Evaluation and Treatment
of Osteoporosis
Kim M. O’Connor, MD
INTRODUCTION
As the population ages, osteoporosis-related and osteoporosis-related fractures pose
a significant public health concern. Although there has been a recent decline in hip
fracture incidence in white women and men in the United States, rates are holding
fairly steady in black, Asian, and Hispanic men and women.1
Because of the aging
of the population, fracture rates are expected to increase by 48% in the United States
over the next 25 years to greater than 3 million fractures associated with a cost of
$25.3 billion.2
Seventy-one percent of all fractures and 75% of all fracture-related
costs occur in women.2
Approximately 20% of patients with a hip fracture do not survive
for more than a year from diagnosis and more than 50% never completely regain
Conflict of Interest: The author has no conflicts of interest to report, and no financial
disclosures.
Division of General Internal Medicine, Department of Internal Medicine, General Internal Medicine
Clinic, University of Washington, Box 354760, 4245 Roosevelt Way Northeast, Seattle, WA
98105, USA
E-mail address: koconnor@u.washington.edu
KEYWORDS
 Osteoporosis  Postmenopausal women  Men  Screening  Diagnosis
 Treatment
KEY POINTS
 Screening for osteoporosis is recommend in all women more than 65 years of age or in
women aged 50 to 64 years with certain risk factors.
 Treatment should be considered in postmenopausal women with osteoporosis on dualenergy
x-ray absorptiometry scan, history of fragility fracture, or osteopenia plus a
FRAX (Fracture Risk Assessment Tool) score of greater than or equal to 3% at the hip
or greater than or equal to 20% at other sites.
 All of the osteoporosis agents decrease the risk of vertebral fractures but only some bisphosphonates,
denosumab, and estrogen decrease hip fracture risk.
 Make sure the medication chosen to treat osteoporosis decreases fracture risk at the site
of decreased bone mineral density or fracture. Also consider side effects, contraindications,
secondary benefits, cost, and likelihood of adherence.
 Bisphosphonates should be first-line therapy in most cases.
Med Clin N Am 100 (2016) 807–826
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their prefunction status.3
Knowing these risks, the aim is for appropriate diagnosis and
treatment of osteoporosis. The focus of this article is on the pharmacologic management
of osteoporosis in postmenopausal women. It is important to recognize that nonpharmacologic
interventions such as exercise, smoking cessation, fall prevention, and
avoidance of heavy alcohol use are also recommended in the treatment of osteoporosis
but these are not addressed in this article.
WHOM TO SCREEN
Most expert groups recommend screening with dual-energy x-ray absorptiometry
(DXA) scan in postmenopausal women at age 65 years or older regardless of risk factors.
For postmenopausal women between the ages of 50 and 64 years, differing
screening recommendations exist. Organizations such as the National Osteoporosis
Foundation (NOF), Endocrine Society, and Canadian Osteoporosis Society recommend
screening in this age group when risk factors are present. Risk factors include
advanced age, previous fracture, long-term glucocorticoid use, low body weight (less
than 58 kg [127 lb]), family history of hip fracture, tobacco use, or excess alcohol use,
with the most robust risk factors being age and previous low-trauma fracture4
(Box 1).
The United States Preventive Services Task Force (USPSTF) proposed the use of the
FRAX calculator (https://www.shef.ac.uk/FRAX/) to determine need for screening in
women aged 50 to 64 years.5
If the FRAX 10-year major osteoporotic risk is greater
than or equal to 9.3%, which is equivalent to a 65-year-old white woman without
risk factors, then the USPSTF recommends screening with dual-energy x-ray absorptiometry
(DXA) scan.6
There are other, less complicated, screening tools, such as the
Osteoporosis Risk Assessment Instrument (ORAI), Osteoporosis Self-assessment
Tool (OST), Osteoporosis Index of Risk (OSIRIS), and Simple Calculated Risk Estimation
Score (SCORE), which performed equally to FRAX in predicting fracture in comparison
studies7,8
(Table 1).
There are limited data to guide recommendations regarding rescreening if initial
testing does not reveal osteoporosis. Most expert groups recommend rescreening
in 1 to 2 years if women are at high risk for accelerated bone loss. In 2012, a prospective
cohort study of almost 5000 women estimated the time interval for 10% of these
women to develop osteoporosis before having a clinical hip or vertebral fracture.
Based on this study the following rescreening recommendations can be considered.
If baseline T score is À2.00 to À2.49 (advanced osteopenia) or if risk factors are present
for accelerated bone loss regardless of T score, then repeat DXA every 2 years. If
baseline T score is À1.50 to À1.99 (moderate osteopenia) with no risk factors for
Box 1
Risk factors for osteoporosis
Advanced age
Previous low-trauma fracture
Long-term glucocorticoid use
Low body weight (<58 kg [127 lb])
Family history of hip fracture
Tobacco use
Excess alcohol use
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accelerated bone loss, then repeat DXA in 3 to 5 years. If baseline bone mineral density
(BMD) is normal or T score is À1.01 to À1.49 (mild osteopenia) with no risk factors
for accelerated bone loss, then consider repeating the DXA in 10 to 15 years9
(Table 2).
WHOM TO TREAT
Osteoporosis can be diagnosed based on BMD or the history of a fragility fracture. A
fragility fracture is defined as a fracture occurring in the absence of major trauma such
as a fall from standing height, coughing, or sneezing. The most common sites for
fragility fracture involve the spine, ribs, hip, pelvis, wrist, or humerus. Based on DXA
scan measurements, osteoporosis is defined as spinal or hip BMD 2.5 standard deviations
or more less than the mean for healthy young women (T score À2.5 or less).
Osteopenia is defined a spinal or hip BMD between 1 and 2.4 standard deviations
less than the mean (T score À1.0 to À2.4) (Table 3). Based on NOF recommendations,
treatment should be considered in postmenopausal women with a history of hip or
vertebral fracture or with osteoporosis on BMD measurements (T À2.5). In addition,
it has been deemed cost-effective to consider treatment in postmenopausal women
with osteopenia (T score between À1.0 and À2.4) if their 10-year probability of hip
fracture reaches 3% or if major osteoporotic fracture (hip, shoulder, or wrist) risk is
Table 1
Screening recommendations
Population DXA Scan Screening Recommendations
Postmenopausal women
aged !65 y
Screen regardless of risk factors
Postmenopausal
women aged 50–64 y
 Screen if 1 or more risk factor present
 National Osteoporosis Foundation (NOF)
 Endocrine Society
 Canadian Osteoporosis Society
 Screen if FRAX 10-y major osteoporotic fracture risk !9.3%
 USPSTF
 Additional screening calculators
 ORAI
 OST
 OSIRIS
 SCORE
Men aged >70 y  Insufficient evidence to screen
 USPSTF
 Screen regardless of risk factors
 NOF
 Endocrine Society
 International Society for Clinical Densitometry
Men aged 50–70 y  Insufficient evidence to screen
 USPSTF
 Screen if 1 or more risk factors present
 NOF
 Endocrine Society
 International Society for Clinical Densitometry
Abbreviations: ORAI, Osteoporosis RIsk Assessment Instrument; OSIRIS, Osteoporosis Index of Risk;
OST, Osteoporosis Self-assessment Tool; SCORE, Simple Calculated Risk Estimation Score; USPSTF, US
Preventive Services Task Force.
Osteoporosis Treatment 809
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greater than or equal to 20% based on the FRAX calculator.10
Although it may be costeffective,
clinical trials have not assessed the benefit on absolute fracture risk using
these FRAX-based treatment criteria (Box 2).
Cost-effectiveness analysis was based on the use of generic bisphosphonates for
treatment of osteoporosis.10
Additional studies are needed to determine at what level
of risk it will remain cost-effective when the more expensive, newer agents are used.
Clearly the emphasis on treatment in women with high absolute fracture risk rather
than BMD criteria alone will increase the number of women treated. In a prospective
cohort of community-dwelling white women greater than or equal to 65 years of age,
recommendations for pharmacotherapy occurred for 72% of women more than 65
years old and 93% of women more than 75 years old when the revised NOF treatment
guidelines were used.11
When considering BMD criteria alone, only 50% of women in
both age groups were recommended treatment. Shared decision making between
provider and patient based on risks and benefits is needed to decide whether treatment
is appropriate.
HOW TO CHOOSE A TREATMENT
Most medications available to treat osteoporosis are antiresorptives, which slow bone
turnover by decreasing resorption. These antiresorptives include the bisphosphonates,
selective estrogen receptor modulators (SERMs), denosumab, estrogen, and
calcitonin. The only anabolic agent that stimulates bone formation is teriparatide.
There are few head-to-head drug comparison trials to help determine efficacy.12
Consequently, choice of drug should be based on site of diminished BMD and/or fracture,
any secondary benefits, and contraindications. In the absence of contraindications,
a generic oral bisphosphonate is recommended as first-line therapy because
of low cost and availability of long-term safety data.
Table 2
Rescreening recommendations
Baseline Screening DXA Results Follow-up Plan
Normal Consider recheck DXA in
10–15 y
Mild osteopenia, T À1.01 to À1.49 Consider recheck DXA in
10–15 y
Moderate osteopenia, T À1.5 to À1.99 Consider recheck DXA in 5 y
Advanced osteopenia, T À2.0 to À2.49 or if risk factors for
accelerated bone loss regardless of baseline T score
Consider recheck DXA in
1–2 y
Osteoporosis Discuss work-up Æ
treatment
Table 3
Interpretation of DXA results
T Score Interpretation
T 10.9 to À0.9 Normal
T À1.0 to À2.4 Osteopenia
T À2.5 or less Osteoporosis
T À2.5 or less 1 fragility fracture Severe osteoporosis
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It is important to recognize that not all agents prevent fracture at all sites. Adequate
data support vertebral fracture reduction with all the medications; however, at this
time, data only support hip fracture reduction with most of the bisphosphonates,
denosumab, and estrogen13
(Tables 4 and 5).
CALCIUM AND VITAMIN D SUPPLEMENTATION
Controversy exists around the use of calcium and vitamin D supplementation for the
prevention of osteoporosis because of the potential increased risks of cardiovascular
outcomes and the small increased risk of kidney stones from supplemental calcium
use. In 2015, with regard to primary prevention of osteoporosis, the USPSTF stated
that there was insufficient evidence for higher-dose calcium (>1000 mg) and vitamin
D supplementation in noninstitutionalized postmenopausal women, premenopausal
women, and men. They recommended against low-dose (<1000 mg) supplementation
in these same populations.14
With regard to secondary prevention, there are some
data that calcium plus vitamin D, but not vitamin D alone, decreases fractures in osteoporotic
patients. Target calcium intake for patients with osteoporosis is 1200 mg/d,
ideally through diet and 800 IU of vitamin D.15,16
In order to increase calcium absorption,
encourage patients to take their supplements with food and to take them in
divided doses if using greater than 500 mg/d. Because calcium supplements can
interfere with bisphosphonate absorption, make sure they are taken at least 1 hour after
taking oral bisphosphonates. In general, calcium carbonate is recommended
because of low cost. If patients are taking an H2 blocker or proton pump inhibitor,
or plan to take the supplements on an empty stomach, they should use calcium citrate
because an acidic environment is needed for absorption. It is important to make sure
that vitamin D levels are replete before starting treatment because there is evidence
that efficacy of bisphosphonate therapy is improved considerably in patients with
serum 25-hydroxyvitamin D (25-OH) levels of greater than 33 ng/mL.
BISPHOSPHONATES
Bisphosphonates work by slowing bone turnover and they prevent fractures at all
sites. The oral bisphosphonates alendronate and risedronate decrease the risk of
vertebral and hip fractures by approximately 50% and nonvertebral fractures by
30%. Intravenous (IV) zoledronate reduces the risk of vertebral fractures by 70%,
hip fractures by 40%, and nonvertebral fractures by 30%. Oral and IV ibandronate
decrease vertebral fracture risk by 50% but there are insufficient data to support
hip fracture and nonvertebral fracture reduction.12,13
In general, the generic oral
bisphosphonate alendronate is recommended as first-line therapy because of substantial
data on fracture reduction and low cost. As mentioned previously, it is important
that vitamin D levels are replete before starting treatment because there is
evidence that bisphosphonates are more effective when 25-OH levels are greater
Box 2
When to consider treatment of osteoporosis
 Osteoporosis based on DXA measurements of BMD
 History of hip or vertebral fracture
 Osteopenia on DXA scan 1 10-year FRAX score of greater than or equal to 3% at hip or
greater than or equal to 20% of major osteoporotic fracture
Osteoporosis Treatment 811
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Table 4
Osteoporosis treatment options
Medication
Vertebral Fracture
Risk Reduction (%)
Hip Fracture Risk
Reduction (%)
Nonvertebral
Fracture Risk
Reduction (%) Risks Secondary Benefits
Bisphosphonates
Alendronate,
risedronate
50 50 30 GERD, esophagitis, jaw osteonecrosis,
atypical femur fracture
—
Ibandronate 50 Not enough data Not enough data
Zoledronate 70 40 30
SERMs
Raloxifene 40 Not enough data Not enough data VTE, stroke
Hot flashes (with raloxifene only)
50% risk reduction of estrogen
receptor–positive breast cancer in
high-risk women with use of
raloxifene
Decrease in hot flashes and atrophic
vaginitis with bazedoxifene 1 CEE
Bazedoxefine 1
CEE
— — —
Teriparatide 70 Not enough data 50 Headaches, myalgias, hypercalcemia,
hypercalciuria, hyperuricemia
Use caution if history of kidney stones
or gout
—
Denosumab 70 40 20 Hypocalcemia, hypercholesterolemia,
musculoskeletal pain, cystitis,
exacerbation of skin conditions,
cellulitis
—
Estrogen 30 30 30 Estrogen 1 progestin: VTE, stroke,
coronary heart disease, breast
cancer
Estrogen: VTE, stroke
—
Abbreviations: CEE, conjugated equine estrogen; GERD, gastroesophageal reflux disease; VTE, venous thromboembolism.
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than 33 ng/mL.17
It is recommended that all oral bisphosphonates be administered on
an empty stomach 30 minutes before breakfast for the best absorption. Superior
bioavailability and suppression of bone turnover was shown in a randomized
controlled trial when taken before breakfast rather than at other times of fasting.18
If
patients have significant gastrointestinal side effects or if adherence is an issue then
once-yearly IV zoledronate may be a better choice. Of note, only 50% of patients
who were prescribed oral bisphosphonates were still taking them by 1 year, therefore
it is important to inquire about adherence.19
There is concern about side effects of gastroesophageal reflux disease (GERD),
esophagitis, and esophageal ulcers; however, if administered properly, these risks
are low. In patients with well-controlled GERD it is appropriate to use a bisphosphonate
if symptoms do not worsen. If treatment of GERD is needed it is probably better to
use H2 blockers rather than proton pump inhibitors (PPIs) because of epidemiologic
evidence that long-term, high-dose PPI use may increase fracture risk and that PPIs
may blunt the effect of bisphosphonates.20,21
An expensive, effervescent, dissolvable
alendronate tablet is now available that may theoretically decrease gastrointestinal
side effects compared with the traditional tablet formulation; however, no comparative
studies are available.19,22
Although data are inadequate to determine whether use of
bisphosphonates increases risk of esophageal cancer, the US Food and Drug Administration
(FDA) currently recommends against its use in patients with Barrett
esophagus.23
IV formulations are associated with flulike symptoms and risks of hypocalcemia.
Vitamin D stores should be replaced if 25-OH levels are less than 15 ng/mL and calcium
replacement doses should be doubled 5 to 7 days before IV therapy. Bisphosphonates
should be avoided in patients with a creatinine clearance of less than
35 mL/min.
Table 5
Special populations
Population Medication Recommendations
High risk for breast
cancer
50% risk reduction of ER-positive breast cancer in high-risk patients
with use of raloxifene
Hot flashes Bazedoxefine 1 CEE
Chronic kidney
disease
 If CrCl <35 mL/min
 Use denosumab (not renally cleared)
 Involve nephrologist/endocrinologist comfortable with CKD-MBD.
May be able to use renally dosed bisphosphonates or SERM
Esophageal
symptoms
 GERD/esophagitis
 Can use oral bisphosphonate if symptoms well controlled. Use H2
blocker rather than PPI for treatment of GERD symptoms
 IV zoledronate
 SERMs
 Teriparatide
 Denosumab
 Barrett esophagus/esophageal stricture/achalasia
 Avoid oral bisphosphonates. Can use IV zoledronate
 SERMs
 Teriparatide
 Denosumab
Abbreviations: CKD-MBD, chronic kidney disease–induced metabolic bone disease; CrCl, creatinine
clearance.
Osteoporosis Treatment 813
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The HORIZON (Health Outcomes and Reduced Incidence with Zoledronic acid
Once Yearly) Pivotal Fracture trial raised concern about increased risk of atrial fibrillation
in patients treated with IV zoledronate.24
Several follow-up randomized-control
and case-control studies both supported and refuted this concern.25–27
The data for
atrial fibrillation risk are conflicting but risk, if present, is likely small. The decision to
treat with bisphosphonates should be weighed against the risk for atrial fibrillation
versus osteoporotic fracture in the individual patient.
Rates of osteonecrosis are small, with 1 case per 10,000 to 100,000 person-years of
treatment.28
Risk is highest in patients receiving IV therapy in the setting of active cancer
(especially metastatic breast cancer or myeloma) or cancer treatment, glucocorticoid
use, poor dentition, and invasive dental procedures. In 2014, the American
Association of Oral and Maxillofacial Surgeons updated their position paper on
medication-related osteonecrosis of the jaw. Data are still limited but recommendations
at this time include postponing initiation of bisphosphonates until after completion
of invasive dental treatments. If already on a bisphosphonate, a drug holiday of
2 months before the procedure is recommended for patients who have been on
bisphosphonates for longer than 4 years regardless of other risk factors. If patients
are at high risk (concomitant corticosteroid or antiangiogenic cancer treatment medications)
then consider a drug holiday even if bisphosphonate use is less than 4 years.
In most cases the bisphosphonate should not be restarted until osseous healing has
occurred.29
Bisphosphonate efficacy has been shown with up to 10 years of use. Determining
length of therapy with bisphosphonates has become complicated because concerns
arose about risk for atypical femur fractures (subtrochanteric or femoral shaft) with
prolonged use. Although no direct causal evidence links long-term bisphosphonate
use to atypical femur fractures (AFF), several case reports, case series, and cohort analyses
show an association between the two. Bisphosphonate use for more than
5 years seems to be associated with an increased relative risk of AFF; however, the
absolute risk is low (3.2–100 cases per 100,000 person-years), with the longer the
duration, the higher the risk.30,31
At the same time, the benefit on typical hip fracture reduction generally outweighs
the risk of AFF, especially in high-risk individuals. Although there is no consensus
regarding length of therapy, clinicians might evaluate the need for a so-called drug holiday
once the patient has been treated for 5 years.32
At that time, if the patient is
considered high risk (T score À2.5, history of previous hip or spine fracture, ongoing
high-dose glucocorticoid use, or FRAX 10-year risk score at hip !3% or !20% at
other sites) therapy should be continued for another 5 years. If moderate risk (T score
now greater than À2.5, no prior hip or spine fracture, or FRAX score 10%–20%)
consider a drug holiday. If low risk (does not meet criteria for treatment based on
BMD, or FRAX score <10%) discontinue therapy23
(Table 6).
If it is decided to take a drug holiday, there are no data to guide when to reinitiate
therapy. A reasonable approach may be to reevaluate BMD via DXA scan every 2 to
3 years and consider restarting therapy if there is a rapid decline in BMD. An alternate
approach would be to reevaluate fracture risk using the FRAX score and other risk factors
every 2 years. Bone turnover markers may also be reasonable to use but there is
no specific recommendation on target values or testing intervals23
(Box 3).
If a patient who has been taking bisphosphonates for more than 3 years complains
of a dull or aching pain in the groin or midthigh, plain radiographs are recommended to
look for cortical thickening (Fig. 1) followed by MRI or bone scintigraphy looking for
atypical fractures or stress reactions. A transverse-orientation fracture may also be
noted on a plain film. If history or images are concerning, stop the bisphosphonate,
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encourage adequate calcium and vitamin D supplementation, and refer to orthopedics
urgently.
In a patient untreated for osteoporosis, the development of a fragility fracture should
trigger a conversation about the importance of treatment because a history of hip fracture
increase the risk of future fracture 3.2 times, especially during the first year after
the fracture, and the risk remains increased for at least 5 years.33
However, there is
some concern that bisphosphonate therapy may disrupt bone remodeling and delay
fracture repair. So how soon after a hip fracture surgery should a bisphosphonate
be started? There is only 1 study of IV zoledronate that addresses this question. According
to these results the ideal time to initiate a bisphosphonate after hip fracture
in order to decrease rate of recurrent fracture and reduce all-cause mortality is between
2 weeks and 90 days.34
SELECTIVE ESTROGEN RECEPTOR MODULATORS
SERMs bind to estrogen receptors and have estrogen agonist and antagonist effects
depending on the target organ. Raloxifene has more than 8 years of safety and fracture
data and decreases the risk of vertebral fracture by approximately 40%.13,35,36
There
are inadequate data to support fracture reduction at hip and nonvertebral sites. Ideal
recipients for raloxifene include women who cannot tolerate bisphosphonates but are
not at high risk for venous thromboembolism (VTE) or stroke.37
Raloxifene is dosed at
60 mg orally per day.
In addition, raloxifene reduces invasive, primarily estrogen receptor (ER)–positive,
breast cancer risk by at least 50%.37
This option may be good in women who are at
high risk for breast cancer. In the studies on breast cancer reduction, the following
constituted high risk: age greater than 60 years, age greater than 35 years with history
of lobular carcinoma in situ, ductal carcinoma in situ or atypical ductal or lobular
Box 3
Monitoring drug holidays: empiric approaches to restarting treatment
 DXA and/or biochemical markers of bone turnover every 2 to 3 years
 Reevaluate risk every 2 to 3 years with FRAX calculator
 Any new fracture
Table 6
Recommendation for drug holiday from bisphosphonates after 5 years of therapy: based on
expert opinion
Patient Category Recommendation
High risk: T score still À2.5 at hip, previous
fracture of hip or spine, ongoing high-dose
glucocorticoids
Drug holiday not justified. Continue
treatment for at least 5 more years
Moderate risk: T score now >À2.5, no
prior hip or spine fracture
Consider drug holiday after 3–5 y of
treatment with alendronate, risedronate
or zoledronatea
Low risk: Did not meet current treatment
criteria at time of treatment initiation
Discontinue therapy
a
No information about ibandronate and drug holidays.
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hyperplasia, age 35 to 59 years with Gail model 5-year risk of breast cancer greater
than 1.66%, or history of BRCA1 or BRCA2 mutation without prophylactic mastec-
tomy.38
As opposed to tamoxifen, raloxifene has not shown an increased risk of endometrial
cancer so it presents less risk in women with an intact uterus.
Because of its risk of promoting VTE, SERMs should stopped at least 4 weeks
before surgeries with moderate to high VTE risks. This recommendation is generally
safe when SERMs are being used for the treatment of osteoporosis or breast cancer
prevention. If a patient is on a SERM for treatment of breast cancer, then discuss the
risks and benefits of stopping it with the patient’s oncologist. Ideally, SERMs are
restarted several weeks after surgery or when the VTE risk decreases.
One limiting side effect may be hot flashes. A new SERM formulation was recently
introduced consisting of bazedoxifene plus conjugated equine estrogen (BZA/CE).
Bazedoxifene alone has shown similar fracture reduction rates to raloxifene; however,
this formulation is not available in the United States.39,40
BZA/CE, which is available in
the United States, has been shown to improve hot flashes and atrophic vaginitis but
fracture and safety data have only been followed for 2 years. In addition, effects on
breast cancer risk are unknown.
As opposed to the prolonged duration of action of bisphosphonates on BMD, when
SERMs are discontinued BMD loss occurs fairly quickly and is similar to the loss in patients
treated with placebo.41
Consequently, unless side effects or contraindications
develop, SERMs should probably be continued long term. Otherwise consider switching
to an alternative osteoporosis treatment agent.
TERIPARATIDE
Teriparatide or recombinant human 1-34 parathyroid hormone is the only anabolic
agent available for the treatment of osteoporosis. Dosing is a 20-mg subcutaneous injection
given in the thigh or abdominal wall daily. It works by activating bone
Fig. 1. (A) Completed atypical femur fracture. Note the beaking of the lateral cortex (red
arrow) and short oblique nature of the fracture. There is also minimal comminution noted.
(B) Incomplete atypical femur fracture. Note the lateral cortex beaking (red arrow). Also
note the black line that represents the incomplete/nondisplaced fracture of the lateral cortex
(inset, white arrow). (From Tyler W, Bukata S, O’Keefe R. Atypical femur fractures. Clin
Geriatr Med 2014;30(2):350; with permission.)
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remodeling rather than slowing bone turnover. It decreases the risk of vertebral fractures
by 70% and nonvertebral fractures by 50%; however, data are inadequate to
determine hip fracture reduction.42,43
BMD gains occur in the first few months of treatment;
however, it takes at least 6 months before antifracture efficacy occurs.42
Teriparatide
should be stopped after 2 years of treatment because the benefits on BMD
begin to level off after 18 months of therapy. In addition, animal studies and 1 human
case report showed an increased risk of osteosarcoma with longer-term treatment,
although causality between teriparatide and osteosarcoma was not established in
the 1 case report.44,45
Consequently, teriparatide should be avoided in patients at
increased risk for osteosarcoma (history of Paget disease, bony radiation, skeletal metastases,
and so forth).
Ideal candidates for teriparatide include postmenopausal women with severe vertebral
osteoporosis (T < À3.5, or T < À2.5 plus fragility fracture). Because prior
bisphosphonate use may blunt the effect of teriparatide, ideally it should be used first
with a plan to transition to an antiresorptive such as a bisphosphonate or SERM after
2 years of treatment.46
Teriparatide is extremely expensive and can cost up to $2000
per month without insurance. Teriparatide is covered by Medicare part D; however,
patients need to show intolerance to or fail bisphosphonate therapy for coverage to
be granted in most cases. Treatment with a bisphosphonate or SERM after discontinuation
of teriparatide preserves or increases gains in BMD acquired with teriparatide
alone. It is unclear how soon after an acute fracture teriparatide should be started
because data are limited and conflicting about whether it accelerates or inhibits fracture
repair.
Common side effects include headaches, myalgias, nausea, hypercalcemia, and
hypercalciuria, so it should be avoided in patients with a history of kidney stones or
persistent hypercalciuria. Uric acid levels can also increase and may precipitate a
gout attack, therefore avoid the use of teriparatide until uric acid levels are controlled
to less than 7.5 mg/dL in patients with a history of gout. Before initiating treatment
check serum calcium, phosphate, creatinine, alkaline phosphatase, albumin,
25-OH, uric acid, and 24-hour urine calcium levels. If hypercalcemia or hypercalciuria
present, evaluate for primary hyperparathyroidism. Replete vitamin D levels if low
before initiating therapy.
DENOSUMAB
Denosumab is a monoclonal antibody that inhibits osteoclast formation and prevents
resorption. Similar to bisphosphonates, it decreases fracture risk at all sites. Fracture
risk decreases by 70% at the spine, 40% at the hip, and 20% at nonvertebral loca-
tions.47,48
Ideal candidates for denosumab may include osteoporotic postmenopausal
women who are intolerant or nonadherent to other medications or those with renal
insufficiency (even if creatinine clearance is <35 mL/min). Dosing is 60 mg subcutaneously
every 6 months and is only covered by Medicare part B, therefore it should be
administered during a clinic visit in Medicare patients.
Most common side effects include musculoskeletal pain, hypercholesterolemia,
and cystitis. There is a small increased risk of exacerbating eczema or causing cellulitis
that requires hospitalization. Denosumab should be avoided in the setting of hypocalcemia
until corrected and any vitamin D deficiency should be corrected before
use. In the extension trial of denosumab after eight years of treatment with denosumab
in 1546 postmenopausal women, one case of atypical femur fracture and five cases of
osteonecrosis of the jaw (ONJ) occurred. There were three cases of ONJ and one
atypical fracture in the 1457 cross-over group patients who received five years of
Osteoporosis Treatment 817
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denosumab therapy.49
Longer-term safety data are needed to learn more about these
risks.49
Data are limited about the effect on acute fracture healing; however, at this
time it seems that, even when administered within 6 weeks preceding or following a
fracture, there is no delay in healing. There are few data on the idea duration of denosumab
therapy or on sequential therapy with other osteoporosis agents. Denosumab
has shown efficacy for 8 years.50
BMD returns to baseline within 2 years after discontinuing
therapy.
HORMONE REPLACEMENT THERAPY
Because of potential increased risks of breast cancer, stroke, VTE, and coronary heart
disease (CHD), hormone replacement therapy (HRT) is no longer first line for the prevention
or treatment of osteoporosis. Data from the Women’s Health Initiative (WHI)
showed an increase risk of CHD, stroke, VTE, and breast cancer in women on combination
estrogen and progestin therapy. In women with hysterectomies who were
treated with unopposed estrogen the risk of stroke and VTE was similar to combination
therapy but there was no increased risk of CHD and a trend toward slightly lower
rates of invasive breast cancer. However, some women who cannot tolerate other
osteoporotic agents or who have hot flashes may consider using HRT. The best
data for fracture reduction come from the WHI, which showed a 30% to 40% reduction
in risk of hip, vertebral, and nonvertebral fractures.51,52
BMD was not a criterion for
randomization into the WHI, therefore baseline BMD may have differed between
groups, thus making these results inconclusive. Maximum BMD improvement seems
to occur when HRT is started shortly after menopause and continued long-term, but
some studies suggest benefit even when started much later in life. Although HRT is
not FDA approved for the treatment of osteoporosis, a few small studies have shown
fracture reduction in osteoporotic women.53
It seems that low-dose estrogen (0.3–
0.45 mg/d) with or without progesterone is as effective as higher-dose estrogen
(0.625 mg/d) in maintaining BMD.54
CALCITONIN
The Agency for Healthcare Research and Quality no longer recommends calcitonin for
the treatment of osteoporosis because the quality of evidence for fracture reduction is
only fair.55,56
Probably the most beneficial use of calcitonin is for the treatment of
acute compression fracture pain. Small studies show a reduction in pain within
4 days of starting the medication for up to 4 weeks of treatment.57
It is not helpful
for treatment of chronic compression fracture pain. Calcitonin, if used for treatment
of acute compression fracture pain, is dosed 200 IU alternating nostrils every day or
100 units subcutaneously or intramuscularly every day or every other day. In general,
the nasal formulation is recommended because side effects of nausea, vomiting, and
flushing are less and analgesia is better compared with the injectable formulations.
STRONTIUM RANELATE
Strontium ranelate is available in Europe for the treatment of osteoporosis. In addition
to its antiresorptive effects, strontium accumulates in the bone tissue, therefore the
magnitude of BMD changes seen may not be representative of fracture risk reduction.
Studies have shown a reduction in vertebral fracture risk by 40% and nonvertebral
fracture risk by 15%. In high-risk groups, hip fracture risk may decrease by approximately
40%.58–61
Strontium ranelate is not available in the Unites States and it is unclear
whether the formulations available in the Unites States (citrate, gluconate,
O’Connor818
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chloride) effectively treat osteoporosis. Side effects and complications, when they
occur, can be severe and include diarrhea, VTE, myocardial infarction, drug reaction
and eosinophilia and systemic symptoms, Stevens-Johnson, and toxic epidermal
necrolysis. It is unclear how long patients should be treated but there are some safety
data for up to 10 years.
MONITORING FOR RESPONSE TO THERAPY
There is no consensus on recommended follow-up after initiating treatment of osteoporosis.
The controversy arises because it is unclear whether fracture risk reduction
correlates with BMD changes while on therapy. Several studies have shown that the
greater the improvement in BMD, the greater the fracture reduction.62–65
However,
other studies have suggested that fracture reduction occurs regardless of whether
BMD increases or decreases with treatment.66,67
Most subspecialist societies,
including the NOF and the North American Menopause Society, recommend repeating
a DXA scan 1 to 2 years after initiating therapy. How often to repeat after that depends
on whether improvement or stability in BMD has been achieved or whether the patient
is at high risk for more rapid decline of BMD caused by medication side effects or
medical conditions. The alternative approach held by the Agency of Health Care
Research and Quality is to not repeat a DXA scan after initiating therapy because treatment
has been associated with a decreased fracture risk regardless of BMD changes
on serial DXAs.12,55
This option may be reasonable for patients who the clinicians
thinks are adherent with medications and are at low risk for rapid decline of BMD
caused by malabsorption or glucocorticoid use. If a follow-up DXA is obtained,
what the clinician decides to do with the results depends on which philosophy the
clinician holds. If BMD is decreasing, assessing for medication adherence and making
sure patients are receiving adequate calcium and vitamin D supplementation is a good
place to start.
Although in clinical trials bone turnover markers (BTMs) reflect the rate of bone turnover,
it is not routinely recommended to check BTMs in patients on antiresorptives
because of biological and laboratory variability confounding their use in clinical practice.
In addition, there is insufficient evidence to support their use in deciding whether
to change therapies based on the results. However, providers may choose to measure
BTM in patients with conditions that might interfere with drug absorption or in patients
reluctant to take these medications regularly. When using BTMs, measurements
should be done at the same time of day in the same laboratory for a given patient in
order to decrease risk of variability of results. BTMs cannot be used for patients on
the anabolic agent, teriparatide. BTMs include fasting urinary N-telopeptide (NTX) or
serum carboxy-terminal collagen cross-links (CTXs). These BTMs can be measured
before initiating therapy and then 3 to 6 months later. A decrease in urinary NTX by
at least 50% or serum CTX by at least 30% suggests adherence and efficacy. However,
a decrease of less than this does not necessarily indicate treatment failure but
may trigger the clinician to question the patient about medication adherence or malabsorption.
Of note, insurance companies may not cover these tests.
GLUCOCORTICOID-INDUCED OSTEOPOROSIS
Glucocorticoids exposure, whether endogenous or exogenous, decreases bone density
and increases the risk of fracture. Dosages as low at 2.5 to 7.5 mg of prednisone
equivalents per day have been associated with increased vertebral and nonvertebral
fractures, with higher daily doses likely more harmful.68
Most BMD loss occurs within
the first few months of therapy; however, continued use is associated with a slow and
Osteoporosis Treatment 819
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steady decline. Screening with DXA scan and vitamin D levels are recommended in all
patients more than 30 years of age who are anticipated to be on glucocorticoids for
greater than or equal to 3 months. These patients should also be encouraged to maintain
calcium intake of 1200 mg/d and vitamin D intake of 800 IU/d through diet and/or
supplements.
In 2010, the American College of Rheumatology (ACR) published recommendations
on evaluation and management of glucocorticoid-induced osteoporosis (GIOP). In
nonosteoporotic postmenopausal women and men greater than or equal to 50 years
old, the FRAX calculator should be used to determine risk of fracture. In postmenopausal
women and men greater than or equal to 50 years old with osteoporosis, history
of fragility fracture, or a high-risk FRAX score (hip >3%, major
osteoporotic >20%), treatment is recommended for patients on any dose of steroid
for any period of time. If they are in the medium-risk category (FRAX score 10%–
20% major osteoporotic), consider treatment if steroid use is anticipated for greater
than or equal to 3 months. If low risk (FRAX score <10% major osteoporotic), consider
treatment if steroids will extend past 3 months with at least 7.5 mg of prednisone
equivalents per day. The 2010 ACR article provides a useful algorithm to determine
need for treatment.68
In premenopausal women and men less than 50 years old, treatment
should be considered if there is a history of fragility fracture or evidence of accelerated
bone loss. There are insufficient data to support treatment in this population if
there is no history of fragility fracture (Table 7).
Bisphosphonates (alendronate, risedronate, zoledronate) or teriparatide are recommended
for the treatment of GIOP in postmenopausal women, premenopausal
women, and men of any age. In general, bisphosphonates are first-line agents
because of their substantial data on fracture reduction and low cost. Because of
higher cost and subcutaneous route of administration, teriparatide is generally not
used as a first-line agent; however, there are some data suggesting that teriparatide
Table 7
Glucocorticoid-Induced Osteoporosis
Risk Categories Consider Treatment Which Treatment
Postmenopausal women and
men !50 y old with
osteoporosis, history of
fragility fracture, or highrisk
FRAX score (>3%
hip, >20% major
osteoporotic fracture risk)
Any patient on any dose of
steroid for any period of
time
Bisphosphonates
(alendronate, risedronate,
zoledronate) or
teriparatide
Postmenopausal women and
men !50 y old with
medium-risk FRAX score
(10%–20% major
osteoporotic fracture risk)
If steroid treatment
anticipated for !3 mo
Bisphosphonates
(alendronate, risedronate,
zoledronate) or
teriparatide
Postmenopausal women and
men !50 y old with low-risk
FRAX score (<10% major
osteoporotic fracture risk)
If steroids will extend past
3 mo with at least 7.5 mg
prednisone equivalents per
day
Bisphosphonates
(alendronate, risedronate,
zoledronate) or
teriparatide
Premenopausal women and
men <50 y old
If there is a history of fragility
fracture or evidence of
accelerated bone loss
Bisphosphonates
(alendronate, risedronate,
zoledronate) or
teriparatide
O’Connor820
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leads to greater increases in BMD and lower rates of vertebral fractures compared
with alendronate in high-risk patients treated with glucocorticoids.69–71
Therefore, in
patients with severe osteoporosis or those who cannot tolerate or fail other therapies,
teriparatide may be the best option (Box 4).
TREATMENT OF OSTEOPOROSIS IN MEN
Bone density screening is uncommon in men. Most often DXA scans are obtained after
the diagnosis of a low-trauma fracture or after osteopenia was incidentally noted on
radiographs. Organizations such as the NOF, Endocrine Society, and International Society
for Clinical Densitometry recommend screening all men more than 70 years of
age and men between 50 and 70 years of age if certain risk factors are present.
Risk factors may include history of fragility fracture, osteopenia on radiograph, loss
of more than 37 mm (1.5 inches) of height, long-term glucocorticoid use, human immunodeficiency
virus medications, androgen deprivation therapy for the treatment of
prostate cancer, hypogonadism, primary hyperparathyroidism, and intestinal disorders.
The same T-score classifications are used to diagnoses osteopenia and osteoporosis
in men as in women. If osteoporosis is identified, then a work-up for secondary
causes should be initiated because there is a high likelihood in men that a secondary
cause will be identified. Men should be evaluated for hypogonadism, vitamin D deficiency,
renal and liver disease, hyperparathyroidism, celiac disease and other causes
of malabsorption, Cushing syndrome, and idiopathic hypercalciuria. Indications for
treatment in men more than 50 years of age include osteoporosis on DXA scan, history
of fragility fracture, or osteopenia plus high FRAX score (10-year probability of hip fracture
!3% or if major osteoporotic fracture risk is !20%).72
Box 4
Common medications that may decrease BMD or increase fracture risk
 Glucocorticoids
 Antiepileptic drugs: phenobarbital, phenytoin, carbamazepine
 Antiretrovirals for human immunodeficiency virus
 Thiazolidinediones for diabetes
 Sodium-glucose cotransporter-2 inhibitors (canagliflozin) for diabetes
 High-dose medroxyprogesterone acetate for contraception (DepoProvera)
 Aromatase inhibitors
 Gonadotropin-releasing hormone agonists
 Methotrexate
 Cyclosporin and FK506 (tacrolimus)
 Proton Pump Inhibitors
 Lithium
 Antidepressants (selective serotonin reuptake inhibitors and tricyclic antidepressants)
 Loop diuretics
 Heparin (long-term use)
 Excessive thyroid HRT
Osteoporosis Treatment 821
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In general, testosterone replacement therapy is recommended if hypogonadal and
there are no contraindications; however, the effect of testosterone therapy on fracture
risk has not been evaluated. Treatment options for men include bisphosphonates, teriparatide,
and denosumab. All three agents have shown improvement in BMD in men.
Only denosumab, when used for treatment of men with nonmetastatic prostate cancer
on androgen deprivation therapy, and bisphosphonates have data supporting reduction
in fracture risk.73,74
When choosing between these therapies the same clinical indications,
contraindications, and lengths of therapy apply as defined earlier. In
general, oral bisphosphonates should be first-line therapy.
SUMMARY
As the population continues to age, the rates of osteoporotic fractures will increase.
DXA scan screening is recommended in postmenopausal women more than 65 years
of age or women aged 50 to 64 years with risk factors or at high risk of fracture based
on FRAX score. DXA should also be considered for all men more than 70 years of age
and men between 50 and 70 years of age if certain risk factors are present. Consider
treatment if osteoporosis is present, there is a history of fragility fracture, or in the
setting of osteopenia plus high risk for fracture based on a FRAX score of greater
than or equal to 3% at the hip or greater than or equal to 20% at other sites. All the
agents used to treat osteoporosis decrease fracture risk at the spine but only certain
bisphosphonates, denosumab, and estrogen have data showing a reduction in hip
fracture. The site of diminished BMD or fragility fracture, side effects, contraindications,
secondary benefits, cost, and likelihood of adherence should influence the
choice of treatment. In most cases, bisphosphonates should be first-line therapy.
REFERENCES
1. Wright NC, Saag KG, Curtis JR, et al. Recent trends in hip fracture rates by race/
ethnicity among older US adults. J Bone Miner Res 2012;27(11):2325–32.
2. Cauley JA. Public health impact of osteoporosis. J Gerontol A Biol Sci Med Sci
2013;68(10):1243–51.
3. Boonen S, Laan RF, Barton IP, et al. Effect of osteoporosis treatments on risk of
non-vertebral fractures: review and meta-analysis of intention-to-treat studies.
Osteoporos Int 2005;16(10):1291–8.
4. Kanis JA, Borgstrom F, De Laet C, et al. Assessment of fracture risk. Osteoporos
Int 2005;16(6):581–9.
5. Kanis J. FRAX. WHO fracture risk assessment tool. 2015. https://www.shef.ac.uk/
FRAX/.
6. US Preventive Services Task Force. Screening for osteoporosis: U.S. preventive
services task force recommendation statement. Ann Intern Med 2011;154(5):
356–64.
7. Laya M. OsteoEd: Osteoporosis Education. 2015. http://depts.washington.edu/
osteoed/.
8. Rubin KH, Abrahamsen B, Friis-Holmberg T, et al. Comparison of different
screening tools (FRAXÒ, OST, ORAI, OSIRIS, SCORE and age alone) to identify
women with increased risk of fracture. A population-based prospective study.
Bone 2013;56(1):16–22.
9. Gourlay ML, Fine JP, Preisser JS, et al. Bone-density testing interval and transition
to osteoporosis in older women. N Engl J Med 2012;366(3):225–33.
10. Cosman F, de Beur SJ, LeBoff MS, et al. Clinician’s guide to prevention and treatment
of osteoporosis. Osteoporos Int 2014;25(10):2359–81.
O’Connor822
Downloaded from ClinicalKey.com at University Health Network June 02, 2016.
For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
11. Donaldson MG, Cawthon PM, Lui LY, et al. Estimates of the proportion of older
white women who would be recommended for pharmacologic treatment by the
new U.S. National Osteoporosis Foundation guidelines. J Bone Miner Res
2009;24(4):675–80.
12. Crandall CJ, Newberry SJ, Diamant A, et al. Treatment To Prevent Fractures in
Men and Women With Low Bone Density or Osteoporosis: Update of a 2007
Report [Internet]. Rockville (MD): Agency for Healthcare Research and Quality
(US); 2012.
13. Crandall CJ, Newberry SJ, Diamant A, et al. Comparative effectiveness of pharmacologic
treatments to prevent fractures: an updated systematic review. Ann
Intern Med 2014;161(10):711–23.
14. Moyer VA, US Preventive Services Task Force. Vitamin D and calcium supplementation
to prevent fractures in adults: U.S. Preventive Services Task Force
recommendation statement. Ann Intern Med 2013;158(9):691–6.
15. Avenell A, Mak JC, O’Connell D. Vitamin D and vitamin D analogues for preventing
fractures in post-menopausal women and older men. Cochrane Database
Syst Rev 2014;(4):CD000227.
16. DIPART (Vitamin D Individual Patient Analysis of Randomized Trials) Group. Patient
level pooled analysis of 68 500 patients from seven major vitamin D fracture
trials in US and Europe. BMJ 2010;340:b5463.
17. Carmel AS, Shieh A, Bang H, et al. The 25(OH)D level needed to maintain a favorable
bisphosphonate response is !33 ng/ml. Osteoporos Int 2012;23(10):
2479–87.
18. Agrawal S, Krueger DC, Engelke JA, et al. Between-meal risedronate does not
alter bone turnover in nursing home residents. J Am Geriatr Soc 2006;54(5):
790–5.
19. Invernizzi M, Cisari C, Carda S. The potential impact of new effervescent alendronate
formulation on compliance and persistence in osteoporosis treatment. Aging
Clin Exp Res 2015;27(2):107–13.
20. FDA drug safety communication: possible increased risk of fractures of the hip,
wrist, and spine with the use of proton pump. US Food and Drug Administration
Web site. http://www.fda.gov/Drugs/DrugSafety/PostmarketDrugSafetyInformation
forPatientsandProviders/ucm213206.htm. Accessed January 12, 2011.
21. Abrahamsen B, Eiken P, Eastell R. Proton pump inhibitor use and the antifracture
efficacy of alendronate. Arch Intern Med 2011;171(11):998–1004.
22. In brief: effervescent alendronate. Med Lett Drugs Ther 2012;54(1401):84.
23. Brown JP, Morin S, Leslie W, et al. Bisphosphonates for treatment of osteoporosis:
expected benefits, potential harms, and drug holidays. Can Fam Physician 2014;
60(4):324–33.
24. Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment
of postmenopausal osteoporosis. N Engl J Med 2007;356(18):1809–22.
25. Loke YK, Jeevanantham V, Singh S. Bisphosphonates and atrial fibrillation: systematic
review and meta-analysis. Drug Saf 2009;32(3):219–28.
26. Sorensen HT, Christensen S, Mehnert F, et al. Use of bisphosphonates among
women and risk of atrial fibrillation and flutter: population based case-control
study. BMJ 2008;336(7648):813–6.
27. Heckbert SR, Li G, Cummings SR, et al. Use of alendronate and risk of incident
atrial fibrillation in women. Arch Intern Med 2008;168(8):826–31.
28. Ruggiero SL, Dodson TB, Fantasia J, et al. American Association of Oral and
Maxillofacial Surgeons position paper on medication-related osteonecrosis of
the jaw–2014 update. J Oral Maxillofac Surg 2014;72(10):1938–56.
Osteoporosis Treatment 823
Downloaded from ClinicalKey.com at University Health Network June 02, 2016.
For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
29. Shane E, Burr D, Ebeling PR, et al. Atypical subtrochanteric and diaphyseal
femoral fractures: report of a task force of the American Society for Bone and Mineral
Research. J Bone Miner Res 2010;25(11):2267–94.
30. Shane E, Burr D, Abrahamsen B, et al. Atypical subtrochanteric and diaphyseal
femoral fractures: second report of a task force of the American Society for Bone
and Mineral Research. J Bone Miner Res 2014;29(1):1–23.
31. Whitaker M, Guo J, Kehoe T, et al. Bisphosphonates for osteoporosis–where do
we go from here? N Engl J Med 2012;366(22):2048–51.
32. Klop C, Gibson-Smith D, Elders PJ, et al. Anti-osteoporosis drug prescribing after
hip fracture in the UK: 2000-2010. Osteoporos Int 2015;26(7):1919–28.
33. Seton M. How soon after hip fracture surgery should a patient start bisphosphonates?
Cleve Clin J Med 2010;77(11):751–5.
34. Seeman E, Crans GG, Diez-Perez A, et al. Anti-vertebral fracture efficacy of raloxifene:
a meta-analysis. Osteoporos Int 2006;17(2):313–6.
35. Ettinger B, Black DM, Mitlak BH, et al. Reduction of vertebral fracture risk in postmenopausal
women with osteoporosis treated with raloxifene: results from a
3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation
(MORE) Investigators. JAMA 1999;282(7):637–45.
36. Barrett-Connor E, Mosca L, Collins P, et al. Effects of raloxifene on cardiovascular
events and breast cancer in postmenopausal women. N Engl J Med 2006;355(2):
125–37.
37. Visvanathan K, Chlebowski RT, Hurley P, et al. American Society of Clinical
Oncology clinical practice guideline update on the use of pharmacologic interventions
including tamoxifen, raloxifene, and aromatase inhibition for breast cancer
risk reduction. J Clin Oncol 2009;27(19):3235–58.
38. Silverman SL, Christiansen C, Genant HK, et al. Efficacy of bazedoxifene in
reducing new vertebral fracture risk in postmenopausal women with osteoporosis:
results from a 3-year, randomized, placebo-, and active-controlled clinical
trial. J Bone Miner Res 2008;23(12):1923–34.
39. Silverman SL, Chines AA, Kendler DL, et al. Sustained efficacy and safety of bazedoxifene
in preventing fractures in postmenopausal women with osteoporosis:
results of a 5-year, randomized, placebo-controlled study. Osteoporos Int 2012;
23(1):351–63.
40. Neele SJ, Evertz R, De Valk-De Roo G, et al. Effect of 1 year of discontinuation of
raloxifene or estrogen therapy on bone mineral density after 5 years of treatment
in healthy postmenopausal women. Bone 2002;30(4):599–603.
41. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of parathyroid hormone (1-34)
on fractures and bone mineral density in postmenopausal women with osteoporosis.
N Engl J Med 2001;344(19):1434–41.
42. Greenspan SL, Bone HG, Ettinger MP, et al. Effect of recombinant human parathyroid
hormone (1-84) on vertebral fracture and bone mineral density in postmenopausal
women with osteoporosis: a randomized trial. Ann Intern Med
2007;146(5):326–39.
43. Harper KD, Krege JH, Marcus R, et al. Osteosarcoma and teriparatide? J Bone
Miner Res 2007;22(2):334.
44. Vahle JL, Sato M, Long GG, et al. Skeletal changes in rats given daily subcutaneous
injections of recombinant human parathyroid hormone (1-34) for 2 years and
relevance to human safety. Toxicol Pathol 2002;30(3):312–21.
45. Obermayer-Pietsch BM, Marin F, McCloskey EV, et al. Effects of two years of daily
teriparatide treatment on BMD in postmenopausal women with severe
O’Connor824
Downloaded from ClinicalKey.com at University Health Network June 02, 2016.
For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
osteoporosis with and without prior antiresorptive treatment. J Bone Miner Res
2008;23(10):1591–600.
46. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of
fractures in postmenopausal women with osteoporosis. N Engl J Med 2009;
361(8):756–65.
47. Boonen S, Adachi JD, Man Z, et al. Treatment with denosumab reduces the incidence
of new vertebral and hip fractures in postmenopausal women at high risk.
J Clin Endocrinol Metab 2011;96(6):1727–36.
48. Bone HG, Chapurlat R, Brandi ML, et al. The effect of three or six years of denosumab
exposure in women with postmenopausal osteoporosis: results from the
FREEDOM extension. J Clin Endocrinol Metab 2013;98(11):4483–92.
49. Papapoulos S, Lippuner K, Roux C, et al. The effect of 8 or 5 years of denosumab
treatment in postmenopausal women with osteoporosis: results from the
FREEDOM Extension study. Osteoporos Int 2015;26(12):2773–83.
50. Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus
progestin in healthy postmenopausal women: principal results from the Women’s
Health Initiative randomized controlled trial. JAMA 2002;288(3):321–33.
51. Anderson GL, Limacher M, Assaf AR, et al. Effects of conjugated equine estrogen
in postmenopausal women with hysterectomy: the Women’s Health Initiative randomized
controlled trial. JAMA 2004;291(14):1701–12.
52. Lufkin EG, Wahner HW, O’Fallon WM, et al. Treatment of postmenopausal osteoporosis
with transdermal estrogen. Ann Intern Med 1992;117(1):1–9.
53. Lindsay R, Gallagher JC, Kleerekoper M, et al. Effect of lower doses of conjugated
equine estrogens with and without medroxyprogesterone acetate on
bone in early postmenopausal women. JAMA 2002;287(20):2668–76.
54. Levis S, Theodore G. Summary of AHRQ’s comparative effectiveness review of
treatment to prevent fractures in men and women with low bone density or osteoporosis:
update of the 2007 report. J Manag Care Pharm 2012;18(4 Suppl B):
S1–15 [discussion: S13].
55. Agency for Healthcare Research and Quality. Treatment to prevent fractures in
men and women with low bone density or osteoporosis: update of a 2007 report.
2012. http://effectivehealthcare.ahrq.gov/index.cfm/search-for-guides-reviews-
and-reports/?pageaction=displayproduct&productid=1007.
56. Knopp-Sihota JA, Newburn-Cook CV, Homik J, et al. Calcitonin for treating acute
and chronic pain of recent and remote osteoporotic vertebral compression fractures:
a systematic review and meta-analysis. Osteoporos Int 2012;23(1):17–38.
57. O’Donnell S, Cranney A, Wells GA, et al. Strontium ranelate for preventing and
treating postmenopausal osteoporosis. Cochrane Database Syst Rev
2006;(3):CD005326.
58. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk
of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med
2004;350(5):459–68.
59. Reginster JY, Seeman E, De Vernejoul MC, et al. Strontium ranelate reduces the
risk of nonvertebral fractures in postmenopausal women with osteoporosis: Treatment
of Peripheral Osteoporosis (TROPOS) study. J Clin Endocrinol Metab 2005;
90(5):2816–22.
60. Reginster JY, Felsenberg D, Boonen S, et al. Effects of long-term strontium ranelate
treatment on the risk of nonvertebral and vertebral fractures in postmenopausal
osteoporosis: results of a five-year, randomized, placebo-controlled trial.
Arthritis Rheum 2008;58(6):1687–95.
Osteoporosis Treatment 825
Downloaded from ClinicalKey.com at University Health Network June 02, 2016.
For personal use only. No other uses without permission. Copyright ©2016. Elsevier Inc. All rights reserved.
61. Hochberg MC, Ross PD, Black D, et al. Larger increases in bone mineral density
during alendronate therapy are associated with a lower risk of new vertebral fractures
in women with postmenopausal osteoporosis. Fracture Intervention Trial
Research Group. Arthritis Rheum 1999;42(6):1246–54.
62. Hochberg MC, Greenspan S, Wasnich RD, et al. Changes in bone density and
turnover explain the reductions in incidence of nonvertebral fractures that occur
during treatment with antiresorptive agents. J Clin Endocrinol Metab 2002;87(4):
1586–92.
63. Eastell R, Vrijens B, Cahall DL, et al. Bone turnover markers and bone mineral
density response with risedronate therapy: relationship with fracture risk and patient
adherence. J Bone Miner Res 2011;26(7):1662–9.
64. Wasnich RD, Miller PD. Antifracture efficacy of antiresorptive agents are related
to changes in bone density. J Clin Endocrinol Metab 2000;85(1):231–6.
65. Sarkar S, Mitlak BH, Wong M, et al. Relationships between bone mineral density
and incident vertebral fracture risk with raloxifene therapy. J Bone Miner Res
2002;17(1):1–10.
66. Cummings SR, Karpf DB, Harris F, et al. Improvement in spine bone density and
reduction in risk of vertebral fractures during treatment with antiresorptive drugs.
Am J Med 2002;112(4):281–9.
67. Grossman JM, Gordon R, Ranganath VK, et al. American College of Rheumatology
2010 recommendations for the prevention and treatment of
glucocorticoid-induced osteoporosis. Arthritis Care Res (Hoboken) 2010;
62(11):1515–26.
68. Langdahl BL, Marin F, Shane E, et al. Teriparatide versus alendronate for treating
glucocorticoid-induced osteoporosis: an analysis by gender and menopausal
status. Osteoporos Int 2009;20(12):2095–104.
69. Saag KG, Shane E, Boonen S, et al. Teriparatide or alendronate in glucocorticoidinduced
osteoporosis. N Engl J Med 2007;357(20):2028–39.
70. Saag KG, Zanchetta JR, Devogelaer JP, et al. Effects of teriparatide versus
alendronate for treating glucocorticoid-induced osteoporosis: thirty-six-month results
of a randomized, double-blind, controlled trial. Arthritis Rheum 2009;60(11):
3346–55.
71. Watts NB, Adler RA, Bilezikian JP, et al. Osteoporosis in men: an Endocrine Society
clinical practice guideline. J Clin Endocrinol Metab 2012;97(6):1802–22.
72. Joy M. Osteoporosis in men. N Engl J Med 2008;359(8):868 [author reply: 869].
73. Smith MR, Egerdie B, Hernandez Toriz N, et al. Denosumab in men receiving
androgen-deprivation therapy for prostate cancer. N Engl J Med 2009;361(8):
745–55.
74. Smith MR, Saad F, Egerdie B, et al. Effects of denosumab on bone mineral density
in men receiving androgen deprivation therapy for prostate cancer. J Urol
2009;182(6):2670–5.
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