Orwoll’s Wordle
Mortality adjusted risk of any fracture, when
people are fracture free at baseline
Dubbo Osteoporosis Epidemiology Study
Nguyen et al JBMR 2007
Fracture distribution by type and cost
US in 2005
2 million incident fractures
$17 billion dollars
Men:
29% of fractures
25% of the cost
Burge et al JBMR 2007
Proportion of fractures
Proportion of cost
Topics
•
•
•
•
Rates of bone loss
Approaches for assessing bone strength
Physical function/dysfunction and obesity
Attempting to wrap together strength and
trauma to predict fracture risk
• Treatment in men
MrOS: a multicenter, observational
study of musculoskeletal health and
fracture in older men
Administrative Center
Oregon Health &
Science University
Stanford University
Coordination Center
UCSF
University of Minnesota
University of Pittsburgh
University of California,
San Diego
University of Alabama
5994 men
MrOS: a multicenter, observational
study of musculoskeletal health and
fracture in older men
• 5994 men > 65 yrs were recruited in 6 communities in
the US in 2000-2002.
• Mean age 74 yrs, range 65 - >100 yrs. 89% Caucasian.
• Few exclusion criteria (unable to walk without
assistance, bilateral hip replacements). Similar to more
representative populations (e.g. NHANES).
• Men were extensively characterized at baseline, and a
biospecimen collection was established.
• Participants have been followed regularly thereafter
(~12+ years) including several repeat clinic visits and
additional phenotyping. Outstanding retention.
BMD from DXA predicts fracture
risk in men
Before MrOS, it was not clear how well DXA
BMD predicted fractures in community
dwelling men
MrOS helped
establish that although
women have a higher
risk of fracture, the
association between
aBMD and fracture
risk is clearly evident,
and similar, in both
sexes.
Cummings et al JBMR 2006
DXA measures and therapy are
cost effective in men
Before MrOS, unclear if BMD screening and
subsequent treatment is cost-effective
Data from MrOS
established that with
cheap bisphosphonate
therapy, screening and
treatment of men age ≥
70 yrs would generally be
considered cost effective
Schousboe et al JAMA 2007
QCT skeletal character in women and men
between the ages of 20 and 97 yr.
Cross sectional population sample of Rochester, Minnesota
men
premenopausal
postmenopausal
Riggs et al. JBMR 2004
The rate of BMD loss accelerates with
age in men
Mean change in femoral neck BMD= 1.7% in 4.6 yrs. (0.4%/yr)
65 year old
75 year old
85 year old
0.008 g/cm2
0.78
Change:
0.014 g/cm2
0.76
0.74
Change:
0.021
Risk of hip fracture
by BMD quartile
12
Hazard ratio
0.80
Femoral neck BMD (g/cm2)
14
Change:
g/cm2
0.72
10
8
6
4
2
0.70
65
70
75
80
85
Age at Enrollment (years)
90
95
0
Lowest
3rd
2nd
Highest
65 yr - BMD loss during follow-up (0.008 mg) = 9% increase in hip fx rate
85 yr - BMD loss during follow-up (0.021 mg) = 25% increase in hip fx rate
Cawthon et al JBMR 2012
The rate of BMD loss varies greatly
Heterogeneity of loss:
Change:
Femoral neck BMD (g/cm2)
0.80
65 year old
0.008 g/cm2
75 year old
Change:
0.78
0 – 22% over 4.6 yrs
85 year old
0.014 g/cm2
0.76
0.74
Change:
0.021 g/cm2
0.72
0.70
65
70
75
80
85
Age at Enrollment (years)
90
95
• 24% no loss/gain
• 63% “expected” loss
• 13% accelerated loss (at
least 1 SD greater than
mean loss)
Cawthon et al JBMR 2009
Fracture risk is higher in men with greater
BMD loss
Hip fractures (per 100 person years)
Non-spine fractures (per 100 person years)
Adjusted rate of non-spine and hip fracture per 100 person years, by
category of BMD change and tertile of baseline BMD
Tertile of femoral
neck baseline BMD
Category of femoral
neck BMD change
Cawthon et al JBMR 2012
Alendronate + exercise to protect against
bone loss during spaceflight
Pre-ARED – 18 on ISS from 2001 to 2004
ARED – 11 on ISS from late 2008 through 2011; used the ARED exercise device
Alendronate + ARED - 7 astronauts
Leblanc et al
Osteop Int 2013
Changes in BMD at the femoral neck
after landing
42 male, 3 female crew members (average age 43.2 ± 5.2 yrs)
56 long-duration flights (MIR, ISIS) 1990–2004
Spaceflight-induced loss - 6.8 % (5.7, 7.9)
50% recovery time would occur at 211 days (129, 346)
Sibonga et al. Bone 2007
Causes of more rapid loss?
Men with accelerated loss:
↑ Age
↑ Diabetes
↓ Baseline weight ↓ Physical activity
↑ Weight loss
↑ Physical activity decline
↓ self-rated health
Cawthon et al ASBMR 2010
Medical conditions
Genetics?
↓ sex steroids, ↓ vit D
Cauley et al JBMR 2010; Ensrud et al JBMR 2010,
Barrett-Connor JCEM 2012
Summary
• Age is associated with increasingly rapid bone loss, especially in
men with existing low BMD.
• Only a fraction of men have accelerated loss.
• Higher rates of bone loss are associated with higher fracture risk
• The causes and remodeling character of the acceleration is
unclear.
• The microstructural consequences of accelerated loss are
unclear (e.g. porosity)
Questions
• Should men with low normal BMD (not yet in the range requiring
treatment) routinely have a repeat measure in ~2-3 yrs?
• Can fracture prediction be improved to identify men loosing
bone more quickly?
• Should men with the greatest rate of bone loss be treated earlier?
Bone strength from QCT scans
predicts fracture risk
Many fractures occur in those who do not have
“osteoporosis” according to DXA BMD. Before MrOS, no
studies had evaluated whether bone strength from QCT
scans was associated with hip fracture.
Bone strength estimates from
QCT are associated with hip
fracture risk, and provided
additional evidence that these
measures can be used as
surrogate outcomes in clinical
trials
Black et al JBMR 2008
FE strength vs DXA BMD in men
with and without incident hip fracture
Areal BMD
17% lower
(p < 0.01)
16000
14000
STRENGTH (N)
12000
Strength
36% lower
(p < 0.01)
10000
8000
6000
4000
2000
0
0.6
Load-to-strength
ratio
SPEARMAN ρ = 0.73, p < 0.01
51% higher
0.8
1.0
1.2
1.4
(p<
0.01 )
TOTAL HIP BMD (g/cm
)
2
Strength
(N)
To
what extent
are these measures of strength
Load-to-strength
clinically
useful?ratio
NON-CASE
CASE
Orwoll et al JBMR 2008
Variation in femoral neck geometry
and strength
• Bending force varies
almost 3 fold depending
on the angle of force
applied.
• Between subject
shape variation is large
• Implications for
fracture risk?
Carpenter et al JBMR 2004
Bone strength from QCT scans
predicts fracture risk
• Distribution of bone density in the proximal
femur and its association with hip fracture risk
in older men
Yang et al JBMR 2012
• Fracture risk predictions based on statistical
shape and density modeling of the proximal
femur
Bredbenner et al JBMR 2014
• Prediction of new clinical
vertebral fractures in elderly men
using finite element analysis of
CT scans
Wang et al JBMR 2012
Total femur vBMD and strength change
during flight, and recovery
16 ISS astronauts (missions 2-8) with QCT before flight, on
landing, and after 1 yr on earth
(%) Flight Ratio Rec/Pre
Total vBMD
-10.4
0.93
Trabecular BMD
-14.4
0.91
Cortical BMD
-3.4
0.97
Cortical volume
-9.2
1.0
Total volume
-0.7
1.06
Comp Strength
-16.8
0.86
Lang et al
JBMR 2006
Change in proximal femoral strength
vs DXA BMD
Change in DXA (%/month)
13 ISS astronauts (10 men); flights of 4.3-6.5 mos
0
R2= 0.05, p= 0.45
-0.4
-0.8
-1.2
-1.6
-4
-3
-2
-1
0
1
Change in FFE fall loading (%/month)
Mean change in FFE fall loading= 2%/month
Keyak et al
Bone 2008
Bone Fracture Risk Module Concept
Meyers J et al. NASA
Monte Carlo Simulation
Probability
and
magnitude
of loading
event
Estimate
relative
skeletal
strength
Est. fx
probability
by load to
strength
ratio
Most likely
probability
of fracture
for event +
uncertainty
Nelson et al.,
Development and Validation of
a Predictive Bone Fracture Risk
Model for Astronauts,
Annals of Biomedical
Engineering, 2009,
Vol. 37, Number 11, 2337-2359.
Estimated Mars Fracture Risk
M: 1.25% (90%CI : 0-3.5%)
F: 3.5% (90%CI: 0-5.25%)
Summary
• Areal bone density is a potent predictor of fracture
risk in men.
• Newer methods of assessing bone strength (QCT)
are evolving and promise to add new, clinically
useful information
Body composition and fracture risk
Thinking through what causes a fracture
BMI and fracture risk in older men
Definitions (BMI)
Underweight = <18.5
Normal = 18.5 -25
Overweight = 25-30
Obese 1 = 30-35
Obese 2 = 35-40
Obese 3 = >40
Underweight
Normal
Overweight
Obese 1
Obese 2
Fracture incidence
1000 person yrs
25
20
Non-spine fx
Hip fx
15
10
5
0
All men
N (%)
6 (0.1%)
1628 (27%)
3049 (52%)
1034 (17%)
207 (4%)
Non-vert fx
N (%)
0
202(32%)
309 (49%)
97 (15%)
24 (4%)
68%
Hip fx
N (%)
0
48 (38%)
61 (48%)
12 (10%)
5 (4%)
62%
Nielson et al JBMR 2010
Obese III
n=27
Obese II
n=201
Obese I
n=1,014
Overweight
n=3,017
Normal
n=1,591
Underweight
n=5
Total hip BMD T score
BMI and areal BMD are correlated
Shen et al ASBMR 2012
QCT measures of hip strength are
higher with increased BMI in older men
QCT measures of hip integral BMD, trabecular BMD,
cortical thickness and size are associated with BMI.
N= 760
Finite element
strength (N)
Obesity is associated with
increased fracture risk after
BMD adjustment
Shen et al ASBMR 2012
Factor of risk (Ф)
Factor of risk and BMI in older
Factor of risk (Ф) = fall
force/hip strength
men
Obese men performed more poorly
on physical function tests that are
associated with falls and fracture.
Shen et al ASBMR 2012
The balance between bone
strength and fall force
Obesity
Bone strength
+
Fall
Fracture
Fall force
Hip fracture incidence among white
NHANES I respondents age 65-74.
160
Hip fracture incidence per 10,000
person-years
140
6 cases
120
100
81 cases
Women
80
Men
74 cases
60
2 cases
40
20 cases
31 cases
20
0
<18.5 kg/m2
Underweight
18.5-24.9 kg/m2
Normal weight
> 25 kg/m2
Over weight or
obese
Nielson et al JBMR 2012
Tissue thickness and hip fracture risk
in older men
70 men with incident hip fracture and 222 non-fractured controls,
all with DXA and QCT finite element analysis
Tissue thickness was minimally lower in hip fx vs controls
(29 vs 31 mm, p= 0.2)(lower in trochanteric fx – 26 mm)
Tissue thickness was not associated with hip fracture risk (RR 1.01,
0.8-1.3)
Tissue thickness was considerably lower in men
than previously reported in women (49 vs 31
mm; Bouxsein et al JBMR 2007). Attenuation of
fall force greater in women (61% vs 27%)
Nielson et al JCEM 2009
Summary
• Falls are very important in determining fracture risk
• Simple measures of physical function have been
developed and validated but are poorly
incorporated into clinical practice to identify fallers
• Most fractures happen in men with high BMI
• Men with higher BMI and relatively lower BMD are
vulnerable to falls and fracture, but are not
generally believed to be at risk. There are not
guidelines to deal with the issue
Treatment of osteoporosis in men
Anti-resorptive agents
Bisphosphonates
Denosumab
(Odanacatib)
Anabolics
Parathyroid hormone 1-34
Alendronate therapy in osteoporotic men
Percent change in lumbar spine BMD and vertebral fracture incidence
after 2 years of alendronate 10 mg/day in 241 men with low BMD
Alendronate
Placebo
*
*
Radiographic vertebral
fracture rate
*
*
Odds ratio 0.10
(95% CI 0.00 - 0.88)
Same response in men with low T
Orwoll et al
NEJM 2000
Very similar results on BMD with other bisphosphonates
in the treatment of men with osteoporosi
•
•
•
Residronate
Ibandronate
Zoledronate
Similar results with denosumab, teriparatide and
odanacatib in the treatment of men with low BMD
Although most trials in men have been small and
designed to evaluate BMD change rather than fracture
rates, the effects of drug therapies in men have been
very similar to those in women
Zoledronate treatment in men reduced the rate of
new vertebral fractures
1199 men with osteoporosis, aged 50-85
Similar results with moderate-severe morphometric
fractures (RR reduction 81% and 63% at 12 and 24 months).
Boonen S et al. N Engl J Med 2012;367:1714-1723.
Original Article
Zoledronic acid and clinical fractures and
mortality after hip fracture
Kenneth W. Lyles, M.D., Cathleen S. Colón-Emeric, M.D., M.H.Sc., Jay S. Magaziner, Ph.D.,
Jonathan D. Adachi, M.D., Carl F. Pieper, D.P.H., Carlos Mautalen, M.D., Lars Hyldstrup, M.D.,
D.M.Sc., Chris Recknor, M.D., Lars Nordsletten, M.D., Ph.D., Kathy A. Moore, R.N., Catherine
Lavecchia, M.S., Jie Zhang, Ph.D., Peter Mesenbrink, Ph.D., Patricia K. Hodgson, B.A., Ken
Abrams, M.D., John J. Orloff, M.D., Zebulun Horowitz, M.D., Erik Fink Eriksen, M.D., D.M.Sc., and
Steven Boonen, M.D., Ph.D. for the HORIZON Recurrent Fracture Trial
N Engl J Med. 2007 Nov 1;357(18):1799-809
Involved men (23.8% of the study population; mean age, 74
years) and women with prior hip fracture. There was a 35%
reduction in relative risk in new clinical fracture with
zoledronic acid, with no sex difference in the response to
therapy.
Alendronate + exercise to protect against
bone loss during spaceflight
Pre-ARED – 18 on ISS from 2001 to 2004
ARED – 11 on ISS from late 2008 through 2011; used the ARED exercise device
Alendronate + ARED - 7 astronauts
Leblanc et al
Osteop Int 2013
Sex steroids and bone
• In vitro, sex steroids have effects on bone cells.
• Sex steroids affect bone mass in animal models and
humans, particularly during development.
• Hypogonadism results in low BMD and fractures
(e.g. therapy for prostate cancer).
Androgens
Aromatase
Estrogens
Cooper et al. JBMR 1992
Bone
Sex steroids and bone ultrastructure
118 men >60 yrs studied with µCT at the ultradistal radius
Age adjusted correlations
Bio-E
Bio-T
BV/TV
0.29**
0.13
Trab number
0.34***
0.08
0.20*
0.14
-0.38***
-0.13
Trab thickness
Trab spacing
* p< 0.05, ** p< 0.01, *** < 0.001
Khosla et al JBMR 2006
Serum sex steroids and fracture risk
in older men
2639 men, 209 fractures, 3.3 yr average follow-up
• Low testosterone levels, especially
low free T, were associated with
increased fracture risk in
univariate models, but they had no
independent effect when estradiol
levels were also in the analyses.
• Well powered study with good sex
steroid assays (mass spec)
• Consistent with previous studies
of threshold effects of E2.
• Measure estradiol rather than
testosterone for osteoporosis?
Mellstrom et al JBMR 2008
Testosterone and fall risk
No associations with estradiol levels
2
Risk of falls by T quartile
Risk Ratio
1.8
1.6
1.4
1.2
1
0.8
1
2
3
4
Bioavailable Testosterone Quartiles
Risk ratios are adjusted for clinic site, participant race, age, history of falls reported at
baseline visit, angina, arthritis, dizziness, use of CNS medications,. The cohort was
restricted to participants who reported good/excellent health, no Parkinson’s disease, no
history of prostate cancer, no use of walking aids and no mobility limitation (n=1705).
Orwoll et al 2006
Testosterone therapy and BMD in men > 65
yrs with low testosterone levels
Relatively high doses of
IM testosterone
No fracture data
Amory et al. JCEM 2004
Original Article
Adverse Events Associated with Testosterone
Administration
Shehzad Basaria, M.D., Andrea D. Coviello, M.D., Thomas G. Travison, Ph.D., Thomas W. Storer,
Ph.D., Wildon R. Farwell, M.D., M.P.H., Alan M. Jette, Ph.D., Richard Eder, B.A., Sharon Tennstedt,
Ph.D., Jagadish Ulloor, Ph.D., Anqi Zhang, Ph.D., Karen Choong, M.D., Kishore M. Lakshman, M.D.,
Norman A. Mazer, M.D., Ph.D., Renee Miciek, M.S., Joanne Krasnoff, Ph.D., Ayan Elmi, B.A., Philip E.
Knapp, M.D., Brad Brooks, B.S., Erica Appleman, M.A., Sheetal Aggarwal, B.S., C.C.R.P., Geeta
Bhasin, B.A., Leif Hede-Brierley, Ashmeet Bhatia, M.B., B.S., Lauren Collins, R.N.P., Nathan
LeBrasseur, Ph.D., Louis D. Fiore, M.D., and Shalender Bhasin, M.D.
N Engl J Med 2010; 363:109-122 July 8, 2010
T therapy appeared to improve physical performance in frail
older men – the group most likely to have low bone density.
But it also increased the risk of cardiovascular events
Association of testosterone therapy with
mortality, myocardial infarction, and stroke in
men with low testosterone levels
Vigen et al JAMA Nov 3, 2013
“There is mounting evidence of a signal of
cardiovascular risk, to which the study by Vigen et al
contributes. This signal warrants both cautious
testosterone prescribing and additional investigation.”
Cappola AR JAMA Editorial
There are major unresolved issues
concerning testosterone therapy for
osteoporosis
Benefits of supplementation (how useful is
supplementation for fracture risk reduction?)
Risks of supplementation (what harm would be
caused?)
∴ It is premature to treat older men with
testosterone for fracture prevention in men with low
testosterone levels. For osteoporosis, proven
osteoporosis therapies are preferred.
MrOS: Major Contributors
OHSU
Carrie Nielson
Christine Lee
Jodi Lapidus
Shannon McWeeney
Ying Wang
Smriti Shresha
Jian Shen
Cathy Pedersen
UCSF/CPMC/UC
Steve Cummings
Peggy Cawthon
Doug Bauer
Dennis Black
Tom Lang
Greg Tranah
Nancy Lane
Robin Fullman
Tony Keaveny
University of Pittsburgh
Jane Cauley
Joe Zmuda
University of Alabama
James Shikany
Beth Lewis
UC San Diego
Elizabeth Barrett-Connor
Stanford University
Marcia Stefanick
University of Minnesota
Kris Ensrud
John Schousboe
Sweden
Osten Ljunngren
Claes Ohlsson
Dan Mellstrom
Magnus Karlsson
Hong Kong
PC Leung
Edith Lau
Funding
NIH
NIAMS
NIA
NIDCR
NHLBI
NCI
MrOS International
International cohorts
Sweden – M Karlsson P.I. (3,000 subjects)
Hong Kong – PC Leung P.I. (2,000 subjects)
Unique advantages
 Large population – 11,000 men studied using a
single protocol
 Wide variation in fracture epidemiology
 Heterogeneity in geographical and environmental
variables
Collaborations and productivity
Good track record of generating
collaborative projects:
– MrOS has spawned 42 additional funded
grants, and multiple career development
awards
– 69 external investigators from 42 institutions
are formally involved in MrOS related-projects
>185 manuscripts have been published
using MrOS data
MrOS: the next phase
Major aims
• Understand the trajectories of change in
musculoskeletal health, and how they affect
important outcomes (e.g. fracture, physical
disability)
• Using high resolution micro CT, assess the
determinants of microstructure and the relationship
of microstructure to fracture risk
• Stimulate new science!!
Obesity is associated with increased
fracture risk after BMD adjustment
Odds ratios for fracture
Normal
Overweight
Obese 1
Obese 2
Non-vertebral
1.0
1.0 (0.9 – 1.3
1.3 (1.0 – 1.7) 1.9 (1.3 – 3.0)
Hip
1.0
1.2 (0.8 – 1.9)
1.8 (0.9 – 3.3)
5.0 (1.7 – 15)
Adjusted for age, race, total hip BMD
Nielson et al JBMR 2010
BMI and fracture risk in older men
Obese men performed more poorly on physical function
tests that are associated with falls and fracture.
Odds ratio (+95 CI) for fracture
Normal
Overweight
Obese 1
Obese 2
Non-vertebral
1.0
1.02 (0.8 – 1.2
1.1 (0.9 – 1.5) 1.4 (0.9 – 2.3)
Hip
1.0
1.2 (0.8 – 2.0)
1.3 (0.7 – 2.7)
3.2 (1.0 – 9.7)
Adjusted for age, race, total hip BMD, baseline history of fracture, self-reported mobility limitation,
and narrow walk pace
Nielson et al JBMR 2010
Low 25(OH)D and increased rate of
decline in hip BMD
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
25OHD levels (ng/mL)
Quintile 1 < 19.1
Quintile 3 < 27
Quintile 5 > 31
Quintile 2 < 24
Quintile 4 < 31
Ensrud et al JBMR 2009
Low 25(OH)D is associated with
increased hip fracture risk
Non-spine Fx
Hip Fx
1.08
1.63
(0.97, 1.21)
(1.21, 2.20)
0.177
0.001
Total 25(OH)D
RH per SD decrease
(95%CI)
P
adjusted for age, race, season, height, weight and clinic.
p trend=0.009
MrOS results show that lower
vitamin D is associated with
bone loss and hip fractures
but not all non-spine
fractures – supported the
need for a clinical trial of
vitamin D & fracture
relationship and influenced
the IOM Vit D report
conclusions
Cauley et al JBMR 2010
Summary
• Vitamin D and sex steroids (estrogen, SHBG?)
influence bone biology, bone mass, and fracture
risk
• The clinical utility of measuring sex steroids to
assess skeletal health in men is unclear
• How to apply measures of sex steroids across
geographies and races is uncertain
Is accelerated loss associated with
increased remodeling?
Age-related reference intervals for bone turnover markers
from an Australian reference population
1143 males. Mean age 60 years; range 20–97 years
Bauer et al JBMR 2009
Jenkins et al Bone 2013
Do sex steroids/SHBG improve the
prediction of 10 yr hip fracture risk?
ROC analyses
Total T
Total E
SHBG
T+E
T + E + SHBG
Continuous
AUC
95% CI
0.52
(0.43, 0.61)
0.52
(0.42, 0.62)
0.56
(0.48, 0.65)
0.55
(0.46, 0.64)
0.58
(0.49, 0.66)
Thresholds
AUC
95% CI
0.51
(0.45, 0.57)
0.52
(0.45, 0.60)
0.54
(0.47, 0.61)
0.53
(0.45, 0.61)
0.56
(0.47, 0.65)
Essentially the same AUC
findings with:
• Major osteoporotic fractures
• BioT, E and BioE
• 3, 5, or 8 years of follow-up
T only
(AUC= 0.52)
Age, BMI, BMD (AUC= 0.80)
+ T (AUC= 0.80)
Orwoll et al ASBMR 2013
Reclassification of fracture risk by
adding a T measurement to FRAX
Example reclassification graph
No Fracture
Fracture
60
Predicted Risk (%)
FRAX + T
50
40
30
20
10
0
0
10
20
30
40
50
60
0
10
Predicted Risk (%)
FRAX only
20
30
40
50
60
Do sex steroid measures add to the
predictive value of FRAX in predicting
hip fracture?
Net Reclassification Improvement (NRI)
(Fracture = 47
No fracture = 1422)
No Fracture
Fracture
60
50
Predicted Risk (%)
FRAX + T
- improve
- worsen
40
30
20
10
0
0
10
20
30
40
50
60
0
10
20
30
NRI (overall) = -0.08
(P50 = 600.59)
40
Predicted Risk (%)
FRAX only
Orwoll et al ASBMR 2013
International
sex steroid
comparisons
MrOS showed
that on a global
scale, there are
important
geographical and
racial differences
in the
concentrations of
serum sex
steroids and
SHBG in older
men.
Orwoll et al JCEM 2008
International sex steroid comparisons:
prevalence of hypogonadism
Insufficient data in men
Eldecalcitol, calcitriol, alphacalcidol
Menatetrenone
Minodronic acid
Newer agents
Odanacatib (clinical trial in men with
osteoporosis completed)
Anti-sclerostin Ab (active studies in men
ongoing)
Calcilytics
Wnt/β-catenin modulators
The rate of bone loss greatest in men with
lower baseline BMD
Femoral neck BMD loss (%)
3
4
1
2
3
4
-1.51
2
-1.63
1
-1.76
4
-1.74
3
-1.24
2
-1.53
1
-1.78
area quartile
-2.09
BMC quartile
-1.35
BMD quartile
-1.50
Femoral neck
-1.67
Femoral neck
-2.11
-0.25
Femoral neck
-0.75
-1.25
-1.75
p <.001
-2.25
p =0.025
p <.001
Adjusted for age,
weight, clinical site
-2.75
Same pattern if analysis is by absolute change
Same pattern if analysis is of BMC
Cawthon et al JBMR 2012
Physical performance, disability,
frailty, falls and injuries
Physical performance and risk
of hip fractures in older men
Hazzard ratio (95% CI) of hip fracture
Test of physical
performance
Age and clinical site
adjusted
Multiply adjusted*
Unable
12.6 (4.1-38.9)
8.2 (2.7-25.0)
Quartile 4 (worst)
4.7 (1.8-12.3)
3.6 (1.4-9.4)
Quartile 3
3.0 (1.1-8.2)
2.7 (1.0-7.3)
Quartile 2
1.9 (0.6-5.4)
1.6 (0.6-4.7)
Quartile 1
1.0 (referent)
1.0 (referent)
Quartile 4 (worst)
3.0 (1.4-6.7)
2.4 (1.1- 3.4)
Quartile 3
1.4 (0.6-3.3)
1.3 (0.6-3.1)
Quartile 2
0.9 (0.3-2.5)
0.9 (0.3-2.3)
Quartile 1
1.0 (referent)
1.0 (referent)
Repeated chair stands
Walking speed
* Age, clinical center, FN BMD, BMI, hx of MI, hx stroke
Cawthon et al. JBMR 2009
Incident vertebral fracture and performance
Change in SQ grade ≥ 1, OR (95% CI)
Walk speed
Q4 (best)
Q3
Q2
Q1(worst)
p=0.11
Chair stands
Q1 (best)
Q2
Q3
Q4(worst)
Unable
(N=61)
Leg power
Q4 (best)
Q3
Q2
Q1(worst)
p<.001
Narrow walk
Q1 (best)
Q2
Q3
Q4(worst)
Unable
(N=218)
p=0.005
Grip strength
Q4 (best)
Q3
Q2
Q1(worst)
Unable
(N=69)
p=0.006
Summary scale
p=0.47
p=p for trend. Models adjusted for age, smoking, clinical center,
race, height, weight, fall, one or more co-morbid medical conditions,
physical activity, lumbar spine BMD
0
1-2
3+
p=0.003
Cawthon et al ASBMR 2012
Circumstances of incident clinical
vertebral fractures
Circumstances of fractures
% participants with clinical
vertebral fractures
Fall from standing height or less
41
Fall on stairs, steps or curbs
8.1
Minimal trauma other than a fall
11.4
Moderate trauma other than a fall
3.3
Fall from more than standing height
8.2
Severe trauma other than a fall
6.6
Circumstance unknown
21.4
57%
Freitas et al. Osteoporos Int 2008