Prevalence of Vertebral Fractures and Non-fracture Deformities in Healthy Adult Men: The Importance of Morphologic Criteria.

Vertebral fractures (VF) are common in older men but data on VF prevalence in young men is limited. The aim of this study was to describe the prevalence of VF and non-fracture vertebral deformities (VD) in healthy young to middle-aged men, and compare the characteristics of men with normal vertebrae, VF and VD. In this cross-sectional study, vertebral fracture assessment by dual-energy X-ray absorptiometry was performed in 650 men, aged 32 to 60 years (mean 46.2), from the population-based SIBLOS-SIBEX cohort. For VF and VD assessment, both the modified algorithm-based qualitative approach (morphologic criteria) to discriminate VF from VD and the semi-quantitative (morphometric) grading system of Genant (GSQ) were used. We found 48 (0.6%) fractured vertebrae, of which 15 were classified grade 1, 29 grade 2 and 4 grade 3 VF. There were 378 (4.7%) VD, of which 296 were scored grade 1, 82 grade 2 and none grade 3 VD. Twenty-six participants (4%) had VF, 15 had one and 11 had 2 or more VF. Two hundred and twenty-eight (35.1%) men had VD. Femoral neck, total hip and lumbar spine areal bone mineral density (aBMD) were lower in men with VF than in those with normal vertebrae or VD. Men with VD, in turn, had aBMD values similar to men with normal vertebrae. Our results suggest that -even in young healthy men-using the GSQ without taking qualitative aspects into account overestimates VF prevalence, confirming the importance of morphologic criteria to correctly diagnose and distinguish VF from VD.

Higher fracture prevalence and smaller bone size in patients with hEDS/HSD-a prospective cohort study.

Increased fracture risk in patients with Ehlers-Danlos syndromes has been reported, but the reasons for it are incompletely understood. We aimed to investigate possible determinants of this increased risk and found that hEDS/HSD patients present with a cortical bone size deficit compared with control subjects, possibly related to lower mechanical loading. INTRODUCTION: The Ehlers-Danlos syndromes (EDS) comprise a group of heritable connective tissue disorders caused by defects in the biosynthesis, secretion, and/or organization of fibrillar collagens which might impair bone strength. Our aim was to compare fracture prevalence, volumetric and areal bone mineral density (BMD), bone geometry, muscle size and the muscle-bone interaction, body composition and longitudinal changes therein between patients with hypermobile EDS (hEDS) or hypermobility spectrum disorder (HSD), and healthy control subjects. METHODS: Cross-sectional data comprised 39 female hEDS/HSD patients (age 41 ± 11 years) and 43 age-matched controls. After 8 years, 27 hEDS/HSD and 17 control subjects were re-evaluated. Tibial trabecular and cortical volumetric BMD, bone mineral content (BMC), cortical bone geometry, and lower leg muscle cross-sectional area (CSA) were measured using pQCT. Body composition, areal BMD, and BMC were determined by DXA. RESULTS: At baseline, patients with hEDS/HSD presented with a smaller cortical bone area, smaller cortical thickness and muscle CSA, and a higher fracture prevalence than control subjects (all p < 0.05). No differences in areal or volumetric BMD were found. Longitudinally, muscle CSA decreased in both groups and muscle density decreased in the hEDS/HSD group (p < 0.001) whereas all bone parameters remained unchanged. CONCLUSION: hEDS/HSD patients have a cortical bone size deficit compared with controls, possibly contributing to their increased fracture risk. They presented with decreased muscle CSA but normal bone/muscle area ratio, suggesting that this bone size deficit is likely secondary to decreased mechanical loading. Further, there were no arguments for accelerated bone loss in hEDS/HSD subjects.

Lower insulin sensitivity is related to lower relative muscle cross-sectional area, lower muscle density and lower handgrip force in young and middle aged non-diabetic men.

OBJECTIVES: This study investigated whether an association between insulin resistance (IR) and muscle parameters is appreciable in young healthy men, independent of obesity. Furthermore, markers of muscle metabolism and hormones/possible determinants, were explored. METHODS: 358 healthy young men were divided into a less and more insulin sensitive (LIS [age=33.2±5.4, BMI=23.4±2.3] and MIS [age=35.5±5.3, BMI=28.1±3.7]) group based on upper and lower quartile of HOMA-IR. Muscle cross-sectional area (CSA), -density, handgrip force, serum testosterone, estradiol, SHBG, Vitamin 25(OH)D, creatinine, IGF-1, IGFBP-3 and leptin levels were compared between these groups, correcting for differences in age, physical activity and fat mass. Correlations between HOMA-IR and these parameters, and between muscle measures and biochemical parameters, were calculated. RESULTS: LIS is related to lower relative muscle CSA, muscle density, muscle/fat CSA ratio, relative handgrip force and level of physical activity. Furthermore, lower levels in SHBG, testosterone, Vitamin 25(OH)D and higher leptin, IGF-1 and IGFBP-3 levels were observed in LIS. Bio available T, FT, TE2, FE2, bioavailable E2, serum and urinary creatinine levels did not differ between groups. CONCLUSION: Differences in muscle performance are already present in healthy men with lower insulin sensitivity and could be possibly modifiable risk factors for the development of type 2 diabetes.

Association between insulin resistance, lean mass and muscle torque/force in proximal versus distal body parts in healthy young men.

OBJECTIVES: The purpose of this study was to investigate whether there is already an association of insulin resistance (IR) with muscle mass and -force/torque in an adult population and whether this relationship is the same in distal and proximal body parts. METHODS: 358 Healthy young men were divided into a more insulin sensitive (MIS) (n=89) and a less insulin sensitive (LIS) group (n=89), respectively using lower and upper quartiles of HOMA-IR index (Homeostasis Model Assessment of IR). Muscle force/torque and lean mass, were compared between the two groups. RESULTS: LIS subjects had higher absolute thigh lean mass, but not higher thigh muscle torque, resulting in a lower torque per kg muscle. In upper arm, lean mass was higher in LIS subjects, but also absolute muscle torque resulted higher. For handgrip force, the LIS and MIS group had similar results, despite a trend towards higher forearm lean mass in LIS subjects. Lean mass % of total lean mass is lower in LIS subjects in more distal body parts. CONCLUSIONS: Already in a young healthy population, IR seems to be associated with lower force/torque per muscle mass and lower lean mass % of total lean mass predominantly in more distal body parts.

Serum sclerostin levels in men with idiopathic osteoporosis.

OBJECTIVE: Sclerostin inhibits osteoblast differentiation and bone formation. If aberrant sclerostin action is involved in less efficient bone acquisition in men with idiopathic low bone mass, this might be reflected in higher serum sclerostin levels. METHODS: In 116 men with idiopathic osteoporosis (≤65 years old), 40 of their sons and healthy controls, areal bone parameters were measured using dual-energy X-ray absorptiometry, and volumetric and geometric bone parameters were measured using peripheral quantitative computed tomography. Serum analytes were measured using immunoassays and estradiol (E2) levels using liquid chromatography-tandem mass spectrometry. RESULTS: Men with idiopathic low bone mass had lower levels of sclerostin than the controls (0.54±0.17 vs 0.66±0.23 ng/ml; P<0.001). In both groups, sclerostin levels were strongly associated with age; when adjusting for age, no associations with anthropometrics were observed (P>0.14). In multivariate analyses, sclerostin levels displayed a positive association with whole-body bone mineral content (BMC) and areal BMD (aBMD), as well as with trabecular and cortical volumetric bone mineral density (vBMD) at the tibia in the probands. No clear associations were observed in the control group, neither were sclerostin levels associated with BMC at the radius or lumbar spine (all P>0.11). Testosterone, but not E2, was inversely related to sclerostin levels in the probands. No difference in sclerostin levels was found in their sons when compared with their controls. CONCLUSION: Lower rather than higher serum sclerostin levels in the probands with idiopathic low bone mass suggest that aberrant sclerostin secretion is not involved in the pathogenesis of low bone mass in these subjects.

The decline of serum testosterone levels in community-dwelling men over 70 years of age: descriptive data and predictors of longitudinal changes.

OBJECTIVE: This study was designed to assess longitudinal changes in serum testosterone levels, explore relationships with aging, genetic-, health-, and lifestyle-related factors, and investigate predictors of changes in healthy elderly men. DESIGN: Population-based, longitudinal, 4-year observational study in 221 community-dwelling men aged 71-86 years at baseline. METHODS: Hormone levels assessed by immunoassay, anthropometry, questionnaires on general health, and genetic polymorphisms. Predictors of changes in testosterone levels explored using linear mixed-effects modeling for longitudinal analyses. RESULTS: Total testosterone (TT), free testosterone, and bioavailable testosterone (BioT) levels decreased with aging, decreases in BioT being most marked. No changes in sex hormone-binding globulin (SHBG) or estradiol (E(2)), while LH and FSH levels increased during follow-up. Subjects who gained weight displayed a greater decline in TT levels, mainly due to decreasing SHBG levels. However, baseline body composition was not predictive of subsequent changes in testosterone levels. Baseline E(2) (P=0.023 to 0.004), LH (P=0.046 to 0.005), and FSH (P<0.002) levels were independently positively associated with a faster decline in testosterone fractions, although only FSH remained significant when adjusting for baseline testosterone (P=0.041-0.035). Carriers of a 'TA' haplotype of the estrogen receptor alpha gene (ER alpha) PvuII and XbaI polymorphisms displayed a slower decline of TT and BioT (P=0.041-0.007). CONCLUSIONS: In elderly men with already low serum testosterone levels, a further decline was observed, independent of baseline age. The identification of FSH levels as a predictor of this decline appears to reflect the testicular mechanisms of aging-related changes in testosterone production, whereas associations with E(2) and ER alpha polymorphisms are suggestive of estrogen-related processes, possibly related to changes in the neuroendocrine regulation of testosterone production.

Part of the interindividual variation in serum testosterone levels in healthy men reflects differences in androgen sensitivity and feedback set point: contribution of the androgen receptor polyglutamine tract polymorphism.

CONTEXT: There is a large interindividual variation in serum (free) testosterone (FT) levels in men, underlain in part by genetic components. OBJECTIVE: The objective of the study was to explore the hypothesis that this variability results in part from differences in androgen sensitivity and feedback loop set point and assess the role of the androgen receptor (AR) polyglutamine tract polymorphism encoded by a CAG repeat of variable length in exon 1 of the AR gene. DESIGN/SETTING/PARTICIPANTS: We performed a cross-sectional analysis in two independent populations of healthy men, consisting of 2322 men aged 35-59 yr (Belstress study) and 358 men aged 25-45 yr (Siblos study), respectively. MAIN OUTCOME MEASURES: Serum hormonal levels and the AR gene CAG repeat length were determined. RESULTS: In the Belstress population, serum testosterone and calculated FT showed a positive linear association with LH (P < 0.001). In the 200 men with lowest FT, CAG repeat number was lower than in the 200 men with highest FT (P = 0.004). As studied in a larger subset of the population consisting of 857 men covering the whole FT range, FT increased progressively with CAG repeat length (P = 0.003). These findings of a positive relation of FT with both LH and CAG repeat length were confirmed in the Siblos study population (both P < or = 0.001). Difference in FT between extreme quartiles of CAG repeat was 10 and 14% in the Belstress and Siblos study, respectively. In both study populations, CAG repeat length was also positively associated with serum total testosterone (P < or = 0.004). CONCLUSIONS: The data support the view that between-subject variability in serum FT in healthy men is underlain in part by differences in androgen sensitivity and feedback set point, with a contributory role of AR polymorphism. These findings have potential implications for the interpretation of epidemiological studies, diagnosis of hypogonadism, and pharmacogenetics of androgen treatment in men.

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.

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 > or =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.

Perturbed sex steroid status in men with idiopathic osteoporosis and their sons.

We reported previously that a gender-specific defect of acquisition of lumbar bone mass plays an important role in the pathogenesis of male idiopathic osteoporosis (IO) and that there is a strong heritability of this maturational defect, which is particularly manifest in sons of men with IO. A hypothetical role of an altered sex steroid status and/or of a (TTTA)(n)- repeat polymorphism of the aromatase (CYP19) gene in male IO remains to be established. We evaluated bone mineral density (BMD) at the lumbar spine and femoral neck in 64 male IO probands (selected on the basis of a z-score of -2 or less), 21 of their sons, 41 of their brothers, and 126 healthy, age-matched controls. Serum testosterone (T), estradiol (E(2)), and SHBG levels were measured by immunoassays. Free T (FT) and free E(2) (FE(2)) levels were calculated from total T, E(2), SHBG, and albumin concentrations using a previously validated equation. Probands, sons, and brothers had lower body weight than age-matched controls, with mean differences of 5.0, 4.6, and 4.0 kg, respectively. In probands, sons, and brothers, SHBG levels were higher compared with controls. Significantly lower FE(2) levels were observed in probands and sons compared with their respective controls (P < 0.05 and P < 0.01, respectively). The brothers had nonsignificantly lower FE(2) levels compared with their controls. In the total group of sons with significantly lower FE(2) levels, tertile analysis according to lumbar spine BMD showed that only in the subgroup of sons belonging to the lowest tertile both FE(2) and FT were decreased compared with their controls. The differences in FE(2) levels in IO probands and their sons remained significant after adjustment for body mass index (BMI), even though in multivariate analyses BMI was a major determinant of BMD. The frequency distribution of the CYP19 gene (TTTA)(n)- repeat length (determined by fragment analysis, GeneScan) was not different between men with IO and their controls. In conclusion, the finding of a relative FE(2) deficit in both men with IO as well as their affected sons, even after adjustment for BMI, suggests that estrogen-related perturbances may be involved in the pathogenesis of the deficient acquisition of peak bone mass in male IO.

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 < or = -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.

Inverse association between bone turnover rate and bone mineral density in community-dwelling men >70 years of age: no major role of sex steroid status.

Bone loss is accelerated in elderly men. Little is known about the pathophysiology of senile bone loss or about the role played by relative sex steroid deficiency in the determination of bone turnover in elderly men. In a population-based sample of 283 healthy, ambulatory men, aged 71-86 years, we sought to determine whether lower bone mineral density (BMD; using dual-energy X ray absorptiometry at the hip and the forearm) is associated with higher bone turnover, and we assessed the impact of sex steroid status on bone turnover. Indices of bone formation, serum osteocalcin (s-Oc), and bone-specific alkaline phosphatase (s-bAP) and indices of bone resorption, serum and urinary telopeptide of type I collagen (s-CTx and u-CTx), and urinary free deoxypyridinoline (u-Dpd) were intercorrelated (r = 0.29-0.76, p < 0.001). Bone turnover indices were negatively associated with BMD (r = -0.17 to -0.34, p < 0.01). In univariate analyses, there was a trend toward weak negative associations of bone turnover markers with serum free testosterone (FT), significant only for s-Oc and s-CTx (r = -0.16 and -0.14, p < 0.01), and with serum free estradiol (FE(2)), significant only for u-CTx and s-CTx (r = -0.18 and -0.19; p < 0.01). The lower quartile for FE(2) was associated with higher values of u-CTx (p = 0.003) and s-CTx (p < 0.001). However, in multivariate models, for the individual markers of bone turnover a negative association between estradiol (E(2)) or FE(2) and s-CTx was the only remaining (marginally) significant association (p < 0.05) for the relationship between sex steroids and any of the bone turnover indices assessed. In community-dwelling men age >70 years, bone turnover rate, as determined by biochemical markers, is a significant negative determinant of prevalent BMD. However, the findings do not support the view that relative differences in sex steroid status, as observed among healthy elderly men, have a major impact on bone turnover.

Candida glabrata arthritis: case report and review of the literature of Candida arthritis.

We report a case of arthritis due to Candida (Torulopsis) glabrata in two different joints at different times in the same patient. The first episode of arthritis was situated in the right ankle and lasted more than 1 year before the patient agreed to the proposed treatment. Therapy with intravenous amphotericin B and oral fluconazole failed. A cure was achieved with weekly intra-articular administration of amphotericin B, which was continued for more than 20 weeks and combined with oral itraconazole. Several weeks later the patient developed Candida glabrata arthritis of the left knee while still taking itraconazole. Immediately, intravenous amphotericin B therapy was started and was successful. Because there were no previous invasive point manipulations or trauma, the infections were considered to be haematogenously disseminated. Chronic corticosteroid and repeated antibiotic therapy for infectious exacerbations of chronic obstructive pulmonary disease and alcohol abuse are the presumed risk factors in this otherwise immunocompetent patient.

Immunologic findings in tissue of thyroid carcinoma.

We studied the occurrence of DR-antigen (DR-Ag) positive thyroid epithelial cells (TEC), lymphocyte (Ly)-subsets, and antigen-presenting cells (APC) in thyroid carcinoma and the influence of thyroid-stimulating hormone (TSH) on immunologic behavior. Tissue slices from various thyroid carcinomas (n = 14) and endemic goiters (n = 12) were investigated by immunohistochemical methods (PAP/APAAP/FITC) using monoclonal antibodies (MoAbs) against DR-Ag, dendritic cells (APC), endothelial cells, CD-3 Ly, CD-4 Ly, and CD-8 Ly. Monolayers of TEC were cultured in the presence or absence of TSH (0.01 mU/ml) and/or PHA (0.1 mg/ml) over 24 h and screened for DR-Ag expression. Various ranges of DR-Ag expression were detectable in 13 thyroid carcinomas. One thyroid carcinoma and all endemic goiters were DR-Ag-. The amount of APC and local infiltrating Ly correlated very well with the presence and intensity of DR-Ag+ TEC. The lymphocytic CD-4/CD-8 ratio varied in a wide range. No prevalence of Ly-distribution for any type of carcinoma was found. PHA induced DR-Ag expression in all thyroid carcinomas and endemic goiters. This effect was enhanced significantly by TSH. DR-Ag expression on thyroid carcinoma cells may be considered as an immune activating factor. These "neoantigens" may be induced by lymphokines released by the local immune competent cells. The distribution of Ly and DR-Ag+ TEC in thyroid carcinoma seems to represent the individual immunologic response against the tumor. Whether TSH acts as an immune modulator directly or indirectly, as described elsewhere, cannot be concluded from these results.

[High dose 7S-immunoglobulin therapy in collagenoses. Clinical observations and effects on the lymphocyte subsets and immunoglobulin production]. / Hochdosierte 7S-Immunglobulintherapie bei Kollagenosen. Klinische Beobachtungen und Effekte auf Lymphozytensubpopulationen und Immunglobulinproduktion.

Therapy with 7S-immunoglobulins in 8 patients with various connective tissue diseases led to a decrease of clinical disease activity. In vitro experiments showed that treatment induces change of B-cell function. Significant quantitative alteration of relative lymphocyte subpopulations did not occur. CRP, C3c, C4 and circulating immune complexes tended to normalization.

[Macrophage activity during high dose steroid pulse therapy and 7S-immunoglobulin administration in patients with collagenoses. Comparison with in vitro studies]. / Makrophagenaktivität unter hochdosierter Steroid-Stosstherapie und 7S-Immunglobulingabe bei Patienten mit Kollagenosen. Vergleich mit In-vitro-Untersuchungen.

Patients with connective tissue diseases show increased neopterin levels indicating the activation of the monocyte system. Corticosteroids reduce the release of neopterin in vivo and in vitro. After i.v. 7S-Ig administration neopterin increases in vivo transiently and decreases beyond the pretherapeutic levels. Addition of 7S-Ig to cell cultures reduces the macrophage activation.