SIBlos EXtension Study (SIBEX)

Osteoporosis is a common disorder affecting both sexes, with a lifetime risk of sustaining a fragility fracture at age 50 y estimated at 40-50% in women and 13-22% in men. The age-specific fracture risk in men is about half that in women, which results in part from the achievement of a higher bone mass in men, in particular of larger bone size during growth. Bone size, mass and strength in the elderly depend on the accrual and loss of bone through time. Not only from an epidemiological but also from a potentially preventive viewpoint, it is important to understand the determinants of the components and to identify risk and protective factors for bone accrual or loss through life.

Hormonal status in men, e.g. gonadal and thyroid hormone levels, has a wide range of effects on different body compartments. For both thyroid and gonadal steroid levels, there exists a wide inter-individual variation, even among healthy young men. Up till now, it is not clear whether this variation represents true differences in hormonal exposure or whether it represents an inter-individual variation in hormonal responsiveness. Since prevalence of both thyroid disorders and age- and obesity-associated hypogonadism is rather high, it is relevant to assess determinant and clinical correlates of the between-subject variation in sex steroid and thyroid hormone status.

Our research department therefore undertook a cross-sectional, population-based study in healthy men aged 25-45 years with the aim to investigate determinants of peak bone mass and between-subject variation in gonadal and thyroid hormone status (SIBLOS study). In total, 1114 men were recruited from 2002 till 2009. Herein, we focused on genetic determinants (SNPs, single nucleotide polymorphisms) contributing to between-subject differences in bone mass, as well as on the interrelationship between body composition, bone mass, density and size, lifestyle and hormonal status (sex steroids, thyroid hormones). In addition, we assessed determinants of sex steroid and thyroid hormone status, again focusing on genetic polymorphisms, body composition and lifestyle factors. The investigations in the SIBLOS study have been performed using state-of-the-art technology such as dual-energy X-ray absorptiometry and peripheral quantitative computed tomography for evaluating bone, muscle and body composition parameters; assessment of anthropometric parameters by well-trained personnel; validated questionnaires regarding lifestyle, physical activity and calcium intake; the use of liquid gas chromatography / mass spectrometry for assessing serum hormonal levels; using KASPar technology for genotyping after a high-yield DNA extraction procedure.

From this cross-sectional study, for example, following results have emerged:

• Estradiol seems to be the main sex steroid associated with bone mineral density and bone geometry, whereas testosterone was weakly associated with parameters reflecting muscle strength. In addition, serum estradiol levels might modulate the impact of physical activity on bone size at the tibia.
• Smokers presented with a higher prevalence of previous fractures, especially if they started smoking at younger age. This could be partly explained by the observation of lower bone mineral density and a thinner cortex in smokers.
• Physical activity, muscle mass and parameters reflecting muscle force are strongly associated with bone size; whereas fat mass displayed an inverse association with bone mass and size.
• Birth weight is associated with higher testosterone levels at adult age; in addition weight gain higher/lower than expected during life associated with lower/higher testosterone levels at adult age.
• Serum levels of sex-hormone binding globulin are positively associated with bone size in adult men.
• Higher serum thyroid hormone levels are associated with lower bone mineral density and cortical bone area.
• A less favorable body composition (higher fat and lower muscle mass) and insulin resistance are associated with higher serum thyroid hormone concentrations.
• Serum thyroid hormone levels are influenced by SNPs in the monocarboxylate transporter (MCT)-8 gene.
• Testosterone serum levels are associated with genetic polymorphisms in the genes encoding for the androgen receptor and sex-hormone binding globulin.

Our initial analyses in this SIBLOS population are cross-sectional. Although revealing, this, as any, cross-sectional study has limitations, mainly because the associations do not allow conclusions about direction nor causality. To add prospective elements to the acquired data and to investigate changes over time, we plan to perform a longitudinal follow-up in this study population (SIBEX - SIBlos EXtension study), and as in the mean time knowledge has increased and new questions have emerged, additional investigations are intended. The general aims of this follow-up study include the evaluation of changes in bone mineral density, bone geometry, body composition, parameters reflecting muscle force and sex steroid status in healthy young men, +-10 years after their initial evaluation in the SIBLOS cohort.

Inclusion criteria

• Full participation in the first SIBLOS study
• Informed consent

Exclusion criteria

• Unwillingness or inability to participate
• Medication or disease known to affect bone metabolism, body composition and/or sex steroid metabolism:
• malignancy (previous or current)
• systemic diseases (auto-immune and rheumatoid pathology, ankylosing spondylitis)
• previous or current systemic use of glucocorticoids for more than 3 months, irrespective or dose
• use of glucocorticoid injections in previous 3 months
• use of inhalation glucocorticoids more than 500 µg / day
• previous or current thyroxin therapy (Graves disease, thyroidectomy)
• current insulin use for diabetes mellitus
• previous or current (anti-) androgen treatment or treated hypogonadism
• previous or current anti-epileptic drugs (phenytoin, valproate, carbamazepine, oxcarbazepine/carbamazepine, primidone)
• previous or current hyperthyroidism
• previous or current hyperparathyroidism or serum calcaemia < 8.5 or > 11 mg/dL
• hypocalcaemia (corrected for albumin, confirmed in 2 measurements)
• cystic fibrosis
• orchidectomy irrespective of underlying cause
• history of immobilisation > 3 months or immobilisation > 4 weeks within previous 6 months
• previous or current history of eating disorder
• serum creatinine > 2 mg% (estimated creatinine clearance < 35 mL/min)
• known diseases affecting growth, collagen, bone development or body composition (OI, otosclerosis, AIDS, ...)
• previous or current gastrointestinal malabsorption (gastrectomy, Crohn's disease, ulcerative colitis, coeliac disease, haemochromatosis)
• alcoholism (> 42 units per week)
• organ transplant recipients
• previous or current treatment for osteoporosis
• previous treatment for cryptorchidism irrespective of age
• current varicocoele or treatment for varicocoele after the age of 25 years (no exclusion if testosterone level in blood is normal)
• BMI > 42.3 kg/m²