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SECTION 12
BONE AND JOINT DISORDERS
103
OSTEOPOROSIS
A Bone to Pick with Osteoporosis. . . . . . . . . . . . . . . . Level II
Emily C. Papineau, PharmD, BCPS
CASE SUMMARY
B.F., a 65-year-old woman, presents to a family medicine clinic
to discuss results of her dual-energy x-ray absorptiometry (DXA)
scan. Her complaints include shortness of breath with exercise and
difficulty remembering to take medications. A recent DXA scan
reveals osteoporosis. The patient reports a 2″ loss in height, and has
evidence of a vertebral compression fracture. The patient requires
an osteoporosis therapy regimen that is both efficacious and one
to which she can adhere. Estrogen and estrogen plus bazedoxifene
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 zoledronic acid, denosumab,
ibandronate, risedronate, alendronate, raloxifene, and teriparatide.
The patient should also receive 1,200 mg of elemental calcium
daily through diet (preferably) and/or supplementation. Vitamin D
(cholecalciferol) 800–1000 international units (IU) daily should be
considered because many elderly patients are deficient in this vitamin. Nonpharmacologic interventions, such as dietary modification,
reduced caffeine, and implementation of a weight-bearing exercise
program, play an important role in the management of osteoporosis.
QUESTIONS
Problem Identification
1.a. Create a list of the patient’s drug therapy problems.
• COPD therapy is inadequate.
✓The patient is currently only using ipratropium/albuterol
twice daily, instead of four times daily, and reports shortness
of breath with prolonged walking. Using the 2016 Global
Initiatives for Chronic Obstructive Lung Disease (GOLD)
guidelines,1 this patient was classified as being in Patient
Group B (GOLD 2, CAT ≥10). The GOLD guidelines indicate that a long-acting bronchodilator be used for patients
in this Group B category. Options for therapy include either
long-acting β-agonists, such as formoterol, arformoterol,
salmeterol, olodaterol, or indacaterol, or long-acting anticholinergics, such as tiotropium, aclidinium bromide, or
umeclidinium. Given that the patient has expressed difficulty remembering to take her medications, a once-daily
regimen with tiotropium, umeclidinium, indacaterol, or
olodaterol (two inhalations once daily) may be preferable
and improve adherence. The patient will still need a medication for quick relief of COPD symptoms. If tiotropium or
umeclidinium is selected as a maintenance medication, then
the short-acting bronchodilator should be switched from
ipratropium/albuterol to albuterol alone. This will avoid
excessive anticholinergic side effects from using two anticholinergic drugs concurrently. If a long-acting β-agonist is
selected, the combination inhaler of ipratropium/albuterol
could still be used. Regardless of which long-acting bronchodilator is used, the patient should be instructed on how
to properly use the inhaler device to administer the medication.1 Again, recommend tips to help the patient to adhere
to her medication regimen.
✓Should this patient’s COPD progress to Group C or D, inhaled
corticosteroids would then be indicated. The GOLD guidelines also highlight the current debate as to whether chronic
administration of inhaled corticosteroids in COPD may lower
bone mineral density (BMD), as some research has shown an
increased risk (triamcinolone being most implicated) and
some has not. Inhaled corticosteroids are preferred to systemic treatment because they have less osteoporosis risk. For
now, this concern can be avoided. In addition to optimizing
medication use for COPD, the pharmacist should recommend the patient participate in a pulmonary rehabilitation
program and verify that the patient has received the influenza
and pneumococcal vaccines, as appropriate.1
• Hypothyroidism is presently controlled. The thyroid stimulating hormone (TSH) level is normal, indicating that the levothyroxine therapy is adequate. The patient’s TSH level should be
routinely monitored because overtreatment of hypothyroidism
that induces hyperthyroidism can contribute to further loss of
BMD.2
• Smoking cessation should be encouraged, as this would help
to lower her blood pressure, decrease the rate of decline of her
lung function, and decrease the risk of osteoporotic fracture.1–4
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 (http://
www.ahrq.gov/professionals/clinicians-providers/guidelines
-recommendations/tobacco/index.html).5
1.b.What information (signs, symptoms, laboratory values,
and FRAX score) indicates the presence or severity of the
patient’s osteoporosis? What are the patient’s risk factors
for osteoporosis?
• The DXA scan results reveal that the patient’s BMD is in the
osteoporotic range. The World Health Organization (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 are2–4:
✓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
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
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✓Osteoporosis: T-score ≥2.5 SD below the young adult mean
value
• Avoid caffeine intake. Caffeine can increase the excretion of
calcium to a small extent and may contribute to low BMD.3
✓Severe osteoporosis: T-score ≥2.5 SD below the young adult
mean value with ≥1 fracture
• Reduce the risk of falls by removing obstacles, such as throw
rugs and extension cords, and by adding assistive devices, such
as handrails to the bathtub and other areas, and obtaining
nonskid mats for slippery surfaces. Clarify the quantity and
frequency of alcohol consumed, as excessive drinking, particularly >3 drinks/day, could contribute to fall risk. Screening and
correcting for vision impairment may also decrease fall risk.4
Bone and Joint Disorders
• This patient’s 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″) and evidence of a vertebral compression
fracture.2 Even if the patient had not obtained a DXA scan, the
diagnosis of osteoporosis can be made based solely on the presence of a vertebral fracture. A patient with a vertebral fracture
is 2–3 times more likely to experience additional fractures.4
• 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. The calculation can be performed (http://
www.shef.ac.uk/FRAX/tool.jsp?locationValue=9) and takes
into account many risk factors for osteoporosis. For B.F., her
osteoporosis risk factors include her Caucasian ethnicity, age
(and postmenopausal status), low body weight evidenced
by BMI <21 kg/m2, history of previous fracture, cigarette
smoking, history of maternal hip fracture, and femoral neck
T-score. B.F. has a 38% chance of experiencing a major osteoporotic fracture and an 11% chance of hip fracture in the
next 10 years if her osteoporosis remains untreated. Even if
this patient’s DXA scores were not osteoporotic, the National
Osteoporosis Foundation (NOF) guidelines and the North
American Menopause Society (NAMS) guidelines state 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%.2,4
Desired Outcome
2.What are the goals of pharmacotherapy for osteoporosis in
this case?
• Prevent or decrease the incidence of fractures with a medication
regimen that will minimize the potential for nonadherence.
• Restore 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 patient’s
osteoporosis?
• Ensure adequate calcium and vitamin D intake through diet
and/or supplementation.2–4 Dairy products are an excellent
dietary source of calcium. One cup of milk or yogurt contains
approximately 300 mg of elemental calcium. In addition to
calcium, milk is often fortified with vitamin D. Cereals are
often another source of a vitamin D fortified food. Exposure to
sunlight can also cause synthesis of vitamin D in the body. Use
of sunlight for this purpose should be balanced against the risk
of skin cancer. Use of supplements to achieve adequate calcium
and vitamin D intake are discussed below.
• Perform regular weight-bearing and muscle-strengthening exercises such as walking, jogging, dancing, and weightlifting.2,4
• Encourage smoking cessation as postmenopausal women who
smoke are more likely to experience fractures.2,4
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
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 it is also vital for achieving adequate response to
other osteoporosis therapies. Since most individuals over the
age of 50 consume 600–700 mg of elemental calcium per day,
increasing dietary calcium or taking calcium supplements will
be necessary for most women with osteoporosis.
✓Both the NOF and Institute of Medicine recommend
1,200 mg/day of elemental calcium in postmenopausal
women.4 Doses >1,500 mg of elemental calcium are not
thought to offer any additional benefit but may increase cardiovascular risk.4 Furthermore, doses >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.2,3
✓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, especially in women who smoke2,3 (http://
www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/ucm213206.htm). Although
calcium citrate contains less elemental calcium than calcium
carbonate, it is not dependent on gastric pH for absorption
and, therefore, is a good nondietary choice for older adults
who may have achlorhydria and those on acid-suppressive
therapy.2,3 It may be taken independent of meals, unlike
calcium carbonate which should be taken with meals.2,3 Side
effects of constipation and gas are more common with calcium carbonate than with calcium citrate.3
✓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.2
✓Both the NAMS and NOF osteoporosis guidelines recommend that postmenopausal women take 800–1000 IU of
vitamin D daily.2,4 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.2 This patient is not at
high risk for pronounced vitamin D deficiency (such as those
with malabsorptive conditions or on phenytoin); however,
checking a serum 25(OH)D level is reasonable as many
individuals with osteoporosis have vitamin D deficiency,
according to the NOF. Vitamin D doses >1000 IU/day may
be needed in individuals with deficiency in order to obtain
vitamin D levels of approximately 30 ng/mL (75 nmol/L).4
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• 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 case-control study also found that
bisphosphonate use reduced the risk of breast cancer in nonobese women.5 While further investigation is needed in this
area, this could be a potential added benefit for the patient.
✓Alendronate (Fosamax, Fosamax Plus D, and Binosto) is
approved by the FDA for both treatment and prevention of osteoporosis. Alendronate 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.2
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. Alendronate is available
in a once-daily dose of 10 mg, which may not be optimal
for a patient who expressed difficulty remembering to take
medications, especially considering this medication should
be taken prior to the first meal of the day. The 70-mg onceweekly dose of alendronate may be easier for the patient to
take and come as both a tablet and a 70 mg/75 mL solution.
Fosamax Plus D is another once-weekly dosage form that
contains either 2,800 or 5,600 IU of cholecalciferol in
combination with 70 mg of alendronate. Alendronate can
also be obtained as a 70-mg effervescent tablet (Binosto).
A potential advantage of Binosto is that it forms a buffered
solution and raises the pH of the stomach. Given that B.F.
has GERD, this may cause less esophageal irritation if
reflux occurs after alendronate ingestion. More studies are
needed to determine if this will have a clinical impact on
the incidence of esophagitis or dyspepsia in patients using
alendronate.
✓Risedronate (Actonel and Atelvia), which is also approved by
the FDA for both treatment and prevention of osteoporosis,
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Osteoporosis
✓Vitamin D replacement will most likely be given for the rest
of the patient’s life. NOF, NAMS, or the American Association of Clinical Endocrinologists (AACE) does not recommend a particular vitamin D supplement over another.2–4
significantly reduces the rate of vertebral and nonvertebral
fractures.2,3 Like alendronate, risedronate has poor oral
absorption, and regular-release products 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. The dose of risedronate (5 mg once daily)
is the same for both treatment and prevention of osteoporosis. Alternative regimens include 35-mg once-weekly or
150-mg once-monthly doses. Risedronate also comes as a
delayed-release tablet, Atelvia. Unlike other oral bisphosphonate products, Atelvia is to be taken with ≥4 oz. of water
immediately after breakfast. As with other oral bisphosphonates, a patient should remain upright for 30 minutes after
swallowing Atelvia.
✓Ibandronate (Boniva), a bisphosphonate similar to risedronate and alendronate, is also approved by the FDA for 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.2 Like alendronate
and risedronate, ibandronate’s 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 150-mg
monthly oral dose of ibandronate is available in generic
form. Ibandronate is also available as a 3-mg IV injection
administered every 3 months by a healthcare 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 requires less frequent dosing,
this product may be a treatment option for this patient but
may not be as effective as other bisphosphonates in preventing nonvertebral fractures.
✓Zoledronic acid (Reclast) is an intravenously administered
bisphosphonate that is FDA-approved for once-yearly treatment of osteoporosis and for treatment 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.2 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 flu-like
symptoms such as fever, arthralgia, and myalgia. These
side effects occur in 33% of patients with the initial dose,
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
flu-like reactions (7% and 3% for the second and third doses,
respectively).4 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 with 0.4%
of patients given placebo, and most episodes of atrial fibrillation occurred greater than 1 month post-infusion. 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
CHAPTER 103
✓As stated previously, dairy products are the most common
dietary source of vitamin D, although adequate amounts of
vitamin D can be obtained through other vitamin D-fortified
foods as well. Vitamin D-containing supplements have
one of two forms of vitamin D, namely, ergocalciferol
(vitamin D2) or cholecalciferol (vitamin D3). Cholecalciferol
is the form of vitamin D synthesized in the skin from sun
exposure and is more potent when administered intermittently than ergocalciferol.3 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.2
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Bone and Joint Disorders
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 (http://www.fda.gov
/Drugs/DrugSafety/PostmarketDrugSafetyInformationforPatientsandProviders/DrugSafetyInformationforHeathcareProfessionals/ucm136201.htm). 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.2,3 This medication would
be a great choice for the patient, as it has excellent fractureprevention data, would avoid GI toxicity, and is conveniently
administered once yearly, which may help improve patient
adherence to the treatment. It is a more costly option than
alendronate, but it is often covered by insurance.
• Denosumab (Prolia) is an FDA-approved option for the treatment of postmenopausal osteoporosis for those at high risk
of fracture, including those with a history of osteoporotic
fracture, multiple risk factors for fracture, or those who have
failed or are intolerant to other available osteoporosis therapies.
It is a human monoclonal antibody which inhibits nuclear
factor-kappa ligand (RANKL) activity. RANKL is a protein that
essentially promotes osteoclast formation. The FREEDOM trial
demonstrated that denosumab, by inhibiting RANKL activity
for 3 years, increased BMD in the lumbar spine and hip and
decreased the risk of vertebral, hip, and nonvertebral fractures
by 68%, 40%, and 20%, respectively.2 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 than did alendronate (3.5% vs 2.6%,
respectively; P< 0.0001).6 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.7
✓Denosumab is administered as 60-mg subcutaneously every
6 months by a healthcare professional and is estimated to
cost approximately $1,000 per injection but is often covered
by insurance (although prior authorization may be required).
It has few reported side effects such as back and musculoskeletal pain, hypercholesterolemia, cystitis, and dermatologic conditions like eczema. 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 and atypical femur
fractures have occurred. A medication guide discussing the
risks of therapy is to be distributed to patients. Denosumab is
contraindicated in pregnancy and in hypocalcemia. The prescribing information specifies patients should take 1,000 mg
of calcium daily and at least 400 IU of vitamin D daily.
• 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 US Preventive Services Task Force recommends against the routine
use of estrogen or estrogen and progestin for the prevention of
chronic conditions, such as osteoporosis, due to the potential
risks associated with their use.6 This recommendation is due
to findings from the Women’s Health Initiative (WHI) study
and the Heart and Estrogen/progestin Replacement Study
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
(HERS) follow-up.6 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.8 Since B.F. is already diagnosed with
osteoporosis and has a history of breast cancer, this would not
be an appropriate therapeutic option for her.
• Estrogen agonist/antagonists also known as selective estrogen
receptor modulators have estrogen-like effects on cortical
bone and antiestrogen-like effects on breast tissue and the
endometrium.
✓Raloxifene (Evista) increases BMD but to a lesser extent than
estrogen. Raloxifene has only been demonstrated to reduce
the incidence of vertebral fractures in postmenopausal
women with osteoporosis.2–4 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 also 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.2,3 The MORE-CORE trial looked
specifically at women with increased cardiovascular risk
and found that raloxifene neither increased nor decreased
cardiovascular outcomes.2,3 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. Like
estrogen, raloxifene use is associated with an increased risk
of thromboembolic events, particularly 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/day. It should be combined with calcium supplementation. This is a therapeutic option for B.F. but may not lower
her risk for hip fracture, which is one of her main concerns.
• Conjugated estrogens/bazedoxifene (Duavee) is estrogen combined with an estrogen agonist/antagonist and is approved for
the treatment of moderate-severe postmenopausal hot flashes
and the prevention of osteoporosis. It has been shown to
increase BMD in the lumbar spine and total hip. Its side effect
profile is like that of estrogen products. Given this patient’s history of breast cancer and that B.F. already has osteoporosis, this
product is not ideal for her.4
• 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.2–4 Teriparatide is administered
subcutaneously daily into the abdomen or thigh with a prefilled
injectable device; however, it is very expensive relative to other
agents used for treating osteoporosis and may require 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 upon the initial administration of teriparatide to prevent orthostatic hypotension with the first dose.
The product also carries a boxed warning due to an increased
incidence of the development of osteosarcoma in rats. Teriparatide is contraindicated in patients with a history of Paget’s
103-5
• Combination or Sequential therapy
✓There is some evidence that alendronate or risedronate may
increase BMD to a greater extent when used in combination
with either estrogen therapy or raloxifene than when used
alone. Most research involving the combination of alendronate and teriparatide, demonstrates an antagonistic effect
when used concomitantly. Conversely, 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. A
small study from 2013 revealed that the combination of
teriparatide and denosumab increased BMD to a significantly greater extent than either agent alone at the lumbar
spine, femoral neck, and total hip.8 Denosumab has also
been shown to improve BMD after alendronate therapy is
concluded.9 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 routinely using concomitant
therapy for the treatment of osteoporosis.2–4
Optimal Plan
4.a. What drug, dosage form, dose, schedule, and duration of
therapy are best for treating this patient’s osteoporosis?
• A nonoral bisphosphonate (zoledronic acid or ibandronate) is
an optimal choice given that this patient has expressed difficulty remembering to take medications. These medications are
administered less frequently. Clinics also often have reminder
systems to alert patients to when their next dose is due. Zoledronic acid is preferred over ibandronate because of zoledronic
acid’s demonstrated efficacy in decreasing nonvertebral and
✓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 recently been debated due to cases of atypical
subtrochanteric femur fractures in patients receiving longterm bisphosphonate therapy (typically >5 years).2 Cases
of these atypical femur fractures have also been reported in
patients not taking bisphosphonate therapy. Information has
been added to the medication guide to inform patients of
this risk (http://www.fda.gov/Drugs/DrugSafety/ucm229009
.htm). In general, bisphosphonate therapy has not been studied beyond 10 years for alendronate and beyond 3 years with
ibandronate or zoledronic acid.2 Despite the long half-life
of bisphosphonates, after discontinuation of therapy, eventual decreases in BMD and fracture prevention have been
observed.2 Most experts agree that initial use of bisphosphonates for 3–5 years is appropriate.4 The NOF recommends
that a risk assessment be performed, including evaluation
of BMD measurements, height loss, fracture history during
bisphosphonate use, or new conditions or medications that
negatively impact BMD. Based upon whether the patient
appears to be at modest or high risk for fracture, decisions
for continuing therapy should be made. The NOF does not
define modest or high risk but states that therapy decisions
should be made on an individual basis, as there is no conclusive data to state how long therapy should be continued.4
The Task Force of the American Society for Bone and
Mineral Research suggests a more specified approach for
postmenopausal women who have been treated with oral
bisphosphonates for ≥5 years or IV bisphosphonates for
≥3 years10:
✓For those who have experienced an osteoporotic fracture
before or during therapy, consider continuing bisphosphonate therapy or switch to another therapy. Alendronate has
been studied for up to 10 years of use and zoledronic acid for
up to 6 years of use.
✓ For those who have not experienced an osteoporotic fracture
before or during therapy, if the hip BMD T-score is more
than 2.5 SD below the mean or the patient is at high risk of
fracture (such as age 70–75 years), consider continuing oral
bisphosphonate therapy for 10 years or IV bisphosphonate
therapy for 6 years or switch to another therapy.
✓ For those who have not experienced an osteoporotic fracture
before or during therapy, if the hip BMD T-score is not more
than 2.5 SD below the mean or the patient is not at high risk
of fracture, consider a drug holiday for 2–3 years.
In any of the three scenarios above, the Task Force
recommends reassessing the need for therapy or lack thereof
every 2–3 years.10
• Denosumab could also be considered a first-line alternative.
This patient is at high risk of fracture, given that she has previously had a vertebral fracture. Optimal duration of therapy for
denosumab is unknown. If treatment is stopped, loss of BMD
occurs quickly.4
✓Denosumab is dosed as 60 mg subcutaneously every
6 months.
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Osteoporosis
• Calcitonin-salmon (Miacalcin) inhibits bone resorption by
inhibiting osteoclast function and is only indicated for the
treatment of osteoporosis in women who are greater than
5 years postmenopause. Calcitonin-salmon significantly
increases BMD and reduces vertebral fracture rates in women
with established osteoporosis. It has not been shown to
decrease nonvertebral or hip fractures.2–4 It also has an analgesic effect and may provide some pain relief in patients with
acute vertebral fractures.2 At the time of the writing of this
chapter, calcitonin-salmon was available as a nasal spray or
subcutaneous injection. Its effect tends to be dose related, and
the usual dose is 100 IU SC–200 IU (1 spray intranasally) per
day. When using the nasal spray, the patient should alternate
nostrils daily. The nasal spray can cause rhinitis, epistaxis, and
headache. In 2013, an FDA-advisory committee voted against
the continued use of the medication due to a small increase
in cancer and in light of its limited efficacy. This cancer risk,
recently observed in trials for an oral formulation of the
drug, prompted a review of clinical trials with the nasal formulation, where a small risk of cancer was detected. It remains to
be seen if the FDA will ultimately permit the product to remain
on the market with enhanced warning labels, or if it will be
removed from the market. Until then, calcitonin-salmon
remains an expensive agent that is less potent than the bisphosphonates, but is an option for patients who cannot tolerate
other antiosteoporotic agents or for patients who experience
back pain as a result of recent vertebral fractures.
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
also makes zoledronic acid a preferred choice for patients as
well. If the patient lacks insurance coverage, zoledronic acid
and ibandronate are expensive; however, most patients have
coverage for this medication through Medicare Part B.
CHAPTER 103
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. Treatment with this agent is often
followed by a bisphosphonate to help maintain the BMD
increase gained by teriparatide use.4
103-6
SECTION 12
Bone and Joint Disorders
• Sufficient calcium intake is essential to increasing bone density. The patient should obtain a total of ~1,200 mg of calcium
daily, preferably via her diet. Discussing the calcium content of
food may help the patient determine what foods would help
her hit this target. The typical diet of a woman >50 years of
age contains approximately 600 mg of elemental calcium per
day. If she does not reach her calcium goal with diet alone, she
needs a calcium supplement to provide the remaining calcium
recommended. An example of an appropriate product is Citracal Regular taken as two tablets once daily. Citracal contains
calcium citrate, which is better absorbed than calcium carbonate in the elderly and in those on a proton pump inhibitor. The
two tablets contain 500 mg of elemental calcium (from calcium
citrate) and 400 IU of vitamin D (as cholecalciferol).
• Because of her age, the patient should take 800–1000 IU
of vitamin D daily. This could be consumed partly from
vitamin D fortified foods and in the form of a combination
product with calcium, as mentioned above.
• Smoking cessation should be encouraged.
• Caffeine intake should be minimized.
• After receiving medical clearance and minimizing her shortness of breath, the patient should be instructed to participate in
an appropriate weight-bearing exercise program for 30 minutes
three to five times weekly. She may resume walking around her
neighborhood to accomplish this.
4.b. What alternatives would be appropriate if the initial therapy
fails or cannot be used?
• If the patient has an additional fracture while supposedly on
osteoporosis therapy, assess whether the patient was adherent
to the regimen.
• If the patient cannot tolerate IV bisphosphonate therapy or
denosumab therapy, raloxifene 60 mg PO daily could be initiated instead. It may be particularly useful because of its safety
in light of the patient’s breast cancer history. Because of its lack
of hip fracture data, an antiresorptive medication is initially
preferred.
• If the patient does not respond to bisphosphonates, denosumab, 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 to be less than
ideal by most patients, although the Forteo pen device has
been redesigned for much easier administration. Giving a
bisphosphonate regimen after the completion of teriparatide
therapy may help to retain the increases in BMD achieved with
teriparatide use.
• The combination of ibandronate or zoledronic acid plus
raloxifene could be given. Denosumab in combination with
teriparatide could also be considered. However, combination
therapy has not been well studied and should not be attempted
unless maximal therapy with either agent individually is
unsatisfactory.2–4
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:
• The NOF and NAMS recommend repeating the DXA scan in
2 years.3,4 With bisphosphonate therapy, increases in BMD can
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
typically be observed after 1 year in the spine and after 2 years
in the hip.3,4 A DXA scan could therefore be performed after
1 year of therapy; however, Medicare generally covers DXA
scans only 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.2 In fact, fracture risk reduction is thought to occur
even before increases in BMD can be measured.2
• The patient should not experience more fractures or any
additional loss of height. Measure the patient’s height at each
subsequent visit. If height loss of 2 cm occurs or new back pain
develops, another vertebral imaging test is indicated.4
• Biochemical markers of bone turnover are not commonly
utilized to evaluate the efficacy of osteoporosis therapy. These
markers may play a future role in determining who is at greater
fracture risk or when to reinitiate therapy after an osteoporosis
drug holiday.4,10
Toxicity monitoring:
• 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/minute in
a patient scheduled to receive ibandronate or <35 mL/minute
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. Furthermore, the prescribing information for zoledronic acid specifies that actual body
weight be used in the Cockcroft-Gault equation when calculating creatinine clearance. This patient’s CrCL is approximately
43 mL/minute, so she may use zoledronic acid without being
overly concerned that it may cause renal dysfunction. 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 B.F. since her calcium level is normal. B.F. 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.2 Increased risks for
developing ONJ include poor oral hygiene, invasive dental
procedures, and concomitant treatment with chemotherapeutic
agents and/or high-dose systemic corticosteroids.2,3
• Rare reports (1 in every 10,000–100,000 patients) of atypical
subtrochanteric and diaphyseal femoral fractures have been
reported in patients on bisphosphonates for greater than
3–5 years (http://www.fda.gov/Drugs/DrugSafety/ucm229009
.htm).10 It is proposed that the antiresorptive nature of bisphosphonates may lead to impaired bone remodeling and subsequent risk for these uncommon fractures. Patients should be
screened for thigh and groin pain, which often preceded these
fractures weeks to months before they occurred.4
• As noted above, after 3–5 years of therapy, the need for therapy
in B.F. should be reassessed.3,4
• If the patient is on denosumab and her creatinine clearance
falls below 30 mL/minute, monitor for hypocalcemia approximately 1 week after administration. Denosumab is generally
well tolerated, but musculoskeletal pain, ONJ, atypical fractures, and infections have been infrequently reported with
denosumab use.
103-7
6.What information should be provided to the patient to
enhance adherence, to ensure successful therapy, and to minimize adverse effects?
General information:
• Educate the patient on nonpharmacologic interventions to
improve bone health such as smoking cessation, avoidance of
excessive alcohol and caffeine, and performing regular weightbearing exercise.2 Encourage her to evaluate her home environment and minimize fall risks, as appropriate.4
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 flu-like symptoms, such as fever
and muscles aches and pains, for about 3 days after receiving this medication. Patients may experience these symptoms
for up to 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
3–4 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 or if you experience a dull, achy pain in your
thigh or groin, as the latter may indicate the potential for an
unusual bone fracture. Here is a medication guide describing
more about the medication and the potential for rare but serious side effects. Obtain a dental examination before starting
this medication, if you have not had one in the last 6 months.
Some patients who have been on this medication for years
and have had a tooth removed experience difficulty with their
jaw healing. It is best to have major dental work done prior to
beginning this medication.
• It is important to get enough calcium by eating foods rich in
calcium such as yogurt, milk, and cheese, or by taking calcium
supplementation if necessary. Take vitamin D supplement containing 800 IU as well. Adequate calcium and vitamin D help
this medication to work properly.
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.
• This injection is given every 3 months. Be sure to keep all
follow-up appointments with your primary care provider.
• Some patients experience flu-like 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
or if you experience a dull, achy pain in your thigh or groin,
as the latter may indicate the potential for an unusual bone
fracture. Here is a medication guide describing more about
the medication and the potential for rare but serious side
effects. Obtain a dental exam before starting this medication,
if you have not had one in the last 6 months. Some patients
who have been on this medication for years and have had a
tooth removed experience difficulty with their jaw healing.
It is best to have major dental work done prior to beginning
this medication.
• It is important to get enough calcium by eating foods rich in
calcium such as yogurt, milk, and cheese, or by taking calcium
supplementation if necessary. Take vitamin D supplement containing 800 IU as well. Adequate calcium and vitamin D help
this medication to work properly.
Denosumab (Prolia) subcutaneous administration:
• Denosumab (Prolia) is a medication prescribed to strengthen
your bones and to prevent 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.
• Most people who take denosumab do not notice any side
effects, but back pain and infections have been reported. If you
notice a dull, achy pain in your thigh or groin, report this to
your primary care provider as this may indicate the potential
for an unusual bone fracture.
• Here is a medication guide describing more about the medication and the potential for rare but serious side effects. Get a
dental exam before starting this medication, if you have not
had one in the last 6 months. Some patients who have been on
this medication for years and have had a tooth removed experience difficulty with their jaw healing. It is best to get major
dental work done prior to beginning this medication.
• It is important to get enough calcium by eating foods rich in
calcium such as yogurt, milk, and cheese, or by taking calcium
supplementation if necessary. Take vitamin D supplement containing 800 IU as well. Adequate calcium and vitamin D help
this medication to work properly.
REFERENCES
1. Global Initiative for Chronic Obstructive Lung Disease. Global strategy for diagnosis, management and prevention of chronic obstructive
pulmonary disease: updated 2016. Available at: http://goldcopd.org
/global-strategy-diagnosis-management-prevention-copd-2016/.
Accessed April 20, 2016.
2. The North American Menopause Society. Management of osteoporosis
in postmenopausal women: 2010 position statement of The North
American Menopause Society. Menopause 2010;17(1):25–54.
3. American Association of Clinical Endocrinologists Osteoporosis Task
Force. AACE medical guidelines for clinical practice for the diagnosis and treatment of postmenopausal osteoporosis. Endocr Pract
2010;16:1–37.
Copyright © 2017 by McGraw-Hill Education. All rights reserved.
Osteoporosis
• Educate the patient on her risk of osteoporotic fractures if
her osteoporosis remains untreated. Discuss the results of her
FRAX scores with her. Encourage adherence to the medication
regimen as typical adherence to medications for osteoporosis
ranges from approximately 25–81%.2,4 Encourage the patient
to record when she is due for her next osteoporosis medication
on her calendar or in her cell phone. Also, make her aware that
while some of these medications have the possibility of rare
side effects, the possibility of a disabling hip fracture that could
even be life-threatening is much more concerning. This is why
treating osteoporosis is so important.10
A routine blood test to check your kidneys and calcium
level is also done every 3 months while you are getting this
medication.
CHAPTER 103
Patient Education
103-8
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Bone and Joint Disorders
4. Cosman F, de Beur SJ, LeBoff MS, et al. Clinician’s guide to prevention
and treatment of osteoporosis. Osteoporosis Int 2014;25:2359–2381.
5. Newcomb PA, Trentham-Dietz A, Hamptom JM. Bisphosphonates for
osteoporosis treatment are associated with reduced breast cancer risk.
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turnover in postmenopausal women with low bone mass: a randomized, blinded, phase 3 Trial. J Bone Miner Res 2009;24:153–161.
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8. Tsai JN, Uihlein AV, Kumbhani, et al. Teriparatide and denosumab,
alone or combined, in women with postmenopausal osteoporosis: the
DATA study randomized trial. Lancet 2013;382:50–56. doi:10.1016/
S0140-6736(13)60856-9.
9. Kendler DL, Roux C, Benhamou CL, et al. Effects of denosumab
on bone mineral density and bone turnover in postmenopausal
women transitioning from alendronate therapy. J Bone Miner Res
2010;25:72–81.
10. Adler RA, Fuleihan GE, Bauer DC, et al. Managing osteoporosis in
patients on long-term bisphosphonate treatment: report of a Task
Force of the American Society for Bone and Mineral Research. J bone
Miner Res 2016;31:16–35.