Relation of collagen type I alpha 1 (COLIA 1) and vitamin D receptor genotypes to bone mass, turnover, and fractures in early postmenopausal women and to hip fractures in elderly people

Background: In a previous study, we showed an association between the vitamin D receptor (VDR) gene BsmI restriction fragment polymorphism and peak bone mass in young Finnish adults. Design: The previous finding prompted us to study the relationship of the same polymorphism, as well as of the polymorphism in the Sp1 binding site of the collagen type I alpha 1 (COLIA 1) gene, to bone mineral density (BMD). BMD was measured by dual-energy X-ray absorptiometry and adjusted for age, weight, height, and lifestyle factors. Also studied was the relationship of VDR and COLIA 1 genotypes to markers of bone turnover [serum osteocalcin, type I procollagen carboxy- (PICP), and aminoterminal (PINP) propeptide, and type I collagen carboxyterminal telopeptide (ICTP)] and bone fractures in 513 early postmenopausal women (1-5 years postmenopausal), as well as hip fractures in 172 very old people. Results: The BB, Bb, and bb genotypes of the VDR gene, as well as the SS, Ss, and ss genotypes of the COLIA 1 gene, were distributed similarly among 402 early postmenopausal women with osteopenia in the lumbar spine and among 111 women with normal BMD (P=0.12 for VDR, P=0.53 for COLIA 1). There was no relation between the VDR and COLIA 1 genotypes and lumbar spine BMD among osteopenic women, among normal women, or in the combined study population. Among the women with vertebral osteopenia, the femoral neck BMD did not associate significantly with the VDR or COLIA 1 polymorphisms. The frequencies of the different VDR and COLIA 1 genotypes were similar among women with or without a history of a low-energy fracture. There was a borderline association between the VDR genotype and serum osteocalcin concentrations, with the Bb genotype associated with the highest median level (P=0.037). In a population-based sample of very old individuals (>85 years), the frequencies of the different VDR and COLIA 1 genotypes were similar among those with (n=64) and without (n=108) a history of hip fracture. Conclusion: The present data suggest that, in the Finnish population, the VDR and COLIA 1 genotypes do not determine the bone mass of early postmenopausal women or their bone turnover rate. The polymorphisms are not associated with risk of hip fractures in elderly people or with low-energy fractures in early postmenopausal women.     

Collagen type I alpha1 Sp1 polymorphism, osteoporosis, and intervertebral disc degeneration in older men and women

OBJECTIVES: To examine whether collagen type I alpha1 (COLIA1) Sp1 polymorphism is associated with osteoporosis and/or intervertebral disc degeneration in older people. METHODS: COLIA1 genotype was determined in 966 men and women (>/=65 years) of the Longitudinal Aging Study Amsterdam. The guanine (G) to thymidine (T) polymorphism in the first intron of the COLIA1 gene was detected by PCR and MscI digestion. In the total sample, quantitative ultrasound (QUS) measurements, serum osteocalcin (OC), and urine deoxypyridinoline (DPD/Cr(urine)) were assessed. A follow up of fractures was done every three months. In a subsample, total body bone mineral content (n = 485) and bone mineral density (BMD) of the hip and lumbar spine (n = 512) were measured by dual energy x ray absorptiometry (DXA). Prevalent vertebral deformities and intervertebral disc degeneration were identified on radiographs (n = 517). RESULTS: People with the TT genotype had a higher risk of disc degeneration than those with the GG and GT genotypes (OR = 3.6; 95% CI 1.3 to 10). For men, higher levels of OC were found in those with the T allele than in those without it (GG v (GT+TT) 1.96 (0.06) nmol/l v 2.19 (0.09) nmol/l). COLIA1 polymorphism was not significantly associated with other measures of osteoporosis in either men or women. CONCLUSION: COLIA1 Sp1 polymorphism may be a genetic risk factor related to intervertebral disc degeneration in older people. Previously reported associations between the COLIAI Sp1 genotype and lower BMD or QUS values, higher levels of DPD/Cr, and an increased fracture risk in either men or women could not be confirmed.     

Collagen type Ialpha1 and vitamin D receptor gene polymorphisms and bone mass in primary biliary cirrhosis

The potential influence of two gene polymorphisms, vitamin D receptor gene (VDR) and the gene encoding collagen type Ialpha1 (COLIA1) Sp1 polymorphisms, in the reduced bone mass observed in patients with primary biliary cirrhosis (PBC) was assessed in 61 women with PBC (age, 54.1 +/- 1.1 years) by restriction enzyme digestion of polymerase chain reaction (PCR)-amplified DNA extracted from whole blood. Bone mineral density (BMD) of the lumbar spine (L2-L4) and proximal femur were measured by X-ray absorptiometry. The severity of liver disease and cholestasis was also evaluated, and changes in BMD were calculated after a mean period of 2.9 +/- 0.3 years in 41 patients. Sixteen patients (26 %) had the BB, 20 the bb (33 %), and 25 Bb (41%) VDR genotypes. There were no significant baseline BMD differences among the 3 VDR genotypes. Forty-one patients (68%) had the SS, 16 the Ss (27%), and 3 the ss (5%) COLIA1 genotypes. The baseline lumbar BMD was significantly lower in patients having the s allele than in the homozygote SS patients (Z-score, -0.76 +/- 0.24 vs. -0.10 +/- 0.17, P =.02). The severity of cholestasis was not related to the VDR or COLIA1 1 polymorphisms. Lumbar bone loss was independent of VDR and COLIA1 genotypes, but it was associated with cholestasis. In conclusion, the COLIA1 but not VDR polymorphism is a genetic marker of peak bone mass in patients with PBC, although the severity of cholestasis is the main factor for osteoporosis since it is associated with the rate of bone loss.     

Association of collagen type 1 alpha1 gene polymorphism with bone density in early childhood

Osteoporosis is a disease characterized by the development of nontraumatic fractures, most commonly in the vertebrae of elderly women. Approximately 500,000 elderly women in the United States are newly diagnosed with vertebral fractures every year, as the compressive strength of the vertebra, mainly determined by the density of cancellous bone and its cross-sectional area, declines with age. A recent study in women suggested that a polymorphism in the Sp1 binding site of the collagen type I gene (COLIA1) was related to decreased vertebral bone mass and vertebral fractures. Determining the phenotypic trait(s) responsible for this relationship and whether this association is manifested in childhood would further define the structural basis for decreased bone mass and help identify children "at risk" for fractures later in life. We therefore studied the COLIA1 gene polymorphism and measurements of the size and the density of vertebral bone in 109 healthy, prepubertal girls. On average, 22 girls with the Ss genotype and one girl with the ss genotype had 6.7% and 49.4% lower cancellous bone density in the vertebrae than girls with the SS genotype. In contrast, there was no association between the size of the vertebrae and the COLIA1 genotypes.     

The bone mineral density in childhood study: bone mineral content and density according to age, sex, and race

CONTEXT: Low bone mass may increase risk of fracture. Several chronic medical conditions, medications, and lifestyle factors affect bone mineral accrual. Appropriate reference values are essential for identification of children with bone deficits. OBJECTIVE: Our objective was to establish reference curves for bone mineral content (BMC) and density (BMD) in children. DESIGN AND SETTING: The Bone Mineral Density in Childhood Study is an ongoing longitudinal study in which measurements are obtained annually at five clinical centers in the United States. PARTICIPANTS: Participants included 1554 healthy children (761 male, 793 female), ages 6-16 yr, of all ethnicities. MAIN OUTCOME MEASURES: Scans of the whole body, lumbar spine, hip, and forearm were obtained using dual-energy x-ray absorptiometry. Percentile curves based on three annual measurements were generated using the LMS statistical procedure. RESULTS: BMC of the whole body and lumbar spine and BMD of the whole body, lumbar spine, total hip, femoral neck, and forearm are given for specific percentiles by sex, age, and race (Black vs. non-Black). BMC and BMD were higher for Blacks at all skeletal sites (P < 0.0001). BMC and BMD increased with age, and a plateau was not evident by age 16 (girls) or age 17 (boys). The variation in BMC and BMD also increased with age. CONCLUSIONS: Age-, race-, and sex-specific reference curves can be used to help identify children with bone deficits and for monitoring changes in bone in response to chronic diseases or therapies.     

Insulin-like growth factor I gene microsatellite repeat, collagen type Ialpha1 gene Sp1 polymorphism, and bone disease in primary biliary cirrhosis

BACKGROUND: Genetic factors have been implicated in the pathogenesis of osteoporosis, a common disorder in primary biliary cirrhosis. Insulin-like growth factor I (IGF-I) gene microsatellite repeat polymorphism was found to be associated with osteoporosis in some studies, and collagen-Ialpha1 (COLIA1) Sp1 s allele was associated with lower bone mineral density in primary biliary cirrhosis. IGF-I treatment restored osteopenia and reduced fibrogenesis in experimental cirrhosis. We investigated IGF-I and COLIA1 gene polymorphisms and bone mineral density in Hungarian primary biliary cirrhosis patients. PATIENTS AND METHODS: Seventy female patients with primary biliary cirrhosis were enrolled (mean age 57.6 years, range 37-76 years; all anti-mitochondrial antibody M2-positive; stage II-IV). One hundred and thirty-nine age-matched female subjects served as controls (mean age 55.9 years, range 43-72 years). COLIA1 and IGF-I polymorphisms were determined by polymerase chain reaction. Bone mineral density was measured by dual-energy X-ray absorptiometry in the lumbar spine and femoral neck. RESULTS: The IGF-I was not different between primary biliary cirrhosis patients and controls. The genotype frequency of COLIA1 polymorphism was also not different between primary biliary cirrhosis patients and controls. However, the s allele was significantly less frequent in patients with primary biliary cirrhosis. Osteoporosis was detected in 22 patients. The IGF-I 192/192 genotype was associated with higher femoral-neck z-scores compared with other genotypes. CONCLUSION: In contrast to previous studies, the s allele was less frequent in patients with primary biliary cirrhosis, and its presence was not associated with bone mineral density. Since IGF-I polymorphism was associated with bone mineral density, it may be hypothesised that not COLIA1 but IGF-I together with other genetic and environmental factors may be involved in the complex regulation of bone mineral density in primary biliary cirrhosis.     

Longitudinal changes of bone mineral density and metabolism in antiretroviral-treated human immunodeficiency virus-infected children

Highly active antiretroviral therapy (HAART) may be a contributory factor for a decreased bone mass and altered bone metabolism in HIV-infected children. However, the evolution of bone mineral density (BMD) and bone metabolism during HAART has not been studied yet. In the current longitudinal study we monitored the changes of BMD and bone metabolism over a period of 12 months. Thirty-two HIV-infected children (15 girls and 17 boys), aged from 6.3 to 17.7 yr, with a long duration of HAART exposure (40.0 months at baseline) were enrolled in the study. As a control group, 381 healthy volunteers of comparable age were assessed. BMD was measured at the lumbar spine and whole skeleton by dual-energy x-ray absorptiometry. Bone-specific alkaline phosphatase (BALP, as bone formation index) and N-terminal telopeptide of type I collagen (as bone resorption index) were measured in serum and urine, respectively. BMD values at baseline were significantly lower at all skeletal sites than those of control subjects. The annual increment of spine BMD was comparable to normal, whereas that of the whole skeleton was significantly lower (P < 0.04). BALP and N-terminal telopeptide of type I collagen concentrations were significantly higher compared with controls at baseline and at follow-up. BALP annual changes of HIV patients were significantly different from normal. Our data confirm the presence of low BMD and bone metabolism derangement in HIV-infected children treated with HAART. The role of possible therapeutic approach to restore bone mass and metabolism should be assessed in pediatrics.     

Haplotypes defined by promoter and intron 1 polymorphisms of the COLIA1 gene regulate bone mineral density in women

CONTEXT: The COLIA1 gene is a strong candidate for susceptibility to osteoporosis. The causal genetic variants are currently unclear, but the most likely are functional polymorphisms in the promoter and intron 1 of COLIA1. OBJECTIVE: The objective of the study was to determine whether promoter and intron 1 polymorphisms of COLIA1 or haplotypes defined by these polymorphisms regulate bone mineral density (BMD) in women. DESIGN: This was a population-based association study involving 3270 women from the United Kingdom who took part in a regional osteoporosis screening program. MAIN OUTCOME MEASURES: BMD at the lumbar spine (LS-BMD) and femoral neck (FN-BMD) was measured on two occasions approximately 6 yr apart, in relation to polymorphisms and haplotypes defined by polymorphisms within the COLIA1 intron 1 (+1245G/T; rs1800012) and promoter (-1997G/T; rs1107946; -1663IndelT; rs2412298). RESULTS: The polymorphisms were in strong linkage disequilibrium, and three haplotypes accounted for more than 95% of alleles at the COLIA1 locus. The individual polymorphisms were associated with BMD, but the most consistent associations were with haplotypes defined by all three polymorphisms. Homozygote carriers of haplotype 2 (-1997G/-1663delT/+1245T) had reduced BMD at baseline (P = 0.007 for LS-BMD; P = 0.008 for FN-BMD), whereas homozygotes for haplotype 3 (-1997T/-1663insT/+1245G) had increased BMD (P = 0.007 for LS-BMD). Similar associations were observed at follow-up for haplotype 3, but the association with haplotype 2 was weaker due to increased uptake of hormone replacement therapy in homozygotes for this haplotype. CONCLUSIONS: Two haplotypes defined by polymorphisms in the 5' flank of the COLIA1 regulate BMD in a bidirectional manner in women.     

A 1-year prospective study on the relationship between physical activity, markers of bone metabolism, and bone acquisition in peripubertal girls

We conducted a 1-yr prospective study to evaluate the association between physical activity and biochemical markers of bone formation and resorption with bone mineral acquisition in 155 peripubertal Caucasian girls (51 gymnasts, 50 runners, and 54 nonathletic controls). The bone mineral density (BMD) of the femoral neck, the greater trochanter, and the lumbar spine were measured by dual energy x-ray absorptiometry. Serum biochemical markers of bone formation (osteocalcin, bone-specific alkaline phosphatase, amino-terminal propeptide of type I procollagen) and bone resorption (degradation product of C-terminal telopeptide of type I collagen) were measured. The 1-yr increase in BMD (adjusted for age, height, Tanner stage, BMD at baseline, and increases in height and weight) of the femoral neck was 0.037 g/cm2 x yr [95% confidence interval (CI), 0.019-0.051 g/cm2 x yr), and that of the greater trochanter was 0.020 g/cm2 x yr (95% CI, 0.003-0.039 g/cm2 x yr) greater in gymnasts than in controls. The corresponding figures for gymnasts compared with runners were 0.038 g/cm2 x yr (95% CI, 0.009-0.041 g/cm2 x yr) and 0.033 g/cm2 x yr (95% CI, 0.006 to 0.043 g/cm2 x yr). The figures for the lumbar spine did not differ significantly between study groups. The baseline serum concentrations of formation markers and resorption marker accounted for 2.3-12.8% (P < 0.05) of the variation in the 1-yr increase in BMD at the femoral neck and lumbar spine. However, there was no significant difference between the levels of adjusted baseline bone turnover markers of the gymnasts, runners, and controls. The present data add considerable support to the argument that high impact mechanical loading is extremely important and beneficial for the acquisition of BMD of the hip during peripubertal years. Our results indicate also that a high rate of bone turnover, reflected as elevated bone markers, is only weakly associated with the 1-yr bone gain in peripubertal girls.     

Estrogen receptor gene polymorphism, but not estradiol levels, is related to bone density in healthy adolescent boys: a cross-sectional and longitudinal study

The purpose of the present study was to investigate the influence of estrogen receptor alpha gene polymorphism and estradiol on height and bone density during and after puberty in males. Using the restriction enzymes XbaI and PvuII, the allelic variants XX, Xx, xx, PP, Pp, and pp were identified in 90 Caucasian boys 16.9+/-0.3 yr of age (mean +/- SD). Bone mineral density (BMD; g/cm2) of the total body, head, femoral neck, and lumbar spine was measured using dual-energy x-ray absorptiometry. Volumetric BMD (vBMD; mg/cm3) was estimated for the spine. The XbaI or PvuII genotypes were not related to the levels of estradiol, and the levels of estradiol were not related to BMD (P > 0.05). The xx allelic variant was associated with a higher spine vBMD than the Xx allelic variant (361 vs. 340 mg/cm3, P = 0.04). In a multivariate analysis including pubertal development, physical activity, and body weight, the XbaI genotype independently predicted total body BMD, head BMD, and spine vBMD (P < 0.05). The PvuII genotype independently predicted spine vBMD (pp > PP, P = 0.01). The 20 boys with the PP allelic variant were found to have a greater body height than the other 70 boys (182 cm vs. 179 cm, P = 0.03). At a 2-yr follow-up the XbaI genotype was still independently related to total body BMD, head BMD, and spine vBMD. In conclusion, estrogen receptor gene polymorphism is related to bone density and height during late puberty and at attainment of peak bone density in young men.     

Osteoporosis in beta-thalassaemia major patients: analysis of the genetic background

Regular blood transfusions from infancy until adulthood in beta-thalassaemia major patients have substituted severe bone deformities with less marked skeletal lesions as osteoporosis. Osteoporosis is characterized by low bone mass and disruption of bone architecture, resulting in reduced bone strength and increased risk of fractures. Genetic factors have an important role in determining bone mineral density (BMD). We have investigated the possible association between BMD and two polymorphisms in 135 beta-thalassaemic patients: (i) a substitution G-->Tau in a regulatory region of the COLIA1 gene encoding for the major protein of bone (type 1 collagen), and (ii) a one-base deletion in intron 4 (713-8del C) of transforming growth factor beta 1 (TGF-beta1) gene. We have found a remarkable incidence (90%) of osteopenia and osteoporosis among regularly transfused patients. Bone mass was lower in men than in women (P = 0.0023), with a more prevalent osteopenia/osteoporosis of the spine in men than in women (P = 0. 001). The sample was stratified on the basis of BMD expressed as Z-score, i.e. normal, osteopenic and osteoporotic patients, and genotype frequencies of each group were evaluated. TGF-beta1 polymorphism failed to demonstrate a statistical difference in BMD groups. However, subjects with heterozygous or homozygous polymorphism of the COLIA1 gene showed a lower BMD than subjects without the sequence variation (P = 0.012). The differences among genotypes were still present when the BMD was analysed as adjusted Z-score and when men and women were analysed separately (P = 0.022 and 0.004 respectively), with men more severely affected. Analysis of COLIA1 polymorphism could help to identify those thalassaemic patients at risk of osteoporosis and fractures.     

TNF-alpha gene polymorphism and plasma TNF-alpha levels are related to lumbar spine bone area in healthy female Caucasian adolescents

OBJECTIVE: The cytokine tumor necrosis factor alpha (TNF-alpha) is an important regulator of bone metabolism. Polymorphisms in the promoter region of the TNF-alpha gene at positions -308 and -863 have been identified. We investigated whether these polymorphisms and circulating TNF-alpha levels were related to bone mineral density and bone area in adolescent girls. DESIGN: Bone mineral density (BMD), bone area (BA), anthropometric characteristics and biochemical analyses were measured in adolescent girls and compared with regard to TNF-alpha genotype. METHODS: Allelic variants of the TNF-alpha gene in 97 girls, aged 16.9+/-1.2 years (mean+/-S.D.), were identified using polymerase chain reaction and the restriction endonucleases NcoI and TaiI. Bone mineral density and bone area of the femoral neck, lumbar spine and total body were measured using dual energy X-ray absorptiometry. RESULTS: Carriers of the rare -863 A allele (n=25) had higher body weight (P=0.03), lumbar spine BMD (P=0.02), and larger total BA (P=0.03), femoral neck area (P<0.05), and lumbar spine area (P=0.01). The independent predictors of BMD and BA were investigated using multiple regression. The TNF-alpha-863 genotypes (beta=0.18, P=0.03) and the TNF-alpha plasma levels (beta=0.19, P=0.04) independently predicted BA of the lumbar spine but not BA or BMD of any other measured sites. No statistically significant differences in body constitution parameters, biochemical parameters, bone density, or bone area at the measured skeletal sites were found when comparing the groups defined by the allelic variants at position -308 (P=0.17-0.84). CONCLUSIONS: We found the TNF-alpha-863 polymorphism and the TNF-alpha plasma levels to be independent predictors of lumbar spine area in healthy Caucasian adolescent females.     

Dual-energy X-ray absorptiometry in clinical practice and its trouble spots in bone mineral measurement

The technique of dual energy X-ray absorptiometry (DXA) is widely used for bone mineral density (BMD) measurement at present. BMD at PA spine should be measured for diagnosis of osteoporosis in all patients. If BMD at PA spine is inappropriate for the evaluation, proximal femur is selected for the measurement site. Various clinical issues pertained to this technique have been known. This paper reviewed clinical practice and trouble spots of BMD measurements at AP spine, proximal femur, and distal forearm.     

Measurement of bone mineral content of the lumbar spine by dual energy x-ray absorptiometry in normal children: correlations with growth parameters

The bone mineral density (BMD) of the lumbar spine (L1-L4) was measured by dual energy x-ray absorptiometry (Hologic QDR 1000) in 135 healthy caucasian children, aged 1-15 yr, and values were correlated with age, height, weight, body surface, bone age, pubertal status, calcium intake, vitamin D supplementation, and serum bone gla protein. BMD increased with age in children of both sexes (r = 0.88; P less than 0.001) from 0.446 +/- 0.048 g/cm2 at 1 yr to 0.625 +/- 0.068 g/cm2 at 10 yr and 0.891 +/- 0.123 g/cm2 at 15 yr of age. The increase was steeper at the time of puberty, reaching values above 0.80 g/cm2 after puberty was achieved. There were no significant differences between boys and girls, except at the age of 12 yr when BMD was higher in girls than in boys (P = 0.007), probably because of the earlier onset of puberty in females. BMD was also highly correlated with height, weight, body surface, and bone age. BMD was not correlated with calcium intake when age was held constant, nor with vitamin D supplementation. Serum bone gla protein showed a steady increase during childhood, with peak values at 11-12 yr of age, and was weakly but significantly correlated with BMD (r = 0.27; P = 0.007). Because of low irradiation exposure, rapid scanning, and high precision, dual energy x-ray absorptiometry is a noninvasive method which is well adapted to the child. It should be helpful in the investigation and follow-up of children with diseases impairing bone metabolism.     

Absence of high-risk "s" allele associated with osteoporosis at the intronic SP1 binding-site of collagen Ialpha1 gene in Southern Chinese

The Sp1 polymorphism in the first intron of the collagen Ialpha1 gene was recently described to be associated with low bone mineral density (BMD) and increased fracture risk in Caucasian populations. The impact of this gene was assessed in a Southern Chinese population. One hundred and eighty-one women, aged 51.1+/-8.8 yr were evaluated for the Sp1 polymorphism. Twenty-two per cent of the women were classified as having osteoporosis on the basis of a T-score at the lumbar spine or the hip below -2.5 with or without a prevalent fracture. Genotype analysis was performed by PCR amplification and restriction enzyme digestion. Single-strand conformational polymorphism analysis (SSCP) was performed in 65 randomly selected samples to search for any polymorphic site in the PCR amplified region. The results showed that no restriction enzyme site could be identified in any of the 181 samples analyzed. Moreover, SSCP analysis revealed no polymorphism in the PCR amplified region of the first intron of the collagen Ialpha1 gene. In conclusion, the "s" allele, associated with low BMD and increased fracture risk in Caucasians, is non-existent or very rare in the Southern Chinese population. The absence of this "high risk" allele may in part account for the reduced fracture risk observed in the Chinese in comparison to Western populations.     

Clinical and anthropometric correlates of bone mineral acquisition in healthy adolescent girls

We studied the acquisition of bone mineral in 45 healthy prepubertal and pubertal girls and related changes in bone mass to age, body mass, pubertal status, calcium intake, and exercise. A subgroup of 12 girls was followed longitudinally. Bone mineral content (BMC) of the lumbar spine, whole body, and femoral neck was measured by dual energy x-ray absorptiometry and that at the midradius by single photon absorptiometry. For comparison, spine and whole body mineral contents were also measured by dual photon absorptiometry. Bone mass was expressed in conventional terms of BMC and area density (BMD). However, we show that BMD fails to account for differences in bone thickness. Since bone size increases during adolescence, we present a new expression, bone mineral apparent density (BMAD), which is BMC normalized to a derived bone reference volume. This term minimizes the effect of bone geometry and allows comparisons of mineral status among bones of similar shape but different size. BMC increased with age at all sites. These increases were most rapid in the early teens and plateaued after 16 yr of age. When bone mineral values at all sites were regressed against age, height, weight, or pubertal stage, consistent relationships emerged, in which BMC was most strongly correlated, BMD was correlated to an intermediate degree, and BMAD correlated only modestly or without significance. Dietary calcium and exercise level did not correlate significantly with bone mass. From these relationships, we attribute 50% of the pubertal increase in spine mineral and 99% of the change in whole body mineral to bone expansion rather than to an increase in bone mineral per unit volume. In multiple regressions, pubertal stage most consistently predicted mineral status. This study emphasizes the importance of pubertal development and body size as determinants of bone acquisition in girls. BMAD may prove to be particularly useful in studies of bone acquisition during periods of rapid skeletal growth.     

Bone mass in prepubertal boys is associated with a Gln223Arg amino acid substitution in the leptin receptor

OBJECTIVE: The contribution of leptin to bone mass acquisition in humans remains unclear. We investigated the association of the Gln223Arg polymorphism in the leptin receptor gene (LEPR) with bone mineral content (BMC) and areal bone mineral density (aBMD) in prepubertal boys and LEPR interaction with vitamin D receptor (VDR) genotypes (Bsm1 and Fok1). DESIGN: In a cross-sectional design with a longitudinal follow-up, dual-energy x-ray absorptiometry measurements at the lumbar spine, hip, femoral diaphysis, and radius were performed at baseline (mean age 7.4 +/- 0.4 yr) and 2 yr later in 222 healthy Caucasian males. RESULTS: LEPR genotypes were significantly associated with baseline BMC at the hip (P = 0.017), femur diaphysis (P = 0.019), and radius (P = 0.007) and with height (P = 0.041) as well as with physical activity (P = 0.016). Associations with height and BMC at femur diaphysis and radius remained significant after 2 yr. Significant differences in 2-yr bone mass gain at the spine and femur neck were also found among LEPR genotypes. In contrast, adjusting BMC for projected bone area (aBMD) and/or weight, height, and physical activity resulted in a weak association only at the femur (P = 0.014-0.054). VDR polymorphisms were not associated with BMC or aBMD, but significant interactions occurred between VDR Fok1 and LEPR genotypes. CONCLUSIONS: The LEPR Gln223Arg polymorphism was associated with bone mass in growing boys. The association, however, was markedly dependent on bone area, body size, and physical activity, in addition to VDR genetic variation, suggesting that the leptin system may modulate bone mass in humans mostly through indirect mechanisms.     

Bone mineral acquisition in healthy Asian, Hispanic, black, and Caucasian youth: a longitudinal study

Ethnic and gender differences in bone mineral acquisition were examined in a longitudinal study of 423 healthy Asian, black, Hispanic, and white males and females (aged 9-25 yr). Bone mass of the spine, femoral neck, total hip, and whole body was measured annually for up to 4 yr by dual energy x-ray absorptiometry. Age-adjusted mean bone mineral curves for areal (BMD) and volumetric (BMAD) bone mineral density were compared for the 4 ethnic groups. Consistent differences in areal and volumetric bone density were observed only between black and nonblack subjects. Among females, blacks had greater mean levels of BMD and BMAD at all skeletal sites. Differences among Asians, Hispanics, and white females were significant for femoral neck BMD, whole body BMD, and whole body bone mineral content/height ratio, for which Asians had significantly lower values; femoral neck BMAD in Asian and white females was lower than that in Hispanics. Like the females, black males had consistently greater mean values than nonblacks for all BMD and BMAD measurements. A few differences were also observed among nonblack male subjects. Whites had greater mean total hip BMD, whole body BMD, and whole body bone mineral content/height ratio than Asian and Hispanic males; Hispanics had lower spine BMD than white and Asian males. The tempo of gains in BMD varied by gender and skeletal site. In females, total hip, spine, and whole body BMD reached a plateau at 14.1, 15.7, and 16.4 yr, respectively. For males, gains in BMD leveled off at 15.7 yr for total hip and at age 17.6 yr for spine and whole body. Black and Asian females and Asian males tended to reach a plateau in BMD earlier than the other ethnic groups. The use of gender- and ethnic-specific standards is recommended when interpreting pediatric bone densitometry data.     

Bone mineral density changes in women with systemic lupus erythematosus

The aim of this study was to analyse the heterogeneity of bone mineral density (BMD) reduction across measurement sites in female systemic lupus erythematosus (SLE) patients on glucocorticoid (CS) treatment. The study population consisted of two subgroups: 32 women at a mean (SD) age of 43.2 (12.0) years, SLE duration of 13.4 (6.2) years, treated with a mean cumulative prednisone dose of 34.4 g; and 16 women at a mean age of 36.1 (9.0) years, SLE duration of 3.2 (2.0) years, never treated with glucocorticoids (control group). The participants underwent a standardised interview, medical record review, blood sampling and BMD examination of the lumbar spine, femoral neck and distal forearm by dual-energy X-ray absorptiometry. CS-treated participants were supplemented with daily calcium (1200 mg) and vitamin D (500 UI). During the study mean daily glucocorticoid dose was 10 mg prednisone equivalent. The controls did not receive either corticosteroids or calcium and vitamin D. BMD and laboratory parameters were re-examined at the end of the second year. At baseline 22 (68.7%) of the CS-treated participants had osteoporosis at least at one major site, compared to 18.8% of the controls. The BMD reduction was proportional to the trabecular bone content at the specific measurement site. At baseline mean T scores in the CS-treated group were the highest at the forearm (–1.03 ± 1.13), followed by the hip (–1.32 ± 1.26), AP spine (–1.87 ± 1.46) and lateral spine (–2.90 ± 1.50). At follow-up lateral spine bone loss was 5.54% per year, the total hip and the forearm lost 3.59% and 0.33%, respectively, compared to annual losses of 1.02% (AP spine), 1.30% (lateral spine), 0.83% (total hip) and 0.11% (forearm) in the control group. The heterogeneity of BMD reduction in our SLE population emphasises the need for the targeted use of bone densitometry in steroid-treated patients. Attention should be paid to trabecular-rich sites, and fracture risk should be specifically determined.     

Vitamin D receptor gene polymorphism is associated with birth height, growth to adolescence, and adult stature in healthy caucasian men: a cross-sectional and longitudinal study

Vitamin D receptor (VDR) polymorphism has been associated with bone mineral density (BMD), but recent data indicate association to parameters of body constitution and growth. We investigated VDR gene polymorphism, defined by BsmI and TaqI, in 90 healthy Caucasian males and any relation with parameters of body constitution at birth, and to parameters of body constitution, BMD and bone area, at age 16.9 +/- 0.3 yr (mean +/- SD) and at age 19.2 +/- 0.7. Using PCR and the restriction enzyme BsmI and TaqI, the allelic variants BB, Bb, and bb, and TT, Tt, and tt were identified. Height (cm) and weight (kg) were measured using standardized equipment, and BMD of the total body, lumbar spine, and femoral neck, and bone area (cm2) of the total body, humerus, femur was measured using dual-energy x-ray absorptiometry. BsmI and TaqI genotypes were related in 89 of the 90 cases; hence, the same associations were found for both genotypes. Boys with the BB genotype were shorter at birth (P = 0.01) and grew less from birth to age 16.9 +/- 0.3 (P = 0.01) than their Bb and bb counterparts. Both during puberty (age 16.9 +/- 0.3) and after puberty (age 19.3 +/- 0.7), the BB boys were shorter (P = 0.005-0.008) and had lower bone area of the humerus, femur, and total body (P < 0.05) than the Bb and bb boys. The allelic variants were not related to BMD at any site. A prediction model including parental height, birth height, birth weight, and VDR alleles could predict up to 39% of the total variation in adult height in our population. The VDR allelic variants alone contributed to 8% of the total variation.