Men with metabolic syndrome have lower bone mineral density but lower fracture risk—the MINOS...

$: Men with metabolic syndrome have lower bone mineral density but lower fracture risk—the MINOS study$
ORIGINAL ARTICLE JJBMR
Men with Metabolic Syndrome Have Lower Bone MineralDensity but Lower Fracture Risk—the MINOS Study
Pawel Szulc ,1 Annie Varennes ,2 Pierre D Delmas ,1 Joelle Goudable ,2 and Roland Chapurlat1

1INSERM 831 Unit, Hopital Edouard Herriot, University of Lyon, Lyon, France2Central Biochemical Laboratory, Hopital Edouard Herriot, University of Lyon, Lyon, France

ABSTRACTData on the association of the metabolic syndrome (MetS) with bone mineral density (BMD) and fracture risk in men are inconsistent. We

studied the association between MetS and bone status in 762 older men followed up for 10 years. After adjustment for age, body mass

index, height, physical activity, smoking, alcohol intake, and serum 25-hydroxycholecalciferol D and 17b-estradiol levels, men with MetS

had lower BMD at the hip, whole body, and distal forearm (2.2% to 3.2%, 0.24 to 0.27 SD, p< .05 to .005). This difference was related to

abdominal obesity (assessed by waist circumference, waist-hip ratio, or central fat mass) but not other MetS components. Men with MetS

had lower bone mineral content (3.1% to 4.5%, 0.22 to 0.29 SD, p< .05 to 0.001), whereas differences in bone size were milder. Men

with MetS had a lower incidence of vertebral and peripheral fractures (6.7% versus 12.0%, p< .05). After adjustment for confounders,

MetS was associated with a lower fracture incidence [odds ratio (OR)¼ 0.33, 95% confidence interval (CI) 0.15–0.76, p< .01]. Among the

MetS components, hypertriglyceridemia was most predictive of the lower fracture risk (OR¼ 0.25, 95%CI 0.10–0.62, p< .005). Lower

fracture risk in men with MetS cannot be explained by differences in bone size, rate of bone turnover rate and bone loss, or history of falls

or fractures. Thus older men with MetS have a lower BMD related to the abdominal obesity and a lower risk of fracture related to

hypertriglyceridemia. MetS probably is not a meaningful concept in the context of bone metabolism. Analysis of its association with

bone-related variables may obscure the pathophysiologic links of its components with bone status. � 2010 American Society for Bone

and Mineral Research.

KEY WORDS: METABOLIC SYNDROME; BONE MINERAL DENSITY; FRACTURE; MEN; ABDOMINAL OBESITY

Introduction

Metabolic syndrome (MetS) is characterized by abdominal

obesity, hypertension, insulin resistance, and dyslipide-

mia.(1) It is a public health problem because about 25% of the

adult population has MetS.(1) MetS is associated with a higher risk

of cardiovascular morbidity and mortality and a higher risk of

onset of type 2 diabetes.(2,3) Several studies have assessed the

association between MetS and bone status with inconsistent

results. Subjects with MetS had lower bone mineral density

(BMD) but also lower fracture risk.(4-7) Cardiovascular diseases

and osteoporosis may coexist in men,(8,9) but their common risk

factors and mechanisms are not known. Thus we studied

various aspects of the link between MetS and bone status in

men followed up for a long period of time in order to

establish whether MetS can be a risk factor for bone fragility in

men.

MetS is an association of clinical and biochemical findings that

coexist more frequently than expected by chance alone, but a

direct cause for their coexistence is not understood.(1,2)

Received in original form June 19, 2009; revised form November 10, 2009; accepte

Address correspondence to: Pawel Szulc, INSERM 831 Unit, Hopital Edouard Herriot,

Journal of Bone and Mineral Research, Vol. 25, No. 6, June 2010, pp 1446–1454

DOI: 10.1002/jbmr.13

� 2010 American Society for Bone and Mineral Research

1446

Components of MetS are associated with higher cardiovascular

risk, and their coexistence increases the cardiovascular risk more

than the sum of the influences of individual components. By

contrast, they may show different associations with bone

metabolism, mass, and fragility.

MetS is characterised by a hormonal and humoral status

whose components (which are risk factors of MetS or its

consequences) may have a protective or a negative effect on

bone.(1) In addition, one component of MetS may act on bone

through various mechanisms. Abdominal obesity is associated

with higher 17b-estradiol level and higher mechanical load,

which may protect bone, but also with low-grade inflammatory

syndrome, characterized by the secretion of proinflammatory

cytokines that stimulate bone resorption.(10,11) MetS is a

heterogeneous syndrome, and predominance of different

components in individual patients may contribute to incon-

sistent results regarding the relationship between MetS and

bone status.

We analyzed various aspects of bone status (ie, BMD,

bone size, bone turnover rate, bone loss, and bone fragility)

d December 17, 2009. Published online January 8, 2010.

Pavillon F, Place d’Arsonval, 69437 Lyon, France. E-mail: [email protected]

according to the presence or absence of MetS in a cohort of

older men followed up prospectively for 10 years. We

undertook this analysis to better understand bone status in

men with MetS, especially the discrepancy between lower areal

BMD and lower risk of fracture. Are they associated with different

components of the MetS? Can they be explained by differences

in bone size, bone turnover, rate of bone loss, propensity to fall,

or hormonal status between the men who do or do not have

the MetS?

Subjects and Methods

Cohort and study design

MINOS is a prospective cohort study of male osteoporosis(12)

with a primary aim to assess predictors of bone loss and fragility

fractures in men. Participants were recruited in 1995–1996 from

the Societe de Secours Miniere de Bourgogne (Social Security in

the Mines of Burgundy) rolls in Montceau les Mines (Saone

et Loire). The study was accepted by the local ethics committee

and performed in accordance with the Helsinki Declaration of

1975, as revised in 1983. Letters inviting participation into the

study were sent to a randomly selected sample of 3400 men

aged 50 to 85 years and living in Montceau les Mines and nearby

villages. Eight-hundred and forty-one men agreed to participate

and provided informed consent. Every 18 months for 7.5 years,

they replied to an epidemiologic questionnaire and had BMD

measurement. After 3 and 7.5 years, lateral spine radiographs

were performed. Then, for 2.5 years, the men were followed up

by phone or by mail to obtain information on incident

nonvertebral fractures.

This study was carried out on 762 men who had BMD

measurements, lateral radiographs of the spine, and blood and

urine collection at the baseline examination in 1995–1996.

Seventy-nine men refused bone densitometry, had radiographs

of poor quality, or did not have measurements of the

biochemical parameters of MetS. Participants were followed

from recruitment to the first of the following: fracture, last

contact, death, or end of follow-up.

Definition of metabolic syndrome

The diagnosis of MetS was established, according to the National

Cholesterol Education Program’s Adult Treatment Panel III

criteria, as the presence of three or more of the following:

fasting blood glucose level of 110mg/dL (6.1mmol/L) or greater,

fasting serum triglyceride level of 150mg/dL (1.695mmol/L) or

greater, serum high-density lipoprotein (HDL)–cholesterol of less

than 40mg/dL (1.04mmol/L), hypertension or antihypertensive

treatment, and waist circumference greater than 102 cm.(1) Waist

circumference was measured at the midpoint between the lower

rib margin and the iliac crest.

Assessment of fractures

At baseline, 108 men reported 143 fractures (vertebra 74 in 66

men, clavicle 4, proximal humerus 3, elbow 3, distal radius 17 in

15men, rib 14 in 12men, pelvis 1, distal femur 1, leg 8, ankle 15,

calcaneum 1, and metatarsal 2). Over 7.5 years, 28 vertebral

FRACTURE RISK: THE MINOS STUDY

fractures occurred in 27 men. A decrease in vertebral height of

3mm, or 15%, was considered an incident vertebral fracture.

During the 10-year follow-up, 65 low-trauma peripheral fractures

occurred in 61 men (clavicle 1, proximal humerus 7, distal radius

17, ulna 1, rib 17, pelvis 2, hip 5, distal femur 2, proximal tibia 2,

ankle 3, calcaneum 1, and metatarsal 7). Jointly, we recorded 93

incident fractures in 82 men.

Bone mineral density

BMD was measured at the lumbar spine (L2–L4), right hip

(femoral neck, trochanter, and total hip), and whole body by

dual-energy X-ray absorptiometry (DXA; Hologic QDR-1500,

Hologic, Inc., Waltham, MA, USA).(12) For the lumbar spine,

the coefficient of variation (CV) was 0.33% using a commercial

phantom and 0.62% using a human lumbar spine phantom

embedded in methyl metacrylate. For the total hip and its

components, CV was 0.81% to 0.94% using a hip phantom. BMD

of two regions of interest (ROIs) of the distal forearm was

measured using single-energy X-ray absorptiometry (Oste-

ometer DTX100, Rodovre, Denmark). The distal region includes

20mm of ulna and radius situated proximally to the site where

the spacing between the two bones is 8mm. The ultradistal

radius ROI is situated distally to the preceding ROI. For the distal

forearm BMD, CV was 0.47% using a commercial calibration

standard. All scans were analyzed manually. Three hip scans and

three forearm scans with positioning errors were excluded.

Biochemical and hormonal meausrements

Fasting serum and 24-hour urine samples were collected at

baseline at 8 a.m. and stored at –80 8C until assayed. Glucose was

mesured by the hexokinase method (Modular Analyzer, Roche,

Meylan, France) with a detection limit of 2mg/dL (0.11mmol/L)

and interassay CV of 1.0%. Triglycerides (TGs) were measured by

enzymatic colorimetric test (Modular Analyzer, Roche) with a

detection limit of 4mg/dL (0.05mmol/L) and interassay CV of

1.5%. HDL-cholesterol was measured by homogeneous enzy-

matic colorimetric test (Modular Analyzer, Roche) with a

detection limit of 3mg/dL (0.08mmol/L) and interassay CV of

0.6% to 0.95%.

Bone formation was assessed by serum levels of osteocalcin

(OC), bone-specific alkaline phosphatase (BAP), and N-terminal

propeptide of type I procollagen (P1NP).(13) Bone resorption was

assessed using 24-hour urinary excretion of total and free

deoxypyridinoline (DPD), as well as by serum and urinary levels

of C-terminal telopeptide of type I collagen (CTX-I).(13) Urinary

bone resorption markers levels were expressed per millimole of

creatinine (cr).

Serum 17b-estradiol and total testosterone were measured by

tritiated radioimmunoassay (RIA) after diethyether extraction.(14)

For testosterone, the detection limit is 0.06 nmol/L, and the

interassay CV is 10% for 1 nmol/L and 7.8% for 6 nmol/L. For 17b-

estradiol, the detection limit is 11 pmol/L, and the interassay CV is

12.1% for 21 pmol/L, 6% for 99 pmol/L, and 9.4% for a 169 pmol/

L. Sex hormone–binding globulin (SHBG) was measured by

immunoradiometric assay (125 I SBP Coatria, Bio-Merieux, Marcy

l’Etoile, France) with an interassay CV of 4.1% for a concentration

of 16 nmol/L and 5.3% for 100 nmol/L. The limit of detection is

Journal of Bone and Mineral Research 1447

Fig. 1. Proportion (%) of men according to the number of components of

the metabolic syndrome and prevalence of the metabolic syndrome

(MetS) in the MINOS cohort.

0.5 nmol/L. The apparent free testosterone concentration (AFTC)

was calculated as described by Vermeulen and colleagues.(15)

Serum concentration of bioavailable 17b-estradiol was calcu-

lated using the equations described by Sodegard.(16) Serum

25-hydroxycholecalciferol [25(OH)D] was measured by RIA

(Incstar Corp., Stillwater, MN, USA) after acetonitril extraction.(17)

This method excludes any interference from lipids. The detection

limit was 7.5 nmol/L, and the intraassay CV was 6.9% for 25 nmol/

L, 5.9% for 47 nmol/L, and 4.9% for 127 nmol/L. Interassay CVs

were 11% to 13%. Serum parathyroid hormone (PTH) was

measured by immunochemoluminometric assay (Magic Lite,

Ciba Corning Diagnostic, Medfield, MA, USA).(17) For the 4 pmol/L

level, intra- and interassay CVs were 5% and 7%, respectively. The

detection limit was 0.2 pmol/L.

Assessment of covariates

Participants completed questionnaires administered by an

interviewer to assess age, smoking, alcohol, education, physical

activity, medical history, and medication use. Alcohol intake was

assessed as the sum of current average weekly intakes of wine,

beer, and spirits expressed in grams per week. Education level

was assessed as greater than 8 years versus 8 or fewer years at

school. Current and past physical activity at work was evaluated

according to a self-reported four-level scale (low, medium, hard,

and very hard). Current leisure physical activity was calculated on

the basis of the overall amount of time (hours pert week) spent

walking, gardening, and participating in leisure sports activity,

including seasonal activities. Assessment of comorbidities

present at baseline was based on self-report, including ischemic

heart disease (history of myocardial infarction, angina pectoris,

taking medications used at the period of recruitment, eg,

nitrates, aspirin, and beta-blockers), hypertension, type I and II

diabetes, Parkinson’s disease, and history of stroke.

Clinical examination

Body weight and height were measured by standard devices.

The physical performance score was calculated according to the

Short Physical Performance Battery (SPPB) as described

previously.(18,19) It takes into account ability and time necessary

to perform four tests (standing up five times from a chair,

assessment of standing balance, 10-step tandem walk forward,

and 10-step tandem walk backward). The global score was

calculated by adding up the four tests: 0 (unable to accomplish

tests) to 16 (all tests accomplished perfectly).

Assessement of aortic calcification score (ACS)

Aortic calcifications were assessed by a semiquantitative method

on lateral radiographs of the lumbar spine.(20) Calcific deposits in

the abdominal aorta adjacent to the first four lumbar vertebrae

were assessed using the 24-point severity scale (ACS) for the

posterior and anterior walls of the aorta using the midpoint of

the intervertebral space above and below the vertebrae as

boundaries. ACS was dichotomized (ACS > 6 versus 0 to 6)

because this threshold was associated with lower BMD and a

higher risk of fracture.(8)

1448 Journal of Bone and Mineral Research

Statistical methods

Analyses were performed using SAS 8.2 software (Cary, NC, USA).

Bivariate comparisons between men who did or did not have

MetS were performed using a t test for variables with Gaussian

distribution, Mann-Whitney’s test for variables with skewed

distribution, and the chi-square test for dichotomous variables.

Comparisons of the qualitative variables were adjusted for age

by the Cochran-Mantel-Haenszel test. Analysis of covariance was

used to assess differences of continuous variables between men

who did or did not have MetS or its components below or above

the threshold from the definition of MetS. Skewed variables were

log-transformed, and the analyses were adjusted for seasonal

variability when appropriate. We used the logistic regression to

calculate odds ratios (ORs) and 95% confidence intervals (95%

CIs) for the association between risk of fracture and presence of

MetS or its components. We did not use Cox’s model for the

nonspine fractures because the proportional-hazard assumption

was not met. Since polytomous logistic regression revealed a

similar trend for spine and nonspine fractures, we analyzed them

jointly. For the analysis of covariance and logistic regression, we

used backward selection to identify potential confounders. In the

models assessing the prediction of fractures, we used whole-

body BMD, which had the strongest association with the

outcome in the models without MetS, in those including MetS

and in those including MetS components. Variables were

retained in the final model if the p value was less than .15 or

if they changed the OR by more than .05. They are specified in

the notes of each table. Various prevalence rates of components

of MetS could influence the results. Thus we repeated the

analyses in randomly selected groups of 95 men with the

investigated component (lowest prevalence in men with MetS)

and of 371 men without the investigated component (lowest

prevalence of the absence of a component in men without

MetS). Criteria of selection were defined to obtain groups

comparable with the original groups. Then we applied the same

multivariate models as for the main analyses.

Results

Bivariate comparisons

MetS was present 23.4% of the cohort (Fig. 1). These men were

heavier, more sedentary, slightly older, and taller (Table 1). They

drank more alcohol, had poorer physical performance, and

reported more falls, but not fractures. Difference in the falls and

SZULC ET AL.

Table 1. Bivariate Comparisons According to the Presence of the Metabolic Syndrome (MetS) in 762 Men Aged 50 to 85 Years: The

MINOS Cohort

Parameter MetS(–) (n¼ 584) MetS(þ) (n¼ 178) p Value

Age (years) 65� 7 66� 7 <.06

Weight (kg) 77� 10 90� 14 <.001

Height (cm) 169� 6 170� 7 <.05

BMI (kg/m2) 26.92� 2.95 31.26� 3.91 <.001

Waist-hip ratio 0.981� 0.075 1.058� 0.076 <.001

Smoking (n, %) 72 (12.4) 17 (9.4) .29

Alcohol intake (g/day) 36.6� 32.8 42.0� 36.0 <.05

Education level (years) 8� 2 8� 3 .69

Leisure physical activity (h/wk) 22� 13 19� 11 <.05

SPPB 12 (9; 14) 11 (8; 13) <.05

First quartile SPPB (<9, n, %) 103 (17.5) 47 (25.7) <.05

History of �2 falls (n, %) 50 (8.5) 26 (14.4) <.05

Prevalent fractures (n, %) 84 (14.4) 22 (13.5) .91

Ischemic disease (n, %) 82 (14.0) 38 (21.0) <.05

Diabetes (n, %) 24 (4.1) 33 (18.2) <.001

ACS 2 [0; 6] 4 [2; 8] <.001

ACS > 6 (n, %) 124 (21.6) 59 (33.2) <.002

Components of the metabolic syndrome

Waist (cm) 94� 8 107� 9 <.001

Glycemia (mg/dL) 104� 18 128� 39 <.001

(nmol/L) 5.77� 1.00 7.11� 2.16

Triglycerides (mg/dL) 154� 82 229� 105 <.001

(mmol/L) 1.73� 0.93 2.59� 1.19

HDL-cholesterol (mg/dL) 52.8� 14.4 40.2� 10.5 <.001

(mmol/L) 1.37� 0.37 1.04� 0.27

Prevalence of the components of the metabolic syndrome

Abdominal obesity (n, %) 82 (14.1) 130 (72.9) <.001

Hypertension (n, %) 101 (17.2) 95 (52.5) <.001

Hyperglycemia (n, %) 118 (20.2) 121 (68.0) <.001

Hypertriglyceridemia (n, %) 213 (36.4) 158 (88.9) <.001

Low HDL-cholesterol (n, %) 84 (14.5) 103 (58.0) <.001

Data are presented as mean� SD or as median (first quartile; third quartile). SPPB¼ Short Physical Performance Battery; ACS¼ aortic calcification score.

physical performance remained significant after adjustment for

age (p< .05 for both). They reported more often ischemic heart

disease and had more extended aortic calcifications.

Hormones

Men with the MetS had lower concentrations of total, free,

and bioavailable testosterone, 17b-estradiol, SHBG, and 25(OH)D

(Table 2). In the adjusted comparisons, differences remained

significant for testosterone and SHBG.

BMD and bone loss

Before adjustement, men with MetS had a higher BMD at the

lumbar spine, hip, and whole body (Table 3). In the fully adjusted

models, men with MetS had a lower BMD at the hip, whole

body, and distal forearm. In the analyses according to the MetS

criteria, only abdominal obesity was associated with a lower BMD

(2.2% to 3.2%, 0.24 to 0.27 SD, p< .05 to .005) at the hip, whole

body, and distal forearm. Men in the highest tertile of waist-hip


ratio (>1.028) had a lower BMD (1.7% to 3.3%, 0.21 to 0.25 SD,

p< .05 to .002) at the hip, whole body, distal forearm,

and ultradistal radius. Men in the highest tertile of fat mass of

trunk (>14.68 kg) had a lower BMD at these sites (3.8% to

5.2%, 0.29 to 0.43 SD, p< .005 to .001). Differences between the

groups defined according to other criteria of MetS were not

significant (<1%, p> .15). Forty-eight men with MetS without

abdominal obesity had BMD values similar to the control

group.

In the comparisons of the randomly selected groups (95 men

with criterion, 371 men without criterion), men with abdominal

obesity had a lower BMD at hip, whole body, and distal radius

(3.6% to 5.0%, 0.4 SD, p< .01). When BMD was compared in

groups classified according to other criteria, differences were

lower and not significant (<1%, p> .30).

In the fully adjusted models, men with MetS had a lower bone

mineral content (BMC; 3.1% to 4.5%, 0.22 to 0.29 SD, p< .05 to

.001) at all the measured sites (Table 4). At the total hip, distal

radius, and ulna, projected area was similar in men who did or


Table 2. Comparisons of Serum Concentrations of Hormones and Levels of Biochemical Markers of Bone Turnover in Men Who Did or

Did Not Have the Metabolic Syndrome (MetS): The MINOS Cohort

Parameter MetS(–) (n¼ 584) MetS(þ) (n¼ 178) p* p**

Hormones

Testosterone (nmol/L) 18.83� 6.88 14.12� 6.23 <0.001 <0.001

Bio-T (nmol/L) 6.55� 4.67 3.97� 3.24 <0.001 <0.01

AFTC (pmol/L) 206.7� 80.6 177.1� 71.7 <0.001 <0.05

17b-estradiol (pmol/L) 114.3� 29.3 111.5� 28.9 0.25 0.29

Bio-17b-estradiol (pmol/L) 62.9� 18.8 66.3� 18.5 <0.05 0.35

SHBG (nmol/L) 89.5� 45.8 69.8� 34.3 <0.001 <0.001

25(OH)D (ng/mL) 27.65� 11.83 25.27� 10.71 <0.05 0.20

PTH (pg/mL) 39.6� 17.1 41.0� 19.0 0.37 0.58

Biochemical markers of bone turnover

Osteocalcin (ng/mL) 19.65� 6.90 18.32� 10.32 <0.001 <0.005

Bone alkaline phosphatase (mU/L) 16.43� 5.28 18.07� 9.04 0.07 0.19

P1NP (ng/mL) 36.3� 16.0 36.9� 22.9 0.49 0.58

Total DPD (nmol/mmol of cr) 6.89� 2.53 7.57� 3.35 <0.01 <0.05

Free DPD (nmol/mmol of cr) 3.42� 1.16 3.73� 1.37 <0.005 <0.05

CTX-I (mg/mmol of cr) 128.1� 75.2 116.9� 7.49 <0.02 0.21

Serum CTX-I (mmol/L) 2.54� 1.24 2.28� 1.53 <0.01 <0.05

Data are presented as unadjusted mean� SD. p*¼ bivariate comparisons; p**¼ for hormones, multivariate models were adjusted for age and body

mass index; for biochemical markers of bone turnover, multivariate models were adjusted for age, BMI, height, leisure physical activity, physical activity atwork, physical performance, educational level, smoking, alcohol intake, serum concentrations of 17b-estradiol and 25(OH)D. AFTC¼ apparent free

testosterone concentration; DPD¼deoxypyridinoline.

did not have MetS. For the whole body and for the upper and

lower limbs analyzed separately, projected bone area was lower

in men with MetS. However, the relative difference between

groups was smaller for the projected area (1.2% to 1.5%, 0.15 to

0.18 SD) than for BMC (3.5 to 4.4%, 0.25 to 0.29 SD).

Rate of bone loss was compared in 162 men with MetS and

538 men without MetS. In the bivariate comparisons, men with

MetS had slower bone loss at the whole body and ultradistal

radius (�0.6� 9.4 versus�2.4� 7.9mg/cm2/year and�1.0� 4.4

versus –1.9� 5.3mg/cm2/year, respectively, p< .05) but not

other sites. However, after adjustment for confounders, the rate

able 3. Bivariate and Multivariate Comparisons of Baseline BMD in 178 Men Who Had Metabolic Syndrome (MetS) and 584 men Who

id Not Have MetS: The MINOS Cohort

keletal site

Bivariate comparisons Multivariate comparisons

MetS(–) MetS(þ) p* MetS(–) MetS(þ) p**

pine 1.022� 0.185 1.065� 0.184 <0.01 1.038� 0.185 1.016� 0.184 .25

emoral neck 0.833� 0.119 0.883� 0.135 <0.01 0.846� 0.119 0.822� 0.125 <.05

rochanter 0.731� 0.108 0.752� 0.112 <0.05 0.741� 0.108 0.718� 0.109 <.05

otal hip 0.954� 0.127 0.983� 0.135 <0.01 0.968� 0.127 0.933� 0.132 <.005

hole body 1.202� 0.108 1.220� 0.121 0.06 1.213� 0.107 1.186� 0.120 <.01

istal forearm 0.522� 0.064 0.518� 0.074 0.50 0.525� 0.063 0.510� 0.075 <.05

istal radius 0.552� 0.067 0.551� 0.077 0.78 0.557� 0.067 0.540� 0.078 <.05

istal ulna 0.475� 0.065 0.466� 0.073 0.13 0.477� 0.064 0.462� 0.074 <.05

ltradistal radius 0.428� 0.064 0.427� 0.072 0.87 0.430� 0.064 0.420� 0.072 0.15

Data are presented as unadjusted mean� SD; p*¼bivariate comparisons; p**¼multivariate models adjusted for age, BMI, height, leisure physical

ctivity, physical activity at work, physical performance, educational level, smoking, alcohol intake, and serum concentrations of 17b-estradiol and5-hydroxycholecalciferol.

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of bone loss did not differ between the men who did or did not

have MetS (p¼ .15 to .68).

Biochemical markers of bone turnover

Men with MetS had a higher urinary excretion of total and free

DPD but a lower serum OC level and a lower serum and urinary

CTX-I level. The differences changed only weakly in the adjusted

models. Men with hyperglycemia had lower serum OC (p< .001)

and P1NP (p< .01) levels. Men with the abdominal obesity had

higher urinary levels of bone-resorptionmarkers (p< .05 to .001).

SZULC ET AL.

Table 4. Comparison of Bone Mineral Content (BMC) and Projected Area of Bones in men Who Did or Did Not Have the Metabolic

Syndrome (MetS) in the MINOS Cohort

Skeletal site MetS(–) (n¼ 584) MetS(þ) (n¼ 178) P

Total-hip BMC (g) 45.00� 7.58 42.96� 8.73 <.002

Area (cm2) 46.45� 4.54 46.08� 4.93 .33

Distal radius BMC (g) 2.620� 0.375 2.538� 0.440 <.05

Width (cm) 2.47� 0.20 2.46� 0.21 .72

Distal ulna BMC (g) 1.508� 0.242 1.454� 0.262 <.05

Width (cm) 1.66� 0.14 1.65� 0.13 .58

Whole-body BMC (g) 2715.5� 396.6 2621.1� 465.9 <.003

Area (cm2) 2223.2� 178.4 2190.5� 199.6 <.001

Upper and lower limbs

BMC (g) 1547.4� 235.8 1479.3� 259.4 <.001

Area (cm2) 1242.7� 119.8 1228.1� 126.2 <.001

Adjusted for age, BMI, height, leisure physical activity, physical activity at work, physical performance, educational level, smoking, alcohol intake, serumconcentrations of 17b-estradiol and 25-hydroxycholecalciferol.

Other criteria of MetS were not associated with the bone

turnover rate.

Risk of fragility fracture

Men with MetS had a lower incidence of osteoporotic fractures

(6.7% versus 12.0%, p< .05). Since MetS was associated with a

slightly nonsignificantly lower incidence of spine and nonspine

fracture (polytomous model, OR¼ 0.28, 95% CI 0.07–1.22 and

OR¼ 0.47, 95% CI 0.21–1.05, respectively), we analyzed both

types of fractures jointly. MetS remained associated with a lower

risk of fragility fracture after adjustment for confounders,

including whole body BMD (Table 5). Subgroups of men with

MetS defined by different criteria were compared one by

one with the men without MetS. All the criteria were associated

with a trend toward a lower risk of fracture, with the strongest

protective effect of hypertriglyceridemia. When different

diagnostic criteria of MetS were analyzed one by one in the

entire cohort, only elevated TG level was associated with a lower

risk of fracture (OR¼ 0.53, 95% CI 0.31–0.92, p< .03). Other

criteria were not associated with the fracture risk (OR¼ 0.77

to 1.31, p> .40). When all the diagnostic criteria of MetS

were included in one multivariate logistic model, only high

Table 5. Odds Ratios (ORs) for the Risk of Low-Trauma Vertebral and P

Syndrome or Its Components

Parameter OR 95% CI

Metabolic syndrome 0.45 0.21–0.96

Waist > 102 vs � 102 cm 0.60 0.25–1.45

Arterial hypertension (yes vs no) 0.48 0.19–1.25

Glycemia >110 vs �110mg/dL 0.49 0.20–1.18

Triglycerides >150 vs �150mg/dL 0.35 0.15–0.81

HDL-cholesterol <40 vs �40mg/dL 0.39 0.15–1.03

Adjusted for age, BMI, education level, prevalent fractures, history of two or m

score (>6 vs 0 to 6), and ischemic heart disease.


TG concentration was associated with lower risk of fracture

(OR¼ 0.53, 95% CI 0.29–0.94, p< .03).

Since MetS criteria had various prevalence, we assessed

fracture risk in randomly selected groups of 95menwith criterion

and 371menwithout criterion. High TG level wasmost predictive

of fracture (OR¼ 0.27, 95% CI 0.08–0.96, p< .05), followed by low

HDL-cholesterol (OR¼ 0.31, 95% CI 0.09–1.08, p¼ .07) and other

criteria (OR¼ 0.40 to 0.56, p> .12).

Discussion

We have shown that in men with MetS, lower BMD is related to

the abdominal obesity, whereas lower risk of fracture is related to

the hypertriglyceridemia. The criteria of MetS were defined on

the basis of their association with cardiovascular risk, not

with osteoporosis. Since any three of the five criteria allow

diagnosis of MetS, patients with MetS are a heterogeneous

group. In addition, results of the analyses depend largely on the

confounders used in the analysis.(21)

In men with MetS, lower BMD was associated with abdominal

obesity but not with other criteria. Obesity is associated

with greater load on the lower limbs and trunk and higher

eripheral Fracture Associated with the Presence of the Metabolic

p

Additionally adjusted for

whole-body BMD

OR 95% CI p

<.05 0.33 0.15–0.76 <.01

.26 0.43 0.17–1.08 .07

.13 0.35 0.13–0.97 <.05

.11 0.36 0.14–0.93 <.05

<.02 0.25 0.10–0.62 <.005

.06 0.29 0.10–0.84 <.05

ore falls during the year preceding recruitment, and aortic calcification


17b-estradiol levels, mainly bioavailable fraction, owing to

higher peripheral aromatization of androgens.(22) Visceral fat

accumulation is associated with higher levels of proinflammatory

cytokines stimulating bone resorption (ie, tumor necrosis factor

a, interleukin 6, and interleukin 18)(23–25) and with low-grade

inflammatory syndrome confirmed by elevated levels of

the inflammatory markers (ie, C-reactive protein and fibrino-

gen).(26,27) However, fat mass also was associated with a lower

BMD and lower bone size in nonobese men.(28,29) Currently, the

mechanism of this association is not clear: mutually exclusive

differentiation of mesenchymal stem cells, effect of sex steroids,

or effect of adipocyte-derived peptides on bone.(30,31)

Fat layer overlying bone may induce an artefactual decrease in

BMD with a parallel artefactual increase in BMC and projected

area.(32,33) Thus our data support the negative relation between

abdominal obesity and low BMD. First, BMD is also lower in

men with abdominal adiposity at the distal and ultradistal

forearm, where the fat layer is thinner. Second, men with MetS

had not only lower BMD but also lower BMC and slightly lower

bone area.

Similarly to our data, BMD was not associated with arterial

pressure in men or women.(34,35) Diabetic men had higher, lower,

or similar BMD values compared with healthy men.(36–38) Unlike

our data, TG level correlated positively with hip BMD and

broadband ultrasound attenuation, whereas HDL-cholesterol

level was correlated negatively with hip BMD in men.(39–41) There

are other possible causes of low BMD in men with MetS. Men

with MetS have lower levels of testosterone.(27,42) Although 17b-

estradiol is the main sex steroid regulating bone turnover in

older men, testosterone may stimulate bone formation.(43)

Depressive symptoms were reported to be more frequent in

MetS but were not correlated with abdominal obesity.(44)

Similar to previous data,(45,46) bone formation was lower in

hyperglycemic men. However, this difference may be influenced

by antidiabetic treatment.(47) Men with abdominal obesity had

higher bone resorption in line with the low-grade inflammatory

syndrome and higher levels of cytokines stimulating bone

resorption. Our data support the heterogeneous character of

MetS. Bone turnover rate, bone-resorption-to-bone-formation

ratio, and subsequent rate of bone loss may depend on the

components of MetS present in an individual.

Data on fracture risk in men with MetS are scanty and

discordant. In the Tromsø study, the incidence of nonspine

fractures was lower in women with MetS but not in men.(4,6)

In the Rancho Bernardo study, fracture incidence was higher in

women with MetS but not in men.(5) Japanese men who had

MetS and higher visceral fat had a lower vertebral fracture

prevalence after adjustment for BMD and other confounders.(7)

However, in these studies, number of fractures was low,

unknown, or unexpectedly high.(5–7) The analyses assessed only

vertebral fractures, only nonvertebral fractures, or only major

osteoporotic fractures.(5–7)

We analyzed factors that could contribute to the lower

incidence of spine and nonspine fractures in our study. Lower

bone width conferred higher fracture risk.(48) However, men with

MetS had a bone width similar or even lower than that of healthy

controls. Faster bone loss was predictive of fracture in men

regardless of initial BMD value.(49) However, bone-loss rate did


not differ between men who did or did not have MetS.

Differences in the bone turnover markers (BTM) levels between

men who did or did not have MetS were inconsistent. Since the

associationbetweenBTMand fracture risk inmen isdoubtful,(50–53)

differences in bone turnover rate cannot explain lower

fracture risk in men with MetS. History of fracture and of fall

is associated with a higher risk of fracture.(54) However, men with

MetS had poorer physical performance and reported more falls

but not more prior fractures than control individuals.

The protective effect of MetS on bone might be driven by

hypertriglyceridemia. Higher TG level was associated with lower

risk of spine and nonspine fractures in some, but not all,

studies.(5,7,55–57) This relationship was significant when adjusted

for BMD and other confounders. Thus its mechanism is not clear.

Experimental data suggest that apolar lipids, including TG, form a

layer between collagen fibers and mineral crystals.(58) TG may

mediate the interaction between protein matrix and bone

mineral and contribute to the improvement of qualitative

properties of bone. Data on the link between other criteria of

MetS and fracture risk are scanty. Impaired glucose tolerance was

associated with lower, higher, or similar risk of fracture compared

with the control individuals.(7,59–60) High abdominal adiposity

was associated with a higher hip fracture risk in women(61) but

with a lower vertebral fracture risk in men.(7) Hypertension

confered higher fracture risk in a large case-control study.(62)

HDL-cholesterol was not associated with the presence of

fractures,(7,55–56) except in men with a high body mass index

(BMI).(4)

Our study has limitations. Inhabitants of Montceau les Mines

may be not representative of the French population. Our

project was not designed to study MetS, and data on the

associated diseases have not been collected on purpose.

Evaluation of the diseases at baseline was limited to self-report.

The recruited volunteers may be healthier and have a lower

morbidity than the general population. A single biochemical

measurement may not fully reflect the metabolic status in an

individual. The number of incident fractures in men with MetS

was low.

Thus men with MetS had a lower BMD, lower risk of fracture,

and inconsistent changes in bone turnover. Lower BMD was

related to abdominal obesity, which also was associated with

higher bone resorption. Hyperglycemia was associated with

lower bone formation. Lower fracture risk was driven by

hypertriglyceridemia and could not be explained by other

bone-related variables (eg, bone width, bone turnover rate, rate

of bone loss, history of fractures and falls). Our data expand on

the association between MetS and bone in men and show that

MetS does not seem to be a risk factor for fragility fracture in

men. In addition, MetS does not explain the association between

cardiovascular diseases and bone fragility in men.

Moreover, previous studies and our data raise doubts about

the validity of the concept of MetS in the context of bone

metabolism. Results of the analyses of BMD in multivariate

models vary based on the confounders. In our study, men had a

higher hip BMD in unadjusted models but a lower BMD when

adjusted for protective factors [eg, 17b-estradiol, 25(OH)D, BMI,

and physical activity], which may unveil the effect of deleterious

factors (inflammatory syndrome). Patients with MetS had a

SZULC ET AL.

higher femoral neck BMD when adjusted for C-reactive protein

(inflammatory marker), which may unveil the effect of protective

factors.(21) Bone variables depend on different components of

MetS. Lower BMD and higher DPD excretion are related to

abdominal obesity. Lower risk of fracture is driven by the higher

TG level. Lower bone formation is related to hyperglycemia.

These data show that the concept of MetS is not meaningful in

the context of bone metabolism and that the analysis of bone-

related variables according to the global criterion MetS may

obscure pathophysiologic links of BMD with its individual

components. Thus the discordant results of the studies analyzing

the association between MetS and bone status may reflect the

heterogeneous character of MetS and partly depend on the

different rates of prevalence of individual components of MetS in

various cohorts.

Disclosures

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

Acknowledgments

This work was supported by a contract bewteen INSERM and

Merck Sharp & Dohme Chibret and by a grant from Abondement

ANVAR.

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