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.     

Bone mineral metabolism in adults with beta-thalassaemia major and intermedia

Bone disease is an important cause of morbidity in older patients with beta-thalassaemia major and intermedia. We studied 27 women and 23 men with beta-thalassaemia major (37) and intermedia (13) whose mean age was 32.3 +/- 9.7 years. Bone mineral density (BMD) of the lumbar spine, femoral neck and distal radius was determined by dual-energy X-ray absorbiometry (DXA). The longitudinal change in BMD over a mean of 5.6 years was determined in 19 patients. Serum 25-hydroxyvitamin D, insulin growth factor-1 (IGF-1), bone formation markers bone-alkaline phosphatase, osteocalcin and the resorption marker urinary N-telopeptide cross-linked type 1 collagen (NTx) were determined. The BsmI vitamin D receptor (VDR) gene polymorphism was analysed. Reduced BMD (Z-score < -2) was present in 89%, 62% and 73% of patients in the spine, hip and radius respectively. Vitamin D deficiency was found in 62%, decreased IGF-1 in 72% and increased urinary NTx in 84% of patients. Serum IGF-1 correlated with spine and hip BMD (r = 0.4, r = 0.39, P < 0.01 respectively), and NTx correlated with the hip BMD Z-score (r = 0.35 P < 0.05). The mean annual percentage change in spine BMD was -1.36%. Patients with the VDR BB genotype had lower spine BMD than patients with the bb genotype. In conclusion, bone loss continues in adult thalassaemia patients and is associated with increased bone resorption and decreased IGF-1. The BsmI VDR gene polymorphism is associated with osteopenia in thalassaemia.     

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.     

Decreased bone mineral density is common after autologous blood or marrow transplantation

Survivors of autologous blood or marrow transplantation (ABMT) are predisposed to decreased bone mineral density (BMD), but data are lacking on the incidence and risk factors for this condition. Therefore, we measured BMD in 64 of 68 consecutive ABMT survivors (35 men and 29 women) attending the University of Toronto ABMT long-term follow-up clinic. Patients were evaluated a median of 4.2 years (range: 4.9 months-11.4 years) after ABMT. Median age at evaluation was 49.6 years (range: 23.5-68.2 years). At the L1-L4 vertebrae, 17 (26%) patients (eight men and nine women) had osteopenia and one male (2%) had osteoporosis. Mean BMD at L1-L4 did not differ from healthy young adults or age and sex matched controls. At the femoral neck, 30 patients (46%) (18 men and 12 women) had osteopenia and five (8%) (two men and three women) had osteoporosis. Mean BMD at the femoral neck was significantly lower than in healthy young adults and age- and sex-matched controls. By regression analysis, patients with decreased BMD were older than those with normal BMD (P = 0.02). Gender, body mass index, time from BMT to evaluation and presence of hypogonadism were not associated with decreased BMD. Treatment of decreased bone density was instituted and follow-up data were obtained 1 year after treatment in 22 of 39 patients with reduced BMD. Nineteen (86%) patients had stabilization or improvement of their bone density at follow-up. We conclude that, after ABMT, over half of the patients have evidence of osteopenia or osteoporosis. Men and women were equally affected. In our study, only older age at evaluation was predictive for loss of BMD. We recommend the measurement of BMD as an integral component to the follow-up of ABMT patients.     

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.     

Relation of bone mineral density to frequency of coronary heart disease

Coronary angiography was performed because of chest pain in 198 patients (146 women, 52 men; mean age 66 years) who had dual-energy x-ray absorptiometry scans of the spine and left hip because of suspected osteoporosis or osteopenia. Of the 198 patients, 53 (27%) had osteoporosis, 79 (40%) had osteopenia, and 66 (33%) had normal bone mineral density (BMD). Obstructive coronary artery disease with >50% narrowing of > or =1 major coronary artery was present in 40 of 53 patients (76%) with osteoporosis, in 54 of 79 patients (68%) with osteopenia, and in 31 of 66 patients (47%) with normal BMD (p <0.005 comparing osteoporosis with normal BMD, p <0.01 comparing osteopenia with normal BMD). In conclusion, in patients who undergo coronary angiography because of chest pain, patients with osteoporosis or osteopenia have a higher prevalence of obstructive coronary artery disease than those with normal BMD.     

Men suffer vertebral fractures with similar spinal T-scores to women

OBJECTIVE: To evaluate the applicability of the WHO densitometric criteria for the diagnosis of spinal osteoporosis in men and to compare it with women with vertebral fractures, as well as to analyze the role of vertebral dimensions in the development of spinal fractures. METHODS: For these purposes we analyzed, using DXA, vertebral projected area and lumbar bone mineral density (BMD), as well as T and Z-scores in lumbar spine in a cohort of 66946 individuals; 2556 of these subjects had one or more atraumatic vertebral fracture (396 men and 2160 postmenopausal women). RESULTS: Men and women with fractures showed significantly lower mean BMD, T-score and Z-score values than individuals without fractures while vertebral dimensions were similar in both groups of patients. When comparing men and women with vertebral fractures, the former showed a significantly greater projected area (46.89+/-5.5 vs. 39.13+/-4.6 cm(2) p<0.001) and lumbar BMD (0.991+/- 0.21 vs. 0.938+/- t0.19 g/cm(2) p<0.001). However, the median lumbar T-score values were similar for both sexes (-2.3 in women vs. -2.2 in men; p: NS). In addition, a similar percentage of men and women with vertebral fractures showed T-score values <-2.5 in the lumbar spine (44% vs. 46%, p=NS). CONCLUSION: We conclude that although men with vertebral fractures have greater vertebral dimensions and BMD than women, the lumbar T-scores are similar. Therefore, it seems reasonable to adopt the same T-score values for the diagnosis of osteoporosis in men and women.     

High prevalence and correlates of low bone mineral density in young adults with sickle cell disease

Sickle cell disease (SCD) is a prevalent genetic disorder in which sickle hemoglobin leads to tissue hypoxia and adverse effects on bone. Published studies suggest that children with SCD often have undiagnosed osteopenia or osteoporosis. Minimal data exist on the prevalence of low bone mineral density (BMD) in adults. Our objective was to describe the prevalence of osteopenia and osteoporosis in adults with SCD and to identify patient or disease characteristics associated with low BMD. We conducted a cross-sectional study of adults with SCD. Through questionnaires, we collected data about disease course and osteoporosis risk factors. Patients underwent dual X-ray absorptiometry (DXA) measurement of BMD at the hip, spine, and forearm and sampling of blood and urine for markers of bone turnover, sickle cell disease severity, and secondary causes of osteoporosis. Our main outcome measure was prevalence of osteopenia and osteoporosis as defined by WHO criteria. Of 32 adults with SCD (14 men and 18 women) with a mean age of 34 years, 72% (95% confidence interval 53-86%) had low BMD at one or more anatomic sites. Thirteen patients were classified as osteoporotic and 10 as osteopenic. The prevalence of low BMD was greatest in the lumbar spine (66% of patients). Significant correlates of decreased BMD included low BMI (P < 0.01), male sex (P = 0.02), and low serum zinc concentrations (P < 0.01). The prevalence of osteopenia and osteoporosis in young adults with SCD is extremely high. Further research is needed to address fracture risk and therapeutic interventions.     

Low bone mineral density and the severity of cholestasis in biliary atresia

AIM To investigate the prevalence of osteopenia and osteoporosis in postoperative biliary atresia(BA) children and the association of bone mineral density(BMD) and biochemical parameters in post Kasai BA subjects. METHODS A total of 70 patients with post Kasai BA were enrolled in this prospective study. The patients were classified into two groups according to their jaundice status. BMD of the lumbar spine was analyzed using dual energyX-ray absorptiometry.RESULTS The prevalence of low bone mass(osteopenia and osteoporosis) in BA patients were 51.4%(36 out of 70). Ten patients(35.7%) in the jaundice group and 8 patients(19.0%) in the non-jaundice group had osteopenia. Sixteen patients(57.1%) in the jaundice group and 2 patients(4.8%) in the no jaundice group had osteoporosis. In addition, lumbar spine BMD Z-score was substantially lower in the jaundice BA patients compared with non-jaundice patients. BA subjects with persistent jaundice had significantly lower serum 25-hydroxyvitamin D than those without jaundice. Further analysis revealed that lumbar spine BMD was correlated with age(r = 0.774, P 0.001), serum albumin(r = 0.333, P = 0.005), total bilirubin(r =-0.476, P 0.001), aspartate aminotransferase(r =-0.583, P 0.001), alanine aminotransferase(r =-0.428, P 0.001), and alkaline phosphatase(r =-0.456, P 0.001).CONCLUSION Low BMD was associated with biochemical parameters reflecting the severity of cholestasis in post Kasai BA patients.     

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.     

Young adults with juvenile arthritis in remission attain normal peak bone mass at the lumbar spine and forearm

OBJECTIVE: To assess the impact of disease activity on acquired peak bone mass and bone turnover in young adult patients with either persistent juvenile arthritis (JA) or a history of JA (JA in remission). METHODS: Two hundred twenty-nine patients with JA were studied after a mean +/- SD of 15.6 +/- 2.4 years in women and 14.9 +/- 2.1 years in men since disease onset. One hundred forty-five women and 84 men were over the age of 20 at the time of examination (mean +/- SD age 24.9 +/- 2.9 years for women and 25.2 +/- 3.1 years for men). Forty-one healthy women (mean +/- SD age 27.4 +/- 3.1 years) and 55 healthy men (mean +/- SD age 25.7 +/- 3.1 years) served as a reference group. Bone mineral density (BMD) was analyzed by dual x-ray absorptiometry. Serum osteocalcin concentrations and urinary concentrations of deoxypyridium (D-Pyd) were measured. Linear regression analyses were performed to evaluate the impact of disease on BMD. RESULTS: Patients with persistent disease had significantly lower BMD compared with healthy subjects (P < 0.001 for women at all measured sites and for men at the femoral neck and total body; P < 0.05 for men at the radius and lumbar spine). Of the patients with a history of JA, only women had significantly lower BMD at the femoral neck and total body (P < 0.05). Patients with persistent JA had significantly more osteopenia and osteoporosis than healthy subjects, while patients with a history of JA had more frequent osteopenia only in the total body. Weight, urinary concentration of D-Pyd, and belonging to the patient group significantly affected BMD at all measured sites in the entire study population, while analysis of all patients found that only the number of months taking corticosteroids significantly affected BMD at all measured sites. However, the impact of the variables differed from site to site. CONCLUSION: Our findings imply that most young adults with JA attain the same BMD as healthy subjects if the disease goes into remission, while young adults with active disease have increased risk for osteopenia and osteoporosis.     

维生素D受体基因和雌激素受体基因多态性与老年人低骨量的关系

目的探讨维生素D受体基因(VDR)和雌激素受体基因(ESR1)多态性与老年男性、女性低骨量的关系。方法 378名老年男性[平均年龄(61.1±7.0)岁,其中260名健康男性、110例骨量减少和8例骨质疏松患者]和334名绝经后妇女[平均年龄(58.4±6.3)岁,其中148名健康女性、153例骨量减少和33例骨质疏松患者]共712人,均为居住在上海30年以上汉族人。用双能X线测量仪检测上述受试者左侧股骨颈骨密度(bone mineral density,BMD)。按照股骨颈BMD低于同性别正常峰值BMD的-1～-2.5和-2.5标准差为标准诊断骨量减少和骨质疏松,排除继发性低骨量。检测VDR基因FokⅠ、ApaⅠ、CDX 2位点ESR 1基因的PvuⅡ和XbaⅠ位点单核苷酸多态性(single nucleotide polymorphisms,SNPs)。结果 378名老年男性中,FokⅠ的基因型频率为FF(28.0%)、Ff(50.0%)和ff(22.0%),ApaⅠ的基因型频率为AA(9.5%)、Aa(43.4%)和aa(47.1%);CDX 2的基因型频率为AA(22.2%)、AG(45.8%)和GG(32.0%);PvuⅡ的基因型频率为PP(14.1%)、Pp(46.0%)和pp(39.9%);XbaⅠ的基因型频率为XX(5.0%)、Xx(36.8%)和xx(58.2%)。334名老年女性中,FokⅠ的基因型频率为FF(25.7%)、Ff(55.1%)和ff(19.2%),ApaⅠ的基因型频率为AA(10.2%)、Aa(44.0%)和aa(45.8%);CDX 2的基因型频率为AA(22.8%)、AG(47.9%)和GG(29.3%);PvuⅡ的基因型频率为PP(9.9%)、Pp(45.2%)和pp(44.9%);XbaⅠ的基因型频率为XX(2.1%)、Xx(36.8%)和xx(61.1%)。等位基因频率分布均符合Hardy-Weinberg定律。老年男性和女性的骨质疏松组、骨量减少组和骨量正常组之间上述基因SNP频率分布未见差异(P均0.05)。结论 VDR的FokⅠ、ApaⅠ及CDX 2位点和ESR 1的PvuⅡ及XbaⅠ位点多态性可能不是纳入本研究汉族老年男性和女性低骨量的风险因子,尚需更大样本量的实验予以证实。     

Bone mineral density of the lumbar spine in patients with advanced rheumatoid arthritis. Influence of functional capacity and corticosteroid use

We investigated factors that are related to generalized osteoporosis in advanced rheumatoid arthritis (RA). In this cross-sectional study we measured trabecular bone mineral density (BMD), by quantitative computerized tomography (QCT), in the lumbar spine of 57 patients with RA, most of whom were premenopausal women. In our material, 27 out of 57 patients (47%) had BMD <-1 SD expressed as Z-score and five patients had suffered from fractures. Our study shows that a cumulative corticosteroid dose (r = -0.41, p<0.010) and functional impairment (r = -0.37, p<0.050) were negatively related to spinal BMD, while daily intake of calcium correlated positively on BMD (r = 0.37, p<0.010). Our results indicate that low BMD is common in patients with advanced RA and it is associated with long-term corticosteroid use. Thus, in clinical practice we have to consider the benefits and harms of corticosteroid treatment and preventive therapy to osteoporosis.     

Bone metabolism in patients more than five years after bone marrow transplantation

We investigated the bone metabolism of 22 patients (median age 38 years) over 6 years after allogeneic bone marrow transplantation (BMT). Biplanar roentgenograms of the thoracic and lumbar spine were used to diagnose vertebral deformities caused by fractures. The actual bone mineral density (BMD) of the lumbar spine and the femoral neck were measured. Laboratory tests included calcium, phosphate, parathyroid hormone, a marker of bone resorption (beta-crosslaps, CTX), markers of bone formation (osteocalcin, bone-specific alkaline phosphatase), osteoprotegerin (OPG)--antagonist of the osteoclast differentiation factor RANKL, and sex hormone status. One patient had a vertebral fracture. Seven patients (28%) had osteopenia in the lumbar spine while 12 patients (48%) had osteopenia in the femoral neck. Bone resorption was increased in nine patients (43%) and bone formation was increased in four patients (20%). BMT recipients had significantly increased serum levels of OPG (P=0.029). Three women (75%) and four men (25%) were hypogonadal. The data showed that BMD is reduced and bone metabolism is still disturbed more than 6 years after BMT. The RANKL/osteoprotegerin system appears to play an important role in the pathophysiology of late post transplantation osteoporosis.     

Evaluation of changes in bone density and biochemical parameters after parathyroidectomy in primary hyperparathyroidism

We examined the relationships between serum levels of intact parathyroid hormone (PTH) and alkaline phosphatase (ALP) versus bone mineral density (BMD) at the lumbar spine and radius in terms of their preoperative values and of their annual percentage and net changes after parathyroidectomy (PTX) in 44 Japanese patients (14 men and 30 women) with primary hyperparathyroidism (pHPT). Lumbar and radial BMD values were measured by dual energy X-ray absorptiometry and single photon absorptiometry and were used for evaluating the cancellous and cortical bone mass, respectively. Age- and sex-adjusted value (Z-score) of the radial BMD was significantly lower than that of the lumbar BMD before and after PTX (P < 0.05). In preoperative patients, serum levels of both intact PTH and ALP were significantly and negatively correlated with Z-score of the radial BMD (P < 0.05 and P < 0.001, respectively), but not with that of the lumbar BMD. After PTX, serum levels of calcium, phosphorus, ALP, and PTH became normal, and both lumbar and radial BMD values markedly increased over 1 year, with percentage changes of 12.2+/-1.4% and 11.6+/-1.6%, respectively, which were larger than those in any other Caucasian study previously documented. Even in patients without osteopenia (Z-score of BMD 20), lumbar and radial BMD values increased considerably after the operation (9.6+/-1.9% and 6.7+/-1.4%, respectively). Annual percentage and net changes in lumbar BMD were significantly and negatively correlated with those in ALP with high correlation coefficients, but those in radial BMD were correlated only with the annual net change in ALP but not with the percentage change. No significant correlations were observed between annual changes in either lumbar or radial BMD and those in intact PTH. Taken together, this study shows that PTX causes dramatic improvements in both the cancellous and cortical bone mass in Japanese pHPT patients regardless of the severity of their osteopenia, and suggests that the cancellous and cortical bones react differently to a preoperative endogenous PTH excess and a high bone turnover rate as well as to the postoperative normalization of a bone turnover rate in the patients.     

Association of the F352V variant of the Klotho gene with bone mineral density

Klotho gene codes for a protein with glucuronidase activity and is thought to influence bone and vascular homeostasis. We studied the relationship of a common T/G polymorphism, resulting in a phenylalanine (F) to valine (V) substitution at aminoacid position 352, with bone mineral density (BMD) and osteoporotic fractures. The study group comprised 914 Spanish women, including 438 control subjects, 190 patients with osteoporosis, 198 with hip fractures, and 88 patients with severe osteoarthritis. BMD was measured by DEXA in 540 women from the control and osteoporosis groups. Allele frequencies were 86% and 14%, for the F and V alleles, respectively. In comparison with the most common FF genotype, postmenopausal women with FV/VV genotypes had higher hip BMD (femoral neck: 0.673 ± 0.011 vs. 0.644 ± 0.006 g/cm²; P = 0.02; total hip: 0.807 ± 0.014 vs. 0.774 ± 0.008 g/cm²; P = 0.03). Klotho alleles explained about 1.5% of BMD variance, but were not associated to the risk of osteoporotic spine or hip fractures. The Klotho genotype was not associated to BMD in premenopausal women. In conclusion, the F352V Klotho polymorphism is associated with BMD in postmenopausal women, suggesting that Klotho gene variants influence skeletal aging.     

Fractures and bone mineral density in adult women with 21-hydroxylase deficiency

CONTEXT: Patients with classical congenital adrenal hyperplasia (CAH) receive lifelong, often supraphysiological, glucocorticoid therapy. Pharmacological doses of glucocorticoids are an established risk factor for osteoporosis. OBJECTIVE: Our objective was to evaluate bone mineral density (BMD), fracture prevalence, and markers of bone metabolism in adult females with CAH. DESIGN: This was a cross-sectional observational study. SETTING: Tertiary care referral centers were used in this study. PARTICIPANTS: We studied 61 women, aged 18-63 yr, with genetically verified CAH due to 21-hydroxylase deficiency. They were patients with salt wasting (n = 27), simple virilizing (n = 28), and nonclassical 21-hydroxylase deficiency (n = 6). A total of 61 age-matched women were controls. MAIN OUTCOME MEASURES: History of fractures was recorded. Total body, lumbar spine, and femoral neck BMD were measured by dual-energy x-ray absorptiometry. The World Health Organization criteria for osteopenia and osteoporosis were used. Serum marker of bone resorption, beta-C telopeptide was studied. RESULTS: The mean glucocorticoid dose in hydrocortisone equivalents was 16.9 +/- 0.9 mg/m2. Patients had lower BMD than controls at all measured sites (P < 0.001). In patients younger than 30 yr old, 48% were osteopenic vs. 12% in controls (P < 0.009). In patients 30 yr or older, 73% were osteopenic or osteoporotic vs. 21% in controls (P < 0.001). BMD was similar in the two classical forms and had no obvious relationship to genotypes. beta-C-telopeptide was decreased in older patients. More fractures were reported in patients than controls (P < 0.001). The number of vertebrae and wrist fractures almost reached significance (P = 0.058). CONCLUSIONS: Women with CAH have low BMD and increased fracture risk. BMD should be monitored, adequate prophylaxis and treatment instituted, and glucocorticoid doses optimized from puberty.     

Forearm endothelial function and bone mineral loss in postmenopausal women

It is widely believed that the vasculature plays an important role in bone remodeling. We investigated the relationship between forearm endothelial function and bone mass in the lumbar spine in early postmenopausal women without a history of smoking or diabetes mellitus. We studied the forearm resistance artery endothelial function in 110 Japanese women-52 postmenopausal women with normal spinal bone mineral density (BMD), 36 postmenopausal women with osteopenia, and 22 osteoporotic postmenopausal women. Forearm blood flow (FBF) during reactive hyperemia and after sublingual nitroglycerin (NTG) administration was measured by strain-gauge plethysmography. BMD of the lumbar spine (L2-L4) was measured by dual-energy X-ray absorptiometry. After adjustment for age, body mass index, years since the start of menopause, and basal FBF, women with osteoporosis had a lower maximal FBF response to reactive hyperemia (28.4 +/- 3.8 mL/min per 100 mL tissue) than those with normal BMD (39.8 +/- 2.8 mL/min per 100mL tissue) or osteopenia (35.6 +/- 2.5 mL/min per 100mL tissue) (P = 0.029). A significant increase in serum angiotensin-converting enzyme (ACE) activity (P = 0.042) and a significant decrease in the serum concentrations of nitrite/nitrate (P = 0.041) were noted in osteoporotic women compared to women with normal BMD or osteopenia. The present findings suggest that postmenopausal women with low BMD, especially those with osteoporosis, have impaired endothelial function in the forearm resistance arteries.     

Selective reduction in cortical bone mineral density in turner syndrome independent of ovarian hormone deficiency

Women with Turner syndrome (TS) are at risk for osteoporosis from ovarian failure and possibly from haploinsufficiency for bone-related X-chromosome genes. To establish whether cortical or trabecular bone is predominantly affected, and to control for the ovarian failure, we studied forearm bone mineral density (BMD) in 41 women with TS ages 18-45 yr and in 35 age-matched women with karyotypically normal premature ovarian failure (POF). We measured BMD at the 1/3 distal radius (D-Rad(1/3); predominantly cortical bone) and at the ultradistal radius (UD-Rad; predominantly trabecular bone) by dual x-ray absorptiometry. Women with TS had lower cortical BMD compared with POF (D-Rad(1/3) Z-score = -1.5 +/- 0.8 for TS and 0.08 +/- 0.7 for POF; P < 0.0001). In contrast, the primarily trabecular UD-Rad BMD was normal in TS and not significantly different from POF (Z-score = -0.62 +/- 1.1 for TS and -0.34 +/- 1.0 for POF; P = 0.26). The difference in cortical BMD remained after adjustment for height, age of puberty, lifetime estrogen exposure, and serum 25-hydroxyvitamin D (P = 0.0013). Cortical BMD was independent of serum IGF-I and -II, PTH, and testosterone in TS. We conclude that there is a selective deficiency in forearm cortical bone in TS that appears independent of ovarian hormone exposure and is probably related to X-chromosome gene(s) haploinsufficiency.