O s t e o p o ro s i s D i a g n o s i s a n d

M e d i c a l Tre a t m e n t
Amy H. Warriner, MDa,*, Kenneth G. Saag, MD, MScb

KEYWORDS
 Osteoporosis  Treatment  Prevention  Diagnosis  Update

KEY POINTS
 Osteoporosis can be diagnosed by measurement of bone mineral density or based on the history of
a nontraumatic fracture.
 Osteoporosis treatment should be considered in all people with an increased risk of future fracture.
Use of fracture risk assessment tools can assist in determining patients who would benefit from
treatment.
 There are several therapies available for the treatment and prevention of osteoporosis. The optimal
treatment option for each patient should be determined after weighing the benefits and potential
risks associated with these medications.
 Further information is needed to assist clinicians in determining the duration of osteoporosis treat-
ment and the potential role of an interrupted treatment regimen.

INTRODUCTION DEFINITION OF OSTEOPOROSIS

Hip fractures and vertebral fractures are 2 of the Osteoporosis can be defined clinically by either:
most common fracture sites related to osteopo-
1. Low bone mineral density (BMD) (T-score of
rosis, and affect nearly 1 million persons in the
 2.5)
United States annually.1 Moreover, nearly one-
2. A history of fragility fracture
quarter of patients who endure a hip fracture die
within a year of the fracture. An even larger propor- BMD is measured by a central dual-energy x-ray
tion requires either extensive physical rehabilitation absorptiometry (DXA) scan. BMD is presented
or a stay in a nursing home facility. In addition to the as gram per centimeter squared, then translated
morbidity and mortality patients may experience into T-scores for postmenopausal women and
after an osteoporotic fracture, there are significant men older than 50 years. Alternatively, Z-scores
health care costs associated with fractures. The are used for premenopausal women and younger
estimated cost of osteoporosis-related fractures men. T-scores and Z-scores represent the patients
in 2005 was $19 billion, but this is estimated to BMD in relation to a 30-year-old normal reference
increase to more than $25 billion per year in the and an age-matched reference, respectively, and
next 2 decades.1,2 However, many of these frac- the difference is presented as a standard deviation
tures could be prevented if osteoporosis and frac- from the normal BMD. The World Health Organi-
ture risk were assessed before a fracture and zation (WHO) defines osteoporosis as a T-score
appropriate measures taken. of 2.5 and lower; osteopenia (or low bone density)
orthopedic.theclinics.com

Disclosures: [A.W.] Research: Amylin; [K.G.S.] Research and/or consulting: Amgen, Eli Lilly, Merck, Novartis.
a
Division of Endocrinology, Metabolism and Diabetes, University of Alabama at Birmingham, 2000 6th
Avenue South, FOT 702, Birmingham, AL 35233, USA; b Division of Clinical Immunology and Rheumatology,
University of Alabama at Birmingham, 2000 6th Avenue South, FOT 702, Birmingham, AL 35233, USA
* Corresponding author.
E-mail address: [email protected]

Orthop Clin N Am 44 (2013) 125135

http://dx.doi.org/10.1016/j.ocl.2013.01.005
0030-5898/13/$ see front matter 2013 Elsevier Inc. All rights reserved.
126 Warriner & Saag

as a T-score between 1.0 and 2.5; and normal age alone, men who are 70 years or older should
bone density as a T-score of 1.0 and higher. In undergo screening. In addition, men aged 50 to
a younger population, Z-scores of 2.0 and lower 69 should also undergo DXA evaluation if addi-
reflect low BMD and any Z-score higher than 2.0 tional risk factors for osteoporosis are present
is normal. (Table 1). Based on the DXA findings, men with
Based on the WHO definition, osteoporosis can T-scores in the osteoporosis range or men with
also be diagnosed based on a prior osteoporotic low BMD and other clinical risk factors for fracture
fracture. Other ways of describing an osteoporotic should be initiated on an osteoporosis prescription
fracture include fractures that would not have typi- medication.
cally occurred in a normal individual, or a fragility It is estimated that 30% to 60% of osteoporosis
fracture. Fragility fracture is frequently described within men is secondary to another underlying con-
as a fracture occurring as the result of minimal dition.6 The most frequent secondary causes are
trauma or a fall from standing height or less. All of glucocorticoid use or hypercortisolism (ie, Cushing
these definitions are subjective and leave room syndrome or disease), excessive alcohol use, hypo-
for clinical judgment. A history of hip or vertebral gonadism, vitamin D deficiency/low calcium intake,
fracture is sufficient for a diagnosis of osteoporosis smoking, and family history of fracture. Other sec-
and recommendation for treatment regardless of ondary causes combined account for approximately
BMD,1 but most other prior fractures also convey 15% of cases. In up to 40% of cases in men no
an increased risk of future fracture.3 However, frac- secondary cause is identified, and the osteoporosis
tures in adults are commonly managed without is considered either primary or idiopathic osteopo-
consideration of future risk. Thus, the American rosis.6 Secondary causes (see Table 1) for osteopo-
Orthopaedic Association launched the Own the rosis and fracture should be assessed clinically (by
Bone program in 2009 in an effort to increase the history and physical examination) in all patients,
awareness of fragility fractures as a teachable and with laboratory evaluation when clinical suspi-
moment. The intent of the program is recognition cion is high. Treatment of secondary causes of oste-
of patients who have an initial fracture and to ensure oporosis is recommended. However, if a patients
that they have proper evaluation for osteoporosis risk of fracture is high, pharmacologic osteoporosis
and treatment where appropriate. treatment should be initiated as well. In lower-risk
There is intentional movement away from the
T-scores alone, which measure relative fracture
risk, toward absolute fracture risk. The WHO devel-
Table 1
oped a fracture risk assessment tool called FRAX,4 Secondary causes of osteoporosis
which allows for the addition of clinical information
to BMD (or body mass index, if BMD is not avail- Men and Hyperparathyroidism
able). FRAX integrates clinical risk factors, such women Untreated thyroid disease
as glucocorticoid use, smoking, alcohol use, family Chronic lung disease
history of fracture, and prior fracture, into the deter- Chronic glucocorticoid use (>3 mo)
mination of 10-year absolute fracture risk. These Alcohol abuse (>3 alcoholic
estimates of fracture risk can then be used to assist beverages daily)
in determining treatment needed in patients with Smoking tobacco use
Vitamin D insufficiency
less clear indications or to discuss potential treat-
Low calcium intake
ment benefits with patients. A similar but more Immobilization
patient-friendly tool called the Garvin Institute Frac- Anorexia nervosa
ture Risk Calculator can be downloaded at http:// Diabetes mellitus (types 1 and 2)
garvan.org.au/promotions/bone-fracture-risk/ Adrenal insufficiency
calculator/index.php. Malabsorptive gastrointestinal
disease (celiac, inflammatory
bowel disease, gastric bypass, etc)
OSTEOPOROSIS IN MEN Rheumatoid arthritis
In contrast to most diseases for which there is Systemic lupus erythematosus
Ankylosing spondylitis
a relative abundance of data and emphasis on
mens health, the opposite is true for osteoporosis. Men Hypogonadism
Gonadotropin-releasing hormone
In 2012, the Endocrine Society published clinical
agonist treatment
guidelines for the treatment of osteoporosis in
men.5 Based on these guidelines, it is now recom- Women Ovarian failure
Amenorrhea (hypogonadotropic
mended that all men at risk of osteoporosis or frac-
hypogonadism)
ture obtain a DXA scan for screening. Based on
 Osteoporosis Diagnosis and Medical Treatment 127

patients treatment of the secondary cause may be Direction of fall is an important predictor of hip
sufficient, but they should be monitored for future fracture,22 lending support to the use of hip
bone loss and fracture risk. protectors. Hip protectors significantly reduce
the force to the hip during a fall.23 A meta-
RISK OF FUTURE FRACTURE analysis showed a slight reduction in the risk of
Prior Fracture hip fracture among nursing home or residential
care patients randomized to a hip protector (rela-
Low-energy trauma fractures have historically
tive risk [RR] 0.77, 95% confidence interval [CI]
been linked to osteoporosis, in part because of
0.620.97) but no significant benefit among
the increased risk of ensuing low-energy fractures.
community dwellers was found (RR 1.16, 95% CI
In one study, an increased risk of subsequent frac-
0.851.59). The differences may be explained by
ture was observed following any fragility fracture,
poor long-term adherence in both patient groups,
with only 2 exceptions: rib fractures in men and
and should be interpreted cautiously because of
ankle fractures in women.7 In a more recent study
cluster randomization.24 Another trial randomized
nearly all fragility fractures were significantly asso-
individual nursing home residents to a one-sided
ciated with future fracture among postmenopausal
hip protector and, despite good adherence, found
women.3 In this study, ankle fractures were associ-
no reduction in hip fractures in the unprotected
ated with an increased risk of future fracture of
versus protected hip.25 Despite these inconsistent
weight-bearing bones and rib fractures were asso-
results, hip protectors may still be a safe and
ciated with a risk of future vertebral fracture. Of
reasonable option.
note, the associations between incident hip and
vertebral fracture following prior hip and vertebral
Calcium and vitamin D
fractures, respectively, were significantly elevated
Randomized trials comparing calcium therapy
(hazard ratio [HR] of 7.3 and 3.5, respectively).
alone versus placebo have shown no consistent
In addition to findings that most fracture types
benefit in the reduction of vertebral and nonverte-
increase the risk of future fracture, there is also
bral fractures.2629 These findings may be partially
evidence that even fractures associated with high-
confounded by nonadherence with treatment,
energy trauma pose a risk for future fracture.8,9
because other trials have shown that when adher-
Several studies have shown that BMD is similar in
ence of 80% or better is achieved, calcium has
those who have had prior fractures, regardless of
been shown to reduce the risk of fracture (HR
the presence or absence of high-energy trauma.
0.66, 95% CI 0.450.97).27
In several studies, individuals with fractures were
Most available studies of calcium are completed
3 times more likely to have osteoporosis at 1 or
in combination with vitamin D supplementation.
more sites regardless of the degree of trauma at
Although there is evidence that calcium and vitamin
the time of fracture.1012 It has also been shown
D reduce the risk of fracture, the benefit has not
that a relationship exists between high-trauma frac-
been seen in all populations.3038 The type and
tures and either low BMD or structural changes in
amount of vitamin D supplementation likely play
bone in both women and men, comparable with
a role in the reduction of fracture risk.37
the relationship seen in those who have had low-
Evidence associating vitamin D intake with frac-
energy trauma fractures.9,10,13 These findings all
ture reduction exists. In a meta-analysis, oral
suggest that any prior fracture as an adult (after
vitamin D supplementation of any dose led to
age 50 years), regardless of the degree of trauma,
a 7% to 10% reduction of fracture risk in older
may merit evaluation for underlying fragility and
people (HR for any nonvertebral fracture 0.93,
may be associated with an increased risk of future
95% CI, 0.870.99; HR for hip fracture 0.90, 95%
fracture.
CI 0.801.01).39 However, in those subjects who
took the highest vitamin D doses (median of
FRACTURE PREVENTION
800 IU/d), the reduction of fracture risk was greater
Nonpharmacologic Treatment Options
(HR for any nonvertebral fracture 0.70, 95% CI
Approximately 90% of hip fractures are caused 0.580.86; HR for hip fracture 0.86, 95% CI
by falls.14 Several modifiable factors that may 0.760.96). These data underscore the importance
mitigate the risk of a fall include a home-safety of the dose when recommending vitamin D
assessment, alcohol cessation, vision evaluation, supplementation.
medication review (specifically psychoactive In addition to its role in fracture reduction, vitamin
medications), and assessment of orthostatic blood D insufficiency has been found to be associated
pressure. Studies of community dwellers have with risk of a fall40 and supplementation has been
shown a significant reduction of falls and fractures found to reduce the risk of falls, likely through
following exercise intervention.1521 improved musculoskeletal function.4143 Two
128 Warriner & Saag

randomized clinical trials confirmed that vitamin D (Table 2).52 These new recommendations state
supplementation (cholecalciferol 700 IU daily) that women 51 years and older and men 71 years
reduced the risk of a fall in elderly persons.44,45 and older should aim to consume 1200 mg of
The effect was shown even in persons with calcium daily, whereas a daily intake of 1000 mg
adequate 25-hydroxyvitamin D (25(OH)D) levels at is recommended for women 19 to 50 and men 19
the start of the study,44,45 and was found to be to 70 years of age. For vitamin D, the recommended
more prominent in the less active women studied.44 daily intake is 600 IU daily for children and adults,
The US Preventive Services Task Force has recently but rises to a recommended dose of 800 IU daily
published recommendations for fall prevention in for men and women 71 years and older.
older, community-dwelling adults, which include Shortly after the recommendations from the
vitamin D supplementation along with exercise for Institute of Medicine were published, the Endo-
fall prevention.46 crine Society published recommendations for
Vitamin D is important in bone health because vitamin D dosing provided by an expert committee
of its ability to counterregulate parathyroid hor- (see Table 2)53. In these latter recommendations,
mone (PTH), a promoter of bone loss, and its the recommended daily intake of vitamin D was
ability to stimulate intestinal and renal calcium much higher (15002000 IU daily for men and
absorption. In the setting of vitamin D deficiency, women) than that proposed by the Institute of
PTH levels typically increase, resulting in sec- Medicine.
ondary hyperparathyroidism. A concern has been raised regarding a potential
The optimal level of serum 25(OH)D remains association between calcium and vitamin D
unclear, as do the optimal doses of vitamin D for supplementation and cardiovascular risk.5457 In
replacement and maintenance. Most agree that a secondary analysis of a prospective, placebo-
vitamin D deficiency can be defined as a 25(OH)D controlled study of calcium supplementation in
level of less than 20 ng/mL.47 Because a 25(OH)D postmenopausal women, an association between
level of less than 30 ng/mL is sometimes associ- calcium supplements and myocardial infarction
ated with PTH elevation, a serum 25(OH)D level of and composite cardiovascular disease was seen,
30 ng/mL has been recommended by some.48,49 but was attenuated after the addition of unre-
Vitamin D intoxication, leading to hypercalcemia, ported cardiovascular events found in the national
generally does not occur until 25(OH)D levels reach hospital admission database.57 Thereafter, meta-
150 ng/mL or higher, except in patients with analyses also found an association between
primary hyperparathyroidism.47,50,51 calcium supplements alone and increased cardio-
Because of the multiple confounders regarding vascular risk,56 and this was further supported by
the absolute benefit of calcium, it is recommended the update of this meta-analysis that included
that persons take calcium and vitamin D supple- calcium with or without concurrent vitamin D.55
ments for general bone health but that these By contrast, another meta-analysis refuted these
supplements should not be used alone for the findings and found no clear association between
reduction of fracture risk. The Institute of Medicine cardiovascular disease and calcium supplementa-
published recommendations for calcium and tion.54 Similarly, in a recent report no association
vitamin D usage in 2011 based on age and gender was found between cardiovascular disease and

Table 2
Recommendations from the Institute of Medicine and the Endocrine Society for daily intake of calcium
and vitamin D in men and women

Institute of Medicine52 Endocrine Society72

Age (y) Recommended Daily Allowance Upper Daily Limit Daily Requirement Upper Daily Limit
Calcium (mg)
1950 1000 2500
5170 1000 (men) 2000
1200 (women)
>70 1200 2000
Vitamin D (IU)
1970 600 4000 15002000 10000
>70 800 4000 15002000 10000
 Osteoporosis Diagnosis and Medical Treatment 129

calcium supplementation in women enrolled in the The armamentarium for osteoporosis manage-
Nurses Health Study, including women taking ment is growing. At present, treatment options
higher daily doses of calcium (>1000 mg of can be divided into antiresorptive medications
calcium daily).58 and anabolic medications (Table 3).
Based on these findings, it is appropriate to
assess each patients daily calcium consumption. Bisphosphonates
If a patient is consuming fewer than 3 servings of Bisphosphonates are the most commonly pre-
calcium-rich foods or beverages daily (ie, milk, scribed antiosteoporosis medications. These agents
yogurt, cheese, calcium-fortified orange juice, and inhibit osteoclast function, thereby reducing bone
so forth), calcium supplementation should be resorption. The bisphosphonates are available
considered. Goal daily calcium intake should be as either oral preparations or intravenous infu-
between 1000 and 1500 mg per day, divided. sions. Under ideal conditions orally administered
Care should be taken to avoid oversupplementation bisphosphonates have a very low estimated absorp-
because of the risk of nephrolithiasis and, poten- tion of 1% of the administered dose. Following
tially, cardiovascular disease. Unlike calcium, absorption, the bisphosphonate is integrated into
vitamin D is more difficult to obtain from common hydroxyapatite.
foods and beverages. Patients older than 70 years Alendronate (Fosamax) and risedronate (Actonel)
are also less likely to obtain adequate vitamin D were among the first bisphosphonates approved
through sun exposure. Therefore, supplementation for the treatment and prevention of osteoporosis
is typically required. The recommended daily intake in postmenopausal women, and were approved
of vitamin D is a minimum of 800 IU daily, but many for the treatment of male osteoporosis thereafter.
patients require 1000 to 2000 IU daily to maintain Both can be taken either daily or weekly (see
stores of vitamin D. Table 3). Risedronate can also be taken in a once-
monthly preparation or as a delayed-release weekly
Pharmacologic Treatment Options preparation that can be taken with food and other
medications (Atelvia). Ibandronate (Boniva) is
The initial question most clinicians have is: who
approved for oral use daily or once monthly, or intra-
should be treated? The second question is deter-
venously every 3 months. The main side effect re-
mining which treatment to begin. The National
ported with the use of oral bisphosphonates is
Osteoporosis Foundation has created some guide-
gastrointestinal intolerance. Oral bisphosphonates
lines to assist with the first question (Box 1), which
have significant reduction of efficacy if not dosed
rely on data obtained through imaging (DXA) and/or
appropriately, owing to its limited absorption (taken
clinical risk factors for fracture. As such, a DXA is
on empty stomach with only water and no further
not essential in determining the need for treatment.
oral intake for at least 3060 minutes, except for
Consequently, in a patient with a recent hip, verte-
Atelvia).
bral, or other weight-bearing osteoporotic fracture,
Zoledronic acid (Reclast) is the newest bi-
treatment should be initiated without the need for
sphosphonate available, and is a once-yearly
BMD measurement, if no other contraindications
intravenous option. In addition to initial trials
exist. Treatment also should be initiated in a patient
completed in postmenopausal women, zoledronic
without a prior fracture but who has other strong
acid has also been found to be effective in the
clinical risk factors for fracture.
prevention of recurrent fractures (over a median
follow-up of 1.9 years) based on a large study of
patients who received this medication within
Box 1
Indications for osteoporosis prescription
90 days of a hip fracture.59 This study also demon-
therapy strated a 28% reduction of mortality risk with the
use of this agent compared with placebo, although
Hip or vertebral fracture the potential mechanism for this benefit was
Osteoporosis based on BMD (T-score  2.5) unclear. The main side effect noted following zole-
after appropriate evaluation for secondary dronic acid infusions is an acute-phase reaction,
causes consisting of flu-like symptoms and fever. The
Low bone density by BMD (T-score of 1.0 to occurrence of this side effect is reduced in
2.5) and risk based on the FRAX algorithm patients who have had prior exposure to other bi-
(10-year probability of a major osteoporosis- sphosphonates, and can also be reduced by
related fracture of 20% or 10-year probability pretreatment with acetaminophen.
of a hip fracture of 3%) All 4 of the bisphosphonates approved in the
Clinical judgment based on overall fracture risk United States have been studied in large,
randomized controlled trials in postmenopausal
 130
Warriner & Saag
Table 3
Prescription osteoporosis prevention and treatment options approved by the Food and Drug Administration, and estimates of associated reduction in
fracture risk

Recommended Use for Osteoporosis Effect on Fracture Risk

Treatment Treatment
Prevention in Women in Men Vertebral Nonvertebral Hip Dosing
Antiresorptive Agents
Bisphosponates
Alendronate (Fosamax)73,74 O O O O O O 70 mg oral weekly
Ibandronate (Boniva)75,76 O O O 150 mg oral monthly
3 mg IV every 3 mo
Risedronate (Actonel, O O O O O O 35 mg oral weekly (Actonel, Atelvia)
Atelvia)77,78 75 mg oral 2 consecutive days each month
(Actonel only)
150 mg oral monthly (Actonel only)
Zolendronic acid (Reclast)64,79 O O O O O O 5 mg IV yearly
Denosumab (Prolia)80,81 O O O O O 60 mg SQ every 6 mo
Calcitonin (Miacalcin, O O 200 IU intranasally daily
Fortical)82,83
Raloxifene (Evista)84,85 O O O 60 mg oral daily
Anabolic Agent
Teriparatide (Forteo)86,87 O O O O 20 mg SQ daily

Abbreviations: IV, intravenous; SQ, subcutaneous.

 Osteoporosis Diagnosis and Medical Treatment 131

women, and have shown efficacy in reducing Risks Associated with Antiresorptive
fracture occurrence and improving BMD, Treatments
although they vary in the relative reduction of
Concerns about long-term risks have been raised
fractures (see Table 3). The initial phase III clin-
with all antiresorptive medications, namely subtro-
ical trial of alendronate for the treatment of post-
chanteric femur fractures and osteonecrosis of
menopausal osteoporosis showed significantly
the jaw. These concerns have led to further discus-
greater gain in BMD at all sites and a 48% reduc-
sions on the long-term safety and recommended
tion in new vertebral fractures when compared
duration of use. Although many clinicians are rec-
with placebo.60 In a separate study, nonvertebral
ommending drug holidays for postmenopausal
fracture rates were reduced by 47% in postmen-
osteoporosis treatment, there has been no justifica-
opausal women with low bone density treated
tion for this recommendation through randomized
with alendronate compared with women treated
trials. Overall, the absolute risk of subtrochanteric
with placebo.61 Risedronate was evaluated in
femur fractures and osteonecrosis of the jaw is
a higher-risk population of postmenopausal
very small and a clear causative effect has not
women with osteoporosis and at least 1 preva-
been found, although accumulating evidence from
lent vertebral fracture.62 Similar to alendronate,
observational studies clearly suggests a strong
BMD increased significantly at all sites. In addi-
association.
tion, new vertebral fracture risk was reduced by
Two commentaries on the duration of use of bi-
65% and nonvertebral fracture risk was reduced
sphosphonates were published in 2012. In the
by 39% in this higher-risk population. Ibandro-
findings from the Food and Drug Administration
nate was evaluated in both a daily dose and an
(FDA) Advisory Committee for Reproductive
intermittent dose (20 mg every other day for
Health Drugs and the Drug Safety and Risk
12 doses every 3 months) in postmenopausal
Management Committees review, continuation
women, and was found to increase spine and
of a bisphosphonate should be determined based
hip BMD and also to lead to a vertebral reduction
on a patients risk of fracture and the prior duration
in fracture risk of 62% for daily dosing and 50%
of treatment.66 The committee relied on 3 long-
for intermittent dosing.63 Zoledronic acid as an
term treatment studies of the bisphosphonates
annual intravenous infusion in postmenopausal
alendronate, risedronate, and zoledronic acid
women was evaluated in comparison with
that reported fracture rates in postmenopausal
placebo.64 In this study, morphometric vertebral
women. Based on post hoc analyses of these
fractures were reduced by 70%, clinical vertebral
studies, it was determined that fracture rates
fractures were reduced by 77%, hip fractures
between women continued on bisphosphonates
were reduced by 41%, and nonvertebral frac-
and those who stopped bisphosphonates were
tures were reduced by 15% in the treatment
relatively similar. Thus, the committee recom-
group.
mends that clinicians consider stopping bi-
sphosphonate treatment after 3 to 5 years in
Denosumab women at lower risk of fracture (no prior fracture,
Denosumab is a fully human monoclonal antibody BMD near normal) and continue treatment in
that inhibits receptor activator of nuclear factor kB women at higher risk of fracture (older women
ligand (RANKL), which is important in the differen- with a history of a fracture and BMD in the osteo-
tiation and activation of osteoclasts. Through this porotic range). There currently are no recommen-
action, denosumab inhibits bone resorption simi- dations for when to consider restarting treatment
larly to bisphosphonates but through a different if it is stopped or if there is a finite duration for
mechanism. Denosumab was approved for use the use of these medications.
in the treatment of osteoporosis in June 2010. Black and colleagues67 reanalyzed the original
Unlike bisphosphonates that require integration alendronate and zoledronic acid extension studies
into the bone matrix and can be found within the and determined the numbers needed to treat to
bone matrix years after administration, denosu- prevent future fracture. Based on this information,
mab concentrations peak in the first 1 to 3 weeks the investigators reached similar conclusions to
after administration and then decline over 4 to those of the FDA but emphasized that these
5 months, and are near nadir levels at the end of recommendations were for alendronate and zole-
its dosing interval (6 months). Concurrently, levels dronic acid only, because long-term data on risedr-
of bone turnover markers decrease quickly after onate and ibandronate were not assessed or
the administration of denosumab and then begin available. Their recommendations were to consider
rising toward pretreatment levels at the end of stopping previously prescribed bisphosphonates
the dosing interval.65 in women with T-scores better than 2.0 and no
132 Warriner & Saag

prior fracture, as their risk for future vertebral frac- calcium and vitamin D supplementation as well
ture is relatively low. Conversely, women with as precautions regarding the risk of falls, are
a history of a fracture and a T-score of 2.5 or lower very important in the care of patients at risk of
should be continued on bisphosphonate treatment fracture. However, for patients with a heightened
and, although the data are slightly weaker, women fracture risk, prescription antiosteoporosis treat-
with a T-score of 2.0 to 2.5 and a prior fracture ment should be considered, several options for
should also continue treatment because of the which are available at present. Each treatment
relatively higher risk of future fracture in these indi- has associated benefits and potential risks, and
viduals. It is hoped that future studies will lend these should be weighed on an individual basis
further understanding of how women whose bi- with each patient. Further research is needed to
sphosphonate has been stopped should be assist clinicians in making decisions about long-
followed. term treatment of patients at risk. Until such ques-
tions are answered with longer-term studies,
Anabolic Treatment duration of use of antiresorptive treatments should
be determined based on each patients fracture
Teriparatide (Forteo), recombinant human PTH
risk; for many patients such treatment may be of
1-34, is the only anabolic treatment option for oste-
finite duration.
oporosis. Intermittent PTH exposure, rather than
constant exposure as in primary hyperparathy-
roidism, results in increased bone mass. The use REFERENCES
of teriparatide results in significant improvement
1. NOF fast facts. Available at: http://www.nof.org/
of BMD and reduction of vertebral and nonvertebral
node/40. Accessed August 27, 2012.
fracture risk. Teriparatide is administered through
2. Burge R, Dawson-Hughes B, Solomon DH, et al.
a daily subcutaneous injection. It is currently
Incidence and economic burden of osteoporosis-
approved for use for those at high risk of fracture
related fractures in the United States, 2005-2025.
and for glucocorticoid-induced osteoporosis.68
J Bone Miner Res 2007;22(3):46575.
Teriparatide should not be used in children or young
3. Gehlbach S, Saag KG, Adachi JD, et al. Previous
patients with open epiphyses, or in persons with
fractures at multiple sites increase the risk for subse-
Paget disease, cancerous bony lesions, a history
quent fractures: the Global Longitudinal Study of
of radiation to the bone, hypercalcemia, or a meta-
Osteoporosis in Women. J Bone Miner Res 2012;
bolic bone disease other than osteoporosis.68
27(3):64553.
Although osteosarcoma has been described in
4. Kanis JA, Johnell O, Oden A, et al. FRAX and the
rodents treated with teriparatide, no clear increase
assessment of fracture probability in men and
in the rate of cases has been reported in humans
women from the UK. Osteoporos Int 2008;19(4):
associated with this therapy.
38597.
5. Watts NB, Adler RA, Bilezikian JP, et al. Osteopo-
Other Prescription Treatments
rosis in men: an Endocrine Society clinical practice
Other available osteoporosis treatments include guideline. J Clin Endocrinol Metab 2012;97(6):
selective estrogen receptor modulators (SERMs) 180222.
(raloxifene [Evista]) and calcitonin (Fortical, Miacal- 6. Ebeling PR. Clinical practice. Osteoporosis in men.
cin). These agents have some benefit in the reduc- N Engl J Med 2008;358(14):147482.
tion of vertebral fracture risk, but no significant risk 7. Center JR, Bliuc D, Nguyen TV, et al. Risk of subse-
reduction at nonvertebral sites.69,70 quent fracture after low-trauma fracture in men and
women. JAMA 2007;297(4):38794.
SUMMARY 8. Cuddihy MT, Gabriel SE, Crowson CS, et al. Forearm
fractures as predictors of subsequent osteoporotic
Osteoporosis is a common disorder seen daily by fractures. Osteoporos Int 1999;9(6):46975.
many orthopedic surgeons. Current recommen- 9. Mackey DC, Lui LY, Cawthon PM, et al. High-trauma
dations from agencies and oversight bodies in fractures and low bone mineral density in older
the United States33,71,72 recommend that all women and men. JAMA 2007;298(20):23818.
women 65 years and older undergo screening 10. Sanders KM, Pasco JA, Ugoni AM, et al. The exclu-
for osteoporosis with a DXA scan. However, sion of high trauma fractures may underestimate the
a DXA is not required to make the diagnosis of prevalence of bone fragility fractures in the commu-
osteoporosis if the patient has a history of a non- nity: the Geelong Osteoporosis Study. J Bone Miner
traumatic fracture. The FRAX calculator tool can Res 1998;13(8):133742.
assist in determining an individuals 10-year abso- 11. Karlsson MK, Hasserius R, Obrant KJ. Individuals
lute fracture risk. Preventive measures, including who sustain nonosteoporotic fractures continue to
 Osteoporosis Diagnosis and Medical Treatment 133

also sustain fragility fractures. Calcif Tissue Int 1993; 27. Prince RL, Devine A, Dhaliwal SS, et al. Effects of
53(4):22931. calcium supplementation on clinical fracture and
12. Melton LJ 3rd, Atkinson EJ, OFallon WM, et al. bone structure: results of a 5-year, double-blind,
Long-term fracture prediction by bone mineral placebo-controlled trial in elderly women. Arch Intern
assessed at different skeletal sites. J Bone Miner Med 2006;166(8):86975.
Res 1993;8(10):122733. 28. Lyons RA, Johansen A, Brophy S, et al. Preventing
13. Hedlund R, Lindgren U. Trauma type, age, and fractures among older people living in institutional
gender as determinants of hip fracture. J Orthop care: a pragmatic randomised double blind placebo
Res 1987;5(2):2426. controlled trial of vitamin D supplementation. Osteo-
14. Marks R, Mason B, Horne A, et al. Hip fractures poros Int 2007;18(6):8118.
among the elderly: causes, consequences and 29. Grant AM, Avenell A, Campbell MK, et al. Oral
control. Ageing Res Rev 2003;2(1):5793. vitamin D3 and calcium for secondary prevention
15. Suzuki T, Kim H, Yoshida H, et al. Randomized of low-trauma fractures in elderly people (Rando-
controlled trial of exercise intervention for the preven- mised Evaluation of Calcium Or vitamin D,
tion of falls in community-dwelling elderly Japanese RECORD): a randomised placebo-controlled trial.
women. J Bone Miner Metab 2004;22(6):60211. Lancet 2005;365(9471):16218.
16. Stevens JA, Olson S. Reducing falls and resulting 30. Chapuy MC, Arlot ME, Duboeuf F, et al. Vitamin D3
hip fractures among older women. MMWR Recomm and calcium to prevent hip fractures in the elderly
Rep 2000;49(RR-2):312. women. N Engl J Med 1992;327(23):163742.
17. Kita K, Hujino K, Nasu T, et al. A simple protocol for 31. Dawson-Hughes B, Harris SS, Krall EA, et al. Effect
preventing falls and fractures in elderly individuals of calcium and vitamin D supplementation on bone
with musculoskeletal disease. Osteoporos Int 2007; density in men and women 65 years of age or older.
18(5):6119. N Engl J Med 1997;337(10):6706.
18. Walker M, Klentrou P, Chow R, et al. Longitudinal 32. Larsen ER, Mosekilde L, Foldspang A. Vitamin D
evaluation of supervised versus unsupervised exer- and calcium supplementation prevents osteopo-
cise programs for the treatment of osteoporosis. rotic fractures in elderly community dwelling
Eur J Appl Physiol 2000;83(45):34955. residents: a pragmatic population-based 3-year
19. Gregg EW, Cauley JA, Seeley DG, et al. Physical intervention study. J Bone Miner Res 2004;19(3):
activity and osteoporotic fracture risk in older 3708.
women. Study of Osteoporotic Fractures Research 33. U.S. Preventive Services Task Force. Screening for
Group. Ann Intern Med 1998;129(2):818. osteoporosis: U.S. preventive services task force
20. Fiatarone MA, ONeill EF, Ryan ND, et al. Exercise recommendation statement. Ann Intern Med 2011;
training and nutritional supplementation for physical 154(5):35664.
frailty in very elderly people. N Engl J Med 1994; 34. Papadimitropoulos E, Wells G, Shea B, et al. Meta-
330(25):176975. analyses of therapies for postmenopausal osteo-
21. Province MA, Hadley EC, Hornbrook MC, et al. The porosis. VIII: meta-analysis of the efficacy of
effects of exercise on falls in elderly patients. A pre- vitamin D treatment in preventing osteoporosis in
planned meta-analysis of the FICSIT trials. Frailty postmenopausal women. Endocr Rev 2002;23(4):
and Injuries: Cooperative Studies of Intervention 5609.
Techniques. JAMA 1995;273(17):13417. 35. Lips P, Graafmans WC, Ooms ME, et al. Vitamin D
22. Greenspan SL, Myers ER, Kiel DP, et al. Fall direc- supplementation and fracture incidence in elderly
tion, bone mineral density, and function: risk factors persons. A randomized, placebo-controlled clinical
for hip fracture in frail nursing home elderly. Am J trial. Ann Intern Med 1996;124(4):4006.
Med 1998;104(6):53945. 36. Heikinheimo RJ, Inkovaara JA, Harju EJ, et al.
23. Laing AC, Robinovitch SN. Effect of soft shell hip Annual injection of vitamin D and fractures of aged
protectors on pressure distribution to the hip during bones. Calcif Tissue Int 1992;51(2):10510.
sideways falls. Osteoporos Int 2008;19(7):106775. 37. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Frac-
24. Parker MJ, Gillespie WJ, Gillespie LD. Hip protec- ture prevention with vitamin D supplementation:
tors for preventing hip fractures in older people. a meta-analysis of randomized controlled trials.
Cochrane Database Syst Rev 2005;(3):CD001255. JAMA 2005;293(18):225764.
25. Kiel DP, Magaziner J, Zimmerman S, et al. Efficacy 38. Jackson RD, LaCroix AZ, Gass M, et al. Calcium
of a hip protector to prevent hip fracture in nursing plus vitamin D supplementation and the risk of frac-
home residents: the HIP PRO randomized controlled tures. N Engl J Med 2006;354(7):66983.
trial. JAMA 2007;298(4):41322. 39. Bischoff-Ferrari HA, Willett WC, Orav EJ, et al.
26. Reid IR, Mason B, Horne A, et al. Randomized A pooled analysis of vitamin D dose requirements
controlled trial of calcium in healthy older women. for fracture prevention. N Engl J Med 2012;367(1):
Am J Med 2006;119(9):77785. 409.
134 Warriner & Saag

40. Flicker L, Mead K, MacInnis RJ, et al. Serum vitamin prospective studies and randomized clinical trials.
D and falls in older women in residential care in Am J Cardiovasc Drugs 2012;12(2):10516.
Australia. J Am Geriatr Soc 2003;51(11):15338. 55. Bolland MJ, Grey A, Avenell A, et al. Calcium
41. Bischoff HA, Stahelin HB, Dick W, et al. Effects of supplements with or without vitamin D and risk of
vitamin D and calcium supplementation on falls: cardiovascular events: reanalysis of the Womens
a randomized controlled trial. J Bone Miner Res Health Initiative limited access dataset and meta-
2003;18(2):34351. analysis. BMJ 2011;342:d2040.
42. Harwood RH, Sahota O, Gaynor K, et al. 56. Bolland MJ, Avenell A, Baron JA, et al. Effect of
A randomised, controlled comparison of different calcium supplements on risk of myocardial infarction
calcium and vitamin D supplementation regimens and cardiovascular events: meta-analysis. BMJ
in elderly women after hip fracture: the Nottingham 2010;341:c3691.
Neck of Femur (NONOF) Study. Age Ageing 2004; 57. Bolland MJ, Barber PA, Doughty RN, et al. Vascular
33(1):4551. events in healthy older women receiving calcium
43. Broe KE, Chen TC, Weinberg J, et al. A higher dose supplementation: randomised controlled trial. BMJ
of vitamin D reduces the risk of falls in nursing home 2008;336(7638):2626.
residents: a randomized, multiple-dose study. J Am 58. Paik J, Curhan G, Rexrode K, et al. A prospective
Geriatr Soc 2007;55(2):2349. study of calcium supplement intake and risk of
44. Bischoff-Ferrari HA, Orav EJ, Dawson-Hughes B. cardiovascular disease in women. American Society
Effect of cholecalciferol plus calcium on falling in for Bone and Mineral Research annual meeting.
ambulatory older men and women: a 3-year random- Abstract 1135. Minneapolis (MN), October 1215,
ized controlled trial. Arch Intern Med 2006;166(4): 2012.
42430. 59. Lyles KW, Colon-Emeric CS, Magaziner JS, et al.
45. Flicker L, MacInnis RJ, Stein MS, et al. Should older Zoledronic acid and clinical fractures and mortality
people in residential care receive vitamin D to after hip fracture. N Engl J Med 2007;357(18):
prevent falls? Results of a randomized trial. J Am 1799809.
Geriatr Soc 2005;53(11):18818. 60. Liberman UA, Weiss SR, Broll J, et al. Effect of oral
46. Moyer VA. Prevention of falls in community-dwelling alendronate on bone mineral density and the
older adults: U.S. Preventive Services Task Force incidence of fractures in postmenopausal osteopo-
Recommendation Statement. Ann Intern Med 2012; rosis. The Alendronate Phase III Osteoporosis Treat-
157(3):197204. ment Study Group. N Engl J Med 1995;333(22):
47. Holick MF. Vitamin D deficiency. N Engl J Med 2007; 143743.
357(3):26681. 61. Pols HA, Felsenberg D, Hanley DA, et al. Multina-
48. Chapuy MC, Preziosi P, Maamer M, et al. Prevalence tional, placebo-controlled, randomized trial of the
of vitamin D insufficiency in an adult normal popula- effects of alendronate on bone density and fracture
tion. Osteoporos Int 1997;7(5):43943. risk in postmenopausal women with low bone mass:
49. Holick MF, Siris ES, Binkley N, et al. Prevalence of results of the FOSIT study. Fosamax International
Vitamin D inadequacy among postmenopausal North Trial Study Group. Osteoporos Int 1999;9(5):4618.
American women receiving osteoporosis therapy. 62. Harris ST, Watts NB, Genant HK, et al. Effects of
J Clin Endocrinol Metab 2005;90(6):321524. risedronate treatment on vertebral and nonvertebral
50. Gertner JM, Domenech M. 25-Hydroxyvitamin D fractures in women with postmenopausal osteopo-
levels in patients treated with high-dosage ergo- rosis: a randomized controlled trial. Vertebral Effi-
and cholecalciferol. J Clin Pathol 1977;30(2):14450. cacy With Risedronate Therapy (VERT) Study
51. Vieth R. Vitamin D supplementation, 25-hydroxyvita- Group. JAMA 1999;282(14):134452.
min D concentrations, and safety. Am J Clin Nutr 63. Delmas PD, Recker RR, Chesnut CH, et al. Daily and
1999;69(5):84256. intermittent oral ibandronate normalize bone turn-
52. Ross AC, Manson JE, Abrams SA, et al. The 2011 over and provide significant reduction in vertebral
report on dietary reference intakes for calcium and fracture risk: results from the BONE study. Osteo-
vitamin D from the Institute of Medicine: what clini- poros Int 2004;15(10):7928.
cians need to know. J Clin Endocrinol Metab 2011; 64. Black DM, Delmas PD, Eastell R, et al. Once-
96(1):538. yearly zoledronic acid for treatment of postmeno-
53. Holick MF, Binkley NC, Bischoff-Ferrari HA, et al. pausal osteoporosis. N Engl J Med 2007;356(18):
Evaluation, treatment, and prevention of vitamin D 180922.
deficiency: an Endocrine Society clinical practice 65. Bekker PJ, Holloway DL, Rasmussen AS, et al.
guideline. J Clin Endocrinol Metab 2011;96(7): A single-dose placebo-controlled study of AMG
191130. 162, a fully human monoclonal antibody to RANKL,
54. Wang L, Manson JE, Sesso HD. Calcium intake and in postmenopausal women. 2004. J Bone Miner
risk of cardiovascular disease: a review of Res 2005;20(12):227582.
 Osteoporosis Diagnosis and Medical Treatment 135

66. Whitaker M, Guo J, Kehoe T, et al. Bisphosphonates 77. Risedronate Package Insert. Available at: http://www.
for osteoporosiswhere do we go from here? actonel.com/global/prescribing_information.pdf.
N Engl J Med 2012;366(22):204851. Accessed August 27, 2012.
67. Black DM, Bauer DC, Schwartz AV, et al. Continuing 78. Wells G, Cranney A, Peterson J, et al. Risedronate
bisphosphonate treatment for osteoporosisfor for the primary and secondary prevention of osteo-
whom and for how long? N Engl J Med 2012; porotic fractures in postmenopausal women. Co-
366(22):20513. chrane Database Syst Rev 2008;(1):CD004523.
68. Deal C, Gideon J. Recombinant human PTH 1-34 (For- 79. Reclast package insert. Available at: http://www.
teo): an anabolic drug for osteoporosis. Cleve Clin J pharma.us.novartis.com/product/pi/pdf/reclast.pdf.
Med 2003;70(7):5856, 58990, 5924. passim. Accessed August 27, 2012.
69. Miacalcin Nasal spray [package insert]. East 80. Prolia package insert. Available at: http://pi.amgen.com/
Hanover (NJ): Novartis Pharmaceuticals Corpora- united_states/prolia/prolia_pi.pdf. Accessed August 27,
tion. 2003. 2012.
70. Evista (raloxifene) [package insert]. Indianapolis (IN): 81. Cummings SR, San Martin J, McClung MR, et al.
Eli Lilly and Company. 2007. Denosumab for prevention of fractures in postmeno-
71. Bone health and osteoporosis: a report of the Surgeon pausal women with osteoporosis. N Engl J Med
General. 2004. Available at: http://www.surgeongeneral. 2009;361(8):75665.
gov/library/reports/bonehealth/chapter_8.html#Step1 82. Miacalcin package insert. Available at: http://www.
IdentifyAtRiskIndividualsWhoRequireFurtherEvaluation. pharma.us.novartis.com/product/pi/pdf/miacalcin_
Accessed February 22, 2011. nasal.pdf. Accessed August 27, 2012.
72. Clinicians guide to prevention and treatment of 83. Overgaard K, Hansen MA, Jensen SB, et al. Effect of
osteoporosis. 2010. Available at: http://www.nof. salcatonin given intranasally on bone mass and frac-
org/files/nof/public/content/file/344/upload/159.pdf. ture rates in established osteoporosis: a dose-
Accessed December 4, 2012 response study. BMJ 1992;305(6853):55661.
73. Alendronate package insert. Available at: http:// 84. Evista package insert. Available at: http://pi.lilly.com/
www.merck.com/product/usa/pi_circulars/f/fosamax/ us/evista-pi.pdf. Accessed August 27, 2012.
fosamax_pi.pdf. Accessed August 27, 2012. 85. Ettinger B, Black DM, Mitlak BH, et al. Reduction of
74. Wells GA, Cranney A, Peterson J, et al. Alendronate vertebral fracture risk in postmenopausal women
for the primary and secondary prevention of osteo- with osteoporosistreated with raloxifene: results
porotic fractures in postmenopausal women. from a 3-year randomized clinical trial. Multiple
Cochrane Database Syst Rev 2008;(1):CD001155. Outcomes of Raloxifene Evaluation (MORE) Investi-
75. Ibandronate package insert. Available at: http://www. gators. JAMA 1999;282(7):63745.
accessdata.fda.gov/drugsatfda_docs/label/2005/ 86. Forteo package insert. Available at: http://pi.lilly.
021455s001lbl.pdf. Accessed August 27, 2012. com/us/forteo-pi.pdf. Accessed August 27, 2012.
76. Chesnut IC, Skag A, Christiansen C, et al. Effects of 87. Neer RM, Arnaud CD, Zanchetta JR, et al. Effect of
oral ibandronate administered daily or intermittently parathyroid hormone (1-34) on fractures and bone
on fracture risk in postmenopausal osteoporosis. mineral density in postmenopausal women with
J Bone Miner Res 2004;19(8):12419. osteoporosis. N Engl J Med 2001;344(19):143441.