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Keywords:

  • SCLEROSTIN;
  • BONE MICROARCHITECTURE;
  • TRABECULAR BONE;
  • MEN

ABSTRACT

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

Sclerostin is predominantly expressed by osteocytes. Serum sclerostin levels are positively correlated with areal bone mineral density (aBMD) measured by dual-energy X-ray absorptiometry (DXA) and bone microarchitecture assessed by high-resolution peripheral quantitative computed tomography (HR-pQCT) in small studies. We assessed the relation of serum sclerostin levels with aBMD and microarchitectural parameters based on HR-pQCT in 1134 men aged 20 to 87 years using multivariable models adjusted for confounders (age, body size, lifestyle, comorbidities, hormones regulating bone metabolism, muscle mass and strength). The apparent age-related increase in serum sclerostin levels was faster before the age of 63 years than afterward (0.43 SD versus 0.20 SD per decade). In 446 men aged ≤63 years, aBMD (spine, hip, whole body), trabecular volumetric BMD (Tb.vBMD), and trabecular number (Tb.N) at the distal radius and tibia were higher in the highest sclerostin quartile versus the three lower quartiles combined. After adjustment for aBMD, men in the highest sclerostin quartile had higher Tb.vBMD (mainly in the central compartment) and Tb.N at both skeletal sites (p < 0.05 to 0.001). In 688 men aged >63 years, aBMD was positively associated with serum sclerostin levels at all skeletal sites. Cortical vBMD (Ct.vBMD) and cortical thickness (Ct.Th) were lower in the first sclerostin quartile versus the three higher quartiles combined. Tb.vBMD increased across the sclerostin quartiles, and was associated with lower Tb.N and more heterogeneous trabecular distribution (higher Tb.Sp.SD) in men in the lowest sclerostin quartile. After adjustment for aBMD, men in the lowest sclerostin quartile had lower Tb.vBMD and Tb.N, but higher Tb.Sp.SD (p < 0.05 to 0.001) at both the skeletal sites. In conclusion, serum sclerostin levels in men are strongly positively associated with better bone microarchitectural parameters, mainly trabecular architecture, regardless of the potential confounders.


Introduction

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

Sclerostin is expressed mainly by osteocytes.[1] It prevents activation of the canonical WNT/β-catenin signaling pathway in osteoblasts.[2] Mutations in the gene encoding sclerostin are associated with higher bone mass.[1] Serum sclerostin levels increased with age[3, 4] and were positively correlated with bone mineral density (BMD) in most,[4-10] but not all,[3] studies.

Limited data indicate that sclerostin is correlated positively with trabecular density, number and thickness.[4] Serum sclerostin levels were associated more strongly with trabecular than cortical parameters. In hemodialysis patients, serum sclerostin was increased and correlated positively with BMD, trabecular density, number, and thickness at the distal radius and tibia.[11]

The relation of serum sclerostin with BMD and bone microarchitecture was assessed mainly in women or patients with various pathologies; data in men are scarce. Many factors affect sclerostin levels. In Saudi women, serum sclerostin correlated positively with age, body mass index (BMI), and parathyroid hormone (PTH) levels.[3] The correlation between sclerostin and 17β-estradiol was negative, but became positive after adjustment for age and BMI.[3] In Caucasian women, 17β-estradiol did not correlate with serum sclerostin regardless of age and menopausal status.[4] However, women receiving estrogen therapy had lower sclerostin levels.[4, 12] In men, 17β-estradiol correlated positively with sclerostin,[4] whereas suppression of estrogen synthesis increased serum sclerostin levels.[12] Correlation of serum sclerostin with testosterone was weak.[4] Acute, but not long-term, exposure to PTH(1-34) decreased serum sclerostin levels.[13, 14] These factors may obscure the association between serum sclerostin and bone status.

Therefore, given the scarcity of data on the association between serum sclerostin and bone microarchitecture in men, we assessed this association cross-sectionally in a cohort of men.

Subjects and Methods

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

Cohort

The STRAMBO study is a single-center cohort study of skeletal fragility in men performed as a collaboration between INSERM and Mutuelle de Travailleurs de la Région Lyonnaise (MTRL).[15] The study was approved by the ethics committee and conducted in agreement with the Helsinki Declaration of 1975/1983. Invitations were sent to a randomly selected sample of men aged 20 to 87 years from the MTRL lists living in greater Lyon, France. Of them, 1169 men provided informed consent to participate in the study. This study was done in 1134 men who had high-resolution peripheral computed tomography (HR-pQCT), dual-energy X-ray absorptiometry (DXA), and valid assays of serum sclerostin level. All men able to provide informed consent, to answer the questionnaire, and to participate in the diagnostic exams were included. No exclusion criteria were used.

Serum measurements

Nonfasting serum was collected at 1:00 p.m. and stored at −80°C. Serum sclerostin levels were measured using the ELISA assay (BioMedica Sclerostin ELISA; BioMedica Medizinprodukte GmbH, Vienna, Austria). Assay buffer (150 μL/well) was followed by 20-μL standards or samples, and 50 μL antisclerostin antibody. Plates were incubated for 20 to 22 hours at 21°C. Then, wells were washed five times, 200 μL conjugate was added. The plates were incubated in the dark for 1 hour. Wells were washed, 200 μL 3,3′,5,5′-tetramethylbenzidine was added per well, and color was allowed to develop for 30 minutes at 21°C, followed by the addition of 50 μL stop solution. Absorbance was read within 10 minutes at 450 nm. Intraassay and interassay coefficients of variation (CV) are 5% to 6% and 2% to 6%, respectively.

PTH was measured by a human-specific immunochemiluminescence assay (ELECSYS; Roche Diagnostics, Mannheim, Germany).[16] 25-Hydroxycholecalciferol (25OHD) was measured with radioimmunoassay (RIA) after acetonitrile extraction (DiaSorin, Stillwater, MN).[17] Osteoprotegerin (OPG) was measured by ELISA (BioMedica).[18] Testosterone was measured by RIA after diethylether extraction.[19] 17β-estradiol was measured using an ultrasensitive RIA (CISBio-International, Gif sur Yvette, France).[18] Sex hormone-binding globulin (SHBG) was measured by RIA (CISBio-International).[19] Apparent free testosterone concentration (AFTC) and bioavailable 17β-estradiol (bio-17β-estradiol) were calculated.[20, 21] High-sensitivity C-reactive protein (CRP) was measured by an immunoturbidimetric assay (Cobas; Roche Diagnostics).[22] Glomerular filtration rate (GFR) was estimated by the Modification of Diet in Renal Disease (MDRD) equation.[23]

Bone microarchitecture assessment

Cross-sectional area (CSA), total volumetric BMD (Tt.vBMD), and bone microarchitecture were assessed by HR-pQCT (XtremeCT; Scanco Medical AG, Brüttisellen, Switzerland) at the nondominant distal radius and right distal tibia.[15, 24] CV of a phantom was 0.7% to 1.5%. Volume of interest (VOI) was automatically separated into cortical (Ct.Ar) and trabecular area (Tb.Ar). Cortical thickness (Ct.Th), cortical vBMD (Ct.vBMD), trabecular vBMD (Tb.vBMD), trabecular number (Tb.N, mm−1), trabecular thickness (Tb.Th, µm), trabecular separation (Tb.Sp, µm), and intraindividual distribution of Tb.Sp (Tb.Sp.SD, µm) were also defined.[15, 24] Trabecular VOI was divided in an outer and an inner compartment, in which trabecular vBMD was assessed (oTb.vBMD and iTb.vBMD).[18] Sixty-five scans of the radius and 27 scans of the tibia were excluded because of poor quality (movement and/or nonuniform external contour).

DXA

Body composition and areal BMD (aBMD) (spine, hip, whole body, distal radius) were estimated by DXA (Hologic-Discovery-A; Hologic Inc., Bedford, MA, USA). Prevalent vertebral fractures were assessed visually on the lateral spine scans. CV of daily measurements of a Hologic spine phantom was 0.35%. Appendicular skeletal muscle mass (ASM) was calculated as the sum of lean soft tissue in the four limbs.[25] Relative appendicular skeletal muscle mass index (RASM) was calculated as ASM/(body height)[2].

Prevalent fragility fractures

Prevalent vertebral and peripheral fractures were assessed as described.[26] Their analysis was limited to 908 men aged ≥50 years who had sclerostin measurements, because they were rare in younger men. Ninety-six men had 161 vertebral fractures. Ninety-eight men self-reported 117 low-trauma peripheral fractures. Fractures of the face, hand, and toes were excluded. Overall, 173 men had prevalent fractures.

Covariates

Participants completed interviewer-administered questionnaire. Lifestyle and medical history were self-reported without formal ascertainment. Smoking was categorized as current smoker versus nonsmoker. Previously, the analysis of sport activities according to the “required” bone (eg, radius in tennis) and the intensity (high or not) allowed better assessment of the action of physical activity on bone.[27] A “high” physical activity was defined as practicing a type of sport for ≥1 year at a competition level. Calcium intake was assessed using a food frequency questionnaire adapted to the French nutritional habits.[28] Chronic diseases (ischemic heart disease [IHD], diabetes mellitus, parkinsonism, hypertension) were self-reported. Weight and height were measured in light clothes without shoes using standard clinical equipment. A composite score of physical performance was calculated using the results of the clinical tests.[27] Grip strength was measured three times by a hand dynamometer (Vigorimeter Martin, MartinMedizintechnik, Tuttlingen, Germany) at the dominant hand.[25]

Statistical analysis

Statistical analyses were performed using the SAS 9.1 software (SAS Institute, Cary, NC, USA). Data are presented as mean ± SD or median (interquartile range). Non-Gaussian distributed variables were log-transformed. Relation of sclerostin levels with age and microarchitectural parameters was modeled by PROC LOESS (option Automatic Smoothing Parameter Selection). The corrected Akaike information criterion (AICC) versus smoothing parameter plot was used to ensure that the selected smoothing parameter value corresponded to the global minimum of the AICC criterion. Associations between linear variables were assessed by simple and partial Pearson's correlation coefficient and linear regression.

The association between classes and continuous variables was assessed by backward analysis of covariance. The initial model included age, weight, height, 25OHD, PTH, AFTC, bio-17β-estradiol, GFR, RASM, grip strength (continuous), high physical activity (yes/no), current smoking (yes/no), comorbidities (IHD, hypertension, diabetes; yes/no), alcohol intake (0, <150, ≥150 g/week), calcium intake (<590 versus ≥590 mg/d), and physical performance score (quartiles). The variables with p < 0.10 for any variable for a given group of variables in a given age range were retained in the final model for this group of variables in this age range. In men aged <63 years, we retained age, weight, height, calcium intake, IHD, diabetes, RASM, grip strength, bio-17β-estradiol, PTH, and CRP. In men aged >63 years, we retained age, weight, height, current smoking, alcohol intake, calcium intake, IHD, diabetes, RASM, grip strength, bio-17β-estradiol, PTH, CRP, OPG, interaction between PTH level and calcium intake, and physical performance score (except for the radius).

If the dependent variable differed significantly between the three lower (or higher) quartiles of the class variable, we calculated the trend across the four quartiles and the difference between the adjusted means in the fourth versus the first quartile. If the dependent variable did not differ in the three lower (or higher) quartiles of the class variable, we calculated the difference between the adjusted means in the extreme quartile and the combined three quartiles. The differences are expressed as percentage and number of SDs. Interactions between the variables were also assessed.

The association between sclerostin levels and fracture prevalence was assessed using the chi-square test and logistic regression adjusted for age, BMI, and femoral neck aBMD.

Results

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

Analyses of the entire cohort

Serum sclerostin levels increased with age (r = 0.48, p < 0.001) with a split point at the age of 63 years (Fig. 1). In 446 men aged ≤63 years serum sclerostin correlated positively with age (r = 0.55, p < 0.001) and increased by 0.43 ± 0.03 SD/decade. In 688 men aged >63 years, serum sclerostin correlated with age less strongly (r = 0.17, p < 0.001) and increased by 0.20 ± 0.03 SD/decade. The correlation and regression coefficients differed between the groups (p < 0.001). Other thresholds between 50 and 70 years provide weaker associations and weaker differences between younger and older men. Therefore, we performed the analyses separately in men aged ≤63 years and >63 years. The correlation between sclerostin levels and weight was weak (r = 0.07, p < 0.05). Sclerostin levels did not correlate with physical activity regardless of the statistical approach or age group. Table 1 presents the descriptive analysis of both groups of men.

image

Figure 1. Association between log-transformed sclerostin concentration and age in 1134 men aged 20 to 87 years from the STRAMBO cohort assessed using the LOESS procedure.

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Table 1. Descriptive Analysis of the Two Groups of Men From the STRAMBO Cohort
 Men aged ≤63 yearsMen aged >63 years
(n = 446)(n = 688)
  1. Values are mean ± SD or median [interquartile range], except where otherwise indicated.

  2. RASM = relative appendicular skeletal muscle mass; AFTC = apparent free testosterone concentration.

Age (years)46 ± 1374 ± 6
Weight (kg)79 ± 1278 ± 11
Height (cm)174 ± 7168 ± 6
Body mass index (kg/m2)26.0 ± 3.627.8 ± 3.6
RASM (kg/m2)8.48 ± 0.958.20 ± 0.86
Grip strength (kPa)89.8 ± 19.867.6 ± 16.4
Smoking
Current, n (%)88 (19.7)35 (5.1)
Former, n (%)157 (35.2)433 (62.9)
Never, n (%)201 (45.1)220 (32.1)
Alcohol intake (g/week)47 [0, 125]109 [16, 234]
Calcium intake (mg/d)803 ± 290765 ± 247
Leisure physical activity (hours/week)2 [1, 4]3 [0, 8]
Ischemic heart disease, n (%)8 (1.8)126 (17.6)
Hypertension, n (%)46 (10.1)314 (43.8)
History of stroke, n (%)3 (0.7)32 (4.5)
Parkinsonism, n (%)0 (0.0)15 (2.1)
Diabetes mellitus, n (%)20 (4.4)99 (13.4)
Testosterone (nmol/L)12.6 ± 5.311.8 ± 5.3
AFTC (pmol/L)299 ± 108236 ± 89
17beta-estradiol (pmol/L)52.1 ± 19.437.3 ± 15.2
Bioavailable 17beta-estradiol (pmol/L)40.6 ± 15.837.3 ± 15.2
Sex hormone-binding globulin (nmol/L)31.0 ± 14.744.8 ± 21.3
25-hydroxycholecalciferol (ng/mL)24.1 ± 10.821.6 ± 9.6
Parathyroid hormone (pg/mL)37 [29, 46]45 [34, 58]
Osteoprotegerin (pmol/L)2.98 [2.47, 3.50]4.11 [3.32, 5.05]
High sensitivity C-reactive protein (mg/L)1.13 [0.54, 2.21]1.70 [0.89, 3.30]
Sclerostin (pmol/L)43.8 [32.2, 59.7]70.1 [52.1, 91.8]
Glomerular filtration rate (mL/min)89 ± 1774 ± 17

Analyses in men aged ≤63 years

As aBMD and microarchitectural parameters did not differ in the three lower sclerostin quartiles (Table 2), the values in the highest sclerostin quartile were compared with the three lower quartiles combined. In multivariable models, aBMD at the lumbar spine, hip, and whole body was 4.6% to 7.5% higher (0.38–0.54 SD, p < 0.05 to <0.001) in the highest versus the three lower quartiles combined. Distal radius aBMD was not associated with serum sclerostin.

Table 2. Comparison of BMD in Men Aged ≤63 Years According to the Quartiles of Sclerostin
 Q1 (<32.2 pmol/L)Q2 (32.2–43.8 pmol/L)Q3 (>43.8–59.7 pmol/L)Q4 (>59.7 ng/mL)In four quartilesQ4 versus Q1–Q3a
p1p2p1p2
  1. Values are mean ± SD or median [interquartile range], unless otherwise indicated.

  2. BMD = bone mineral density; Q1–Q4 = quartiles 1–4; p1 = p value for sclerostin in the multivariable model adjusted for age, weight, height, relative appendicular skeletal muscle mass, grip strength, calcium intake, ischemic heart disease, diabetes mellitus, bioavailable 17β-estradiol, PTH, and hsCRP; p2 = p1 value with additional adjustment for aBMD (ultradistal radius aBMD for the distal radius, total hip aBMD for the distal tibia); PTH = parathyroid hormone; hsCRP = high-sensitivity C-reactive protein; CSA = ; vBMD = volumetric BMD; Tt.vBMD = total vBMD; Ct.Th = cortical thickness; Ct.vBMD = cortical vBMD; Tb.Ar = trabecular area; Tb.vBMD = trabecular vBMD; Tb.N = trabecular number; Tb.Th = trabecular thickness; Tb.Sp = trabecular spacing; Tb.Sp.SD = intraindividual distribution of Tb.Sp.

  3. a

    Comparison of the fourth quartile of sclerostin versus the three lower quartiles combined unless otherwise stated.

  4. b

    Comparison of the first quartile versus three higher quartiles of sclerostin combined.

Areal BMD (g/cm2)
Lumbar spine0.990 ± 0.1361.006 ± 0.1541.025 ± 0.1341.087 ± 0.188<0.001<0.001
Total hip0.978 ± 0.1470.997 ± 0.1331.007 ± 0.1271.046 ± 0.135<0.005<0.001
Whole body1.140 ± 0.0981.154 ± 0.0981.165 ± 0.1011.205 ± 0.119<0.001<0.001
Distal radius0.659 ± 0.0510.654 ± 0.0490.659 ± 0.0570.657 ± 0.0660.880.95
Distal radius(n = 113)(n = 105)(n = 107)(n = 104)    
CSA (cm2)3.73 ± 0.543.72 ± 0.633.81 ± 0.663.80 ± 0.610.600.550.550.50
Tt.vBMD (mg/cm3)327.9 ± 57.2330.4 ± 54.2325.6 ± 56.3328.0 ± 62.30.940.380.970.36
Ct.Th (mm)0.82 ± 0.190.83 ± 0.180.81 ± 0.200.80 ± 0.210.770.160.350.17
Ct.vBMD (mg/cm3)850.5 ± 46.5854.9 ± 47.7846.9 ± 56.9841.1 ± 64.80.370.070.160.12
Tb.Ar (cm2)2.96 ± 0.562.96 ± 0.633.04 ± 0.663.06 ± 0.620.560.420.390.28
Tb.vBMD (mg/cm3)188.6 ± 36.5188.0 ± 35.0187.7 ± 31.3197.2 ± 36.60.18<0.05<0.05<0.01
Outer vBMD248.0 ± 35.1247.0 ± 34.7244.5 ± 31.6252.2 ± 36.40.420.100.130.11
Inner vBMD147.7 ± 38.5147.3 ± 36.3148.7 ± 32.3159.3 ± 38.00.08<0.05<0.01<0.005
Tb.N (1/mm)1.90 ± 0.241.91 ± 0.231.88 ± 0.191.98 ± 0.25<0.001<0.05<0.001<0.001
Tb.Th (μm)82.8 ± 12.581.9 ± 11.283.4 ± 12.182.7 ± 10.80.830.650.980.53
Tb.Sp (μm)436 [392, 484]440 [395, 498]455 [420, 499]432 [383, 478]<0.05<0.005<0.005<0.001
Tb.Sp.SD (μm)178 [155, 199]178 [161, 206]188 [172, 209]174 [157, 197]<0.05<0.01<0.005<0.001
Distal tibia(n = 115)(n = 113)(n = 110)(n = 105)    
CSA (cm2)8.42 ± 1.148.24 ± 1.288.37 ± 1.268.37 ± 1.360.550.480.750.44
Tt.vBMD (mg/cm3)310.0 ± 58.4321.7 ± 52.3318.3 ± 49.5334.2 ± 56.2<0.020.49<0.010.49
Ct.Th (mm)1.27 ± 0.291.35 ± 0.251.33 ± 0.271.36 ± 0.290.100.21<0.001b0.24b
Ct.vBMD (mg/cm3)879.3 ± 33.2889.1 ± 35.9880.7 ± 42.4879.6 ± 52.00.200.080.430.08
Tb.Ar (cm2)6.93 ± 1.206.68 ± 1.326.82 ± 1.286.80 ± 1.440.410.350.920.37
Tb.vBMD (mg/cm3)184.7 ± 44.1185.0 ± 38.7186.7 ± 34.1202.8 ± 36.1<0.0010.06<0.001<0.05
Outer vBMD249.1 ± 45.3250.7 ± 39.0251.6 ± 34.4267.1 ± 37.0<0.0050.17<0.001<0.05
Inner vBMD141.1 ± 44.2140.4 ± 40.0142.6 ± 35.7159.2 ± 37.1<0.001<0.05<0.001<0.01
Tb.N (1/mm)1.80 ± 0.321.82 ± 0.311.82 ± 0.281.97 ± 0.26<0.001<0.005<0.001<0.001
Tb.Th (μm)85.0 ± 12.484.8 ± 12.785.8 ± 11.286.1 ± 12.00.890.810.600.44
Tb.Sp (μm)450 [391, 500]459 [410, 530]469 [422, 547]444 [401, 493]<0.001<0.005<0.001<0.001
Tb.Sp.SD (μm)200 [170, 237]209 [179, 254]217 [191, 254]204 [172, 229]<0.001<0.005<0.001<0.001

In the bivariate and multivariable analyses, CSA, Tb.Ar, and Ct.vBMD at the distal radius and tibia did not differ according to the sclerostin level. Ct.Th was lower in the lowest versus the three higher quartiles combined. The association of trabecular parameters with sclerostin levels showed that below ∼45 pmol/L, Tb.vBMD, TbN, and Tb.Sp.SD did not correlate with sclerostin: r = |0.04| to |0.10|, p > 0.10 (Fig. 2). By contrast, these parameters correlated with sclerostin for sclerostin >45 pmol/L: r = |0.18| to |0.29|, p = 0.01 to p < 0.001. Tb.vBMD was higher in the fourth quartile (versus three lower ones) at the distal radius (4.8%, 0.25 SD, p < 0.05) and distal tibia (8.4%, 0.47 SD, p < 0.001). The trend was stronger for the inner than outer compartment. The difference in Tb.vBMD was due to higher TbN in the highest quartile at the distal radius (5.7%, 0.44 SD, p < 0.001) and the distal tibia (8.4%, 0.59 SD, p < 0.001), whereas Tb.Th did not differ by sclerostin level. As expected, Tb.Sp and Tb.Sp.SD were lower in the highest versus the three lower quartiles.

image

Figure 2. Association between microarchitectural parameters (upper panel: Tb.vBMD; middle panel: Tb.N; lower panel: Tb.Sp.SD) and log-transformed sclerostin concentration in 446 men aged ≤63 years from the STRAMBO cohort assessed using the LOESS procedure.

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After adjustment for aBMD (ultradistal radius for radius, total hip for tibia), Tb.vBMD were higher in the fourth quartile (versus three lower ones) at the distal radius (3.5%, 0.19 SD) and tibia (4.5%, 0.22 SD) (both p < 0.05). The difference was due to higher Tb.N in the highest versus three lower quartiles (4.3%, 0.37 SD and 5.7%, 0.38 SD, p < 0.001). After adjustment for aBMD, Tb.Sp and Tb.Sp.SD remained lower in the highest versus three lower quartiles (2.1% to 4.0%, 0.34–0.38 SD).

Analyses in men aged >63 years

After adjustment for confounders, aBMD was positively associated with serum sclerostin levels (Table 3). For most of the sites, aBMD increased across serum sclerostin quartiles (p-trend < 0.001). aBMD increased by 0.23 to 0.62 SD per SD of serum sclerostin and was 11.3% to 16.6% higher (0.66–1.05 SD, p < 0.001) in the fourth versus the first quartile. At the distal radius, aBMD was higher in the fourth versus the three lower quartiles combined.

Table 3. Comparison of BMD in Men Aged >63 Years According to the Quartiles of Sclerostin
 Q1 (<52.1 pmol/L)Q2 (52.1–70.1 pmol/L)Q3 (>70.1–91.8 pmol/L)Q4 (>91.8 pmol/L)In four quartilesQ1 versus Q2–Q4a
p1p2p1p2
  1. Values are mean ± SD or median [interquartile range], unless otherwise indicated.

  2. BMD = bone mineral density; p1 = p value for sclerostin in the multivariable model adjusted for age, weight, height, current smoking, alcohol intake, calcium intake, relative appendicular skeletal muscle mass, grip strength, ischemic heart disease, diabetes mellitus, bioavailable 17β-estradiol, PTH, hsCRP, OPG, interaction between PTH level and calcium intake, and composite physical performance score (except for the distal radius); p2 = p1 value with additional adjustment for aBMD (ultradistal radius aBMD for the distal radius, total hip aBMD for the distal tibia); PTH = parathyroid hormone; hsCRP = high-sensitivity C-reactive protein; OPG = osteoprotegerin ; CSA = cross-sectional area; vBMD = volumetric BMD; Tt.vBMD = total vBMD; Ct.Th = cortical thickness; Ct.vBMD = cortical vBMD; Tb.Ar = trabecular area; Tb.vBMD = trabecular vBMD; Tb.N = trabecular number; Tb.Th = trabecular thickness; Tb.Sp = trabecular spacing; Tb.Sp.SD = intraindividual distribution of Tb.Sp.

  3. a

    Comparison of the first quartile of sclerostin versus the three higher quartiles combined unless otherwise stated.

  4. b

    Trend across the quartiles of sclerostin.

  5. c

    Comparison of the fourth quartile of sclerostin versus the three lower quartiles combined.

Areal BMD (g/cm2)(n = 170)(n = 173)(n = 172)(n = 173)    
Lumbar spine0.957 ± 0.1511.034 ± 0.1641.053 ± 0.1831.116 ± 0.193<0.001<0.001b
Total hip0.898 ± 0.1360.936 ± 0.1230.956 ± 0.1320.999 ± 0.144<0.001<0.001b
Whole body1.072 ± 0.1061.110 ± 0.1011.123 ± 0.1111.151 ± 0.114<0.001<0.001b
Distal radius0.586 ± 0.0790.611 ± 0.0710.610 ± 0.0690.618 ± 0.070<0.001<0.001
Distal radius(n = 155)(n = 161)(n = 157)(n = 163)    
CSA (cm2)3.85 ± 0.583.94 ± 0.583.97 ± 0.713.97 ± 0.680.210.07<0.05<0.01
Tt.vBMD (mg/cm3)272.3 ± 66.9286.9 ± 66.4286.4 ± 60.9298.8 ± 62.3<0.0010.18<0.001b0.20
Ct.Th (mm)0.64 ± 0.220.68 ± 0.230.68 ± 0.220.70 ± 0.220.070.13<0.050.08
Ct.vBMD (mg/cm3)780.9 ± 75.9793.2 ± 70.3794.1 ± 72.1800.4 ± 73.60.070.76<0.050.43
Tb.Ar (cm2)3.18 ± 0.623.23 ± 0.623.27 ± 0.723.25 ± 0.690.55<0.050.18<0.01
Tb.vBMD (mg/cm3)158.3 ± 40.9169.0 ± 38.3170.7 ± 38.2181.6 ± 40.0<0.0010.61<0.001b0.46
Outer vBMD215.4 ± 39.3224.8 ± 37.1226.2 ± 40.2237.1 ± 40.5<0.0010.49<0.001b0.84
Inner vBMD119.1 ± 43.6130.7 ± 40.7132.5 ± 38.6149.5 ± 41.4<0.0010.66<0.001b0.32
Tb.N (1/mm)1.74 ± 0.281.83 ± 0.251.86 ± 0.261.90 ± 0.26<0.0010.07<0.001<0.02
Tb.Th (μm)74.9 ± 12.076.6 ± 12.276.0 ± 11.079.4 ± 12.8<0.010.13<0.005c0.64
Tb.Sp (μm)490 [431, 566]461 [423, 520]467 [413, 517]451 [400, 499]<0.0010.11<0.001<0.05
Tb.Sp.SD (μm)211 [180, 264]202 [174, 231]201 [170, 232]190 [165, 226]<0.0010.10<0.001b<0.05b
Distal tibia(n = 166)(n = 167)(n = 172)(n = 164)    
CSA (cm2)8.37 ± 1.198.42 ± 1.188.42 ± 1.378.52 ± 1.310.630.080.400.08
Tt.vBMD (mg/cm3)263.9 ± 61.6283.9 ± 54.2288.9 ± 56.5295.8 ± 52.9<0.0010.14<0.001<0.05
Ct.Th (mm)1.08 ± 0.311.16 ± 0.311.17 ± 0.291.21 ± 0.29<0.0010.57<0.0010.24
Ct.vBMD (mg/cm3)800.7 ± 79.0824.9 ± 58.9832.9 ± 60.6837.6 ± 60.1<0.001<0.01<0.001<0.001
Tb.Ar (cm2)7.02 ± 1.287.01 ± 1.257.00 ± 1.427.06 ± 1.380.960.130.990.14
Tb.vBMD (mg/cm3)155.3 ± 40.2169.8 ± 36.8173.2 ± 36.6178.8 ± 34.8<0.0010.06<0.001<0.01
Outer vBMD227.1 ± 38.1237.8 ± 36.3240.5 ± 36.6244.4 ± 34.9<0.0010.43<0.0010.13
Inner vBMD106.6 ± 43.5123.6 ± 38.7127.6 ± 38.4134.3 ± 36.9<0.001<0.01<0.001<0.001
Tb.N (1/mm)1.59 ± 0.311.72 ± 0.291.77 ± 0.291.79 ± 0.29<0.001<0.001<0.001<0.001
Tb.Th (μm)81.4 ± 13.482.9 ± 14.281.7 ± 12.082.8 ± 13.20.310.580.240.68
Tb.Sp (μm)543 [476, 641]501 [442, 574]486 [428, 552]474 [420, 539]<0.001<0.001<0.001<0.001
Tb.Sp.SD (μm)257 [221, 326]239 [201, 277]224 [190, 260]223 [184, 252]<0.001<0.001<0.001<0.001

In the bivariate model, Ct.vBMD, Ct.Th, Tb.N, Tb.Sp, and Tb.Sp.SD correlated with sclerostin for sclerostin levels <∼67 pmol/L: r = |0.12| to |0.32|, p = 0.07 to p < 0.001 (Fig. 3). The correlations were nonsignificant for higher sclerostin levels: r = |0.02| to |0.06|, p > 0.25. In the multivariable models, CSA and Tb.Ar did not correlate with the sclerostin level, except for lower CSA at the radius in the first sclerostin quartile. Tt.vBMD correlated positively with serum sclerostin. Ct.Th and Ct.vBMD were lower in the fourth versus the three lower quartiles combined. After adjustment for confounders, Tb.vBMD was associated positively with serum sclerostin level and lower in the lowest sclerostin quartile with a similar trends in the inner and outer compartments. This trend was mainly due to the lower Tb.N in the lowest sclerostin quartile, whereas the association with Tb.Th was weak. Tb.Sp and Tb.Sp.SD correlated negatively with serum sclerostin and were the highest in the lowest sclerostin quartile.

image

Figure 3. Association between microarchitectural parameters (upper panel: Ct.vBMD; middle panel: Ct.Th; lower panel: Tb.N) and log-transformed sclerostin concentration in 688 men aged >63 years from the STRAMBO cohort assessed using the LOESS procedure.

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The trends at the distal radius weakened after adjustment for ultradistal radius aBMD. In the lowest quartile, Tb.N was lower (2.61%, 0.18 SD versus the three higher quartiles combined) and Tb.Sp.SD was higher (1.62%, 0.17 SD versus the highest quartile) (both p < 0.05). After adjustment for hip aBMD, distal tibia Tb.vBMD and Ct.vBMD remained lower in the lowest versus the three higher quartiles combined (5.0%, 0.22 SD, p < 0.05 and 2.1%, 0.28 SD, p < 0.001). After adjustment for aBMD, Tb.N was lower (6.0%, 0.34 SD) and Tb.Sp.SD was higher (4.1%, 0.36 SD) in the lowest versus the three higher quartiles combined (both p < 0.001).

Serum sclerostin and prevalent fractures

The frequency of fractures across the sclerostin quartiles was as follows: 21%, 20%, 22%, and 13%, p < 0.05. After adjustment for age, BMI, and femoral neck aBMD, odds of fracture decreased with increasing sclerostin levels (odds ratio [OR] = 0.79; 95% confidence interval [CI], 0.66–0.96; p < 0.05) and was lower in the highest versus the three lower quartiles combined (OR = 0.54; 95%CI, 0.34–0.86; p < 0.01).

Discussion

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

Higher serum sclerostin levels in men were associated with higher aBMD and better bone microarchitecture, mainly in the trabecular bone. This relation tended to be stronger in the older men and significant after adjustment for the confounders. The positive relation of sclerostin level with Tb.vBMD, Tb.N, and Tb.Sp.SD remained significant after adjustment for aBMD. Prevalence of vertebral and peripheral fractures was lower in the highest sclerostin quartile after adjustment for age, BMI, and femoral neck aBMD.

We confirm that serum sclerostin levels correlate positively with age.[4, 9] The age-related increase (inferred from cross-sectional data) is faster in younger versus older men. Because sclerostin is produced mainly by mature osteocytes in the mineralized bone,[29, 30] age-related changes in serum sclerostin levels may reflect changes in bone mass and turnover rate. Because young adult men have high bone turnover,[31] bone tissue may enter a new remodeling cycle sooner after the previous cycle in young men than in older men, which results in lower mass of mature osteocytes producing sclerostin despite high total bone mass. Thus, the parallel decrease in bone turnover rate and increase in the sclerostin levels may reflect a positive feedback: lower bone turnover results in higher mass of mature osteocytes producing sclerostin, which further decreases bone turnover. Accordingly, the age-related increase in the sclerostin would slow down in older men, when bone turnover increases and bone loss accelerates. This slower increase in the sclerostin levels may be related to decreasing bone mass and lower mass of osteocytes. This slowdown coincides with an increase in bone turnover, leading to a decrease in the mass of mature and quiescent osteocytes. Thus, the increased bone turnover may limit the age-related increase in the serum sclerostin levels, consistent with our data showing negative correlation between the levels of sclerostin and bone turnover markers.[32]

We confirm the positive relation between sclerostin levels and aBMD. The difference in aBMD between men with the highest versus the lowest sclerostin levels tended to be greater in older than in younger men. The association between aBMD and sclerostin levels is determined by the relation of higher sclerostin levels with higher Tb.vBMD, mainly greater Tb.N. Higher sclerostin levels are also associated with lower Tb.Sp.SD. The link between sclerostin levels and Tb.vBMD is stronger in the central than in the subendocortical compartment. By contrast, the relation between the sclerostin levels and cortical parameters is weaker and, in younger men, nonsignificant. Sclerostin levels are not associated with bone geometry (CSA, Tb.Ar). These data are consistent with the previous results.[4, 11]

Sclerostin levels are associated with higher Tb.vBMD, mainly iTb.vBMD, higher Tb.N, and lower Tb.Sp.SD after adjustment for aBMD. Men with higher sclerostin levels had fewer prevalent fractures, similar to our prospective study showing a lower fracture risk in men with higher sclerostin levels.[32] Moreover, men with severe vertebral fractures had low Tb.N and high Tb.Sp.SD after adjustment for aBMD (albeit vertebral fractures were associated mainly with poor cortical bone).[26] These data support the speculation that the lower fracture risk in men with higher sclerostin is related to the better trabecular bone. The stronger link between sclerostin levels and iTb.vBMD is interesting because, in older men, high bone turnover marker (BTM) levels were associated with poor trabecular microarchitecture mainly in the central compartment.[15]

Sclerostin inhibits osteoblasts but stimulates osteoclast differentiation and bone resorption,[1, 33] whereas anti-sclerostin antibodies decreased bone resorption.[34] If sclerostin levels reflected its biological activity, one would expect lower Tb.N and Tb.Th in men with higher sclerostin levels. However, this is not the case. Lower Tb.N is associated with lower bone strength and higher load in the remaining bone. Our data are consistent with higher sclerostin expression in the bone submitted to high mechanical loading.[35, 36] By contrast, in men with higher aBMD and better bone microarchitecture, the mechanical strain would be lower, leading to a higher sclerostin secretion.[37, 38] Thus, serum sclerostin may reflect the adaptation of bone to the load; ie, men with low aBMD and poor bone microarchitecture may have higher mechanical strains in the remaining bone and lower sclerostin levels. However, this speculation is weakened by two facts. The relations between sclerostin levels are similar in the non–weight-bearing radius and weight-bearing tibia. Moreover, the association between sclerostin and bone microarchitecture is strongest in central trabecular compartment (where the mechanical strain is lower) and weakest in the cortical bone (where the mechanical strain is higher). In addition, the relation of the sclerostin levels with weight and physical activity is weak. The independent effect of hormones and lifestyle factors on the sclerostin secretion and bone microarchitecture is possible; however, we adjusted for them. Interestingly, sclerostin levels are positively correlated with fat mass,[9, 39] thus, sclerostin levels may correlate with cytokines secreted by fat tissue, which influence bone metabolism.[40]

Our study has limitations. Our cohort may be not representative of the French population. The men were recruited from the rolls of a complementary insurance company. Thus social groups with lower income levels and poorer health status may be underrepresented in our cohort. Volunteers participating in research studies are often healthier among older men and in poorer health among younger men. The cross-sectional design limits inference on the cause and effect; eg, we cannot apportion the age-related changes in the synthesis and inactivation of sclerostin. With HR-pQCT, Tb.Th, Tb.Sp, and Ct.Th are calculated. Despite high-resolution, partial-volume effects exist and contribute to erroneous estimations of Ct.vBMD and Ct.Th in men with the lowest C.Th values, thus mainly in the oldest men. This may contribute to the poorer association between sclerostin and cortical parameters at the radius compared with tibia in the older men. In men with very thin trabeculae, the partial volume effect may result in underestimation of Tb.N. We collected blood samples in the standardized manner, but in the early afternoon and after a nonstandardized lunch. However, to the best of our knowledge, data on the circadian rhythm of sclerostin levels are not available.

Thus, we confirm the positive association between sclerostin levels and aBMD in men. This association is independent of the confounders and apparently related to higher Tb.vBMD. The link between sclerostin and Tb.vBMD depended on higher Tb.N in men with higher serum sclerostin, whereas the correlation between Tb.Th and sclerostin was not significant. Lower Tb.N and higher Tb.Sp.SD may increase bone fragility in men with low sclerostin levels. Because serum sclerostin levels increase with age, but higher sclerostin levels are associated with better bone microarchitecture and lower fracture risk in men, the biological relevance of serum sclerostin is not fully understood. In postmenopausal women, higher sclerostin levels were associated with higher fracture risk in some,[6, 41] but not all, studies.[5] For instance, in a case-cohort study nested in the Study of Osteoporotic Fractures (SOF) cohort, higher sclerostin levels were associated with much higher risk of hip fracture when adjusted for confounders including aBMD.[6] Given the positive link between Tb.N and circulating sclerostin in older women,[4] such association seems counterintuitive. The difference between men and women may depend partly on the effect of sex steroids on the sclerostin expression. Exogenous 17β-estradiol suppressed serum sclerostin in both sexes, in contrast to testosterone, which tended to increase serum sclerostin.[12] Sclerostin expression is sensitive to loading/unloading stimulation.[35-38] In male mice with the androgen receptor knockout, the increase in periosteal bone formation induced by loading was greater than in the wild-type littermates or males with the knockout of the estrogen receptor alpha,[42] indicating substantial gender differences. Thus, we cannot fully explain the discrepancy in the association between the sclerostin level and the fracture risk in men and women. In conclusion, serum sclerostin levels in men are strongly positively associated with better bone microarchitectural parameters, mainly trabecular architecture, regardless of the potential confounders.

Acknowledgments

  1. Top of page
  2. ABSTRACT
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References

This work was supported by grants from the Roche pharmaceutical company, Basle, Switzerland, from Agence Nationale de la Recherche and from Hospices Civils de Lyon, France as well as by Deutsche Forschungsgemeinschaft SPP ImmunoBone RA 1923/4-2 and HO 1875/8-2 to MR as well as SKELMET Forschergruppe-1586 to LCH and Transregio-67 (B2) to both CH and LCH.

Authors' roles: All the authors contributed to the study conception and design, interpreted the data, critically revised the content of the manuscript, and approved its final version. SB and NV performed the HR-pQCT measurements. MR, CH, and LCH measured sclerostin serum levels, PS did the statistical analysis. PS and LCH drafted the manuscript. PS takes responsibility for the integrity of the data analysis.

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  2. ABSTRACT
  3. Introduction
  4. Subjects and Methods
  5. Results
  6. Discussion
  7. Disclosures
  8. Acknowledgments
  9. References
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