102-1

Section 12

BONE AND JOINT DISORDERS

102
OSTEOPOROSIS
Bona Fide Treatment Level II
Emily C. Farthing-Papineau, PharmD, BCPS

INSTRUCTORS GUIDE TO
CHANGES IN THIS EDITION
CASEBOOK
Patient Presentation
New problem and chief complaint of intolerance to bisphosphonate therapy has been added.
Additional laboratory result (calcium) has been added to aid in
assessment of pharmacotherapeutic options.
Additional risk factors for osteoporosis (cigarette smoking,
maternal history of hip fracture) have been added.
Medications for Stage II chronic obstructive pulmonary disease
(COPD) modified to reflect a commonly used, but potentially
suboptimal regimen for this patient.
New medication for osteoporosis (alendronate) has been added.
INSTRUCTORS GUIDE
Problem Identification
Tiotropium is an alternative to adding an inhaled corticosteroid (recommended by the Global Initiatives for Chronic
Obstructive Lung Disease [GOLD] guidelines for COPD) and
avoids the potential for inhaled corticosteroids to decrease
bone mineral density (BMD) in this patient.
Use of the World Health Organization (WHO) FRAX score to
quantify the patients risk for osteoporotic fracture has been
added.
Patient has high cardiovascular risk and therefore has a lower
low-density lipoprotein (LDL) goal, which is not being met.
Hypertriglyceridemia has been removed as a concurrent problem in this case.
Added tobacco smoking as a problem to be addressed.
Therapeutic Alternatives
Updated recommendations on the daily recommended
amounts of calcium and vitamin D.
Risedronate dosages have been updated.
Discussion of bisphosphonates and raloxifene has been
updated.
Discussion of denosumab has been added.

Optimal Plan
IV zoledronic acid and ibandronate are preferred, since the
patient does not tolerate an oral bisphosphonate.
More information on teriparatide as an option is provided.
Denosumab is identified as a therapeutic alternative if preferred therapy fails.
Patient Education
Information added on new dosages and routes of administration of bisphosphonates and nonpharmacologic treatment
options.
References
Revised and updated to include recent information from
major guidelines, new data on denosumab, and atypical femur
fractures.

CASE SUMMARY
E.S., a 66-year-old woman, presents to a family medicine clinic for
a routine follow-up visit for hypertension, dyslipidemia, and osteoporosis. Her complaints include heartburn and stomach pain with
alendronate use. A recent dual-energy x-ray absorptiometry (DXA)
scan reveals severe osteoporosis; the patient reports a 2-in loss in
height since she was 35 years old, and has evidence of a vertebral
compression fracture. The patient requires an osteoporosis therapy
that is both efficacious and tolerable. Estrogen therapy should be
withheld in this patient not only due to her history of breast cancer,
but also because estrogen therapy is no longer recommended solely
for the prevention of chronic diseases. Feasible treatment alternatives include IV ibandronate or zoledronic acid, oral raloxifene, subcutaneous or intranasal calcitonin, and subcutaneous teriparatide.
The patient should also receive 1,500 mg of elemental calcium daily
through diet and/or supplementation. Vitamin D (cholecalciferol)
8001,000 IU daily should be considered because many elderly
patients are deficient in this vitamin. Nonpharmacologic interventions such as dietary modification, reduced caffeine and cola intake,
and implementation of a weight-bearing exercise program play an
important role in the management of osteoporossis.

QUESTIONS
Problem Identification
1.a. Create a list of the patients drug therapy problems.
Suboptimal calcium supplementation. Calcium carbonate is
not absorbed well in a patient on acid-suppressive therapy.1
Calcium citrates absorption is less dependent on gastric pH
and is a better option for this patient.
Osteoporosis therapy with alendronate is not being tolerated
and needs to be altered.
Copyright 2011 by The McGraw-Hill Companies, Inc. All rights reserved.

102-2

SECTION 12
Bone and Joint Disorders

Hypertension is uncontrolled. The patients blood pressure

is currently not controlled on atenolol and ramipril (blood
pressure 148/92 mm Hg). According to the Seventh Report
of the Joint National Committee on Prevention, Detection,
Evaluation, and Treatment of High Blood Pressure (JNC 7),
-blockers are preferred in postmyocardial infarction patients
and have been shown to reduce mortality and the incidence
of myocardial infarction recurrence.2 However, -blockers
can provoke bronchospasm, and such agents should be used
with caution in patients with bronchospastic diseases such as
COPD.
This patient is taking a 1-selective -blocker (atenolol),
but the risk of bronchospasm and current COPD control
should be weighed against the benefits of cardioprotection
as indicated in the JNC 7 report.2 The case information does
not depict intolerance related to COPD to be an issue for
the patient. The dose of atenolol could also be increased to
100 mg daily.
Angiotensin-converting enzyme (ACE) inhibitors (e.g.,
ramipril) are also a good choice in postmyocardial infarction patients, as they have been shown to prevent cardiac remodeling and improve long-term outcomes in such
patients.2 This patient is already receiving the maximum
dose of ramipril (20 mg per day).
Thiazide diuretics have been shown to reduce morbidity and mortality in hypertension. According to JNC 7
guidelines and the findings of the Antihypertensive and
Lipid-Lowering Treatment to Prevent Heart Attack Trial
(ALLHAT), thiazide-type diuretics should be used either
alone or in combination with drugs from other classes in
the treatment of hypertension.2 In addition, there is some
evidence that thiazide diuretics may improve bone density
by reducing urinary calcium excretion and inhibiting bone
resorption.3 A thiazide diuretic would be a reasonable addition. To increase adherence to the medication regimen, a
combination product of thiazide diuretic and -blocker or
ACE inhibitor may be useful. Examples of these combinations include Tenoretic (atenolol and chlorthalidone) and
Zestoretic (lisinopril and hydrochlorothiazide).
Dyslipidemia is inadequately treated. The patients triglycerides are at goal, but her LDL is not. Because this patient has
known coronary artery disease, her goal LDL cholesterol is at
least <100 mg/dL.4 Further lowering to <70 mg/dL may provide greater cardiovascular benefit for those with a history
of coronary heart disease.5 Her lipid levels are responding to
therapy (as evidenced by reductions in total cholesterol, LDL
cholesterol, and TGs and an increase in HDL over the past 3
months with no substantial increase in LFTs), but the lovastatin dose should be increased to at least 40 mg to provide an
LDL below 100 mg/dL. Other statins, such as atorvastatin 10
mg or pravastatin 20 mg daily, could also achieve an LDL of
<100 mg/dL in this patient. To achieve an LDL of <70 mg/dL,
her baseline LDL should be lowered by 50%. The only statins
capable of this percentage of LDL lowering are atorvastatin 40
mg and rosuvastatin 10 mg.
The patient should also receive information on therapeutic
lifestyle changes, specifying both diet and lifestyle changes,
such as weight loss and increased physical activity.4
COPD therapy poses risks for adverse effects. Inhaled fluticasone (the corticosteroid component of Advair) was added to
the patients regimen 9 months ago following a COPD exacerbation. The guidelines from the GOLD suggest that inhaled
corticosteroids may be useful in patients with severe or very
Copyright 2011 by The McGraw-Hill Companies, Inc. All rights reserved.

severe (Stage III or IV) COPD or who have experienced three

or more exacerbations in the previous 3 years.6 The GOLD
guidelines also highlight the current debate as to whether
chronic administration of inhaled corticosteroids in COPD
may lower BMD.6 Inhaled corticosteroids are preferred to systemic treatment because they have less osteoporosis risk. This
patient currently has Stage II COPD and has not had multiple
COPD exacerbations. Since an inhaled corticosteroid is not yet
indicated in this patient according to the GOLD guidelines, the
clinician may switch therapy from fluticasone/salmeterol to
a long-acting -agonist in addition to tiotropium, which will
also avoid the potential for inhaled corticosteroids to adversely
affect bone health. Furthermore, tiotropium therapy has also
been shown to decrease COPD exacerbations.
Smoking cessation should be encouraged, as this would help
to lower her blood pressure and cholesterol, decrease the rate
of decline of her lung function, and decrease the risk of osteoporotic fracture.2,4,69 Use the 5 As to guide this process, and
discuss the various options to help minimize nicotine withdrawal, including nicotine replacement products, bupropion,
and varenicline.10
Hypothyroidism is presently controlled. The thyroid-stimulating hormone (TSH) level is normal, indicating that the
levothyroxine therapy is adequate. The patients TSH level
should be routinely monitored because overtreatment of
hypothyroidism that induces hyperthyroidism can contribute to further loss of BMD.7
1.b. What information (signs, symptoms, laboratory values,
FRAX score) indicates the presence or severity of the patients
osteoporosis? What are the patients risk factors for developing osteoporosis?
The DXA scan results indicate severe osteoporosis. The WHO
classifies bone mass based on T scores, which represent the
number of standard deviations (SDs) away from the mean
BMD for the young normal adult population. Criteria for
interpreting the results of a DXA scan are79:
Normal: T score within 1.0 SD of young adult mean value.
Osteopenia: T score between 1.0 and 2.5 SD below the
mean.
Osteoporosis: T score 2.5 SD below the young adult mean
value.
This patients worst T score is >3 SD from the young adult
mean value, and she has one or more fragility fractures (loss of
height of >1.5 in).7
The WHO FRAX score can be calculated to estimate the likelihood of the occurrence of a hip fracture or major osteoporotic
fracture (defined as hip, spine, forearm, or shoulder fracture)
within the next 10 years in a patient not on osteoporosis treatment. Since this patient has only taken two doses of alendronate,
it is acceptable to perform a FRAX score calculation. The calculation can be performed at the Web site http://www.shef.ac.uk/
FRAX/ and takes into account many risk factors for osteoporosis. For E.S., her osteoporosis risk factors include her Caucasian
ethnicity, age (and postmenopausal status), low body weight
evidenced by BMI less than 21 kg/m2, history of previous fracture, cigarette smoking, history of maternal hip fracture, and
femoral neck T score. E.S. has a 38% chance of experiencing
a major osteoporotic fracture and a 13% chance of hip fracture in the next 10 years if her osteoporosis remains untreated.
Even if this patients DXA scores were not osteoporotic, the
National Osteoporosis Foundation (NOF) guidelines and the
North American Menopause Society (NAMS) guidelines state

102-3

Based on the information presented in the case, there is no

reason to suspect a secondary cause of osteoporosis; however,
both the NAMS and the NOF recommend checking various
laboratory values such as a parathyroid hormone level, vitamin D level, and TSH (normal in this patient) when clinically
appropriate.7,9

Desired Outcome
2. What are the goals of pharmacotherapy for osteoporosis in
this case?
Prevent or decrease the incidence of fractures with a medication the patient can tolerate.
Replenish bone mass and/or prevent further bone loss and loss
of height.
Prevent falls that can result in debilitating fractures and negatively impact quality of life.
Provide optimal calcium and vitamin D supplementation, in
addition to prescription drug therapy.

Therapeutic Alternatives
3.a. What nondrug therapies might be useful for this patients
osteoporosis?
Ensure adequate calcium and vitamin D intake through diet and/
or supplementation.79 (Refer to the textbook chapter on osteoporosis for the calcium content of various foods.)
Perform regular weight-bearing and muscle-strengthening exercises, such as walking, jogging, dancing, and weightlifting.7,9
Encourage smoking cessation because postmenopausal women
who smoke are more likely to experience fractures.7,9
Avoid caffeine intake. Caffeine can increase the excretion of
calcium to a small extent and may contribute to low BMD.9
Cola beverages containing phosphorus can also decrease
BMD. This is thought to be due to the increased acid environment caused by the phosphorus and subsequently neutralized
by calcium.11
Reduce the risk of falls by removing throw rugs and extension
cords, adding handrails to the bathtub and other areas, and
obtaining nonskid mats for slippery surfaces such as bathtubs.
Clarify the quantity and frequency of alcohol consumed, as
excessive drinking, particularly >3 drinks per day, could contribute to fall risk.9
3.b. What feasible pharmacotherapeutic alternatives are available for treatment of the osteoporosis?
Adequate calcium ingestion should be recommended for all
patients with osteoporosis. Adequate calcium intake is not only
essential for achieving peak bone mass and reducing the rate
of bone loss but also vital for achieving adequate response to
other osteoporosis therapies. Since most individuals over the
age of 50 consume 600700 mg of elemental calcium per day,

The recommended daily intake varies slightly among the

NOF, National Institute of Health, and National Academy
of Sciences; however, it should be at least 1,2001,500 mg
per day of elemental calcium in postmenopausal women not
taking estrogen and 1,0001,200 mg per day in postmenopausal women taking estrogen.7,9 (Refer to textbook chapter
on osteoporosis for the content of elemental calcium in oral
calcium supplementation products.) Doses greater than
1,500 mg of elemental calcium are not thought to offer any
additional benefit, and doses greater than 2,500 mg can
increase the risk of developing kidney stones.
Because calcium absorption is rate-limited, calcium supplements should be given in divided doses of approximately
500 mg of elemental calcium.7,12
Calcium carbonate should be taken with food not only to
minimize GI side effects but also to increase calcium absorption.7 It is important to note that this patient is on acid-suppressive therapy for GERD and that long-term proton pump
inhibitor use has been associated with increased risk of hip
fractures.1 Although calcium citrate contains less elemental
calcium than calcium carbonate, it is not dependent on
gastric pH for absorption and, therefore, is a good choice
for older adults who may have achlorhydria and those on
acid-suppressive therapy.7,8 It may be taken independent of
meals.7,8 Side effects of constipation and gas are more common with calcium carbonate than with calcium citrate.8
Therapy typically should be lifelong.
Vitamin D enhances calcium absorption in the small intestine,
and when combined with calcium, it has been shown to reduce
the incidence of nonvertebral fractures in the elderly. It is not
necessary for vitamin D and calcium to be administered concurrently for vitamin D to enhance the absorption of calcium
because of the long half-life of vitamin D.7
Both the NAMS and NOF osteoporosis guidelines recommend that postmenopausal women take 8001,000 IU of
vitamin D daily.7,9 This is because most individuals are
thought to be vitamin D deficient, and elderly patients are
even more at risk for vitamin D deficiency as a result of
inadequate or limited exposure to sunlight.7 The American
College of Rheumatology (ACR) also recommends 800 IU
of vitamin D daily or calcitriol 0.5 mcg daily in those taking
systemic glucocorticoids or who plan to be on systemic glucocorticoids for 3 months.13 Dairy products are the most
common dietary source of vitamin D, although adequate
amounts of vitamin D can be obtained through other
vitamin Dfortified foods as well. Vitamin Dcontaining
supplements have one of the two forms of vitamin D, namely, ergocalciferol (vitamin D2) and cholecalciferol (vitamin
D3). Cholecalciferol is the form of vitamin D synthesized
in the skin from sun exposure. It is better at increasing and
sustaining vitamin D levels than ergocalciferol.14 This form
of vitamin D can be found in many common supplements,
such as Caltrate +D, Os-Cal 500 +D, and Cal-Citrate with
vitamin D. Cholecalciferol is also the form of vitamin D in
Fosamax Plus D. Use of vitamin D has also been associated
with decreased risk of falls, and improvement in muscle
strength.7
Calcitriol (oral Rocaltrol; injectable Calcijex) is a synthetic
vitamin D analog. It is not approved by the FDA for the
treatment of osteoporosis and is generally used only in
patients who have had vertebral fractures or those who
Copyright 2011 by The McGraw-Hill Companies, Inc. All rights reserved.

Osteoporosis

Note: The clinical role of serum or urinary biochemical markers of bone remodeling (e.g., serum osteocalcin, bone-specific
alkaline phosphatase, and urine pyridinoline) is not well established, as no clear relationship has been identified between
levels of biochemical markers and fracture risk. Neither the
NAMS nor the NOF recommends routine testing of biochemical markers, and they are not commonly obtained in clinical
practice.7,9

increasing dietary calcium or taking calcium supplements will

be necessary for most women with osteoporosis.

CHAPTER 102

that treatment is pharmacoeconomically beneficial if the risk

of hip fracture is at least 3% or if the risk of major osteoporotic
fracture is at least 20%.7,9

102-4

SECTION 12

have renal disease and cannot activate vitamin D. According

to the ACR, calcitriol is better at preventing bone loss in
patients taking oral glucocorticoids than those taking calcium and vitamin D alone.13 The recommended dose is
0.52.0 mcg per day orally or 0.5 mcg injected three times
per week. Monitoring for hypercalcemia and hypercalciuria
is recommended if calcitriol is initiated.13

Bone and Joint Disorders

Vitamin D or calcitriol replacement will most likely be given

for the rest of the patients life. Neither the NOF, NAMS, nor
the American Association of Clinical Endocrinologists (AACE)
recommends one particular vitamin D supplement over
another.79
Bisphosphonates are considered drugs of choice for the treatment of osteoporosis. They block osteoclast resorptive activity with no effect on osteoblasts. Alendronate, risedronate,
and zoledronic acid are the only FDA-approved agents that
can decrease the risk of vertebral and nonvertebral fractures,
including hip fractures. A casecontrol study also found that
bisphosphonate use reduced the risk of breast cancer in nonobese women (Br J Cancer, 2010;102(5):799802). While further investigation is needed in this area, this could be a potential
added benefit for the patient.
Alendronate (Fosamax) is approved by the FDA for both
treatment and prevention of osteoporosis, and is commonly selected for osteoporosis therapy due to its availability as a lower-cost generic medication. It reduces vertebral
fractures and increases BMD in the spine, femoral neck,
trochanter, and total body. Specifically, it decreases the risk
of fractures in women with established osteoporosis and
prevents bone loss in nonosteoporotic women. Alendronate
(either alone or in combination with hormone replacement
therapy) was shown to be superior to hormone replacement
therapy alone for preventing bone loss in elderly women.7
Alendronate has poor oral absorption (0.78%) and must
be taken on an empty stomach, which increases side effects.
The most common adverse effects are abdominal pain, acid
reflux, constipation, diarrhea, musculoskeletal pain, headache, and esophagitis. Unfortunately, the patient is currently
experiencing heartburn and abdominal pain from taking
the medication in the once-weekly 70-mg dose. Alendronate
is also available in a once-daily dose of 10 mg, but that may
cause more frequent GI irritation for the patient. Other
forms of alendronate, including the liquid dosage form and
Fosamax Plus D, which contains 70 mg of alendronate and
either 2,800 or 5,600 IU of cholecalciferol in a once-weekly
tablet, would also be expected to cause similar undesirable
GI side effects for this patient.
Risedronate (Actonel), which is also approved by the FDA for
both treatment and prevention of osteoporosis, significantly
reduces the rate of vertebral and nonvertebral fractures.7,8
Like alendronate, risedronate has poor oral absorption and
must be administered on an empty stomach. The side-effect
profile is similar to that of alendronate and would be expected to cause similar GI side effects in this patient. The dose of
risedronate is the same (5 mg once daily) for both treatment
and prevention of osteoporosis. Alternative regimens include
35 mg once-weekly or 150 mg once-monthly dose. Actonel
plus calcium is also available as a monthly package containing 4 tablets of risedronate 35 mg and 24 tablets of calcium
carbonate 500 mg. The calcium is intended to be taken on
the days of the week when the risedronate is not taken.
Ibandronate (Boniva), a bisphosphonate similar to risedronate and alendronate, is also approved by the FDA for
Copyright 2011 by The McGraw-Hill Companies, Inc. All rights reserved.

the treatment and prevention of osteoporosis. In patients

with established osteoporosis, ibandronate has been shown
to increase BMD and reduce the incidence of vertebral
fractures. With a T score below 3, ibandronate has been
shown to decrease nonvertebral fractures as well.7 Like alendronate and risedronate, ibandronates oral absorption is
significantly reduced by the presence of food, and the drug
must therefore be administered on an empty stomach, 60
minutes prior to eating or drinking. The oral form also has
similar GI side effects as the other oral bisphosphonates. The
dose of ibandronate for the prevention and treatment of
osteoporosis is 2.5 mg once daily; a dose of 150 mg monthly
may be used for the treatment of osteoporosis. Ibandronate
is also available as a 3-mg IV injection administered every
3 months by a health care professional for the treatment of
osteoporosis. This dosage form has been shown to increase
BMD to a greater degree than daily oral ibandronate.
Because it also has less GI side effects associated with its use,
this product may be a treatment option for this patient.
Zoledronic acid (Reclast) is the first bisphosphonate FDA
approved for IV once-yearly treatment of osteoporosis and
once every 2 years for osteopenia. The once-yearly injection for the treatment of postmenopausal osteoporosis was
found to decrease the risk of vertebral fractures by 70%, hip
fractures by 41%, and other fractures by 25% over a 3-year
period.7 It is also the first bisphosphonate to receive FDA
approval to reduce the incidence of new clinical fractures in
patients with low-trauma hip fracture. The most common
side effects of this treatment include an acute phase reaction
of flulike symptoms, such as fever (44%), athralgia, and
myalgia. These side effects typically resolve within 3 days
after drug infusion and can be minimized with the use of
acetaminophen prior to and for 3 days following zoledronic
acid administration. Subsequent administration of the zoledronic acid tends to cause less flulike reactions. There was
concern about zoledronic acid being associated with a statistically significant increase in the incidence of arrhythmia
(6.9% zoledronic acid group compared to 5.3% in the placebo group) in the HORIZON trial. Of these arrhythmias,
1.3% of patients given zoledronic acid experienced serious
atrial fibrillation, compared to 0.4% of patients given placebo, and most episodes of atrial fibrillation occurred more
than 1 month postinfusion. The FDA reviewed all the data
surrounding atrial fibrillation with all bisphosphonates and
determined that a causal relationship between the use of
these medications, including zoledronic acid, and the onset
of atrial fibrillation was unclear. The FDA recommends
against changing prescribing habits for this class of medications at this time and will continue to monitor postmarketing reports.15 Use of zoledronic acid has also been associated
with osteonecrosis of the jaw (ONJ) predominately when
used in much higher doses for the treatment of malignancy
and in patients who were also receiving chemotherapy and
corticosteroids.7 This medication would be an excellent
choice for the patient, as it has excellent fracture prevention
data, would avoid GI toxicity, and is conveniently administered once yearly, which may help improve patient adherence to the treatment.
Estrogen therapy was once considered the treatment of choice
for osteoporosis in postmenopausal women. Estrogen preserves
BMD and inhibits bone resorption by decreasing the rate of the
bone activation cycle. This results in a lower incidence of hip
fractures. Estrogen also provides relief from conditions associated with menopause, such as hot flashes. The U.S. Preventive

102-5

Selective estrogen receptor modulators (also known as estrogen

agonist/antagonists) have estrogenlike effects on cortical bone
and antiestrogenlike effects on breast tissue and the endometrium.
Raloxifene (Evista) increases BMD but to a lesser extent than
estrogen. It has also been demonstrated to reduce the incidence of vertebral fractures in postmenopausal women with
osteoporosis.7,8 It is indicated for both the prevention and
treatment of osteoporosis, as well as decreasing the risk of
invasive breast cancer in postmenopausal women. Raloxifene
decreases serum total and LDL cholesterol concentrations
with no effect on HDL or TGs. The 4-year results from the
Multiple Outcomes of Raloxifene Evaluation (MORE) trial
revealed that raloxifene did not significantly affect overall
risk for cardiovascular events in the overall cohort of postmenopausal women, although a reduction in risk was noted
in a subset of high-risk women and women with established
CHD. The MORE-CORE trial looked specifically at women
with increased cardiovascular risk and found that raloxifene
neither increased nor decreased cardiovascular outcomes.7,9
Raloxifene is safe in patients with breast cancer or a history
of breast cancer because it is an estrogen antagonist in uterine and breast tissues. There is an increased risk of thromboembolic events similar to estrogen; the risk is greatest
during the first 4 months of treatment. The most common
side effects are hot flashes and leg cramps. The usual dose
of raloxifene is 60 mg per day. It should be combined with
calcium supplementation.
Calcitonin-salmon (Fortical, Miacalcin) inhibits bone resorption by inhibiting osteoclast function and is only indicated for
the treatment of postmenopausal osteoporosis. It significantly
increases BMD and reduces vertebral fracture rates in women
with established osteoporosis. It has not been shown to decrease
nonvertebral or hip fractures.79 It also has an analgesic effect
and may provide some pain relief in patients with acute vertebral fractures.7 Calcitonin-salmon is available as a nasal spray
or subcutaneous injection. Its effect tends to be dose related,
and the usual dose is 100 IU SC or 200 IU intranasally per
day. When using the nasal spray, the patient should alternate
nostrils daily. The nasal spray can cause rhinitis, epistaxis, and
headache. Calcitonin-salmon is an expensive agent and is less
potent than the bisphosphonates, but it is a viable option for
patients who cannot tolerate other antiosteoporotic agents or
for patients who experience back pain as a result of vertebral
fractures.

Denosumab (Prolia) is a newer FDA-approved option for the

treatment of postmenopausal osteoporosis for those at high
risk of fracture, including those with a history of osteoporotic
fracture or multiple risk factors for fracture, or those who have
failed or are intolerant to other available osteoporosis therapies. It is a human monoclonal antibody that inhibits nuclear
factor-kappa ligand (RANKL) activity. RANKL is a protein
that essentially promotes osteoclast formation. The FREEDOM
trial demonstrated that denosumab increased BMD in the lumbar spine and hip and decreased the risk of vertebral, hip, and
nonvertebral fractures by 68%, 40%, and 20%, respectively.17
One head-to-head trial comparing denosumab to once-weekly
70-mg alendronate showed that denosumab increased BMD
at the total hip to a greater degree after 1 year, at 3.5% versus
2.6% with alendronate (P < .0001).18 Denosumab also increased
BMD to a greater degree than alendronate at all tested sites and
lowered markers of bone turnover more effectively than alendronate. The study was not powered to detect a difference in
osteoporotic fractures.18
Denosumab is administered as 60 mg subcutaneously every
6 months by a health care professional and costs approximately
$825 per injection. It has few reported side effects, such as back
and musculoskeletal pain, hypercholesterolemia, cystitis, and
dermatologic conditions like eczema.17 RANKL is also located
on activated T and B lymphocytes and in lymph nodes, so
its inhibition may explain the small increased risk of serious
infection, such as cellulitis and endocarditis. Because it is an
antiresorptive medication, reports of ONJ have occurred.
A medication guide discussing the risks of therapy is to be
distributed to patients. Denosumab is contraindicated in pregnancy and hypocalcemia. The package insert specifies patients
should take 1,000 mg of calcium daily and at least 400 IU of
vitamin D daily. Denosumabs place in osteoporotic therapy
remains to be determined.
Combination therapy:
There is some evidence that alendronate or risedronate may
increase BMD to a greater extent when used in combination
with estrogen therapy or raloxifene than when used alone.
Alendronate and teriparatide appear to be antagonistic when
Copyright 2011 by The McGraw-Hill Companies, Inc. All rights reserved.

Osteoporosis

For the treatment of postmenopausal symptoms, hormone

therapy (estrogen alone, or the combination of an estrogen
and progestogen for women with an intact uterus) can be
very effective. If used for the treatment of postmenopausal
symptoms, however, hormone therapy should be prescribed
in the smallest effective dose(s) for the shortest possible
time. It should no longer be recommended for osteoporosis
prevention alone.16

Teriparatide (Forteo) is a recombinant human parathyroid hormone with a unique mechanism of action of increasing osteoblast lifespan and function. When administered once daily, it
leads to increased bone formation and improved bone quality.
Teriparatide is indicated in postmenopausal women who are at
high risk for fractures. In postmenopausal women with osteoporosis and a history of prior vertebral fractures, teriparatide
significantly improves BMD and reduces the incidence of
subsequent fractures.79 Teriparatide is administered subcutaneously daily into the abdomen or thigh with a prefilled injectable device. It is very expensive relative to other agents used
for treating osteoporosis and often requires special approval
from insurance companies before it is available at a reduced
price to the patient. Side effects, although uncommon, include
dizziness, leg cramps, and arthralgias. The patient should sit or
lie down on the initial administration of teriparatide to prevent orthostatic hypotension with the first dose. The product
also carries a black box warning due to an increased incidence
of the development of osteosarcoma in rats. Teriparatide is
contraindicated in patients with a history of Pagets disease,
unexplained elevations in alkaline phosphatase, open epiphyses, or prior radiation therapy involving the skeleton. Use of
teriparatide for more than 2 years is not recommended due to
a lack of safety data.

CHAPTER 102

Services Task Force now recommends against the routine use

of estrogen or estrogen and progestogen for the prevention of
chronic conditions, such as osteoporosis, due to the potential
for risks associated with its use.16 This recommendation is due
to findings from the Womens Health Initiative (WHI) study
and the Heart and Estrogen/Progestin Replacement Study
(HERS) follow-up.16 According to these studies, women receiving hormone therapy were at a higher risk for coronary heart
disease, invasive breast cancer, pulmonary embolism, stroke,
and biliary tract surgery.16

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SECTION 12

used in combination. Yet, when alendronate is added after

the completion of therapy with teriparatide, alendronate
appears to maintain or further increase BMD. This strategy is
often employed after teriparatide use. However, due to a lack
of data on the long-term safety or effect on fracture rates, the
AACE, the NAMS, and the NOF do not recommend using
concomitant therapy for the treatment of osteoporosis.79

Bone and Joint Disorders

Optimal Plan
4.a. What drug, dosage form, dose, schedule, and duration of
therapy are best for treating this patients osteoporosis?
A nonoral bisphosphonate (ibandronate or zoledronic acid) is
an appropriate choice given that this patient experienced GI side
effects from an oral bisphosphonate and is unwilling to experience these side effects again. Zoledronic acid is preferred over
ibandronate due to zoledronic acids demonstrated efficacy in
decreasing nonvertebral fractures in addition to vertebral fractures and in preventing recurrent osteoporotic fractures. The
convenience of a once-yearly infusion of zoledronic acid compared to a quarterly infusion of ibandronate may make zoledronic acid a preferred choice for patients, as well. If the patient
lacks insurance, zoledronic acid and ibandronate are expensive; however, most patients have coverage for this medication
through Medicare Part B. As a practical tip, patients and clinicians can find individualized information on insurance coverage for IV ibandronate and zoledronic acid via the Boniva and
Reclast reimbursement hotlines accessed through their respective Web sites. The Reclast & You program will also locate a
nearby infusion center for zoledronic acid administration.
Zoledronic acid given as 5 mg IV every 12 months.
Ibandronate given as 3 mg IV every 3 months.
The optimal duration of bisphosphonate therapy remains
unclear and has been recently debated due to cases of atypical
subtrochanteric femur fractures in patients receiving bisphosphonate therapy.7 It remains to be determined whether or not
these patients were predisposed to these types of fractures due
to their underlying condition of osteoporosis or by bisphosphonates suppressing bone remodeling and affecting the bone
architecture. Cases of these atypical femur fractures have also
been reported in patients not taking bisphosphonate therapy.
The FDA does not recommend altering prescribing patterns
for these medications until more information confirms or
refutes this concern. In general, bisphosphonate therapy has
not been studied beyond 10 years for alendronate and beyond
3 years with ibandronate or zoledronic acid.7 Despite the long
half-life of bisphosphonates, after discontinuation of therapy,
eventual decreases in BMD and fracture prevention have been
observed.7
Raloxifene 60 mg po daily is another potential option for this
patient. It may be particularly useful because of its beneficial
lipid-lowering effects and safety in light of the patients breast
cancer history. Bisphosphonates have greater efficacy data, but
raloxifene may be beneficial in this patient because of its positive effects on the lipid profile and its lack of GI side effects.
Because of the severity of her osteoporosis, a bisphosphonate
would be preferred.
A different calcium salt should be used in this patient to increase
calcium absorption, since she is elderly and on a proton pump
inhibitor. Sufficient calcium intake is essential to increasing
bone density. The patient should obtain a total of ~1,500 mg
of calcium daily via diet and/or a supplement. Assuming the
patient has a typical diet and ingests approximately 600 mg of
Copyright 2011 by The McGraw-Hill Companies, Inc. All rights reserved.

elemental calcium per day, she needs a calcium supplement

to provide the remaining calcium needed. An example of an
appropriate product is Citracal Regular taken as two tablets
twice daily. The serving size of two tablets contains 500 mg of
elemental calcium (from calcium citrate) and 400 IU of vitamin D (as cholecalciferol).
Because of her age, the patient should take 8001,000 IU of
vitamin D daily. This could be taken in the form of a combination product with calcium, as mentioned above.
The importance of ingesting calcium and vitamin D via dietary
sources should be stressed to the patient and could reduce the
amount of calcium and vitamin D supplements needed.
Smoking cessation should be encouraged.
Caffeine and phosphate-containing cola intake should be
minimized.
After receiving medical clearance, the patient should be
instructed to begin an appropriate weight-bearing exercise
program for 30 minutes three to five times weekly.
4.b. What alternatives would be appropriate if the initial therapy
fails or cannot be used?
If the patient cannot tolerate IV bisphosphonate therapy, raloxifene could be initiated instead. Conversely, if the patient was
initiated on raloxifene (rather than an IV bisphosphonate), an
IV bisphosphonate could be used if intolerance occurs.
If the patient does not respond to either bisphosphonates or
raloxifene or sustains further fractures while taking those medications, teriparatide may be considered. Due to its high cost,
teriparatide should be reserved for patients who fail to respond
to less expensive therapies. Its daily subcutaneous route of
administration is also considered less than ideal by patients,
although the Forteo pen device has been redesigned for much
easier administration. Giving a bisphosphonate after the completion of teriparatide therapy may help to retain the increases
in BMD achieved with teriparatide use.
Denosumab could also be considered as an alternative if the
patient fails or cannot tolerate IV therapy with a bisphosphonate or oral therapy with raloxifene.
Calcitriol (0.51 mcg po once daily or Calcijex 0.5 mcg injected
thrice weekly) could be added to either a bisphosphonate or
raloxifene, instead of a traditional vitamin D supplement.
However, calcitriol is not FDA-approved for the prevention or
treatment of osteoporosis and should be used only when standard therapy fails or is contraindicated.
The combination of ibandronate or zoledronic acid plus raloxifene could be given. However, combination therapy has not
been well studied and should not be attempted unless maximal
therapy with either agent individually is unsatisfactory.79
There are other SERMS currently in drug development, such as
bazedoxifene, lasofoxifene, and ospemifene. These drugs may
have clinical differences relative to raloxifene, namely, differences
in fracture reduction, lipid effects, and hot flushes. These products
cannot be recommended until further information is known.

Outcome Evaluation
5. What clinical and laboratory parameters are necessary to
evaluate the therapy for achievement of the desired therapeutic
outcome and to detect or prevent adverse effects?

Efficacy parameters:
The NOF and NAMS recommend repeating the DXA scan
in 2 years.7,9 With bisphosphonate therapy, increases in BMD

102-7

Toxicity parameters:
For both intravenous ibandronate and zoledronic acid, the
manufacturer recommends checking a serum creatinine level
prior to each dose. If the creatinine clearance is <30 mL/min
in a patient scheduled to receive ibandronate or <35 mL/min
in a patient scheduled to receive zoledronic acid, then the
medications should not be administered due to lack of clinical
experience and renal safety data. Since E.S.s CrCL is approximately 46 mL/min, this is not currently an issue for her. The
patient should also have serum calcium levels checked prior
to subsequent infusions to rule out hypocalcemia, which is
a contraindication with bisphosphonate use. This is also not
currently an issue for E.S., since her calcium level is normal.
E.S. should be questioned about the occurrence of any side
effects such as flulike symptoms, abdominal pain, nausea,
vomiting, diarrhea, or bone/muscle pain at each subsequent
office visit. Encourage the patient to have good oral hygiene
and get any necessary invasive dental procedures done prior
to medication administration, because rare reports of ONJ
have been described in patients taking bisphosphonates for
osteoporosis.7 Increased risks for developing ONJ include
poor oral hygiene, invasive dental procedures, and concomitant treatment with chemotherapeutic agents and/or highdose systemic corticosteroids.7
Raloxifene: Question the patient about side effects such as
pain in the legs, lower extremity swelling, or hot flashes at each
office visit.

Patient Education
6. What information should be provided to the patient to enhance
adherence, ensure successful therapy, and minimize adverse
effects?

General information:
Educate the patient on her risk of osteoporotic fractures if her
osteoporosis remains untreated. Encourage adherence to the
medication regimen because typical adherence to medications
for osteoporosis ranges from approximately 25% to 81%.7,9
Educate the patient on nonpharmacologic interventions to
improve bone health, such as smoking cessation, avoidance of
excessive alcohol, caffeine, or colas, and regular weight-bearing
exercise.7

Ibandronate (Boniva) intravenous administration:

Your primary care provider has prescribed ibandronate
(Boniva) to help strengthen your bones and to prevent any further bone fractures in your spine.

Some patients experience flulike symptoms, such as fever and

muscles aches and pains for about 2 days after receiving this
medication. You can often prevent this from occurring by taking acetaminophen just before and for a couple of days after
getting your medication. These side effects often diminish with
future doses of the medication. Let your primary care provider
know if you experience severe muscle or bone pain.
It is important to get enough calcium by eating foods rich in
calcium such as yogurt, milk, and cheese, or by taking calcium
supplementation. Continue to take your vitamin D supplement, as well. Adequate calcium and vitamin D help this medication to work properly. Ibandronate does not take the place of
these supplements.

Zoledronic acid (Reclast) intravenous administration:

Your primary care provider has recommended zoledronic acid
to help strengthen your bones and to prevent any bone fractures in your hips or spine.
This injection is given once every year. Be sure to keep all follow-up appointments with your primary care provider. A routine blood test to check your kidneys and calcium level is also
done every year prior to your injection while you are getting
this medication. Be sure to drink at least two glasses of water a
few hours before you receive this medication.
Some patients experience flulike symptoms, such as fever and
muscles aches and pains for about 3 days after receiving this
medication. Patients may experience these symptoms for 1 or
2 weeks after getting this medication, although this is uncommon. You can often prevent these symptoms from occurring by
taking acetaminophen just before and for 3 or 4 days after you
receive your medication. These side effects often diminish with
future doses of the medication. Let your primary care provider
know if you experience severe muscle or bone pain.
It is important to get enough calcium by eating foods rich in
calcium such as yogurt, milk, and cheese, or by taking calcium
supplementation. Continue to take your vitamin D supplement, as well. Adequate calcium and vitamin D help this medication to work properly. Zoledronic acid does not take the
place of these supplements.

Raloxifene (Evista):
Raloxifene (Evista) is a medication prescribed to prevent further weakening of your bones. This medication acts like estrogen on your bones but does not act like estrogen on the breast
or uterus and is therefore safe for you to use, even though you
have had breast cancer. In fact, it has been shown to reduce the
chance of invasive breast cancer. It will not cause you to have
menstrual periods like estrogen could.
Take one 60-mg raloxifene tablet each day, preferably at the
same time each day. You may take it with or without food.
If you miss a dose, take the medicine as soon as you remember.
If you do not think of it until the next day, skip the missed dose
and just resume taking it once a day.
Raloxifene may cause leg cramps and hot flashes. Tell your prescriber if these side effects become troublesome.
A rare but serious side effect of raloxifene is blood clots in the
veins. If you have pain in your calves, leg swelling, sudden chest
pain, shortness of breath, coughing of blood, or change in your
vision, contact your primary care provider immediately.
Copyright 2011 by The McGraw-Hill Companies, Inc. All rights reserved.

Osteoporosis

The patient should not experience more fractures or any additional loss of height. Question the patient at each subsequent
visit, and evaluate any sudden onset of bone pain radiologically. Measure the patients height at this appointment and at
each subsequent visit.

This injection is given every 3 months. Be sure to keep all follow-up appointments with your primary care provider. A routine blood test to check your kidneys and calcium level is also
done every 3 months while you are getting this medication.

CHAPTER 102

can typically be observed after 1 year in the spine and after 2

years in the hip.7,8 A DXA scan could therefore be performed
after 1 year of therapy; however, Medicare generally only covers DXA scans every 2 years. The optimal therapeutic goal is a
significant improvement in lumbar spine and/or femoral neck
density, but given her severity of osteoporosis, stabilization of
her BMD would also be acceptable. A stable or improved BMD
indicates successful treatment, and a reduction in fracture risk
is expected.7 In fact, fracture risk reduction is thought to occur
even before increases in BMD can be measured.7

102-8

SECTION 12

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