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Bone metabolism in men is in part determined by sex steroid exposure. This is especially clear during puberty and senescence but it remains to be established whether declines in sex steroid levels during young and middle adulthood are associated with changes in bone mass and size. This study investigated changes in bone mineral content (BMC), areal bone mineral density (aBMD), volumetric BMD (vBMD), and bone size in relation to sex steroid levels in 999 young adult men (age 24-46 years) of whom 676 were re-evaluated after a mean period of 12 years. Sex hormone-binding globulin (SHBG) levels were measured using immunoassay, testosterone (T) and estradiol (E2) using liquid chromatography-tandem mass spectrometry (LC-MS/MS), and free fractions were calculated (cFT and cFE2, respectively). Areal bone parameters and BMC were measured at the hip and lumbar spine using dual-energy X-ray absorptiometry (DXA). Radial and tibial vBMD and bone size were determined using peripheral quantitative computed tomography (pQCT). Linear mixed models were used for statistical analyses. With aging, we observed decreases in almost all bone mass and density indices, whereas changes in bone geometry resulted in larger bones with thinner cortices. These changes in bone mass and size appeared related to sex steroid levels. Specifically, decreases in cFT (but not total T) levels were associated with larger decreases in lumbar spine BMC and especially with geometric changes in cortical bone at the tibia. Similarly, decreases in total E2 and cFE2 were associated with larger decreases in bone mass (all sites) and also with some geometric changes. Also increases in SHBG were independently associated with aging-related changes in bone mass and size in these men. In summary, even small changes in T, E2, and SHBG levels during young and middle adulthood in healthy men are associated with changes in bone mass and size. © 2022 American Society for Bone and Mineral Research (ASBMR).
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Densidad Ósea , Espectrometría de Masas en Tándem , Absorciometría de Fotón , Adulto , Cromatografía Liquida , Hormonas Esteroides Gonadales , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Testosterona , Adulto JovenRESUMEN
INTRODUCTION: This study investigates peri-pubertal changes in bone turnover markers, Wnt-signalling markers, insulin-like growth factor-1 (IGF-1) and sex steroid levels, and how they reflect skeletal development in peri-pubertal boys. MATERIALS AND METHODS: Population-based study in 118 peri-pubertal boys from the NINIOS cohort (age range at baseline 5.1-17.3 years) with repeated measurements at baseline and after two years. Serum levels of the classical bone turnover markers (BTM) procollagen type 1 N-terminal propeptide and carboxy-terminal collagen crosslinks, as well as sex-hormone binding globulin, IGF-1, osteoprotegerin, sclerostin and dickkopf-1 were measured using immunoassays. Sex steroids (estradiol, testosterone, and androstenedione) were measured using mass spectrometry and free fractions calculated. Dual energy x-ray absorptiometry was used for bone measurements at the lumbar spine and whole body. Volumetric bone parameters and bone geometry at the proximal and distal radius were assessed by peripheral QCT. Pubertal development was categorized based on Tanner staging. RESULTS: During puberty, sex steroid and IGF-1-levels along with most parameters of bone mass and bone size increased every next Tanner stage. In contrast, classical bone turnover markers and sclerostin peaked around mid-puberty, with subsequent declines towards adult values in late puberty. Especially classical BTM and sex steroid levels showed consistent associations with areal and volumetric bone parameters and bone geometry. However, observed associations differed markedly according to pubertal stage and skeletal site. CONCLUSION: Serum levels of sex steroids, IGF-1 and bone metabolism markers reflect skeletal development in peri-pubertal boys. However, skeletal development during puberty is nonlinear, and the relations between skeletal indices and hormonal parameters are nonlinear as well, and dependent on the respective maturation stage and skeletal site.
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Factor I del Crecimiento Similar a la Insulina , Pubertad , Adolescente , Densidad Ósea , Remodelación Ósea , Niño , Preescolar , Estradiol , Humanos , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , TestosteronaRESUMEN
This European expert consensus statement provides recommendations for the diagnosis and management of primary hyperparathyroidism (PHPT), chronic hypoparathyroidism in adults (HypoPT), and parathyroid disorders in relation to pregnancy and lactation. Specified areas of interest and unmet needs identified by experts at the second ESE Educational Program of Parathyroid Disorders (PARAT) in 2019, were discussed during two virtual workshops in 2021, and subsequently developed by working groups with interest in the specified areas. PHPT is a common endocrine disease. However, its differential diagnosing to familial hypocalciuric hypercalcemia (FHH), the definition and clinical course of normocalcemic PHPT, and the optimal management of its recurrence after surgery represent areas of uncertainty requiring clarifications. HypoPT is an orphan disease characterized by low calcium concentrations due to insufficient PTH secretion, most often secondary to neck surgery. Prevention and prediction of surgical injury to the parathyroid glands are essential to limit the disease-related burden. Long-term treatment modalities including the place for PTH replacement therapy and the optimal biochemical monitoring and imaging surveillance for complications to treatment in chronic HypoPT, need to be refined. The physiological changes in calcium metabolism occurring during pregnancy and lactation modify the clinical presentation and management of parathyroid disorders in these periods of life. Modern interdisciplinary approaches to PHPT and HypoPT in pregnant and lactating women and their newborns children are proposed. The recommendations on clinical management presented here will serve as background for further educational material aimed for a broader clinical audience, and were developed with focus on endocrinologists in training.
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Hipercalcemia , Hiperparatiroidismo Primario , Hipoparatiroidismo , Enfermedades de las Paratiroides , Adulto , Calcio , Femenino , Humanos , Hipercalcemia/complicaciones , Hiperparatiroidismo Primario/complicaciones , Hiperparatiroidismo Primario/diagnóstico , Hiperparatiroidismo Primario/terapia , Hipoparatiroidismo/diagnóstico , Recién Nacido , Lactancia , Hormona Paratiroidea , EmbarazoRESUMEN
We describe two unrelated women who in their fifth decade developed a severe disorder characterized by large joint osteonecrosis and multiple minimal trauma fractures in both the axial and appendicular skeleton, including unusual metaphyseal fractures of the proximal tibia. Bone density testing showed borderline osteoporosis of the spine and osteopenia of the femur. Therapy with bisphosphonates and teriparatide failed to prevent further fractures. To our knowledge, this disorder has not been described previously. Investigations to date, including a genetic screen, have not revealed its cause. © 2020 The Authors. JBMR Plus published by Wiley Periodicals, Inc. on behalf of American Society for Bone and Mineral Research.
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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.
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Composición Corporal/efectos de los fármacos , Densidad Ósea/efectos de los fármacos , Desarrollo Óseo/fisiología , Acetato de Ciproterona/uso terapéutico , Linestrenol/uso terapéutico , Personas Transgénero , Transexualidad/tratamiento farmacológico , Absorciometría de Fotón , Adolescente , Composición Corporal/fisiología , Densidad Ósea/fisiología , Niño , Acetato de Ciproterona/administración & dosificación , Estradiol/sangre , Femenino , Hormona Folículo Estimulante/sangre , Fuerza de la Mano/fisiología , Humanos , Vértebras Lumbares/diagnóstico por imagen , Hormona Luteinizante/sangre , Linestrenol/administración & dosificación , Masculino , Progestinas/sangre , Globulina de Unión a Hormona Sexual/metabolismo , Testosterona/sangre , Transexualidad/sangre , Transexualidad/diagnóstico por imagen , Resultado del TratamientoRESUMEN
Biochemical markers of bone turnover are higher in young adult men than in middle-aged men or young adult women. Nonetheless, little is known about the determinants and clinical significance hereof. The present study examined determinants of serum bone turnover markers in men around peak bone mass age, and explored whether bone turnover at this age predicts subsequent changes in bone mass. We used cross-sectional and longitudinal data from 973 and 428 healthy men, respectively, aged 25 to 45 years at baseline, including baseline procollagen type I amino-terminal propeptide (P1NP), osteocalcin, and C-terminal telopeptide of type I collagen (CTX) from fasting serum samples, baseline questionnaire-assessed physical activity levels, and baseline and follow-up dual-energy X-ray absorptiometry-derived areal bone mineral density (aBMD) and body composition. Mean follow-up time was 12.4 ± 0.4 years. At baseline, all bone turnover markers were inversely associated with total body fat mass (ß ≤ -0.20, p < 0.001), and positively with physical activity during sports activities (ß ≥ 0.09, p ≤ 0.003), and, albeit not independently from fat mass, total body lean mass (ß ≥ 0.20, p ≤ 0.003). Mean annual aBMD changes in the longitudinal cohort were -0.19% ± 0.24% at the total body, -0.14% ± 0.42% at the spine, -0.49% ± 0.47% at the femoral neck, and -0.25% ± 0.37% at the total hip (all p < 0.001). Higher bone turnover markers at baseline were associated with larger decreases in aBMD at all measurement sites (ß ≤ -0.08, p ≤ 0.081 for P1NP; ß ≤ -0.16, p ≤ 0.002 for osteocalcin; and ß ≤ -0.21, p < 0.001 for CTX). In conclusion, our findings show that sports activities and body composition, primarily fat mass, are the main identified determinants of bone turnover in men around peak bone mass age. Further, bone turnover at this age is an important determinant of subsequent changes in bone mass, with higher levels of bone turnover markers being associated with greater decreases in aBMD. © 2017 American Society for Bone and Mineral Research.
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Remodelación Ósea/fisiología , Resorción Ósea/fisiopatología , Adulto , Biomarcadores/sangre , Composición Corporal , Densidad Ósea , Estudios Transversales , Ejercicio Físico , Estudios de Seguimiento , Humanos , Masculino , Persona de Mediana Edad , Estudios Prospectivos , Adulto JovenRESUMEN
Context: The increased fracture risk associated with type 1 diabetes mellitus (T1DM) remains unexplained by traditional risk factors such as low areal bone mineral density (aBMD). Nonetheless, few data exist on other determinants of bone strength in T1DM, including volumetric bone mineral density (vBMD) and bone geometry. Objective: We compared areal and volumetric bone parameters and cortical bone geometry in adult T1DM patients and sex- and age-matched controls. Design: Cross-sectional study including 64 adult T1DM patients (38 men; mean age, 41.1 ± 8.1 years) and 63 sex- and age-matched controls. Main Outcome Measures: Areal bone parameters using dual-energy X-ray absorptiometry; volumetric bone parameters and cortical bone geometry using peripheral quantitative computed tomography. Results: T1DM was associated with lower aBMD at the total body, femoral neck, and total hip; lower trabecular vBMD at the distal radius; and higher cortical but lower total vBMD at the radial shaft. In addition, subjects with T1DM had a similar periosteal but larger endosteal circumference, smaller cortical thickness, and lower cortical over total bone area ratio. Differences in bone parameters could not be explained by differences in bone turnover markers or body composition, but cortical area was inversely associated with glycemic variability and long-term glycemic control. Conclusions: Besides decreased aBMD and trabecular vBMD, adult T1DM patients present with a cortical bone size deficit, which may contribute to their increased fracture risk. This deficit is mainly situated at the endosteal envelope, suggesting imbalanced remodeling rather than compromised modeling processes as the underlying mechanism.
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Hueso Esponjoso/diagnóstico por imagen , Hueso Cortical/diagnóstico por imagen , Diabetes Mellitus Tipo 1/metabolismo , Osteoporosis/diagnóstico por imagen , Absorciometría de Fotón , Adulto , Densidad Ósea , Enfermedades Óseas Metabólicas/complicaciones , Enfermedades Óseas Metabólicas/diagnóstico por imagen , Enfermedades Óseas Metabólicas/patología , Hueso Esponjoso/patología , Estudios de Casos y Controles , Hueso Cortical/patología , Estudios Transversales , Diabetes Mellitus Tipo 1/complicaciones , Femenino , Cuello Femoral/diagnóstico por imagen , Hemoglobina Glucada/metabolismo , Humanos , Masculino , Persona de Mediana Edad , Tamaño de los Órganos , Osteoporosis/complicaciones , Osteoporosis/patología , Radio (Anatomía)/diagnóstico por imagen , Tomografía Computarizada por Rayos XRESUMEN
OBJECTIVE: Maternal age at childbirth is increasing worldwide, but studies investigating the consequences of this trend on offspring metabolic health are scarce. We investigated the associations of maternal age at childbirth with metabolic outcomes in adult male siblings. METHODS: We used data from 586 men aged 25-45 participating in a cross-sectional, population-based sibling-pair study, including maternal age at childbirth and offspring birthweight, adult weight, height, dual-energy X-ray absorptiometry (DXA)-derived body composition, blood pressure, and total cholesterol, glucose and insulin levels from fasting serum samples. Insulin sensitivity was evaluated using the homeostasis model assessment of insulin resistance (HOMA-IR). RESULTS: Maternal age at childbirth was 27·1 ± 4·7 years and was inversely associated with glucose levels (ß = -0·10, P = 0·022) and HOMA-IR (ß = -0·06, P = 0·065) in age- and body composition-adjusted analyses. Moreover, sons of younger (aged <25 and 25-29) and older (aged ≥35) mothers had higher HOMA-IR values than sons of mothers aged 30-34 (1·39, 1·35 and 1·42 vs 1·19, P = 0·028). Additional adjustment for birthweight did not substantially alter these results. Maternal age was inversely associated with cholesterol levels in unadjusted (ß = -0·09, P = 0·032), but not in age- and body composition-adjusted analyses. No associations of maternal age were observed with blood pressure, leptin, or adiponectin levels or with any of the body composition measurements. CONCLUSIONS: Increasing maternal age at childbirth is associated with lower fasting glucose levels and higher insulin sensitivity in adult male offspring. However, this association might not hold true in offspring of women aged ≥35 years at childbirth.
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Orden de Nacimiento , Resistencia a la Insulina , Edad Materna , Adolescente , Adulto , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Embarazo , Adulto JovenRESUMEN
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 (ß ≤ -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.
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Hueso Cortical/diagnóstico por imagen , Resistencia a la Insulina , Radio (Anatomía)/diagnóstico por imagen , Tibia/diagnóstico por imagen , Absorciometría de Fotón , Adiponectina/metabolismo , Adulto , Glucemia/metabolismo , Composición Corporal , Densidad Ósea , Cromatografía Liquida , Colágeno Tipo I/metabolismo , Hueso Cortical/patología , Estradiol/metabolismo , Humanos , Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Leptina/metabolismo , Masculino , Persona de Mediana Edad , Fuerza Muscular , Músculo Esquelético/diagnóstico por imagen , Músculo Esquelético/patología , Tamaño de los Órganos , Osteocalcina/metabolismo , Hormona Paratiroidea/metabolismo , Fragmentos de Péptidos/metabolismo , Péptidos/metabolismo , Procolágeno/metabolismo , Radio (Anatomía)/patología , Albúmina Sérica/metabolismo , Globulina de Unión a Hormona Sexual/metabolismo , Espectrometría de Masas en Tándem , Testosterona/metabolismo , Tibia/patología , Tomografía Computarizada por Rayos X , Vitamina D/análogos & derivados , Vitamina D/metabolismoRESUMEN
Jumping mechanography has been developed to estimate maximum voluntary muscle forces. This study assessed associations of jumping mechanography-derived force and power measurements with tibial cortical bone geometry, compared to other estimates of muscle mass, size, and function. Healthy men (n = 181; 25-45 years) were recruited in a cross-sectional, population-based sibling-pair study. Muscle parameters include isokinetic peak torque of the quadriceps, DXA-derived leg lean mass, mechanography-derived peak jump force and power, and pQCT-derived mid-tibial (66 %) muscle cross-sectional area (CSA). Mid-tibial cortical bone parameters were assessed by pQCT. In age, height, and weight-adjusted analyses, jump force and power correlated positively with cortical bone area, cortical thickness, and polar strength-strain index (SSIp) (ß = 0.23-0.34, p ≤ 0.001 for force; ß = 0.25-0.30, p ≤ 0.007 for power) and inversely with endosteal circumference adjusted for periosteal circumference (ECPC) (ß = -0.16, p < 0.001 for force; ß = -0.13, p = 0.007 for power). Force but not power correlated with cortical over total bone area ratio (ß = 0.25, p = 0.002). Whereas leg lean mass correlated with all cortical parameters except cortical over total bone area ratio (ß = 0.25-0.62, p ≤ 0.004), muscle CSA only correlated with cortical bone area, periosteal circumference, and SSIp (ß = 0.21-0.26, p ≤ 0.001), and quadriceps torque showed no significant correlations with the bone parameters. Multivariate models indicated that leg lean mass was independently associated with overall bone size and strength reflected by periosteal and endosteal circumference and SSIp (ß = 0.32-0.55, p ≤ 0.004), whereas jump force was independently associated with cortical bone size reflected by ECPC, cortical thickness, and cortical over total bone area ratio (ß = 0.13-0.28; p ≤ 0.002). These data indicate that jumping mechanography provides relevant information about the relationship of muscle with bone geometry.
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Fenómenos Biomecánicos/fisiología , Músculo Cuádriceps/fisiología , Tibia/anatomía & histología , Tibia/fisiología , Adulto , Hueso Cortical/anatomía & histología , Hueso Cortical/fisiología , Estudios Transversales , Ejercicio Físico , Humanos , Masculino , Persona de Mediana Edad , HermanosRESUMEN
INTRODUCTION: Phalloplasty using the radial forearm flap is currently the most frequently used technique to create the neophallus in transsexual men (formerly described as female-to-male transsexual persons). Although it is considered the gold standard, its main disadvantage is the eventual donor-site morbidity in a young, healthy patient population. AIM: The study aims to examine the long-term effects of radial forearm flap phalloplasty in transsexual men and to evaluate aesthetic outcome, scar acceptance, bone health, and daily functioning. MAIN OUTCOME MEASURES: Scars were evaluated with the patient and observer scar assessment scale, the Vancouver Scar Scale, and self-reported satisfaction. Bone health was assessed using dual X-ray absorptiometry and peripheral quantitative computed tomography, and daily functioning using a physical activity questionnaire (Baecke). These measurements were compared with 44 age-matched control women. METHODS: This is a cross-sectional study of 44 transsexual, a median of 7 years after radial forearm flap phalloplasty, recruited from the Center for Sexology and Gender Problems at the Ghent University Hospital, Belgium. RESULTS: We observed no functional limitations on daily life activities, a pain-free and rather aesthetic scar, and unaffected bone health a median of 7 years after radial foreram flap phalloplasty. Over 75% of transsexual men were either satisfied or neutral with the appearance of the scar. CONCLUSIONS: Transsexual men, despite scarring the forearm, consider the radial forearm flap phalloplasty as worthwhile.
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Antebrazo/cirugía , Pene/cirugía , Procedimientos de Reasignación de Sexo , Colgajos Quirúrgicos , Transexualidad/cirugía , Adulto , Imagen Corporal , Huesos/diagnóstico por imagen , Estudios de Casos y Controles , Cicatriz/etiología , Estudios Transversales , Femenino , Humanos , Masculino , Persona de Mediana Edad , Satisfacción del Paciente , Radiografía , Autoinforme , Procedimientos de Reasignación de Sexo/efectos adversos , Colgajos Quirúrgicos/efectos adversos , Factores de Tiempo , Resultado del Tratamiento , Adulto JovenRESUMEN
OBJECTIVE: Thyroid disorders affect metabolism and body composition. Existing literature has been conflicting on whether this is also the case for thyroid hormone levels within the euthyroid range. Therefore, we have investigated the relationship between thyroid hormone concentrations and body composition together with metabolic parameters in a population of healthy euthyroid men. METHODS: Healthy male siblings (n=941, 25-45 years, median BMI 24.6) were recruited in a cross-sectional, population-based study; a history or treatment of thyroid disease and thyroid autoimmunity were exclusion criteria. Body composition and muscle cross-sectional area were assessed by dual-energy X-ray absorptiometry and peripheral quantitative computed tomography. Total (triiodothyronine (T(3); TT(3)) thyroxine and (T(4); TT(4))) and free thyroid hormones (FT(3) and FT(4)), TSH, and reverse T(3) (rT(3)) and thyroid-binding globulin (TBG) were determined using immunoassays. RESULTS: BMI was positively associated with (F)T(3) (P<0.0001). Whole body fat mass displayed positive associations with TT(3) and with (F)T(4) and TBG (P≤0.0006). Positive associations were further observed between leptin and (F)T(3), TT(4), and TBG (P≤0.0002). Inverse associations between lean mass and muscle cross-sectional area and (F)T(3), (F)T(4), and TBG were observed (P≤0.0003). Higher levels of (F)T(3) and TBG were associated with lower insulin sensitivity, assessed by homeostatic model assessment of insulin resistance (IR; P≤0.0001). No associations between TSH and body composition or metabolic parameters were seen. CONCLUSION: We show that a less favorable body composition (with higher fat and lower muscle mass and accompanying higher leptin concentrations) and IR are associated with higher thyroid hormone levels in healthy young men with well characterized euthyroidism.
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Tejido Adiposo , Composición Corporal , Índice de Masa Corporal , Resistencia a la Insulina , Leptina/sangre , Hormonas Tiroideas/sangre , Adulto , Biomarcadores/sangre , Proteínas Portadoras/sangre , Factores de Confusión Epidemiológicos , Estudios Transversales , Estradiol/sangre , Humanos , Proteína 3 de Unión a Factor de Crecimiento Similar a la Insulina/metabolismo , Factor I del Crecimiento Similar a la Insulina/metabolismo , Masculino , Proteínas de la Membrana/sangre , Persona de Mediana Edad , Globulina de Unión a Hormona Sexual/metabolismo , Testosterona/sangre , Tiroglobulina/sangre , Tirotropina/sangre , Tiroxina/sangre , Proteínas de Unión a Tiroxina/metabolismo , Triyodotironina/sangre , Proteínas de Unión a Hormona TiroideRESUMEN
Paget's disease of bone (PDB) is, after osteoporosis, the second most common metabolic bone disorder in the elderly Caucasian population. Mutations in the sequestosome 1 gene (SQSTM1) are responsible for the etiology of PDB in a subset of patients, but the disease pathogenesis in the remaining PDB patients is still unknown. Therefore association studies investigating the relationship between genetic polymorphisms and sporadic PDB have been performed in order to find the susceptibility polymorphisms. In this paper, we sought to determine whether polymorphisms in 3 functional candidate genes play a role in the development of sporadic PDB: TNFSF11 (receptor activator of nuclear factor κB ligand, RANKL), VCP (valosin-containing protein) and IL-6 (interleukin 6). Analyzing 9 tag SNPs and 2 multi-marker tests (MMTs) in TNFSF11, 3 tag SNPs and 1 MMT in VCP and 8 tag SNPs in IL-6 in a population of 196 Belgian patients with sporadic PDB and 212 Belgian control individuals revealed that one VCP SNP (rs565070) turned out to be associated with PDB in this Belgian study population (p=5.5×10(-3)). None of the tag SNPs or MMTs selected for TNFSF11 or IL-6 was associated with PDB. Still, replication of our findings in the VCP gene in other populations is important to confirm our results. However, when combining data of VCP with those from other susceptible gene regions from previous association studies (i.e. TNFRSF11A, CSF1, OPTN and TM7SF4), independent effect of each gene region was found and the cumulative population attributable risk is 72.7%.
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Adenosina Trifosfatasas/genética , Proteínas de Ciclo Celular/genética , Predisposición Genética a la Enfermedad/genética , Interleucina-6/genética , Osteítis Deformante/genética , Polimorfismo de Nucleótido Simple/genética , Ligando RANK/genética , Alelos , Femenino , Frecuencia de los Genes/genética , Haplotipos , Humanos , Masculino , Persona de Mediana Edad , Proteína que Contiene ValosinaRESUMEN
CONTEXT: The hormonal factors involved in the regulation of peak bone mass (PBM) in men have not been fully investigated. Apart from gonadal steroids and somatotropic hormones, thyroid hormones are known to affect bone maturation and homeostasis and are additional candidate determinants of adult bone mass. OBJECTIVE: We aimed to investigate between-subject physiological variation in free and total thyroid hormone concentrations, TSH, and thyroid binding globulin (TBG) in relation to parameters of bone mass, geometry, and mineral density in healthy men at the age of PBM. DESIGN AND SETTING: We recruited 677 healthy male siblings aged 25-45 years in a cross-sectional, population-based study. Areal and volumetric bone parameters were determined using dual-energy x-ray absorptiometry (DXA) and peripheral quantitative computed tomography (pQCT). Total and free thyroid hormones, TBG, and TSH were determined using immunoassays. RESULTS: Free and total thyroid hormone concentrations were inversely associated with bone mineral density (BMD) and bone mineral content (BMC) at the hip and total body (free triiodothyronine (FT(3)), total T(3) (TT(3)), and total T(4) (TT(4))) and at the spine (FT(3)). TBG was negatively associated with BMC and areal BMD at all sites. At the radius, cortical bone area was inversely associated with TT(3), TT(4), and TBG, and trabecular bone density was inversely associated with free thyroxine, TT(4), and TBG. We observed inverse associations between cortical bone area at the mid-tibia and FT(3), TT(3), TT(4), and TBG. No associations between TSH and DXA or pQCT measurements were found. CONCLUSION: In healthy men at the age of PBM, between-subject variation in thyroid hormone concentrations affects bone density, with higher levels of FT(3), TT(3), TT(4), and TBG being associated with less favorable bone density and content.
Asunto(s)
Densidad Ósea/fisiología , Desarrollo Óseo/fisiología , Huesos/anatomía & histología , Hormonas Tiroideas/metabolismo , Absorciometría de Fotón , Adulto , Envejecimiento/fisiología , Antropometría , Biomarcadores , Composición Corporal/fisiología , Estudios Transversales , Hormonas Esteroides Gonadales/sangre , Humanos , Estilo de Vida , Masculino , Persona de Mediana Edad , Globulina de Unión a Hormona Sexual/metabolismo , Fumar/metabolismo , Hormonas Tiroideas/sangre , Tomografía Computarizada por Rayos XRESUMEN
Paget's disease of bone (PDB) is one of the most frequent metabolic bone disorders (1-5%), next to osteoporosis, affecting individuals above age 55. Sequestosome1 mutations explain a part of the PDB patients, but still the disease pathogenesis in the remaining PDB patients is largely unknown. Therefore, association studies investigating the relationship between genetic polymorphisms and sporadic PDB have been performed to find the genetic risk variants. Previously such studies indicated a role of the OPG and RANK gene. The latter was recently confirmed in a genome-wide association study (GWAS) which also indicated the involvement of chromosomal regions harbouring the CSF1 and OPTN gene. In this study, we sought to replicate these findings in a Belgian and a Dutch population. Similar significant results were obtained for the single nucleotide polymorphisms and the haplotypes. The most significant results are found in the CSF1 gene region, followed by the OPTN and TNFRSF11A gene region (p values ranging from 1.3 × 10(-4) to 3.8 × 10(-8), OR = 1.523-1.858). We next obtained significant association with a polymorphism from the chromosomal region around the TM7SF4 gene (p = 2.7 × 10(-3), OR = 1.427), encoding DC-STAMP which did not reach genome-wide significance in the GWAS, but based on its function in osteoclasts it can be considered a strong candidate gene. After meta-analysis with the GWAS data, p values ranged between 2.6 × 10(-4) and 8.8 × 10(-32). The calculated cumulative population attributable risk of these four loci turned out to be about 67% in our two populations, indicating that most of the genetic risk for PDB is coming from genetic variants close to these four genes.
Asunto(s)
Factor Estimulante de Colonias de Macrófagos/genética , Proteínas de la Membrana/química , Proteínas de la Membrana/genética , Osteítis Deformante/genética , Polimorfismo de Nucleótido Simple , Receptor Activador del Factor Nuclear kappa-B/genética , Factor de Transcripción TFIIIA/genética , Proteínas Adaptadoras Transductoras de Señales , Adulto , Anciano , Anciano de 80 o más Años , Proteínas de Ciclo Celular , Femenino , Predisposición Genética a la Enfermedad , Estudio de Asociación del Genoma Completo , Haplotipos , Humanos , Masculino , Proteínas de Transporte de Membrana , Persona de Mediana EdadRESUMEN
RANK (receptor activator of nuclear factor-κB), encoded by TNFRSF11A, is a key protein in osteoclastogenesis. TNFRSF11A mutations cause Paget's disease of bone (PDB)-like diseases (ie, familial expansile osteolysis, expansile skeletal hyperphosphatasia, and early-onset PDB) and an osteoclast-poor form of osteopetrosis. However, no TNFRSF11A mutations have been found in classic PDB, neither in familial nor in isolated cases. To investigate the possible relationship between TNFRSF11A polymorphisms and sporadic PDB, we conducted an association study including 32 single-nucleotide polymorphisms (SNPs) in 196 Belgian sporadic PDB patients and 212 control individuals. Thirteen SNPs and 3 multimarker tests (MMTs) turned out to have a p value of between .036 and 3.17 × 10(-4) , with the major effect coming from females. Moreover, 6 SNPs and 1 MMT withstood the Bonferroni correction (p < .002). Replication studies were performed for 2 nonsynonymous SNPs (rs35211496 and rs1805034) in a Dutch and a British cohort. Interestingly, both SNPs resulted in p values ranging from .013 to 8.38 × 10(-5) in both populations. Meta-analysis over three populations resulted in p = .002 for rs35211496 and p = 1.27 × 10(-8) for rs1805034, again mainly coming from the female subgroups. In an attempt to identify the underlying causative SNP, we performed functional studies for the coding SNPs as well as resequencing efforts of a 31-kb region harboring a risk haplotype within the Belgian females. However, neither approach resulted in significant evidence for the causality of any of the tested genetic variants. Therefore, further studies are needed to identify the real cause of the increased risk to develop PDB shown to be present within TNFRSF11A.
Asunto(s)
Predisposición Genética a la Enfermedad , Variación Genética , Osteítis Deformante/genética , Receptor Activador del Factor Nuclear kappa-B/genética , Adulto , Anciano , Anciano de 80 o más Años , Bélgica , Exones/genética , Femenino , Genes Reporteros , Genética de Población , Haplotipos/genética , Humanos , Intrones/genética , Luciferasas/metabolismo , Masculino , Metaanálisis como Asunto , Persona de Mediana Edad , FN-kappa B/metabolismo , Polimorfismo de Nucleótido Simple/genética , Control de Calidad , Reproducibilidad de los Resultados , Análisis de Secuencia de ADNRESUMEN
Low areal bone mass is a risk factor for fractures in men. Limited data are available on fractures and bone geometry in men, and the relation with sex steroids is incompletely understood. We investigated prevalent fractures in relation to peak bone mass, bone geometry, and sex steroids in healthy young men. Healthy male siblings (n = 677) at the age of peak bone mass (25 to 45 years) were recruited in a cross-sectional population-based study. Trabecular and cortical bone parameters of the radius and cortical bone parameters of the tibia were assessed using peripheral quantitative computed tomography (pQCT). Areal bone mineral density (aBMD) was determined using dual-energy X-ray absorptiometry (DXA). Sex steroids were determined using immunoassays, and fracture prevalence was assessed using questionnaires. Fractures in young men were associated with a longer limb length, shorter trunk, lower trabecular BMD, smaller cortical bone area, and smaller cortical thickness (p < .005) but not with bone-size-adjusted volumetic BMD (vBMD). With decreasing cortical thickness [odds ratio (OR) 1.4/SD, p Asunto(s)
Huesos/patología
, Fracturas Óseas/epidemiología
, Salud
, Adulto
, Antropometría
, Bélgica/epidemiología
, Fracturas Óseas/sangre
, Hormonas Esteroides Gonadales/sangre
, Humanos
, Modelos Logísticos
, Masculino
, Persona de Mediana Edad
, Oportunidad Relativa
, Tamaño de los Órganos
, Prevalencia
, Fumar
RESUMEN
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.
Asunto(s)
Desarrollo Óseo/fisiología , Huesos/anatomía & histología , Globulina de Unión a Hormona Sexual/análisis , Absorciometría de Fotón , Adulto , Antropometría , Composición Corporal/fisiología , Estudios de Cohortes , Estudios Transversales , Hormonas Esteroides Gonadales/sangre , Gonadotropinas/sangre , Humanos , Insulina/sangre , Factor I del Crecimiento Similar a la Insulina/análisis , Factor I del Crecimiento Similar a la Insulina/metabolismo , Leptina/sangre , Modelos Lineales , Masculino , Persona de Mediana Edad , Tamaño de los Órganos/fisiología , Globulina de Unión a Hormona Sexual/metabolismo , Tomografía Computarizada por Rayos XRESUMEN
Smoking is associated with lower areal bone mineral density (aBMD) and higher fracture risk, although most evidence has been derived from studies in elderly subjects. This study investigates smoking habits in relation to areal and volumetric bone parameters and fracture prevalence in young, healthy males at peak bone mass. Healthy male siblings (n = 677) at the age of peak bone mass (25 to 45 years) were recruited in a cross-sectional population-based study. Trabecular and cortical bone parameters of the radius and cortical bone parameters of the tibia were assessed using peripheral quantitative computed tomography (pQCT). Areal bone mass was determined using dual energy X-ray absorptiometry (DXA). Sex steroids and bone markers were determined using immunoassays. Prevalent fractures and smoking habits were assessed using questionnaires. Self-reported fractures were more prevalent in the current and early smokers than in the never smokers (p < .05), with a fracture prevalence odds ratio for early smokers of 1.96 (95% confidence interval 1.18-3.24) after adjustment for age, weight, educational level, and alcohol use and exclusion of childhood fractures. Current smoking was associated with a larger endosteal circumference (beta = 0.027 +/- 0.009, p = .016) and a decreased cortical thickness (beta = -0.034 +/- 0.01, p = .020) at the tibia. In particular, early smokers (< or =16 years) had a high fracture risk and lower areal BMD, together with a lower cortical bone area at the tibia and lower trabecular and cortical bone density at the radius. An interaction between free estradiol and current smoking was observed in statistical models predicting cortical area and thickness (beta = 0.29 +/- 0.11, p = .01). In conclusion, smoking at a young age is associated with unfavorable bone geometry and density and is associated with increased fracture prevalence, providing arguments for a disturbed acquisition of peak bone mass during puberty by smoking, possibly owing to an interaction with sex steroid action.
Asunto(s)
Densidad Ósea , Fracturas Óseas/etiología , Fumar , Absorciometría de Fotón , Adulto , Familia , Fracturas Óseas/epidemiología , Hormonas Esteroides Gonadales/metabolismo , Humanos , Masculino , Actividad Motora/fisiología , Factores de Riesgo , Fumar/efectos adversos , Encuestas y Cuestionarios , Tomografía Computarizada por Rayos XRESUMEN
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.