The Sp1 COLIA1 Gene Polymorphism, and Not Vitamin D Receptor or Estrogen Receptor Gene Polymorphisms, Determines Bone Mineral Density in Postmenopausal Greek Women

Several genetic polymorphisms are implicated as determinants of bone mineral density (BMD) in postmenopausal women. These include the Sp1 polymorphism of the collagen type Iα 1 (COLIA1) gene, the FokI and BsmI polymorphisms of the vitamin D receptor (VDR) gene, and the PvuII and XbaI polymorphisms of the estrogen receptor (ER) gene. The relative importance and the independence of these genetic effects have not been studied simultaneously in the same population. We evaluated the effects of these polymorphisms on lumbar spine BMD among 154 postmenopausal Greek women. BMD tended to differ across Sp1 genotypes (mean 0.842 g/cm² in SS, 0.851 g/cm² in Ss, 0.763 in ss, age-adjusted p = 0.056), mostly because ss homozygotes had lower BMD (p = 0.018 compared with SS and Ss). No other polymorphisms were associated with BMD in this population (p= 0.53 for FokI, p= 0.94 for BsmI, p = 0.80 for PvuII, p = 0.91 for XbaI). In multivariate modeling, the effect of ss homozygosity was clinically and statistically significant (–0.105 g/cm², p= 0.013) after adjusting for age, weight, height, hormone replacement use, and the other four polymorphisms. None of the other four polymorphisms was retained as an independent predictor of BMD in a backward elimination model and no significant synergistic effects were observed when gene interactions were tested. When all five polymorphisms are considered simultaneously, the Sp1 COLIA1 polymorphism seems to have the most unequivocal effect on BMD, at least in postmenopausal women. Received: 3 July 2000 / Accepted: 14 November 2000     

The Vitamin D Receptor Start Codon Polymorphism (Fok1) and Bone Mineral Density in Premenopausal Women in Taiwan

The vitamin D receptor gene (VDRG) polymorphism as a factor of bone turnover rate or bone mineral density (BMD) is a controversial issue, especially in different ethnic populations. In addition to intron 8 (Bsm1, Taq1) and exon 9 (Apa1), VDRG polymorphism is present at its translation initiation site on exon 2. The VDRG has two translation initiation sites. The first shows a thymine/cytosine polymorphism and can be detected by restriction fragment length polymorphism (RFLP) using the endonuclease Fok1. This start codon polymorphism (SCP) of the VDRG was detected by polymerase chain reaction and then by RFLP with Fok1. While the f allele was assigned for the presence of the restriction site, the F allele was assigned for the absence of the restriction site, and the encoded vitamin D receptor is shorter by three amino acids. We examined the association between this SCP of the VDRG and bone turnover as well as BMD in 101 premenopausal Taiwanese women aged 40–53 years. Total body bone mineral content and BMD of proximal femur and lumbar spine were measured by dual-energy X-ray absorptiometry. We found a prevalence of 39.6% for the f allele of the VDRG. The frequencies of FF, Ff and ff genotypes were 35.6%, 49.5% and 14.9%, respectively. There was no statistically significant difference in BMD at any site or bone turnover markers among the three Fok1 genotypes (FF, Ff and ff). The SCP is independent of Bsm1, Apa1 or Taq1 polymorphisms of the VDRG at intron 8 and exon 9. In conclusion, the SCP polymorphism detected by endonuclease Fok1 does not significantly influence BMD or bone turnover in premenopausal women in Taiwan. Received: 7 July 1998 / Accepted: 10 November 1998     

Polymorphism of the Vitamin D Receptor Gene and Corticosteroid-Related Osteoporosis

Corticosteroid therapy (CST) is associated with reduced intestinal calcium absorption, bone loss and increased fracture risk. As polymorphisms of the vitamin D receptor (VDR) gene may be associated with bone mineral density (BMD) and intestinal calcium absorption, we asked whether patients with a given VDR genotype receiving CST may be at increased or decreased risk for corticosteroid-related bone loss and osteoporosis. We measured areal BMD (g/cm²) by dual-energy X-ray absorptiometry in 193 women (50 premenopausal, 143 postmenopausal) and 70 men with rheumatoid arthritis (n= 44), obstructive airway diseases (n= 128) and other corticosteroid-treated diseases (n= 91). All patients received a cumulative dose greater than 1.8 g per year or a minimum of 5 mg daily of prednisolone or equivalent for at least 1 year. VDR alleles were typed by polymerase chain reaction assay based on the polymorphic BsmI and TaqI restriction sites. BMD in patients was expressed as a Z-score (mean ± SEM) derived from age- and gender-matched controls. BMD was reduced in patients at the lumbar spine (bb, −0.52 ± 0.12; Bb, −0.47 ± 0.11; BB, −0.65 ± 0.18 SD; p<0.01), femoral neck (bb, −0.46 ± 0.10; Bb, −0.34 ± 0.10; BB, −0.54 ± 0.14 SD; p<0.01), Ward’s triangle (bb, −0.44 ± 0.10; Bb, −0.31 ± 0.10; BB, −0.45 ± 0.13 SD; p<0.01), and trochanter (bb, −0.50 ± 0.10; Bb, −0.30 ± 0.10; BB, −0.44 ± 0.14 SD; p<0.01). However, there was no significant difference in the deficit in BMD in any of the genotypes, either before or after adjusting for age, sex, body mass index, disease type, age at onset of disease, disease duration, cumulative steroid dosage, smoking status and dietary calcium intake. Similarly, there were no detectable differences between the BsmI genotypes and the rate of bone loss in 79 patients with repeated BMD measurements at an interval of 4–48 months. The data suggest that the VDR genotypes may not be a means of identifying patients at greater risk of corticosteroid-related bone loss. Received: 23 December 1997 / Accepted: 26 May 1998     

Vitamin D Receptor Gene Polymorphisms and Bone Mineral Density in Elderly Chinese Men and Women in Hong Kong

Although genetic factors have been strongly implicated in determining bone mineral density (BMD), the role of the vitamin D receptor (VDR) polymorphism remains controversial. An overall consensus is difficult, as the populations studied have been heterogeneous with respect to menopausal status and ethnicity. Moreover, some studies have examined only small populations, and relatively few studies have been conducted in Asian populations. There is mounting evidence that calcium homeostasis in Asian populations differs from that in Caucasians. This difference may be mediated, in part, through VDR effects. In a cross-sectional study we have examined the relationship between the VDR polymorphism and BMD in 272 women (mean age 75 years) and 237 men (mean age 73 years) of Chinese origin from Hong Kong. Consistent with other studies in Asian populations we found higher frequencies of the T, b and a alleles compared with those reported in Caucasian populations. Moreover, no significant difference in BMD was observed when subjects were grouped by a combination of the genotypes (bbAATT, bbAaTT, bbaaTT, BbAaTt, BbAATt). These results suggest that VDR polymorphism is not associated with BMD in elderly Hong Kong Chinese men and women. Received: 16 July 1998 / Accepted: 15 February 1999     

Vitamin D Receptor Start Codon Polymorphism (Fok I) and Bone Mineral Density in Chinese Men and Women

The relationship between Fok I polymorphism of the vitamin D receptor start codon, bone mineral density (BMD) and vertebral fractures was studied in 684 Chinese men and women. A significant trend was observed only in Chinese women aged 70–79 years. The mean BMD at the total body was 0.85 ± 0.01 g/cm², 0.82 ± 0.01 g/cm²and 0.84 ± 0.01 g/cm² for elderly women of the FF, Ff and ff genotypes respectively (p= 0.06 by ANOVA). Similar but statistically non-significant trends were observed at the hip and spine. However, no association between BMD and the Fok I genotype was observed in younger women (aged 50–59 years) and elderly men (aged 70–79 years). In all study groups, there was no effect of an interaction between Fok I polymorphism and calcium intake on BMD (p>0.05 for the interaction effects by two-way ANOVA). No significant association was observed between Fok I polymorphism and vertebral fracture in elderly men or women (p>0.05 by the chi-square test). We conclude that the Fok I polymorphism may have a weak effect on the BMD of elderly Chinese women. Received: 2 February 2001 / Accepted: 27 August 2001     

Vitamin D Receptor Gene Polymorphism: Correlation with Bone Mineral Density in a Brazilian Population with Insulin-Dependent Diabetes Mellitus

Patients with insulin-dependent diabetes mellitus (IDDM) are at higher risk of developing osteoporosis. Among the genetic factors related to the development of osteoporosis, a possible association between vitamin D receptor (VDR) gene polymorphism and bone mineral density (BMD) has been described in some populations. We characterized the VDR gene polymorphism in a healthy adult Brazilian population and in a group of patients with IDDM and correlated these findings with densitometric values in both groups. The Brazilian population is characterized by an important racial heterogeneity and therefore is considered an ethnically heterogeneous population. We recruited 94 healthy adult Brazilian volunteers (63 women and 31 men), mean (+ SD) age 32.4 + 6.5 years (range 18–49 years), and 78 patients with IDDM (33 women and 45 men) diagnosed before 18 years of age, mean (+ SD) age 23.3 + 5.5 years (range 18–39 years). VDR genotype was assessed by polymerase chain reaction amplification followed by BsmI digestion on DNA isolated from peripheral blood leukocytes. Statistical analysis included Bonferroni t-test to compare densitometric values within different genotypes in both groups and multiple regression analysis of bone density adjusted for potential confounding factors. The IDDM group had a lower BMD compared with the control group. The VDR genotype distribution in the control group was 43 Bb (45.7%), 39 bb (41.5%) and 12 BB (12.8%). This distribution did not differ from that observed in the IDDM group: 39 Bb (50%), 26 bb (33.3%) and 13 BB (16.7%). In the IDDM group, patients with the Bb genotype had a higher body weight when compared with the BB genotype (p= 0.02). However, when diabetic patients were controlled for age, sex and body mass index, BB genotype was associated with a lower mean BMD at lumbar spine and femoral neck than in Bb and bb patients. BB patients had a shorter duration of IDDM than bb and Bb patients. These findings suggest a small influence of VDR gene polymorphism on BMD of a racially heterogeneous population with IDDM. Received: 5 March 1997 / Accepted: 23 September 1997     

Correlation Between Vitamin D Receptor Genotypes and Bone Mineral Density in Japanese Patients with Osteoporosis

In order to better understand the pathogenesis of osteoporosis, we investigated the correlation between the vitamin D receptor (VDR) genotypes defined by BsmI restriction enzyme, as well as other related factors, and the bone mineral density (BMD) at the lumbar spine in 90 Japanese patients with osteoporosis. The same study was performed in 36 patients with osteoarthrosis of the hip joint and 92 healthy volunteers. The majority of the VDR genotypes were bb, and a few of the population showed either the BB or Bb genotype in all three groups. There was no statistical difference in the frequencies of these VDR genotypes in the three groups. The mean age-matched value of BMD (Z scores) at the lumbar spine in patients with osteoporosis was significantly lower than that in patients with osteoarthrosis or healthy volunteers. The mean Z scores of the healthy volunteers with bb genotype were significantly higher than those with BB genotype, whereas those of the osteoporosis patients with BB genotype were significantly higher than those with Bb genotype. There was no significant difference in the mean Z scores between bb and Bb genotypes in patients with osteoporosis and healthy volunteers. No significant difference was seen in the mean Z scores in patients with osteoarthrosis regardless of genotype. On the other hand, body weight significantly correlated with BMD in patients with osteoporosis by simple- and multiple-regression analysis. These results indicate that the BMD at the lumbar spine in Japanese patients with osteoporosis is affected by body weight, and might be affected partially by the VDR genotypes defined by BsmI. Received: 22 September 1995 / Accepted: 24 September 1996     

Non-association of Estrogen Receptor Genotypes with Bone Mineral Density and Bone Turnover in Korean Pre-, Peri-, and Postmenopausal Women

Estrogen is known to play a critical role in both skeletal maturity and the rate of bone loss. This suggests the possibility that the estrogen receptor (ER) gene is one of the candidate genes that determines peak bone density and/or bone turnover rate. We investigated two established restriction fragment length polymorphisms (RFLPs) in intron 1 at the ER gene, represented as PvuII and XbaI. In 598 healthy Korean women aged 20–74 years, we examined the association of these ER genotypes with bone mineral density (BMD) and bone turnover status. The distribution of the PvuII and XbaI RFLPs was as follows: pp 205 (34.3%), Pp 308 (51.5%), PP 85 (14.2%) and xx 384 (64.2%), Xx 180 (30.1%), XX 34 (5.7%), respectively (where capital letters signify the absence of, and lower-case letters signify the presence of, the restriction site of each RFLP). No significant genotypic differences were found in BMD and bone markers. We grouped the subjects into three categories according to their menstrual status: 104 premenopausal women with regular menstruation, 182 perimenopausal women who had amenorrhea of not less than 3 months and not more than 12 months’ duration, and 312 postmenopausal women whose last menstruation was at least 12 months previously. No significant genotypic difference in either BMD or bone markers was found in any of these three groups. Furthermore we categorized women in peri- and postmenopause into a high loser group and a normal loser group according to the level of bone resorption markers. There was no difference in genotypic proportions between the high and normal loser groups. Our data suggest that these ER polymorphisms are not associated with BMD or bone turnover in Korean women. Received: 16 March 1998 / Accepted: 17 August 1998     

Early and Late Postmenopausal Bone Loss is Associated with BsmI Vitamin D Receptor Gene Polymorphism in Japanese Women

To determine whether vitamin D receptor (VDR) gene polymorphisms are associated with bone mineral density (BMD) and bone loss in the Japanese population, VDR BsmI RFLPs were analyzed in 191 postmenopausal Japanese women by comparing B allele and b allele DNA sequences, and a point mutation was confirmed. We examined VDR BsmI restriction fragment length polymorphism (RFLP) with an amplification refractory mutation system (ARMS) using this point of mutation. The frequency of VDR BsmI alleles in the Japanese population was significantly different from that in whites. The bb genotype was identified in 79.6%, of the subjects, the Bb genotype in 19.3%, and the BB genotype was in only 1.1%. We find no significant differences in lumbar spine baseline BMD between the bb genotype and the Bb genotype. In both early and late postmenopausal periods, serial measurements of vertebral BMD revealed that subjects with the Bb genotype lost BMD faster than those with the bb genotype (P= 0.001). We conclude that there is a significant relationship between RFLPs of BsmI VDR and the annual rates of bone loss during early and late postmenopausal periods in the Japanese population. Received: 14 May 1997 / Accepted: 9 July 1998     

Vitamin D Receptor Gene Polymorphisms, Bone Mass, Bone Loss and Prevalence of Vertebral Fracture: Differences in Postmenopausal Women and Men

Bone mineral density (BMD), the major determinant of fracture risk, is under strong genetic control. Although polymorphisms of the vitamin D receptor (VDR) gene have been suggested to account for some of the genetic variation in bone mass, the influence of VDR genotypes on osteoporosis remains controversial. Previous published studies have focused mainly on women, but the pattern of response in men has not been determined. Using the BsmI restriction enzyme, we studied the influence of the different VDR genotypes on bone mass, bone loss and the prevalence of vertebral fractures in a population-based sample of both sexes (n = 326). BMD was measured at the lumbar spine and femoral neck, with a 4-year interval, using dual-energy X-ray absorptiometry. Vertebral fractures were assessed by two lateral radiographs at the beginning and end of the study. The prevalence of the three possible VDR genotypes was similar to those in other Caucasian populations and no differences were found between men and women. Women with the favorable bb genotype showed significantly higher BMD values at the lumbar spine and femoral neck, and a positive rate of BMD change at the femoral neck compared with women with the BB and Bb genotypes. Moreover, women with the bb genotype showed a trend toward a lower prevalence and incidence of vertebral fractures (p= 0.07). We have not found any differences between VDR genotypes in men. In conclusion, VDR gene polymorphisms are related to bone mass and bone loss in women; also a trend in the prevalence of vertebral fractures was observed in postmenopausal women but not in men. Received: 8 June 1998 / Accepted: 7 December 1998     

Vitamin D Receptor Translation Initiation Codon Polymorphism and Markers of Osteoporotic Risk in Older African-American Women

A polymorphism at the first of two potential translation initiation codons in the vitamin D receptor (VDR) gene defined by the FokI restriction endonuclease has been associated with reduced bone mineral density (BMD) among Caucasian, Asian, and Mexican-American women. We tested the hypothesis that the FokI polymorphism is related to markers of osteoporotic risk in 104 community-dwelling African-American women aged 65 years and older. Six percent of the African-American women had the ff genotype, 32% were heterozygous, and 63% had the FF genotype. FokI genotype frequencies did not differ from Hardy–Weinberg expectations. Hip and calcaneal BMD, calcaneal ultrasound attenuation and hip geometry from pelvic radiographs did not differ significantly by FokI genotypes or between women with and without the rare FokI allele. There was also no association between the FokI polymorphism and biochemical markers of bone turnover or fractional calcium absorption. We conclude that the VDR start codon polymorphism does not have a major influence on osteoporotic risk in older African-American women. Received: 20 November 1997 / Accepted: 29 June 1998     

The Association of Bone Mineral Density with Vitamin D Receptor Gene Polymorphisms

A recent meta-analysis of 16 publications suggested that bone mineral density (BMD) is not associated with vitamin D receptor (VDR) gene polymorphism (VDRGP) at the 0.05 significance level when a study with genotyping mistakes is excluded. We wished to determine whether ‘positive’ findings supporting the BMD–VDRGP association may be explained by chance, and what factors affect the outcomes of these studies. Seventy-five articles and abstracts on the association of VDRGP with BMD and related skeletal phenotypes published before January 1997 were identified. Twenty-three of 67 (34.3%) studies on spinal BMD and 22 of 51 (43.1%) on femoral neck BMD had found a BMD–VDRGP association at p<0.05, significantly (p= 7 × 10^–14 for spinal BMD, p= 9 × 10^–16 for hip BMD) higher than the expected 5% false positive rate under the null hypothesis of ‘no association’. ‘Positive’ results were more frequently observed in studies on females before the menopause than those on females after the menopause (p<0.02) or on male and female subjects combined (p<0.05) when skeletal phenotypes at any bone sites were considered. The ‘positive rate’ among studies was also influenced by the age range of subjects studied and by the inclusion of subjects with osteoporosis. It is concluded that: (1) BMD is associated with VDRGP with high levels of confidence and (2) non-genetic factors and genetic heterogeneity interfere with the detection of the effects of VDRGP on bone phenotypes. Received: 20 January 1998 / Accepted: 7 April 1998     

Low Vitamin D Levels in Outpatient Postmenopausal Women from a Rheumatology Clinic in Madrid, Spain: Their Relationship with Bone Mineral Density

To evaluate a possible relationship between vitamin D levels and bone mineral density (BMD) and the prevalence of hypovitaminosis in a population of postmenopausal women from a rheumatologic outpatient clinic in Madrid, Spain, 171 postmenopausal women (aged 47–66 years) divided into two groups (osteoporotic and nonosteoporotic, according to WHO criteria) were studied between November and June. Liver and kidney function were normal in all subjects. Serum parathyroid hormone (PTH) and calcidiol levels were determined and bone densitometry carried out at the lumbar spine and hip level. PTH and calcidiol serum levels did not show any correlation. Serum PTH was inversely related to BMD at both hip and lumbar spine in the total group, and at the hip with calcidiol levels lower than 37 nmol/l. Calcidiol was directly related to hip BMD only when levels were lower than 37 nmol/l. Results of a stepwise multiple regression analysis showed that the single factor which affected BMD at the hip was calcidiol in the subgroup with serum calcidiol levels below 37 nmol/l, while in the subgroup with serum calcidiol levels above 37 nmol/l, the main factor affecting hip BMD was serum PTH. The prevalence of vitamin D deficiency at a cutoff of 37 nmol/l was 64%. In summary, calcidiol serum levels below 37 nmol/l seem to affect bone mass, regardless of the effect of PTH. Vitamin D deficiency is a frequent finding in the postmenopausal women who attend a rheumatology outpatient clinic in Madrid. Vitamin D supplementation should therefore be considered in this population during the winter season. Received: 2 July 1999 / Accepted: 3 March 2000     

Vitamin D and Estrogen Receptor Polymorphisms and Bone Mineral Changes in Postpartum Women

BsmI restriction fragment length polymorphism (RFLP) of the vitamin D receptor (VDR) gene and PvuII RFLPs of the estrogen receptor (ER) gene and their relation to changes in areal bone mineral density (BMD) were examined in 43 healthy postpartum Finnish women aged 31.3 (SD 4.7) years. BMD was measured by dual energy X-ray absorptiometry at lumbar spine, right femoral neck, and dominant distal radius immediately after delivery, 1 month after resumption of menses, and 1 year thereafter. The RFLPs were represented as Bb (BsmI) and Pp (PvuII), the capital letters denoting the absence of and the small letters the presence of the restriction sites. The frequency of VDR alleles was as follows: bb (20.9%), Bb (60.5%), and BB (18.6%), and that of ER alleles was pp (39.5%), Pp (51.2%), and PP (9.3%). Altogether, BMD decreased significantly during postpartum amenorrhea at all sites [the mean bone loss ranging from −1.2 (SD 3.6)% at the distal radius to −3.7 (2.9)% at the femoral neck], and increased after resumption of menses [the 1-year follow-up BMD values ranging from −1.0 (2.4)% at the femoral neck to +3.3 (4.0)% at the lumbar spine as compared with baseline]. No obvious genotype-related differences were found between these changes. These results suggest that the BsmI and PvuII polymorphisms may not have substantial influence on BMD changes postpartum. Received: 20 November 1998 / Accepted: 30 September 1999     

The Association between Parathyroid Hormone, Vitamin D and Bone Mineral Density in 70-Year-Old Icelandic Women

Parathyroid hormone (PTH) may be an important determinant of cortical bone remodeling in the elderly. Vitamin D status is one of the determining factors in this relationship. The aim of this study was to quantify the relationship between serum PTH, vitamin D and bone mineral density (BMD) in elderly women in Reykjavik (64° N), where daily intake of cod liver oil is common and mean calcium intake is high. ln PTH correlated inversely with 25(OH)D (r=−0.26, p<0.01). In multivariate analysis PTH correlated inversely with whole body BMD (mostly cortical bone) (R ²= 2.2%, p = 0.04) but not with the lumbar spine BMD, reflecting more cancellous bone. No association was found between 25(OH)D levels and BMD at any site in univariate or multivariate analysis. Osteocalcin, a measure of bone turnover, was negatively associated with BMD and this association remained significant when corrected for PTH levels. In summary, in this fairly vitamin D replete population with high calcium intake, PTH was negatively associated with total body BMD. We infer that suppression of PTH may reduce cortical bone loss, but other factors are likely to contribute to age-related bone remodeling and osteoporosis. Received: 3 January 2000 / Accepted: 10 April 2000     

Association Study of Parathyroid Hormone Gene Polymorphism and Bone Mineral Density in Japanese Postmenopausal Women

Association of BST B1 restriction fragment length polymorphism (RFLP) of the parathyroid hormone (PTH) gene with bone mineral density (BMD) was examined in 383 healthy postmenopausal women in Japan who were unrelated. The RFLP was represented as B or b, the capital letter signifying the presence of and the small letter the absence of restriction site for BST B1. The frequency of each genotype—BB, Bb, and bb—was 82.5%, 16.7%, and 0.8%, respectively. When we statistically compared age, years after menopause, body height, and body weight between the BB genotype and the Bb genotype groups, there was no significant difference between the groups. However, the lumbar BMD and the score of BMD adjusted for age and body weight (Z score) were significantly lower in the group of genotype Bb than in the BB: 0.859 ± 0.019 g/cm² versus 0.925 ± 0.011 (mean ± SE, P= 0.01) and −0.412 ± 0.138 versus 0.067 ± 0.082 (mean ± SE, P= 0.01). In addition, the Z score of total body BMD in the Bb genotype group was lower than that in the BB group. Comparison of serum and urinary biochemical bone metabolic markers suggested that the subjects with Bb genotype might be in a relatively higher state of bone turnover than those with BB genotype. These results suggest that the polymorphism in the PTH gene would be a useful genetic marker for lower BMD and the susceptibility for osteoporosis. Received: 19 March 1998 / Accepted: 24 June 1998     

Vitamin D and Bone Mineral Density in Ambulatory Women Living in Buenos Aires, Argentina

The aim of this study was to determine possible associations between bone mineral density (BMD), 25-hydroxyvitamin D (25(OH)D) and intact parathyroid hormone (PTH). In a retrospective study we examined the case notes of free-living postmenopausal women living in our city (34° S). We also report a low prevalence of vitamin D deficiency (25(OH)D <25 nmol/l, 5.6%) and of secondary hyperparathyroidism (intact PTH >65 pg/ml, 7.5%). Age was correlated with BMD at the lumbar spine (r=−0.25, p = 0.00038) and femoral neck (r=−0.252, p = 0.0003). Body mass index (BMI) was correlated with BMD at the femoral neck (r= 0.177, p = 0.021) but not at the lumbar spine. 25(OH)D was positively correlated with BMD at the femoral neck (r = 0.149, p=0.036) but not at the lumbar spine. PTH was positively correlated with age (r= 0.279, p = 0.012) and negatively correlated with 25(OH)D (r=−0.322, p = 0.0036). PTH was also negatively correlated with BMD at the lumbar spine (r=−0.258, p=0.02) and the femoral neck (r=−0.282, p = 0.011). Forward stepwise multiple regression showed that BMI, age and 25(OH)D made significant contributions to BMD at the femoral neck. PTH also showed a significant contribution to BMD at both sites. In conclusion, weak correlations found between PTH and 25(OH)D and BMD suggest these biochemical variables, among other factors, contribute to lumbar spine and femoral neck BMD. Received: 19 February 2000 / Accepted: 20 June 2000     

Comparison of Bone and Total Alkaline Phosphatase and Bone Mineral Density in Postmenopausal Osteoporotic Women Treated with Alendronate

Alendronate therapy in osteoporotic women decreases bone turnover and increases bone mineral density (BMD). Optimal patient management should include verification that each patient is responding to therapy. Markers of bone turnover and BMD have both been proposed for this purpose. We have investigated changes resulting from alendronate therapy with an enzyme immunoassay for bone alkaline phosphatase (BAP) and compared it with total alkaline phosphatase (TAP) and BMD of the lumbar spine, hip, and total body. Subjects were drawn from a multicenter randomized, placebo-controlled trial of alendronate in postmenopausal women with osteoporosis. BAP and TAP levels were measured at baseline and following 3, 6 and 12 months of therapy with either placebo (n= 180) or alendronate 10 mg/day (n= 134). All subjects also received 500 mg/day supplemental calcium. BMD was measured at baseline and following 3, 6, 12, 18, 24 and 36 months of therapy. To compare BAP, TAP and BMD at each site for identifying women that experienced a skeletal effect of alendronate, we calculated least significant change (LSC) values from the long-term intraindividual variability in each placebo-treated woman. Median levels of BAP decreased by 34%, 44% and 43% at 3, 6 and 12 months, respectively, in alendronate-treated women (p<0.0001 compared with baseline and with placebo). These changes were significantly greater (p<0.0001) than changes observed for TAP. Following 6 months of alendronate therapy, 90% of the women had experienced a decrease in BAP exceeding the LSC compared with only 71% for TAP. The greatest number of women similarly identified with BMD at any site (i.e. a gain in BMD exceeding the LSC) was 81% for spinal BMD at 36 months. All other sites were less than 70% at 36 months. Short-term changes in BAP and TAP were modestly associated with subsequent changes in BMD at all sites (Spearman’s rho −0.22 to −0.52, p<0.05). Compared with TAP and BMD, BAP testing rapidly and sensitively identified skeletal effects of alendronate thus enabling appropriate drug monitoring of osteoporotic women. Though BAP and TAP changes were modestly predictive of BMD changes, the value of the bone marker tests is their ability to detect rapidly a skeletal effect of therapy. Received: 19 May 2000 / Accepted: 31 October 2000     

Occupational Activity and Bone Mineral Density in Postmenopausal Women in England

Few studies have assessed the relationship between occupational activity and bone mineral density (BMD), although two case–control studies have reported a protective effect of occupational activity on hip fracture. In the present study 580 postmenopausal women aged 45–61 years completed a risk factor questionnaire including a detailed occupational history. For each job, hours spent sitting, standing, walking, lifting and carrying were recorded; these measures, evaluated at ages 20, 30, 40 years, in the current job and over the working lifetime, were used in the analysis. BMD was measured with dual-energy X-ray absorptiometry, and measurements at five sites were used in a multiple regression analysis adjusting for potential confounding variables. There was a significant negative association between sitting at age 20 years and BMD at the radius (p= 0.037), with negative relationships of borderline significance at the anteroposterior spine (p = 0.091) and whole body (p= 0.078). There were significant positive associations between standing at age 30 years and BMD at all five sites (p<0.05), but no significant linear associations for standing at ages 20 and 40 years. No significant associations were found for lifetime or current occupational measures of sitting, standing, walking and lifting or carrying. The lack of consistency of these significant findings suggests that they may have occurred by chance, and that occupational activity has little if any effect on BMD in postmenopausal women. Received: 12 March 1999 / Accepted: 17 September 1999     

Age-Related Bone Mineral Density, Accumulated Bone Loss Rate and Prevalence of Osteoporosis at Multiple Skeletal Sites in Chinese Women

We investigated the age-related bone mineral density (BMD), accumulated bone loss rate (ABLR) and the prevalence of osteoporosis at different skeletal sites in Chinese women. BMD was measured at the anteroposterior (AP) spine, supine lateral spine (areal BMD at the midarea [mLat] and the whole region [Lat], volumetric BMD at the middle region [MVD] and total region [TVD]), hip (femoral neck [FN], trochanter [Troc] and Ward’s triangle [Ward’s]) and forearm (radius + ulna ultradistal [RUUD], 1/3 region [RU1/3] and total region [RUT]) using a dual-energy X-ray absorptiometry (DXA) fan-beam bone densitometer (Hologic QDR 4500A) in 2702 females aged from 5 to 96 years old. Data were analyzed by eight different regression models. We found that the cubic regression model was the best for describing age-related changes in BMD. The coefficients of determination (R ²) of the fitting curve were 0.398 to 0.612 (p= 0.000). The data were then analyzed by 5-year age groups. This showed that the earliest peak BMD was at the age of 20–24 years at Troc and Ward’s, and the latest at the age of 40–44 years at RU1/3 and RUT of the distal forearm. Compared with BMD, the ABLRs were highest at Ward’s (−66.2%) and the lowest at RU1/3 of the distal forearm (−31.3%) in subjects over 80 years old. The prevalence of osteoporosis at at least one site in these women was 0.5 ± 0.4% in those 30–39, 4.6 ± 4.4% in those 40–49, 23.9 ± 13.3% in those 50–59, 56.3 ± 20.3% in those 60–69, 71.8 ± 16.7% in those 70–79 and 83.2 ± 12.1% those over 80 years of age, respectively. The prevalence of osteoporosis in these women was 8.6–11.1% at the age of 40–49 and 36.5–40.6% at the age of 50–59 at the lateral spine regions (mLat, Lat, MVD and TVD), and 0.5–3.7% at the age of 40–49 and and 3.9–21.7% at the age of 50–59 years at the other skeletal sites (AP, FN, Troc, Ward’s, RUUD, RU1/3 and RUT). Significant differences were found in the prevalence of osteoporosis between the lateral spine regions and other skeletal sites (p<0.001) at the age of 40–59 years. In summary, we demonstrated significant age-related differences in peak BMD, ABLR and osteoporosis prevalence among various skeletal sites. Our data suggest that the supine lateral spine is the most sensitive site for the diagnosis of osteoporosis, especially in the early menopausal period, although the prevalence of osteoporosis varied with age and with different sites measured. Received: 20 November 2001 / Accepted: 13 February 2002