Hans-Georg Zmierczak

Anti-citrullinated peptide antibodies may occur in patients with psoriatic arthritis

Background: Anti-cyclic citrullinated peptide (anti-CCP) antibodies are considered highly specific markers of rheumatoid arthritis. Despite the high specificity of the test, anti-CCP antibodies have also been observed in psoriatic arthritis. Objective: To determine the frequency of anti-CCP antibodies in psoriatic arthritis and to describe the clinical characteristics of such patients. Methods: Serum samples from 192 patients with psoriatic arthritis were analysed for anti-CCP antibodies. A previously defined cut off point was applied at a specificity level of ⩾98.5% (42 U/ml). Antibodies against pepA and pepB (two synthetic citrullinated peptides) were determined on samples containing anti-CCP antibodies by line immune assay. The swollen joint count and the numbers of affected joints (present or past) were recorded. Clinical features were noted and if available radiographs of hands and feet were scored for erosions. Rheumatoid factor was determined in all samples. Results: Anti-CCP antibodies were found in 15 patients (7.8%); 13 of 15 anti-CCP2 positive samples were also positive for anti-pepA or pepB antibodies. The prevalence of anti-CCP antibodies was higher than expected in view of the highly specific cut off applied in the test. Detailed analysis of the clinical and radiological features makes it improbable that the high prevalence of anti-CCP antibodies resulted solely from concomitant psoriasis and rheumatoid arthritis or from misclassification. Conclusions: Anti-CCP antibodies may be present in patients with psoriatic arthritis. Although some of the present cohort could have had psoriasis with concomitant rheumatoid arthritis, a proportion at least had the typical characteristics of psoriatic arthritis as the primary diagnosis.

Deficient Acquisition of Bone During Maturation Underlies Idiopathic Osteoporosis in Men: Evidence From a Three-Generation Family Study†‡

To address the issue whether deficient acquisition of bone during maturation or adult‐onset bone loss is primarily to blame for idiopathic osteoporosis in men, we assessed indices of bone mineral density and size, as well as biochemical markers of bone turnover in 61 probands (ages 20–65 years) with idiopathic osteoporosis (z‐score ≤ −2.0 at the spine or hip), their first‐degree relatives (n = 130), and age‐matched controls. There was no indication of accelerated bone loss. Indeed, in probands, the observed bone deficit versus controls was unrelated to the age of probands, and indices of bone turnover were not significantly different from controls. On the other hand, a specific deficit in bone acquisition was suggested by findings of lower bone mineral density values in three generations of male and female relatives of the probands, including their offspring; bone turnover in relatives was not different from controls. The bone mineral density deficit was more pronounced in male compared with female relatives; approximately 60% of the sons had a spinal bone mineral density z‐score of less than −2.0. There also was a skeletal site‐specificity in probands and their male relatives with a larger areal bone mineral density deficit at the spine compared with the hip and the forearm. The deficit at the spine corresponded to a reduction of both volumetric bone mineral density and bone size; a similar less pronounced deficit in volumetric bone mineral density, but not in bone size, was observed at the femoral neck. These findings in probands and their first‐degree relatives point toward a major contributory role of a genetically determined maturational defect in bone acquisition in the pathogenesis of idiopathic osteoporosis in men.

Serum Estradiol Is Associated With Volumetric BMD and Modulates the Impact of Physical Activity on Bone Size at the Age of Peak Bone Mass: A Study in Healthy Male Siblings

This study investigates determinants of peak bone mass (PBM) in healthy men, focusing on effects and interactions of parameters reflecting mechanical loading and sex steroids. Healthy male siblings (n = 677; 25–45 yr) were recruited in a cross‐sectional, population‐based study. Physical activity score was assessed by a self‐reported questionnaire. Cross‐sectional muscle area (CSMA) and bone parameters of radius (4% and 66% site) and tibia (66% site) were assessed using pQCT. Peak torque of biceps and quadriceps muscles was assessed by isokinetic dynamometry. Serum testosterone (T) and estradiol (E2) levels were measured using immunoassays; free hormone fractions were calculated. Relations between indices of bone strength, CSMA, muscle strength, and sex steroids were studied using linear mixed‐effects modeling. Physical activity, CSMA, and muscle strength were positively associated with indices of bone strength, except for volumetric BMD (vBMD). After controlling for age, weight, and height, free E2 levels were positively associated with trabecular and cortical vBMD, negatively associated with endosteal circumference at the radius, and positively associated with cortical vBMD at the tibia. In addition, positive interactions between physical activity and serum E2 concentrations were observed for bone size at the tibia. No associations between free T levels and pQCT bone parameters were found. In this population of healthy men at the age of PBM, parameters reflecting mechanical loading are confirmed as important determinants of bone size. E2, but not T, levels are positively associated with vBMD and modulate the impact of physical activity on bone size at the tibia.

Identification of Sex-Specific Associations Between Polymorphisms of the Osteoprotegerin Gene, TNFRSF11B, and Paget's Disease of Bone†

We studied the role of TNFRSF11B polymorphisms on the risk to develop Pagets disease of bone in a Belgian study population. We observed no association in men, but a highly significant association was found in women, and this was confirmed in a population from the United Kingdom.

Telomere length versus hormonal and bone mineral status in healthy elderly men.

Telomeres, the termini of linear chromosomes, exert a key role in the process of cellular ageing. Progressive telomere shortening is implicated in senescence in vitro and ample evidence exists to support the hypothesis that telomere length is correlated with chronological age and ageing phenotypes in vivo. In this study, we assessed whether mean telomere length of peripheral blood leukocytes predicts age-associated bone loss and/or is related to sex steroid status in an elderly healthy male population (71-86 years). Out of this population, we selected 110 samples for telomere restriction fragment (TRF) length analysis. Fasting blood was analysed for testosterone, estradiol, sex hormone binding globulin and biochemical markers of bone turnover. Also, the bioavailable fractions of sex steroids were calculated. Bone mineral density was measured at baseline and longitudinal follow-up was available for 84 men. We found that mean TRF length was inversely correlated with age (r=-0.19; P=0.049). Although no correlations were found with sex steroids or BMD at baseline, age corrected mean TRF length was associated with longitudinal bone loss for different distal forearm sites (P<0.05). Further studies are required to confirm our results, yet in this study, the predictive value of telomere length for bone loss appears to be substantial, hence underscoring the role of telomere length as a biomarker of ageing phenotypes.

Sex Hormone-Binding Globulin as an Independent Determinant of Cortical Bone Status in Men at the Age of Peak Bone Mass

CONTEXT Sex steroids are important determinants of the skeletal development, growth, and maintenance after achievement of peak bone mass. A large fraction of these hormones are bound by SHBG, and previous studies have shown that SHBG could be a determinant of bone characteristics. OBJECTIVE We investigated associations of serum SHBG levels with cortical and trabecular bone characteristics in young healthy men. DESIGN AND SETTINGS A total of 677 healthy male siblings aged 25-45 yr were recruited in a cross-sectional, population-based study. MAIN OUTCOMES Areal bone parameters were assessed using dual-energy x-ray absorptiometry. Cortical bone parameters at the tibia and radius and trabecular vBMD at the radius were assessed using peripheral quantitative computed tomography. Serum testosterone, estradiol, and SHBG levels were measured using immunoassays. RESULTS Regression models including age, height, and weight showed that SHBG levels were positively associated with bone area at the hip and the whole body, but not with areal bone mineral density (BMD). Higher SHBG levels were associated with a larger cortical bone area and periosteal and endosteal circumferences at both the tibia and the radius, whereas trabecular volumetric BMD at the radius was negatively associated with SHBG levels. Associations persisted after adjustment for (free) sex steroid levels. No associations were found with cortical volumetric BMD or cortical thickness. CONCLUSION In this population of healthy adult men at the age of peak bone mass, SHBG levels were positively associated with cortical bone size, independently from sex-steroid levels. This suggests a possible independent role of SHBG in the determination of adult bone size.

Anthropometric and Skeletal Phenotype in Men with Idiopathic Osteoporosis and Their Sons Is Consistent with Deficient Estrogen Action during Maturation

CONTEXT Pathophysiology of deficient bone mass acquisition in male idiopathic osteoporosis (IO) remains poorly understood. OBJECTIVE Our objective was to investigate volumetric and geometric parameters of the appendicular skeleton, biochemical markers, and anthropometrics in men with IO. DESIGN, SETTING, AND PARTICIPANTS Our cross-sectional study included 107 men diagnosed with idiopathic low bone mass, 23 of their adult sons, and 130 age-matched controls. MAIN OUTCOME MEASURES Body composition and areal bone parameters (dual-energy x-ray absorptiometry) and volumetric and geometric parameters of radius and tibia (peripheral quantitative computed tomography) were assessed. Serum levels of testosterone, estradiol (E(2)), and SHBG, and bone turnover markers were measured using immunoassays. Free hormone fractions were calculated. RESULTS Men with idiopathic low bone mass had lower weight (-9.6%), truncal height (-3.3%), and upper/lower body segment ratio (-2.7%; all P < 0.001) and presented at the radius and tibia lower trabecular (-19.0 and -23.6%, respectively; both P < 0.001) and cortical volumetric bone mineral density (vBMD) (-2.4 and -1.7%; both P < 0.001) and smaller cortical areas (-9.7 and -13.6%; both P < 0.001) and thicknesses (-13.5 and -14.5%, both P < 0.001) due to larger endosteal circumferences (+11.8 and +7.4%, both P < 0.001) than controls. Furthermore, (free) E(2) was lower and SHBG higher (both P < 0.01). Their sons had lower trabecular vBMD (-10.3%, P = 0.036) and a thinner cortex (-8.3%, P = 0.024) at the radius. CONCLUSION Bone mass deficits in men with idiopathic low bone mass involve trabecular and cortical bone, resulting from lower vBMD and smaller cortical bone cross-sectional areas and thicknesses. A similar bone phenotype is present in at least part of their sons. The lower E(2), together with characteristics as lower upper/lower body segment ratio, larger endosteal circumferences and lower vBMD, may indicate an estrogen-related factor in the pathogenesis of male IO.

A genome-wide linkage scan for low spinal bone mineral density in a single extended family confirms linkage to 1p36.3

Osteoporotic fractures are an increasing cause of mortality and morbidity in ageing populations. A major risk determinant for these fractures is bone mineral density (BMD). Variation on BMD is thought, on the basis of twin and family studies, to be subject to a large amount of genetic variation and it has been hypothesised that this may be due to the influence of multiple genes. However, in families showing segregation of low or high BMD, single major genes have been shown to play a crucial role. We performed a genome-wide screen using 380 microsatellite markers in a single extended family (n=34) in which early-onset low spinal areal BMD segregates in an autosomal dominant-like fashion. A two-point linkage analysis was performed, revealing a maximum LOD score of 3.07 on 1p36.3 (D1S468), confirming results of previous linkage studies of BMD, while no other suggestive linkage peaks (LOD>2.2) were detected elsewhere in the genome. Microsatellite markers were subsequently genotyped for a ±6.9 Mb region surrounding D1S468. This revealed critical recombination events restricting the candidate region to 1.2 Mb and 19 genes. Sequencing analysis of the coding region of candidate genes WDR8 and EGFL3 revealed no mutations or disease-associated polymorphisms. Our results provide some evidence supporting the hypothesis that there are genetic determinants for spinal BMD on 1p36.3. Although no specific disease causing mutation has yet been found, the delineation of a relatively small candidate region in a single extended family opens perspectives to identify a major gene for spinal BMD.

INSULIN RESISTANCE IS ASSOCIATED WITH SMALLER CORTICAL BONE SIZE IN NON-DIABETIC MEN AT THE AGE OF PEAK BONE MASS.

Context In type 2 diabetes mellitus, fracture risk is increased despite preserved areal bone mineral density. Although this apparent paradox may in part be explained by insulin resistance affecting bone structure and/or material properties, few studies have investigated the association between insulin resistance and bone geometry. Objective We aimed to explore this association in a cohort of nondiabetic men at the age of peak bone mass. Design, Setting, and Participants Nine hundred ninety-six nondiabetic men aged 25 to 45 years were recruited in a cross-sectional, population-based sibling pair study at a university research center. Main Outcome Measures Insulin resistance was evaluated using the homeostasis model assessment of insulin resistance (HOMA-IR), with insulin and glucose measured from fasting serum samples. Bone geometry was assessed using peripheral quantitative computed tomography at the distal radius and the radial and tibial shafts. Results In age-, height-, and weight-adjusted analyses, HOMA-IR was inversely associated with trabecular area at the distal radius and with cortical area, periosteal and endosteal circumference, and polar strength strain index at the radial and tibial shafts (β ≤ -0.13, P < 0.001). These associations remained essentially unchanged after additional adjustment for dual-energy X-ray absorptiometry-derived body composition, bone turnover markers, muscle size or function measurements, or adiponectin, leptin, insulin-like growth factor 1, or sex steroid levels. Conclusion In this cohort of nondiabetic men at the age of peak bone mass, insulin resistance is inversely associated with trabecular and cortical bone size. These associations persist after adjustment for body composition, muscle size or function, or sex steroid levels, suggesting an independent effect of insulin resistance on bone geometry.

Proandrogenic and Antiandrogenic Progestins in Transgender Youth: Differential Effects on Body Composition and Bone Metabolism

Context Progestins can be used to attenuate endogenous hormonal effects in late-pubertal transgender (trans) adolescents (Tanner stage B4/5 and G4/5). Currently, no data are available on the effects of progestins on the development of bone mass or body composition in trans youth. Objective To study prospectively the evolution of body composition and bone mass in late-pubertal trans adolescents using the proandrogenic or antiandrogenic progestins lynestrenol (L) and cyproterone acetate (CA), respectively. Design and Outcome Measurements Forty-four trans boys (Tanner B4/5) and 21 trans girls (Tanner G4/5) were treated with L or CA for 11.6 (4 to 40) and 10.6 (5 to 31) months, respectively. Anthropometry, grip strength, body composition, and bone mass, size, and density were determined by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography before the start of progestin and before addition of cross-sex hormones. Results Using L, lean mass [+3.2 kg (8.6%)] and grip strength [+3 kg (10.6%)] significantly increased, which coincided with a more masculine body shape in trans boys. Trans girls showed loss of lean mass [-2.2 kg (4.7%)], gain of fat mass [+1.5 kg (9.4%)], and decreased grip strength Z scores. CA limited normal bone expansion and impeded pubertal bone mass accrual, mostly at the lumbar spine [Z score: -0.765 to -1.145 (P = 0.002)]. L did not affect physiological bone development. Conclusion Proandrogenic and antiandrogenic progestins induce body composition changes in line with the desired appearance within 1 year of treatment. Bone health, especially at the lumbar spine, is of concern in trans girls, as bone mass accrual is severely affected by androgen suppressive therapy.