ORIGINAL RESEARCH

Poor Trabecular Microarchitecture at the Distal Radius in OlderMen with Increased Concentration of High-Sensitivity C-ReactiveProtein—The Strambo Study

T. Rolland • S. Boutroy • N. Vilayphiou •

S. Blaizot • R. Chapurlat • P. Szulc

Received: 21 December 2011 / Accepted: 19 March 2012 / Published online: 15 April 2012

� Springer Science+Business Media, LLC 2012

Abstract Low-grade inflammation, assessed by serum

high-sensitivity C-reactive protein (hsCRP) concentration,

is associated with higher fracture risk irrespective of areal

bone mineral density (aBMD). We assessed the association

of hsCRP with bone microarchitecture (measured by high-

resolution pQCT) at the distal radius and tibia in 1,149 men,

aged 19–87 years. hsCRP concentration increased with age

until the age of 72, then remained stable. aBMD was not

correlated with hsCRP level. After adjustment for con-

founders, bone microarchitecture was not associated with

hsCRP level in men aged\72. After the age of 72, hsCRP

[5 mg/L was associated with lower trabecular density,

lower trabecular number, higher trabecular spacing, and

more heterogenous trabecular distribution (p \ 0.05–0.005)

at the distal radius versus hsCRP B 5 mg/L. Similar

differences were found for the fourth hsCRP quartile

([3.69 mg/L) versus the three lower quartiles combined.

Cortical parameters of distal radius and microarchitectural

parameters of distal tibia did not vary according to hsCRP

concentration in men aged C72. Fracture prevalence

increased with increasing hsCRP level. After adjustment for

confounders (including aBMD), odds for fracture were

higher in men with hsCRP [5 mg/L compared to hsCRP

\1 mg/L (OR = 2.22, 95 % CI 1.29–3.82) and did not

change after additional adjustment for microarchitectural

parameters. The association between hsCRP level and bone

microarchitecture was observed only for trabecular

parameters at the radius in men aged C72. Impaired bone

microarchitecture does not seem to explain the association

between elevated CRP level and higher risk of fracture.

Keywords Men � High-sensitivity C-reactive protein �Cortical bone � Trabecular bone � Osteoporosis

A large number of fragility fractures occur in men [1].

Morbidity, loss of independence, and mortality after frac-

ture are higher in men than women [2, 3]. Osteoporosis is

characterized by low areal bone mineral density (aBMD)

and poor bone microarchitecture [4]. Poor bone microar-

chitecture was associated with fragility fractures regardless

of aBMD [5–7]. Thus, study of the determinants of bone

microarchitecture may contribute to the development of

new therapies for osteoporosis.

Chronic inflammatory diseases are associated with

lower aBMD, faster bone loss, and higher fracture risk [8,

9]. C-reactive protein (CRP) is produced mainly by the

liver and increases during inflammation [10]. Its synthesis

is induced by interleukin-6 (IL-6), IL-1, and tumor necrosis

factor a (TNF-a), which stimulate strongly bone resorption

[11–14]. Therefore, serum CRP may reflect the overall

metabolic effect of inflammatory cytokines on bone

metabolism and the activity of the inflammatory process.

In patients with rheumatoid arthritis (RA), a high CRP

level was associated with lower aBMD and faster bone

loss. In men and women with RA, patients with CRP

concentration [14 mg/L had lower hand aBMD (vs.

patients with CRP \14 mg/L) [15]. In patients with RA

followed up prospectively for 2 years, elevated CRP was

the strongest predictor of accelerated bone loss [8]. In

women with RA followed up for 5 years, a high CRP level

The authors have stated that they have no conflict of interest.

T. Rolland � S. Boutroy � N. Vilayphiou � S. Blaizot �R. Chapurlat � P. Szulc (&)

INSERM UMR 1033, Universite de Lyon and Hospices

Civils de Lyon, Lyon, France

e-mail: pawel.szulc@inserm.fr

123

Calcif Tissue Int (2012) 90:496–506

DOI 10.1007/s00223-012-9598-1

was associated with faster bone loss at the metacarpals

[16].

Specific immunoassays measuring low CRP levels

(high-sensitivity CRP, hsCRP) show the association of

hsCRP with fragility fractures in subjects without inflam-

matory diseases. In older individuals, high levels of

inflammatory markers, including hsCRP, were associated

with a higher risk of fracture [17]. In a population-based

cohort, subjects in the highest tertile of serum CRP level

had a 7.8-fold higher risk of fragility fracture (vs. the

lowest tertile) [18]. Older Japanese women with higher

hsCRP levels had higher risk for fracture compared to a

lower hsCRP group [19]. In women aged C65, fracture risk

was increased 24–32 % for each SD increase in hsCRP

level [20].

Data on the correlation between aBMD and hsCRP are

discordant. Higher hsCRP levels were associated with

lower femoral neck aBMD in Korean women [21]. In

elderly Japanese women, distal forearm aBMD increased

across the tertiles of hsCRP [19]. In contrast, hsCRP was

not associated with aBMD in other cohorts [22, 23].

Baseline hsCRP was not associated with the rate of bone

loss at the spine, hip, and whole body in men and women

aged 50–79 [14]. Thus, the mechanism linking CRP and

bone fragility is not clear.

Since elevated hsCRP level and poor bone microarchi-

tecture are associated with higher risk of fracture, indi-

viduals with higher hsCRP levels may have poor bone

microarchitecture. Such a defect of bone microarchitecture

may not be detected by aBMD. Therefore, we assessed

cross-sectionally the association of serum hsCRP level with

bone microarchitecture measured by high-resolution

peripheral quantitative computed tomography (HR-pQCT)

at the distal radius and tibia and with prevalent fractures in

a cohort of men.

Materials and Methods

Cohort

The STRAMBO study is a single-center prospective cohort

study of the skeletal fragility and its determinants in men

[24]. It is a collaboration between INSERM (National

Institute of Health and Medical Research) and the private

health insurance company MTRL (Mutuelle de la Region

Lyonnaise). The study obtained authorization from the

ethics committee and was performed in agreement with the

Helsinki Declaration of 1975 and 1983. Men were recruited

in 2006–2008 from the MTRL rolls in Lyon. Invitation

letters were sent to a random sample of men aged

20–87 years living in Greater Lyon, and 1,169 men pro-

vided informed consent. This analysis was performed on

1,149 men who had dual-energy X-ray absorptiometry,

bone microarchitecture evaluation by HR-pQCT and col-

lection of biological samples. No specific exclusion criteria

were used.

Biochemical Measurements

Nonfasting serum and urine were collected at 1:00 p.m. and

stored at -80 �C until assayed. hsCRP was measured

by immunoturbidimetric latex CRP assay (Roche Diag-

nostics, Mannheim, Germany). Detection limit was

0.15 mg/L. Intra- and interassay coefficients of variation

(CV) were \10 %. Serum testosterone, 17b-estradiol

(17b-E2), sex hormone-binding globulin (SHBG), 25-hy-

droxyvitamin-D (25OHD), and parathyroid hormone

(PTH) were measured as described previously [25–28].

Apparent free testosterone concentration (AFTC) and bio-

available 17b-E2 (bio-17b-E2) were calculated [29]. Bone

turnover markers (BTMs) were measured as described

previously [24]. Serum osteocalcin (OC), N-terminal

extension propeptide of type I collagen (PINP), and b-

isomerized C-terminal telopeptide of type I collagen (CTX-

I) were measured by human-specific two-site immuno-

chemiluminescence assay (ELECSYS; Roche, Indianapolis,

IN). Bone-specific alkaline phosphatase (bone ALP) was

measured by enzymatic immunoassay (MetraBAP; Quidel,

San Diego, CA). Urinary deoxypyridinoline (DPD) was

measured after acid hydrolysis by ELISA (Metra Total DPD,

Quidel).

BMD and Bone Microarchitecture Measurement

Cross-sectional area (CSA), volumetric BMD (vBMD), and

microarchitecture were assessed at the nondominant distal

radius and right distal tibia by HR-pQCT (XtremeCT;

Scanco Medical, Bruttisellen, Switzerland) as described

previously [24, 30]. A stack of 110 CT slices with an iso-

tropic voxel size of 82 lm was obtained, with the most

distal CT slice placed 9.5 and 22.5 mm proximal to the

endplate of the radius and tibia, respectively. The CV of a

phantom containing HA rods embedded in resin (QRM,

Moehrendorf, Germany) was 0.7–1.5 %. Cortical thickness

(Ct.Th) was defined as the cortical volume divided by the

outer surface. Trabecular (Tb.vBMD) and cortical vBMD

(Ct.vBMD) were average vBMD in the respective volumes

of interest. Trabeculae were identified by the 3D mid-axis

transformation method. Trabecular number (Tb.N, mm-1)

was defined as the inverse of the mean spacing of mid-axes.

Trabecular thickness (Tb.Th, lm) and separation (Tb.Sp,

lm) were calculated. Intraindividual distribution of sepa-

ration (Tb.Sp.SD, lm) reflects the heterogeneity of the

trabecular network. It is quantified by the standard deviation

of the distance between the mid-axes. Scans of poor quality

T. Rolland et al.: Bone Microarchitecture and CRP Level in Men 497

123

(movement, disrupted contour of cortical bone) were

excluded (93 radii, 8 %; 46 tibiae, 3.9 %).

DXA

aBMD was measured at the lumbar spine, total hip, and

nondominant forearm by DXA (Discovery A; Hologic,

Waltham, MA) [5]. The long-term CV of the device

assessed by daily measurements of a commercial phantom

of the lumbar spine was 0.35 %.

Prevalent Fragility Fractures

Prevalent vertebral and peripheral fractures were assessed

as previously described [5]. Their analysis was limited to

men aged 50 years and older because they were rare in men

aged\50. Using the semiquantitative method, 164 vertebral

fractures were identified in 98 men. Peripheral fractures

were assessed using an interviewer-assisted questionnaire.

One hundred men self-reported 119 low-trauma fractures

that occurred after the age of 18. Fractures of the face, hand,

and toes were excluded. Overall, 177 men had at least one

prevalent fracture.

Covariates

Participants responded to an interviewer-assisted ques-

tionnaire. Men self-reported lifestyle factors: smoking

(current smoker vs. nonsmoker), alcohol intake (quantified

as the average amount of alcohol consumed weekly), and

physical activity. Separating sport activities according to

the ‘‘required’’ bone (e.g., radius in tennis) and the intensity

(high or not) distinguished better the action of physical

activity on bone [31]. A ‘‘high’’ physical activity means

that participant practiced sport for C1 year at a competition

level. Calcium intake was estimated by a food-frequency

questionnaire [32]. Chronic diseases (ischemic heart dis-

ease, hypertension, diabetes, RA, hepatitis, ulcerative

colitis, Crohn disease) as well as current oral and inhaled

corticotherapy were self-reported and not further ascer-

tained. Weight and height were measured in light clothes

without shoes using standard clinical equipment.

Statistical Analysis

Statistical analyses were performed using the SAS 9.1

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

mean ± SD. Variables with nongaussian distribution, pre-

sented as median and interquartile range in Table 1, were

log-transformed for the analyses. The relationship between

hsCRP and age was modeled by the PROC LOESS

(Automatic Smoothing Parameter Selection). The corrected

Akaike information criterion (AICC) versus smoothing

Table 1 Descriptive analysis of men from the STRAMBO cohort

Men aged \72

(n = 731)

Men aged C72

(n = 417)

Age (years) 54 ± 5 78 ± 4

Body weight (kg) 79 ± 12 77 ± 11

Body height (cm) 173 ± 7 167 ± 6

Current smokers (n, %) 105 (14.3) 20 (4.8)

Alcohol intake (g/week)a 63 (16–188) 109 (16–234)

Calcium intake (mg/day) 793 ± 274 748 ± 245

Physical activity: upper arms

(n, %)

189 (25.6) 49 (11.8)

Physical activity: lower arms

(n, %)

244 (33.1) 65 (15.6)

Rhumatoid arthritis (n, %) 1 (0.1) 2 (0.5)

Hepatitis (n, %) 2 (0.2) 0 (0.0)

Crohn disease (n, %) 1 (0.1) 0 (0.0)

Ulcerative colitis (n, %) 6 (0.8) 1 (0.2)

Current corticotherapy

(oral, inhaled)

34 (4.6) 27 (6.3)

C-reactive protein (mg/L)a 2.33 ± 4.21 3.98 ± 8.75

1.20 (0.61–2.45) 2.00 (1.07–3.69)

Osteocalcin (ng/mL) 24.8 (19.6–31.6) 23.6 (18.1–30.4)

Bone alkaline phosphatase

(lmol/L)

20.3 (17.0–25.1) 20.3 (16.5–25.9)

PINP (ng/mL) 39 (31–51) 35 (27–47)

b-CTX-I (lg/mL) 0.21 (0.15–0.30) 0.20 (0.14–0.29)

Deoxypyridinoline

(nmol/mg creat)

6.8 (5.3–8.8) 7.5 (5.9–9.9)

Testosterone (nmol/L) 12.4 ± 5.1 11.5 ± 5.5

AFTC (pmol/L) 283.8 ± 102.4 219.3 ± 84.7

17b-estradiol (pmol/L) 53.2 ± 19.9 51.9 ± 20.7

Bioavailable 17b-estradiol

(pmol/L)

40.4 ± 15.7 35.4 ± 14.4

SHBG (nmol/L)a 32 (23–42) 43 (32–59)

25-Hydroxycholecalciferol

(ng/mL)

23.6 ± 10.0 20.7 ± 9.8

Parathyroid hormone

(pg/mL)a38 (30–47) 49 (37–63)

aBMD (g/cm2)

Lumbar spine 1.031 ± 0.164 1.043 ± 0.192

Total hip 0.997 ± 0.136 0.925 ± 0.139

Femoral neck 0.828 ± 0.135 0.759 ± 0.131

Trochanter 0.771 ± 0.119 0.723 ± 0.105

Distal radius 0.650 ± 0.059 0.584 ± 0.072

Whole body 1.156 ± 0.104 1.094 ± 0.113

Distal radius

CSA (cm2) 3.79 ± 0.63 4.00 ± 0.61

Total vBMD (mg/cm3) 322 ± 59 267 ± 59

Ct.vBMD (mg/cm3) 840 ± 56 766 ± 73

Ct.Th (lm) 798 ± 201 605 ± 206

Tb.vBMD (mg/cm3) 189 ± 36 163 ± 41

Tb.N (/mm) 1.91 ± 0.23 1.80 ± 0.28

498 T. Rolland et al.: Bone Microarchitecture and CRP Level in Men

123

parameter plot was used to ensure that the selected

smoothing parameter value corresponded to the global

minimum of the AICC. Relations of hsCRP with other

variables were assessed using Pearson’s correlation coeffi-

cient and linear regression (simple and multivariable).

The International Federation of Clinical Chemistry set

the upper limit of the normal range of hsCRP for adults at

5 mg/L [33]. The Centers for Disease Control and Pre-

vention and the American Heart Association recommended

the following thresholds for evaluation of cardiovascular

risk: hsCRP \1.0 mg/L, low relative risk; 1.0–3.0 mg/L,

medium risk; and[3.0 mg/L high risk [34]. Analyses were

made using four groups (hsCRP \1, 1–3, 3–5, [5 mg/L)

and the age-specific hsCRP quartiles.

Unadjusted comparisons were made using the test of

medians. The association of hsCRP level with aBMD, bone

microarchitetural parameters, and BTM levels was assessed

using backward analysis of covariance. The initial models

included all the potential confounders selected on the basis

of the preliminary analyses and data from the literature: age,

weight, height, alcohol and calcium intake, testosterone (or

AFTC), 17b-E2 (or bio-17b-E2), PTH, 25OHD (continuous),

smoking, physical activity (classes), comorbidities (ische-

mic heart disease, diabetes, hypertension, chronic inflam-

matory diseases; yes/no), and interactions between the

variables. Variables with p \ 0.15 for at least one parameter

were retained in the final models for aBMD of all the skeletal

sites and all the microarchitectural parameters (age, weight,

height, physical activity, calcium intake, 17b-E2, and PTH).

As the variables did not differ between the three lower

hsCRP groups (\5 mg/L or three lower quartiles), we cal-

culated the difference between the adjusted means in the

highest group and in the combined three lower groups.

Differences are expressed as percentage and SD. Sidak’s

correction was used to adjust for multiple comparisons, and

p \ 0.01 was considered statistically significant.

The relation between fractures and hsCRP level was

assessed by the Cochran-Mantel-Haenzel Chi-squared test

for trend and by logistic regression adjusted for age,

weight, aBMD, bone microarchitecture (continuous),

smoking, chronic inflammatory diseases, and current cor-

ticotherapy (yes/no). Weight, smoking, and inflammatory

diseases were not retained in the final model. hsCRP was

analyzed as a continuous variable and as classes.

Results

Association between Serum hsCRP Concentration

and Age

Serum hsCRP concentration increased with age (Fig. 1). On

the basis of the analysis of the LOESS curve and comparison

of correlation and regression coefficients for various age

thresholds between 60 and 80 years, we found that hsCRP

level increased until the age of 72 (n = 731, r = 0.19,

p \ 0.001) by 0.12 ± 0.02 SD/10 years (p \ 0.001) and then

remained stable (n = 417, r = -0.01, -0.01 ± 0.12 SD/

10 years, p = 0.96) (p \ 0.005 for comparison of correlation

coefficients and regression coefficients). Thus, further anal-

yses were made in two groups:\72 and C72 years of age.

Descriptive Analysis

Table 1 presents a descriptive analysis of both groups.

Three men reported RA, two men hepatitis, one man Crohn

disease, seven men ulcerative colitis, and 61 men current

oral or inhaled corticotherapy.

Analyses in Men Aged \72

hsCRP was positively correlated with age, weight, 17b-E2,

and bio-17b-E2 (Table 2). Testosterone, AFTC, SHBG,

and OC levels correlated negatively with hsCRP. hsCRP

was higher in current smokers (p \ 0.005) and in men

reporting hypertension (p \ 0.001), diabetes mellitus

(p \ 0.05), or ischemic heart disease (p = 0.05).

After adjustment for confounders, aBMD at all of the

skeletal sites and BTM levels did not differ across classes

of hsCRP (\1, 1–3, 3–5,[5 mg/L) (p [ 0.18) (Table 3) or

across CRP quartiles (p [ 0.39). Similarly, aBMD and

BTM levels did not differ between men with the highest

CRP level (highest quartile or [5 mg/L) and men in the

three lower classes combined (three lower quartiles or

CRP B 5 mg/L) (p \ 0.25).

Table 1 continued

Men aged \72

(n = 731)

Men aged C72

(n = 417)

Tb.Th (lm) 80.1 ± 11.7 74.9 ± 12.2

Tb.Sp (lm)a 443 (399–491) 481 (428–540)

Tb.Sp.SD (lm)a 183 (162–210) 211 (181–254)

Distal tibia

CSA (cm2) 8.36 ± 1.29 8.46 ± 1.20

Total vBMD (mg/cm3) 314 ± 56 269 ± 55

Ct.vBMD (mg/cm3) 869 ± 48 807 ± 70

Ct.Th (mm) 1.30 ± 0.27 1.08 ± 0.30

Tb.vBMD (mg/cm3) 186 ± 38 163 ± 38

Tb.N (/mm) 1.82 ± 0.30 1.69 ± 0.32

Tb.Th (lm) 85.5 ± 12.4 80.3 ± 13.0

Tb.Sp (lm)a 466 (414–532) 507 (445–592)

Tb.Sp.SD (lm)a 213 (181–251) 241 (203–287)

Mean ± SDa Non-normally distributed variables, median (interquartile range)

T. Rolland et al.: Bone Microarchitecture and CRP Level in Men 499

123

At the distal radius, microarchitectural parameters did not

differ in the four classes of hsCRP (p [ 0.27). In the fourth

hsCRP quartile ([2.49 mg/L), Tb.vBMD was 5.8 % lower

(0.31 SD, p \ 0.05) and Tb.Th was 4 % lower (0.28 SD,

p \ 0.05) compared with the first quartile (\0.61 mg/L).

The differences lost significance after Sidak’s correction.

At the distal tibia, bone microarchitectural parameters

did not differ in the four classes of hsCRP (p [ 0.35). In

the fourth hsCRP quartile, Tb.vBMD was 5 % lower than

in the first quartile (0.26 SD, p \ 0.05, nonsignificant after

Sidak’s corection).

Analyses in Men Aged C72

Average hsCRP was higher in this group than in men aged

\72 (p \ 0.001). More men had hsCRP [5 mg/L in this

group than in men aged \72 (19 vs. 10 %, p \ 0.001).

Among men with hsCRP[5 ng/L, the median hsCRP level

was higher in older men than in younger men (8.5 vs.

7.0 mg/L, p \ 0.05). hsCRP correlated positively with

weight, 17b-E2, and bio-17b-E2 (Table 2). hsCRP corre-

lated negatively with SHBG, testosterone, and AFTC.

hsCRP level did not differ between men who did or did not

self-report current smoking, hypertension, diabetes melli-

tus, or ischemic heart disease (p [ 0.10).

After adjustment for confounders, aBMD at all of the

skeletal sites and BTM levels did not differ across the four

predefined classes of hsCRP (p [ 0.20) (Table 4). Simi-

larly, aBMD and BTM levels did not differ across the

quartiles of CRP level (p [ 0.39). There was no difference

in aBMD when the group with the highest CRP level

(highest quartile or[5 mg/L) was compared with the three

lower classes combined (p [ 0.25).

At the distal radius, all parameters were similar in the

three lower classes of hsCRP level (\1, 1–3, and 3–5 mg/L).

In comparison with 294 men who had hsCRP B 5 mg/L, 75

men with hsCRP [5 mg/L had 6.7 % lower total vBMD

(0.31 SD, p \ 0.05), 2.7 % lower Ct.vBMD (0.30 SD,

p \ 0.05), 8.5 % lower Tb.vBMD (0.34 SD, p \ 0.05), and

6 % lower Tb.N (0.39 SD, p \ 0.01). Tb.Sp was 3.4 %

higher (0.40 SD, p \ 0.005) and Tb.Sp.SD was 5 % higher

Fig. 1 Age-related evolution of

hsCRP concentration

Table 2 Simple correlation coefficients between hsCRP and the

investigated variables in the two groups of men

Men aged \72 Men aged C72

(n = 731) (n = 371)

Age 0.19d 0.00

Weight 0.21d 0.23d

Height -0.17d -0.01

Calcium intake -0.01 0.01

Alcohol intake 0.08a 0.06

Glomerular filtration rate -0.08a -0.05

Osteocalcin -0.13d -0.06

Bone alkaline phosphatase 0.07 -0.05

PINP -0.05 -0.06

b-CTX-I -0.04 -0.04

Deoxypyridinoline -0.01 0.09

Testosterone -0.14d -0.19d

AFTC -0.06 -0.14c

17b-estradiol 0.28d 0.28d

Bioavailable 17b-estradiol 0.30d 0.32d

Sex hormone-binding globulin -0.07a -0.15d

25-hydroxycholecalciferol 0.00 0.02

Parathyroid hormone 0.04 0.00

a p \ 0.05, b p \ 0.01, c p \ 0.005, d p \ 0.001

500 T. Rolland et al.: Bone Microarchitecture and CRP Level in Men

123

(0.48SD, p \ 0.001) in men with hsCRP [5 mg/L (vs.

hsCRP B 5 mg/L). After Sidak’s correction, the differences

remained significant for Tb.N, Tb.Sp, and Tb.Sp.SD. Other

parameters did not differ across the classes of hsCRP

concentration.

Similar results were found in quartiles of hsCRP.

Microarchitectural parameters did not differ in the three

lower hsCRP quartiles (\1.07, 1.07–1.99, [1.99–

3.69 mg/L). Men in the highest hsCRP quartile had

6.6 % lower Tb.vBMD (0.27SD, p \ 0.05) and 4.5 %

lower Tb.N (0.29 SD, p \ 0.05) compared with the

three lower quartiles combined. Tb.Sp was 2.5 % higher

(0.29 SD, p \ 0.05) and Tb.Sp.SD was 3.5 % higher

(0.34 SD, p \ 0.01) in the highest hsCRP quartile

Table 3 Association between microarchitectural parameters at the distal radius and distal tibia and hsCRP concentration (mg/L) in men aged

\72 years

Parameter hsCRP \ 1 1 B hsCRP \ 3 3 B hsCRP \ 5 hsCRP C 5 p(n = 307) (n = 283) (n = 64) (n = 74)

Osteocalcina 25.6 (20.7–32.8) 23.6 (19.1–29.9) 25.4 (18.0–30.4) 23.3 (16.9–29.0) 0.51

Bone ALPa 20.0 (16.3–24.4) 20.2 (17.2–25.1) 21.8 (17.8–26.9) 20.9 (17.5–26.1) 0.06

PINPa 40 (31–52) 38 (30–49) 41 (33–50) 38 (28–52) 0.07

b-CTX-Ia 0.22 (0.15–0.30) 0.20 (0.14–0.30) 0.22 (0.16–0.28) 0.21 (0.14–0.31) 0.75

DPDa 6.8 (5.2–8.7) 6.6 (5.1–8.5) 7.0 (5.8–8.8) 7.4 (5.4–9.7) 0.33

aBMD (g/cm2) (n = 307) (n = 283) (n = 64) (n = 74)

Lumbar spine 1.025 ± 0.164 1.037 ± 0.159 1.032 ± 0.147 1.043 ± 0.193 0.78

Fem. neck 0.829 ± 0.143 0.829 ± 0.135 0.820 ± 0.115 0.829 ± 0.117 0.95

Trochanter 0.774 ± 0.120 0.774 ± 0.119 0.741 ± 0.110 0.770 ± 0.124 0.21

Total hip 0.996 ± 0.138 1.004 ± 0.136 0.970 ± 0.128 0.997 ± 0.138 0.32

Distal radius 0.652 ± 0.056 0.651 ± 0.061 0.635 ± 0.051 0.652 ± 0.065 0.19

Whole body 1.162 ± 0.101 1.155 ± 0.101 1.132 ± 0.087 0.162 ± 0.131 0.20

Distal radius (n = 292) (n = 265) (n = 58) (n = 67)

CSA 3.81 ± 0.56 3.78 ± 0.55 3.82 ± 0.55 3.76 ± 0.55 0.91

Total vBMD 327 ± 58 322 ± 57 306 ± 57 320 ± 57 0.11

Ct.vBMD 844 ± 56 840 ± 55 835 ± 55 831 ± 55 0.34

Ct.Th 806 ± 200 802 ± 195 763 ± 196 790 ± 195 0.45

Tb.vBMD 190 ± 35 186 ± 33 176 ± 34 187 ± 34 0.08

Tb.N 1.92 ± 0.23 1.91 ± 0.22 1.89 ± 0.23 1.90 ± 0.23 0.80

Tb.Th 82.7 ± 11.6 80.8 ± 11.2 77.6 ± 11.3 82.0 ± 11.4 0.07

Tb.Spa 443 (402–491) 438 (396–490) 457 (405–502) 439 (398–475) 0.60

Tb.Sp.SDa 183 (162–208) 182 (161–210) 188 (165–216) 180 (161–206) 0.75

Distal tibia (n = 305) (n = 279) (n = 62) (n = 72)

CSA 8.41 ± 1.05 8.32 ± 1.01 8.38 ± 1.03 8.35 ± 1.03 0.80

Total vBMD 318 ± 53 313 ± 51 306 ± 52 311 ± 52 0.46

Ct.vBMD 872 ± 45 870 ± 44 869 ± 44 858 ± 44 0.12

Ct.Th 1314 ± 262 1304 ± 250 1287 ± 257 1281 ± 257 0.83

Tb.vBMD 190 ± 36 184 ± 35 176 ± 35 187 ± 35 0.06

Tb.N 1.84 ± 0.26 1.80 ± 0.25 1.82 ± 0.26 1.80 ± 0.26 0.65

Tb.Th 86.4 ± 12.3 85.2 ± 11.7 80.8 ± 12.2 86.9 ± 12.2 0.05

Tb.Spa 463 (414–527) 469 (414–538) 486 (434–548) 460 (396–525) 0.46

Tb.Sp.SDa 210 (181–247) 213 (184–252) 231 (195–261) 209 (177–245) 0.68

All analyses are adjusted for age, weight, height, 17b-estradiol, calcium supplementation, parathyroid hormone, and interaction between calcium

supplementation and parathyroid hormone. p value corresponds to the specific value for the investigated parameter in the multivariable modela Non-normally distributed variables, median (interquartile range); analyses were performed on log-transformed variables

T. Rolland et al.: Bone Microarchitecture and CRP Level in Men 501

123

(vs. three lower quartiles combined). After Sidak’s cor-

rection, the difference remained significant for Tb.Sp.SD.

Other parameters did not differ across the hsCRP

quartiles.

At the distal tibia, no association was found between

bone microarchitectural parameters and serum hsCRP

concentration regardless of the statistical approach.

hsCRP and Prevalent Fractures

In men aged C50, fracture prevalence increased with

increasing hsCRP level (adjusted for age, corticotherapy,

and ultradistal radius aBMD: odds ratio [OR] = 1.25 per

SD, 95 % confidence interval [95 % CI] 1.04–1.51). Frac-

ture prevalence increased across the classes of hsCRP (p for

Table 4 Association between microarchitectural parameters at the distal radius and distal tibia and hsCRP concentration in men aged 72 years

and older

Parameter hsCRP \ 1 1 B hsCRP \ 3 3 B hsCRP \ 5 hsCRP C 5 p(n = 92) (n = 186) (n = 51) (n = 78)

Osteocalcina 26.0 (18.9–33.5) 22.9 (18.1–30.1) 25.5 (18.9–30.0) 21.8 (17.3–29.7) 0.15

Bone ALPa 20.7 (16.9–26.4) 19.7 (16.0–26.6) 21.2 (17.6–25.8) 20.4 (16.6–25.1) 0.85

PINPa 37 (29–49) 35 (27–46) 38 (29–47) 35 (25–47) 0.39

b-CTX-Ia 0.31 (0.20–0.48) 0.20 (0.14–0.28) 0.21 (0.15–0.30) 0.21 (0.14–0.30) 0.47

DPDa 7.5 (5.8–9.5) 6.8 (5.7–9.2) 7.8 (6.6–10.4) 8.3 (6.3–10.5) 0.09

aBMD (n = 92) (n = 186) (n = 51) (n = 78)

Lumbar spine 1.017 ± 0.192 1.053 ± 0.192 1.045 ± 0.163 1.051 ± 0.195 0.48

Fem. neck 0.737 ± 0.125 0.766 ± 0.152 0.774 ± 0.108 0.761 ± 0.131 0.21

Trochanter 0.708 ± 0.134 0.730 ± 0.122 0.734 ± 0.121 0.719 ± 0.117 0.47

Total hip 0.901 ± 0.143 0.934 ± 0.137 0.936 ± 0.126 0.931 ± 0.143 0.24

Distal radius 0.586 ± 0.076 0.589 ± 0.071 0.578 ± 0.068 0.571 ± 0.070 0.31

Whole body 1.098 ± 0.127 1.096 ± 0.109 1.092 ± 0.085 1.089 ± 0.120 0.96

Distal radius (n = 87) (n = 163) (n = 44) (n = 75)

CSA 4.01 ± 0.59 3.99 ± 0.56 3.91 ± 0.57 4.06 ± 0.59 0.57

Total vBMD 274 ± 60.9 270.3 ± 57.3 266.4 ± 58.4 252.3 ± 61.1 0.26

Ct.vBMD 771.9 ± 75.1 771.0 ± 71.3 764.7 ± 72.1 752.8 ± 74.8 0.55

Ct.Th 624 ± 213 611 ± 201 589 ± 203 580 ± 212 0.81

Tb.Ar 3.34 ± 0.61 3.32 ± 0.58 3.26 ± 0.59 3.41 ± 0.61 0.61

Tb.vBMD 169.1 ± 42.2 165.1 ± 40.1 162.7 ± 40.1 151.3 ± 42.3 \0.05

Tb.N 1.84 ± 0.28 1.82 ± 0.25 1.80 ± 0.26 1.71 ± 0.26 \0.05

Tb.Th 76.2 ± 13.9 75.2 ± 11.4 74.6 ± 9.8 73.2 ± 12.6 0.82

Tb.Spa 477 (428–553) 478 (424–520) 492 (431–535) 502 (431–551) \0.05

Tb.Sp.SDa 208 (173–258) 206 (177–245) 218 (182–253) 223 (190–286) \0.01

Distal tibia (n = 87) (n = 177) (n = 48) (n = 75)

CSA 8.65 ± 1.05 8.38 ± 1.01 8.21 ± 1.02 8.56 ± 1.04 0.08

Total vBMD 275 ± 56 271 ± 54 268 ± 54 268 ± 44 0.34

Ct.vBMD 811 ± 70 812 ± 67 811 ± 68 786 ± 69 0.10

Ct.Th 1111 ± 278 1101 ± 265 1080 ± 274 1008 ± 284 0.22

Tb.Ar 7.25 ± 1.14 7.04 ± 1.09 6.90 ± 1.11 7.27 ± 1.13 0.10

Tb.vBMD 168 ± 39 163 ± 37 160 ± 38 159 ± 38 0.39

Tb.N 1.73 ± 0.30 1.70 ± 0.28 1.64 ± 0.29 1.67 ± 0.29 0.33

Tb.Th 81.8 ± 13.2 80.1 ± 12.4 81.5 ± 11.1 78.7 ± 13.2 0.54

Tb.Spa 547 (458–602) 503 (447–583) 530 (439–615) 499 (442–580) 0.36

Tb.Sp.SDa 250 (208–296) 237 (204–283) 262 (203–305) 236 (200–285) 0.31

a Non-normally distributed variables, median (interquartile range); analyses were performed on log-transformed variables. p value corresponds

to the specific value for the investigated parameter in the multivariable model. All analyses are adjusted for age, weight, height, 17b-estradiol,

calcium supplementation, parathyroid hormone, and interaction between calcium supplementation and parathyroid hormone

502 T. Rolland et al.: Bone Microarchitecture and CRP Level in Men

123

trend \0.001) (Fig. 2). Odds for fracture increased across

classes of hsCRP (p \ 0.01 for trend) and were higher in

men with hsCRP [5 mg/L versus \1 mg/L (OR = 2.22,

95 % CI 1.29–3.82). Odds for fracture did not change after

additional adjustment for microarchitectural parameters,

e.g., adjusted for Tb.Sp (OR = 2.24, 95 % CI 1.30–3.85).

In men aged C72 years (105 fractures), the results were

similar. Fracture prevalence increased with increasing

hsCRP level (OR = 1.50 per SD, 95 % CI 1.17–1.94).

Fracture prevalence increased across the classes of hsCRP

level (18 %, 22 %, 26 %, and 37 %; p \ 0.005 for trend).

Odds for fracture increased across classes of hsCRP

(p \ 0.001 for trend) and were higher in men with hsCRP

[5 versus \1 mg/L (OR = 3.20, 95 % CI 1.49–6.86).

Odds did not change after adjustment for microarchitec-

tural parameters, e.g., TbSp (OR = 3.25, 95 % CI

1.51–6.98).

Discussion

At the distal radius, Tb.vBMD and Tb.N were lower and

Tb.Sp and Tb.Sp.SD were higher in men aged C72 with

elevated hsCRP level. The link between hsCRP level and

bone microarchitecture was not significant in men aged

\72 and at the distal tibia in men aged C72. BTM levels

and aBMD did not correlate with CRP level regardless of

age. Fragility fracture prevalence increased with increasing

hsCRP level after ajustment for aBMD and trabecular

microarchitecture parameters.

hsCRP level increased with age, then leveled off. An

age-related increase in CRP was found in people younger

than 75 [35, 36]. Higher CRP level is associated with poor

health status [37, 38]. Thus, the stable CRP levels after the

age of 72 may be due to the fact that elderly men with poor

health status and high CRP levels declined to participate in

our study.

The relation between bone microarchitecture and hsCRP

was found only in elderly men. Age-related chronic sub-

clinical inflammation (‘‘inflammaging’’) is characterized

by higher secretion of CRP, TNF-a, and IL-6 [39–41].

These cytokines stimulate bone resorption, leading to bone

loss [42–45]. A higher percentage of older men had hsCRP

[5 mg/mL (vs. men \72), and among men with hsCRP

[5 mg/mL, hsCRP was higher in older men. Thus, in older

men, more severe inflammation operating in bone deteri-

orated by various factors (e.g., hypogonadism, secondary

hyperparathyrodism, low physical activity) may result in

bone loss. Conversely, in younger men with healthy bone,

less active inflammatory status may be insufficient to

impact upon bone remodeling. However, a trend was found

for some parameters. Thus, given the low percentage of

young men with high hsCRP level and its weak association

with bone microarchitecture, very large cohorts would be

necessary to detect such an effect.

The relation between bone microarchitecture and hsCRP

was found only in the trabecular compartment. The relative

metabolically active bone surface is greater in trabecular

than cortical bone. Thus, trabecular bone can react more

strongly to stimuli such as inflammatory cytokines. Corti-

cal bone may be more influenced by mechanical stimuli

acting on the outer periosteal surface. As aBMD is deter-

mined mainly by the mass of cortical bone, this speculation

may explain the lack of association between aBMD and

hsCRP level.

Bone microarchitecture was associated with hsCRP at

the non-weight-bearing distal radius but not at the weight-

bearing distal tibia. Body weight exerts a mechanical

load on the lower limbs and is positively correlated

with their aBMD [46], whereas bed rest induced a greater

Fig. 2 Association between the

presence of fragility fractures

and the concentration of hsCRP

in men aged 50 years and

above: a unadjusted prevalence

(p \ 0.001 for trend) and

b logistic regression adjusted

for age, current corticotherapy,

and ultradistal radius aBMD

(data are presented as OR and

95 % confidence interval)

T. Rolland et al.: Bone Microarchitecture and CRP Level in Men 503

123

deterioration of bone microarchitecture at the distal tibia

than the distal radius [47].

However, higher fat mass in men with higher BMI can

also exert its effect on bone through humoral factors.

Obesity is associated with higher secretion of insulin,

amylin, and preptin, which exert a protective effect on bone

[48–51]. Adipocytes also secrete leptin and aromatize

androgens to estrogens. Leptin may increase osteoblast and

osteoclast activity; however, the effect of leptin on bone

mass is not straightforward [52]. Estrogens preserve bone

mass [53, 54]. However, obesity, especially accumulation

of visceral fat, is associated with a chronic inflammatory

status and lower aBMD [55–57]. Thus, more active

inflammatory status may exert its deleterious effect more

easily at the distal radius, which is protected only by hor-

monal factors, compared with the weight-bearing distal

tibia, which is protected both by the hormonal factors and

by the mechanical load of body weight. This speculation is

supported by our previous data showing a greater increase

in some microarchitectural parameters (cortical area, TbN)

in obese men at the distal tibia than at the distal radius [58].

However, variants of the CRP gene influenced baseline

CRP level [59] and its acute-phase rise in active inflam-

mation. Using erythrocyte sedimentation rate as a marker

of inflammation in patients with RA, there was a 3.5-fold

difference in serum CRP levels between carriers of two

common CRP haplotypes [60]. Furthermore, the selective

mortality of men with higher hsCRP levels may attenuate

the relation between hsCRP and bone microarchitecture

[61].

Strengths of our study are the large cohort covering a

large age range and representing various social groups and

the assessment of bone microarchitecture at the weight-

bearing tibia and non-weight-bearing radius. Our study has

limitations. Our cohort may not be representative of the

French population. The men were recruited from the rolls

of a private insurance company. Thus, social groups with

lower income level and poorer health status may be

underrepresented. Volunteers participating in a research

study are often healthier among older men and in poorer

health for young men. The cross-sectional design limits

inference on cause and effect. We used a single measure-

ment of one inflammatory marker; however, CRP is a

‘‘downstream’’ marker and may reflect the overall effect of

various pro- and anti-inflammatory stimuli. Despite high

resolution, a partial volume effect exists and contributes to

an erroneous estimation of Ct.vBMD and Ct.Th in men

with the lowest Ct.Th, thus mainly in the oldest men. In

men with very thin trabeculae, it may result in underesti-

mation of Tb.N. Tb.Th is calculated, not measured. In the

analysis of fractures, it is not possible to establish the

temporal sequence. Some fractures may have occurred

many years before blood collection.

A higher hsCRP level was associated with a poor tra-

becular, but not cortical, microarchitecture at the distal

radius in men aged C72 but not in younger ones. No

change related to hsCRP level was found for the distal

tibia. The association between hsCRP level and bone

microarchitecture in the elderly men may be due to more

active inflammatory status operating in bone deteriorated

by other factors and due to possible interaction with these

factors. The association was significant only for trabecular

parameters at the radius, probably because cortical bone

and trabecular microarchitecture at the tibia depend more

strongly on other determinants. A higher hsCRP concen-

tration was associated with higher odds for prevalent

fracture regardless of the adjustment for aBMD and mi-

croarchitectural parameters. Thus, the impairment of bone

microarchitecture does not seem to explain the positive

association between CRP level and fracture risk.

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