vitamin D has other potential nonskeletal benefits. Improvement
in muscle strength and cardiovascular function, decreased cancer
risk (e.g., breast, colon, and prostate cancers), and positive immu-
nomodulatory effects (e.g., multiple sclerosis, type 1 diabetes, rheu-
matoid arthritis) have been proposed.15,36
Administration. Seniors and patients being treated for osteopo-
rosis should take at minimum 800 units of vitamin D through food
and supplementation with a goal to maintain their 25(OH) D
concentration within the sufficient range.18,36
Cholecalciferol (vita-
min D3) is more efficient than ergocalciferol (vitamin D2) at raising
25(OH) D concentrations and is the preferred form of vitamin D
supplementation. Usual supplementation is with daily nonprescrip-
tion vitamin D products (see Table 93–10). However, higher-dose
prescription oral or intramuscular regimens administered weekly,
monthly, or quarterly have been studied in seniors residing in the
community or nursing home environments.56
In patients with
measured insufficient 25(OH) D concentrations, higher daily
intakes of vitamin D may be needed. More than one multivitamin
or large doses of cod liver oil daily are no longer advocated because
of the risk of hypervitaminosis A, which increases 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) D concentration can be obtained.16
Individuals with deficient concentrations of vitamin D are at risk
for osteomalacia. Their management is discussed in Other Meta-
bolic Bone Diseases below. In patients with disorders affecting
vitamin D absorption (e.g., celiac disease, cystic fibrosis, or Crohn’s
disease), higher doses and more frequent monitoring. In patients
with severe hepatic or renal disease, the activated form of vitamin D
(calcitriol) might be more appropriate.
TABLE 93-10 Calcium and Vitamin D Product Selection
Product (% calcium)a
Elemental
Calcium (mg) Vitamin D (units)
Calcium carbonateb
(40%)
Trade and generic products 200–600 100–200
Mylanta Supreme liquid (5 mL) 160
Tums Chewable 200
E-X 300
Ultra 400
Rolaids chewable 471
Os-Cal sugar-free chewable 500 400
Viactiv chewsc
500 200
CalMax powder (10 mL) 400
Bayer’s Womend
300
Ensure high calciumc
(8 oz) 400 140
Calcium citrate (24%)
Generic 315 200
Citracal + Vit D 200–315 200
Citracal chew 500 200
Tricalcium phosphate (39%)
Posture-D 600 125
Vitamin D3 (cholecalciferol) 0 400, 700, 800, or 1,000
Multivitamin (D3)c
40–250 400
Ergocalciferol (D2)e
Liquid (1 mL) 8,000
Tablets/capsules 25,000 or 50,000
Intramuscular (1 mL) 500,000
a
Many products are adding magnesium, boron, zinc, copper, vitamin K, and/or manganese;
sometimes adding “Plus” or “Ultra” to their name. These “bone designer” products are not listed
here, see reference 45.
b
There are many trade-name products for calcium carbonate (e.g., Calel-D, Caltrate, and Os-Cal).
Only calcium carbonate alternative dosage forms (i.e., chewable, liquid, powder) are specifically
listed.
c
Contains vitamin K.
d
Contains aspirin 81 mg.
e
Prescription products.
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Some experts believe that the upper tolerable limit for vitamin D
should be raised and that the recommended daily allowance for
vitamin D should be 2,000 units per day. This is the amount of
vitamin D that would be needed for approximately 90% of the
population to maintain 25(OH) D concentrations at ≥30 ng/mL
with a low risk for toxicity.18,36
Bisphosphonates ᕧ Bisphosphonates mimic pyrophosphate, an
endogenous bone resorption inhibitor. Bisphosphonate antiresorp-
tive activity results from blocking prenylation and inhibiting guano-
sine 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 significan-
ces are not clearly known.57
All bisphosphonates become incorpo-
rated into bone, giving them long biologic half-lives of up to 10 years.
Alendronate, risedronate, and oral ibandronate are currently FDA
indicated for the prevention and treatment of postmenopausal
osteoporosis (see Table 93–9). Intravenous ibandronate and
zoledronic acid are indicated only for treatment of postmenopausal
women. Risedronate and alendronate are also FDA indicated in male
and glucocorticoid-induced osteoporosis. Clinical trials with iban-
dronate and zoledronic acid are ongoing for these indications.
Efficacy. Of the antiresorptive agents, bisphosphonates consis-
tently provide the greatest fracture risk reductions and BMD
increases (see Table 93–8). Fracture data trials used daily oral
bisphosphonate or annual intravenous therapy, not weekly,
monthly, or quarterly regimens.5,58,59
Although hip fracture reduc-
tion was not seen with daily oral ibandronate, the hip fracture
incidence in the placebo group was low. Furthermore, not all studies
for alendronate and risedronate have documented hip fracture
prevention. Fracture reductions are demonstrated as early as 6
months,60
with the greatest fracture reduction seen in patients with
lower initial BMD and in those with the greatest BMD changes with
therapy. (Note added in poof: Secondary fracture prevention has
been documented after a hip fracture with annual intravenous
zoledronic acid [Lyles KW, Colo-n-Emeric CS, Magaziner JS, et al.
Zoledronic acid and clinical fractures and mortality after hip frac-
ture. N Engl J Med 2007;357(18):1799-1809.])
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. After discontinuation, the increased BMD is sustained for
a prolonged period of time that varies depending on the bisphospho-
nate used. Weekly alendronate and risedronate therapy produce
equivalent BMD changes to their respective daily regimens. Weekly
alendronate therapy increases BMD more than weekly risedronate
therapy; however, there is no evidence that this difference would
equate to greater fracture efficacy.60
Monthly oral and quarterly
intravenous ibandronate therapies produce greater BMD changes
than daily therapy.61
The BMD increases with alendronate and risedronate in men are
similar to postmenopausal women.62
Because of a lack of fracture
data in men, bisphosphonates are only FDA indicated to increase
BMD, not to reduce fracture risk in men.
Women without evidence of a low-trauma fracture and who
have responded well to alendronate therapy, with BMD increas-
ing into the osteopenic range, are being considered for a “drug
holiday.” Patients are taken off their alendronate therapy and
followed serially with bone turnover markers and central DXA
BMD. Studies demonstrate prolonged suppression of bone turn-
over and maintenance of BMD in some women after discontin-
uation.63
The impact of this practice on fracture risk and
application to other bisphosphonates is unknown.
Adverse Events/Precautions. Bisphosphonate GI adverse effects
are minimal if the medication is taken correctly. Weekly and
monthly therapies have similar common but less-serious GI effects
(perforation, ulceration, GI bleeding) than daily therapy. The GI
event rates were not increased with concomitant nonsteroidal anti-
inflammatory drug use. Patients should be encouraged to discuss GI
complaints with a healthcare provider. Intravenous ibandronate and
zoledronic acid can be used for patients with contraindications or
intolerances to oral bisphosphonates.
The most common adverse effects of intravenous bisphospho-
nates include fever, flu-like symptoms, and local injection-site
reactions.59,60
Osteonecrosis of the jaw has been increasingly reported as a rare
side effect of bisphosphonate therapy.64
Most cases occur in patients
who are receiving high-dose intravenous bisphosphonate therapy for
multiple myeloma and metastatic carcinoma of the skeleton and
after tooth extraction, mouth trauma, or oral surgery. Additional
risk factors include advanced age and concomitant estrogen or
glucocorticoid therapy. The incidence of osteonecrosis of the jaw in
women taking alendronate has been estimated at 0.7 cases per
100,000 person-years of exposure.65
Although the mechanism is
incompletely understood, oversuppression of bone turnover is
thought to play a primary role. Controversy exists about preventing
and treating this condition. Routine dental care and good oral
hygiene should be encouraged in anyone beginning bisphosphonate
therapy. In addition, major dental work probably should be com-
pleted prior to beginning bisphosphonates if possible. There is no
evidence that discontinuing bisphosphonate therapy prior to major
dental work is beneficial. If osteonecrosis of the jaw develops, oral
chlorhexidine washes, systemic antibiotics, and systemic analgesics
are used based on severity.
Administration. Because bioavailability is very poor for bisphos-
phonates (<1% to 5%) and to minimize GI side effects, each oral
dose should be taken with at least 6 ounces of plain tap water (not
coffee, juice, mineral water, or milk) at least 30 (60 for ibandronate)
minutes before consuming any food, supplement (including cal-
cium and vitamin D), or medication. The weekly, raspberry fla-
vored, oral solution only needs to be taken with 2 ounces of water
and can be used for patients with swallowing difficulties (e.g., after
stroke, tube feeding). 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.
Before intravenous bisphosphonates are used, the patient’s serum
calcium level must be normal. The quarterly ibandronate injection
comes as a prefilled syringe (3 mg/mL) kit with a butterfly needle.
The injection is given intravenously 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 administration of
zoledronic acid should be infused over at least 15 minutes. Aceta-
minophen or ibuprofen can be given to decrease adverse effects.
Although these medications are effective, adherence is poor. In
one study, oral bisphosphonate adherence for 1 year was only 58%
to 61% with only approximately 20% continuing therapy for at least
1 year.66
Most patients prefer once-weekly or once-monthly bis-
phosphonate administration to daily therapy. If a patient misses a
weekly dose, they can take it the next day. If more than 1 day has
lapsed, that dose is skipped until the next scheduled ingestion. If a
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1497
patient misses a monthly dose, they can take it up to 7 days before
the next administration. For patients with adherence issues, the
monthly e-mails or postcards sent by the ibandronate manufacturer
might be helpful. Intravenous ibandronate could be used as replace-
ments. Alendronate plus vitamin D can potentially help to ensure
better adherence with vitamin D intake.
Mixed Estrogen Agonists/Antagonists ᕧ Raloxifene, a second-
generation mixed estrogen agonist/antagonist (EAA) approved for
prevention and treatment of postmenopausal osteoporosis, is an
estrogen agonist on bone but an antagonist on the breast and uterus
(see Table 93–9). Newer second-generation EAAs will be approved
soon. Bazedoxifene (Viviant) received an approvable letter for the
prevention of osteoporosis and lasofoxifene (Oporia) is under review.
Efficacy. Raloxifene decreases vertebral fractures and increases
spine and hip BMD, but to a lesser extent than bisphosphonates (see
Table 93–8).58,60
Eight-year data support long-term effects and
safety. After raloxifene discontinuation, the medication effect is lost,
with bone loss returning to age- or disease-related rates. For women
with severe osteoporosis, particularly when hip fracture risk reduc-
tion is desired, a bisphosphonate is likely a better choice.
Raloxifene decreased invasive estrogen receptor positive breast
cancer similarly to tamoxifen in the STAR (Study of Tamoxifen and
Raloxifene) trial; however, tamoxifen had fewer (not significantly
different) noninvasive breast cancer cases in women at high risk for
breast cancer.67
Raloxifene has an FDA-approved indication for
invasive breast cancer risk reduction. Thus in a subset of women,
this additional benefit might warrant raloxifene use for dual osteo-
porosis and breast cancer prevention.
Raloxifene causes some positive lipid effects (decreased total and
low-density lipoprotein cholesterol, neutral effect on high-density
lipoprotein cholesterol, slightly increased triglycerides); however,
no reduction in cardiovascular effects was demonstrated in the
RUTH (Raloxifene Use for the Heart)68
or MORE-CORE (Multiple
Outcomes with Raloxifene study and its continuation) trials.69
Adverse Events/Precautions. Hot flushes occur with a greater
likelihood in women recently finishing menopause or discontinuing
estrogen therapy. Raloxifene rarely causes endometrial bleeding.
Raloxifene is contraindicated for women with an active or past
history of venous thromboembolic event. Therapy should be
stopped if a patient anticipates extended immobility.
In large trials, no change in overall death, cardiovascular death, or
overall stroke incidence was seen; however, a slight increase in fatal
stroke was documented.68
Women at high risk for a stroke 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.
Administration. Similar to bisphosphonates, adherence and per-
sistence problems exist. At 1 year, adherence was 54% and persis-
tence was only 6%.66
Calcitonin Calcitonin is released from the thyroid gland when
serum calcium is elevated. Salmon calcitonin is more potent and
longer lasting than the mammalian form. Calcitonin is FDA indicated
for osteoporosis treatment for women who are at least 5 years past
menopause (see Table 93–9). Although limited data document some
benefits in men and concomitantly with glucocorticoids, these indica-
tions are not approved. Because efficacy is less robust than the other
antiresorptive therapies, calcitonin is reserved as third-line treatment.
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 93–8).5,60
Calcitonin does not consistently affect hip BMD and does not
decrease hip fracture risk.
Calcitonin might provide pain relief to some patients with acute
vertebral fractures, about a 2.5-point change on a visual analog
scale. 70
If used, 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.
Administration. Subcutaneous administration with 100 units
daily is available but rarely used because of adverse effects and costs.
Estrogen Therapy Although estrogens are FDA indicated for pre-
vention of osteoporosis, they should only be used short-term in
women who need estrogen therapy for the management of meno-
pausal symptoms such as hot flushes. The risks of estrogen therapy
outweigh the bone benefits.60
Even though the Women’s Health
Initiative trials only assessed one dose of conjugated equine estro-
gens, most clinicians extrapolate the results to all postmenopausal
estrogen therapies until data indicate otherwise.
Efficacy. Estrogen with (HT)71
or without (ET)72
progestin ther-
apy significantly decreases fracture risk (see Table 93–8).5
Increases
in BMD are less than bisphosphonates or teriparatide, but greater
than 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. Fracture risk reduction has not been
demonstrated with lower dose therapy. When ET or HT is discon-
tinued, bone loss accelerates and fracture protection is lost.
Adverse Events/Precautions/Administration. The lowest
effective dose of ET and HT should still be used for preventing and
controlling menopausal symptoms with use discontinued with
symptom abatement. A complete discussion of adverse events,
precautions, and administration for all estrogen and estrogen and
progestin combination products can be found in Chap. 85.
Testosterone ᕨ Decreased testosterone concentrations are seen
with certain gonadal diseases, eating disorders, glucocorticoid ther-
apy, oophorectomy, menopause, and andropause. Testosterone
replacement is not approved for the prevention or treatment of
osteoporosis.
Efficacy. A few studies of testosterone replacement in women have
demonstrated increases in BMD.73
Testosterone, in various salt
forms, was associated with increased BMD in some studies when
given to hypogonadal men and senior men with normal or mild
hormonal deficiency.74,75
The impact of testosterone replacement
on fracture risk in women and men have not been prospectively
evaluated. Testosterone replacement should not be used solely for
the prevention or treatment of osteoporosis, but might be beneficial
to reduce bone loss in patients needing therapy for hypogonadal
symptoms.
Adverse Events/Precautions. Patients using these products
should be evaluated within 1 to 2 months of initiation and then
every 3 to 6 months thereafter.76
Testosterone and methyltestoster-
one are in pregnancy category X, indicating that the agents are
contraindicated.
Administration. Testosterone products are schedule III drugs.
The gel products can rub off and be absorbed by the patient’s
partner.
Thiazide Diuretics Thiazide diuretics increase urinary calcium
reabsorption. Observational studies suggest that patients who
receive thiazide diuretics have a greater bone mass, lower rates of
bone loss, and fewer fractures.77
Two prospective, controlled trials
demonstrated small increases in bone mass over placebo. Prescrib-
ing thiazide diuretics solely for osteoporosis is not recommended
but is a reasonable choice for the patient with osteoporosis who
www.PharmaDost.info

requires a diuretic and for patients on glucocorticoids with greater
than 300 mg of calcium excreted in the urine over 24 hours.
Anabolic Therapies
Currently teriparatide is the only available medication that increases
bone formation.
Teriparatide Teriparatide is a recombinant product representing
the first 34 amino acids in human PTH (see Table 93–9). Teri-
paratide increases bone formation, the bone remodeling rate, and
osteoblast number and activity. Both bone mass and architecture
are improved. Teriparatide is FDA indicated for postmenopausal
women and men who are at high risk for fracture. Patients who have
a history of osteoporotic fracture, multiple risk factors for fracture,
very low bone density (e.g., T-score < –3.5), or have failed or are
intolerant of previous bisphosphonate therapy are candidates for
PTH therapy. Human PTH (1–84), PTH analog (1–31), oral PTH,
and intranasal, transdermal, and once-weekly subcutaneous teri-
paratide administration are being investigated.
Efficacy. Teriparatide reduces fracture risk in postmenopausal
women (see Table 93–8); however, no fracture data are available in
men. Lumbar spine BMD increases are higher than any other osteo-
porosis therapy.60,78
Although wrist BMD is decreased, wrist fractures
are not increased. Discontinuation of teriparatide therapy results in a
decrease in BMD, although some antifracture efficacy appears to be
maintained.78
Sequential therapy with PTH followed by an antire-
sorptive agent (e.g., bisphosphonates) should be considered to main-
tain BMD gains.60
Adverse Events/Precautions. Transient hypercalcemia rarely
occurs. A trough serum calcium concentration is recommended 1
month after initiation of therapy. If high (>10.6 mg/mL), calcium
intake should be decreased to 1,000 mg daily. If the serum calcium
is still high, lowering the dose by 25% or switching to every-other-
day calcium therapy can be tried. 78
Because of an increased incidence of osteosarcoma in rats, teri-
paratide contains a black 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). In addition, teriparatide should not
be used in patients with hypercalcemia, metabolic bone diseases
other than osteoporosis, metastatic or skeletal cancers, or premeno-
pausal women of child-bearing potential. Therapy is not recom-
mended beyond 2 years because of a lack of efficacy and safety data.
Administration. Teriparatide is commercially available as a pre-
filled 3-mL “pen” delivery device that administers subcutaneous
injections in the thigh or abdominal area. The administration of the
initial dose should take place with the patient either sitting or lying
down in case orthostatic hypotension occurs. The patient should be
reeducated with each refill. The pen must be kept refrigerated and
can be used immediately after removing from the refrigerator. The
pen must be discarded 28 days after the initial injection. Teri-
paratide is the most expensive antiosteoporosis therapy.
Combination Therapy
Greater increases in BMD have been demonstrated in some small
studies of combination antiresorptive therapy in postmenopausal
women.60
Greater fracture risk reduction has not been demon-
strated. Combination antiresorptive and anabolic therapies have
been evaluated with conflicting results.78
Greater increases in BMD
were demonstrated when a less-potent antiresorptive agent, ralox-
ifene or HT, was used with PTH, whereas a blunting of the BMD
effect was seen when combination therapy included alendronate.
The effects of other bisphosphonates in combination with PTH are
unknown. Because of lack of a clear benefit and potential for
increased cost, side effects, and nonadherence, combination therapy
is not recommended at this time.
Investigational Therapies
Besides the above mentioned investigational products, new drug
classes are also being developed.
Denosumab Denosumab is a promising new antiresorptive agent
with a unique mechanism of action. It is a fully human monoclonal
antibody (immunoglobulin G2) that binds to RANKL, blocking its
ability to bind to its receptor activator of nuclear factor kappa B on
the surface of osteoclast precursor cells and mature osteoclasts. Thus
denosumab inhibits osteoclastogenesis and increases osteoclast apop-
tosis.79–81
In a phase II study, greater increases in total hip and distal
radius BMD were demonstrated in the intermittent (every 3 to 6
months) denosumab subcutaneous groups compared to once-weekly
alendronate.79
Adverse effects were similar between all groups. The
60-mg subcutaneous injection every 6 months is being evaluated in a
phase III trial of postmenopausal women with osteoporosis.
Other Investigational Drug Classes Additional new classes of
medications are beginning to show promise.13
Although injectable
OPG, a competitive inhibitor of RANKL, blocked osteoclastic dif-
ferentiation and decreased bone resorption biomarkers in phases I
and II, further development has ceased. Agents to enhance endoge-
nous OPG, decrease RANKL production, or block RANKL binding
to receptor activator of nuclear factor kappa B are being developed.
Agents to block osteoclast attachment (αVβ3 integrin receptor
antagonists—preclinical), inhibit bone matrix degradation (cathep-
sin K inhibitors—phase I; nitrosylated nonsteroidal antiinflamma-
tory drugs—phase II), or change osteoclast cell structure (Src
inhibitors—preclinical) have been effective in animal studies, and
for some, in early human studies. Strontium ranelate and tibolone
(Canada as well) are approved in Europe but most likely will not be
marketed in the United States.
■ VERTEBROPLASTY AND KYPHOPLASTY
Sometimes patients with debilitating pain between 6 and 52 weeks
after a vertebral fracture might undergo vertebroplasty or kypho-
plasty during which bone cement is injected into the fractured
vertebral space.82
The procedure stabilizes the damaged vertebrae
and reduces pain in 70% to 95% of patients. Cement leakage into
the spinal column can result in complicating nerve damage. Long-
term benefits are unknown, but some vertebral fracturing around
the cement has been documented.
SPECIAL POPULATIONS
Osteoporosis is a threat to all age groups and in some subgroups
because of genetic abnormalities, diseases, and medications.
CHILDREN
Although rare, osteoporosis in children and adolescents can lead to
significant pain, deformity, and chronic disability. The main causes of
osteoporosis in children are secondary, such as chronic medications,
genetic defects (e.g., osteogenesis imperfecta, cystic fibrosis), chromo-
somal defects (e.g., Turner’s or Klinefelter’s syndromes), endocrine
disorders (e.g., growth hormone deficiency), malabsorptive or nutri-
tional disorders (e.g., celiac sprue), malignancies, other chronic dis-
eases (e.g., juvenile rheumatoid arthritis), and conditions associated
with disuse (e.g., paralysis, muscular dystrophy).83
Idiopathic juvenile
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