Osteoporosis

Mark S. Nanes, MD, PhD,* and Caleb B. Kallen, MD, PhD

Osteoporotic fractures are common and result in extensive morbidity and mortality. It is
possible to decrease the risk of fracture in postmenopausal, male, and glucocorticoid-induced
osteoporosis with appropriate screening and treatment. The assessment of fracture risk, for
which bone densitometry is only 1 component, should be the main focus of patient evaluation.
Epidemiologically derived risk-assessment tools such as World Health Organization Fracture
Risk Assessment Tool (FRAX) provide physicians with a way to determine the 10-year risk of
osteoporotic fracture and effectively choose candidates for therapy. A number of potent
skeletal antiresorptive and anabolic drugs have become available to treat osteoporosis and
prevent up to 70% of fractures. Here, we provide a detailed update on clinical osteoporosis, the
contribution of bone densitometry, and the approach to patients using risk assessment in the
consideration of treatments. Progress in osteoporosis is an example of successful bench-tobedside research benetting populations worldwide.
Semin Nucl Med 44:439-450 Published by Elsevier Inc.

Introduction

steoporosis is dened as a skeletal disorder characterized by compromised bone strength that predisposes
to increased risk of fracture.1 Bone strength comprises bone
density and bone quality. Bone quality is not readily
measured in the clinical setting but depends on factors that
include bone architecture and geometry, mineralization,
microdamage accumulation, and properties of the collagen
and mineral matrix. Osteopenia describes a reduction in
bone density that has a lower risk of fracture than osteoporosis. After 30 years of age, bone density continues to fall in
both sexes, with loss accelerating in women after menopause. In postmenopausal women, bone resorption exceeds
bone formation leading to high rates of bone loss. Menopausal women experience, on average, a sustained doubling
of bone turnover. This effect is reduced by estrogen replacement therapy. As the accelerated menopausal resorption
abates, the rate of loss becomes similar in older men and
*Division of Endocrinology, Metabolism, and Lipids, Department of Medicine,
VA Medical Center and Emory University School of Medicine, Decatur,
GA.
Division of Reproductive Endocrinology and Infertility, College of Medicine,
Thomas Jefferson University, Philadelphia, PA.
Address reprint requests to Mark S. Nanes, MD, PhD, Division of Endocrinology, Metabolism, and Lipids, Department of Medicine, VA Medical
Center and Emory University School of Medicine, Medical Service (111)
Veterans Affairs Medical Center, 1670 Clairmont Rd, Decatur, GA 30033.
E-mail: mnanes@emory.edu

http://dx.doi.org/10.1053/j.semnuclmed.2014.06.006
0001-2998/Published by Elsevier Inc.

postmenopausal women. An osteoporotic fracture is one that

occurs as a result of a fall from standing height or less. Three
fracture sites are most typical of fragility fractures: vertebral
fractures, fractures of the femoral neck, and Colles fracture
of the distal radius. Provided there is no other cause of the
fracture such as cancer or trauma, a fragility fracture becomes
diagnostic of osteoporosis regardless of the measured bone
mineral density (BMD).2
Osteoporosis affects an estimated 34 million Americans
leading to 2 million fractures annually. As a comparison, 36
million Americans have uncontrolled hypertension and 48
million have elevated cholesterol level. Thus, osteoporosis is
a serious public health problem. A recent estimate assigned a
direct cost of $17-$19 billion in osteoporosis-related
expenditures per year. Of affected women, only
4%-6%
are diagnosed and treated, an estimated 80% are neither
diagnosed nor treated, and
16% are diagnosed but not
treated (3-5 and related publications). Hip fractures account
for 14% of all fractures, whereas Colles and vertebral
account for 19% and 27%, respectively. As with other
disorders, lifetime risk assessment (in this case fracture risk)
represents a more useful metric when considering public
health policy or individual patient management. The lifetime risk of fracture in women calculated at 50 years of age is
50%, higher than the 12% risk of breast cancer. Similarly,
the lifetime risk of fracture in 50-year-old men is 20%,
compared with a 17% risk of prostate cancer. Morbidity and
mortality of hip fractures is high, with death in 430%
within 6 months. Men are more likely to die following a hip
439

M.S. Nanes and C.B. Kallen

440
fracture than women.6-12 Survivors may remain permanently immobile within 1 year of the fracture. Depression is
common in older patients following a hip fracture.13
Despite the development of screening tools and efcacious
treatments to lower fracture risk, there is a persistent screening
and treatment gap for osteoporosis compared with other
National Committee for Quality Assurance Healthcare Effectiveness Data and Information Set measures (2012 data). For
example, compliance prescribing beta blockade after myocardial infarction is 81%, for breast cancer screening 70%, and for
colorectal cancer screening 62%, whereas screening for osteoporosis is done only 23% of the time.

Diagnosing Osteoporosis
Osteoporosis is asymptomatic until a fracture occurs. An
important part of diagnosing osteoporosis begins with understanding the risk factors that predispose to fracture (Table 1).
Dual-energy x-ray absorptiometry (DXA) remains the gold
standard for assessing bone density. As noted earlier, osteoporosis is due to both low bone density and low bone quality.
Thus, low BMD, as measured by DXA, accounts for only 40%
of the overall fracture risk for a patient. The residual risk can be
attributed to other physical and architectural attributes of the
skeleton such as stiffness, strength, trabecular architecture, and
accumulated discrete areas of damage in cortical bone. The
clinical measurement of these and other parameters as they
relate to fracture risk is investigational. However, it is possible
to strengthen the prediction of fracture risk in a patient by
combining BMD with known epidemiologic risk factors. The
World Health Organization (WHO) and National Osteoporosis Foundation (NOF) recommend that all evaluations of
fracture risk consider the contribution of statistically independent predictors, including age, current smoking, family
history of osteoporotic fracture, low body mass index,
hypogonadism (man or woman), rheumatoid arthritis, alcohol
use (more than 3 drinks/d), and glucocorticoid treatment.
Until recently, the relative weight of each risk factor was
difcult to quantify in the clinical setting. This left health care
providers ill-equipped to counsel patients regarding their

precise fracture risks or to guide therapeutic decision making.

For example, at any given BMD, fracture risk is higher in 80year-old women than in women younger than 65 years.
Similarly, fracture risk at any measured BMD has increased
4-fold for patients on glucocorticoids.
It is important to recognize that although osteopenia
predisposes to osteoporosis, and osteoporosis predisposes to
bone fractures, most patients with osteoporosis will not
experience a fracture. Conversely, patients who have a fracture
may not meet diagnostic criteria for osteoporosis by BMD
measurement alone. Thus, more than 50% of patients with a
hip fracture have a T score 42.5 and more than 35% of
spine fractures have normal or osteopenic BMD (T 4 2.5
but o1.0). A T score is standard deviations (SDs) from age,
sex, and race adjusted peak bone mass.14 Nevertheless, there
exists a strong correlation between decreasing bone density
and increased risk of fracture.15
The WHO implemented a web-based tool, Fracture Risk
Assessment Tool (FRAX), into which 12 independent risk
factors for fracture can be entered, including femoral neck
BMD, to produce a 10-year probability of fracture (www.shef.
ac.uk/FRAX). FRAX assessment can be calculated for 4
ethnicities (white, Hispanic, Asian, and black) in a genderand geographic-specic manner. The model is based on
fracture rates in untreated subjects and does not account for
current or prior treatment with osteoporosis drugs. The FRAX
calculator allows entry of ages between 40 and 90 years; there is
no validation of FRAX in younger or older patients because of
limited data. A similar web-based tool, FORE 10-Year Fracture
Risk Calculator (http://riskcalculator.fore.org), closely aligns
with the US regional data from the WHO-FRAX model
offering similar risk estimates for men and women older than
45 years. FORE also allows entry of glucocorticoid dosing;
allows information on spine fracture; and adds a graphic
display showing low, moderate, or high 10-year fracture risk
for use in patient education.
Although treatment decisions must be individualized, a
general guideline would be to consider pharmacologic therapy
for a 10-year fracture probability Z3% for the hip or Z20%
for all osteoporosis sites combined (vertebral, Colles, ankle,
and hip). These treatment thresholds assume a risk reduction

Table 1 Independent Risk Factors for Osteoporotic Fracture*

Risk Factor

Comment

Prior fragility fracture

Age
Low BMI
Sex
Race
Secondary osteoporosis
Alcohol
Rheumatoid arthritis
Smoking
Family history hip fracture
Glucocorticoid use
Low bone density

Fall from standing height or spontaneous morphometric fracture

Continuous variable
o25 kg/m2
Female 4 male
White 4 black
Vitamin D deciency and hypogonadism
43 units/d
Current smoker
Parent
Dose-dependent effect
Exponential increase or SD reduction from mean

BMI, body mass index.

*For detailed denitions see www.shef.ac.uk/FRAX.

Osteoporosis
of
35% with therapy and have been suggested to be cost
effective in the US population.16,17 Prior NOF recommendations included initiation of treatment for postmenopausal
women with T scores o2.0 (no risk factors) or o1.5
(with risk factors). By contrast, WHO had recommended a
diagnostic threshold for osteoporosis of T o 2.5. Using the
FRAX circumvents this inconsistency in guidelines by relying
on population-specic 10-year fracture risk estimates.
Physicians should remain alert to additional independent
risk factors for fracture such as falls, chronic hyponatremia,
poor vision, and neurologic impairment.18-23 FRAX should
not be used to monitor therapy, it considers only femoral neck
bone density in calculation of risk, allows only yes or no input
rather than gradations of secondary risk factors, and does not
circumvent clinical judgment.

Screening for Osteoporosis

WHO, American Association of Family Practitioners, and NOF
now recommend a screening BMD for women and men older
than 65 years and 70 years, respectively, regardless of risk
factors, and also for postmenopausal women and men between
the ages of 50 and 69 years with one or more risk factors. Any
adult with a fragility fracture (fall from a standing height) has
osteoporosis but should still have a baseline BMD established
by DXA. Finally, these recommendations pertain to postmenopausal or age-related osteoporosis. Different guidelines have
been published for glucocorticoid-induced osteoporosis,
which has a distinct pathophysiology.24-26 WHO and
NOF guidelines for men are concordant. Physicians must
keep in mind the potent effect of androgen deprivation therapy
used to treat prostate cancer on the subsequent rapid bone
loss.27-29
DXA has been the gold standard for BMD testing for several
years. Although other modalities are useful in the research
setting such as MRI with nite element analysis, no modality has
replaced DXA for clinical screening. DXA results are expressed
as SDs from age- and sex-matched standards (Z score) or from
the population mean peak bone mass (T score). The WHO
denes normal bone mass as T 4 1.0, with osteopenia being
T r 1.0 and Z2.5, and osteoporosis T r 2.5. Because
each SD represents a difference of 10%-15% in BMD, osteoporosis is indicative of a 25% loss from peak bone mass. Fracture
risk increases exponentially with lower BMD. For T scores of
1.0, 2.0, and 3.0, the relative risks of fracture are 1.7-, 3.4, and 6.8-fold, respectively. For glucocorticoid-induced osteoporosis, this BMD-fracture relationship is steeper owing to a
relatively greater loss in bone quality.
DXA uses x-rays to assess BMD by area (not volume) and the
radiation dose is approximately one-tenth that of a standard
chest x-ray. It is important for patients to have repeat BMD
measured by the same machine, if possible, to minimize
between device error. For premenopausal women, men
younger than 50 years, and children, the International Society
for Clinical Densitometry (ISCD) (www.iscd.org) recommends
the use of ethnic- or race-adjusted Z scores (Z o 2.0
indicating low bone density and warranting evaluation for
secondary causes of osteoporosis). There is value in combining

441
DXA with imaging of vertebral fractures. Some densitometry
devices provide a dual function by reporting the number of
vertebral fractures and bone density, as this may detect cases of
osteoporosis that might have been classied as osteopenia based
on BMD alone. NOF recommends vertebral imaging based on
T score, age, and sex. Clinical judgment is paramount. Any
patient who has lost height, had a fragility fracture, or has recent
or long-term glucocorticoid therapy should be considered for
vertebral imaging given the higher risk of vertebral fractures.

The Bone Density Report

The bone density report should provide sufcient information
for the ordering provider to make a treatment decision with
Food and Drug Administration (FDA)approved drugs. In
addition to patient identication, demographic data, sites of
measurements, and T score, the report should contain the
DXA-derived aerial BMD (g/cm2) for use in following changes
over time and response to therapy. Potential inaccuracies
should be noted, such as compression fracture of the spine,
calcication of tissues in the path of measurement, deformities,
false readings due to implanted devices or surface artifacts, and
obesity. BMD measurements of a vertebra should not be
included in the average of vertebral measurements if it differs
from the mean by 41 SD, as this suggests a prior fracture or
measurement error. If a previous DXA was obtained on the
same machine, the report should state whether the measured
bone density has changed signicantly (dependent on the
precision of the DXA and site of measurement) between tests. It
is helpful if the ordering provider sees the results expressed as a
10-year probability of fracture based on FRAX calculation. This
calculation requires clinical information about the patient that
can be included in the FRAX calculator. Alternatively, the
report could include the web address of the FRAX calculator
for provider use, as the ordering provider will have the
smoking history, family history of hip fracture, glucocorticoid
use, gonadal status, etc. More detailed information is available
from the ISCD (www.iscd.org), which offers training, certication, and ofcial position statements on clinical densitometry, FRAX, and measurements in adults and children.

Follow-Up of Patients
As noted earlier, when interpreting results of serial DXA scans
for a patient, it is best to consider actual bone density changes
over time (g/cm2) rather than T scores, as T-score calculations
are age dependent. Alternative modalities to BMD testing
include quantitative ultrasound densitometry and peripheral
DXA. Although these techniques are accurate and reproducible
for the purpose of screening, the T scores cannot be interpreted
using FRAX. DXA is the only bone density test that is currently
useful for assessment of changes in BMD over time and for
determining the response to therapy. Quantitative CT is a true,
3-dimensional, measurement that may be more useful for
follow-up of anabolic therapies such as teriparatide (discussed
later). CT is a higher cost test, provides greater radiation
exposure, and is not as readily available worldwide.

M.S. Nanes and C.B. Kallen

442
The NOF recommends DXA every 1-2 years; however,
earlier or more frequent BMD testing may be considered for
patients with severe osteoporosis, chronic disorders associated
with bone loss (human immunodeciency virus, inammatory
arthritis, and iatrogenic hypogonadism), and for patients
taking glucocorticoids. Patients with a normal screening
BMD may not require repeat testing for up to 5 years. The
least detectable signicant difference in bone density measurements depends on the precision of the densitometer and the
technologist. Precision should be calculated for each machine
and technologist using duplicate measurements from at least
30 patients. Guidelines for calculating precision are available
from the ISCD (www.iscd.org). As an example, a densitometer
with a precision of 1% at the spine will provide a least
detectable difference in measured bone density of 2.8%.
A bone loss of 2.8% is unlikely to occur in most postmenopausal osteoporotic patients by 6 months but can easily occur
in glucocorticoid-induced osteoporosis. It is also important to
choose a relevant site to compare for follow-up. For
glucocorticoid-induced osteoporosis, rapid bone loss will be
evident in the vertebral bodies rst, where the rate of bone
turnover is faster than in the femoral neck. For hyperparathyroidism, the forearm is most relevant as cortical bone is most
affected. Clinical judgment is required when deciding on the
frequency of repeat testing.30
A single BMD measurement does not indicate the rate of
bone turnover. Although serum and urine markers of bone
turnover may provide additional information regarding bone
turnover for research purposes, their use is controversial. Some
bone markers currently in clinical use include the resorption
markers deoxypyridinoline, C-terminal cross-linking telopeptide of type I collagen (or C-telopeptide), N-terminal crosslinking telopeptide of type I collagen (or N-telopeptide), the
osteoclast marker tartrateresistant acid phosphatase, and the
bone formation markers bone-specic alkaline phosphate,
osteocalcin, and C-terminal propeptide type I collagen.
Because bone resorption and formation are coupled processes,
and because there exists considerable day-to-day variation in
the aforementioned biomarkers, interpretation of results as
excess resorption or reduced formation could be misleading. Such specic interpretations require a bone biopsy, which
is not recommended in routine cases of osteoporosis. Some
health care providers test for a reduction in bone markers after
the initiation of bone-sparing therapy to promote patient
compliance; however, there is no organizational guideline that
links changes in metabolic markers of bone turnover to make a
diagnosis or therapeutic decision.

Diagnosing Secondary Causes of

Osteoporosis
Numerous medications and conditions are known to predispose to osteoporosis. Secondary causes of osteoporosis should
be evaluated, as these require additional interventions, such as
thiazides to prevent a renal calcium leak (
3%-6% of general
population31), vitamin D repletion, or optimal treatment of
clinical hypothyroidism or hyperthyroidism. The level of

25-OH-vitamin D and a 24-hour urine calcium excretion

should be measured in all patients with osteoporosis. Because
renal excretion of calcium is not uniform throughout the day, a
spot urine calcium measurement is unreliable for assessment
of hypercalciuria or hypocalciuria. Further, the screening of
renal disorders using a 24-hour urine collection is difcult to
interpret after initiation of bisphosphonate therapy and, thus, is
best performed in a treatment-naive patient. Additionally, 24hour urine collection should not be performed on patients
taking a thiazide diuretic. Thiazide diuretics should be discontinued several weeks before a urine collection. In a eucalcemic
patient, hypercalciuria suggests a need to intervene with
drugs that prevent urinary calcium loss (chlorthalidone and
hydrochlorothiazide), whereas hypocalciuria suggests vitamin
D deciency.
In the setting of osteoporosis, physicians should screen for
hyperthyroidism (thyroid-stimulating hormone), hyperparathyroidism (fasting serum calcium and phosphorous level,
followed by parathyroid hormone (PTH) level, if hypercalcemia is detected), celiac sprue (tissue transglutaminase, endomysial antibody, total IgA, or antigliadin IgA and IgG),
cirrhosis (liver function tests), renal failure (creatinine), hypercalciuria and hypocalciuria (24-hour urine calcium, creatinine,
and sodium levels, discussed earlier), and hematologic disorders (complete blood count and urine and serum protein
electrophoresis for elderly patients).32 A formal medication
history for drugs associated with bone loss may identify
glucocorticoid therapy, excess thyroid hormone replacement,
and medications such as phenytoin, phenobarbital,
gonadotropin-releasing hormone agonists, aromatase inhibitors, cyclosporine or tacrolimus, aluminum-containing antacids, progestins, long-term heparinization, methotrexate,
excess vitamin A (retinol), lithium, serotonin-specic reuptake
inhibitors, and proton pump inhibitors, and thiazolidenediones. Men undergoing androgen deprivation therapy are
likely to have extensive bone loss requiring baseline DXA
documentation and treatment. Certain secondary causes of
osteoporotic fracture are not mentioned in the FRAX; however,
the relative risk from these conditions may be attributable to
associated hypogonadism, glucocorticoid use, smoking, or low
body mass index. One example is chronic pulmonary
disease.33

Therapeutic Approaches
Lifestyle and Exercise
Universal recommendations for osteoporosis are emphasized.
Regular weight-bearing and muscle-strengthening exercise is
an important part of bone maintenance. All exercise is
benecial to optimize balance and stability. Fall prevention
can include measures to improve eyesight, hearing, strength,
stability, and home safety (home lighting, safe stairways, railing
and grips, at rubbersoled shoes, and minimizing sleep
medication). Exercise programs have been reported to reduce
falls, though few are sufciently powered to conrm a
reduction in fractures.34-41 Use of tobacco or excessive alcohol
consumption should be avoided.

Osteoporosis

443

Nutritional Considerations
Calcium and Vitamin D
Adequate consumption of calcium and vitamin D, whether
through diet, supplements, or both, is essential to maintaining
bone strength.42-46 At least 3 doses of a calcium preparation a
day is needed to adequately replete calcium as the ceiling for
maximal fractional absorption of calcium is quickly reached.47
Adequate repletion of vitamin D reduces falls in patients who
were unequivocally vitamin D decient.48
Table 2 shows available preparations of calcium and vitamin
D. Calcium citrate is the most bioavailable form of oral calcium.
Calcium carbonate should be given with meals, because it
requires acid for maximal absorption. It can be seen from
Table 2 that a 600-mg calcium carbonate pill provides only
240 mg of elemental calcium (600 mg  40% 240 mg).
Thus, 4 pills a day in divided doses would be required for
nearly 1000 mg/d elemental calcium. A common clinical
mistake is to assume that only 2 such pills a day meet the
1000-mg requirement. Similar calculations must be done for
other calcium preparations unless the formulation label is listed
as elemental calcium (Table 2). Dietary calcium can be
calculated and subtracted from any supplement requirements.
The average dairy-free diet contains 250 mg of calcium per day
and calcium-rich foods should be encouraged for motivated
patients. Some, but not all, recent studies have suggested an
association between prescribed calcium intake and cardiovascular disease; however, these relationships have been difcult
to conrm for patients taking both calcium plus vitamin
D.46,49-58 There is no evidence that calcium supplements
change carotid intimal thickness, a surrogate of vascular
disease.54 Analysis of one cohort did not nd a relationship
between osteoporosis and atherosclerosis.59 Nevertheless, it is
prudent to maximize dietary calcium so that prescribed
calcium pills can be minimized while achieving the recommended intake.
The active metabolite of vitamin D, 1,25-dihydroxyvitamin
D3, is the physiological stimulus for intestinal absorption of
calcium. Vitamin D3 (cholecalciferol) is synthesized in the skin
following direct exposure to sunlight; however, there are many
different factors that affect a persons ability to make adequate
amounts of vitamin D. Vitamin D3 and commercial vitamin D2
(ergocalciferol) will both support bone health as both are

metabolized to 25(OH) vitamin D in the liver and nally to the

active metabolite 1,25(OH)2 vitamin D in the kidney. The
serum level of 25(OH) vitamin D3 is the best indicator of
nutritional repletion and is the appropriate test to evaluate
vitamin D status. Recent evidence suggests that the total
25-hydroxyvitamin D level may underestimate the bioactivefree level in African American populations with polymorphisms of the vitamin Dbinding protein.60 Patients should
be treated with maintenance cholecalciferol or ergocalciferol
(800-1000 units/d) to maintain a serum 25-hydroxyvitamin D
level of at least 20 ng/mL.
For patients with markedly low 25(OH) vitamin D3 values
(o20 ng/mL), consider high-dose supplementation using
ergocalciferol, 50,000 IU once per week for 1-2 months.
Repletion should normalize the previously elevated serum
PTH level, and 24-hour urine calcium should rise to the
normal range. Vitamin D can also be obtained from fortied
dairy products, egg yolks, saltwater sh, liver, and fortied
orange juice, though nutrition alone is unlikely to replete a
markedly decient patient.

Medications
Postmenopausal osteoporosis is characterized by an elevated
bone-resorption-to-formation ratio during the perimenopausal
and immediate postmenopausal period. Thus, antiresorptive
therapies are effective in maintaining bone and reducing
fractures.61,62 In practice, antiresorptives are also effective after
the perimenopausal period and in men. An alternative strategy
to reduce fractures is anabolic therapy, which aims to stimulate
bone formation.63-67 Anabolic agents are intended to increase
the number of osteoblast precursors or stimulate their maturation to mature osteoblasts, enhance osteoblast function, or
increase osteoblast survival. A large number of efcacious
medications are now available for osteoporosis, dramatically
changing the treatment options for physicians. Current FDAapproved pharmacologic options for osteoporosis prevention
or treatment are bisphosphonates (alendronate, ibandronate,
risedronate, and zolendronic acid), teraparatide (PTH
N-terminal amino acids 1-34), estrogens, the estrogen receptor
modulators raloxifene or bazedoxifene, calcitonin, and the
receptor activator of nuclear factor kappa-B ligand (RANKL)

Table 2 Preparations of Calcium and Vitamin D

Form

Comment

Calcium carbonate
Calcium citrate
Calcium gluconate
Calcium lactate
Calcium glubionate
Ergocalciferol
Cholecalciferol
Calcitriol
Dihydrotachysterol

40% Elemental calcium

20% Elemental calcium
12.8% Elemental calcium (liquid preparation)
9% Elemental calcium (liquid preparation)
8.8% Elemental calcium
Vitamin D2 (synthetic or plant derived)*
Vitamin D3 (synthesized in skin)*
1,25-Dihydroxyvitamin D (not recommended for osteoporosis)
Synthetic (not recommended for osteoporosis treatment)

*Low risk of hypercalcemia with ergocalciferol or cholecalciferol. Evidence from trials suggests 4800 units/d needed for
maintenance. Repletion requires higher doses (50,000 units/wk for 4 weeks). Deposited in fat depot resulting in long
period of storage.

High risk of hypercalcemia, evidence from trials inconsistent. Benet is rapid metabolism and limited storage.

M.S. Nanes and C.B. Kallen

444
inhibitor denosumab. Treatment decisions must be based on
the clinical scenario and intervention threshold. FDA-approved
drugs are shown in Table 3 and summarized later.
Antiresorptive Agents
Bisphosphonates prevent bone loss and reduce fracture risk of
the hip and spine.68-73 In recent studies, once yearly zolendronic acid infusion decreased fracture risk and increased
overall patient survival.74,75 Few head-to-head studies have
compared different bisphosphonates. The optimal duration of
therapy remains uncertain, and recommendations are based on
pharmacokinetic properties, minimizing potential adverse reactions, the theoretical persistence of action by stored bisphosphonates leached from bone after discontinuation of therapy, and
the individual fracture risk of the patient.76,77 Risks of the oral
bisphosphonates include esophageal and gastric irritation,
which can be avoided by drinking 0.2 L of water and remaining
upright for 30 minutes. There is a relative contraindication for
patients with renal insufciency (glomerular ltration rate
o30 mL/min). Rarely, oral bisphosphonates are associated
with osteonecrosis of the jaw, though this is far more common
using intravenous agents in higher doses for patients with
cancer.78,79 Patients should be informed of this low risk of
osteonecrosis of the jaw and advised to stop treatment several
months before dental extraction or orthodontic surgery.80
A proposed complication of bisphosphonates is an atypical
fracture of the femoral neck. These fractures are rare and poorly
understood. The benet of bisphosphonate therapy outweighs
the small risk of atypical femoral fractures.81,82
Alternative antiresorptive therapies include raloxifene and
bazedoxifene, the selective estrogen receptor modulators
(SERMs).83-87 SERMs are also efcacious in the prevention of
glucocorticoid-induced osteoporosis.88 Follow-up of the large
Multiple Outcomes of Raloxifene Evaluation89,90 and subsequent Raloxifene Use for the Heart91 trials showed that
raloxifene reduced the incidence of breast cancer. Raloxifene
potency in preventing breast cancer is similar to that of
tamoxifene.92 Estrogen and raloxifene increase the risk of deep
venous thrombosis and fatal stroke, and raloxifene may

exacerbate postmenopausal vasomotor symptoms.91,93

Consequently, discontinue SERM therapy in hospitalized or
otherwise immobile patients as the risk of thromboembolism is
increased. Raloxifene does not appear to increase the overall
cardiovascular risk in patients.94 Estrogen, although shown to
be effective in preventing fractures in the womens health
study, is not recommended solely for bone maintenance as
more effective drugs are available that avoid the complications
of hypercoagulability and controversial issue of possible breast
cancer.95 Estrogen remains a valuable drug if needed to treat
menopausal symptoms and, if used, will delay the loss of bone
during menopause. Calcitonin, although FDA approved, is no
longer recommended in light of superior alternatives and the
fact that hip fracture protection for calcitonin has never been
established.96 Denosumab is a monoclonal antibody that
neutralizes RANKL, a potent stimulus to osteoclastogenesis
and bone resorption.97-104 Neither denosumab nor bisphosphonates appear to interfere with fracture healing.105 Denosumab
provides one of the most potent treatments for osteoporosis
and has also been useful, as has zolendronic acid, in preventing
cancer metastases to bone and the resulting skeletal events
from malignancy.106 As with bisphosphonate treatment,
Denosumab use should be initiated after conrming vitamin
D repletion to avoid the possibility of hypocalcemia. Metaanalysis suggests a possible small increase in infections in
patients on denosumab; however, the safety prole to date has
been excellent.99,107-109
Anabolic Agents
Teriparatide (N-terminal peptide 1-34), given by daily subcutaneous injection, potently reduces the risk of fractures of the
spine, hip, and other sites.64,110,111 Teriparatide can be
associated with dizziness (9%) and leg cramps (3%). Sequential
therapies (teriparatide followed by bisphosphonate) may
confer benet with regard to BMD, as may teriparatide
followed by raloxifene.112 Patients should be monitored for
hypercalcemia after starting teriparatide. Some, but not all,
studies show that concurrent or prior bisphosphonate therapy
may temporarily blunt the effects of teriparatide; therefore, a

Table 3 Efcacious Drugs for Prevention and Treatment of Osteoporotic Fractures

FDA Approved
Drug

Class

Estrogen
Alendronate
Risedronate
Zoledronate
Ibandronate
Raloxifene
Denosumab
Teriparatide
Calcitonin
Odanacitib
Romosozumab
Strontium ranelate*

Steroid hormone
Bisphosphonate
Bisphosphonate
Bisphosphonate
Bisphosphonate
SERM
Monoclonal Ab: RANKL
Protein: PTH
Protein: calcitonin
Enzyme inhibitor: cathepsin K
mAb: sclerostin
Element

PMO
P
PT
PT
PT
PT
PT
T
T
T

GIO

Male

T
PT
PT

PT
PT
PT

T
T

GIO, glucocorticoid-induced osteoporosis; mAb, monoclonal antibody; P, FDA approved for prevention; PMO, postmenopausal osteoporosis; T, FDA
approved for treatment.
*Approved in Europe.

Osteoporosis
clinical decision on use of teriparatide as an initial treatment
should be made early.113-119 A comparison of pretreatment
with bisphosphonates vs raloxifene revealed that blunting of
the expected anabolic effect of teriparatide was not observed
with raloxifene.114 Teriparatide is associated with transient
hypercalciuria.120 Retreatment after the initial course of
therapy is effective.121 Several studies have shown that bone
loss resumes after discontinuation of teriparatide therapy. The
gains in bone density can be sustained by following teriparatide
treatment with an antiresorptive agent such as a bisphosphonate or a SERM.122-125
Emerging Therapies
New therapies to promote skeletal health target the pathways
of osteoblast and osteoclast differentiation and survival of these
cells. Osteoblasts are derived from mesenchymal precursors
under the inuence of growth factors that commit pluripotent
precursor toward a bone-forming lineage rather than toward
adipocyte, skeletal muscle, broblast, or tendon cell.66,126-128
The factors involved include bone morphogenic proteins
(BMPs),129 growth hormone (GH),130 insulinlike growth
factor-1 (IGF-1),131,132 and modulators of Wnt pathway
signaling.133 Osteocytes, the small buried cells with spindlelike
processes extending through the matrix, have yet to be targeted
by specic therapeutic agents. The osteocyte may be the next
bench-to-bedside frontier for therapeutic advances in clinical
applications. Osteocytes are increasingly recognized as key
regulators in bone as they respond to loading forces and are the
major sources of RANKL, the osteoclastogenic protein bound
by denosumab. Osteoclast differentiation occurs from
hematopoietic precursors of the monocyte-macrophage lineage, pushed toward their bone resorbing phenotype by
macrophage colony-stimulating factor, the RANKL/osteoprotegerin system, and inammatory cytokines. Complex regulation of many of the osteoblastogenic and osteoclastogenic
pathways can occur via alterations in protein expression,
receptor expression, and through the effects of extracellular
and intracellular regulatory proteins.134-138 Thus, the potential
therapeutic targets that might rationally be expected to affect
osteoblast or osteoclast activity are numerous and remain the
subject of intense investigation.
The most successful new anabolic agents in development
modulate the Wnt signaling system to promote osteoblastogenesis. Wnt signaling through their canonical pathway is
necessary for osteoblast differentiation, thus, mutations in an
inhibitor of the Wnt receptor results in high bone density and
bone strength in families with van Buchem disease and
sclerosteosis, as examples.128 The mutations of sclerostin in
these disorders or a mutation in the sclerostin-binding site of
the Wnt receptor render excessive Wnt activity, leading to
osteoblast differentiation and high bone mass. Unlike osteopetrosis, a disorder of osteoclasts, bone in von Buchem disease,
and sclerosteosis continues to be remodeled without compromise of the marrow cavity or hematocytopenia. Experimentally, inhibition of 2 Wnt inhibitors, sclerostin or Dickkopf-1,
stimulates bone anabolism.135,139
The targeted inhibition of skeletal Wnt antagonists using a
humanized monoclonal antibody against the Wnt inhibitor

445
sclerostin has completed an international, multicenter,
placebo-controlled phase 2 trial, revealing potent anabolic
effects that exceed those achieved with bisphosphonates or
teriparatide.140 Strikingly, the accrual of bone at the femoral
neck was substantial. Monoclonal antibody treatments require
less frequent subcutaneous injection than teriparatide, suggesting that they may be better received by patients.
Additional drugs in development include inhibitors of
cathepsin K, an osteoclast enzyme responsible for digestion
of bone matrix protein in the space beneath the tightly
adherent osteoclast seal on bone. Early clinical trials suggest
that inhibition of cathepsin K with the monoclonal antibody
odanacatib enhances bone density in both men and women
with osteoporosis and reduces markers of bone turnover.141-148 Cathepsin K inhibition is expected to provide
an antiresorptive alternative to bisphosphonates and
SERMs. Whether odanacatib reduces fractures remains to
be determined.
BMPs have been applied locally to enhance spine fusion
with varied success, but no systemic BMP treatment has been
developed. Additional agents have been in prolonged development with varying success. IGF-1, which is secreted downstream of PTH and required for PTH action, has been shown to
be anabolic in rodent bone cultures in vitro and in vivo in
rodent models.149-151 IGF-1 administration to humans for the
purposes of bone maintenance has been studied in very limited
circumstances (such as anorexia nervosa, where IGF-1 levels
are ordinarily low).152,153 Long-term efcacy, side effects, and
safety of systemic IGF-1 therapies remain unknown,152 and
therapeutic effects of IGF-1 on postmenopausal patients with
osteoporosis have not been reported.
In the United States, GH is not approved for the treatment of
osteoporosis and long-term fracture reduction studies are not
available. GH stimulates bone turnover and BMD for up to
4 years, after which a plateau occurs. No GH study has been
powered to determine fracture reduction. The response to GH
may differ in diverse clinical situations (ie, hypopituitarism,
Shehan syndrome, postmenopause, idiopathic osteoporosis in
men, children).130,132,154-163
In an earlier meta-analysis, uoride, a mineral that is
incorporated into bone, increased the risk of fractures when
administered in high doses but reduced fractures at low
doses.164-169 Fluoride is approved as an osteoporosis therapy
in Europe but not in the United States. A recent trial did not
show efcacy with low-dose uoride in the treatment of
postmenopausal osteoporosis.170 Strontium ranelate, also
incorporated into bone, appears to both enhance bone
formation and reduce bone resorption in animal models. In
humans, strontium ranelate protects against fractures of the
spine and likely reduces fractures of the hip as well.171-177 The
treatment is generally well tolerated with some gastrointestinal
side effects (diarrhea) and has been associated with increased
risk of thromboembolism for reasons that remain unclear.
Strontium ranelate is not FDA approved for use in the United
States.
Advances in osteoporosis treatment are an example of tremendous return on basic and clinical research investment. The
eld has rapidly advanced as a result of the bench-to-bedside

446
approach, producing therapies that reduce fractures by 45%70% in patients who would otherwise suffer the morbidity,
immobility, nursing home placement, and mortality associated
with osteoporosis-related fractures.

Summary
Osteoporosis is a serious, common, and costly disorder. The
physician can have a major effect on fracture prevention and
patients quality of life through appropriate screening, diagnosis, and treatment of patients at risk for fracture. The
assessment of fracture risk should be the main focus of a
patient evaluation, now incorporating epidemiologically
derived risk-assessment tools with bone densitometry such
as FRAX. Risk stratication of a patient can then be followed by
treatment with an ever-widening array of effective bonesparing therapies. Although well-established therapies are
available, novel therapies are under development with increasing focus on anabolic agents to enhance bone strength. The
efcacy, safety, and tolerability of newer bone-sparing agents,
or combinations of agents, may further enhance the clinical
armamentarium of osteoporosis therapy.

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