U p d a t e o n O s t e o p o ro s i s

S cree ning an d Man ag e m e nt

Anika K. Anam, MD*, Karl Insogna, MD

KEYWORDS

Bone loss
Dual-energy X-ray absorptiometry
Fracture
Menopause

Osteoporosis

KEY POINTS

All postmenopausal women and men aged 50 and older should be evaluated for risk of
osteoporosis.

Evaluation for osteoporosis should include a detailed history, physical exam, and labora-
tory tests to assess for secondary causes of bone loss and mineral metabolism.

Osteoporosis treatment should be individualized to the patient and includes optimizing
nutrition, weight-bearing exercise, fall prevention strategies, and use of anti-resorptive
or anabolic pharmacologic therapies.

INTRODUCTION

Osteoporosis is a metabolic bone disease characterized by low bone mass and micro-
architectural deterioration of the bone tissue, leading to reduced bone strength and
increased risk of low-energy fractures or fragility fractures. Worldwide, osteoporosis
is estimated to affect 200 million women, and 1 in 3 women over age 50 will experience
osteoporosis-related fractures, as will 1 in 5 men aged over 50.1–3 The most common
osteoporotic-related fractures are those of the vertebrae (spine), proximal femur (hip),
and distal forearm (wrist). Osteoporosis has many etiologies; the most common cause
is estrogen deficiency-related bone loss, such as that occurring after menopause. This
article mainly focuses on postmenopausal osteoporosis and newer pharmacologic
therapies, although the therapeutic interventions discussed here are often but not al-
ways relevant to other pathophysiologic types of osteoporosis, including male osteo-
porosis. It provides guidance for health care providers on the proper screening,
identification of secondary causes, and appropriate treatment of osteoporosis in post-
menopausal women.

Department of Internal Medicine, Section of Endocrinology, Yale Bone Center, Yale University
School of Medicine, 333 Cedar Street, FMP 107, PO Box 208020, New Haven, CT 06519, USA
* Corresponding author.
E-mail address: [email protected]

Med Clin N Am - (2021) -–-

https://doi.org/10.1016/j.mcna.2021.05.016 medical.theclinics.com
0025-7125/21/ª 2021 Elsevier Inc. All rights reserved.

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2 Anam & Insogna

PATHOPHYSIOLOGY OF OSTEOPOROSIS

The skeleton provides structural support for the body and storage for two essential
minerals, calcium and phosphorus. Individual bone mass reaches a peak between
25 and 30 years of age and begins to decline around 40. The skeleton consists of a
mineralized matrix with a highly active cellular fraction that includes osteocytes, oste-
oblasts, and osteoclasts. Osteoblasts are derived from marrow mesenchymal cells
and form new bone and initiate bone resorption, which are the first steps in replacing
old or damaged bone. Osteoclasts are involved in bone resorption and derived from
hematopoietic progenitors. Both osteocytes and osteoblasts release receptor acti-
vator of nuclear factor kappa B ligand (RANKL), which is essential for osteoclastogen-
esis. In addition to RANKL, osteoblasts produce osteoprotegerin (OPG), an inhibitor of
osteoclastogenesis. OPG is a soluble receptor for RANKL that binds this ligand and
prevents interaction of RANKL with its cognate receptor, receptor activator of nuclear
factor kappa B. RANKL is the primary stimulator of osteoclast formation. Osteoblasts
and osteoclasts play critical roles in bone remodeling, a dynamic process during
which old bone is removed and new bone is added to the skeleton. Osteocytes are
thought to be the principal cell regulating remodeling, producing RANKL and a critical
inhibitor of bone formation, sclerostin. Bone remodeling is affected by systemic hor-
mones, including parathyroid hormone (PTH), 1,25-dihydroxyvitamin D, calcitonin,
growth hormone, glucocorticoids, gonadal hormones, thyroid hormones, and cyto-
kines. In addition, changes in mechanical force activate bone remodeling to improve
skeletal strength and repair bone that has undergone microdamage. In the young adult
skeleton, the amount of new bone formed by osteoblasts is equal to the amount
resorbed by osteoclasts. However, bone loss occurs when this cycle is uncoupled,
resulting in more removal than replacement of bone.4
The cycle of bone remodeling becomes uncoupled with menopause and advancing
age, resulting in more bone resorption than bone formation. During the menopausal
transition, serum estradiol levels decrease by 85% to 90%, and serum
estrone decreases by 65% to 75%, relative to premenopausal values. With the decline
in estrogen levels during menopause, the rate of bone remodeling increases by 2-fold
to 4-fold. Increased bone resorption leads to a phase of accelerated bone loss and
efflux of skeletal-derived calcium to the extracellular fluid. These changes lead to a
negative balance of total body calcium, which further exacerbates skeletal losses.5
At menopause, women undergo rapid trabecular bone loss that usually continues
for 5 to 8 years after the cessation of menses. Initially, about 20% to 30% of the
trabecular bone and 5% to 10% of the cortical bone are lost. During the second phase
of bone loss, occurring 8 to 10 years after menopause, trabecular and cortical bone
are lost at equal rates. Bone loss leads to deterioration in skeletal microarchitecture
and increased fracture risk.
Later in menopause, age-related bone loss and accompanying changes in the ma-
terial properties of bone further exacerbate estrogen deficiency-related bone loss.
Increased osteoclast number and activity disrupt trabecular connectivity and in-
crease cortical porosity. Resorption pits caused by accelerated bone remodeling
remain incompletely filled because new bone formation does not keep pace with
bone resorption. Reduced bone density and quality cause increases in fracture risk.
Many other hormonal and systemic disorders can lead to accelerated bone loss
regardless of age and estrogen status. These secondary causes of osteoporosis
include vitamin D deficiency, hyperparathyroidism, hypercortisolism, hyperthyroidism,
anorexia nervosa, inflammatory diseases (eg, rheumatoid arthritis), gastrointestinal dis-
ease (eg, chronic liver disease, celiac disease, and inflammatory bowel disease),

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 Update on Osteoporosis Screening and Management 3

plasma cell dyscrasias (eg, multiple myeloma and monoclonal gammopathy of undeter-
mined significance), chronic renal disease, renal calcium leak, and drugs (eg, steroids,
antiepileptics, depot medroxyprogesterone acetate, chronic heparin use, vitamin A,
loop diuretics, and selective serotonin receptor uptake inhibitors). Excessive alcohol
consumption and hypogonadism are secondary causes of bone loss in men.

DIAGNOSIS AND EVALUATION

Screening for Osteoporosis
The decision to perform bone density assessment should be based on the patient’s
fracture risk profile and skeletal health assessment. Regardless of clinical risk factors,
women aged 65 and older and men aged 70 and older should undergo bone mineral
density (BMD) testing. Bone density assessment should be considered in younger
postmenopausal women, women in the menopausal transition, and men aged 50 to
69 with clinical risk factors for fracture. In addition, individuals who have a fracture
at or over age 50 and those with conditions that predispose to low bone mass or
bone loss (rheumatoid arthritis) or taking medications (chronic glucocorticoids) should
be considered for bone density assessment. Individuals being considered for pharma-
cologic therapy for osteoporosis, anyone being treated for osteoporosis, anyone not
receiving therapy and in whom evidence of bone loss would lead to treatment, and
all postmenopausal women discontinuing estrogen should also be considered for
bone density testing. BMD measurement is not routinely indicated in healthy young
men or premenopausal women unless there is a significant fracture history or there
are specific risk factors for bone loss.6

Measurement of Bone Mineral Density

Dual-energy x-ray absorptiometry (DXA) measurement of the hip (femoral neck and to-
tal hip) and spine is the preferred method of diagnosing osteoporosis, predicting future
fracture risk, and monitoring patients. If the hip or spine cannot be measured, BMD
measured by DXA at the one-third radius site can be used for diagnosis. DXA mea-
sures bone mineral content (BMC) in grams and bone area (BA) in square centimeters.
The areal BMD in grams per square centimeter is calculated by dividing BMC by BA.
The T-score, a value used for diagnosing osteoporosis, is calculated by subtracting
the mean BMD of a young-adult reference population from the patient’s BMD and
dividing it by the standard deviation (SD) of the young-adult population. The Z-score,
used to compare the patient’s BMD with that of a population of peers, is calculated by
subtracting the mean BMD of an age-matched, ethnicity-matched, and sex-matched
reference population from the patient’s BMD and dividing by the SD of the reference
population.7 BMD diagnoses of normal bone mass, osteopenia, and osteoporosis are

Table 1
The World Health Organization definition of osteoporosis based on bone mineral density
(BMD) measurement of the spine, hip, or forearm by dual-energy x-ray absorptiometry
devices

Normal BMD within 1 SD of a young normal adult (T-score  1)

Low bone mass BMD between 1 and 2.4 SD less than that of a young normal adult
(osteopenia) (T-score between 1 and 2.4)
Osteoporosis BMD 2.5 SD or more less than that of a young normal adult
(T-score  2.5)
Severe osteoporosis T-score  2.5 with one or more fractures

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4 Anam & Insogna

based on the World Health Organization (WHO) diagnostic classification (Table 1).6
This classification should be used for postmenopausal women and should not be
applied to premenopausal women. Of note, even if the BMD is in the normal range,
osteoporosis can be diagnosed based on the presence of a previous fragility fracture.
A fragility fracture is defined as a fracture in adult life occurring spontaneously or a
fracture arising from trauma that, in a healthy individual, would not have resulted in
a fracture. In premenopausal women, a diagnosis of osteoporosis should not be
made from densitometric criteria alone. The International Society for Clinical Densi-
tometry (ISCD) recommends that instead of T-scores, ethnic or race-adjusted
Z-scores should be used in premenopausal women. Z-scores of 2.0 or lower are
defined as either low BMD for chronologic age or less than the expected range for
age; those more than 2.0 are defined as within the expected range for age.7 When
using DXA to monitor change in BMD with time and therapy, the absolute BMD value
(grams per square centimeter) should be used. Statistically significant change in BMD
is calculated as 2.77 multiplied by precision at the site of measurement to provide the
least significant change. In an individual patient, an adequate time interval (usually 18–
24 months) is required between measurements to show significant change unless
larger changes in BMD are anticipated (eg, glucocorticoid treatment).7 When using
DXA to monitor change in BMD, it is important to use the same scanner and software
because different manufacturers use different edge-detection algorithms and different
x-ray beam technologies. Although not universally adopted, ISCD has recommended
that T-scores for both men and women, regardless of race, should be calculated using
a Caucasian female database. Z-scores are generated using sex and race reference
databases.7

Additional Technologies to Measure Bone Mass

Peripheral dual-energy x-ray absorptiometry, computed tomography–based absorp-
tiometry, quantitative computed tomography (QCT), peripheral QCT, and quantitative
ultrasonography densitometry can predict both site-specific and overall fracture risk.
When performed according to accepted standards, these techniques are accurate
and highly reproducible. However, T-scores from these technologies are not equiva-
lent to T-scores derived from DXA, and they cannot be used to diagnose osteoporosis
based on the WHO classification.6 Notably, DXA is the only method that has been
used in all osteoporosis treatment trials.

Assessment of Fracture Risk

All postmenopausal women, and men aged 50 and older, should be evaluated for
osteoporosis risk to determine the need for BMD testing. Generally, the greater the
number of risk factors present, the higher the risk of fracture. Validated risk factors in-
dependent of BMD include advanced age, previous fracture, long-term glucocorticoid
therapy, low body weight, family history of hip fracture, cigarette smoking, and excess
alcohol intake.8 Several of these risk factors are included in the University of Sheffield-
launched Fracture Risk Assessment Tool—FRAX—available at (https://www.sheffield.
ac.uk/FRAX/), which provides the 10-year probability of hip and major osteoporotic
fracture and has developed from studying population-based cohorts from Europe,
North America, Asia, and Australia. This set of risk factors increases fracture risk inde-
pendently of BMD and is integrated with BMD measurements to assess an individual
patient’s risk of future fracture. Limitations of FRAX include underestimation of fracture
risk when a patient is taking high-dose glucocorticoid therapy or has had multiple
recent fragility fractures. Furthermore, FRAX is validated only in untreated patients
and may overestimate fracture risk if an individual is already being treated.

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 Update on Osteoporosis Screening and Management 5

Initial Evaluation
Initial evaluation for osteoporosis includes a detailed history to assess for clinical risk fac-
tors for fracture and secondary causes of bone loss, a thorough physical examination,
and laboratory tests to assess general health, and specifically, mineral metabolism.
The medical history should focus on risk factors for fracture (eg, prior fractures, family his-
tory of osteoporosis or hip fracture, recent falls), height loss, medications associated with
bone loss, smoking, alcohol intake, and kidney stones. Patients should be clinically
assessed for underlying medical conditions that may contribute to bone loss, including
rheumatoid arthritis, hyperthyroidism, Cushing syndrome, hyperparathyroidism, multiple
myeloma, celiac disease, and inflammatory bowel disease. Physical examination may
reveal skeletal deformities due to unrecognized fractures (eg, kyphosis or diminished
rib–pelvis space), identify possible secondary causes of skeletal fragility (eg, blue sclera
with osteogenesis imperfecta or bone tenderness with osteomalacia). Height should be
measured yearly, preferably with a stadiometer. Evaluating a patient’s risk for falling
should include inquiring about recent falls, assessing visual acuity, Romberg test, prox-
imal muscle strength, and gait assessment.
Initial laboratory evaluation includes serum creatinine, calcium, phosphorus, magne-
sium, 25-hydroxyvitamin D, and liver function tests. If clinically indicated, a complete
blood count, PTH, thyroid-stimulating hormone, serum protein electrophoresis, and
24-hour urine calcium and cortisol should be measured. If kyphosis is identified or a
height loss of 2.5 cm (1 inch) or more is confirmed, radiographs of the thoracolumbar
spine should be obtained to exclude vertebral compression fractures. The vertebral frac-
ture assessment algorithm, an analysis that can be performed on certain DXA machines,
is another way to determine whether a patient has a prevalent vertebral fracture.9
Increasingly used in the management of osteoporosis, bone turnover markers can offer
prognostic information on fracture risk and supplement bone density measurements.
Bone turnover marker assays measure protein or protein derivative biomarkers released
during bone remodeling by osteoblasts or osteoclasts. Bone-specific alkaline phospha-
tase, osteocalcin (OC), and N-terminal propeptide of type I procollagen (PINP) are
markers specific to bone formation. N-terminal telopeptide of type I collagen (NTX)
and C-terminal telopeptide of type I collagen (CTX) are available to assess bone resorp-
tion.10 Although bone turnover markers are helpful in determining patient response to
pharmacologic therapies for osteoporosis, testing must consider coexisting medical
conditions and factors that can affect results. For example, CTX, NTX, monomeric
PINP, and OC are renally cleared and generally increase with renal insufficiency.11
Most bone turnover markers display circadian variation; serum CTX, NTX, and OC con-
centrations peak in the early morning between midnight and 8 AM with a nadir in the af-
ternoon and early evening.12 Thus, bone turnover markers should be measured on a
fasting morning serum sample or a first or second voided urine to minimize variability.

TREATMENT
Nutrition
Optimal bone health requires a combination of mechanical load and adequate intake
of macronutrients and micronutrients. The most important nutrients are calcium,
vitamin D, and protein. Calcium is important for the bone formation phase of bone
remodeling. Inadequate calcium intake can result in decreased calcium absorption
and secondary hyperparathyroidism, which can cause increased bone resorption.
With aging, the efficacy of intestinal calcium declines; thus, adequate calcium intake
is crucial in maintaining bone health. Vitamin D generated from sunlight, food, or sup-
plements is converted in the liver to 25-hydroxy vitamin D that serves as the substrate

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6 Anam & Insogna

for 1,25-dihydroxyvitamin D, a key regulator of active intestinal calcium absorption.

Recent systematic reviews and meta-analyses showed that supplementation with cal-
cium and vitamin D results in a reduced risk of fractures and a modest increase in
BMD.13–15 The optimal amounts of calcium and vitamin D intake remain controversial,
but generally, 1200 mg of calcium and 800 IU of vitamin D daily are recommended for
most postmenopausal women and for men above age 70.6 Calcium supplements have
been associated with an increased risk of kidney stones in randomized clinical trials.16
The preponderance of evidence indicates that neither calcium (up to 1000 mg daily)
nor vitamin D supplements have been shown to increase cardiovascular or all-
cause mortality.17–19 Calcium supplements should be limited to patients who cannot
achieve adequate dietary calcium intake. Although many studies have demonstrated
a positive association between serum 25-hydroxyvitamin D levels and BMD, and low
serum levels of 25-OH D have been associated with higher fracture risk, the optimal
serum level of 25-OH D for fracture prevention remains unestablished.20–23
Nonetheless, a serum 25-hydroxyvitamin D level of 20 ng/mL seems to be adequate
in protecting most of the population from adverse skeletal outcomes.13 Data on the
effect of protein intake on bone density are conflicting. Some studies suggest that
higher protein intake is associated with a lower risk of hip fractures and bone loss,
while others indicate increased bone resorption and calcium excretion with high pro-
tein intake.24–26 Overall, available data suggest that an intake of 1.2 g/kg/d allows for
normal calcium homeostasis.

Exercise
Although the beneficial effect of physical activity on bone density is small, it is asso-
ciated with decreased risk of hip fractures in older women and decreased risk of falls
by improving muscle strength, balance, and mobility. Individuals with osteoporosis (or
seeking to prevent it) should exercise for at least 30 minutes 3 times per week. A meta-
analysis of 43 randomized trials showed that multiple weight-bearing exercises,
including resistance training, jogging, tennis, and walking, were effective. The most
effective type of exercise for BMD of the femoral neck was non-weight-bearing,
high-force exercise (eg, progressive resistance strength training), while a mixture of
more than one exercise type was most effective for lumbar spine BMD.27

Fall Prevention
Given that the majority of osteoporosis-related fractures result from falls, risk factors
for falling should be addressed. Risk factors for falls include a personal history of fall-
ing, muscle weakness, gait instability, medications (eg, narcotic analgesics, anticon-
vulsants, benzodiazepines, and antidepressants), home hazards, and visual deficits.28
Falls can be reduced by several interventions, such as initiation of an exercise regimen
that improves balance and strength, avoidance of polypharmacy, vision assessment
and correction, and the use of assistive devices. Exercise programs tailored to reduce
falls have consistently been shown to reduce fractures,29,30 whereas hip protectors
have not consistently been shown to decrease the risk of fractures.

PHARMACOLOGIC TREATMENT
Indications for Treatment
Currently, there are over 50 national guidelines in more than 30 countries regarding
osteoporosis treatment. In the United States, pharmacologic therapy is recommended
for postmenopausal women and men age 50 and older with hip or vertebral fractures;
those with T-scores of 2.5 or less at the femoral neck, total hip, or lumbar spine; and

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 Update on Osteoporosis Screening and Management 7

those with T-scores of 1 to 2.5 and a 10-year probability of 20% for major oste-
oporotic fractures or 3% for hip fractures based on the US-adapted FRAX tool (NOF
guidelines). An area of uncertainty is the efficacy of pharmacologic agents in otherwise
healthy osteopenic patients with all central DXA T-scores better than 2.5, no preva-
lent vertebral fracture or recent fragility fracture, and FRAX scores in the treatment
range. Because drug therapy trials only enroll patients based on BMD values and
not FRAX scores, direct evidence to support treatment of such individuals based on
FRAX scores is lacking. One recent study suggested a benefit to treatment in osteo-
penic older women, but the study included some women with osteoporosis.31
Treatment should be started without delay in patients with recent fractures to pre-
vent more fractures, based on their fracture risk. Little data are available on the optimal
timing of initiating therapy after a fracture. However, it is reasonable to start therapy
2 or more weeks after a hip fracture.32 A suggested algorithm for diagnosis and man-
agement of postmenopausal osteoporosis is outlined in Fig. 1.

Approved Therapies
The pharmacologic arsenal for osteoporosis treatment includes drugs that inhibit bone
resorption—bisphosphonates, estrogens, selective estrogen receptor modulators
(SERMs), denosumab, and calcitonin; and anabolic agents that stimulate new bone
formation—teriparatide, abaloparatide, and romosozumab (Table 2). Antiresorptive
agents increase BMD in part by decreasing the rate of bone remodeling and altering
the extracellular matrix. Teriparatide and abaloparatide are PTH and PTH-related pro-
tein analogs that stimulate new bone formation by directly activating PTH type 1 re-
ceptor to induce more bone formation than resorption, thus leading to an increase

Fig. 1. Suggested algorithm for diagnosis and management of postmenopausal osteopo-

rosis. Of note, a high FRAX score should not be the sole determinant for drug treatment.

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8 Anam & Insogna

Table 2
Summary of fracture risk reduction of pharmacologic therapies approved for postmenopausal
osteoporosis

Vertebral Hip Nonvertebral

Drug Fracture Fracture Fracture
Alendronate U U U
Risedronate U U U
Ibandronate U - Ua
Zoledronic acid U U U
Denosumab U U U
Teriparatide U - U
Abaloparatide U - U
Romosozumab U U U
Estrogen U U U
Raloxifene U - -
Bazedoxifene U - -
Bazedoxifene and - - -
conjugated estrogen
Calcitonin U - -
a
Effect shown in a post hoc analysis.

in BMD. Romosozumab is another anabolic agent and works by blocking the actions
of sclerostin, an inhibitor of bone formation. These medications have been shown to
decrease fracture risk in patients who have had fragility fractures or osteoporosis by
DXA. These drugs may also reduce fractures in patients with low bone mass (osteo-
penia) without fractures, but that evidence is not as strong.

THE ANTIRESORPTIVE DRUGS

Bisphosphonates
Bisphosphonates are a cornerstone of osteoporosis treatment and are chemically sta-
ble derivatives of inorganic pyrophosphate. With their high affinity for calcium crystals,
bisphosphonates concentrate selectively in the bone, decreasing bone resorption.
Bisphosphonates are preferentially incorporated into sites of active bone remodeling
and inhibit bone resorption by rapidly inhibiting the activity of osteoclasts. This abrupt
reduction in bone resorption eventually results in the concomitant slowing of bone for-
mation. A steady state is reached 3 to 6 months after exposure to these medications.
Bisphosphonates also maintain or improve trabecular and cortical architecture and in-
crease bone mineralization and BMD, with the net effect of decreasing fracture
risk.33,34 Bisphosphonates have low bioavailability with poor intestinal absorption
(1%–5%) and rapid clearance from the circulation. About half of the absorbed dose
concentrates in the bone, whereas the other half is excreted unmetabolized in the
urine. Skeletal uptake primarily depends on renal function, bone turnover, binding
site availability in bone, and bisphosphonate affinity for bone matrix. First-
generation non–nitrogen-containing bisphosphonates (etidronate, clodronate, and
tiludronate) are now rarely used because of low potency and increased risk of osteo-
malacia. Second-generation and third-generation bisphosphonates (alendronate,
risedronate, ibandronate, pamidronate, and zoledronic acid) contain nitrogen and
act primarily by inhibiting the enzyme farnesyl pyrophosphate (FPP) synthase in the

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 Update on Osteoporosis Screening and Management 9

mevalonate pathway (cholesterol biosynthetic pathway). Inhibition of FPP synthase

disrupts protein prenylation, which creates cytoskeletal abnormalities in the osteo-
clast and ultimately leads to osteoclast apoptosis.35,36 Alendronate, risedronate,
ibandronate, and zoledronic acid have been shown to improve BMD in postmeno-
pausal women with underlying low bone density and to significantly decrease the
risk of vertebral fractures. Alendronate, risedronate, and zoledronic acid have been
proven to reduce the risk of hip and other nonvertebral fractures.37–41 The most com-
mon adverse effects of bisphosphonates include gastrointestinal problems such as
esophagitis and esophageal ulcers with the oral preparations and myalgia and
arthralgia with both oral and intravenous (IV) bisphosphonates. Flu-like symptoms
(arthralgia, myalgia, fever, headache) occur in about 30% of patients after the first
dose of IV zoledronic acid.42 Because IV bisphosphonates have been associated
with hypocalcemia, serum calcium and 25-hydroxyvitamin D levels should be checked
before initiating treatment, and adequate supplementation should be provided. Kidney
function should be checked before initiating treatment and then periodically because
bisphosphonates are generally not recommended for patients with creatinine clear-
ance of less than 30 to 35 mL/min. Ocular inflammation has rarely been reported.
Other potential associations with bisphosphonate use include atrial fibrillation and
esophageal cancer; however, a clear causal relationship has not been established.
Many articles have been published on the association of bisphosphonate therapy
and the occurrence of osteonecrosis of the jaw (ONJ).43 The incidence of ONJ is
extremely low, and it occurs primarily in patients with cancer treated with high-dose
IV bisphosphonates. Beginning in 2005, unusual fragility fractures in the subtrochan-
teric region and along the femoral diaphysis in bisphosphonate-treated patients, now
known as atypical femur fractures (AFFs), were first reported.44,45 One possible under-
lying mechanism of AFF is severely suppressed bone turnover. Because of concerns
about atypical fractures, bisphosphonate use has declined considerably, and the
magnitude of the association between these drugs and AFF remains controversial.
Several studies have shown that the absolute risk of AFF is very low compared with
the much greater number of fractures effectively prevented by bisphosphonates. In
a large prospective cohort of women, risk factors for developing AFF include duration
of bisphosphonate treatment (particularly with 8 or more years of use), Asian ancestry,
shorter height, higher weight, and glucocorticoid use for 1 year or more.46 Patients on
long-term bisphosphonates (for example, greater than 3 years) reporting femoral shaft
or hip pain should undergo a bone scan or MRI to exclude the presence of an insuf-
ficiency fracture, which could be a harbinger for AFF. Because of the risk of ONJ
and AFFs, there has been an increased focus on the optimal duration of bisphospho-
nate therapy. The American Society for Bone and Mineral Research Task Force on
Long-Term Bisphosphonates has proposed that AFF risk might be reduced by taking
a temporary holiday from oral bisphosphonates after 5 years and IV bisphosphonates
after 3 years in patients who are not at high risk of fracture.47 The suggested approach
for long-term bisphosphonate use does not replace the need for clinical judgment, and
continuation of therapy may be warranted in patients remaining at high fracture risk,
such as those continuing to have osteoporosis of the femoral neck (T-score  2.5)
after 3 to 5 years of treatment or those with an existing vertebral fracture and a femoral
neck T-score less than 2.48 However, it has to be acknowledged that if a femoral
neck T-score remains  2.5 after a complete course of bisphosphonate therapy, it
is less likely that continued therapy will further improve the BMD at that site. Several
studies support the notion that fracture efficacy is maintained during a bisphospho-
nate holiday. Long-term randomized trials with alendronate and zoledronic acid indi-
cate that after stopping treatment, BMD gains remain but are slowly lost over the next

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10 Anam & Insogna

3 to 5 years. Bone turnover marker levels initially remain low but slowly increase,
though the risk of nonvertebral fractures is not increased more than 5 years after
discontinuation.48,49 After starting a drug holiday, fracture risk and BMD should be
reevaluated every 2 to 4 years after discontinuation. A significant decrease in BMD
or increase in bone turnover markers should lead to restarting osteoporosis therapy,
depending on the patient’s fracture risk before the 5-year maximum holiday is
completed.

Menopausal Hormone Therapy—Estrogen

Estrogen therapy is suggested for use in women under 60 years of age or less than
10 years past menopause, who have vasomotor or climacteric symptoms associated
with menopause, and those in whom bisphosphonates or denosumab are not appro-
priate. However, given potential risks (eg, myocardial infarction, stroke, invasive
breast cancer, pulmonary emboli, and deep vein thrombophlebitis) associated with
hormonal therapy, especially when combined with a progestin, non-estrogen treat-
ments should first be considered for treatment and prevention of osteoporosis. In
the Women’s Health Initiative, 5 years of combined estrogen and progestin therapy
(Prempro) reduced the risk of clinical vertebral fractures and hip fractures by 34%
and other osteoporotic fractures by 23%.50

Selective Estrogen Receptor Modulators—Raloxifene (Brand Name Evista),

Bazedoxifene (Duavee)
SERMs bind with high affinity to the estrogen receptor and have estrogen agonist and
antagonist properties depending on the target organ. Raloxifene (60 mg once daily) has
estrogenic activity in bone, thus preventing bone loss, improving BMD, and reducing
fracture risk. In a 3-year trial, raloxifene reduced the risk of vertebral fractures by about
30% in patients with a prior vertebral fracture and by about 55% in patients without a
prior vertebral fracture. Raloxifene does not reduce the risk of hip or nonvertebral frac-
tures.51,52 Several side effects limit use, including venous thromboembolism, stroke,
hot flashes, and leg cramps.53 The effect of raloxifene on BMD is less than that of meno-
pausal hormone therapy, but there are no comparative fracture data.54 Bazedoxifene is
only approved in the United States and Canada in combination with conjugated estro-
gens for the treatment of hot flashes or prevention of osteoporosis in patients for whom
other treatments are not suitable. The combination of conjugated estrogens and baze-
doxifene results in less increase in spinal BMD at 1 year compared with conjugated es-
trogens and progestin, but less breast tenderness and more amenorrhea.55 Conjugated
estrogens/bazedoxifene have not been shown to reduce the risk of fracture.

Denosumab (Brand Name Prolia)

Denosumab is a fully human monoclonal antibody to RANKL. It reduces osteoclasto-
genesis, induces osteoclast apoptosis, decreases bone resorption, increases BMD,
and reduces fracture risk. Denosumab can be offered as an alternative initial treatment
to postmenopausal women with osteoporosis at high risk for fractures. A meta-analysis
that compared denosumab with placebo found that fracture risk was reduced by 68%
for vertebral fractures, 39% for hip fractures, and 19% for nonvertebral fractures.52
Denosumab increases lumbar spine BMD by 9% and total hip BMD by 4%.56 In the
7-year extension of the denosumab registration trial, the FREEDOM Extension study,
continued low rates of new radiographic vertebral, nonvertebral, and hip fractures sup-
ported a stable level of fracture reduction for up to 10 years.57 The recommended
dosage of denosumab is 60 mg subcutaneously every 6 months. Decreased bone
remodeling by denosumab is reflected in bone turnover markers, but these changes

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 Update on Osteoporosis Screening and Management 11

reverse after 6 months if the drug is not taken on schedule. In addition, several studies
have shown that stopping denosumab treatment is associated with a risk of multiple or
severe vertebral fractures.58 To decrease the risk of rebound rapid BMD loss and to pre-
vent fractures, denosumab administration should not be delayed or stopped without
subsequent antiresorptive (e.g., bisphosphonate, hormone therapy, or SERM) therapy.
Unlike bisphosphonates, denosumab is not cleared by the kidney. It may be used in pa-
tients with CKD and those with eGFRs of 35 mL/min. However, patients should be
monitored for hypocalcemia because the drug rapidly and significantly lowers bone
turnover, blocking calcium mobilization from bone. Adverse effects of denosumab
include ONJ, AFFs, and hypocalcemia. Adequate calcium and vitamin D levels should
be ensured before initiating denosumab. In the FREEDOM trial, denosumab was also
associated with increased infections (cellulitis, cystitis), but it was not statistically sig-
nificant.59 A recent meta-analysis evaluating the risk of infection with denosumab
reached essentially the same conclusion.60 There are no published data on the use of
denosumab beyond 10 years of treatment.

Calcitonin (Brand Names Miacalcin or Fortical)

Salmon calcitonin (intranasal or injectable) is approved to treat osteoporosis in women
who are at least 5 years postmenopausal. The intranasal preparation at a dose of 200
IU daily is almost exclusively used in clinical practice. Studies show that calcitonin re-
duces the risk of vertebral but not nonvertebral fractures.61,62 There is some evidence
for an analgesic effect in patients with acute painful vertebral fractures.63 Nasal calci-
tonin has been withdrawn from the market in Europe and Canada because of con-
cerns about a possible association with certain malignancies, prompting the FDA to
request that prescribing information note this possible association. A recent meta-
analysis has concluded that there is no plausible mechanism for this association.64

THE ANABOLIC DRUGS

Parathyroid Hormone and Related Protein Analogs—Teriparatide (Brand Name
Forteo), Abaloparatide (Brand Name Tymlos)
Anabolic agents increase BMD by increasing bone formation when administered inter-
mittently. There are now two approved peptides that are anabolic for bone: PTH (1–34)
(teriparatide) and a PTH-related protein analog (abaloparatide). Switching to an
anabolic agent may be considered when a patient on bisphosphonates continues to
lose bone mass or sustains a fracture. A meta-analysis comparing teriparatide with
placebo showed a 74% reduction in the risk of vertebral fractures and 39% reduction
in the risk of nonvertebral fractures. Comparison of abaloparatide with placebo
showed an 87% reduction in the risk of vertebral fractures and a 46% reduction in
the risk of nonvertebral fractures.52 Since benefits of anabolic therapy are quickly
lost after discontinuation, most clinical guidelines recommend a course of teriparatide
or abaloparatide followed by a bisphosphonate, raloxifene, denosumab, or meno-
pausal hormone therapy. There is some controversy about the efficacy of anabolic
agents following bisphosphonate therapy. Several studies have suggested that while
teriparatide retains its anabolic effect, the magnitude of the effect is blunted, and the
timing of onset may be delayed.65 Both teriparatide and abaloparatide are limited to a
maximum of 24 months of therapy based on increased osteosarcoma in rats given life-
long treatment with these agents. However, since the introduction of teriparatide in
2002, with more than 1 million human users, the rate of osteosarcoma has not been
greater than expected, and no cases have been reported in the Forteo Patient Registry
established since 2009.66,67 Adverse effects of teriparatide include dizziness and leg

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12 Anam & Insogna

cramps, and side effects of abaloparatide include nausea, postural hypotension,

headache, and palpitations.68 Both agents can cause hypercalciuria and increase
serum calcium, but persistent hypercalcemia is uncommon. These agents should
be used cautiously in patients with calcium oxalate nephrolithiasis. Serum calcium
should be assessed before treatment, and neither agent should be used in patients
with hypercalcemia. It may be preferable to administer these drugs in the evening to
avoid complications from occasional hypotension.

Romosozumab (Brand Name Evenity)

Romosozumab is the newest anabolic agent approved for the treatment of osteopo-
rosis, and it increases bone formation as it reduces bone resorption. Romosozumab
blocks the actions of sclerostin, an inhibitor of bone formation that binds to the low-den-
sity lipoprotein receptor-related protein (LRP)5/6 component of the LRP5/6-frizzled cor-
eceptor complex that transduces Wnt signaling.69 The drug is administered as a 210 mg
monthly subcutaneous injection for 12 months. There have been 2 large phase 3 trials of
romosozumab. In the Fracture Study in Postmenopausal Women with Osteoporosis
(FRAME) trial, romosozumab led to a 73% reduction in the risk of vertebral fractures
but with no significant effect on the risk of hip or nonvertebral fractures compared
with placebo. At 24 months, those treated with romosozumab (initial 12 months) fol-
lowed by denosumab demonstrated a 75% lower risk for new vertebral fractures.70
The Active-Controlled Fracture Study in Postmenopausal Women with Osteoporosis
at High Risk (ARCH) trial compared 1 year of treatment with romosozumab followed
by 1 year of alendronate to 2 years of treatment with alendronate only in postmeno-
pausal women at high risk of fracture.59 The ARCH trial suggests that romosozumab/
alendronate versus alendronate/alendronate resulted in a 48% reduction in the risk of
vertebral fractures, a 38% reduction in the risk of hip fractures, and a 19% reduction
in the risk of nonvertebral fractures at 24 months. Romosozumab should be considered
a first-line therapy in patients with severe osteoporosis and multiple vertebral fractures
or hip fracture (eg, T-score < 2.5 and fractures) and can also be used in individuals
who have failed antiresorptive treatments. In the ARCH trial, a composite endpoint of
cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke was more
common in the romosozumab group. Thus, individuals at high risk of cardiovascular dis-
ease or stroke or those with prior myocardial infarction or stroke within the past year
should not be offered romosozumab.71,72 Additional adverse effects observed with
romosozumab included small numbers of ONJ, AFFs, and injection-site reactions.
Romosozumab treatment resulted in large increases in BMD compared with controls
in both FRAME and ARCH trials. In FRAME at 12 months, the difference in BMD be-
tween romosozumab and placebo was 13% (spine), 7% (total hip), and 5% (femoral
neck). In ARCH at 12 months, BMD had significantly increased with romosozumab,
by 14% (spine), 6% (total hip), and 5% (femoral neck), compared with increased
BMD with alendronate of 5% (spine), 3% (total hip), and 1.7% (femoral neck).71 At
12 months, romosozumab appears to be more potent than teriparatide in its effect on
BMD. A head-to-head comparison of teriparatide and romosozumab showed that
BMD had significantly increased with romosozumab, by 11% (spine), 4% (total hip),
and 4% (femoral neck), compared with increased BMD with teriparatide of 7% (spine),
1.3% (total hip), and 1.1% (femoral neck).
Romosozumab should be followed by an antiresorptive agent to maintain BMD
gains and prevent accelerated bone loss after completing the treatment course.

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 Update on Osteoporosis Screening and Management 13

CHOOSING ANTIOSTEOPOROTIC THERAPY

In addition to recommending adequate calcium and vitamin D intake, resistance and

weight-bearing exercises, smoking cessation, limited alcohol consumption, pharma-
cologic therapy should be selected based on cost, safety profile, and efficacy. For pa-
tients with osteoporosis of the hip, drugs proven to be effective at this site should be
used, and thus, ibandronate, raloxifene, and calcitonin should not be considered in
this scenario. Owing to their lower costs and lengthier clinical experience, bisphosph-
onates are often used as first-line treatment for osteoporosis. However, drug choice
should be individualized to the patient, and there may be specific patient factors
that help determine the optimal drug. For example, IV bisphosphonates or denosumab
could be alternatives for patients who cannot tolerate oral bisphosphonates because
of gastrointestinal side effects. As noted, adherence to oral antiresorptive therapy is
often poor. Despite their greater cost, this has led to increased use of parenterally
administered drugs in this class.
Combination Therapy
Combination therapy, usually a bisphosphonate with a nonbisphosphonate, is not rec-
ommended. It can provide additional, small increases in BMD compared with mono-
therapy; however, the effect on fracture rates is unknown. The added cost and
potential side effects, such as oversuppression of bone turnover, should be weighed
against potential benefits. From a practical standpoint, insurers can be reluctant to
provide coverage for combined therapy.
Monitoring Response to Treatment
Several studies have shown poor adherence with osteoporosis medications. One year
after initiating treatment of osteoporosis, about 45% of patients do not refill the pre-
scriptions. Thus, it is important to confirm whether patients are taking their medica-
tions and to encourage adherence.
Sharing the bone density results with patients modestly increases adherence to
therapy. Various approaches have also been suggested to improve adherence,
such as counseling programs and health care system interventions.73,74 Central
DXA measurement of the spine and hip is the preferred method for serial assessment
of BMD. There is no consensus on the optimal frequency of monitoring and the
preferred site to monitor. The NOF recommends repeating the BMD assessment every
2 years but recognizes that testing more frequently may be warranted in certain clinical
situations.6 A stable or increasing BMD is an acceptable response to therapy. Gener-
ally, a loss of BMD greater than the least significant change (typically 5% in the lumbar
spine, 4% in the total hip, and 5% in the femoral neck) over 2 years and a less than
expected reduction in bone turnover markers on antiresorptive drugs is considered
“failure” of therapy. In addition, poor adherence, malabsorption, secondary diseases
affecting skeletal health should be investigated if there is a decrease in BMD during
ongoing antiosteoporotic therapy. Bone turnover markers can be followed to evaluate
the efficacy of therapy. A significant decrease in bone turnover markers with antire-
sorptive therapy or an increase in bone turnover with anabolic therapy provides evi-
dence of compliance and drug efficacy.

SUMMARY

Osteoporosis is a global public health concern that is underdiagnosed and under-

treated. Fragility fractures of the spine and hip can result in chronic pain, depression,
disability, and death. Central DXA measurements are the gold standard for the

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14 Anam & Insogna

assessment of BMD. Secondary causes and risk factors for bone loss should be iden-
tified and treated. Pharmacologic agents in conjunction with a well-balanced diet, ex-
ercise, smoking cessation, and fall prevention should be recommended in all patients
at high risk for fracture.

CLINICS CARE POINTS

Pharmacologic therapies should be recommended in postmenopausal women at high risk for

fracture.

Bisphosphonates or denosumab can be offered as initial treatments.

Anabolic therapy with teriparatide, abaloparatide, or romosozumab is recommended in
postmenopausal women with osteoporosis and at very high risk for fracture, especially
those with severe fragility fractures or multiple vertebral fractures.

DISCLOSURE

The authors have nothing to disclose.

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