Jcem 1802

S P E C I A L F E A T U R E
C l i n i c a l P r a c t i c e G u i d e l i n e
Osteoporosis in Men: An Endocrine Society Clinical

Practice Guideline
Nelson B. Watts, Robert A. Adler, John P. Bilezikian, Matthew T. Drake,

Richard Eastell, Eric S. Orwoll, and Joel S. Finkelstein
Mercy Health Osteoporosis & Bone Health Services (N.B.W.), Cincinnati Ohio 45236; McGuire Veterans
Affairs Medical Center and Virginia Commonwealth University School of Medicine (R.A.A.), Richmond,
Virginia 23298; Columbia University College of Physicians and Surgeons (J.P.B.), New York, New York
10032; College of Medicine, Mayo Clinic (M.T.D.), Rochester, Minnesota 55905; Medical School at the
Downloaded from https://academic.oup.com/jcem/article/97/6/1802/2536476 by guest on 20 May 2024

University of Sheffield (R.E.), Sheffield S10 2RX, United Kingdom; Oregon Health & Sciences University
(E.S.O.), Portland, Oregon 97239; and Massachusetts General Hospital, Harvard Medical School (J.S.F.),
Boston, Massachusetts 02114
Objective: The aim was to formulate practice guidelines for management of osteoporosis in men.
Evidence: We used the Grading of Recommendations, Assessment, Development, and Evaluation

(GRADE) system to describe the strength of recommendations and evidence quality.
Consensus Process: Consensus was guided by systematic evidence reviews, one in-person meeting,
and multiple conference calls and e-mails. Task Force drafts were reviewed successively by The
Endocrine Society’s Clinical Guidelines Subcommittee and Clinical Affairs Core Committee; repre-
sentatives of ASBMR, ECTS, ESE, ISCD; and members at large. At each stage, the Task Force received
written comments and incorporated needed changes. The reviewed document was approved by
The Endocrine Society Council before submission for peer review.
Conclusions: Osteoporosis in men causes significant morbidity and mortality. We recommend

testing higher risk men [aged ⱖ70 and men aged 50 – 69 who have risk factors (e.g. low body
weight, prior fracture as an adult, smoking, etc.)] using central dual-energy x-ray absorptiometry.
Laboratory testing should be done to detect contributing causes. Adequate calcium and vitamin
D and weight-bearing exercise should be encouraged; smoking and excessive alcohol should
be avoided. Pharmacological treatment is recommended for men aged 50 or older who have
had spine or hip fractures, those with T-scores of ⫺2.5 or below, and men at high risk of fracture
based on low bone mineral density and/or clinical risk factors. Treatment should be monitored
with serial dual-energy x-ray absorptiometry testing. (J Clin Endocrinol Metab 97: 1802–1822,
2012)
Summary of Recommendations sons for testing men aged 50 – 69 include diseases/conditions

such as delayed puberty, hypogonadism, hyperparathyroid-
1.0. Evaluation ism, hyperthyroidism, or chronic obstructive pulmonary dis-
1.1. We suggest testing men at increased risk for os- ease; drugs such as glucocorticoids or GnRH agonists; life
teoporosis by measurement of bone mineral density choices such as alcohol abuse or smoking; or other causes
(BMD). Age 70 is a sufficient risk factor. Younger men of secondary osteoporosis. FRAX, Garvan, or other
(aged 50 – 69) should be tested if additional risk factors fracture risk calculators can improve the assessment of
are present. A history of fracture after age 50 is a par- fracture risk and the selection of patients for treatment.
ticularly important indication for evaluation. Other rea- (2|QQEE)
ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: ADT, Androgen-deprivation therapy; b-ALP, bone alkaline phosphatase;
Printed in U.S.A. BMD, bone mineral density; BMI, body mass index; BTM, bone turnover marker; CI, con-
Copyright © 2012 by The Endocrine Society fidence interval; CTX, C-telopeptide of type I collagen; DXA, dual-energy x-ray absorpti-
doi: 10.1210/jc.2011-3045 Received November 7, 2011. Accepted March 27, 2012. ometry; NTX, N-telopeptide of type I collagen; 25(OH)D, 25-hydroxyvitamin D; PINP, pro-
collagen I N-propeptide; VFA, vertebral fracture assessment.
1802 jcem.endojournals.org J Clin Endocrinol Metab, June 2012, 97(6):1802–1822

J Clin Endocrinol Metab, June 2012, 97(6):1802–1822 jcem.endojournals.org 1803
1.2. We recommend dual-energy x-ray absorptiometry tation to achieve blood 25(OH)D levels of at least 30 ng/ml
(DXA) of the spine and hip in men at risk for osteoporosis. (75 nmol/liter). (2|QQQE)
(1|QQEE) 2.3. We suggest that men at risk of osteoporosis par-
1.3. We suggest measuring forearm DXA (1/3 or 33% ticipate in weight-bearing activities for 30 – 40 min per
radius) when spine or hip BMD cannot be interpreted and session, three to four sessions per week. (2|QEEE)
for men with hyperparathyroidism or receiving androgen- 2.4. We suggest that men at risk of osteoporosis who
deprivation therapy (ADT) for prostate cancer. (2|QQEE) consume three or more units of alcohol per day reduce
1.4. We suggest a complete history and physical exam- their alcohol intake. (2|QEEE)
ination for men being evaluated for osteoporosis or con- 2.5. We recommend that men at risk of osteoporosis
sidered for pharmacological treatment (e.g. those with low who smoke cease smoking. (1|QQEE)
BMD and/or high fracture risk). Important information
includes medications used, chronic diseases, alcohol or 3.0. Treatment

tobacco abuse, falls and/or fractures as an adult, and fam- 3.1. Selection of men for treatment
ily history of osteoporosis. Physical examination should
assess patient height in comparison with maximum height, All men
kyphosis, balance, mobility, overall frailty, and evidence 3.1. We recommend pharmacological therapy for men
of causes of secondary osteoporosis, including testicular at high risk for fracture including, but not limited to:
atrophy, signs of hyperthyroidism, and evidence of • Men who have had a hip or vertebral fracture without
chronic obstructive pulmonary disease. Men for whom major trauma. (1|QQQE)
bisphosphonate therapy is considered should have an ex- • Men who have not experienced a spine or hip fracture
amination of the teeth. (2|QQEE) but whose BMD of the spine, femoral neck, and/or total
1.4.1. We suggest measuring serum calcium, phos- hip is 2.5 SD or more below the mean of normal young
phate, creatinine (with estimated glomerular filtration white males. (1|QQEE)
rate), alkaline phosphatase, liver function, 25-hydroxyvi- • In the United States, men who have a T-score between
tamin D [25(OH)D], total testosterone, complete blood ⫺1.0 and ⫺2.5 in the spine, femoral neck, or total hip
count, and 24-h urinary calcium (creatinine and sodium) plus a 10-yr risk of experiencing any fracture ⱖ 20% or
excretion in men being evaluated for osteoporosis or con- 10-yr risk of hip fracture ⱖ 3% using FRAX; further
sidered for pharmacological treatment with bone-active studies will be needed to determine appropriate inter-
agents. (2|QQEE) vention levels using other fracture risk assessment al-
1.4.2. If history or physical examination suggest a spe- gorithms. For men outside the US, region-specific
cific cause of osteoporosis, further testing should be done. guidelines should be consulted. (1|QQEE)
Depending on the findings of the history and physical ex- • Men who are receiving long-term glucocorticoid ther-
amination, such testing may include (but is not limited to) apy in pharmacological doses (e.g. prednisone or equiv-
calculated free or bioavailable testosterone (using mea- alent ⬎7.5 mg/d), according to the 2010 guidelines of
surements of SHBG), serum protein electrophoresis with the American Society of Rheumatology. (1|QQEE).
free ␬ and ␭ light chains and/or urine protein electropho-
resis, tissue transglutaminase antibodies (for celiac dis- 3.2. Selection of therapeutic agent
ease), thyroid function tests, and PTH levels. (2|QQEE) 3.2. We recommend that men at high risk of fracture be
1.4.3. In men with low bone mass (osteopenia) or os- treated with medication approved by regulatory agencies
teoporosis who might have previously undiagnosed ver- such as the U.S. Food and Drug Administration (FDA) or
tebral fractures, we recommend vertebral fracture assess- the European Union (EU) European Medicines Agency
ment (VFA) using DXA equipment. If VFA is not available (EMA) (at the time of this writing, alendronate, risedro-
or is technically limited, lateral spine radiographs should nate, zoledronic acid, and teriparatide; also denosumab
be considered. (1|QQEE) for men receiving ADT for prostate cancer) and that the
selection of therapeutic agent be individualized based on
2.0. Lifestyle factors including fracture history, severity of osteoporosis
2.1. We recommend that men with or at risk for osteo- (T-scores), the risk for hip fracture, patterns of BMD [i.e.
porosis consume 1000 –1200 mg calcium daily, ideally whether BMD is worse at sites where cortical bone (e.g.
from dietary sources, with calcium supplements added if 1/3 radius) or trabecular bone (e.g. spine) predominate],
dietary calcium is insufficient. (1|QQQE) comorbid conditions (e.g. peptic ulcer disease, gastro-
2.2. We suggest that men with low vitamin D levels esophageal reflux, malabsorption syndromes, malig-
[⬍30 ng/ml (75 nmol/liter)] receive vitamin D supplemen- nancy, etc.), cost, and other factors. In men with a recent
1804 Watts et al. Guidelines on Treatment of Osteoporosis in Men J Clin Endocrinol Metab, June 2012, 97(6):1802–1822
hip fracture, we suggest treatment with zoledronic acid. marker [such as serum procollagen I N-propeptide
When teriparatide is administered, we suggest that it not (PINP)] for anabolic therapy. (2|QQQE)
be given with concomitant antiresorptive therapy. Agents
that have not been approved by regulatory agencies for
treatment of osteoporosis in men (calcitonin, ibandronate, Method of Development of
strontium ranelate, etc.) should be used only if the ap- Evidence-Based Clinical Practice
proved agents for male osteoporosis cannot be adminis- Guidelines
tered. (1|QQEE)
The Clinical Guidelines Subcommittee of The Endocrine
Management of hypogonadal men at high risk of Society deemed the subject of osteoporosis in men a pri-
fracture ority and appointed this Task Force to formulate evidence-
based recommendations. Consensus was guided by sys-
3.3. For men at high risk of fracture who are receiving

tematic reviews of evidence and discussions through a
testosterone therapy, we suggest adding an agent with
series of conference calls, e-mails, and one in-person meet-
proven antifracture efficacy (e.g. a bisphosphonate or
ing. An initial draft was prepared by the chair of the Task
teriparatide). (2|QEEE)
Force and was reviewed successively by The Endocrine
3.4. We suggest testosterone therapy in lieu of a “bone
Society’s Clinical Guidelines Subcommittee and Clinical
drug” for men at borderline high risk for fracture who
Affairs Core Committee; representatives of the American
have serum testosterone levels below 200 ng/dl (6.9 nmol/
Society for Bone and Mineral Research (ASBMR), Euro-
liter) on more than one determination, if accompanied by
pean Calcified Tissue Society (ECTS), European Society of
signs or symptoms of androgen deficiency (e.g. low libido,
Endocrinology (ESE), and International Society for Clin-
unexplained chronic fatigue, loss of body hair, hot flushes,
ical Densitometry (ISCD); and members at large. At each
etc.) or “organic” hypogonadism (e.g. due to hypotha-
stage, the Task Force received written comments and in-
lamic, pituitary, or specific testicular disorder). If testos- corporated needed changes. The reviewed document was
terone treatment does not alleviate symptoms of androgen approved by The Endocrine Society Council before sub-
deficiency after 3– 6 months, it should be discontinued and mission for peer review.
other therapy considered. (2|QQEE) Evidence was rated using the Grading of Recommen-
3.5. We suggest testosterone therapy for men at high dations, Assessment, Development, and Evaluation
risk for fracture with testosterone levels below 200 (GRADE) system. The GRADE group has expertise in
ng/dl (6.9 nmol/liter) who lack standard indications for development and implementation of evidence-based
testosterone therapy but who have contraindications guidelines (1); a detailed description has been published
to approved pharmacological agents for osteoporosis. elsewhere (2). The Task Force used the best available
(2|QQEE) evidence and two commissioned systematic reviews and
meta-analyses (3, 4). The Task Force also used consis-
Men with prostate cancer receiving ADT tent language and graphical descriptions of the strength
3.6. We recommend pharmacological treatment for os- of a recommendation and the quality of evidence.
teoporosis for men with prostate cancer receiving ADT Strong recommendations use the phrase “we recom-
who have a high risk of fracture (see Section 3.1). mend” and the number 1; weak recommendations use
(1|QQQE) the phrase “we suggest” and the number 2. Cross-filled
circles indicate the quality of the evidence: QEEE de-
4.0. Monitoring therapy notes very low quality; QQEE, low quality; QQQE,
4.1. We suggest that clinicians monitor BMD by moderate quality; and QQQQ, high quality. The Task
DXA at the spine and hip every 1–2 yr to assess the Force has confidence that persons who receive care ac-
response to treatment. If BMD appears to reach a pla- cording to strong recommendations will derive, on av-
teau, the frequency of BMD measurements may be erage, more good than harm. Weak recommendations
reduced. (2|QQQE) require more careful consideration of the person’s cir-
4.2. We suggest that clinicians consider measuring a cumstances, values, and preferences to determine the
bone turnover marker (BTM) at 3– 6 months after ini- best course of action. Linked to each recommendation
tiation of treatment using a bone resorption marker is a description of the evidence and the values that pan-
[such as serum C-telopeptide of type I collagen (CTX) elists considered; in some instances, there are remarks,
or serum or urine N-telopeptide of type I collagen a section in which panelists offer technical suggestions
(NTX)] for antiresorptive therapy and a bone formation for testing conditions, dosing, and monitoring. These
comments reflect the best available evidence applied to men than in women. Of the 3.5 million fractures in men
most men being treated. Often this evidence comes from worldwide in 2000, 14% were at the hip, 10% at the
the unsystematic observations of the panelists and their forearm, 16% at the vertebrae, 5% at the humerus, and
values and preferences; therefore, these remarks should 55% elsewhere (16).
be considered suggestions. The incidence of fractures due to osteoporosis varies
The Endocrine Society maintains a rigorous conflict of with race/ethnicity and geography. The highest rates in
interest review process for the development of clinical men are in Northern Europe and North America (17, 18).
practice guidelines. All Task Force members must declare Lowest rates are in blacks and Asians (17, 18) as well as in
any potential conflicts of interest, which are reviewed be- some parts of South America (19, 20). The ratio of hip
fore they are approved to serve on the Task Force and fractures between women and men also varies by geogra-
periodically during the development of the guideline. The phy. Although the female-to-male ratio among Cauca-
conflict of interest forms are vetted by the Clinical Guide- sians is about 3– 4:1, the ratio is much closer to 1:1 or even

lines Subcommittee (CGS) before the members are ap- higher in Asia (18, 21, 22).
proved by the Society’s Council to participate on the Before puberty, BMD measured with DXA is similar in
guideline Task Force. Participants in the guideline devel- boys and girls and increases slowly but progressively. At
opment must include a majority of individuals without puberty, bone turnover increases dramatically, followed
conflict of interest in the matter under study. Participants by a rapid increase in BMD (23). Androgens increase peri-
with conflicts of interest may participate in the develop- osteal bone apposition, increasing the cross-sectional di-
ment of the guideline but they have disclosed all conflicts. ameter of bone (24). Because BMD measured by DXA is
The CGS and the Task Force have reviewed all disclosures directly related to bone size, part of the apparent pubertal
for this guideline and resolved or managed all identified BMD increase is due to a projection artifact from increas-
conflicts of interest. ing bone size. Peak spine BMD as measured by DXA is
Conflicts of interest are defined by remuneration in any generally reached by age 18 in males. Peak trabecular vol-
amount from the commercial interest(s) in the form of umetric BMD as measured by quantitative computed to-
grants; research support; consulting fees; salary; owner- mography, and peak BMD of the hip, as measured by
ship interest (e.g., stocks, stock options, or ownership in- DXA, are reached several years later (25). As men and
terest excluding diversified mutual funds); honoraria or women age, bone resorption exceeds formation, leading to
other payments for participation in speakers’ bureaus, ad- bone loss (26 –30). BMD may begin to decline in men as
visory boards, or boards of directors; or other financial early as age 30 to 40, decreasing slowly (about 0.5–1.0%
benefits. Completed forms are available through The En- annually), without the acceleration that is seen in women
docrine Society office. at menopause. In elderly men, however, degenerative
Funding for this guideline was derived solely from The change often increases DXA-measured BMD in the spine.
Endocrine Society and thus the Task Force received no fund-
ing or remuneration from commercial or other entities. Bone quality
Microarchitectural deterioration with advancing age is
Epidemiology and pathophysiology an important feature of osteoporosis (31). Because of dif-
Osteoporosis is a silent disorder characterized by references in bone remodeling with age, trabeculae become
duced bone strength predisposing to increased fracture thinner in men, whereas in women, trabeculae lose their
risk (5). Although osteoporosis affects women more often connectivity (32).
than men, approximately 20% of the 44 million Ameri-
cans who have osteoporosis or low BMD are men (6). Sex steroids
Between 30 and 40% of fractures due to osteoporosis oc- There are many studies on the roles of gonadal ste-
cur in men; the lifetime risk of fracture for men aged 50 or roids in bone development and adult bone homeostasis,
older is between 13 and 30% (7). but there are also many unanswered questions. Fully
Men with hip fractures have a mortality rate two to androgenized men are believed to benefit from anabolic
three times higher than women (8, 9, 202). Fractures in properties of endogenous androgens with regard to
childhood and teenage years are more common in males, bone mass and bone geometry (33). However, it is clear
probably due to differences in lifestyle and trauma; most that estrogen is at least as important in men, particularly
are at peripheral sites (10 –15). Past middle age, frac- for skeletal accrual (34). Men with inactivating muta-
tures due to osteoporosis are more common in women. tions of the aromatase or estrogen receptor genes (35)
In later years, fracture risk rises exponentially in both have markedly reduced bone mass despite normal or
sexes, but the increase occurs about a decade later in increased levels of testosterone (34 –37). Whereas tes-
TABLE 1. Summary of risk factors for fractures in males (4)

95% CI
Risk factor No. of studies OR LL UL P value I2a
Age
Age (continuous variable)b 11 1.12 1.07 1.18 0.00 87
Age (every 5–10 yr)c 6 1.29 1.17 1.43 0.00 52
Age ⬎70d 5 1.52 1.11 2.08 0.01 69
Race (vs. White)
Black 3 0.69 0.57 0.85 0.00 91
Hispanic 2 1.05 0.62 1.78 0.84 60
BMI
BMI (all studies) 23 0.89 0.83 0.96 0.00 71
BMI (quintile or 1 SD increase) 18 0.77 0.68 0.87 0.00 62

BMI (1 kg/m2) 5 1.01 0.95 1.08 0.76 66
Alcohol (daily or ⬎10 drinks/week) 22 1.28 1.08 1.53 0.01 81
Smoking (current) 27 1.49 1.29 1.72 0.00 54
Chronic corticosteroid use (various definitions) 8 1.29 1.03 1.61 0.03 38
Prior fracture 9 2.08 1.57 2.77 0.00 75
Parental fractures
Fracture, father 2 1.18 0.70 1.98 0.54 NA
Fracture, mother 2 1.32 0.97 1.81 0.08 NA
Fracture, parents 1 1.30 1.00 1.69 0.05 NA
History of falls within the last year 7 2.11 1.44 3.10 0.00 83
Hypogonadism (all studies) 8 1.76 1.37 2.26 0.00 85
Hypogonadism (nonpharmacological) 4 2.77 1.30 5.87 0.01 51
Hypogonadism (drug-induced) 4 1.53 1.19 1.96 0.00 91
Kidney stones 2 0.53 0.35 0.80 0.00 NA
History of stroke 4 3.73 1.75 7.92 0.00 73
DM 8 1.57 1.14 2.15 0.01 77
Asthma 2 1.01 0.56 1.84 0.96 56
Cardiovascular disease (CHF/MI) 6 1.07 0.86 1.33 0.55 86
Dementia 2 2.84 0.93 8.64 0.07 97
Osteoarthritis 4 1.03 0.57 1.88 0.91 87
Rheumatoid arthritis 5 1.46 0.97 2.19 0.07 60
NA, Not applicable (I2 is not meaningful if the number of studies is less than three); CHF, congestive heart failure; DM, diabetes mellitus; LL, lower
limit; MI, myocardial infarction; OR, odds ratio; UL, upper limit.
a 2
I statistic is defined as the proportion of heterogeneity not attributable to chance or random error.
b
Age as a continuous variable reflects that the OR represents increases in odds per year of age.
c
OR (95% CI) for studies: 5 yr ⫽ 1.41 (1.12–1.78); 7.7 yr ⫽ 1.16 (1.03–1.31); 10 yr ⫽ 1.39 (1.15–1.67).
d
Age ⬎70 is compared vs. age ⱕ70 in studies with mean age of 40 – 80.
tosterone administration had no effect on bone turn- PTH levels increase with age (52–54), to a large extent
over in a man with an inactivating mutation in the es- due to declining kidney function and reduced synthesis of
trogen receptor ␣ gene, estrogen increased BMD in a 25(OH)D.
man with a null mutation of his aromatase gene (38). In Many factors may contribute to differences in the
older men, stronger associations have been reported be- incidence and prevalence of osteoporosis and fractures
tween blood levels of estradiol and BMD than between between men and women (24, 55, 56). Men’s larger
levels of testosterone and BMD, although the differ- bones contribute to greater bone strength (57). Risk
ences are small and the associations weak (27, 39 – 43). factors that may be more common in men include de-
Controlled physiological studies in which androgens, layed puberty (58) and hypercalciuria. Men fall less of-
estrogens, or both are selectively suppressed have demon- ten than women (59, 60); higher androgen levels have
strated that both androgens and estrogens are important reg- been associated with reduced fall risk (39). Finally, men
ulators of bone turnover in adult men (41, 44).
have a shorter life expectancy.
Hormonal abnormalities
1.0. Evaluation
25(OH)D levels are higher in men than in women at all
ages but decline with age in both sexes (45, 46) due to Recommendation
decreased sun exposure, skin production, and dietary in- 1.1. We suggest testing men at increased risk for osteo-
take (47–51). porosis by measurement of BMD. Age 70 is a sufficient
risk factor. Younger men (aged 50 – 69 yr) should be tested ture risk similarly (82). Femoral neck BMD identifies
if additional risk factors are present. A history of fracture fewer men than women who suffered a hip fracture (83).
after age 50 is a particularly important indication for eval- Using only hip BMD would identify a small proportion of
uation. Other reasons for testing men ages 50 – 69 include the men who will experience a fracture. Although spine
diseases/conditions such as delayed puberty, hypogonad- BMD is useful in younger men, a high frequency of arti-
ism, hyperparathyroidism, hyperthyroidism, or chronic facts and degenerative change reduce its utility in older
obstructive pulmonary disease; drugs such as glucocorti- men.
coids or GnRH agonists; life choices such as alcohol abuse DXA is helpful in choosing men for therapy because
or smoking; or other causes of secondary osteoporosis. men with DXA-proven osteoporosis or “osteopenia” plus
FRAX, Garvan, or other fracture risk calculators can im- a previous fracture respond to currently available therapy
prove the assessment of fracture risk and the selection of
(84 – 88).
patients for treatment. (2|QQEE)

1.2. Remarks
1.1. Evidence
Third-party payers, including Medicare, vary in their
In addition to low BMD, age is an independent risk
coverage of DXA testing in men. For example, Medicare
factor for osteoporosis and for fracture (61– 65). Table 1
covers initial DXA only in men who have vertebral frac-
lists other risk factors for low BMD or fractures in men
tures, radiographic osteopenia, hyperparathyroidism or
(27, 42, 66 –74). These were assessed in a systematic re-
view and meta-analysis (4). Most of the associations were are on oral glucocorticoid therapy (89).
weak (i.e. adjusted odds ratios were in general ⬍2), and
Recommendation
the level of evidence was low; therefore, the strength of this
recommendation is low. 1.3 We suggest measuring forearm DXA (1/3 or 33%
radius) when spine or hip BMD cannot be interpreted and
1.1. Remarks for men with hyperparathyroidism or receiving ADT for
The FRAX calculator (www.shef.ac.uk/FRAX/) and prostate cancer. (2|QQEE)
the Garvan nomogram (www.fractureriskcalculator.
com) are commonly-used algorithms for predicting 1.3. Evidence
fracture risk. Both use age, weight, history of fracture, Radius BMD predicts fractures in men (90, 91). BMD
and femoral neck BMD, although other variables differ measurement at skeletal sites where osteoarthritis is un-
(75, 76). In a validation study from Australia, FRAX common, such as the 1/3 (33%) radius, may be more sen-
underestimated fracture risk in men (77). A simple score sitive for detecting bone loss in elderly men (91, 92). A
using BMD, prior fracture, and corticosteroid use de- large study found osteoporosis (T-scores of ⫺2.5 or be-
veloped for Canadian women (78) has been applied to low) at the 1/3 radius in about 15% of men aged 70 or
men (79). Simple risk calculators such as the Osteopo- older who had T-scores better than ⫺2.5 in the spine and
rosis Self-Assessment Tool (OST) and Male Osteopo- hip (92). In the Geelong Study, mean spine BMD was
rosis Screening Tool (MOST) (80, 81) may be useful to about the same in men aged 20 – 85 yr; however, after age
identify men likely to have osteoporosis by DXA. Age 47, there was a considerable, progressive decrease in the
has been shown to be an important predictor of fracture midforearm BMD (93).
risk (63, 71, 74). Radius BMD declines to a greater extent than hip or
spine BMD in men with prostate cancer receiving ADT
Recommendation
(94 –96). Moreover, radius BMD measurements per-
1.2. We recommend DXA of the spine and hip in men
formed as well as spine or hip BMD for distinguishing
at risk for osteoporosis. (1|QQEE)
between effects of denosumab and placebo (97).
1.2. Evidence Because artifacts and localized degenerative change in
In men as in women, BMD correlates strongly with the spine and hip are common in men, particularly those
fracture risk (64). In a large study of men and women over older than 60 (98), radius BMD may provide a more re-
age 65, BMD (total hip and femoral neck) was strongly alistic measure of skeletal status. In some subjects, such as
associated with hip fracture risk, with a stronger associ- patients with hyperthyroidism or hyperparathyroidism,
ation in men (82). Spine BMD was also significantly as- T-scores for radius BMD are often lower than T-scores for
sociated with hip fracture risk, although less strongly than the spine or hip (99). The ISCD recommends only consid-
hip DXA. Spine and hip BMD predict nonvertebral frac- ering the T-score from the 1/3 (33%) radius site (100).
1.3. Remarks well established. Nevertheless, in men at increased risk

Medicare and other payers may not cover forearm of fracture, laboratory tests may be useful to determine
BMD testing (89). Although radius BMD predicts frac- factors that contribute to low BMD or fracture risk and
tures in men (91) and appears to be particularly important to design appropriate therapy. History and physical ex-
in men on ADT (94), there are no studies showing that men amination may provide important information. Osteo-
with osteoporosis in the radius and not at other sites re- malacia, usually due to severe vitamin D deficiency, is
spond to current treatments. common in men with hip fractures. Other causes of bone
loss, such as hyperparathyroidism, kidney and liver dis-
Recommendations ease, hypogonadism, and hypercalciuria, are sufficiently
1.4. We suggest a complete history and physical exam- common in high-risk men to warrant evaluation (101). A
ination for men being evaluated for osteoporosis or con- 24-h urine calcium measurement is useful to identify id-
sidered for pharmacological treatment (e.g. those with low iopathic hypercalciuria or calcium malabsorption. Hyper-

BMD and/or high fracture risk). Important information calciuria can be managed with thiazide diuretics (102).
includes medications used, chronic diseases, alcohol or Moderate vitamin D deficiency is common in men and is
tobacco abuse, falls and/or fractures as an adult, and fam- associated with low bone mass and increased fracture risk.
ily history of osteoporosis. Physical examination should Other laboratory tests may be appropriate, depending on
assess patient height in comparison with maximum height, the clinical context.
kyphosis, balance, mobility, overall frailty, and evidence VFA is a low-cost, low-risk method for detecting ver-
of causes of secondary osteoporosis, including testicular tebral fractures using standard DXA devices. The ISCD
atrophy, signs of hyperthyroidism, and evidence of recommends VFA for men over age 80 with osteopenia
chronic obstructive pulmonary disease. Men for whom or younger men with historical height loss greater than
bisphosphonate therapy is considered should have an ex- 6 cm (103). Additionally, younger men (aged 70 –79)
amination of the teeth. (2|QQEE) are candidates for VFA if they have a chronic disease
1.4.1. We suggest measuring serum calcium, phosphate, such as rheumatoid arthritis, Crohn’s disease, or
creatinine (with estimated glomerular filtration rate), alka- chronic obstructive pulmonary disease. Although VFA
line phosphatase, liver function, 25(OH)D, total testoster- detects many vertebral fractures, imaging quality may be
one, complete blood count, and 24-h urinary calcium (cre- limited, particularly in the midthoracic spine and higher,
atinine and sodium) excretion in men being evaluated for where radiographs may be needed. Still, VFA can provide
osteoporosis or considered for pharmacological treatment useful clinical information, particularly if there is clinical
with bone-active agents. (2|QQEE) suspicion of occult vertebral fractures.
1.4.2. If history or physical examination suggest a spe-
cific cause of osteoporosis, further testing should be done. 2.0. Lifestyle
Depending on the findings of the history and physical ex- Recommendation
amination, such testing may include (but is not limited to) 2.1. We recommend that men with or at risk for osteo-
calculated free or bioavailable testosterone (using mea- porosis consume 1000 –1200 mg calcium daily, ideally
surements of SHBG), serum protein electrophoresis with from dietary sources, with calcium supplements added if
free ␬ and ␭ light chains and/or urine protein electropho- dietary calcium is insufficient. (1|QQQE)
resis, tissue transglutaminase antibodies (for celiac dis-
ease), thyroid function tests, and PTH levels. (2|QQEE) 2.1. Evidence
1.4.3. In men with low bone mass (osteopenia) or os- Several studies have addressed the effects of calcium on
teoporosis who might have previously undiagnosed ver- BMD and fracture risk in men, with inconsistent findings.
tebral fractures, we recommend VFA using DXA equip- No benefit for BMD was observed from calcium/vitamin
ment. If VFA is not available or is technically limited, D supplementation in well-nourished men (mean dietary
lateral spine radiographs should be considered. (1|QQEE) calcium intake ⬎1000 mg/d) (104). However, an increase
in BMD was seen in healthy older men given calcium and
1.4. Evidence vitamin D supplements (105). Calcium- and vitamin D-
Potentially important information can come from the fortified milk increased BMD (106) and improved femoral
history and physical examination. An oral exam is im- bone structure in older men (107). Dietary calcium was
portant; clinicians should assess whether additional not related to fractures in men in the Health Professionals
dental evaluation or care may be needed before starting Follow-Up Study (108), but low dietary calcium intake
bisphosphonate therapy. The yield and cost-effective- was associated with higher fracture risk in a cohort of
ness of laboratory studies in men with low BMD are not Australian men (109). Calcium supplementation alone
has not been demonstrated to reduce fracture risk in men Serum 25(OH)D measurement is recommended in men
with prior fractures (110). In clinical trials of alendronate at high risk for vitamin D deficiency (120). This includes
(84), risedronate (86), and teriparatide (87) for osteopo- men with osteomalacia, osteoporosis, malabsorption (e.g.
rosis in men, calcium (500 –1000 mg/d) and vitamin D celiac disease, bariatric surgery, etc.), and liver disease, as
[400 –1200 IU/d (10 –30 ␮g/d)] supplementation was pro- well as older men with a history of falls and those taking
vided for all subjects. medications that alter vitamin D status, such as some an-
In women, calcium supplementation is more beneficial ticonvulsants (121).
in those with low calcium intake (111) and, together with International consensus is lacking on a reference range
vitamin D, reduces hip fracture risk in compliant subjects for 25(OH)D levels, partly due to assay variability. Many
(112). There are no similar studies in men. experts support a minimum desirable 25(OH)D level of 30
The Institute of Medicine (IOM) recommends a cal- ng/ml (75 nmol/liter) for bone health (122), although a
committee of the IOM concluded that 20 ng/ml (50 nmol/

cium intake of 1000 mg/d for men aged 51–70 and 1200
mg/d for men (and women) older than 70 (113). liter) was adequate for bone health (113); it should be
A meta-analysis showed that calcium supplements noted that the IOM recommendations are for healthy in-
may be associated with an increased risk of myocardial dividuals and may not be appropriate for patients with
infarction but no other cardiovascular end points or osteoporosis. For men at high risk of fracture, we are
death in women (114). This finding has not been con- recommending a target 25(OH)D level of 30 ng/ml, con-
sistent with The Endocrine Society 2011 Clinical Practice
firmed in men (115).
Guidelines on Evaluation, Treatment, and Prevention of
In older women, calcium supplementation increases the
Vitamin D Deficiency (123).
risk of kidney stones (112). The prevalence of kidney
For most people, optimal vitamin D levels can be
stones is higher in men than in women, but no increase in
achieved with 1000 –2000 IU (25–50 ␮g) of vitamin D
kidney stones has been demonstrated in men at the level of
daily. Larger doses [e.g. 50,000 IU (1.25 mg) orally weekly
calcium intake recommended for optimal bone health. An
for 8 wk or 300,000 IU (7.5 mg) by im injection every 3
observational study suggested that the risk of metastatic
months] may be required for patients with more severe
prostate cancer was higher in men who received high doses
vitamin D deficiency.
of supplemental calcium (1500 –2000 mg/d) (116), but
Vitamin D at high doses may result in toxicity (hyper-
this has not been substantiated in clinical trials (117).
calcemia or hypercalciuria), but this is rarely seen unless
25(OH)D levels exceed 150 ng/ml (375 nmol/liter) (121),
Recommendation
and such levels are unlikely with the doses of vitamin D
2.2. We suggest that men with low vitamin D levels
recommended here. In a recent report of high-dose vitamin
[⬍30 ng/ml (75 nmol/liter)] receive vitamin D supplemen-
D [500,000 IU (12.5 mg) orally once a year] given to
tation to achieve blood 25(OH)D levels of at least 30 ng/ml
women older than 70 yr, there was an increased risk of
(75 nmol/liter). (2|QQQE)
fracture and falling, especially in the first 3 months after
administration, when 25(OH)D levels were on average 50
2.2. Evidence
ng/ml (125 nmol/liter) (124). This finding needs to be con-
Vitamin D deficiency is common in older men (118) and
firmed in women and has not been documented in men,
has been associated with an increased risk of hip and non-
but it raises caution about giving high doses of vitamin D
vertebral fractures (119).
intermittently.
Severe vitamin D deficiency [25(OH)D levels ⱕ10
ng/ml (25 nmol/liter)] may lead to osteomalacia, which 2.2. Remarks
should be treated with calcium and vitamin D; treatment Measurement of serum 25(OH)D is challenging be-
results in symptomatic and biochemical improvement and cause assay variability is high and between-assay calibra-
sometimes large increases in BMD. This degree of vitamin tion is poor. Not unexpectedly, the intra- and interassay
D deficiency should be at least partially corrected before variability is much greater at lower 25(OH)D levels (125).
considering treatment for osteoporosis. Although mean serum 25(OH)D differs depending on the
Vitamin D status can be assessed by measuring serum assay method (RIA, chemiluminescence, or liquid chro-
25(OH)D. Because vitamin D is a threshold nutrient, the matography-tandem mass spectrometry), the relative
usual approach to defining normality in a “healthy” pop- ranking is similar between assays (125). The International
ulation is inappropriate. Insufficiency needs to be defined Vitamin D External Quality Assessment Scheme is an ef-
with reference to changes in calcium homeostasis, BMD, fort to harmonize 25(OH)D assays (126). Still, the latitude
or fracture risk. between “reference” and “toxic” levels is quite wide.
Recommendation 2.5. Evidence

2.3. We suggest that men at risk of osteoporosis par- A meta-analysis of more than 15,000 men suggested
ticipate in weight-bearing activities for 30 – 40 min per that the association of smoking with fracture risk was
session, three to four sessions per week. (2|QEEE) higher in men than in women (136). The relative hazard
for a current male smoker was 1.5 for all fractures (95%
2.3. Evidence CI, 1.3 to 1.8), 1.5 for osteoporosis-related fractures (95%
Low physical activity in older men is associated with CI, 1.3 to 1.8), and 1.8 for hip fractures (95% CI, 1.3 to
poor health (127). Studies of exercise interventions in men 2.5); the increase in risk was independent of age. The con-
tribution of low BMD to increased fracture risk was 40%.
and in postmenopausal women at risk for osteoporosis
BMD contributed more than BMI to the effect of smoking
have generally been of poor quality (128). However,
on fracture risk. As with alcohol, the mechanisms by
weight-bearing activities, such as walking 30 – 40 min for
which smoking may increase fracture risk have not been

three to four sessions per week, is a logical recommenda-
determined. The offset of effects in men is not known, but
tion (129), supported by small studies showing improve- in women, the benefits of stopping smoking on hip frac-
ment in BMD (130) and decreased fall risk (131). ture risk were not apparent until after 10 yr (137). This
observation is in keeping with the Framingham Study;
Recommendation men who were current smokers had greater bone loss from
2.4. We suggest that men at risk of osteoporosis who the proximal femur (but not spine or forearm) than former
consume three or more units of alcohol per day reduce smokers or men who never smoked (138).
their alcohol intake. (2|QEEE)
2.5. Values and preferences
2.4. Evidence Smoking is harmful to health, and smoking cessation
High alcohol intake is associated with increased bone reduces risk not only of fractures but also of other diseases.
loss, falling, and fractures in older men (132), although the Smoking cessation should be recommended as a general
mechanism is unclear. There may be a threshold effect health measure for current smokers. Panel members
(133–135), with no excess risk 2 U/d of alcohol [one unit placed higher value on preventing other smoking-related
of alcohol is defined as 10 ml in the United Kingdom and complications because data showing that smoking cessa-
tion reduces fracture risk are limited.
as 10 g (12.7 ml) in Australia—approximately half a pint
of beer, one small glass of wine, or a single measure of
2.5. Remarks
spirits]. The relative hazard for alcohol consumption of at Medical support may be required to assist with smok-
least 3 U/d was 1.33 for all fractures [95% confidence ing cessation (139).
interval (CI), 1.10 to 1.60] and 1.92 for hip fractures (95%
CI, 1.28 to 2.88), with no contribution from BMD, body 3.0. Treatment
mass index (BMI), or age. If the association with alcohol
3.1. Selection of men for treatment
intake is causal, then it accounts for approximately 7% of
hip fractures in men (133). The risk of fractures remains Recommendation
elevated even when alcohol consumption is reduced (134). All men
Self-reported alcohol intake may be underestimated, 3.1. We recommend pharmacological therapy for men
and the intakes in populations studied (Dutch, Canadian, at high risk for fracture including, but not limited to:
Australian) appeared lower than reported for the United
• Men who have had a hip or vertebral fracture without
Kingdom (133). This may indicate that the threshold ob-
major trauma. (1|QQQE)
served in U.S. and Danish studies may be more accurate • Men who have not experienced a spine or hip fracture
(ⱖ4 U/d). but whose BMD of the spine, femoral neck, and/or total
hip is 2.5 SD or more below the mean of normal young
2.4. Remarks white males. (1|QQEE)
A strategy should be in place to support men who wish • In the United States, men who have a T-score between
to reduce their alcohol intake. ⫺1.0 and ⫺2.5 in the spine, femoral neck, or total hip
plus a 10-yr risk of experiencing any fracture ⱖ 20% or
Recommendation 10-yr risk of hip fracture ⱖ 3% using FRAX; further
2.5. We recommend that men at risk of osteoporosis studies will be needed to determine appropriate inter-
who smoke cease smoking. (1|QQEE) vention levels using other fracture risk assessment al-
gorithms. For men outside the US, region-specific perience a fracture after age 60 (142), and a majority of
guidelines should be consulted. (1|QQEE) men who fracture have T-scores that are better than ⫺2.5
• Men who are receiving long-term glucocorticoid ther- (83). T-score-only criteria ignore important, independent
apy in pharmacological doses (e.g. prednisone or equiv- contributions to fracture risk from factors other than
alent ⬎7.5 mg/d) according to the 2010 guidelines of BMD, such as age, previous fractures, and comorbidities.
the American Society of Rheumatology. (1|QQEE) This along with other factors can now more accurately
predict risk fractures. The use of FRAX identifies a larger
3.1. Evidence proportion of older men in whom therapy appears to be
In contrast to the large fracture-end point trials of os- cost-effective (141) than use of T-scores alone. However,
teoporosis therapies in women, studies in men have gen- these algorithms may not be sufficiently sensitive because
erally been small, with change in BMD as the primary end they do not incorporate risk factors that also are likely to
point. Thus, recommendations regarding treatment effi- affect fracture risk (e.g. malabsorption, renal insuffi-

cacy in men are provided with lesser confidence. Never- ciency, fall risk, some medications) and because they con-
theless, treatment trials in men have yielded effects on sider only hip BMD.
BMD, biochemical markers of bone remodeling, and Acknowledging the shortcomings of the available data,
trends in fracture reduction that closely mirror those seen we recognize the need to be sufficiently inclusive to iden-
in larger trials in postmenopausal women with osteopo- tify both an adequate number of the men at risk and to
rosis. A systematic review and meta-analysis came to this incorporate multivariable risk models. Therefore, we rec-
conclusion (3). Therefore, we conclude that available ther- ommend that several criteria be considered in making
apies are likely to be effective in men and that it is appro- treatment choices.
priate to recommend pharmacological therapy in men Men who have suffered fragility hip or clinical vertebral
with increased fracture risk. Alendronate increased BMD fractures are at high risk of additional fractures and should
and reduced the incidence of radiographic vertebral frac- be considered for pharmacological treatment. A T-score of
tures (by quantitative morphometry but not by semiquan- ⫺2.5 or below in the spine, femoral neck, or total hip
titative assessment) in men with low femoral neck or spine (using the young male reference range) should also be a
T-scores or whose femoral neck BMD T-score was at least factor in the decision to treat. Finally, we recommend the
⫺1 with at least one vertebral deformity or a history of use of FRAX or Garvan or another risk assessment tool in
nonvertebral fracture (84). Risedronate increased BMD men who have not sustained a fragility fracture and in
and reduced the incidence of vertebral fractures in men whom the T-score is between ⫺1.0 and ⫺2.5, and, at least
with T-scores in the spine of ⫺2.0 or below and femoral in the United States, to recommend pharmacological ther-
neck ⫺1.0 or below (85, 86). Teriparatide increased BMD apy for men who have a 10-yr risk of greater than 3% for
in men with osteoporosis (87) and appeared to reduce the hip fracture or at least 20% for major osteoporosis-related
risk of vertebral fractures in men whose T-score for spine, fracture using FRAX.
femoral neck, and/or total hip was ⫺2.0 or below (87). We endorse the 2010 guidelines of the American Col-
Similarly, zoledronic acid has been shown to have positive lege of Rheumatology (143) for selecting men who require
effects in men with low BMD (140). Based on a cost-ef- long-term systemic glucocorticoid therapy for pharmaco-
fectiveness analysis specific to the United States, the Na- logical treatment with bone-active agents.
tional Osteoporosis Foundation (NOF) concluded that a
10-yr risk of hip fracture of at least 3% or 10-yr risk of Recommendation
major fracture of at least 20% was sufficient to justify 3.2. Selection of therapeutic agent
treatment of women (141). Cost-effectiveness has not We recommend that men at high risk of fracture be
been studied adequately in men. Because FRAX may untreated with medication approved by regulatory agencies
derestimate fracture in men (77) and because the NOF such as the U.S. FDA or EU EMA (at the time of this
study assumed a treatment cost higher than present costs, writing, alendronate, risedronate, zoledronic acid, and
we believe that it is conservative to use the NOF treatment teriparatide; also denosumab for men receiving ADT for
thresholds in men. prostate cancer) and that the selection of therapeutic agent
The evidence available to provide guidance about who be individualized based on factors including fracture his-
is at sufficient risk to warrant pharmacological therapy is tory, severity of osteoporosis (T-scores), the risk for hip
inadequate and controversial. Criteria based only on fracture, patterns of BMD [i.e. whether BMD is worse at
BMD T-scores (T-score ⫺2.5 or below in the spine or hip) sites where cortical bone (e.g. 1/3 radius) or trabecular
are too restrictive because they identify too few men for bone (e.g. spine) predominates], comorbid conditions (e.g.
therapy (⬍10%), whereas approximately 25% of men ex- peptic ulcer disease, gastroesophageal reflux, malabsorp-
tion syndromes, malignancy, etc.), cost, and other factors. be used in men with impaired kidney function (estimated
In men with a recent hip fracture, we suggest treatment glomerular filtration rate ⱕ30 –35 ml/min). Potential
with zoledronic acid. When teriparatide is administered, safety concerns with bisphosphonates include osteonecro-
we suggest that it not be given with concomitant antire- sis of the jaw (151) and atypical femur fractures (152). The
sorptive therapy. Agents that have not been approved by optimal duration of bisphosphonate therapy has not been
regulatory agencies for treatment of osteoporosis in men determined (153). Teriparatide should not be used in men
(calcitonin, ibandronate, strontium ranelate, etc.) should with prior irradiation. Full prescribing information
be used only if the approved agents for male osteoporosis should be consulted.
cannot be administered. (1|QQEE)
Recommendations
3.2. Evidence Management of hypogonadal men at high risk of
The effects of bisphosphonates and teriparatide on

fracture
BMD and BTM appear to be similar in men and women 3.3. For men at high risk of fracture who are receiving
(144). Of the FDA-approved agents used to treat osteo- testosterone therapy, we suggest adding an agent with
porosis in men, alendronate, risedronate, and zoledronic proven antifracture efficacy (e.g. a bisphosphonate or
acid have been shown to reduce the risk of hip fractures in teriparatide). (2|QEEE)
women with postmenopausal osteoporosis (145–147). 3.4. We suggest testosterone therapy in lieu of a “bone
Denosumab has been shown to increase BMD and reduce drug” for men at borderline high risk for fracture who
the incidence of vertebral fractures in men receiving ADT have serum testosterone levels below 200 ng/dl (6.9 nmol/
for non-metastatic prostate cancer. Once-yearly treatment liter) on more than one determination, if accompanied by
with iv zoledronic acid reduced risk of recurrent fractures signs or symptoms of androgen deficiency (e.g. low libido,
in more than 2100 subjects (⬃25% were men) who had unexplained chronic fatigue, loss of body hair, hot flushes,
undergone repair of a hip fracture within 90 d of treatment etc.) or “organic” hypogonadism (e.g. due to hypotha-
initiation (148). Teriparatide increases spine BMD more lamic, pituitary, or specific testicular disorder). If testos-
than alendronate; combining teriparatide with alendro- terone treatment does not alleviate symptoms of androgen
nate seems to attenuate the anabolic effect of teriparatide deficiency after 3– 6 months, it should be discontinued and
on BMD in both the spine and the hip (149, 150). The other therapy considered. (2|QQEE)
effects of combining teriparatide with an antiresorptive 3.5. We suggest testosterone therapy for men at high
agent on fracture risk have not been examined. risk for fracture with testosterone levels below 200
ng/dl (6.9 nmol/liter) who lack standard indications for
3.2. Remarks testosterone therapy but who have contraindications
For most men who are candidates for pharmacological to approved pharmacological agents for osteoporosis.
therapy, generic alendronate will often be preferred be- (2|QQEE)
cause of: 1) extensive experience with its use; 2) lack of
evidence that other agents are more effective or better tol- 3.3.–3.5. Evidence
erated; and 3) low cost. For men with upper or lower In men with congenital hypogonadal disorders, such as
gastrointestinal problems, a nonoral therapy (e.g. zole- Kallmann’s or Klinefelter syndromes, BMD is thought to
dronic acid or teriparatide) may be preferred. In post- be reduced because of inadequate pubertal bone accretion
menopausal women, risedronate has been shown to re- leading to a lower peak bone mass (154, 155). In men with
duce hip fracture risk and is a reasonable alternative for acquired disorders that reduce testosterone levels, such as
men at risk for hip fractures. For men at high risk of ver- primary gonadal failure, pituitary or hypothalamic tu-
tebral fracture, teriparatide may be preferred because it mors, or hemochromatosis, BMD declines because of ac-
increases spine BMD more than alendronate, although it celerated bone resorption (156 –160).
is more expensive (149). Teriparatide could also be con- Normalization of testosterone levels increases BMD in
sidered for men who fail to tolerate or respond adequately men with hypogonadism due to GnRH deficiency, partic-
to other agents. Because concomitant antiresorptive ther- ularly in subjects who have not yet reached skeletal ma-
apy seems to reduce the efficacy of teriparatide, increase turity (161). Even with prolonged androgen replacement,
costs, and expose patients to additional potential side ef- however, BMD fails to normalize in these men (161). Nor-
fects, it should be discontinued when teriparatide is ad- malization of testosterone increases BMD in men with
ministered. Clinical and social context should be consid- acquired hypogonadism due to prolactin-secreting adeno-
ered in selecting therapeutic agents, as well as side effects mas (162), other pituitary-hypothalamic disorders, or pri-
and safety concerns. Bisphosphonate therapy should not mary testicular disorders (159, 160). In men with acquired
hypogonadism, testosterone therapy reduces BTM, sug- ng/dl, 12 months of testosterone increased spine and total
gesting that the testosterone-induced increases in BMD are hip BMD, but there was no significant change at the
due to antiresorptive effects (159, 163) possibly mediated femoral neck (167). Twelve months of testosterone pre-
through conversion of testosterone to estradiol. vented a decline in femoral neck BMD in men age 65 or
Our recommendation to treat men with testosterone if older with baseline bioavailable testosterone levels be-
they have hypogonadism due to organic disease or symp- low normal (168).
toms of androgen deficiency is consistent with the current Measurements of serum testosterone levels are useful to
standard of care in these men (164). Our suggestion to add identify men who have androgen deficiency and who may
a pharmacological agent to treat osteoporosis if fracture be candidates for testosterone replacement. Low levels of
risk is high reflects the convincing fracture-prevention both testosterone and estradiol are associated with bone
data in women treated with bisphosphonates or teripa- loss and fractures in men, although the associations are
ratide and the lack of fracture-prevention data in men weak (43, 169, 170). Low estradiol levels are more

treated with testosterone. Our suggestion that testoster- strongly associated with increased fracture risk and accel-
one alone be considered if such men have a modest or erated bone loss in older men (27, 171, 172). Measure-
borderline risk of fracture reflects our desire to manage ment of estradiol levels in clinical situations in men is not
both the hypogonadism and the low BMD with a single recommended because of the lack of easily available, ac-
agent, thus reducing costs and the risk of medication side curate assay methods (mass spectrometry) and the absence
effects, as well as our belief that it is likely that the bene- of validated clinical algorithms that incorporate estradiol
ficial effects of testosterone on BMD in hypogonadal men measurements into treatment decisions. High SHBG levels
indicate that it will also reduce fracture risk. are associated with increased fracture incidence and bone
Because testosterone and estradiol levels decline as men loss in older men.
age, it has been suggested that this decline may be respon- Skeletal health may be compromised when serum tes-
sible, at least in part, for the decrease in BMD that occurs tosterone levels fall below 200 –250 ng/dl (6.9 – 8.7 nmol/
in aging men. The effects of testosterone therapy on BMD liter). As noted above, testosterone administration in-
in aging men with low or borderline low testosterone lev- creased BMD in elderly men whose baseline testosterone
els and no known disorders of the hypothalamic-pituitary- levels were 200 –300 ng/dl (6.9 –10.4 nmol/liter) but not in
gonadal axis have been examined in several small (n ⫽ men with higher baseline levels (166). Second, in the Os-
13–108) placebo-controlled studies of varying durations teoporotic Fractures in Men study, the odds of having
(6 –36 months). The effect of testosterone on BMD ap- osteoporosis at the hip tripled, as did the odds of experi-
pears to be related to baseline levels; testosterone therapy encing rapid hip bone loss in men with baseline testoster-
fails to increase BMD in men whose testosterone levels are one levels below 200 ng/dl (6.9 nmol/liter) vs. men with
within the reference range, whereas it increases BMD in testosterone levels above 200 ng/dl (6.9 nmol/liter) (42).
men whose levels are below the reference range. For ex- Additionally, in the Dubbo Osteoporosis Epidemiology
ample, in men aged 65 yr or older with serum testosterone Study, the risk of low-trauma fracture was higher in men
levels below 470 ng/dl (16.3 nmol/liter) [mean ⫾ SE base- with baseline testosterone levels in the lowest quartile [me-
line level of 399 ⫾ 10 ng/dl (13.8 ⫾ 0.3 nmol/liter)], tes- dian level of 227 ng/dl (7.9 nmol/liter)] (142). Finally, in
tosterone for 6 months had no significant effect on BMD healthy men given a GnRH agonist with testosterone gel
(165). Similarly, in 108 men more than 65 yr of age with for 16 wk, bone resorption increased when serum testos-
serum testosterone levels below 475 ng/dl (16.5 nmol/li- terone levels fell below 200 ng/dl (6.9 nmol/liter), al-
ter), spine BMD increased to the same extent in men though there did not appear to be a distinct threshold
treated with testosterone compared with those receiving (173). Thus, men whose serum testosterone level is 200 –
with placebo for 3 yr (166). A post hoc analysis, however, 300 ng/dl (6.9 –10.4 nmol/liter) or below appear to be at
suggested that testosterone therapy increased BMD more higher risk for bone loss and fracture and are more likely
than placebo in men with baseline testosterone levels be- to have a favorable response to testosterone therapy. Be-
low 200 ng/dl (6.9 nmol/liter). Three placebo-controlled cause the benefits of testosterone therapy are not well es-
trials have examined the effect of testosterone adminis- tablished and the risks of therapy are not clear, we feel that
tration on BMD in older men with low baseline testoster- a more conservative level [i.e. 200 ng/dl (6.9 nmol/liter)]
one levels. Spine, trochanter, and total hip BMD increased should be used for intervention until further data are
with testosterone compared to placebo over 36 months in available.
men more than 65 yr of age with baseline testosterone No studies have assessed the effects of combining tes-
levels below 350 ng/dl (12.1 nmol/liter) (163). In men age tosterone with bisphosphonates or other osteoporosis
60 or older with baseline testosterone levels below 320 drugs in hypogonadal men. The available data from both
controlled and uncontrolled trials, together with data ADT; after 36 months of treatment, denosumab increased
from animal studies, suggest that testosterone is an effec- spine, hip, and distal radius BMD and decreased the in-
tive therapy for hypogonadal men with osteoporosis. For cidence of vertebral fractures by 62% (97, 185); deno-
men with hypogonadism due to organic disease and/or sumab is now approved by the FDA and EU EMA for
symptomatic hypogonadism who have a marginal in- treatment of men with non-metastatic prostate cancer re-
crease in fracture risk, testosterone therapy may be ade- ceiving ADT. Denosumab in higher doses than used to
quate. However, in men who need testosterone therapy for treat osteoporosis has been shown to improve the outcome
hypogonadism and who have a high fracture risk, we rec- of men with advance prostate cancer metastatic to bone
ommend adding an approved pharmacological agent. (denosumab 60 mg SQ every 6 months is the dose for
treatment of osteoporosis; 120 SQ monthly is the dose for
Recommendation treatment of bone metastases) (203).
Clinical trials of zoledronic acid on BMD have shown

Men with prostate cancer receiving ADT
3.6. We recommend pharmacological treatment for benefits in men with prostate cancer receiving ADT and
osteoporosis for men with prostate cancer receiving men with prostate cancer metastatic to bone (186). If treat-
ADT who have a high risk of fracture (see Section 3.1). ment with zoledronic acid is not feasible due to prior side
(1|QQQE) effects, cost, or other logistical issues, oral alendronate
therapy is a reasonable alternative, based on a single ran-
3.6. Evidence domized controlled trial in men with prostate cancer re-
Orchiectomy or administration of long-acting GnRH ceiving ADT and on the more extensive data in men with
agonists to men with prostate cancer lowers serum tes- primary osteoporosis and women with postmenopausal
tosterone and estradiol levels to the prepubertal range, osteoporosis.
increasing bone resorption and inducing rapid bone
loss. Several small studies have examined rates of bone 4.0. Monitoring therapy
loss during the first year of GnRH agonist therapy in Recommendation
men with prostate cancer. In general, spine BMD de- 4.1. We suggest that clinicians monitor BMD by
clines by 3– 4% in the first year (95, 174 –178). De- DXA at the spine and hip every 1 to 2 yr to assess the
creases in hip BMD are more modest (95, 174 –178). response to treatment. If BMD appears to reach a pla-
Interestingly, BMD declined more rapidly in the radius teau, the frequency of BMD measurements may be
than in the spine or hip (95, 97). Fracture risk is in- reduced. (2|QQQE)
creased in men receiving ADT (179 –181).
Randomized controlled trials have been performed to 4.1. Evidence
determine whether antiresorptive agents prevent bone loss Treatments for osteoporosis increase BMD but only
in men receiving ADT for prostate cancer. Intravenous modestly. Alendronate increased BMD of the spine and
pamidronate every 12 wk prevented bone loss in men with femoral neck by about 7 and 2.5%, respectively, after 2 yr
locally advanced or recurrent prostate cancer initiating (84). Similarly, risedronate increased BMD of the spine
GnRH agonist therapy (175, 177). Similar results have and femoral neck by about 6 and 1.5%, respectively, after
been reported with other bisphosphonates, including iv 2 yr (86). Teriparatide (20 ␮g/d) increased BMD of the
zoledronic acid (177, 182) and oral alendronate (183, spine and femoral neck by about 6 and 1.5%, respectively,
184). Two randomized controlled trials have examined after 9 months (87). In hypogonadal men, testosterone
the effects of selective estrogen receptor modulators on enanthate therapy (200 mg every 2 wk) increased spine,
bone health in men with prostate cancer receiving chronic trochanter, and total hip BMD by about 8, 5, and 3.5%,
GnRH agonist therapy. Administration of raloxifene for respectively, after 2 yr (163). Evidence to support the use
12 months increased BMD of the hip and tended to in- BMD for monitoring treatment response is weak but sug-
crease BMD of the spine compared with placebo (183). In gests that it can be used for this purpose (187).
a study of men with prostate cancer and low BMD of the It has been suggested that serial BMD measurements in
spine and/or hip receiving GnRH agonist therapy for at treated subjects may identify patients who are not adher-
least 6 months, toremifene reduced the risk of new or ing to treatment or patients who have an overlooked cause
worsening morphometric vertebral fractures, clinical for bone loss. Although there is evidence that total hip
fragility fractures, or significant bone loss after 24 BMD changes reflect medication compliance (185), use of
months (184). serial BMD to identify subjects with secondary osteopo-
A placebo-controlled trial showed the benefits of de- rosis is anecdotal. It has also been suggested that serial
nosumab in men with early prostate cancer receiving BMD measurements may identify subjects who fail ther-
apy. A retrospective study in men showed that BMD mon- throughout therapy. Bone formation and resorption
itoring was associated with good compliance (188). markers increase dramatically during the first 6 –12
months of teriparatide therapy in men, after which they
4.1. Remarks gradually decline toward baseline levels (150). BTM de-
There is uncertainty over what constitutes an ade- cline consistently when hypogonadal men receive physi-
quate BMD response to treatment. Stable or increasing ological doses of testosterone, indicating that testosterone
BMD appears to indicate a good response (187). One in physiological doses acts as an antiresorptive agent
approach is to consider whether any BMD change ex- (159), perhaps through conversion to estradiol.
ceeds that expected due to normal variation (the least There is uncertainty over what constitutes an optimal
significant change approach); this requires information BTM response to treatment. Decreasing bone resorption
about normal BMD variability. There are no formal markers (for antiresorptive agents) or increasing bone for-
reports of variability in men. In women with osteopenia, mation markers (for anabolic agents) indicates a good re-

estimates of least significant change at the spine and hip sponse to treatment. Clinical experience suggests that in-
made in research settings are between 3 and 5% in the adequate response may be due to secondary osteoporosis
short term (189). In all of the studies above, changes in or noncompliance with treatment. Extrapolating data
spine BMD were greater than least significant change in from women to men, we assume that change in BTM re-
most men treated for 2 yr, whereas changes in hip BMD lates to fracture risk reduction with treatments.
were generally within the expected reproducibility
error. 4.2. Remarks
Whether change in BMD is a suitable surrogate for Monitoring treatment with BTMs requires attention to
fracture risk reduction in men is unclear. In women, it has detail. Because of diurnal variation (higher turnover in the
been estimated that BMD response to treatment accounts morning) and effect of food (bone resorption markers de-
for 4 – 41% of the fracture risk reduction with treatments crease after eating), samples for bone resorption markers
for osteoporosis (190, 191). The least significant change (urinary NTX, and serum CTX) should be collected with
approach can also be used to identify significant bone loss the patient in the fasting state, in the morning. Because
in men who are untreated or to identify offset of effect after manual and automated assays give different results for the
stopping treatment for osteoporosis. Because the expected same analysis, changes can be compared only if the lab
rate of bone loss is slower in these situations than the rate continues to use the same assay.
of gain during treatment, it may be better to wait longer As with changes in BMD, changes in BTMs can be com-
between measurements (e.g. 2–3 yr) in untreated men. pared with the least significant change to determine
Assessing change in BMD on serial measurements re- whether observed changes exceed those likely to occur as
quires careful attention to detail. Using the same machine a result of normal variation. This requires information
and a trained technologist aware of the pitfalls of bone about normal variability in BTMs, but for men, little is
densitometry can mitigate these problems. The provider known. Variability appears similar for bone resorption
responsible for reporting the results also needs to be aware markers (such as urinary deoxypyridinoline, NTX, and
of these limitations. Degenerative change in the spine is CTX) for men and women (192). In women with osteope-
particularly common in older men and may falsely give the nia, estimates of least significant change for bone alkaline
impression of a gain in BMD. phosphatase (b-ALP) activity and urinary NTX made in
research settings are between 14% (for b-ALP) and 37%
Recommendation (for urinary NTX) in the short term (192). Thus, in all of
4.2. We suggest that clinicians consider measuring a the studies above, in more than half of men receiving stan-
BTM at 3– 6 months after initiation of treatment using a dard treatments for 1–2 yr, changes in BTMs would ap-
bone resorption marker (such as serum CTX or serum or pear to exceed the least significant change, and patients
urine NTX) for antiresorptive therapy and a bone forma- would be considered to be “responders” using these mark-
tion marker (such as serum PINP) for anabolic therapy. ers. The response of BTMs could be identified as early as
(2|QQQE) within 3 months of starting treatment. Newer markers
have been developed and evaluated for treatment response
4.2. Evidence in women, including serum PINP and CTX (193). They
Treatments for osteoporosis in men produce significant have performed well in studies of drugs such as alendro-
changes in BTMs. As in women, alendronate reduces nate (194) and teriparatide (195).
BTMs by about 40 –50% (84). Reductions in BTMs be- Evidence that change in BTM is a suitable surrogate for
come maximal within several months and remain stable fracture risk reduction in men is lacking. In women, it has
been estimated that BTM response to treatment may ac- Financial Disclosure of Task Force
count for 30 –75% of the fracture risk reduction with stan-
dard treatments for osteoporosis (196 –200). Also, the Nelson B. Watts, M.D. (Chair)—Financial or Business/
magnitude of the BTM response has been shown to be Organizational Interests: American Association of Clini-
cal Endocrinologists, International Society for Clinical
associated with the level of compliance (201).
Densitometry, OsteoDynamics; Journal of Clinical Endo-
Some experts recommend measuring a BTM before and
crinology & Metabolism; Significant Financial Interest or
3– 6 months after starting treatment. Because there have
Leadership Position: Amgen, Baxter, Bristol-Myers
only been publications on the association of BTMs and
Squibb, Eli Lilly, Johnson & Johnson, Imagepace, Med-
fracture risk reduction in women (and not in men), there
pace, Merck, Pfizer/Wyeth, Warner Chilcott. Robert A.
is some disagreement among experts regarding this issue.
Adler, M.D.—Financial or Business/Organizational In-
Urine NTX or serum CTX can be used to monitor anti-
terests: International Society of Clinical Densitometry;

resorptive treatment; PINP or b-ALP can be used to mon-
Significant Financial Interest or Leadership Position:
itor anabolic treatment. If the change in markers exceeds
Amgen, Eli Lilly, Genentech, Merck, Novartis, Virginia
the least significant change (⬃40%; see 4.2. Remarks),
Commonwealth University. John P. Bilezikian, M.D.—
then one goal has been met. With women, a low risk of
Financial or Business/Organizational Interests: Endo-
fractures on treatment is associated with BTMs that are
crine Fellows Foundation, International Osteoporosis
below the median of the reference interval for young
Foundation, GSK; Significant Financial Interest or
women (196); this could be a target for men, but it has not
Leadership Position: Amgen, Novartis, Merck, Warner-
yet been studied. If markers do not change, there are sev-
Chilcott, Eli Lilly, NPS Pharmaceuticals. Matthew T.
eral options, including questioning the patient about com-
Drake, M.D., Ph.D.* — Financial or Business/Organi-
pliance with medication, considering causes of secondary
zational Interests: KER unit (Mayo Clinic); Significant
osteoporosis, or changing the medication or its route of
Financial Interest or Leadership Position: none
administration.
declared. Richard Eastell, M.D., FRCP, FRCPath,
FMedSci—Financial or Business/Organizational Inter-
ests: European Calcified Tissue Society, European Society
Acknowledgments of Endocrinology, International Bone and Mineral Soci-
The members of the Task Force thank The Endocrine Society’s ety, Amgen, AstraZeneca, GSK, Medtronics, Nastech,
staff (especially Lisa Marlow), Clinical Guidelines Subcommit- Nestle, Fonterra Brands, Novartis, Ono Pharma, Oste-
tee, Clinical Affairs Core Committee, and Council for their care- ologix, Pfizer, Lilly, Sanofi-Aventis, Tethys, unilever,
ful, critical review of earlier versions of this manuscript and their Unipath, Iverness Medical, Johnson & Johnson, SPD,
helpful comments and suggestions. We also thank the leadership MSD, IDS, Roche; Significant Financial Interest or Lead-
of the American Society for Bone and Mineral Research, Euro- ership Position: Amgen, Novo Nordisk, Pfizer, Sanofi-
pean Calcified Tissue Society, European Society of Endocrinol- Aventis. Eric S. Orwoll, M.D.—Financial or Business/Or-
ogy, and the International Society for Clinical Densitometry for ganizational Interests: Merck, Lilly, Amgen, Wright;
their review and comments. Finally we thank the many members Significant Financial Interest or Leadership Position:
of The Endocrine Society who reviewed the draft version of this American Society for Bone and Mineral Research, Inter-
manuscript when it was posted on the Society’s web site and who
national Osteoporosis Foundation Joel S. Finkelstein,
sent a great number of additional comments and suggestions,
M.D.—Financial or Business/Organizational Interests:
most of which were incorporated into the final version of the
Astra Zeneca, Solvay Pharmaceuticals, Abbott, Up-to-
guideline.
Address all correspondences to: The Endocrine Society, 8401
Date; Significant Financial Interest or Leadership Posi-
Connecticut Avenue, Suite 900, Chevy Chase, Maryland 20815. tion: none declared.
E-mail: govt-prof@endo-society.org, Telephone: 301-941- *Evidence-based reviews for this guideline were pre-
0200. Address all commercial reprint requests for orders 101 and pared under contract with The Endocrine Society.
more to: http://www.endo-society.org/journals/reprints.cfm. Ad-
dress all reprint requests for orders for 100 or fewer to Society
Services, Telephone: 301-941-0210, E-mail: societyservices@endo- References
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S P E C I A L F E A T U R E

Osteoporosis in Men: An Endocrine Society Clinical

Nelson B. Watts, Robert A. Adler, John P. Bilezikian, Matthew T. Drake,

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Evidence: We used the Grading of Recommendations, Assessment, Development, and Evaluation

Conclusions: Osteoporosis in men causes significant morbidity and mortality. We recommend

Summary of Recommendations sons for testing men aged 50 – 69 include diseases/conditions

1802 jcem.endojournals.org J Clin Endocrinol Metab, June 2012, 97(6):1802–1822

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TABLE 1. Summary of risk factors for fractures in males (4)

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1.3. Remarks well established. Nevertheless, in men at increased risk

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Recommendation 2.5. Evidence

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