Annals of Internal Medicine

In the Clinic

Osteoporosis Screening and Prevention

O
steoporosis is a common systemic skel-
etal disorder resulting in bone fragility Diagnosis
and increased fracture risk. However,
management of osteoporosis and fracture pre-
vention strategies are often not addressed by Treatment for Fracture
primary care clinicians, even in older patients
with recent fractures. Evidence-based screening Prevention
strategies will improve identication of patients
who are most likely to benet from drug treat-
ment to prevent fracture. In addition, careful Practice Improvement
consideration of when pharmacotherapy should
be started and choice of medication and dura-
tion of treatment will maximize the benets of
fracture prevention while minimizing potential
harms of long-term drug exposure.

CME/MOC activity available at Annals.org.

Physician Writers doi:10.7326/AITC201708010

Kristine E. Ensrud, MD, MPH
Carolyn J. Crandall, MD, MS
From the University of
Minnesota and Veterans
Affairs Health Care System,
Minneapolis, Minnesota; and
the University of California,
Los Angeles, California.
CME Objective: To review current evidence for screening, prevention, diagnosis, treatment for
fracture prevention, and practice improvement of osteoporosis.
Funding Source: American College of Physicians.
Acknowledgment: The authors thank E. Michael Lewiecki, author of the previous version of
this In the Clinic.
With the assistance of additional physician writers, the editors of Annals of Internal
Medicine develop In the Clinic using MKSAP and other resources of the American College
of Physicians.
In the Clinic does not necessarily represent ofcial ACP clinical policy. For ACP clinical
guidelines, please go to https://www.acponline.org/clinical_information/guidelines/.
Disclosures: Dr. Ensrud, ACP Contributing Author, reports personal fees from from Merck
Sharpe & Dohme, outside the submitted work; Dr. Crandall, ACP Contributing Author, has
disclosed no conicts of interest. Disclosures can also be viewed at www.acponline.org
/authors/icmje/ConictOfInterestForms.do?msNum=M17-1218.

2017 American College of Physicians

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 Osteoporosis is a systemic skele- clinical vertebral fractures are the
tal disease characterized by low most devastating consequences
1. Wright NC, Looker AC,
bone mass and microarchitec- of osteoporosis and are associ-
Saag KG, et al. The recent tural deterioration in bone tissue, ated with increased morbidity and
prevalence of osteoporosis
and low bone mass in the leading to enhanced bone fragil- mortality. Drug treatment has
United States based on ity and increased fracture risk. been found to reduce risk for sub-
bone mineral density at
the femoral neck or lum- The operational denition of os- sequent clinical fractures among
bar spine. J Bone Miner teoporosis is based on bone min-
Res. 2014;29:2520-6. postmenopausal women with ex-
[PMID: 24771492] eral density (BMD) measurement. isting vertebral fractures or osteo-
2. U.S. Preventive Services
Task Force. Screening for An estimated 10.3% of noninsti- porosis (as dened by BMD) and
osteoporosis: U.S. Preven- tutionalized adults aged 50 years
tive Services Task Force among adults aged 50 years or
recommendation state- or older in the United States had
ment. Ann Intern Med.
older with recent hip fracture.
2011;154:356-64. [PMID:
osteoporosis in 2010 (1). Hip and
21242341]
3. National Osteoporosis
Foundation. 2014 clini-
cian's guide to prevention
and treatment of osteopo-
Screening and Prevention
rosis. Accessed at www.nof Who should be screened? for hip fracture begins to increase.
.org/news/nofs-clinicians
-guide-published-by-osteo- All women aged 65 years or older Some guidelines (3, 4, 8) encour-
porosis-international/ on
16 June 2017. should be screened for osteoporo- age BMD measurement for
4. International Society for sis by BMD measurement at the women in this age group who
Clinical Densitometry.
2015 ISCD Ofcial hip and lumbar spine using dual- have risk factors for fracture. How-
PositionsAdult. Accessed
energy x-ray absorptiometry ever, there is no consensus regard-
at www.iscd.org/ofcial
-positions/2015-iscd-of- (DXA). This recommendation is ing all the specic risk factors that
cial-positions-adult/ on 15
August 2013. universally endorsed by the U.S. should be considered in this
5. Looker AC, Frenk SM. Preventive Services Task Force decision.
Percentage of adults aged
65 and over with osteopo- (USPSTF) (2) and other profes-
rosis or low bone mass at
sional societies (3, 4). Despite a Another strategy is to use the Os-
the femur neck or lumbar
spine: United States, prevalence of osteoporosis in this teoporosis Self-Assessment Tool
2005-2010. Acceesed at
patient population of nearly 25% (OST) (see the Box), a simple cal-
www.cdc.gov/nchs/data
/hestat/osteoporsis/ (5), recent data (6) suggest that 1 culator that uses age and weight
osteoporosis2005_2010 and is designed to identify individ-
.htm on 18 April 2017. in 4 women aged 65 85 years has
6. National Committee for
never had BMD testing. uals who are more likely to have
Quality Assurance. Osteo-
porosis testing and man- low BMD. Studies (9, 10) have sug-
agement in older women. The risk assessment strategy to gested that an OST score less than
Accessed at www.ncqa.org
/report-cards/health-plans select younger postmenopausal 2 is an appropriate cutoff to select
/state-of-health-care-
quality/2016-table-of women for osteoporosis screen- younger postmenopausal women
-contents/osteoporosis on ing is uncertain. Despite rapid for BMD testing. In 2011, the
5 May 2017.
7. Doherty DA, Sanders KM, rates of bone loss at the lumbar USPSTF (2) recommended select-
Kotowicz MA, Prince RL. ing younger postmenopausal
Lifetime and ve-year
spine during the menopausal
age-specic risks of rst transition, the absolute fracture women for BMD measurement
and subsequent osteopo-
rotic fractures in post- risk for any given BMD is much who have a 10-year fracture prob-
menopausal women. lower in younger postmeno- ability, as calculated by the Frac-
Osteoporos Int. 2001;12:
16-2. [PMID: 11305078] pausal women than in older ture Risk Assessment Tool (FRAX)
8. Camacho PM, Petak SM,
Binkley N, et al. American
women. In particular, the abso- (11), that is the same as or greater
Association of Clinical lute 5-year probability of hip frac- than that of a 65-year-old white
Endocrinologists and
American College of Endo- ture is less than 1.0% until age woman without additional risk fac-
crinology clinical practice 70 79 years, when it begins to tors (i.e., 10-year probability of ma-
guidelines for the diagno-
sis and treatment of post- increase exponentially (7). Data jor osteoporotic fracture [hip, clini-
menopausal osteoporo-
sis2016. Endocr Pract. on the benets and harms of cal vertebral, distal forearm, or
2016;22:1-42. [PMID: drug treatment beginning at age humerus] 9.3% when estimated
27662240]
9. Cadarette SM, McIsaac 50 64 years and continuing over without BMD). Comparisons of the
WJ, Hawker GA, et al. The
validity of decision rules
the next 3 decades of life are un- OST and USPSTF approaches
for selecting women with available. Use of drug treatment have reported superior combined
primary osteoporosis for
bone mineral density in younger women leaves them sensitivity and specicity, but the
testing. Osteoporos Int. with fewer options for pharmaco- OST has better discrimination (10,
2004;15:361-6. [PMID:
14730421] therapy in their 70s, when the risk 12). Thus, use of an OST cutoff less

2017 American College of Physicians ITC18 In the Clinic Annals of Internal Medicine 1 August 2017

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Osteoporosis Self-assessment
Tool
Score = [weight (kg) age
(years)] 0.2
than 2 is a reasonable strategy to
identify younger postmenopausal
women for BMD testing if it is
agreed that drug treatment will be
initiated for a BMD T-score of
2.5.
Osteoporosis screening in older
men has been proposed be-
cause it is an accepted strategy in
older women. However, it is less
common in men; the prevalence
of BMD-dened osteoporosis
among men aged 65 years or
older is 5.6% (5). Data on the ef-
cacy of pharmacotherapy in pre-
venting fractures in men are
limited; randomized trials in os-
teoporotic men have only evalu-
ated radiographic vertebral frac-
ture as an end point. Some
guidelines (3, 13) recommend
BMD testing in all men aged 70
years or older and in those aged
50 69 years with risk factors.
Other research has suggested
using the OST to identify men for
screening (14). The USPSTF (2)
made no recommendation about
osteoporosis screening in men,
citing insufcient evidence, but
commented that those who are
most likely to benet from
screening have a 10-year FRAX
probability of fracture equal to or
greater than that of a 65-year-old
white woman without additional
risk factors. A study (15) that
compared proposed strategies
for selecting men aged 70 years
or older for osteoporosis screen-
ing reported that the OST (cutoff
<2) performed slightly better
than the more complex FRAX
strategy; use of either tool sub-
stantially reduced the proportion
of men referred for BMD mea-
surement compared with univer-
sal screening. Future research on
osteoporosis risk assessment
1 August 2017 Annals of Internal Medicine
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tools and randomized trials with
clinical fracture end points are
needed to clarify whether tar-
geted screening strategies or
universal screening are war-
ranted in this patient population.
How often should older adults
be screened, and when should
screening stop?
Studies indicate that the baseline
BMD T-score is important in de-
termining how often older adults
without osteoporosis at the initial
assessment should be tested.
Those with lower BMD at base-
line should have a shorter re-
screening interval.
A study (16) that estimated the cumulative inci-
dence of osteoporosis in older community-
dwelling women without osteoporosis at initial
assessment reported that fewer than 10% be-
came osteoporotic during follow-up if rescreen-
ing intervals were 15 years for those with normal
BMD (T-score 1.0) or mild osteopenia (T-score
<1.0 and >1.5), 5 years for those with mod-
erate osteopenia (T-score <1.5 and >2.0),
and 1 year for those with advanced osteopenia
(T-score <2.0 and >2.5).
A similar study in community-
dwelling older men without osteo-
porosis at initial assessment re-
ported that only 0.2% of those with
normal BMD or mild osteopenia
transitioned to osteoporosis dur-
ing follow-up; the time for 10% of
men to transition to osteoporosis
was 8.5 years among those with
moderate osteopenia and 2.7
years among those with advanced
osteopenia (17).
The age at which to stop or de-
crease BMD testing to screen for
osteoporosis has not been exam-
ined. Older women with higher
BMD T-scores (>1.5) have a
very low risk for disabling frac-
ture before their estimated time
to death, and they may benet
less from rescreening. In con-
trast, older women with lower
BMD T-scores (<2.0 and >2.5)
have a high risk for disabling
fracture before their estimated
time to death, so they may bene-
In the Clinic
FRAX Clinical Risk Factors*
Age
Sex
Weight
Height
Previous fracture
Parental history of hip
fracture
Smoking status
Glucocorticoid use
Rheumatoid arthritis
Secondary osteoporosis
3 units of alcohol per day
Femoral neck BMD (g/cm2)
BMD = bone mineral density.
* Calculator freely available at
www.shef.ac.uk/FRAX.
The quantity of alcohol that
constitutes 1 unit varies
slightly by country. For FRAX,
1 unit of alcohol is equivalent
to 9 10 oz of beer, 4 oz of
wine, 1 oz of spirits, or 2 oz of
aperitif.
10. Leslie WD, Lix LM, Jo-
hansson H, Oden A,
et al; Manitoba Bone
Density Program. Selec-
tion of women aged
50-64 yr for bone density
measurement. J Clin
Densitom. 2013;16:
570-8. [PMID:
23452870]
11. Centre for Metabolic
Bone Diseases. FRAX
WHO fracture risk assess-
ment tool. Accessed at
www.shef.ac.uk/FRAX/ on
15 June 2017.
12. Crandall CJ, Larson J,
Gourlay ML, et al. Osteo-
porosis screening in
postmenopausal women
50 to 64 years old: com-
parison of US Preventive
Services Task Force strat-
egy and two traditional
strategies in the Wom-
en's Health Initiative. J
Bone Miner Res. 2014;
29:1661-6. [PMID:
24431262]
13. Watts NB, Adler RA,
Bilezikian JP, et al; Endo-
crine Society. Osteoporo-
sis in men: an Endocrine
Society clinical practice
guideline. J Clin Endocri-
nol Metab. 2012;97:
1802-22. [PMID:
22675062]
14. Adler RA, Tran MT, Pet-
kov VI. Performance of
the Osteoporosis Self-
assessment Screening
Tool for osteoporosis in
American men. Mayo
Clin Proc. 2003;78:
723-7. [PMID:
12934782]
ITC19 2017 American College of Physicians

15. Diem SJ, Peters KW,
Gourlay ML, et al.
Screening for osteoporo-
sis in older men: operat-
ing characteristics of
proposed strategies for
selecting men for BMD
testing. J Gen Intern
Med [Forthcoming].
16. Gourlay ML, Fine JP,
Preisser JS, et al; Study
of Osteoporotic Fractures
Research Group. Bone-
density testing interval
and transition to osteo-
porosis in older women.
N Engl J Med. 2012;
366:225-33. [PMID:
22256806]
17. Gourlay ML, Overman
RA, Fine JP, et al; Osteo-
porotic Fractures in Men
(MrOS) Research Group.
Time to osteoporosis and
major fracture in older
men: The MrOS Study.
Am J Prev Med. 2016;
50:727-36. [PMID:
26821835]
18. ClinRisk. QFracture-2016
risk calculator. Accessed
at www.qfracture.org/ on
1 June 2016.
19. Garvan Institute of Medi-
cal Research. Bone frac-
ture risk calculator. gar-
van org au/bone-fracture-
risk. Accessed at www
.garvan.org.au/bone
-fracture-risk on 1 June
2016.
20. Kanis JA, Hans D, Cooper
C, et al; Task Force of the
FRAX Initiative. Interpre-
tation and use of FRAX in
clinical practice. Osteopo-
ros Int. 2011;22:2395-
411. [PMID: 21779818]
21. Collins GS, Michaelsson
K. Fracture risk assess-
ment: state of the art,
methodologically un-
sound, or poorly re-
ported? Curr Osteoporos
Rep. 2012;10:199-207.
[PMID: 22688862]
22. van den Bergh JP, van
Geel TA, Lems WF,
Geusens PP. Assessment
of individual fracture
risk: FRAX and beyond.
Curr Osteoporos Rep.
2010;8:131-7. [PMID:
20563901]
23. Rubin KH, Friis-
Holmberg T, Hermann
AP, Abrahamsen B,
Brixen K. Risk assess-
ment tools to identify
women with increased
risk of osteoporotic frac-
ture: complexity or sim-
plicity? A systematic
review. J Bone Miner
Res. 2013;28:1701-17.
[PMID: 23592255]
24. Ensrud KE, Lui LY, Taylor
BC, et al; Study of Osteo-
porotic Fractures Re-
search Group. A compari-
son of prediction models
for fractures in older
women: is more better?
Arch Intern Med. 2009;
169:2087-94. [PMID:
20008691]
2017 American College of Physicians
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t more from rescreening. The
age to stop screening may be
lower in men than in women be-
cause of the higher competing
risk for death.
How should a patient's
absolute risk be assessed?
Because clinical factors contribute
to fracture risk beyond that re-
ected by BMD, researchers have
developed fracture risk assess-
ment tools (11, 18, 19) to estimate
a patient's absolute long-term risk
for fracture. Of note, the World
Health Organization (WHO) does
not endorse the use of any specic
instrument. FRAX (the tool most
commonly endorsed in the United
States for use in clinical decision
making) is a computer-based algo-
rithm that uses selected clinical risk
factors (see the Box) with or with-
out femoral neck BMD to estimate
10-year probability of hip and ma-
jor osteoporotic fracture (11).
FRAX has several strengths (20).
Country-specic models are
available that take into account
countrywide fracture and mortal-
ity rates. Performance has been
evaluated in several studies, and
the algorithm is readily revised
and updated. It also has several
limitations (21, 22). Most impor-
tant, there are no data from ran-
domized trials demonstrating the
benet of pharmacotherapy for
clinical fracture prevention in pa-
tients who are enrolled based on
FRAX intervention thresholds rec-
ommended by such organiza-
tions as the National Osteoporo-
sis Foundation (NOF) (3) for use
in clinical decision making re-
garding whether to initiate drug
treatment. FRAX is not transpar-
entinformation used to derive
the equations is not publicly
available. Other limitations are
that it includes only femoral neck
BMD and underestimates frac-
ture probability among patients
whose spine BMD is markedly
lower than femoral neck measure-
ments. It does not account for the
ITC20 In the Clinic
doseresponse relationship that
exists for some clinical risk factors.
For example, prior fracture is a
FRAX clinical risk factor, but the
algorithm does not consider re-
cency, number, severity, or site of
prior fractures, all of which affect
subsequent risk. By design, fall
history or propensity was not in-
cluded as a clinical risk factor be-
cause the developers noted that
markers of fall propensity identify a
fracture risk that probably is not
amenable to treatment with medi-
cations affecting bone metabo-
lism. Hence, the tool may underes-
timate fracture risk in a patient with
a higher fall propensity. Finally, it
should only be used to estimate
fracture probability in treatment-
naive patients.
A systematic review (23) of stud-
ies in postmenopausal women
concluded that no fracture risk
assessment tool is optimal. The
evidence (23, 24) suggests that
simple tools often perform as
well as more complex ones. Sub-
optimal performance of existing
tools has been reported in spe-
cic patient populations, includ-
ing younger postmenopausal
women (25) and older men (26,
27). This indicates that predicting
fracture risk in these patient
groups requires assessment of
factors not incorporated into
available strategies. The benet
of including fracture risk assess-
ment tools into shared decision
making is also uncertain. Current
evidence (28) suggests that a de-
cision aid incorporating FRAX
probability may improve patient
knowledge, but no effect on
rates of treatment initiation or
adherence was demonstrated.
Further research to improve
identication of patients at
higher absolute risk for fracture is
needed, with special attention to
simple models that t into the
time constraints and competing
demands of primary care
practice.
Annals of Internal Medicine 1 August 2017
 What lifestyle measures are
recommended for prevention?
Lifestyle measures for fracture
prevention include maintaining a
healthy body weight (body mass
index >20 kg/m2) and adequate
dietary protein intake (i.e., 0.8
g/kg of body weight per day).
Patients should be counseled to
avoid cigarette smoking and ex-
cessive alcohol intake. Physical
activity is widely recommended
to improve skeletal health, but ran-
domized trials have not been con-
ducted to identify the type, fre-
quency, or duration necessary to
prevent fractures. Guidelines (3, 8)
endorse lifelong physical activity
(both weight-bearing exercise and
muscle-strengthening exercise) for
osteoporosis prevention. Fre-
quency and intensity of activity are
not specied in guidelines. None-
theless, a common clinical practice
is to recommend both 30 minutes
of walking per day and gentle re-
sistance exercises.
The vast majority of fractures result
from falls, but only 10%15% of
falls in older adults result in frac-
tures. The pathogenesis of falls in
older adults is complex. Several
factors are associated with in-
creased risk, including age-related
decits in visual, proprioceptive,
and vestibular systems; decreased
lower extremity performance;
medical conditions and comorbid-
ity burden; use of selected medi-
cations and polypharmacy; and
environmental factors (29).
Guidelines (3, 8) recommend
evaluation of risk factors for falls
in all osteoporotic patients. Al-
though minimizing use of medi-
cations associated with increased
fall risk is appropriate, the extent
to which other risk factors can be
mitigated by home safety evalua-
tion and fall prevention programs
is controversial. Most trials of
home-based exercise or fall pre-
vention programs have not ro-
bustly decreased fall risk (30). A
systematic review of trials (31)
1 August 2017 Annals of Internal Medicine
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concluded that exercise or physi-
cal therapy interventions mod-
estly reduced falls in community-
dwelling older adults but noted
that evidence for efcacy in pre-
venting fall-related fractures was
scant and inconclusive.
The USPSTF (32) recommends
individualized decision making
and advocates exercise or physi-
cal therapy and vitamin D supple-
mentation (800 IU/d) to prevent
falls in community-dwelling older
adults at increased risk. A reason-
able strategy is to request physi-
cal therapy evaluation and inter-
vention (e.g., gait assessment,
balance training, and lower ex-
tremity strengthening programs)
in older patients with decondi-
tioning, reduced mobility, or bal-
ance or gait abnormalities.
What is the recommended
intake of calcium and
vitamin D?
The recommended dietary allow-
ance (RDA) is calculated to meet
the intake requirements of more
than 97% of the U.S. population.
For women, the RDA for calcium is
1000 mg/d for ages 19 50 years
and increases to 1200 mg/d above
age 50 years; for men, the RDA is
1000 mg/d for ages 19 70 years
and increases to 1200 mg/d above
age 70 years (33). Intake above
2500 mg/d should be avoided.
Preferred sources of calcium are
calcium-rich foods and beverages
(34).
The RDA for vitamin D is 600 IU/d
for men and women aged 19 70
years and increases to 800 IU/d
for those older than 70 years
(33). These allowances were cal-
culated assuming minimal or no
sun exposure. The RDA for vita-
min D corresponds to a serum
25-hydroxyvitamin D (25-[OH]D)
level of 20 ng/mL. Because few
foods in nature contain it, vitamin
D in the U.S. diet is primarily pro-
vided by fortied foods.
In the Clinic
25. Crandall CJ, Larson JC,
Watts NB, et al. Compari-
son of fracture risk pre-
diction by the US Preven-
tive Services Task Force
strategy and two alterna-
tive strategies in women
50-64 years old in the
Women's Health Initia-
tive. J Clin Endocrinol
Metab. 2014;99:4514-
22. [PMID: 25322268]
26. Ensrud KE, Taylor BC,
Peters KW, et al; Osteo-
porotic Fractures in Men
Study Group. Implica-
tions of expanding indi-
cations for drug treat-
ment to prevent fracture
in older men in United
States: cross sectional
and longitudinal analysis
of prospective cohort
study. BMJ. 2014;349:
g4120. [PMID:
24994809]
27. Ettinger B, Ensrud KE,
Blackwell T, et al; Osteo-
porotic Fracture in Men
(MrOS) Study Research
Group. Performance of
FRAX in a cohort of
community-dwelling,
ambulatory older men:
the Osteoporotic Frac-
tures in Men (MrOS)
study. Osteoporos Int.
2013;24:1185-93.
[PMID: 23179575]
28. Montori VM, Shah ND,
Pencille LJ, et al. Use of a
decision aid to improve
treatment decisions in
osteoporosis: the osteo-
porosis choice random-
ized trial. Am J Med.
2011;124:549-56.
[PMID: 21605732]
29. Ensrud KE. Epidemiology
of fracture risk with ad-
vancing age. J Gerontol
A Biol Sci Med Sci. 2013;
68:1236-42. [PMID:
23833201]
30. Hill KD, Hunter SW,
Batchelor FA, Cavalheri V,
Burton E. Individualized
home-based exercise
programs for older peo-
ple to reduce falls and
improve physical perfor-
mance: A systematic
review and meta-
analysis. Maturitas.
2015;82:72-84. [PMID:
25989701]
31. Michael YL, Whitlock EP,
Lin JS, et al; US Preven-
tive Services Task Force.
Primary care-relevant
interventions to prevent
falling in older adults: a
systematic evidence
review for the U.S. Pre-
ventive Services Task
Force. Ann Intern Med.
2010;153:815-25.
[PMID: 21173416]
32. Moyer VA; U.S. Preven-
tive Services Task Force.
Prevention of falls in
community-dwelling
older adults: U.S. Preven-
tive Services Task Force
recommendation state-
ment. Ann Intern Med.
2012;157:197-204.
[PMID: 22868837]
ITC21 2017 American College of Physicians
 Screening and Prevention... Women aged 65 years or older should be
screened for osteoporosis with DXA hip and spine BMD measurements.
Use of an OST cutoff less than 2 is a reasonable strategy to identify
younger postmenopausal women (aged 50 64 years) for BMD testing if
there is agreement that drug treatment will be initiated for a BMD T-score
2.5. Data are insufcient to endorse a specic screening strategy in
older men, but universal screening of men aged 70 years or older may be
premature. The initial BMD T-score is the major determinant of the screen-
ing interval among older adults without osteoporosis at the initial assess-
ment. No optimal fracture risk assessment tool is available, and simple
tools often perform as well as more complex ones. Adequate exercise and
intake of protein, calcium, and vitamin D are recommended for bone
health. Potentially reversible risk factors for falls with particular attention to
polypharmacy should be addressed in patients with osteoporosis.

CLINICAL BOTTOM LINE

Diagnosis
33. Institute of Medicine.
Dietary reference intakes
for calcium and vitamin
D. Washington, DC:
National Academies Pr;
2011.
34. Bauer DC. Clinical prac-
tice. Calcium supple-
ments and fracture pre-
vention. N Engl J Med.
2013;369:1537-43.
[PMID: 24131178]
How should osteoporosis be
diagnosed?
The diagnosis of osteoporosis in
adults aged 50 years or older can
be in patients with a history of hip
or clinical vertebral fracture not
due to excessive trauma, those
with existing vertebral fractures
identied on the basis of a spinal
imaging study alone (radio-
graphic vertebral fractures), and
those with a BMD at or below the
cutoff value (i.e., 2.5 SDs below
that of a young white woman).
BMD should be measured at the
hip and its subregions and the
lumbar spine (posterioranterior
view of the L1L4 vertebrae) us-
ing DXA. Measurement of BMD
at the hip is preferred for diag-
nosing osteoporosis because it is
a strong predictor of risk for non-
vertebral fracture, including hip
fracture. Measurements at the
total hip and femoral neck sub-
region (but not those at Ward's
area or greater trochanter sub-
regions) should be used to make
the diagnosis. Of note, spine
BMD may increase with aging
because of calcium deposition
related to degenerative joint
disease and abdominal aortic
calcication.
BMD results on DXA are re-
ported as T-scores and Z scores
(see the Box). The T-score should
be reported in postmenopausal
women and in men aged
50 years or older. It compares
the patient's BMD with the aver-
age BMD in the young adult ref-
erence population and is the SD
below or above the mean BMD
for young adults. The reference
group of young adults for calcu-
lation of total hip and femoral
neck BMD T-scores in both men
and women and individuals of all
racial/ethnic groups should be
non-Hispanic white women aged
20 29 years from NHANES III
(Third National Health and Nutri-
tion Examination Survey) (4). Be-
cause there is no internationally
recommended reference group
for lumbar spine measurements,
the reference group for calcula-
tion of lumbar spine BMD
T-scores should be the DXA
manufacturer-specic reference
database of young white women.
BMD within 1 SD of this reference
group is classied as normal
BMD, 1.0 2.5 SDs below that of a
young white woman is consid-
ered to be osteopenia or low
bone mass, and 2.5 SDs below
that of a young white woman is
dened as osteoporosis.
BMD Z scores should be reported
in premenopausal women and in

2017 American College of Physicians ITC22 In the Clinic Annals of Internal Medicine 1 August 2017

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 men younger than 50 years. The Z high alkaline phosphatase levels were more
score provides a comparison of common in men with osteoporosis than in Classication of Bone Mineral
the patient's BMD with average those without. Density by Dual-Energy
age-, sex-, and race-matched BMD X-Ray Absorptiometry
Measurement of 25-(OH)D levels In postmenopausal women and
and is the number of SDs below or
is widely recommended in osteo- men aged 50 years or older,
above mean BMD for people of
porotic patients. However, there apply the WHO diagnostic
the same age, sex, and race. criteria:
is no evidence that vitamin D
When should clinicians supplementation to achieve a Normal: T-score 1.0
Low bone mass (osteopenia):
consider laboratory testing to target serum level (e.g., 30 ng/ T-score <1.0 and >2.5
assess for underlying secondary mL) is superior to a more conser- Osteoporosis: T-score 2.5
causes or to determine whether vative approach (e.g., supple- In premenopausal women and
consultation is necessary? mentation if needed to reach the men younger than 50 years,
do not apply the WHO
The clinical utility of laboratory RDA of 600 800 IU/d) in reduc- diagnostic criteria:
testing to identify secondary ing risk for falls or fractures. The
Z scores, not T-scores, are
causes of osteoporosis is unclear, clinical utility of this measure- preferred
but some organizations (3, 8, 13) ment is likely to be greatest in Z score 2.0 is dened as
recommend ordering laboratory patients with problems absorb- below the expected range
for age
tests in patients with osteoporosis ing or metabolizing vitamin D. Z score >2.0 is within the
or high fracture risk or patients in expected range for age
whom a specic secondary, treat- Patients with specic presumed WHO = World Health
able cause of osteoporosis is be- secondary causes of osteoporo- Organization.
ing considered. Most studies that sis should be referred to subspe-
evaluated the utility of laboratory cialists for further evaluation and
evaluation for secondary causes of management. Those with sus-
osteoporosis had small sample pected celiac disease or inam-
sizes or were based on tertiary matory bowel syndrome should
care patient populations (35, 36). be referred to a gastroenterolo-
Thus, results may not be generaliz- gist. Patients with probable Cush-
able to patients seen in the pri- ing syndrome, hyperthyroidism,
mary care practice setting. hyperparathyroidism, or hyper-
prolactinemia should be referred
A large study of community-dwelling post-
to an endocrinologist. Patients
menopausal women (37) found that the prev-
alence of each specic laboratory test abnor- with suspected Paget disease of
35. Romagnoli E, Del Fiacco
mality was similar among women with and bone or autoimmune disease R, Russo S, et al. Second-
without osteoporosis, except that low thyroid- should be referred to a rheuma- ary osteoporosis in men
and women: clinical
stimulating hormone levels were slightly more tologist, those with possible sys- challenge of an unre-
solved issue. J Rheuma-
common among women with osteoporosis. temic mastocytosis should be tol. 2011;38:1671-9.
referred to an allergist/immunol- [PMID: 21632675]
Similarly, in a large study of community- 36. Ryan CS, Petkov VI, Adler
dwelling older men (38), most had more than ogist, and those with multiple RA. Osteoporosis in men:
the value of laboratory
1 laboratory test abnormality, regardless of myeloma or other types of cancer testing. Osteoporos Int.
whether they had osteoporosis; only vitamin D should be referred to a 2011;22:1845-53.
[PMID: 20936403]
insufciency (but not vitamin D deciency) and hematologist/oncologist. 37. Jamal SA, Leiter RE,
Bayoumi AM, Bauer DC,
Cummings SR. Clinical
utility of laboratory test-
ing in women with os-
Diagnosis... The diagnosis of osteoporosis in adults aged 50 years or older teoporosis. Osteoporos
should be made in patients with a history of hip or clinical vertebral fracture not Int. 2005;16:534-40.
[PMID: 15340801]
due to excessive trauma; those with existing radiographic vertebral fractures; 38. Fink HA, Litwack-Harrison
and those with a BMD T-score at the femoral neck, total hip, or lumbar spine S, Taylor BC, et al; Osteo-
porotic Fractures in Men
2.5, calculated using a young white woman as a reference database. Cur- (MrOS) Study Group.
rent evidence is insufcient to support routine laboratory testing in patients Clinical utility of routine
with osteoporosis to identify possible secondary causes. Referral to a sub- laboratory testing to
identify possible second-
specialist is indicated in patients with complex diagnostic issues. ary causes in older men
with osteoporosis: the
Osteoporotic Fractures in
Men (MrOS) Study. Os-
CLINICAL BOTTOM LINE teoporos Int. 2016;27:
331-8. [PMID:
26458388]

1 August 2017 Annals of Internal Medicine In the Clinic ITC23 2017 American College of Physicians

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 Treatment for Fracture Prevention
39. Watts NB, Geusens P,
Barton IP, Felsenberg D.
Relationship between
changes in BMD and
nonvertebral fracture
incidence associated with
risedronate: reduction in
risk of nonvertebral frac-
ture is not related to
change in BMD. J Bone
Miner Res. 2005;20:
2097-104. [PMID:
16294263]
40. Cummings SR, Karpf DB,
Harris F, et al. Improve-
ment in spine bone
density and reduction in
risk of vertebral fractures
during treatment with
antiresorptive drugs. Am
J Med. 2002;112:281-9.
[PMID: 11893367]
41. Chen P, Miller PD, Del-
mas PD, Misurski DA,
Krege JH. Change in
lumbar spine BMD and
vertebral fracture risk
reduction in teriparatide-
treated postmenopausal
women with osteoporo-
sis. J Bone Miner Res.
2006;21:1785-90.
[PMID: 17002571]
42. U.S. Department of
Health and Human Ser-
vices. Bone health and
osteporosis: a report of
the Surgeon General.
2004. Rockville, MD,
U.S. Department of
Health and Human Ser-
vices, Ofce of the Sur-
geon General.
43. Chung M, Lee J, Tera-
sawa T, Lau J, Trikalinos
TA. Vitamin D with or
without calcium supple-
mentation for prevention
of cancer and fractures:
an updated meta-
analysis for the U.S.
Preventive Services Task
Force. Ann Intern Med.
2011;155:827-38.
[PMID: 22184690]
2017 American College of Physicians
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What are the goals of treatment?
The primary goal of osteoporosis
treatment is to reduce the risk for
clinical fractures, especially those
of the hip and vertebrae. Change
in BMD during drug treatment is
far less important than the treat-
ment effect on subsequent frac-
ture risk. Most reduction of frac-
ture risk with drug treatment is
not explained by its effect on
BMD (39 41). Even if BMD de-
clines during pharmacotherapy,
whether the patient would have
had a much greater BMD decline
without treatment is uncertain.
Clinicians should emphasize to
patients that the goal of treatment
is to prevent disabling fractures.
However, because drug treatment
does not always achieve this goal,
a single fracture during treatment
is not necessarily evidence of treat-
ment failure, but it does indicate a
higher risk for future fractures. Pa-
tients who have fractures while
receiving drug treatment should
be assessed for adherence, evalu-
ated for underlying medical condi-
tions (e.g., secondary causes), and
assessed for fall propensity with
consideration of preventive mea-
sures. In patients who have had
multiple fractures or fractures with
severe clinical consequences dur-
ing treatment, clinicians may con-
sider starting an alternate therapy
or referring to a subspecialist.
Clinicians should also review medi-
cation lists to determine whether
those with adverse effects on bone
metabolism can be decreased or
discontinued. Medications re-
ported to be associated with os-
teoporosis and higher fracture risk
include long-term heparin, antiepi-
leptic drugs, cyclosporine, tacroli-
mus, such chemotherapeutic
agents as aromatase inhibitors,
glucocorticoids, gonadotropin-
releasing hormone agonists, thia-
zolidinediones, excessive doses of
ITC24 In the Clinic
L-thyroxine, proton-pump inhibi-
tors, selective serotonin reuptake
inhibitors, parenteral nutrition,
depo-medroxyprogesterone con-
traception, methotrexate, and alu-
minum antacids (42).
Which patients should take
calcium and vitamin D
supplementation?
Clinicians should follow the Insti-
tute of Medicine's 2011 recom-
mendations regarding calcium
and vitamin D intake (33). They
should encourage patients to
obtain these nutrients through
dietary sources and recommend
supplementation only in patients
who do not meet intake levels.
Calcium supplements include
calcium carbonate and calcium
citrate; determination of the dose
required to meet daily require-
ments should be based on the
elemental calcium content (34).
Vitamin D3 supplements are avail-
able in several doses, and many
multivitamins contain 400 IU of
vitamin D3. Excessive calcium in-
take can result in nephrolithiasis,
so patients should not assume that
more is better and exceed rec-
ommended doses (33).
A systematic review of trials of
combined calcium and vitamin D
supplementation (43) reported a
reduction in fracture risk with sup-
plementation, but effects were
smaller and not signicant among
community-dwelling older adults
than among institutionalized el-
derly persons. Thus, combined
calcium and vitamin D supplemen-
tation at prudent doses should be
recommended in older institution-
alized patients and community-
dwelling older adults with inade-
quate dietary intake.
Which patients are candidates
for drug treatment?
Among postmenopausal women
with osteoporosis (dened as a
BMD T-score 2.5 or existing
Annals of Internal Medicine 1 August 2017
 radiographic vertebral fractures), creases 3.7-fold in men and almost 2-fold in
treatment with alendronate, rise- women (45).
dronate, zoledronic acid, or deno-
Although basing a treatment de-
sumab reduces risk for clinical frac-
cision on a patient's absolute risk
tures, including those of the hip
for fracture is tempting, whether
and vertebrae. Several drug treat-
pharmacotherapy reduces risk 44. Siris ES, Adler R,
ments lower risk for new radio- Bilezikian J, et al. The
for clinical fractures among clinical diagnosis of
graphic vertebral fractures.
adults without osteoporosis is osteoporosis: a position
Among men and women aged 50 statement from the Na-
unproven. Systematic reviews of tional Bone Health Alli-
years or older with recent low- ance Working Group.
bisphosphonate trials in post- Osteoporos Int. 2014;25:
trauma hip fracture, treatment with
menopausal women have not re- 1439-43. [PMID:
zoledronic acid reduces the risk for 24577348]
ported signicantly reduced risk 45. Wright NC, Saag KG,
clinical fractures. Although alen-
for nonvertebral fractures among Dawson-Hughes B, Kho-
dronate, risedronate, or zoledronic sla S, Siris ES. The impact
women without osteoporosis (de- of the new National
acid decrease risk for new radio- Bone Health Alliance
ned as BMD T-score 2.5) or (NBHA) diagnostic crite-
graphic vertebral fracture in men
existing vertebral fractures (46, 47). ria on the prevalence of
with osteoporosis, the efcacy of osteoporosis in the USA.
Pivotal trials of alendronate, rise- Osteoporos Int. 2017;28:
drug treatment in preventing clini- 1225-1232. [PMID:
dronate, and denosumab found
cal or nonvertebral fractures in 27966104]
that treatment did not reduce risk 46. MacLean C, Newberry S,
men is uncertain. Maglione M, et al. Sys-
for clinical fractures in post- tematic review: compara-
Some U.S. guidelines (3, 8, 13) menopausal women who did tive effectiveness of treat-
ments to prevent
endorse the use of specic FRAX not meet these criteria (48 50). fractures in men and
women with low bone
intervention thresholds (10-year Thus, adoption of the guide- density or osteoporosis.
absolute probability of hip frac- lines labels a substantial pro- Ann Intern Med. 2008;
148:197-213. [PMID:
ture 3% or 10-year absolute portion of older adults with a 18087050]
probability of major osteoporotic problem that might not benet 47. Wells GA, Cranney A,
Peterson J, et al. Alen-
fracture 20%) to aid clinicians in from pharmacologic therapy. It dronate for the primary
and secondary preven-
deciding whether to recommend also increases demands on the tion of osteoporotic frac-
drug treatment in adults aged 50 health care system to identify tures in postmenopausal
women. Cochrane Data-
years or older with osteopenia. and treat the excess patients base Syst Rev. 2008:

These guidelines recommend meeting the expanded criteria CD001155. [PMID:

18253985]
initiation of drug treatment in (51). 48. Cummings SR, Black
DM, Thompson DE, et al.
adults with osteopenia who have a The American College of Physi- Effect of alendronate on
risk of fracture in women
10-year fracture probability at or cians (ACP) (52) recommends with low bone density
above either NOF-endorsed FRAX that clinicians use shared deci-
but without vertebral
fractures: results from
intervention thresholds. In addi- sion making to decide whether to the Fracture Intervention
Trial. JAMA. 1998;280:
tion, the National Bone Health Alli- initiate drug treatment in os- 2077-82. [PMID:
ance (NBHA) (44) has proposed teopenic women aged 65 years 9875874]
49. McClung MR, Geusens P,
changes in the diagnostic criteria or older who are at high risk for Miller PD, et al; Hip
for osteoporosis and recommends fracture (weak recommendation,
Intervention Program
Study Group. Effect of
that adults aged 50 years or older low-quality evidence). ACP notes risedronate on the risk of
hip fracture in elderly
be diagnosed with osteoporosis that clinicians can use their judg- women. Hip Intervention
regardless of BMD if they have a ment for assessing fracture risk
Program Study Group. N
Engl J Med. 2001;344:
FRAX score at or above either of by an evaluation of risk factor sta- 333-40. [PMID:
the NOF FRAX intervention thresh- 11172164]
tus or application of an assess- 50. McClung MR, Boonen S,
olds. Adoption of NOF or NBHA ment tool. Randomized trials are Torring O, et al. Effect of
denosumab treatment
guidelines greatly expands the needed to determine whether on the risk of fractures in
proportion of older adults identi- drug treatment is efcacious in
subgroups of women
with postmenopausal
ed as having an indication for preventing clinical fractures osteoporosis. J Bone
Miner Res. 2012;27:
drug treatment (26, 45). among middle-aged and older 211-8. [PMID:
21976367]
In the United States, it has been estimated that adults with osteopenia who have 51. Schousboe JT, Ensrud
4.3% of men and 15.4% of women aged 50 a higher estimated fracture risk. KE. Diagnostic criteria for
osteoporosis should not
years or older have osteoporosis according to These data would inform treat- be expanded. Lancet
ment guidelines for this patient Diabetes Endocrinol.
BMD criteria. With use of the expanded NBHA 2015;3:236-8. [PMID:
denition, the prevalence of osteoporosis in- population. 25797770]

1 August 2017 Annals of Internal Medicine In the Clinic ITC25 2017 American College of Physicians

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 How is a specic pharmacologic
agent chosen for patients who
are candidates for drug
treatment?
Bisphosphonates (Table) are the
rst-line agents for treatment of
osteoporosis. All are now avail-
able in generic form. Ibandro-
nate is rarely prescribed be-
cause there is no evidence from
randomized trials that it reduces
risk for nonvertebral fractures.
Bisphosphonates are not recom-
mended for patients with severe
renal impairment. Thus, assess-
ment of renal function is appro-
priate before treatment is be-
gun, and creatinine clearance
(CrCl) in patients prescribed bis-
phosphonates should exceed 35
mL/min/1.73 m2. Oral bisphos-
phonates should be taken with a
glass of water on an empty
stomach to maximize absorp-
tion. These drugs are contraindi-
cated in cases of esophageal
stricture, achalasia, or Barrett
esophagus; however, they are
often tolerated in patients with a
remote history of peptic ulcer
disease or those with gastro-
esophageal reux controlled
with medications. Common
adverse effects of oral bisphos-
phonates include upper gastro-
intestinal tract irritation and mus-
culoskeletal problems. Risk for
gastrointestinal irritation is mini-
mized by adherence to dosing
instructions. Common adverse
effects of zoledronic acid in-
clude u-like symptoms or bone
paintypically with the initial
doseand musculoskeletal
symptoms. Rare but serious ad-
verse effects of oral and intrave-
nous bisphosphonates include
osteonecrosis of the jaw (exposed
bone in the maxillofacial region
that does not heal within 8 weeks)
and atypical femoral fractures
(low-trauma subtrochanteric or
femoral shaft fractures).
Denosumab, the rst biologic
therapy approved to treat post-
2017 American College of Physicians
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menopausal osteoporosis, re-
duces risk for vertebral and non-
vertebral fractures, including hip
fractures. It is administered twice
yearly by subcutaneous injection.
Common adverse effects include
eczema, nausea, and injection
site reactions. Rare but serious
adverse effects include osteo-
necrosis of the jaw and atypical
femoral fractures. Candidates for
denosumab include patients with
contraindications or intolerance
to oral or intravenous bisphos-
phonates or those with severe
renal impairment (e.g., CrCl
<30 35 mL/min/1.73 m2). Hy-
pocalcemia must be corrected
before denosumab is started, so
serum calcium level should be
checked in advance. In patients
predisposed to hypocalcemia
and disturbances of mineral me-
tabolism (e.g., patients with CrCl
<30 35 mL/min/1.73 m2), check-
ing serum calcium, phosphorus,
and magnesium levels is recom-
mended within 2 weeks of deno-
sumab injection.
Raloxifene, a selective estrogen
receptor modulator, reduces risk
for vertebral fractures in post-
menopausal women with osteo-
porosis but has no effect on risk
for nonvertebral fractures. Thus,
it is not a rst-line agent for post-
menopausal osteoporosis. Long-
term use of raloxifene decreases
risk for breast cancer among
women at higher risk for this con-
dition but increases the risk for
venous thromboembolic events.
Use of estrogen therapy or com-
bined hormone therapy (estro-
gen plus progestin) is not recom-
mended or approved by the U.S.
Food and Drug Administration
(FDA) for treatment of postmeno-
pausal osteoporosis. Although
use of estrogen plus progestin or
estrogen alone is moderately
benecial in reducing the risk for
fractures, these benets do not
outweigh the harms in most post-
menopausal women (53).
ITC26 In the Clinic
Treatment with teriparatide, an
anabolic agent, reduces risk for
vertebral and nonvertebral frac-
tures among women with post-
menopausal osteoporosis but
has not been found to reduce the
risk for hip fracture. It is adminis-
tered by daily subcutaneous in-
jection. Because its efcacy and
safety have not been evaluated
beyond 2 years of treatment, the
FDA recommends limiting the
treatment period to a maximum
of 2 years during a lifetime. Com-
mon adverse effects of teripa-
ratide include nausea, arthralgia,
leg cramps, hypercalcemia, and
hypercalcuria. Rare adverse ef-
fects include hyperuricemia and
hypotension. In light of results of
long-term studies of teriparatide
in rodents, it has a black box
warning about risk for osteosar-
coma. Candidates for teripa-
ratide treatment include patients
with contraindications to oral and
intravenous bisphosphonates,
those who have had a major os-
teoporotic fracture while receiv-
ing oral bisphosphonates, and
treatment-naive persons with
very low BMD T-scores (3.5).
Abaloparatide, a human parathy-
roid hormone peptide analogue
that is administered by daily sub-
cutaneous injection, was recently
approved by the FDA for treat-
ment of postmenopausal women
with osteoporosis who are at
high risk for fracture. The efcacy
and safety proles and treatment
period of abaloparatide are simi-
lar to those of teriparatide.
Combination pharmacotherapy for
osteoporosis is not recom-
mended. The antifracture efcacy
of combination medication regi-
mens has not been adequately
evaluated in randomized clinical
trials, and safety has not been as-
sessed.
ACP (52) recommends that clini-
cians offer drug treatment with
alendronate, risedronate, zole-
dronic acid, or denosumab to
Annals of Internal Medicine 1 August 2017
 Table. Pharmacologic Agents for Treatment of Osteoporosis
Medication Method/Dosage Fracture Risk Reduction Side Effects/Risks
Bisphosphonates* Oral alendronate, ibandronate, and
Alendronate Oral, 70 mg weekly Vertebral, risendronate. Common: upper
nonvertebral, hip gastrointestinal irritation, musculoskeletal
complaints; uncommon: esophageal ulcer,
Ibandronate Oral, 150 mg monthly; Vertebral bone pain; rare: ONJ, atypical femur fractures
Intravenous, 3 mg every Intravenous ibandronate and zoledronic acid.
3 mo Common: bone pain with rst dose
Risedronate Oral, 35 mg weekly or Vertebral, zoledronic acid), musculoskeletal symptoms;
150 mg monthly nonvertebral, hip uncommon: hypocalcemia; rare: ONJ,
Zoledronic Acid Intravenous, Vertebral, atypical femur fractures
5 mg annually nonvertebral, hip

RANKL inhibitor
Denosumab Subcutaneous, Vertebral, Common: eczema, nausea, injection site
60 mg every 6 mo nonvertebral, hip reactions; rare: ONJ, atypical femur fractures

SERMs
Raloxifene Oral, 60 mg daily Vertebral Common: leg cramps, hot ashes; uncommon:
uterine polyps, deep venous thrombosis

Parathyroid hormone
and related peptide
analogues
Teriparatide Subcutaneous, 20 mcg Vertebral, Common: nausea, arthralgia, leg cramps,
daily nonvertebral hypercalcemia, hypercalcuria; uncommon:
Approved for 2 y of use hyperuricemia, hypotension
Abaloparatide Subcutaneous, 80 mcg Vertebral, Common: dizziness, headache, nausea,
daily nonvertebral palpitations, hypercalcemia, hypercalcuria
Approved for 2 y of use

ONJ = osteonecrosis of the jaw; SERM = selective estrogen receptor modulator.

* Approved by the U.S. Food and Drug Administration (FDA) for treatment of postmenopausal osteoporosis; all except ibandronate
are approved for treatment of osteoporosis in men. All bisphosphonates are available in generic form.
FDA approved for treatment of postmenopausal osteoporosis and osteoporosis in men.
FDA approved for treatment of postmenopausal osteoporosis; available in generic form.
FDA approved for treatment of postmenopausal women with osteoporosis at high risk for fracture; teriparatide also approved for
increasing bone mass in men with osteoporosis at high risk for fracture.

women with osteoporosis to re-
duce the risk for hip and vertebral
fractures. It recommends against
use of estrogen therapy, com-
bined hormone therapy, or ralox-
ifene in this group. Among men
with osteoporosis, ACP recom-
mends that clinicians offer treatment
with bisphosphonates to reduce the
risk for vertebral fractures.
Should patients receiving drug
treatment be monitored with
serial BMD or bone turnover
marker measurements?
To monitor response to drug treat-
ment, some organizations (3, 8, 13)
recommend spine and hip DXA
BMD measurements every 12
years until ndings stabilize. How-
ever, there are no data from ran-
domized trials demonstrating that
this improves fracture risk predic-
tion. Among postmenopausal
women losing BMD in trials of
alendronate (54) and raloxifene
(55), those who were receiving
drug treatment had a lower risk for
new radiographic vertebral frac-
tures than those in the placebo
group.
Analysis of data from a large alendronate trial
(56) found that when BMD is measured annually,
the observed response to bisphosphonate ther-
apy may not reect the true response because the
within-person (measurement-related) variation in
treatment effects on BMD is large compared with
the smaller between-person (treatment-related)
variation.
Failure to recognize the large
within-person BMD measure-
ment variation may lead clini-
cians to make inappropriate
decisions about continuing or
changing medication. Because
of the large background within-
person variation, monitoring
BMD is also likely to be a subopti-
mal method of detecting nonad-
herence to treatment. Further-
more, there are no randomized
trial data demonstrating improve-
ments in treatment adherence
with serial BMD monitoring. ACP
(52) recommends against BMD
monitoring during the 5-year
drug treatment period for osteo-
porosis in postmenopausal
women.
Some organizations (3, 8, 13)
also advocate obtaining bone

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52. Qaseem A, Forciea MA,
McLean RM, Denberg
TD; Clinical Guidelines
Committee of the Ameri-
can College of Physi-
cians. Treatment of low
bone density or osteopo-
rosis to prevent fractures
in men and women: a
clinical practice guideline
update from the Ameri-
can College of Physi-
cians. Ann Intern Med.
2017;166:818-839.
[PMID: 28492856]
53. Moyer VA; U.S. Preven-
tive Services Task Force.
Menopausal hormone
therapy for the primary
prevention of chronic
conditions: U.S. Preven-
tive Services Task Force
recommendation state-
ment. Ann Intern Med.
2013;158:47-54. [PMID:
23090711]
54. Chapurlat RD, Palermo L,
Ramsay P, Cummings
SR. Risk of fracture
among women who lose
bone density during
treatment with alendro-
nate. The Fracture Inter-
vention Trial. Osteoporos
Int. 2005;16:842-8.
[PMID: 15580479]
55. Sarkar S, Mitlak BH,
Wong M, et al. Relation-
ships between bone
mineral density and
incident vertebral frac-
ture risk with raloxifene
therapy. J Bone Miner
Res. 2002;17:1-10.
[PMID: 11771654]
56. Bell KJ, Hayen A, Ma-
caskill P, et al. Value of
routine monitoring of
bone mineral density
after starting bisphos-
phonate treatment:
secondary analysis of trial
data. BMJ. 2009;338:
b2266. [PMID:
19549996]
57. Schousboe JT, Bauer DC.
Clinical use of bone
turnover markers to
monitor pharmacologic
fracture prevention ther-
apy. Curr Osteoporos
Rep. 2012;10:56-63.
[PMID: 22286411]
58. Boudreau DM, Yu O,
Balasubramanian A,
et al. A survey of wom-
en's awareness of and
reasons for lack of post-
fracture osteoporotic
care. J Am Geriatr Soc.
2017. [PMID:
28422273]
59. Khan AA, Morrison A,
Kendler DL, et al; Inter-
national Task Force on
Osteonecrosis of the Jaw.
Case-based review of
osteonecrosis of the jaw
(ONJ) and application of
the international recom-
mendations for manage-
ment from the Interna-
tional Task Force on ONJ.
J Clin Densitom. 2017;
20:8-24. [PMID:
27956123]
2017 American College of Physicians
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turnover markers (BTMs) before
and 3 6 months after starting
antiresorptive therapy to monitor
treatment efcacy and patient
adherence. However, evidence is
insufcient to support this
practice (57). At present, BTM
measurement in the primary care
setting is limited by high within-
patient variability, biologic vari-
ability, and poor standardization
of most assays. Although evi-
dence from randomized trials
suggests that reductions in BTMs
after initiation of antiresorptive
therapy are associated with sub-
sequent decreases in fracture,
the optimal level of reduction in a
specic BTM that identies a re-
sponder to treatment has not
been established. Similarly, mea-
surement of these markers has
been recommended as a method
to detect nonadherence and im-
prove adherence to pharmaco-
therapy. However, whether this
strategy is superior to practical
methods of achieving this goal
(e.g., simply asking patients in a
nonjudgmental manner if they
are having problems taking treat-
ment and reviewing pharmacy
records) remains unclear.
How long should patients be
treated, and when should
clinicians consider instituting a
drug holiday?
The ideal duration of antiresorp-
tive treatment is controversial,
especially because of the recog-
nition that osteonecrosis of the
jaw and atypical femoral frac-
tures, although rare, are serious
potential harms of longer-term
treatment with potent agents (bi-
sphosphonates and denosumab).
Concerns of many women re-
garding these adverse effects
may contribute to the reluctance
to receive drug treatment, even
among those who have had a
major osteoporotic fracture (58).
The association of bisphospho-
nate use with osteonecrosis of
the jaw was rst reported in pa-
ITC28 In the Clinic
tients with metastatic cancer who
were treated with high-dose intrave-
nous bisphosphonates for hypercal-
cemia of malignancy. Although the
frequency of this disorder in oncol-
ogy patients receiving high-dose
bisphosphonates or denosumab
has been reported to be 1%15%
(59), estimates of its incidence in
patients with osteoporosis receiv-
ing smaller doses of bisphospho-
nates or denosumab treatment are
substantially lower, ranging from
about 0.001% 0.01% (60). Risk
factors in patients treated with po-
tent antiresorptive agents include
poor oral hygiene, concomitant
use of systemic glucocorticoids or
chemotherapy, smoking, diabetes,
and a recent history of invasive
dental procedures.
Atypical femoral fractures (61)
usually occur with little or no an-
tecedent trauma, may be pre-
ceded by thigh or groin pain,
and may occur bilaterally. They
are rare in the general popula-
tion and have a markedly lower
incidence than hip fractures. In
studies that examined the associ-
ation of antiresorptive treatment
(primarily bisphosphonates) with
rates of these fractures, incidence
ranged from 1 out of 100 000 per-
sons to 5 out of 10 000 persons
among bisphosphonate users (62).
A meta-analysis of studies (63) re-
ported a 1.7-fold increase in risk
for these fractures with bisphos-
phonate use, but the studies were
heterogeneous. The pooled ad-
justed relative risk was 11.1 based
on the case control studies versus
1.5 based on the cohort studies.
Evidence has found that increasing duration of
bisphosphonate use is associated with increas-
ing incidence of atypical femoral fractures. In
an analysis of 188 814 patients receiving bis-
phosphonates, the age-adjusted incidence
rates increased from 1.8 per 100 000 persons
per year with a 2-year exposure to 113 per
100 000 persons per year with an 8- to 10-year
exposure (64).
Thus, although the benets of
potent antiresorptive treatment
Annals of Internal Medicine 1 August 2017
 likely outweigh the risk for rare
atypical femoral fractures early in
treatment, this benet is less
clear for long-term users (65).
Bisphosphonates have a long
half-life in bone. Thus, unlike
most drugs, stopping them does
not result in cessation of action.
Two randomized trials have eval-
uated the benets of stopping
versus discontinuing bisphos-
phonate treatment on fracture
risk. Among older women who
had received alendronate treat-
ment for 5 years, those randomly
assigned to alendronate versus
those assigned to placebo for an
additional 5 years had a similar
rate of nonvertebral fracture and
new radiographic fracture but a
lower rate of clinical vertebral
fracture (66). Among women as-
signed to placebo for an addi-
tional 5 years, older age and
lower hip BMD T-score (2.5) at
the time of alendronate discon-
tinuation were associated with a
higher risk for clinical fractures
after discontinuation (67). Among
older women who had received
zoledronic acid infusions annu-
ally for 3 years, those randomly
assigned to annual zoledronic
acid infusions versus those as-
signed to annual placebo infu-
sions for an additional 3 years
had similar rates of nonvertebral
fracture and clinical vertebral
fracture but a lower rate of new
radiographic vertebral fracture
(68). These ndings suggest that
reduction in fracture risk may
persist years after discontinuation
of bisphosphonate treatment and
that there is no clear benet of
long-term use for prevention of
nonvertebral fractures.
Because of concerns about a
higher risk for atypical femoral
fractures with long-term bisphos-
phonate treatment, some organi-
zations have suggested a drug
holiday (e.g., temporary discon-
tinuation for up to 5 years, fol-
lowed by reassessment) in cer-
1 August 2017 Annals of Internal Medicine
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tain patients, although evidence
is insufcient to make recom-
mendations regarding the exact
timing and duration. A task force
of the American Society for Bone
and Mineral Research (60) rec-
ommended that clinicians con-
sider a drug holiday in postmeno-
pausal women after 5 or more
years of oral bisphosphonate ther-
apy (or 3 years of intravenous
bisphosphonate therapy) if the
patients satisfy the following 3 cri-
teria: 1) they have had no hip,
spine, or multiple other osteopo-
rotic fractures before or during the
initial treatment period; 2) hip
BMD T-score is >2.5 after the
initial treatment period; and 3)
they are not at high fracture risk.
The task force also suggested that
patients on a drug holiday be reas-
sessed every 23 years.
No guidelines have specically
addressed the role of a drug holi-
day for patients treated with
medications other than bisphos-
phonates. Treatment with deno-
sumab, raloxifene, or teriparatide
results in BMD gains that rapidly
wane after discontinuation of
treatment. Use of an antiresorp-
tive agent is recommended after
discontinuation of teriparatide
due to the ensuing rapid bone
loss. Although the risk for atypi-
cal femoral fractures may in-
crease with longer duration of
denosumab treatment, stopping
results in accelerated bone loss.
In addition, rebound fractures
after discontinuation have re-
cently been reported (69, 70).
Some experts believe that recipi-
ents of denosumab should not
have a drug holiday and recom-
mend initiation of an alternative
medication after discontinuation.
ACP (52) recommends that
women with osteoporosis be
treated with pharmacologic ther-
apy (i.e., alendronate, risedronate,
zoledronic acid, or denosumab)
for 5 years (weak recommenda-
tion, low-quality evidence). This
In the Clinic
60. Adler RA, El-Hajj
Fuleihan G, Bauer DC,
et al. Managing osteopo-
rosis in patients on long-
term bisphosphonate
treatment: report of a
task force of the Ameri-
can Society for Bone and
Mineral Research. J Bone
Miner Res. 2016;31:16-
35. [PMID: 26350171]
61. Shane E, Burr D, Abra-
hamsen B, et al. Atypical
subtrochanteric and
diaphyseal femoral frac-
tures: second report of a
task force of the Ameri-
can Society for Bone and
Mineral Research. J Bone
Miner Res. 2014;29:1-
23. [PMID: 23712442]
62. Black DM, Rosen CJ.
Clinical Practice. Post-
menopausal Osteoporo-
sis. N Engl J Med. 2016;
374:254-62. [PMID:
26789873]
63. Gedmintas L, Solomon
DH, Kim SC. Bisphospho-
nates and risk of subtro-
chanteric, femoral shaft,
and atypical femur frac-
ture: a systematic review
and meta-analysis. J
Bone Miner Res. 2013;
28:1729-37. [PMID:
23408697]
64. Dell RM, Adams AL,
Greene DF, et al. Inci-
dence of atypical non-
traumatic diaphyseal
fractures of the femur. J
Bone Miner Res. 2012;
27:2544-50. [PMID:
22836783]
65. Ott SM. Long-term bis-
phosphonates: primum
non nocere. Menopause.
2016;23:1159-1161.
[PMID: 27676636]
66. Black DM, Schwartz AV,
Ensrud KE, et al; FLEX
Research Group. Effects
of continuing or stop-
ping alendronate after 5
years of treatment: the
Fracture Intervention
Trial Long-term Extension
(FLEX): a randomized
trial. JAMA. 2006;296:
2927-38. [PMID:
17190893]
67. Bauer DC, Schwartz A,
Palermo L, et al. Fracture
prediction after discon-
tinuation of 4 to 5 years
of alendronate therapy:
the FLEX study. JAMA
Intern Med. 2014;174:
1126-34. [PMID:
24798675]
68. Black DM, Reid IR,
Boonen S, et al. The
effect of 3 versus 6 years
of zoledronic acid treat-
ment of osteoporosis: a
randomized extension to
the HORIZON-Pivotal
Fracture Trial (PFT). J
Bone Miner Res. 2012;
27:243-54. [PMID:
22161728]
ITC29 2017 American College of Physicians
 recommendation is based on the
treatment duration of up to 5 years
in randomized trials. ACP also ac-
knowledges that continuing treat-
ment after 5 years may benet
some patients.
Prescribing oral bisphospho-
nates for 5 years (or intravenous
bisphosphonates for 3 years)
should be effective in preventing
fractures and minimizing poten-
tial harms of long-term exposure.
This strategy should also result in
a decline in initiation of bisphos-
phonates in younger postmeno-
pausal women and an increase in
bisphosphonate initiation among
older women who have a higher
absolute fracture risk (71). It is
increasingly important that clini-
cians counsel patients with osteo-
porosis to alleviate fears about
taking these medications for
5 years, because the reduction in
risk for disabling fractures out-
weighs the risk for short-term po-
tential harms of treatment, and
the potential risks for long-term
harms of treatment are avoided
with this strategy.
When should consultation be
considered?
Referral to an osteoporosis spe-
cialist should be considered if
there is uncertainty regarding
whether a patient will benet from
pharmacotherapy for fracture pre-
vention, when to resume medica-
tion after a drug holiday, or which
medication should be used after a
drug holiday. Consultation may
also be warranted in patients with
intolerance to standard drug treat-
ments or those in whom treatment
failure is suspected. Consultation
with orthopedic or physical medi-
cine and rehabilitation specialists
is often required for management
of patients presenting with an
acute fracture.

Treatment for Fracture Prevention... Reducing risk for clinical fractures

is the primary goal of treatment. Among postmenopausal women with os-
teoporosis, treatment with alendronate, risedronate, zoledronic acid, or
denosumab reduces risk for clinical fractures and new radiographic verte-
bral fractures. Bisphosphonates lower risk for new radiographic vertebral
fractures in osteoporotic men. Treatment with zoledronic acid decreases
risk for clinical fractures among patients with recent hip fracture. Calcium
and vitamin D supplementation at prudent doses should be recom-
mended in older adults with inadequate dietary intake. Evidence does not
support routine use of serial BMD or BTM measurements after initiation of
drug treatment to monitor response or adherence with therapy. A treat-
ment period of 5 years with oral bisphosphonates (3 years for intravenous
bisphosphonates) is a reasonable strategy for many patients. Patients with
69. Anastasilakis AD, Yavro-
osteoporosis should be counseled not to be fearful of receiving bisphos-
poulou MP, Makras P, phonates for 35 years, because the reduction in risk for disabling fractures
et al. Increased osteoclas- outweighs the risk for short-term harms of treatment, and the potential
togenesis in patients
with vertebral fractures
risks for long-term harms of treatment are avoided with this approach.
following discontinuation
of denosumab treat-
ment. Eur J Endocrinol.
2017;176:677-683. CLINICAL BOTTOM LINE
[PMID: 28283537]
70. Aubry-Rozier B, Gonzalez-
Rodriguez E, Stoll D,
Lamy O. Severe sponta-
neous vertebral fractures
after denosumab discon-
tinuation: three case
Practice Improvement
reports. Osteoporos Int. What measures do U.S. years: osteoporosis testing and
2016;27:1923-5. [PMID:
26510845] stakeholders use to evaluate osteoporosis management in
71. Lee DR, Ettinger B, Chan-
dra M, Hui RL, Lo JC. quality of care? women who had a fracture.
Changing Patterns in
Oral Bisphosphonate The Healthcare Effectiveness Data In 2015 (6), the proportion of
Initiation in Women
between 2004 and 2012
and Information Set includes 2 women aged 65 85 years who
[Letter]. J Am Geriatr Soc. measures in the domain of osteo- had ever undergone BMD mea-
2017;65:656-658.
[PMID: 28152162] porosis in women aged 65 85 surement for osteoporosis was

2017 American College of Physicians ITC30 Annals of Internal Medicine 1 August 2017

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 73.8% for HMOs and 79.3% for
PPOs. Among women aged
65 85 years who had had a frac-
ture, the proportion of women in
the 6 months after the fracture
who either had BMD measure-
ment or received a prescription
for drug treatment to prevent
fracture was 40.7% for HMOs and
32.8% for PPOs. Management of
patients after fracture is problem-
atic and must be addressed by a
In the Clinic
Tool Kit
Osteoporosis
1 August 2017 Annals of Internal Medicine
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concerted effort of health care
systems, primary care physicians,
specialists, and patients.
A recent survey (58) of postmenopausal
women who had had osteoporotic fractures re-
ported that 93% had contact with their primary
care physician during the 6 months after frac-
ture; 73% indicated that their primary care
physician knew about the fracture, but 63%
and 55% reported that management of osteo-
porosis and fracture prevention, respectively,
were not discussed at these visits.
Clinical Guidelines
www.annals.org/aim/article/2625385/treatment-low
-bone-density-osteoporosis-prevent-fractures-men
-women-clinical
Recent guideline from the American College of Physicians
on treatment of low bone density or osteoporosis to
prevent fractures.
www.annals.org/aim/article/746858/screening
-osteoporosis-u-s-preventive-services-task-force
IntheClinic
-recommendation-statement
www.uspreventiveservicestaskforce.org/Page
/Document/UpdateSummaryFinal/osteoporosis
-screening
2011 U.S. Preventive Services Task Force guidelines on
screening for osteoporosis and recommendations for
screening in postmenopausal women.
www.aace.com/les/postmenopausal-guidelines.pdf
Clinical practice guideline for the diagnosis and treatment
of postmenopausal osteoporosis from the American
Association of Clinical Endocrinologists.
Patient Information
www.niams.nih.gov/health_info/bone/osteoporosis
/osteoporosis_hoh.asp
Patient handout from the National Institutes of Health.
www.acog.org/Patients/FAQs/Osteoporosis
Information from the American College of Obstetrics and
Gynecology.
www.mayoclinic.org/diseases-conditions/osteoporosis
/manage/ptc-20207963
Self-management information from the Mayo Clinic.
www.nof.org/patients/
Information from the National Osteoporosis Foundation.
www.medlineplus.gov/osteoporosis.html
Information from Medline Plus.
ITC31 2017 American College of Physicians
 WHAT YOU SHOULD KNOW In the Clinic
Annals of Internal Medicine
ABOUT OSTEOPOROSIS
What Is Osteoporosis?
Osteoporosis is a disease that reduces the density
of bones, which can cause them to weaken.
Weak bones can easily break. These breaks,
sometimes called fractures, can be painful and
may make it hard to take care of yourself. The
risk for osteoporosis increases with age.

Who Should Be Screened?

All women aged 65 years or older.
Women younger than 65 years may need
screening if they have certain risk factors,
including low weight, smoking cigarettes, and
history of bone fractures. Talk to your doctor
about other risks you may have.

How Is It Diagnosed? Avoid drinking heavily.

Your doctor can check for bone loss using a
test called a DXA scan. This test takes pictures
of your bones.
If your DXA results are below a certain
number, your doctor may diagnose you with
osteoporosis and you may need treatment.
How Is It Treated?
There are medicines for osteoporosis called
bisphosphonates that help prevent fractures.
They are usually taken for at least 5 years.
After 5 years, you may have another DXA scan
and your treatment may change.
Don't smoke.
Exercise regularly.
Eat foods with calcium and vitamin D. These
include dairy, tofu, leafy greens, and fatty sh
like salmon.
Questions for My Doctor
How do I know if I am at risk for osteoporosis?
Should I take calcium or vitamin D
supplements?
I was diagnosed with osteoporosis. Can I still
do the things I like to do?
Should I make changes to my diet?
What can I do to prevent falls?
What side effects does the medicine have?

Patient Information
How Can It Be Prevented? How much will the medicine cost?
Keep a healthy body weight. Will my osteoporosis ever go away?
Eat enough protein. What happens if I stop taking the medicine?

For More Information

National Osteoporosis Foundation
www.nof.org
American College of physicians
www.acponline.org/patient_ed/rheumatology
Medline Plus
www.nlm.nih.gov/medlineplus/osteoporosis.html

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