No effect of vitamin A intake on bone mineral density and fracture risk in perimenopausal women.

In recent studies from Sweden and the United States, a high vitamin A intake has been associated with low bone mineral density (BMD) and increased fracture risk. In Sweden and the United States, food items such as milk and breakfast cereals are fortified with vitamin A, whereas in Denmark there is no mandatory fortification with vitamin A. In the present study, we investigated relations between vitamin A intake and BMD and fracture risk in a Danish population consuming mostly unfortified food items. Within a population-based cohort study in 2,016 perimenopausal women, associations between BMD and vitamin A intake were assessed at baseline and after 5-year follow-up. Moreover, associations between baseline vitamin A intake and 5-year changes in BMD were studied. Finally, fracture risk was assessed in relation to vitamin A intake. In our cohort, dietary retinol intake (0.53 mg/day) was lower than the intake reported in recent studies form Sweden (0.78 mg/day) and the United States (1.66 mg/day). Cross-sectional and longitudinal analyses showed no associations between intake of vitamin A and BMD of the femoral neck or lumbar spine. Neither did BMD differ between those 5% who had the highest, and those 5% who had the lowest, vitamin A intake. During the 5-year study period, 163 subjects sustained a fracture (cases). Compared to 978 controls, logistic regression analyses revealed no difference in vitamin A intake. Thus, in a Danish population, average vitamin A intake is lower than in Sweden and the United States and not associated with detrimental effects on bone.     

Dietary Intake of Folate,but not Vitamin B<Subscript>2</Subscript> or B<Subscript>12</Subscript>, Is Associated with Increased Bone Mineral Density 5 Years after the Menopause: Results from a 10-Year Follow-Up Study in Early Postmenopausal Women

Folate, vitamin B₂ (riboflavin), and vitamin B₁₂ may affect bone directly or through an effect on plasma homocysteine levels. Previously, a positive association has been found between plasma levels and bone mineral density (BMD) as well as risk of fracture. However, there are limited data on whether dietary intakes affect bone. Our aim was to investigate whether intake of folate, vitamin B_2, and vitamin B₁₂, as assessed by food records affects BMD and fracture risk. In a population-based cohort including 1,869 perimenopausal women from the Danish Osteoporosis Prevention Study, associations between intakes and BMD were assessed at baseline and after 5 years of follow-up. Moreover, associations between intakes and 5- and 10-year changes in BMD as well as risk of fracture were studied. Intakes of folate, vitamin B₂, and vitamin B₁₂ were 417 (range 290–494) μg/day, 2.70 (range 1.70–3.16) mg/day, and 4.98 (range 3.83–6.62) μg/day, respectively, i.e., slightly above the intakes recommended by the United Nations Food and Agriculture Organization. At year 5, but not at baseline, cross-sectional analyses showed positive correlations between daily intake from diet and from diet plus supplements of folate and BMD at the femoral neck (P < 0.01). However, no associations were found between intakes and changes in BMD. During 10 years of follow-up, 360 subjects sustained a fracture. Compared with 1,440 controls, logistic regression analyses revealed no difference in intakes between cases and controls. A high dietary intake of folate, but not vitamin B₂ or B₁₂, exerts positive effects on BMD; but further studies are needed to confirm this association.     

Fracture Risk in Perimenopausal Women Treated with Beta-Blockers

β2-adrenergic receptors have been identified on human osteoblastic and osteoclastic cells, raising the question of a sympathetic regulation of bone metabolism. We investigated effects of treatment with β-adrenergic receptor antagonists (β-blockers) on bone turnover, bone mineral density (BMD), and fracture risk. Within the Danish Osteoporosis Prevention Study (DOPS) a population based, comprehensive cohort study of 2016 perimenopausal women, associations between treatment with β-blockers and bone turnover and BMD were assessed in a cross-sectional design at the start of study. Moreover, in a nested case-control design, fracture risk during the subsequent 5 years was assessed in relation to treatment with β-blockers at baseline. Multiple regression- and logistic regression-analyses were performed. Treatment with β-blockers was associated with a threefold increased fracture risk (OR_adj 3.3; 95% CI: 1.1–9.4). Analyses on duration of treatment showed that women who had been treated for more than 8 years had a higher fracture risk (OR_adj 5.3; 95% CI: 1.1–26.3) than those treated for less than 8 years (OR_adj 2.4; 95% CI: 0.6–9.5). In addition, cross-sectional data showed 20% lower serum osteocalcin levels (an osteoblastic marker of bone formation) in women treated with β-blockers compared to untreated women (P < 0.001), whereas BMD at the lumbar spine and femoral neck did not differ between groups. β-blockers may decrease the activity of bone-forming cells and thereby increase fracture risk. However, confirmative studies and studies exploring mechanisms of action are needed.     

Dietary vitamins K1, K2 and bone mineral density: the Hordaland Health Study

Summary

Associations between bone mineral density (BMD) and dietary vitamins K1 and K2 in 4,461 individuals were studied. For women, odds ratio of low BMD was 1.48 in lowest to highest quartile of K1. A weak positive association was found for K2. Our results do not support dietary vitamins K as being major determinants of BMD.

Purpose

Some studies suggest a positive association between intake of vitamin K1 (phylloquinone) or vitamin K2 (menaquinone) and BMD. The objective was to examine associations between BMD and dietary vitamins K1 and K2.

Methods

BMD of the total hip was measured in 2,575 women and 1,886 men, 47-50 and 71-75 years, in the community-based Hordaland Health Study. Dietary vitamins K1 and K2 were assessed by a food frequency questionnaire. Low BMD was defined as the lowest BMD-quintile for each age-sex group. Multiple linear, logistic and fractional polynomial regression analyses were applied.

Results

No significant associations between vitamin K1 or K2 intake and BMD were found in linear regression analyses. Comparing women in the highest to lowest quartile of vitamin K1 intake, an odds ratio of 1.48 (95% confidence interval (CI): 1.08, 2.04) for low BMD was found. This was not found among men or for vitamin K2 intake in either gender. A weak, positive association between log (vitamin K2) intake and BMD was found by fractional polynomial regression analyses in women (beta coefficient: 0.018; 95% CI: 0.009, 0.027; p?=?0.001), but not in men.

Conclusions

Although we observed an increased risk of low BMD with low intake of vitamin K1 and a weak positive association between BMD and vitamin K2 intake among women, this study does not support dietary intake of vitamins K1 or K2 as major determinants of BMD. Future studies should investigate possible associations between intake of vitamin K1, K2 and fracture risk.     

Methylenetetrahydrofolate reductase polymorphism interacts with riboflavin intake to influence bone mineral density

Bone mineral density is a complex trait regulated by an interaction between genetic and environmental factors. Recent studies have identified a functional polymorphism affecting codon 677 of the methylenetetrahydrofolate reductase (MTHFR) gene that is associated with reduced bone mineral density (BMD) in Japanese and Danish postmenopausal women and increased risk of fracture in elderly Danish women. Since dietary B vitamins can influence circulating homocysteine (tHcy) levels, we examined the relationship among MTHFR genotype, B complex vitamins (folate, vitamin B12, vitamin B6 and riboflavin), BMD, and rate of change in BMD in a longitudinal study of 1241 Scottish women aged 45-54 years, at the time of initial study, who were followed up for a mean (SD) of 6.6 (0.7) years. There was no significant association between BMD and either MTHFR genotype or B complex vitamins when examined separately. However, we detected a significant interaction among quartile of energy-adjusted riboflavin intake, MTHFR 'TT' genotype, and BMD (P = 0.01 for baseline FN BMD, P = 0.02 for follow-up FN BMD). Increasing dietary riboflavin intake correlated with LS BMD and FN BMD in homozygotes for the MTHFR 'T' allele, which remained significant for FN after adjustment for confounders (r = 0.192, P = 0.036 for baseline; r = 0.186, P = 0.043 at follow-up) but not in the other genotypes. This raises the possibility that riboflavin intake and MTHFR genotype might interact to regulate BMD. Further work is required to determine if this association holds true for other populations and ethnic groups.     

Response of serum carboxylated and undercarboxylated osteocalcin to alendronate monotherapy and combined therapy with vitamin K<Subscript>2</Subscript> in postmenopausal women

Alendronate decreases the risk of femoral neck fracture by suppressing bone turnover, and also decreases the serum total osteocalcin level. A low serum carboxylated osteocalcin level or high undercarboxylated osteocalcin level could be risk factors for femoral neck fracture. Vitamin K mediates the carboxylation of osteocalcin, but the effect of alendronate therapy with or without vitamin K₂ supplementation remains unknown. Forty-eight postmenopausal women were enrolled in a 1-year prospective randomized trial and assigned to alendronate monotherapy (5 mg/day) (group A, n = 26) or vitamin K₂ (45 mg/day) plus alendronate (5 mg/day) (group AK, n = 22). Bone mineral density was measured by dual-energy X-ray absorptiometry at 0 and 12 months; bone turnover parameters were measured at 0, 3, and 12 months. Four patients discontinued alendronate therapy, and we analyzed the remaining 44 patients (23 in group A and 21 in group AK) who completed 1 year of treatment. Alendronate decreased undercarboxylated osteocalcin; carboxylated osteocalcin was not affected. Addition of vitamin K₂ enhanced the decrease of undercarboxylated osteocalcin levels and led to a greater increase of femoral neck bone mineral density. Alendronate monotherapy does not decrease carboxylation of osteocalcin, and combination of vitamin K₂ and alendronate brings further benefits on both osteocalcin carboxylation and BMD of femoral neck in postmenopausal women with osteoporosis.     

Risk Factors for Perimenopausal Fractures: A Prospective Study

This prospective study was aimed at determining the risk factors for the development of fractures in perimenopausal women. The study group (n= 3068) was comprised of a stratified population sample of women aged between 47 and 56 years. During the follow-up period of 3.6 years, 257 (8.4%) of the women sustained a total of 295 fractures. After adjustment for covariates, the relative risk (RR) of sustaining a fracture was found to be 1.4 [95% confidence interval (CI) 1.2–1.6] for a 1 standard deviation (SD) decrease in the spinal and femoral neck bone mineral density (BMD). Women with a previous fracture history were found to have an increased risk of fracture [RR 1.7 (95% CI 1.3–2.2)] and those reporting three or more chronic illnesses exhibited a RR of 1.4 (95% CI 1.0–1.9). Women not using hormone replacement therapy (HRT) had a RR of 1.5 (95% CI 1.1–2.2) for all fracture types. When osteoporotic fractures (vertebral, hip, proximal humerus and wrist fractures; n= 98) were used as an endpoint, the independent risk factors were found to be a low BMD (RR for a 1 SD decrease in both spinal and femoral neck BMD was 1.6, 95% CI 1.3–2.0), a previous fracture history (RR 1.9, 95% CI 1.3–2.9) and nonuse of HRT (RR 2.2, 95% CI 1.3–4.0). The independent risk factors for all other fractures (n = 158) were a low BMD (RR for a 1 SD decrease in the spinal BMD was 1.4, 95% CI 1.2–1.6 and in the femoral neck BMD was 1.3, 95% CI 1.1–1.5), a previous fracture history (RR 1.6, 95% CI 1.1–2.2), smoking (RR 1.8, 95% CI 1.1–2.7) and having had three or more chronic illnesses (RR 1.6, 95% CI 1.1–2.2). Weight, height, age, menopausal status, maternal hip fracture, use of alcohol, coffee consumption or dietary calcium intake were not independently associated with the development of any particular type of fracture. We conclude that the independent risk factors for perimenopausal fractures are a low bone density, previous fracture history, nonuse of HRT, having had three or more chronic illnesses and smoking, the gradient of risk being similar for spinal and femoral neck BMD measurements in the perimenopausal population. The risk factors are slightly different for perimenopausal osteoporotic than for other types of fractures. Received: 6 April 1999 / Accepted: 18 August 1999     

Associations of 25‐Hydroxyvitamin D and 1,25‐Dihydroxyvitamin D With Bone Mineral Density,Bone Mineral Density Change,and Incident Nonvertebral Fracture

Relationships between 1,25‐dihydroxyvitamin D (1,25(OH)₂D) and skeletal outcomes are uncertain. We examined the associations of 1,25(OH)₂D with bone mineral density (BMD), BMD change, and incident non‐vertebral fractures in a cohort of older men and compared them with those of 25‐hydroxyvitamin D (25OHD). The study population included 1000 men (aged 74.6 ± 6.2 years) in the Osteoporotic Fractures in Men (MrOS) study, of which 537 men had longitudinal dual‐energy X‐ray absorptiometry (DXA) data (4.5 years of follow‐up). A case‐cohort design and Cox proportional hazards models were used to test the association between vitamin D metabolite levels and incident nonvertebral and hip fractures. Linear regression models were used to estimate the association between vitamin D measures and baseline BMD and BMD change. Interactions between 25OHD and 1,25(OH)₂D were tested for each outcome. Over an average follow‐up of 5.1 years, 432 men experienced incident nonvertebral fractures, including 81 hip fractures. Higher 25OHD was associated with higher baseline BMD, slower BMD loss, and lower hip fracture risk. Conversely, men with higher 1,25(OH)₂D had lower baseline BMD. 1,25(OH)₂D was not associated with BMD loss or nonvertebral fracture. Compared with higher levels of calcitriol, the risk of hip fracture was higher in men with the lowest 1,25(OH)₂D levels (8.70 to 51.60 pg/mL) after adjustment for baseline hip BMD (hazard ratio [HR] = 1.99, 95% confidence interval [CI] 1.19–3.33). Adjustment of 1,25(OH)₂D data for 25OHD (and vice versa) had little effect on the associations observed but did attenuate the hip fracture association of both vitamin D metabolites. In older men, higher 1,25(OH)₂D was associated with lower baseline BMD but was not related to the rate of bone loss or nonvertebral fracture risk. However, with BMD adjustment, a protective association for hip fracture was found with higher 1,25(OH)₂D. The associations of 25OHD with skeletal outcomes were generally stronger than those for 1,25(OH)₂D. These results do not support the hypothesis that measures of 1,25(OH)₂D improve the ability to predict adverse skeletal outcomes when 25OHD measures are available. © 2015 American Society for Bone and Mineral Research.     

围绝经期妇女骨折风险与内脏脂肪量的相关性研究

目的应用骨折风险评估工具(FRAX)计算围绝经期妇女(40~50岁)骨质疏松性骨折风险,探讨围绝经期妇女骨折风险与内脏脂肪量的内在联系。方法分析2017年3月至2018年3月334例围绝经期妇女的问卷资料(年龄、体重、烟酒史、既往骨折史、激素应用情况等),通过双能X线扫描获得定量指标骨密度值及内脏脂肪量,采用FRAX软件计算骨折风险,并与内脏脂肪量进行相关性分析。结果围绝经期妇女随年龄增加,骨密度值逐渐减少,骨折风险逐渐增高;内脏脂肪量与骨密度呈负相关(r=-0.35,P<0.05);内脏脂肪量与骨折风险呈正相关(r=0.58,P<0.05)。结论FRAX能精准反映围绝经期妇女骨折风险,有助临床提前干预;内脏脂肪是导致骨质疏松性骨折的致病因子之一。     

Vitamin K1 Supplementation Retards Bone Loss in Postmenopausal Women Between 50 and 60 Years of Age

Although several observational studies have demonstrated an association between vitamin K status and bone mineral density (BMD) in postmenopausal women, no placebo-controlled intervention trials of the effect of vitamin K₁ supplementation on bone loss have been reported thus far. In the trial presented here we have investigated the potential complementary effect of vitamin K₁ (1 mg/day) and a mineral + vitamin D supplement (8 µg/day) on postmenopausal bone loss. The design of our study was a randomized, double-blind, placebo-controlled intervention study; 181 healthy postmenopausal women between 50 and 60 years old were recruited, 155 of whom completed the study. During the 3-year treatment period, participants received a daily supplement containing either placebo, or calcium, magnesium, zinc, and vitamin D (MD group), or the same formulation with additional vitamin K₁ (MDK group). The main outcome was the change in BMD of the femoral neck and lumbar spine after 3 years, as measured by DXA. The group receiving the supplement containing additional vitamin K₁ showed reduced bone loss of the femoral neck: after 3 years the difference between the MDK and the placebo group was 1.7% (95% Cl: 0.35–3.44) and that between the MDK and MD group was 1.3% (95% Cl: 0.10–3.41). No significant differences were observed among the three groups with respect to change of BMD at the site of the lumbar spine. If co-administered with minerals and vitamin D, vitamin K₁ may substantially contribute to reducing postmenopausal bone loss at the site of the femoral neck.     

Effect of vitamin D receptor and estrogen receptor gene polymorphism on the relationship between dietary calcium and bone mineral density in Japanese women

In a longitudinal analysis of the results of bone mineral density (BMD) screenings conducted in local communities, we examined the effect of lifestyle improvements on BMD and investigated the influence of allelic variations of the vitamin D receptor (VDR) and estrogen receptor (ER) genes. The subjects were 484 women (age, 24–80 years) who underwent BMD screenings at least twice between 1994 and 2002. We conducted BMD measurements of the lumbar spine by dual-energy X-ray absorptiometry and performed a simple questionnaire survey of lifestyle factors. Women receiving pharmacotherapy, or those with bone fractures, were excluded, leaving 338 women eligible for the study. They were retrospectively divided into three groups: (i) premenopause, women who were at least 5 years preceding menopause; (ii) perimenopause, women who were within 5 years before or after menopause; and (iii) postmenopause, women who were at least 5 years past menopause. There was no correlation at all between improvements of lifestyle factors (i.e., calcium intake from dairy products and time spent walking) and fluctuations in lumbar-spine BMD after 1, 3, or 5 years in the pre-, peri-, and postmenopausal groups. For women in the postmenopausal group, the PP genotype for the ER gene correlated with a significantly higher initial BMD than those with the Pp and pp genotypes (P = 0.04). After 3 years, presence of the TT genotype of Taq I of VDR gene polymorphism exhibited positive correlations (r = 0.29, P = 0.03) with the improvements in calcium intake and in lumbar spine BMD for the perimenopausal group, whereas the Tt genotype showed negative correlations (r = –0.48, P = 0.04). After 1, 3, and 5 years, presence of the Tt genotype showed a tendency toward a negative correlation with the increases in calcium intake and in lumbar spine BMD for the pre- and perimenopausal groups, although almost of these were not significantly different. In this study, we could not prove a positive correlation between the improvement of lifestyle and the fluctuation of BMD within a 5-year timeframe, although the polymorphisms within the VDR gene may have some influence.     

The -1997 G/T and Sp1 Polymorphisms in the Collagen Type I alpha1 (<Emphasis Type="Italic">COLIA1</Emphasis>) Gene in Relation to Changes in Femoral Neck Bone Mineral Density and the Risk of Fracture in the Elderly: The Rotterdam Study

The COLIA1 Sp1 polymorphism has been associated with bone mineral density (BMD) and fracture. A promoter polymorphism, -1997 G/T, also has been associated with BMD. In this study, we examined whether these polymorphisms alone and in the form of haplotypes influence bone parameters and fracture risk in a large population-based cohort of elderly Caucasians. We determined the COLIA1 -1997 G/T (promoter) and Sp1 G/T (intron) polymorphisms in 6,280 individuals and inferred haplotypes. Femoral neck BMD and BMD change were compared across COLIA1 genotypes at baseline and follow-up (mean 6.5 years). We also investigated the relationship between the COLIA1 polymorphisms and incident nonvertebral fractures, which were recorded during a mean follow-up period of 7.4 years. Vertebral fractures were assessed by radiographs on 3,456 genotyped individuals. Femoral neck BMD measured at baseline was 3.8% lower in women carrying two copies of the T-Sp1 allele (P for trend = 0.03). No genotype dependent differences in BMD loss were observed. In women homozygous for the T allele of the Sp1 polymorphism, the risk of fragility fracture increased 2.3 times (95% confidence interval 1.4–3.9, P = 0.001). No such association was observed with the promoter polymorphism. In men, no association with either the Sp1 or the -1997 G/T promoter polymorphism was seen with BMD or fracture. High linkage disequilibrium (LD; D′ = 0.99, r ² = 0.03) exists between the two studied polymorphisms. We observed three haplotypes in our population: haplotype 1 (G_promoter–G_intron) frequency (f) = 69%, haplotype 2 (G_promoter–T_intron) f = 17.6%, and haplotype 3 (T_promoter–G_intron) f = 13.4%. Haplotype 2 was associated with a 2.1-fold increased risk of fragility fracture in women (95% confidence interval 1.2–3.7, P = 0.001). We confirm that the COLIA1 Sp1 polymorphism influences BMD and the risk of fracture in postmenopausal Caucasian women. In contrast, we found no independent effect of the -1997 G/T promoter polymorphism on BMD or fracture.     

Sister’s fracture history may be associated with perimenopausal bone fragility and modifies the predictability of fracture risk

Summary  The present study investigated the effects of first degree relatives’ fractures on fracture incidence after the menopause. Sister’s, but not other relatives’, wrist or hip fracture history was associated with increased risk of fragility fractures after the menopause. This suggests genetic predisposition to bone fragility among postmenopausal women. Objective  The aim of the present study was to investigate the association between first degree relatives’ fractures and perimenopausal bone fragility. Materials and methods  The study sample of 971 perimenopausal women was extracted from randomly selected Kuopio Osteoporosis Risk Factor and Prevention cohort and measured with dual X-ray absorptiometry in femoral neck (FN) in baseline (1989–1991), in 5 years (1994–97), and in 10 years (1999–2001). All low-trauma energy fractures during the 10-year follow-up were recorded based on self-reports and validated from medical records. First degree relatives’ history of life-time hip and wrist fractures (exact classification or trauma energy not specified) was questioned by postal inquiries. Results  There was a significant correlation between fathers’ vs. brothers’ and mothers’ vs. sisters’ fractures (p < 0.01 in Pearson bivariate correlations). Sister’s, but not mother’s, father’s, or brother’s wrist and hip fractures were associated with significantly lowered 10-year fragility fracture-free survival rate (HR = 0.56, p = 0.006). Sisters’ or other relatives’ fractures were not associated with FN bone loss rate or bone mineral density (BMD) in the follow-up measurements (p = NS in ANCOVA). The predictive power of BMD for fragility fractures differed according to sisters’ fracture history: Baseline FN T score predicted fracture-free survival only among women without sisters’ fracture history (HR 0.62, p < 0.001 vs. women with sisters’ fracture in Cox regression). Conclusions  In conclusion, sisters’ fracture history is associated with 10-year fracture-free survival in perimenopausal women but not with BMD or its changes. Predictability of fragility fracture risk with BMD may depend on sister’s fracture history. This may indirectly suggest genetic predisposition to bone fragility independently of BMD.     

Role of chronic health disorders in perimenopausal fractures

Only a few studies have examined the risk of individual chronic health disorders on perimenopausal (i.e., around menopause) fractures in a single study. We evaluated the effect of chronic illnesses on fracture rate in a prospective cohort study of 3,078 women. These women were a stratified sample from the population base of 14,220 women aged 47–56 years and residing in the province of Kuopio in eastern Finland in 1989. Data on physician-diagnosed chronic diseases were collected by a baseline questionnaire in 1989. For certain diseases, questionnaire information of self-reported chronic disorders were compared with drug reimbursement data provided by the Social Insurance Institution of Finland. Axial bone mineral density (BMD) measurements from the femoral neck and lumbar spine were performed in 1989–91. Two hundred sixty-five (265) women experienced at least one fracture during the follow-up period of 3.6 years (SD±0.78). The first fracture during the follow-up period was taken to be the end-point event. The risk of follow-up fracture for an individual health disorder was estimated with the Coxs proportional hazards model. Several chronic health disorders increased the fracture risk in perimenopausal women. However, hypertension was a statistically significant ( p=0.018) risk factor for fracture (adjusted hazard ratio [HR], 1.4; 95% confidence interval [CI], 1.1–1.9), especially in overweight and obese (body mass index 28) women (HR, 2.0; 95% CI, 1.4–3.0). In addition, coronary heart disease (adjusted HR, 1.76; 95% CI, 1.13–2.76), hyperthyroidism (adjusted HR, 1.7; 95% CI, 1.0–2.9), epilepsy (adjusted HR, 2.0; 95% CI, 1.1–3.6), alcoholism (adjusted HR, 3.5; 95% CI, 1.3–9.5) and chronic hepatic disease (adjusted HR, 5.2; 95% CI, 1.7–16.4) predicted fracture. BMD was either normal or even elevated in disease groups. However, women with a fracture during the follow-up usually had decreased bone density, although the difference was statistically significant only in women with hypertension and hyperthyroidism. We conclude that hypertension, coronary heart disease, alcoholism, epilepsy and hyperthyroidism can markedly increase the risk of fracture in perimenopausal women and should be taken into account when assessing the risk of future fracture in an individual patient. Furthermore, in contrast to previous data, obesity alone does not increase the risk of perimenopausal fracture, but in association with hypertension the risk seems to be markedly elevated.     

The relationship between endogenous estrogen,sex hormone-binding globulin,and bone loss in female residents of a rural Japanese community: the Taiji Study

 The aim of this study was to clarify the relationship between endogenous estrogen, sex hormone-binding globulin (SHBG), and bone loss in pre-, peri-, and postmenopausal female residents of Taiji, a rural Japanese community. From a list of inhabitants aged 40 to 79 years, 200 participants—50 women in each of four age decades—were randomly selected, and baseline bone mineral density (BMD) at the lumbar spine and proximal femur were measured by dual-energy X-ray absorptiometry in 1993. Total estradiol (total E2) and SHBG were measured, and SHBG-unbound E2 (UBE2) was calculated using SHBG and the percent SHBG-unbound fraction ratio. BMD was measured again 3 years later, in 1996. Participants with ovariectomy or hysterectomy were excluded, and the remaining participants were categorized into four groups: premenopausal (n= 38), perimenopausal (n= 14), postmenopausal group 1 (5 years or less since menopause; n= 18), and postmenopausal group 2 (6 years or more since menopause; n= 74). The mean value of total E2 was highest in the premenopausal group (49.1 pg/ml), followed by the perimenopausal group (26.4 pg/ml), and the postmenopausal groups (0.83 pg/ml in postmenopausal group 1 and 0.96 pg/ml in postmenopausal group 2). The means for UBE2 showed the same pattern across the groups. After the multiple regression analysis of BMD at follow-up and endogenous estrogens, in premenopausal women, there were no significant associations between BMD at follow-up and serum total E2 and UBE2. In perimenopausal women, however, serum total E2 and UBE2 were significantly correlated with trochanteric BMD at follow-up (P < 0.05); and in postmenopausal group 2, they were significantly correlated with lumbar spine and Ward's triangle BMD at follow-up (P < 0.001 at lumbar spine, P < 0.05 at Ward's triangle). Concerning the association between BMD at follow-up and SHBG, in the premenopausal group, serum levels of SHBG were negatively correlated with BMD at the femoral neck (P < 0.05). In regard to partial regression coefficients for the change rates of BMD over 3 years and serum estrogens and SHBG concentrations, in perimenopausal women, UBE2 was correlated with the change rate of BMD at Ward's triangle (P < 0.05), and in postmenopausal group 1, serum levels of SHBG were significantly negatively related to change in BMD at the trochanter (P < 0.01). No other relationships with change in BMD were observed at any sites. These findings suggest that serum E2, UBE2, and SHBG levels differentially predict BMD levels in groups of differing menstrual status. It would, however, be difficult to predict bone loss in middle-aged and elderly Japanese women over a 3-year period using these indices alone. Received: November 29, 2001 / Accepted: February 28, 2002     

Effect of combined administration of vitamin D3 and vitamin K2 on bone mineral density of the lumbar spine in postmenopausal women with osteoporosis

The effect of the combined administration of vitamin D₃ and vitamin K₂ on bone mineral density (BMD) of the lumbar spine was examined in postmenopausal women with osteoporosis. Ninety-two osteoporotic women who were more than 5 years after menopause, aged 55–81 years, were randomly divided into four administration groups: vitamin D₃ (1α hydroxyvitamin D₃, 0.75 μg/day) (D group; n = 29), vitamin K₂ (menatetrenone, 45 mg/day) (K group; n = 22), vitamin D₃ plus vitamin K₂ (DK group, n = 21), and calcium (calcium lactate, 2 g/day) (C group; n = 20). BMD of the lumbar spine (L2–L4) was measured by dual energy X-ray absorptiometry at 0, 1, and 2 years after the treatment started. There were no significant differences in age, body mass index, years since menopause, and initial BMD among the four groups. One-way analysis of variance (ANOVA) with repeated measurements showed a significant decrease in BMD in the C group (P < 0.001). Two-way ANOVA with repeated measurements showed a significant increase in BMD in the D and K groups compared with that in the C group (P < 0.05 and P < 0.001, respectively), and a significant increase in BMD in the DK group compared with that in the C, D, and K groups (P < 0.0001, P < 0.05 and P < 0.01, respectively). These findings indicate that combined administration of vitamin D₃ and vitamin K₂, compared with calcium administration, appears to be useful in increasing the BMD of the lumbar spine in postmenopausal women with osteoporosis. Received: January 13, 2000 / Accepted: June 5, 2000     

Risk factors for low bone mineral density and the 6-year rate of bone loss among premenopausal and perimenopausal women

Risk factors that are associated with lower bone mineral density (BMD) may not necessarily be associated with increased bone loss among premenopausal and perimenopausal women. We determined risk factors for lower premenopausal and perimenopausal BMD while simultaneously determining risk factors for increased 6-year rate of bone loss among women aged 24–50 years within a population-based prospective cohort study. BMD of the lumbar spine and femoral neck, reported as t scores, were measured five times within the 6-year study among 614 women who were between the ages of 24 and 44 in 1992/1993. Rates of bone loss were calculated from the repeated BMD measurements. Risk factors for lower BMD over time at the lumbar spine included history of any fracture (P=0.005). The major risk factor for lower BMD over time at the femoral neck was family history of osteoporosis (P<0.002). The major protective factor for greater BMD over time at both skeletal sites was additional body weight (P<0.0001). Other protective factors for greater BMD over time at the femoral neck were modest alcohol consumption (P=0.0002) and high-school sports participation (P=0.002). Risk factors for greater bone loss at either skeletal site included postmenopausal status (P<0.0001 at the lumbar spine; P=0.01 at the femoral neck), and the reporting of a reproductive cancer (P<0.0001 at the lumbar spine; P=0.0008 at the femoral neck). Body weight was protective against bone loss at both skeletal sites (P<0.0001). Baseline age, calcium intake, smoking, and current physical activity were not associated with BMD or bone loss. The understanding of the relative importance of risk factors for both low BMD and bone loss may assist in the identification of women at greater risk for subsequent low postmenopausal BMD.     

Grip Strength May Facilitate Fracture Prediction in Perimenopausal Women with Normal BMD: A 15-Year Population-Based Study

The aim of the present study was to investigate the ability of grip strength measurements to predict fracture risk in perimenopausal women according to bone mineral density (BMD). A random sample of 971 perimenopausal women from the Kuopio Osteoporosis Risk Factor and Prevention study cohort was measured with dual-energy X-ray absorptiometry (DXA) at the femoral neck and grip strength with a pneumatic squeeze dynamometer in 5-year intervals from baseline (1989-1991). Fractures during the 15-year follow-up were recorded based on self-reports and validated from medical records. In the total sample and in osteopenic or osteoporotic women (T score < -1, n = 284) grip strength was not significantly associated with fracture-free survival rate (P = nonsignificant in Cox regression). In women with normal baseline BMD (N-BMD, T score > -1, n = 687) the lowest grip strength quartile had a significantly lower fracture-free survival rate in the Cox proportional hazard model (P = 0.005, hazard ratio [HR] = 2.0). In the multivariate Cox regression model, T score and grip strength were the only significant predictors of 15-year fracture-free survival in the N-BMD group and a risk index (RI) was formed according to HRs of these two variables. High RI (0-5 points) was associated with significantly lower 15-year fracture-free survival rate (P = 0.001, HR = 0.137) in the N-BMD group. In contrast, 5-year T score was no better a predictor of fractures in the baseline N-BMD group (P = 0.04, HR = 0.36). In conclusion, grip strength predicts 15-year fracture-free survival in perimenopausal women with N-BMD, while 5-year DXA does not seem to be any better a predictor of fracture risk. DXA measurements could be coupled with simple and cost-effective grip strength measurements. Controlling BMD in women with N-BMD could be abandoned.     

Does Vitamin D Strengthen the Increase in Femoral Neck BMD in Osteoporotic Women Treated with Estrogen?

The long-term effects on bone of estrogen therapy (HRT) combined with vitamin D₃ supplementation were evaluated and compared with the effects of HRT without vitamin D₃ supplementation in a 4-year prospective, partly randomized study among 60 osteoporotic women (mean age 55.4 years; range 49.7–59.4 years). The women studied were a subgroup of the population-based Kuopio Osteoporosis Risk Factor and Prevention Study (OSTPRE) (n = 13100). The bone mineral densities (BMD) of the lumbar spine and femoral neck were determined by dual-energy X-ray absorptiometry (DXA) in 3236 perimenopausal women. Those 106 women with baseline BMD more than 2 SDs less than the mean value in this population, either at the lumbar spine (BMD < 0.826 g/cm²) and/or femoral neck (BMD < 0.684 g/cm²), were offered treatment for osteoporosis. After exclusions, 60 women were included in the analyses. Group allocation was: HRT (estradiol valerate (2 mg) plus cyproterone acetate, 1 mg, sequentially: Climen^R) (n = 21); HRT + Vit D: Climen + vitamin D₃ (cholecalciferol, 300 IU/day, no intake during June–August) (n = 23); controls: 16 women who refused all treatment served as a non-randomized control group. In the HRT group, the highly significant increase in lumbar BMD was 5.4%, 5.3%, 4.7% and 4.0% after 1, 2, 3 and 4 years of treatment, respectively, all compared with the baseline values and with the control group. The increase in femoral neck BMD was statistically insignificant (1.4%, 2.2%, 1.9% and 2.1%, respectively; p > 0.05). In the HRT + Vit D group, the lumbar BMD increased by 3.7%, 4.9%, 4.9% and 4.9% (p < 0.001), whereas the 5.8% increase in femoral neck BMD reached significance at 4 years (p < 0.01) when compared with the control group as well as with the baseline values. However, there were no statistically significant differences in lumbar or femoral BMD changes between the two HRT groups. In conclusion, estrogen can substantially increase lumbar bone mass in patients with postmenopausal osteoporosis. In addition, the combination of HRT and vitamin D₃ may increase femoral neck BMD in osteoporotic women more than estrogen alone.     

Interpretation of lumbar spine densitometry in women with fractures

Identification of postmenopausal women at risk of developing osteoporotic fractures is a major clinical problem. In this study the use of projected planar lumbar bone density values for individual fracture risk assessment was questioned. Osteodensitometry (DXA) results from 415 normal women, 62 women with previous vertebral compressions, and 76 women with previous low-energy fractures were analyzed, together with their body size and lumbar vertebral body size variables. The following were found: (1) Lumbar vertebral projected bone mineral areal density (BMD) and bone mineral content (BMC) of normal women correlated with body size variables (p<0.001). (2) Lumbar vertebral body size variables also correlated with body size variables (p<0.001). Logistic regression analysis of measured and derived physical variables from women without and with vertebral compression fractures (n=477) showed: (3) The best compression fracture discriminator, significantly better than BMD, was BMC divided by (H_max/165 cm)¹⁵×(D/4.35 cm)^1.5, where H_max is the body height (cm) at the menopause, and D the mean lumbar vertebral diameter of the three mid-lumbar vertebral bodies (cm). This parameter was termed BMC_corr.. ROC analysis showed: (4) At a BMC_coor. true positive ratio of 80% the corresponding uncorrected BMC or BMD true positive ratio was only 60%. The corresponding false positive ratio was 6%. Lumbar osteodensitometry could not be used to identify women with a history of peripheral low-energy fractures. (5) BMC_coor. did not, unlike BMC and BMD, correlate with body size and vertebral size variables. (6) Likewise, an observed correlation between BMC and lean body mass in a subpopulation of 116 normal women was abolished when BMC_corr. replaced BMC. We suggest that vertebral compression fracture risk limits based on BMC, corrected for individual differences in body size and vertebral body size, replace the commonly used BMD fracture risk limits. The discriminatory ability of BMC_corr. for low-energy fractures needs to be tested in a different population.This investigation was carried out as part of a collaborative study by the Danish Osteoporosis Study Group (DOPS: O. Helmer Sørensen, L. Mosekilde, P. Charles, H. Beck-Nielsen and S. Pors Nielsen).