Cross-sectional analysis of the association between fragility fractures and bone microarchitecture...

$: Cross-sectional analysis of the association between fragility fractures and bone microarchitecture in older men: The STRAMBO study$
ORIGINAL ARTICLE JJBMR
Cross-Sectional Analysis of the Association BetweenFragility Fractures and Bone Microarchitecture inOlder Men: The STRAMBO Study
Pawel Szulc, Stephanie Boutroy, Nicolas Vilayphiou, Ali Chaitou, Pierre D Delmas, andRoland Chapurlat

INSERM UMR 1033, Universite de Lyon, Hospices Civils de Lyon, Lyon, France

ABSTRACTAreal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry (DXA) identifies 20% of men who will sustain fragility

fractures. Thus we need better fracture predictors in men. We assessed the association between the low-trauma prevalent fractures and

bone microarchitecture assessed at the distal radius and tibia by high-resolution peripheral quantitative computed tomography (HR-

pQCT) in 920 men aged 50 years of older. Ninety-eight men had vertebral fractures identified on the vertebral fracture assessment

software of the Hologic Discovery A device using the semiquantitative criteria, whereas 100 men reported low-trauma peripheral

fractures. Men with vertebral fractures had poor bone microarchitecture. However, in the men with vertebral fractures, only cortical

volumetric density (D.cort) and cortical thickness (C.Th) remained significantly lower at both the radius and tibia after adjustment for

aBMD of ultradistal radius and hip, respectively. Low D.cort and C.Th were associated with higher prevalence of vertebral fractures

regardless of aBMD. Severe vertebral fractures also were associated with poor trabecular microarchitecture regardless of aBMD. Menwith

peripheral fractures had poor bone microarchitecture. However, after adjustment for aBMD, all microarchitectural parameters became

nonsignificant. In 15 men with multiple peripheral fractures, trabecular spacing and distribution remained increased after adjustment for

aBMD. Thus, in men, vertebral fractures and their severity are associated with impaired cortical bone, even after adjustment for aBMD.

The association between peripheral fractures and bone microarchitecture was weaker and nonsignificant after adjustment for aBMD.

Thus bonemicroarchitecture may be a determinant of bone fragility in men, which should be investigated in prospective studies.� 2011

American Society for Bone and Mineral Research.

KEY WORDS: BONE MICROARCHITECTURE; VERTEBRAL FRACTURE; FRAGILITY FRACTURE; MEN

Introduction

Osteoporotic fractures in men are a public health problem

because of the morbidity, mortality, and cost.(1) However,

prediction of fractures in men by areal bone mineral density

(aBMD) assessed by dual-energy X-ray absorptiometry (DXA) is

disappointing. Low aBMD (gender-specific T-score<�2.5)

identified 20% of men who later sustained fragility fractures.(2,3)

Quantitative ultrasound (QUS) parameters identify men at high

fracture risk similarly to aBMD, but DXA and QUS used jointly do

not predict more fractures.(4) Classic biochemical bone turnover

markers do not improve fracture prediction in men.(5,6)

Quantitative computed tomography (QCT) assesses trabecular

and cortical bone separately. Low-trauma fractures were

associated with low trabecular and cortical volumetric BMD

(vBMD), but QCT parameters of femoral neck (ie, cortical volume,

Received in original form September 2, 2010; revised form October 27, 2010; acce

Address correspondence to: Pawel Szulc, MD, PhD, INSERM UMR 1033, Hopital Edo

E-mail: [email protected]

Journal of Bone and Mineral Research, Vol. 26, No. 6, June 2011, pp 1358–1367

DOI: 10.1002/jbmr.319

� 2011 American Society for Bone and Mineral Research

1358

trabecular vBMD) did not predict more hip fractures in men than

DXA alone.(7,8) Peripheral QCT (pQCT) assesses trabecular and

cortical bone at the distal radius and tibia. In young and older

men, a history of fracture was associated with lower cortical and

trabecular vBMD.(9,10) In addition, cortical bone mineral content

measured by pQCT predicted incident peripheral fractures after

adjustment for femoral neck aBMD.(11)

Thus we need better fracture predictors in men. Several

studies suggest that assessment of bone microarchitecture may

improve the prediction of peripheral fractures in men. Bone

strength depends onmicroarchitecture of cortical and trabecular

bone.(12) In women with vertebral fractures, trabecular para-

meters were impaired in those with normal cortical bone,

whereas cortex was thinner in those with normal trabecular

bone.(13) Women with vertebral fractures had thinner cortex and

poor trabecular connectivity, as assessed by histomorphome-

pted December 1, 2010. Published online December 16, 2010.

uard Herriot, Place d’Arsonval, Lyon 69437, France.

try.(14) More severe vertebral fractures were associated with

poorer bone microarchiteture.(15) However, the bone biopsy is

invasive, which limits the use of histomorphometry.

High-resolution peripheral QCT (HR-pQCT) permits assessment of

trabecular and cortical bone microarchitecture in clinical studies.(16)

Postmenopausal women with fractures had lower trabecular and

cortical thickness at the tibia after adjustment for aBMD compared

with age-matched controls.(17) The microarchitectural defect was

associated with poor mechanical properties, as assessed with

micro–finite element analysis.(18) The increasing severity of

vertebral fractures was associated with a progressive decrease in

cortical thickness and density measured by HR-pQCT.(19)

In men, the association between bone microarchitecture and

fracture is poorly studied. In iliac crest biopsy, osteoporotic men

with vertebral fractures had decreased trabecular number and

poor trabecular connectivity,(20) and men with idiopathic

osteoporosis and vertebral fractures had increased cortical

porosity.(21) Men reporting childhood fractures had lower cortical

thickness than controls.(10) Therefore, the aim of our study was to

assess the association between low-trauma prevalent fractures

and bone microarchitecture assessed at the distal radius and

tibia by HR-pQCT in 920 men aged 50 years and older from the

Structure of Aging Man’s Bone (STRAMBO) cohort.

Subjects and Methods

Cohort

The STRAMBO study is a single-center prospective cohort study

of skeletal fragility and its determinants in men.(22) It was carried

out as a collaboration between INSERM (National Institute of

Health and Medical Research) and MTRL (Mutuelle des

Travailleurs de la Region Lyonnaise). MTRL is a complementary

health insurance company open to all citizens. Its insured are

representative of the French population from the point of view of

age groups and of the proportion between white-collar and

blue-collar workers. The study obtained authorization from the

local ethics committee and was performed in agreement with

the Helsinki Declaration of 1975 and 1983. Participants were

recruited in 2006–2008 from the MTRL lists in Lyon. Letters

inviting participation were sent to a randomly selected sample of

men aged 20 to 85 years living in greater Lyon. Informed consent

was provided by 1169 men. All men replied to an interviewer-

administered epidemiologic questionnaire that covered lifestyle

factors and health status. All men able to give informed consent,

to answer the questions, and to participate in the diagnostic

examinations were included. No specific exclusion criteria were

used. This analysis was made in 920 men aged 50 years and

older.

Fracture assessment

Vertebral fractures were assessed on the lateral scans of thoracic

and lumbar spine obtained in the dorsal decubitus position by

the Vertebral Fracture Assessment (VFA) software using the

Hologic Discovery A device equipped with the C-arm (Hologic,

Bedford, MA, USA). Using this method, vertebral bodies from T7to L4 were assessable for all the patients, whereas the T5 and T6

FRAGILITY FRACTURES AND BONE MICROARCHITECTURE IN OLDER MEN

vertebrae were not assessable in 10% to 11% of the men and the

T4 vertebral body was not assessable in 23% of the men.

Vertebral fractures were assessed by one reader (PS) using the

semiquantitative method of Genant,(23) as modified for men by

Szulc and colleagues.(24) Vertebral fractures were identified in

98 men who were classified according to the most severe

fracture as follows: grade 1 (n¼ 18), grade 2 (n¼ 60), and grade 3

(n¼ 20). Sixty-one men had one fracture, 23 men had 2 fractures,

7 men had 3 fractures, 2 men had 4 fractures, 1 man had

5 fractures, 3 men had 6 fractures, and 1 man had 7 fractures.

Vertebral fractures sustained after a major trauma were

excluded. Mild vertebral deformities supposedly related to other

conditions (eg, arthritis, Scheuerman disease) were excluded,

specificity being preferred to sensitivity. The reproducibility of

diagnosis of vertebral fracture was assessed using the simple k

score per fracture (yes versus no) and per grade (no fracture,

grade 1, grade 2, or grade 3). The intraobserver agreement scores

were k¼ 0.93 [95% confidence interval (CI) 0.89–0.98] and

k¼ 0.89 (95% CI 0.84–0.94), respectively. The interobserver

agreement scores were k¼ 0.88 (95% CI 0.81–0.95) and k¼ 0.87

(95% CI 0.82–0.92), respectively.

Peripheral fractures were assessed using an interviewer-

assisted questionnaire. Only fractures that occurred after the age

of 18 and after a low trauma were retained as fragility fractures.

One hundred men reported 119 fractures at the following

skeletal sites: clavicle, 1; scapula, 2; proximal humerus, 11; distal

radius, 34; other forearm, 5; ribs, 18; pelvis, 1; hip, 6; femur, 2; tibia,

8; fibula, 7; ankle, 16; heel bone, 3; and metatarsal, 5. Fractures of

the face, hand, and toes were excluded. Fractures were self-

reported and not ascertained further. Twenty-one men had both

vertebral and peripheral fractures.

BMD and bone microarchitecture measurement

Volumetric BMD (vBMD) and microarchitecture were assessed at

the nondominant distal radius and right distal tibia by HR-pQCT

(XtremeCT, Scanco Medical, Bruttisellen, Switzerland). The arm or

leg of the patient was immobilized in a carbon-fiber shell. An

anteroposterior scout view was used to define the measured

volume of interest (VOI).(17) At each site, a stack of 110 parallel CT

slices with an isotropic voxel size of 82mm was obtained, thus

delivering a 3D representation of approximately 9mm in the

axial direction. The most distal CT slice was placed 9.5 and

22.5mm proximal to the endplate of the radius and tibia,

respectively. Quality control was performed by daily scans of

a phantom containing rods of HA (densities of 0 to 800mg HA/

cm3) embedded in a soft-tissue–equivalent resin (QRM,

Moehrendorf, Germany). The coefficient of variation (CV) for

the phantom densities varied from 0.05% to 0.9%.

The VOI is separated into cortical and trabecular regions using

a threshold-based algorithm. This threshold was set to one-third

the cortical vBMD (D.cort). Cortical thickness (C.Th) was defined

as the mean cortical volume divided by the outer bone surface.

Trabecular vBMD (D.trab, mg HA/cm3) was computed as the

average vBMD in the trabecular VOI. Trabecular bone volume

(BV) fraction [BV/trabecular volume (TV), %] was derived

from D.trab assuming fully mineralized bone to have a mineral

density of 1200mg HA/cm3 {ie, BV/TV (%)¼ 100� [D.trab

Journal of Bone and Mineral Research 1359

(mg HA/cm3)/1.2 g HA/cm3]}. Trabecular elements were identi-

fied by the midaxis transformation method, and the distance

between themwas assessed three-dimensionally by the distance

transformmethod. Trabecular number (Tb.N, mm�1) was defined

as the inverse of the mean spacing of the midaxes. Trabecular

thickness (Tb.Th, mm) and separation (Tb.Sp, mm) were derived

from BV/TV and Tb.N: Tb.Th¼ (BV/TV)/Tb.N and Tb.Sp¼ (1 – BV/

TV)/Tb.N. Intraindividual distribution of separation (Tb.SpSD, mm)

was quantified by standard deviation of Tb.Sp, a parameter

reflecting the heterogeneity of the trabecular network. The CVs

for the parameters of the radius and tibia, respectively, were as

follows: total vBMD (D.tot), 0.9% and 1.3%; D.cort, 0.7% and 0.9%;

C.Th, 1.2% and 0.9%; D.trab, 1.0% and 1.5%; Tb.N, 3.0% and 3.8%;

Tb.Th, 3.2% and 4.4%; Tb.Sp, 2.8% and 4.3%; and Tb.NSD, 2.5%

and 3.3%. Sixty-nine scans of the distal radius and 29 scans of the

distal tibia were excluded because of poor quality owing to

movement (nonuniform contour of the cortical bone).

Dual-energy X-ray absorptiometry (DXA)

Areal bone mineral density (aBMD) was measured at the lumbar

spine, total hip, and ultradistal nondominant forearm by DXA

using the Hologic Discovery A device. The long-term stability of

the device was assessed by daily measurements of the

commercial phantom of the lumbar spine. The long-term CV

of the phantom was 0.35%.

Table 1. Comparison of Men Who Did and Did Not Have Prevalent

Fracture (�), n¼ 743

Age (years) 69� 9

Weight (kg) 79� 12

Height (cm) 169.3� 6.6

Areal bone mineral density (g/cm2)

Lumbar spine 1.052� 0.185

Total hip 0.971� 0.133

UD radius 0.469� 0.072

Distal radius

D.tot (mg/cm3) 299.8� 63.2

D.cort (mg/cm3) 809.1� 70.2

C.Th (mm) 0.721� 0.220

D.trab (mg/cm3) 177.0� 38.7

Tb.N (1/mm) 1.87� 0.25

Tb.Th (mm) 78.6� 11.8

Tb.Sp (mm) 458 [408; 507]

Tb.SpSD (mm) 194 [168; 223]

Distal tibia

D.tot (mg/cm3) 294.3� 56.5

D.cort (mg/cm3) 840.6� 57.0

C.Th (mm) 1.22� 0.29

D.trab (mg/cm3) 175.0� 37.4

Tb.N (1/mm) 1.75� 0.29

Tb.Th (mm) 83.3� 13.0

Tb.Sp (mm) 487 [429; 555]

Tb.SpSD (mm) 228 [191; 267]

�p adjusted for age and weight; ��p adjusted for age, weight, and aBMD [ultra

total hip aBMD for the parameters of the distal tibia]. D.tot¼ total vBMD; D.cTb.N¼ trabecular number; Tb.Th¼ trabecular thickness; Tb,Sp¼ trabecular spa

1360 Journal of Bone and Mineral Research

Statistical analysis

All calculations were performed using the SAS Version 9.1

software (SAS Institute, Inc., Cary, NC, USA). Data are presented as

mean and SD or as median and interquartile range. Analysis of

covariance was used for multivariate comparisons of continuous

variables. Tb.Sp and Tb.SpSD had skewed distributions and were

log-transformed. The odds ratios (ORs) for the presence of

fracture were calculated using logistic regression. The analysis of

covariance and logistic regression models for all fractures and

vertebral fractures were adjusted for age andweight. Themodels

for the assessment of peripheral fractures were adjusted for age,

weight, and height. The variable that was most strongly

associated with vertebral fractures was assessed using the

stepwise logistic regression. In the logistic regression, we had

90% power to detect a 1.4 increase in the fracture risk per 1 SD

change as significant at the level of p< .05. In the bivariate

comparisons of two groups, we had 90% power to detect a 0.35

SD difference as significant at the level of p< .05.

Results

All prevalent fractures

Men who had low-trauma fractures were older, slightly shorter,

and had a lower aBMD (Table 1). At the distal radius and distal

Fractures

Fracture (þ), n¼ 177 p� p��

73� 8 <.001

78� 11 .45

167.1� 6.1 <.001

0.965� 0.164 <.001

0.892� 0.138 <.001

0.423� 0.069 <.001

265.3� 60.4 <.001 .85

775.2� 79.4 <.001 .79

0.609� 0.204 <.001 .64

157.0� 37.2 <.001 .70

1.76� 0.26 <.001 .25

73.9� 11.7 <.001 .58

494 [440; 546] <.001 .25

215 [185; 256] <.001 .32

264.4� 57.6 <.001 .22

807.0� 85.2 <.001 .08

1.06� 0.31 <.001 .07

157.3� 36.9 <.001 .15

1.63� 0.31 <.001 .05

80.6� 13.2 .06 .93

529 [459; 603] <.001 <.05

248 [211; 304] <.001 .06

distal radius aBMD (UD aBMD) for the parameters of the distal radius and

ort¼ cortical vBMD; C,Th¼ cortical thickness; D.trab¼ trabecular vBMD;cing; Tb.SpSD¼ trabecular distribution.

SZULC ET AL.

Table 2. Age- and Weight-Adjusted Association of the Microarchitectural Parameters at the Distal Radius and the Distal Tibia With the

Presence of Fractures (All, Vertebral, Peripheral) Without and With Additional Adjustment for Areal Bone Mineral Density

Distal radius (OR, 95% CI) Distal tibia (OR, 95% CI)

þ UD aBMD þ Total-hip aBMD

All fractures

D.tot 1.61 (1.32, 1.97)d 1.03 (0.73, 1.46) 1.59 (1.32, 1.92)d 1.15 (0.91, 1.46)

D.cort 1.36 (1.13, 1.64)d 1.00 (0.79, 1.26) 1.44 (1.22, 1.71)d 1.15 (0.94, 1.39)

C.Th 1.54 (1.26, 1.89)d 1.08 (0.81, 1.43) 1.59 (1.31, 1.91)d 1.22 (0.98, 1.52)

D.trab 1.57 (1.30, 1.90)d 1.06 (0.77, 1.45) 1.54 (1.28, 1.85)d 1.17 (0.94, 1.46)

Tb.N 1.45 (1.21, 1.72)d 1.11 (0.89, 1.38) 1.53 (1.27, 1.83)d 1.22 (0.99, 1.49)

Tb.Th 1.39 (1.15, 1.68)d 0.93 (0.73, 1.19) 1.18 (0.99, 1.41) 0.99 (0.82, 1.19)

Tb.Sp 1.38 (1.19, 1.61)d 1.08 (0.88, 1.31) 1.44 (1.24, 1.68)d 1.19 (1.01, 1.41)a

Tb.SpSD 1.22 (1.07, 1,39)c 1.01 (0.88, 1.17) 1.25 (1.10, 1.43)b 1.09 (0.97, 1.23)

Vertebral fractures

D.tot 1.79 (1.38, 2.33)d 1.46 (0.91, 2.33) 1.79 (1.40, 2.29)d 1.28 (0.94, 1.75)

D.cort 1.66 (1.32, 2.07)d 1.39 (1.06, 1.84)a 1.64 (1.34, 2.01)d 1.33 (1.05, 1.68)a

C.Th 1.89 (1.44, 2.49)d 1.61 (1.12, 2.32)a 1.77 (1.40, 2.25)d 1.36 (1.02, 1.79)a

D.trab 1.48 (1.17, 1.86)d 0.95 (0.64, 1.40) 1.57 (1.25, 1.97)d 1.13 (0.85, 1.49)

Tb.N 1.37 (1.11, 1.69)c 1.04 (0.80, 1.37) 1.56 (1.25, 1.95)d 1.19 (0.92, 1.54)

Tb.Th 1.35 (1.06, 1.71)a 0.91 (0.67, 1.23) 1.17 (0.93, 1.46) 0.95 (0.74, 1.20)

Tb.Sp 1.34 (1.13, 1.59)d 1.08 (0.87, 1.36) 1.45 (1.23, 1.72)d 1.19 (0.97, 1.26)

Tb.SpSD 1.21 (1.05, 1.39)b 1.05 (0.90, 1.23) 1.25 (1.09, 1.43)c 1.11 (0.97, 1.26)

Peripheral fractures

D.tot 1.43 (1.12, 1.83)c 0.91 (0.58, 1.42) 1.43 (1.14, 1.79)c 1.04 (0.78, 1.40)

D.cort 1.12 (0.89, 1.42) 0.79 (0.58, 1.06) 1.28 (1.05, 1.55)a 0.99 (0.78, 1.25)

C.Th 1.26 (0.98, 1.61) 0.81 (0.57, 1.16) 1.42 (1.13, 1.78)c 1.07 (0.82, 1.39)

D.trab 1.55 (1.23, 1.96)d 1.30 (0.87, 1.94) 1.45 (1.15, 1.79)c 1.05 (0.80, 1.37)

Tb.N 1.47 (1.19, 1.82)d 1.25 (0.95, 1.63) 1.49 (1.19, 1.87)d 1.11 (0.86, 1.44)

Tb.Th 1.32 (1.04, 1.67)a 0.97 (0.71, 1.32) 1.10 (0.89, 1.37) 0.94 (0.78, 1.19)

Tb.Sp 1.33 (1.13, 1.58)d 1.14 (0.91, 1.43) 1.32 (1.11, 1.56)c 1.06 (0.87, 1.30)

Tb.SpSD 1.19 (1.04, 1.37)a 1.06 (0.91, 1.24) 1.17 (1.03, 1.33)d 1.04 (0.90, 1.19)

UD aBMD¼ultradistal radius areal bonemineral density; D.tot¼ total vBMD; D.cort¼ cortical vBMD; C.Th¼ cortical thickness; D.trab¼ trabecular vBMD;

Tb.N¼ trabecular number; Tb.Th¼ trabecular thickness; Tb.Sp¼ trabecular spacing; Tb.SpSD¼ trabecular distribution.ap< .05; bp< .01; cp< .005; dp< .001.

tibia, almost all microarchitectural parameters differed

between the men who did and did not have fractures. At

the radius, all the parameters became nonsignificant after

adjustment for the ultradistal radius aBMD. Some parameters

of the distal tibia remained weakly significant after adjust-

ment for total-hip aBMD. In the logistic regression models

adjusted for age and weight, almost all the microarchitectural

parameters of the distal radius and tibia were significantly

associated with the presence of fractures (Table 2). However,

almost all the odds ratios became nonsignificant after adjust-

ment for aBMD.

One hundred and seventeen men who had one fracture had

lower D.tot, C.Th, D.trab, and Tb.N (3.0% to 8.5%, 0.20 to 0.36 SD,

p< .05 to p< .001) at both skeletal sites compared with men

without fracture. Sixty men who had more than one fracture had

lower D.tot, D.trab, Tb.N, D.cort, and C.Th (4.1% to 15.7%, 0.47 to

0.70 SD, p< .005 to p< .001). All the differences became

nonsignificant after adjustment for aBMD. At both skeletal sites,

Tb.Sp and Tb.SpSD were higher in men with multiple fractures

(11.6% to 27.0%, 0.77 to 0.87 SD, p< .001), not in men with one


fracture. The differences remained significant after ajustment for

aBMD (p< .005).

In the age- and weight-adjusted polytomous logistic regres-

sion models, all microarchitectural parameters of distal radius

(except D.cort) and tibia (except Tb.Th) were associated with the

presence of one fracture (OR¼ 1.16 to 1.47 per 1 SD change,

p¼ .05 to .001). However, ORs lost significance after additional

adjustment for aBMD. In similar models, all the parameters

(except Tb.Th) of the distal radius and tibia were associated with

the multiple fractures (OR¼ 1.50 to 2.07 per 1 SD change,

p< .001). After adjustment for aBMD, only distal radius Tb.N as

well as Tb.Sp and Tb.SPSD of both skeletal sites remained

significantly associated with the multiple fractures (OR¼ 1.50 to

1.82 per 1 SD change, p< .05).

Vertebral fractures

Menwho had vertebral fractures were older and had lower aBMD

values (Table 3). All the microarchitectural parameters except

Tb.Th at the distal tibia differed significantly between the men


Table 3. Comparison of Bone Microarchitecture Parameters at the Distal Radius and Distal Tibia According to the Presence of Vertebral

Fractures and of Peripheral Fractures

Vertebral fractures Peripheral fractures

Fx (�) (n¼ 822) Fx (þ) (n¼ 98) p� Fx (�) (n¼ 820) Fx (þ) (n¼ 100) p��

Age (years) 69� 9 74� 8 <.001 70� 9 72� 8 <.05

Weight (kg) 79� 11 77� 11 .26 79� 11 78� 11 .27

Height 169� 7 166� 6 <.001 169� 7 167� 6 <.05

Hip aBMD (g/cm2) 0.966� 0.133 0.875� 0.140 <.001 0.964� 0.135 0.894� 0.142 <.001

UD aBMD (g/cm2) 0.465� 0.072 0.419� 0.075 <.001 0.464� 0.073 0.427� 0.068 <.001

Distal radius

D.tot (mg/cm3) 298.2� 62.9 255.2� 61.6 <.001 295.9� 64.0 274.2� 62.4 <.005

D.cort (mg/cm3) 809.0� 69.9 755.0� 82.6 <.001b 804.7� 72.8 792.1� 75.3 .35

C.Th (mm) 0.718� 0.217 0.561� 0.206 <.001a 0.706� 0.223 0.654� 0.206 .09

D.trab (mg/cm3) 177.3� 38.7 155.3� 38.7 <.001 175.0� 39.1 157.3� 36.8 <.001

Tb.N (1/mm) 1.86� 0.25 1.75� 0.29 <.005 1.86� 0.26 1.75� 0.25 <.001

Tb.Th (mm) 78.3� 11.9 73.3� 11.2 <.01 78.1� 11.9 74.6� 12.3 <.05

Tb.Sp (mm) 460 [412; 511] 494 [438; 550] <.001 459 [412; 511] 496 [452; 545] <.001

Tb.SpSD (mm) 195 [169; 225] 216 [185; 260] <.001 195 [169; 225] 216 [186; 263] <.001

Distal tibia

D.tot (mg/cm3) 293.0� 56.1 255.5� 58.5 <.001 291.3� 57.1 268.9� 59.9 <.001

D.cort (mg/cm3) 839.9� 57.8 791.5� 96.3 <.001b 837.2� 61.1 814.8� 86.5 <.005

C.Th (mm) 1.21� 0.29 1.01� 0.33 <.001a 1.20� 0.30 1.08� 0.31 <.001

D.trab (mg/cm3) 173.9� 37.3 154.3� 36.2 <.001 173.4� 37.6 158.2� 37.5 <.005

Tb.N (1/mm) 1.75� 0.29 1.61� 0.33 <.001 1.75� 0.30 1.63� 0.30 <.005

Tb.Th (mm) 83.1� 13.1 80.1� 12.1 .10 83.0 �12.9 81.3� 14.3 .18

Tb.Sp (mm) 490 [432; 558] 541 [464; 625] <.001 490 [433; 558] 528 [469; 603] <.005

Tb.SpSD (mm) 229 [193; 270] 252 [218; 303] <.001 228 [193; 270] 253 [211; 308] <.05

�Adjusted for age and weight.��Adjusted for age, weight, and height.ap< .05; bp< .005—after additional adjustment for areal bone mineral density (ultradistal radius for the parameters of the distal radius and total hip

for the parameters of the distal tibia). D.tot¼ total volumetric bone mineral density (vBMD); D.cort¼ cortical vBMD; C.Th¼ cortical thickness;

D. trab¼ trabecular vBMD; Tb.N¼ trabecular number; Tb.Th¼ trabecular thickness; Tb.Sp¼ trabecular spacing; Tb.SpSD¼ trabecular distribution.

who did and did not have vertebral fractures. After adjustment

for aBMD, men with vertebral fractures still had lower D.cort and

C.Th at both skeletal sites.

In the age- and weight-adjusted logistic regression models, all

the microarchitectural parameters except Tb.Th at the distal tibia

were associated with the presence of vertebral fractures

(Table 2). After adjustment for aBMD, D.cort and C.Th were

associated with the presence of vertebral fractures, whereas the

ORs for the trabecular parameters became nonsignificant at both

sites. In the stepwise logistic regression, D.cort entered the

model as the first and strongest parameter (before aBMD) for

both the radius and the tibia. When D.cort was removed from the

variables, only C.Th and aBMD were retained in the models for

both skeletal sites.

Thenmenwere analyzed according to the number of vertebral

fractures. Compared with the controls, 61 men with one fracture

had lower D.tot, D.cort, and C.Th at both skeletal sites (p< .01 to

p< .001; Fig. 1). D.cort at both skeletal sites and C.Th at the radius

were lower (p< .005) after adjustment for aBMD. In 37 men who

had two or more vertebral fractures, all the microarchitectural

parameters except Tb.Th were significantly different (p< .005 to

p< .001) from the controls. After adjustment for aBMD, only


Tb.Sp and Tb.SpSD at both skeletal sites (p< .05) remained

significantly different from the controls.

In men who had grade 1 fractures, no microarchitectural

parameter differed from the control group (Table 4). Men who

had grade 2 fractures had lower D.tot, D.cort, and D.trab at both

skeletal sites. At the distal tibia, they also had lower Tb.N and

higher Tb.Sp and Tb.SpSD. After adjustment for aBMD, D.cort and

C.Th at both skeletal sites remained lower compared with

controls. In 20 men who had grade 3 fractures, all the

microarchitectural parameters except Tb.Th differed significantly

from the controls. After adjustment for aBMD, Tb.N, Tb.Sp, and

Tb.SpSD remained significantly different from the controls at

both skeletal sites.

In the polytomous logistic regression models adjusted for age

and weight, all the microarchitectural parameters of the distal

radius and tibia were significantly associated with the grade 2

and 3 fractures (OR¼ 1.25 to 1.94 per 1 SD change, p¼ .05 to

p< .001) but not with the grade 1 fractures (OR¼ 1.02 to 1.68,

p> .10). After adjustment for aBMD, only D.cort remained weakly

significantly associated with the grade 2 and 3 fractures (radius:

OR¼ 1.33, 95% CI 1.00–1.79, p¼ .05; tibia: OR¼ 1.34, 95% CI

1.03–1.75, p< .05).

SZULC ET AL.

Fig. 1. Association between the number of vertebral fractures (0¼ no fracture, n¼ 822; 1¼ one vertebral fracture, n¼ 61; �2¼ 2 or more vertebral

fractures, n¼ 37) and bone microarchitectural parameters at the distal tibia after adjustment for age and body weight.

All the calculations provided similar results when men who

reported peripheral fractures but did not have vertebral fractures

were excluded from the analysis.

Peripheral fractures

At the distal radius and tibia, almost all the microarchitectural

parameters differed between the men who did and did not

report low-trauma peripheral fractures (Table 3). After adjust-

ment for aBMD, all the differences became nonsignificant. In the

logistic regression models adjusted for age and weight, the

microarchitectural parameters of the distal radius (except D.cort

and C.Th) and the distal tibia (except Tb.Th) were significantly

associated with the presence of peripheral fractures. All the ORs

lost significance after adjustment for aBMD.

Eighty-five men who had one peripheral fracture had lower

D.trab at both skeletal sites, lower C.Th at the distal tibia as well as

at the distal radius, lower Tb.N, and higher Tb.Sp and Tb.SpSD (all

p< .05; Fig. 2). After adjustment for aBMD, all the differences

became nonsignificant. Fifteen men who had two or more

peripheral fractures had lower D.tot, D.trab, and Tb.N as well as

higher Tb.Sp and Tb.SpSD at both skeletal sites (p< .05 to

p< .001). They also had lower C.Th and D.cort at the distal tibia

(p< .005). After adjustment for aBMD, Tb.Sp and Tb.SpSD at both

skeletal sites (p< .05 to p< .005) as well as Tb.N at the distal

radius and D.cort at the distal tibia (both p< .05) remained

significantly different in men with multiple peripheral fractures

compared with controls.


Using polytomous logistic regression adjusted for age, weight,

and height, D.trab, Tb.N, Tb.Sp, and Tb.SpSD at the distal radius

and tibia were associated with multiple fractures (OR¼ 1.68 to

2.66 per 1 SD change, p< .001). At the distal radius, Tb.N, Tb.Sp,

and Tb.SpSD remained associated weakly significantly with

multiple fractures after adjustment for the ultradistal radius

aBMD (OR¼ 1.55 to 1.93, p< .05). Associations of D.trab, Tb.N,

Tb.Sp, and Tb.SpSD with single peripheral fractures were weaker

(OR¼ 1.23 to 1.47, p< .05) and nonsignificant after adjustment

for aBMD. At the distal tibia, D.cort and C.Th were associated with

the presence of multiple peripheral fractures (OR¼ 1.87 and

OR¼ 2.40 per 1 SD change, p< .005). After adjustment for aBMD,

the associations of cortical parameters with peripheral fractures

became nonsignificant.

When the analyses were limited to 49 men who had sustained

the most recent low-trauma peripheral fractures 10 years or less

prior to recruitment, all the OR values were similar although less

significant owing to lower statistical power. All the calculations

provided similar results when men who had vertebral fractures

but did not report peripheral fractures were excluded from the

analysis.

Discussion

In older men, poor cortical bone status was associated with the

presence of vertebral fracture independent of aBMD. Multiple

fractures and severe (grade 3) vertebral fractures were associated


Table 4. Comparison of Bone Microarchitecture Parameters at the Distal Radius and Tibia According to the Severity of the Vertebral

Fractures

No fracture (n¼ 822) Grade 1 (n¼ 18) Grade 2 (n¼ 60) Grade 3 (n¼ 20)

Age (years) 70� 9 72� 9 75� 8d 74� 9a

Weight (kg) 79� 11 81� 11 79� 11 71� 11c

Bone mineral density (g/cm2)

Lumbar spine 1.044� 0.184 1.018� 0.160 0.969� 0.182c 0.921� 0.142b

Total hip 0.964� 0.133 0.962� 0.115 0.881� 0.124d 0.843� 0.158d

UD radius 0.464� 0.072 0.437� 0.054 0.434� 0.071c 0.414� 0.095c

Distal radius

D.tot (mg/cm3) 296.4� 62.1 274.4� 57.5 268.4� 57.1c 251.2� 77.4c

D.cort (mg/cm3) 806.4� 69.9 777.6� 69.4 771.6� 38.7d,� 761.8� 114.2b

C.Th (mm) 0.712� 0.218 0.621� 0.217 0.598� 0.191d,� 0.598� 0.246a

D.trab (mg/cm3) 174.8� 38.7 166.2� 28.3 163.9� 38.7a 140.5� 41.4d

Tb.N (1/mm) 1.86� 0.25 1.85� 0.19 1.80� 0.28 1.60� 0.34d,�

Tb.Th (mm) 78.1� 11.9 74.7� 10.1 75.2� 10.7 72.7� 14.1

Tb.Sp (mm) 460 [412; 511] 468 [433; 507] 487 [419; 550] 530 [473; 675]d,§

Tb.SpSD (mm) 196 [169; 226] 214 [183; 221] 211 [183; 264] 249 [212; 312]d,�

Distal tibia

D.tot (mg/cm3) 292.0� 58.0 815.9� 87.7 799.7� 96.3d 797.4� 106.0b

D.cort (mg/cm3) 838.2� 58.0 815.9� 87.7 799.7� 96.3d,# 797.4� 106.0b

C.Th (mm) 1.20� 0.29 1.11� 0.35 1.03� 0.29d,� 1.03� 0.41a

D.trab (mg/cm3) 173.5� 37.4 165.0� 21.6 160.2� 34.1a 142.2� 45.8d

Tb.N (1/mm) 1.75� 0.29 1.70� 0.33 1.65� 0.27a 1.49 �0.39d,�

Tb.Th (mm) 83.1� 13.1 82.8� 14.5 80.8� 11.0 78.8� 13.3

Tb.Sp (mm) 490 [433; 559] 494 [418; 594] 526 [453; 589]a 578 [502; 883]d,§

Tb.SpSD (mm) 229 [194; 271] 227 [190; 298] 249 [211; 285]a 303 [240; 412]d,§

D.tot¼ total volumetric bone mineral density (vBMD); D.cort¼ cortical vBMD; C.Th¼ cortical thickness; D.trab¼ trabecular vBMD;

Tb.N¼ trabecular number; Tb,Th¼ trabecular thickness; Tb.Sp¼ trabecular spacing; Tb.SpSD¼ trabecular distribution.ap< .05; bp< .01; cp< .005; dp< .001—adjusted for age and weight.�p< .05; #p< .01; §p< .005—after additional adjustment for areal bone mineral density (ultradistal radius for the parameters of the distal radius and

total hip for the parameters of the distal tibia).

with impaired trabecular microarchitecture. The association

between bone microarchitecture and prior peripheral fractures

was weaker and, for most of the parameters, became

nonsignificant after adjustment for aBMD. Men with vertebral

fractures, but not peripheral fractures, were shorter, most

probably owing to the vertebral fractures.

Moderate and severe vertebral fractures were associated with

poor bone microarchitecture. We excluded high-trauma frac-

tures and nonfracture deformities. Specificity was preferred to

sensitivity. The retained fractures are probably fragility fractures.

Mild vertebral deformities are often due to arthritis or Scheuer-

man disease. The incidence of vertebral fractures and arthritic

deformities increases with age; however, only fractures are

related to low aBMD.(25,26) High-trauma vertebral fractures and

Scheuerman disease are more frequent in men than in women,

whereas the reverse is the case for the osteoporotic vertebral

fracture.(27,28)

Vertebral fractures are a hallmark of osteoporosis. Many of

them occur without preceding trauma. Bonemicroarchitecture is

a determinant of the strength of vertebral bodies.(13) Both men

and women with vertebral fractures had poor trabecular

microarchitecture.(15,29,30) Patients with severe or multiple

vertebral fractures have lower aBMD values than those with

mild or one fracture.(31,32) In postmenopausal women, more


severe vertebral fractures were related to poorer bone

microarchitecture assessed by HR-pQCT or bone histomorpho-

metry.(15,19) Similar association for bone microarchitecture

assessed by bone histomorphometry was found in osteoporotic

men.(20,21) Here we show similar trends for HR-pQCT.

Cortical bone seems to play amajor role in the pathogenesis of

vertebral fractures in men. D.cort entered the stepwise logistic

regression models as the strongest predictor of vertebral

fractures, even before aBMD. Our results are in line with the

data that men with vertebral fractures had higher porosity than

men without fractures.(17) Men with vertebral fractures also had

decreased Tb.N and poor trabecular connectivity in bone

biopsy.(16,17) However, in these studies, more men had multiple

vertebral fractures than in our cohort. Moreover, in both studies,

the men with vertebral fractures were compared not with the

general population but with men who had osteoporosis

diagnosed by DXA (without fracture).

In postmenopausal women, poor trabecular microarchitecture

was the major determinant of vertebral fragility, whereas cortical

deterioration played a secondary role.(14,19,29,33) However, the

morphologic basis of age-related bone loss differs between the

sexes. Age-related decrease in trabecular vBMD at the spine and

hip and deterioration of trabecular connectivity are greater in

women than in men.(34–36) The decrease in Tb.N underlying

SZULC ET AL.

Fig. 2. Association between the number of peripheral fractures (0¼no fracture, n¼ 820; 1¼one peripheral fracture, n¼ 85;�2¼ two or more peripheral

fractures, n¼ 15) and bone microarchitectural parameters at the distal tibia after adjustment for age, weight, and height.

trabecular bone loss in women is more deleterious for bone

strength than the trabecular thinning predominating in

men.(37,38) Moreover, the age-related decrease (number of SDs

below the mean in young men) is greater for D.cort and C.Th

than for Tb.N and Tb.Th.(39) Thus, in older men, cortical

deterioration may be the weakest link determining vertebral

fragility.

Men with peripheral fractures had lower D.cort and D.trab, in

line with previous data.(7–11) In addtion, we show that lower

D.trab in these men can be due to the lower number of more

heterogeneously distributed trabeculae. However, only men

with multiple peripheral fractures had poor bone microarchi-

tecture after adjustment for aBMD. Since peripheral fractures

often occur after a fall, health status prior to the fracture may

determine the risk of fall and fracture.(40,41) Mechanisms of

peripheral fractures vary according to the skeletal site (eg, crush

at the wrist, bending for the cervical fracture, torsion at the

ankle). Resistance to bending and torsion depends on the bone

tissue placed far from the neutral axis of the tubular bone.(42)

Thus, in the pathogenesis of peripheral fractures, bone size and

shape may play a more important role than bone microarchi-

trecture inside bone.(43,44)

Most of the associations became nonsignificant after adjust-

ment for aBMD. For the distal radius, the analyses were adjusted

for aBMD of the same skeletal site. Since aBMD subsumes various

bone components, it may reflect bone strength better than any

single microarchitectural parameter. The associations between

bone microarchitecture of the distal tibia and the presence of


fragility fractures also weakened after adjustment for aBMD of

the total hip, which is a distant skeletal site. It indicates that bone

mass at one skeletal site reflects the general skeletal status. This

is also consistent with the data that aBMD at one skeletal site

predicts fractures at other sites.(45)

The occurrence, skeletal site, and circumstances of peripheral

fractures were self-reported and not ascertained further. There

was no formal adjudication or inspection of radiographs or

medical records. In half the men who reported peripheral

fractures, the most recent fracture had occurred more than 10

years before recruitment. Thus the current status of bone

microarchitecture may not correspond with that at the moment

when the fracture occurred. By contrast, current microarchitec-

tural status may predict future peripheral fracture regardless of

aBMD, especially in a short-term study, as described by Scheu

and colleagues.(11) In addition, in the study by Scheu and

colleagues, incident fractures were ascertained systematically by

a physician, and the parameters that were most predictive

depended in part on bone size.

The relationship between bone microarchitecture and

fractures varied according to the severity and number of

fractures. D.cort and C.Th are lower in grade 1 fractures (although

nonsignificantly, probably owing to the low number of patients

and insufficient power), but they did not differ among the three

fracture groups (<0.2 SD between grade 1 and grade 3 groups).

D.trab, Tb.N, Tb.Sp, and Tb.SpSD were nearly normal in the grade

1 group and deteriorated with increasing fracture severity (>0.6

SD between grade 1 and grade 3 groups). In men with multiple


vertebral or peripheral fractures, microarchitectural parameters

were poor compared with controls. However, in these men and

in men with grade 3 fractures, only Tb.N, Tb.Sp, and Tb.SpSD

were higher than in the controls after adjustment for aBMD.

Thus cortical degradation may be the first signal of lower bone

strength in men. D.cort and C.Th in the grade 2 group were

significant after adjustment for aBMD, which is moderately

decreased and partly driven by the well-preserved trabecular

bone. In men with grade 3 vertebral fractures or men with

multiple vertebral or peripheral fractures, the decrease in aBMD

was driven by the parallel severe cortical and trabecular bone

loss. Thus only the parameters of trabecular number and

distribution that are more poorly reflected by aBMD remained

significant after adjustment for aBMD.

The strengths of our study are the large cohort, evaluation of

vertebral fractures using validated criteria, and assessment of the

bone microarchitecture at the weight-bearing and non-weight-

bearing sites by HR-pQCT. We recognize limitations. The cross-

sectional design limits inferences on cause and effect. Older

volunteers may not be representative of men in their age range.

Semiquantitative diagnosis of vertebral fractures and differentia-

tion between mild vertebral fractures and nonosteoporotic

deformities is subjective. Peripheral fractures were not formally

adjudicated. In HR-pQCT, Tb.Th Tb.Sp, and C.Th are calculated,

not measured. Assessment of microarchitectural parameters may

be inaccurate owing to partial-volume effects. In particular,

estimation of D.cort and C.Th may be erroneous mainly in the

oldest men with thin cortex who had more vertebral fractures.

HR-pQCT does not account for the intrinsic age-related

deterioration of the cortical bone charaterized by microdamage,

imperfections of bone mineral, and abnormalities in posttransla-

tional modifications of bone proteins.(46)

Thus, in older men, vertebral fractures are associated with poor

bone microarchitecture, even after adjustment for aBMD. The

association between peripheral fractures and bone microarch-

itecture was weaker and lost significance after adjustment for

aBMD. These cross-sectional data point to the role of bone

microarchitecture as an independent determinant of bone

fragility in men; however, they need to be confirmed in

prospective studies.

Disclosures

All the authors state that they have no conflicts of interest.

Acknowledgments

This work was supported by grants from the Roche Pharmaceu-

tical Company, Basle, Switzerland, from Agence Nationale de la

Recherche, and from Hospices Civils de Lyon, France.

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