Osteoporosis and Apolipoprotein E Genotype in Older Adults: The Rancho Bernardo Study

Recent studies reported an association between apolipoprotein E (ApoE) 4 and osteoporosis. We examined the association of ApoE 4 genotype with bone mineral density (BMD), bone loss and fracture risk in 596 men and 332 community-dwelling women aged 45–95 years. Women were postmenopausal and not using estrogen. At the baseline visit, BMD was measured at the ultradistal and midshaft radius using single photon densitometry, and at the hip and lumbar spine using dual-energy X-ray absorptiometry. Hip and lumbar spine BMD levels were remeasured 4 years later. Self-reported fractures were confirmed by radiology reports in 95% of cases. ApoE allele distribution did not vary by age; 25% of men and 20% of women had one ApoE 4 allele. There were no differences in BMD at the lumbar spine, total hip, ultradistal or midshaft radius in men or women with the ApoE 4 allele compared with men or women without the ApoE 4 allele. After an average 4 year interval, there were also no differences in the annualized percent change in BMD at the hip or lumbar spine in men or women with or without an ApoE 4 allele. One or more clinical fractures were reported by 55 men and 109 women. Fewer, not more, clinical fractures were reported in men and women with an ApoE 4 allele; these differences were not statistically significant (p= 0.21 and p= 0.62, respectively). These data do not support the hypotheses that there is an association between ApoE genotype and BMD, bone loss or osteoporotic fractures in older community-dwelling men or women. Received: 26 July 2000 / Accepted: 13 October 2000     

Retinol intake and bone mineral density in the elderly: the Rancho Bernardo Study.

Retinol is involved in bone remodeling, and excessive intake has been linked to bone demineralization, yet its role in osteoporosis has received little evaluation. We studied the associations of retinol intake with bone mineral density (BMD) and bone maintenance in an ambulatory community-dwelling cohort of 570 women and 388 men, aged 55-92 years at baseline. Regression analyses, adjusted for standard osteoporosis covariates, showed an inverse U-shaped association of retinol, assessed by food-frequency questionnaires in 1988-1992, with baseline BMD, BMD measured 4 years later, and BMD change. Supplemental retinol use, reported by 50% of women and 39% of men, was an effect modifier in women; the associations of log retinol with BMD and BMD change were negative for supplement users and positive for nonusers at the hip, femoral neck, and spine. At the femoral neck, for every unit increase in log retinol intake, supplement users had 0.02 g/cm2 (p = 0.02) lower BMD and 0.23% (p = 0.05) greater annual bone loss, and nonusers had 0.02 g/cm2 (p = 0.04) greater BMD and 0.22% (p = 0.19) greater bone retention. However, among supplement users, retinol from dietary and supplement sources had similar associations with BMD, suggesting total intake is more important than source. In both sexes, increasing retinol became negatively associated with skeletal health at intakes not far beyond the recommended daily allowance (RDA), intakes reached predominately by supplement users. This study suggests there is a delicate balance between ensuring that the elderly consume sufficient vitamin A and simultaneously cautioning against excessive retinol supplementation.     

Sex Differences in the Association Between Adiponectin and BMD,Bone Loss,and Fractures: The Rancho Bernardo Study

We evaluated sex differences in the prospective association between adiponectin with BMD, bone loss, and fractures. Adiponectin, an adipose‐derived protein with insulin‐sensitizing properties, is also expressed in bone‐forming cells. Conflicting results and sex differences in the adiponectin‐BMD association have been reported in cross‐sectional studies. Serum adiponectin was measured in fasting blood samples obtained in 1984–1987 in 447 postmenopausal women (mean age: 76 yr) and 484 men (mean age: 75 yr). Four years later, BMD was measured at the midshaft radius by single photon absorptiometry and at the femoral neck, total hip, and lumbar spine by DXA. In 1992–1996, axial BMD was remeasured in 261 women and 264 men. Multivariable analysis adjusted for age, weight, calcium intake, type 2 diabetes, alcohol intake, and exercise. Among women, adiponectin was inversely associated with BMD at the femoral neck (β = ?0.002, p = 0.007), total hip (β = ?0.002, p = 0.009), lumbar spine (β = ?0.003, p = 0.008), and midshaft radius (β = ?0.002, p = 0.01) after 4.4 yr and at the femoral neck and total hip 8.6 yr later. Among men, adiponectin was inversely associated with BMD at the femoral neck, (β = ?0.002, p = 0.03), total hip (β = ?0.004, p < 0.001), and midshaft radius (β = ?0.003, p < 0.001) after 4.4 yr and at the hip 8.6 yr later. Adiponectin was not associated with 4‐yr bone loss in either sex but was associated with vertebral fractures (adjusted OR: 1.13; 95% CI: 1.08–1.23; p = 0.009) among men only. Adiponectin was inversely associated with BMD; however, sex differences were observed by anatomical site and with regards to vertebral fractures.     

Risk factors for longitudinal bone loss in elderly men and women: the Framingham Osteoporosis Study.

Few studies have evaluated risk factors for bone loss in elderly women and men. Thus, we examined risk factors for 4-year longitudinal change in bone mineral density (BMD) at the hip, radius, and spine in elders. Eight hundred elderly women and men from the population-based Framingham Osteoporosis Study had BMD assessed in 1988-1989 and again in 1992-1993. BMD was measured at femoral neck, trochanter, Ward's area, radial shaft, ultradistal radius, and lumbar spine using Lunar densitometers. We examined the relation of the following factors at baseline to percent BMD loss: age, weight, change in weight, height, smoking, caffeine, alcohol use, physical activity, serum 25-OH vitamin D, calcium intake, and current estrogen replacement in women. Multivariate regression analyses were conducted with simultaneous adjustment for all variables. Mean age at baseline was 74 years +/-4.5 years (range, 67-90 years). Average 4-year BMD loss for women (range, 3.4-4.8%) was greater than the loss for men (range, 0.2-3.6%) at all sites; however, BMD fell with age in both elderly women and elderly men. For women, lower baseline weight, weight loss in interim, and greater alcohol use were associated with BMD loss. Women who gained weight during the interim gained BMD or had little change in BMD. For women, current estrogen users had less bone loss than nonusers; at the femoral neck, nonusers lost up to 2.7% more BMD. For men, lower baseline weight and weight loss also were associated with BMD loss. Men who smoked cigarettes at baseline lost more BMD at the trochanter site. Surprisingly, bone loss was not affected by caffeine, physical activity, serum 25-OH vitamin D, or calcium intake. Risk factors consistently associated with bone loss in elders include female sex, thinness, and weight loss, while weight gain appears to protect against bone loss for both men and women. This population-based study suggests that current estrogen use may help to maintain bone in women, whereas current smoking was associated with bone loss in men. Even in the elderly years, potentially modifiable risk factors, such as weight, estrogen use, and cigarette smoking are important components of bone health.     

Breast cancer and bone mass in older women: is bone density prescreening for mammography useful?

Introduction The utility of screening mammography for older women with low bone mineral density (BMD) is controversial. This case-control study compares BMD at multiple sites in women with and without breast cancer to determine if BMD prescreening is useful in selecting women for continued screening mammograms.Methods Women diagnosed with breast cancer in the preceding 4 months and age-matched controls (±2 years) with a normal mammogram, all aged 65 years and older, were recruited on a 1:2 basis; 237 women participated: 79 women (cases) with breast cancer and 158 controls. BMD at the lumbar spine, hip, radius, and whole body was measured with dual x-ray absorptiometry (DXA).Results Among women with breast cancer, 17.1% had stage 0, 41.5% stage I, 40.0% stage II, and 1.4% stage III. Women with breast cancer had larger waist circumferences (p=0.002) and waist-hip ratios (p=0.01), and they exercised less (p=0.002) than women of the control group. However, there were no differences between the cases and controls for age, obesity, and reproductive and menopausal history variables, or other covariates (p>0.10). There were no differences in lumbar spine, total hip, femoral neck, midshaft radius, or total body BMD (p>0.10), although the cases had higher BMD at the ultradistal radius than the controls (means: 0.527 vs. 0.516, respectively; p=0.014). There were no differences in breast cancer risk by tertile of BMD or osteoporosis status at the hip or spine.Conclusion There is little difference in BMD between women with and without breast cancer. BMD is not useful as a prescreening predicator of mammography in older women and using it as such would result in cases of breast cancer being missed.     

Forearm Bone Mineral Densitometry Cannot be Used to Monitor Response to Alendronate Therapy in Postmenopausal Women

Alendronate significantly increases bone mass and reduces hip and spine fractures in postmenopausal women. To determine whether forearm densitometry could be used to monitor the efficacy of alendronate, we examined changes in bone mineral density (BMD) at the forearm (one-third distal, mid-distal, ultradistal radius) versus changes at the hip (femoral neck, total hip) and spine (posteroanterior and lateral) in a double-masked, randomized, placebo-controlled clinical trial of 120 elderly women (mean age 70 ± 4 years) treated with alendronate for 2.5 years. We found that among women in the treatment group, BMD increased by 4.0–12.2% at the hip and spine sites (all p<0.001), whereas BMD increased only nominally at the one-third distal radius (1.3%, p<0.001) and mid-radius (0.8%, p<0.05), and remained stable at the ultradistal radius. At baseline, forearm BMD correlated with that of the hip (r= 0.55–0.64, p<0.001), femoral neck (r= 0.54–0.61, p<0.001) and posteroanterior spine (r= 0.56–0.63, p<0.001). Changes in radial BMD after 1 year of therapy were not correlated with changes in hip and spine BMD after 2.5 years of therapy. In contrast, short-term changes in total hip and spine BMD were generally positively associated with long-term changes in total hip, femoral neck and spine BMD (r= 0.30–0.71, p<0.05). Furthermore, long-term BMD changes at the forearm did not correlate with long-term hip and spine BMD changes, in contrast to the moderate correlations seen between spine and hip BMD at 2.5 years (r= 0.38–0.45, p<0.01). We conclude that neither short- nor long-term changes in forearm BMD predict long-term changes in overall BMD for elderly women on alendronate therapy, suggesting that measurements of clinically relevant central sites (hip and spine) are necessary to assess therapeutic efficacy. Received: 18 February 1999 / Accepted: 20 May 1999     

Leptin predicts BMD and bone resorption in older women but not older men: the Rancho Bernardo study.

We studied the relation of leptin to bone, bone loss, and bone turnover in community-dwelling men and women. Leptin predicted higher BMD and lower bone turnover only in women. Leptin was not associated with 4-year bone loss in either sex. INTRODUCTION: Leptin, the protein product of the obesity (OB) gene produced in fat tissue, was originally thought to be involved only in the regulation of food intake and energy balance. Recent evidence suggests that leptin may play a role in the pathophysiology of several chronic diseases. Studies of the association between leptin and bone have been numerous yet inconclusive. Only one previous longitudinal study has been reported, which showed no association of leptin with BMD after adjusting for body size. MATERIALS AND METHODS: We report the association of serum leptin with BMD at the hip, spine, and midshaft radius in community-dwelling men (n = 498) and nonestrogen-using postmenopausal women (n = 411) 45-92 years of age. Serum leptin was measured in blood obtained between 1984 and 1987. Between 1988 and 1991, BMD was measured at the midshaft radius by single photon absorptiometry and at the femoral neck, total hip, and lumbar spine by DXA; at the same visit, height, weight, and body fat (by bioelectrical impedance analysis) were measured, and bone resorption was assessed in a subset of men (n = 286) and women (n = 241) using urine N-telopeptide (NTX). Four years later, axial BMD was remeasured in 536 participants. Sex-specific associations of leptin with BMD, NTX, and bone loss were tested using regression analysis. RESULTS: In unadjusted analyses, leptin was associated with BMD at the femoral neck, total hip, lumbar spine, and midshaft radius in both sexes (p < 0.01). In multiple regression analyses, adjusted for age, BMI, and other bone-related factors, only women showed a graded stepwise positive association between serum leptin and BMD at all sites and a negative stepwise association with NTX (all p for trend < 0.01). Baseline leptin levels did not predict 4-year bone loss in either sex. CONCLUSIONS: A favorable dose-dependent leptin-BMD association unexplained by obesity was observed only in women. The reason for the sex difference is unknown.     

Raloxifene and Vitamin K2 Combine to Improve the Femoral Neck Strength of Ovariectomized Rats

We evaluated the skeletal effects of two osteoporosis therapies in an ovariectomized rat model, raloxifene and vitamin K₂, as well as the vitamin K₂ plus raloxifene (K + Ral) combination. In two studies, 6-month-old rats were ovariectomized, except for sham-ovariectomy controls (Sham), and dosed orally with vehicle, 30 mg/kg vitamin K₂, 1 mg/kg raloxifene, or the combination of K + Ral for 6 weeks following surgery. Vitamin K₂ had no effect on serum estrogen, low-density lipoprotein cholesterol (LDL-C), or urinary deoxypyridinoline levels, but slightly increased osteocalcin levels compared to Ovx. Raloxifene lowered total cholesterol, LDL-C, osteocalcin, and urinary deoxypyridinoline levels to below Ovx levels, while having no effect on estrogen levels. Raloxifene, but not vitamin K₂, prevented ovariectomy-induced loss of bone in the distal femoral metaphysis and proximal tibial metaphysis, as did the K + Ral combination. Raloxifene, but not vitamin K₂, partially prevented, loss of vertebral bone mineral density (BMD), whereas K + Ral had BMD greater than that of Ovx. Vitamin K₂ increased bone formation rate to above Ovx, whereas raloxifene and K + Ral reduced bone formation rate to Sham levels. Vitamin K₂ had no effect on eroded surface compared to Ovx, while raloxifene and K + Ral reduced eroded surface to Sham levels. Groups were not different in the BMD of femoral midshaft; however vitamin K₂ was observed to increase periosteal mineralizing surface of the tibial shaft to above Ovx, while raloxifene reduced periosteal mineralizing surface toward Sham levels. Femoral neck strength was not different between groups, indicating no significant beneficial effect of either raloxifene or vitamin K₂ at this site. However, K + Ral had reproducibly greater femoral neck strength than Ovx or Sham. Raloxifene, but not vitamin K₂, partially prevented loss of lumbar vertebra strength; but K + Ral was not different from Sham or Ovx. Therefore, raloxifene and vitamin K₂ had complementary effects on bone resorption and formation activities, respectively, resulting in a reproducible, significant improvement of femoral neck strength. These rat data suggest interesting therapeutic possibilities that may require clinical verification. This work was supported by Lilly Research Laboratories.     

The Relation of Dietary Vitamin C Intake to Bone Mineral Density: Results from the PEPI Study

Ascorbic acid is a required cofactor in the hydroxylations of lysine and proline necessary for collagen formation; its role in bone cell differentiation and formation is less well characterized. This study examines the cross-sectional relation between dietary vitamin C intake and bone mineral density (BMD) in women from the Postmenopausal Estrogen/Progestin Interventions Trial. BMD (spine and hip) was measured using dual energy X-ray absorptiometry (DXA). The PEPI participants (n = 775) included in this analysis were Caucasian and ranged in age from 45 to 64 years. At the femoral neck and total hip after adjustment for age, BMI, estrogen use, smoking, leisure physical activity, calcium and total energy intake, each 100 mg increment in dietary vitamin C intake, was associated with a 0.017 g/cm² increment in BMD (P= 0.002 femoral neck; P= 0.005 total hip). After adjustment, the association of vitamin C with lumbar spine BMD was similar to that at the hip, but was not statistically significant (P= 0.08). To assess for effect modification by dietary calcium, the analyses were repeated, stratified by calcium intake (>500 mg/day and ≤500 mg/day). For the femoral neck, women with higher calcium intake had an increment of 0.0190 g/cm² in BMD per 100 mg vitamin C (P= 0.002). No relation between BMD and vitamin C was evident in the lower calcium stratum. Similar effect modification by calcium was observed at the total hip: the β coefficient in the higher calcium stratum was similar to that for the total sample (β= 0.0172, P= 0.01), but no statistically significant relation between total hip BMD and vitamin C was found in the lower calcium subgroup. Although the relation between vitamin C and lumbar spine BMD was of marginal statistical significance in the total sample, among women ingesting higher calcium, a statistically significant association was observed (β= 0.0199, P= 0.024). These data are consistent with a positive association of vitamin C with BMD in postmenopausal women with dietary calcium intakes of at least 500 mg. Received: 12 September 1997 / Accepted: 27 January 1998     

Vitamin D Supplementation After Parathyroidectomy: Effect on Bone Mineral Density—A Randomized Double‐Blind Study

Patients with primary hyperparathyroidism (PHPT) have higher bone turnover, lower bone mineral density (BMD), and an increased risk of fractures. They also have a high incidence of low vitamin D levels (25‐OH‐vitamin D <50 nmol/L) that could worsen the negative effect on the bone. In this double‐blinded clinical trial, 150 patients with PHPT were randomized, after successful parathyroidectomy (PTX), to 1‐year daily treatment with either cholecalciferol 1600 IU and calcium carbonate 1000 mg (D +) or calcium carbonate alone (D–). BMD was measured in the lumbar spine, femoral neck, total hip, distal and 33% radius using dual‐energy X‐ray absorptiometry (DXA) before surgery and after 1 year of study medication. Median age was 60 (range 30–80) years and there were 119 (79%) women and 31 (21%) men; 76% had 25‐OH‐D <50 nmol/L before PTX and 50% had persistent elevated parathyroid hormone (PTH) 6 weeks after PTX. A similar increase in BMD in the lumbar spine, femoral neck, and total hip was observed in both groups (D + : 3.6%, 3.2%, and 2.7%, p < 0.001, respectively; and D–: 3.0%, 2.3%, and 2.1%, respectively, p < 0.001). Patients with vitamin D supplementation also increased their BMD in distal radius (median 2.0%; interquartile range, ?1.7% to 5.4%; p = 0.013). The changes in BMD, especially in the hips, were correlated to the baseline concentrations of PTH, ionized calcium, and bone markers (p < 0.001). A benefit from vitamin D substitution was observed among patients with a persistent postoperative PTH elevation, who also improved their BMD at 33% radius and radius ultradistal (p < 0.05). In conclusion, except for a minor improvement of radius BMD, our data show no beneficial effect on BMD or bone turnover markers of vitamin D supplementation after PTX. Preoperative PTH seems to have the strongest association with improvement in BMD. © 2014 American Society for Bone and Mineral Research.     

Association between a functional interleukin-6 gene polymorphism and peak bone mineral density and postmenopausal bone loss in women: the OFELY study

Genetic factors play an important role in determining bone mass and several genes are involved in this process. Interleukin-6 (IL-6) is a candidate gene for regulation of bone mineral density (BMD) and it has been suggested recently that novel IL-6 -174 G/C allelic variants may be associated with peak BMD in young men and with bone resorption in elderly women. In this study, we assessed the relationships between IL-6 gene polymorphism, peak BMD, rate of postmenopausal BMD loss, and bone turnover in women. BMD was measured by dual-energy X-ray absorptiometry in 255 healthy premenopausal women, aged 31-57 years. BMD loss at the forearm was measured over 4 years in 298 healthy untreated postmenopausal women, 50-88 years (mean 64 years). We also measured levels of serum osteocalcin, bone alkaline phosphatase, and N-propeptide of type I collagen for bone formation and three markers of bone resorption, including urinary and serum C-terminal cross-linking telopeptide of type I collagen and urinary N-terminal telopeptide of type I collagen, in both pre- and postmenopausal women at baseline. In premenopausal women we found a significant association between IL-6 genotypes and BMD at the whole body (analysis of variance [ANOVA], p = 0.03), femoral neck (p = 0.03), trochanter (p = 0.014), Ward's triangle (p = 0.03), and total hip (p = 0.006), with subjects having the CC genotype showing 3%-7% higher BMD levels than their GG counterparts. However, after matching women with CC and GG genotypes for body height the differences decreased (2%-4%), and were no longer significant (p = 0.10-0.23). In postmenopausal women the mean rate of loss at the ultradistal radius was significantly associated with IL-6 genotypes (ANOVA, p = 0.049), with women having the CC genotype showing a significantly greater rate of bone loss (p < 0.05) compared with their GC and GG counterparts. After adjustment for weight changes, the difference in the rate of ultradistal radius bone loss between genotypes decreased and was not significant (p = 0.06 for CC vs. GG). A similar trend was observed for distal radius bone loss (p = 0.10, ANOVA), but not for the middle radius. We found no significant association between genotypes, bone turnover markers in premenopausal women, and either bone turnover or BMD in postmenopausal women. We conclude that this new functional IL-6 polymorphism was weakly associated with level of peak BMD and the rate of forearm trabecular postmenopausal bone loss in this cohort of healthy French women. IL-6 genotypes accounted only for a small proportion of the interindividual variation of both peak BMD and rate of bone loss and were not significant after adjustment for height and changes in body weight, respectively, suggesting that part of the effect may have been due to the differences in body size. Larger long-term studies are necessary to assess adequately the relationships between IL-6 genotype, rate of bone loss, and risk of fracture.     

Bone Mineral Density in Femoral Neck is Positively Correlated to Circulating Insulin-Like Growth Factor (IGF)-I and IGF-Binding Protein (IGFBP)-3 in Swedish Men

Studies on the hormonal regulation of bone metabolism in men have indicated covariation between insulin-like growth factor-I (IGF-I) and sex hormones with bone mineral density (BMD). In this study the relationships between BMD in total body, lumbar spine, femoral neck, distal and ultradistal (UD) radius and circulating levels of IGFs, IGF binding proteins (IGFBPs), and sex steroids were investigated in 55 Swedish men between 22 and 85 (52 +/- 18, mean +/- SD) years of age. BMD in total body, distal and UD radius, and femoral neck was positively correlated with serum IGF-I (r = 0.31 to 0.49), IGF-II (r = 0.32 to 0.48), IGFBP-3 (r = 0.37 to 0.53), and free androgen index (FAI) (r = 0.32 to 0.40), and negatively with IGFBP-1 (r = -0.37 to -0.41) and IGFBP-2 (r = -0.29 to -0.41) levels. A positive correlation was observed between BMD in femoral neck and estradiol/SHBG ratio (r = 0.34, P = 0.01). Age correlated negatively with serum IGF-I, IGF-II, IGFBP-3, FAI, estradiol/SHBG ratio, and BMD in total body, distal and UD radius, and femoral neck, and positively with IGFBP-1, IGFBP-2, and SHBG levels. According to stepwise multiple regression analyses, a combination of weight, IGFBP-3, and testosterone accounted for 43% of the variation in BMD in femoral neck, 34% in ultradistal radius and 48% in total body (P < 0.0001). These findings indicate that sex hormones and the different components of the IGF system are associated with BMD in Swedish men, suggesting that age-related changes in these systems could contribute to the development of osteoporosis in elderly men.     

Two-year randomized controlled trial of vitamin K1 (phylloquinone) and vitamin D3 plus calcium on the bone health of older women.

Dietary supplementation with vitamin K(1), with vitamin D(3) and calcium or their combination, was examined in healthy older women during a 2-year, double-blind, placebo-controlled trial. Combined vitamin K with vitamin D plus calcium was associated with a modest but significant increase in BMC at the ultradistal radius but not at other sites in the hip or radius. INTRODUCTION: The putative beneficial role of high dietary vitamin K(1) (phylloquinone) on BMD and the possibility of interactive benefits with vitamin D were studied in a 2-year double-blind, placebo-controlled trial in healthy Scottish women > or =60 years of age. MATERIALS AND METHODS: Healthy, nonosteoporotic women (n = 244) were randomized to receive either (1) placebo, (2) 200 microg/day vitamin K(1), (3) 10 microg (400 IU) vitamin D(3) plus 1000 mg calcium/day, or (4) combined vitamins K(1) and D(3) plus calcium. Baseline and 6-month measurements included DXA bone mineral scans of the hip and wrist, markers of bone turnover, and vitamin status. Supplementation effects were tested using multivariate general linear modeling, with full adjustment for baseline and potential confounding variables. RESULTS: Significant bone mineral loss was seen only at the mid-distal radius but with no significant difference between groups. However, women who took combined vitamin K and vitamin D plus calcium showed a significant and sustained increase in both BMD and BMC at the site of the ultradistal radius. Serum status indicators responded significantly to respective supplementation with vitamins K and D. Over 2 years, serum vitamin K(1) increased by 157% (p < 0.001), the percentage of undercarboxylated osteocalcin (%GluOC) decreased by 51% (p < 0.001), serum 25-hydroxyvitamin D [25(OH)D] increased by 17% (p < 0.001), and PTH decreased by 11% (p = 0.049). CONCLUSIONS: These results provide evidence of a modest synergy in healthy older women from nutritionally relevant intakes of vitamin K(1) together with supplements of calcium plus moderate vitamin D(3) to enhance BMC at the ultradistal radius, a site consisting of principally trabecular bone. The substantial increase in gamma-carboxylation of osteocalcin by vitamin K may have long-term benefits and is potentially achievable by increased dietary intakes of vitamin K rather than by supplementation.     

Does weight gain induce cortical and trabecular bone regain in anorexia nervosa? A two-year prospective study

This prospective study examines bone density and structure over a two-year time period in women with anorexia nervosa (AN) under weight gain treatment. Twenty-four women with AN were examined at baseline and at two annual follow-up examinations. In 9 AN patients BMI increased whereas in 15 it remained unchanged or decreased. Dual energy X-ray absorptiometry (DXA) was performed on the lumbar spine, the femoral neck and the whole hip and three-dimensional peripheral quantitative computer tomography (3D-pQCT) was performed on the ultradistal radius. ANOVAs for repeated measures were used to examine change over time in BMI and bone parameters. At baseline, patients with increased BMI had significantly higher bone density of femoral neck and total hip, and higher levels in all 3D-pQCT parameters of the ultradistal radius, compared to the group with unchanged or decreased BMI. The two groups did not differ at baseline in bone density of the spine. ANOVAs showed that bone density of the total hip increased significantly and that overall bone density (D100), the density of the trabecular area (D.Trab.) and the cortical thickness (C.Th.) in the ultradistal radius decreased significantly. Group x time interactions showed that changes over time were different in the two groups with regard to spine density and in the parameters D100, D.Trab. and C.Th. of the ultradistal radius. In the group with increased BMI the spine density dropped at the first follow-up whereas at the second follow-up it rose again to baseline. Patients with unchanged or decreased BMI showed a small but steady increase in spine density. The group changes of D100, D.Trab. and C.Th. of the ultradistal radius all followed the same pattern. Bone mineral density at all locations measured with both technologies (DXA and 3D-pQCT) did not vary according to BMI changes. The course of bone density and structure at different locations was different, and, despite weight increase, bone regain appeared to need different time periods.     

Low plasma vitamin B12 is associated with lower BMD: the Framingham Osteoporosis Study.

Vitamin B12 is important to DNA synthesis and may affect bone formation. We examined the association between this vitamin and BMD in 2576 adults. Men with plasma B12 < 148 pM had significantly lower BMD at the hip, and women at the spine, relative to those with higher B12, and trends were similar for both at all sites. Low vitamin B12 may be a risk factor for low BMD. INTRODUCTION: Vitamin B12 is important to DNA synthesis and may affect bone formation. It has been linked to osteoblastic activity in clinical studies and cell culture. MATERIALS AND METHODS: We examined the relationship between plasma vitamin B12 status and BMD in 2576 adult participants in the Framingham Offspring Osteoporosis Study (1996-2001). BMD was measured by DXA at the hip and spine. Plasma vitamin B12 was measured by radioassay. Mean BMD measures were estimated for four categories of vitamin B12 concentration, based on commonly used cut-offs, using analysis of covariance, adjusted for age, BMI, physical activity score for the elderly (PASE), alcohol use, smoking status, total calcium and vitamin D intake, season of bone measurement, and for women, menopause status and current estrogen use. Further adjustment for protein intake and total homocysteine concentration was also performed. RESULTS: Both men and women with vitamin B12 concentrations <148 pM had lower average BMD than those with vitamin B12 above this cut-off. These differences were significant (p < 0.05) for men at most hip sites and for women at the spine. Significance remained after further adjustment for protein intake and plasma homocysteine. CONCLUSIONS: Vitamin B12 deficiency may be an important modifiable risk factor for osteoporosis.     

Genetic and environmental determinants of bone mineral density in Chinese women

BMD is a complex trait determined by genetic and lifestyle factors. To assess the genetic and environmental determinants of BMD in southern Chinese women, we studied a community-based cohort of 531 pre- and postmenopausal southern Chinese women and assessed the influence of 12 candidate gene loci and lifestyle risk factors on spine and hip BMD. The candidate genes studied include estrogen receptor alpha (ESR1) and beta (ESR2), calcium sensing receptor (CASR), vitamin D receptor (VDR), collagen type Ialpha1 (COLIA1), and LDL receptor-related protein 5 (LRP5). Social, medical, reproductive history, dietary habits and lifestyle factors were determined using a structured questionnaire. Single nucleotide polymorphisms (SNPs) of the COLIA1 and LRP5 gene in Chinese were determined by direct sequencing. Nucleotide (nt) -1363C/G and -1997 G/T of COLIA1, nt 266A/G, 2220C/T and 3989C/T of LRP5 gene were analyzed. Using stepwise multiple linear regression analyses, body weight was the strongest predictor for BMD in premenopausal women (n = 262), which accounted for 15.9% of the variance at the spine, 20% at femoral neck, 17.1% at trochanter, 24.3% at total hip and 10.9% at the Ward's triangle. Other significant predictors were ESR1 Ivs1-397T/C genotype (2.2% at the spine); LRP5 2220C/T genotype (1.3% at the spine, 1.6% at the trochanter); LRP5 266A/G genotype (1.1% at Ward's triangle); age at menarche (1.3% at trochanter) and age (2.0% at Ward's triangle). As for postmenopausal women (n = 269), body weight ( approximately 25% at various sites) and age (approximately 16% at femoral neck, trochanter, total hip and Ward's triangle sites) were the strongest predictors of BMD. Other significant predictors were age at menarche (4.4% at spine, 0.7% at femoral neck, 1.4% at trochanter, and 1.4% at Ward's triangle); weight bearing physical activity (2.1% at trochanter and 1% at total hip); calcium intake (1.1% at femoral neck, 0.9% at trochanter, and 1.7% at total hip) ; height (0.7% at trochanter); and ESR2 1082A/G genotype (0.8% at trochanter). We conclude that BMD at various sites and at different time span of a woman is modified by different genetic and lifestyle factors, suggesting that BMD is highly dependent on gene-environmental interactions.     

Effects of current and discontinued estrogen replacement therapy on hip structural geometry: the study of osteoporotic fractures.

It is assumed that estrogen influences bone strength and risk of fractures by affecting bone mineral density (BMD). However, estrogen may influence the mechanical strength of bones by altering the structural geometry in ways that may not be apparent in the density. Repeated dual energy X-ray absorptiometry (DXA) hip scan data were analyzed for bone density and structural geometry in elderly women participating in the Study of Osteoporotic Fractures (SOF). Scans were studied with a hip structural analysis program for the effects of estrogen replacement therapy (ERT) on BMD and structural geometry. Of the 3,964 women with ERT-use data, 588 used ERT at both the start and end of the approximately 3.5-year study, 1,203 had past use which was discontinued by clinic visit 4, and 2,163 women had never used ERT. All groups lost BMD at the femoral neck, but the reduced BMD among users of ERT was entirely due to subperiosteal expansion and not bone loss, whereas both bone loss and expansion occurred in past or nonusers. BMD increased 0.8%/year at the femoral shaft among ERT users but decreased 0.8%/year among nonusers. Section moduli increased at both the neck and shaft among ERT users but remained unchanged in past and nonusers. Current, but not past, use of estrogen therapy in elderly women seems to increase mechanical strength of the proximal femur by improving its geometric properties. These effects are not evident from changes in femoral neck BMD.     

A potentially deleterious role of IGFBP-2 on bone density in aging men and women.

The role of the IGFs and IGFBPs on age-related changes in BMD in adult men and women is not well understood. Studying an age-stratified community based sample of 344 men and 276 women, we found higher IGFBP-2 levels to be associated with lower BMD. IGFBP-2, which increases with age in both men and women, was the strongest, most consistent predictor of BMD among the IGF/IGFBPs studied. INTRODUCTION: Insulin-like growth factors (IGFs) and their binding proteins (IGFBPs) are important regulators of tissue growth and metabolism, but their association with BMD in adult men and women is controversial. MATERIALS AND METHODS: In an age-stratified, random sample of the community population, we examined the role of serum levels of IGF-I, IGF-II, and IGFBP-1, -2, and -3 on BMD of the proximal femur (total hip), lateral spine, midshaft, and ultradistal radius as measured by DXA. We explored the association before and after adjustment for potential confounders, including age, bioavailable estradiol and testosterone, sex hormone binding globulin (SHBG), and measures of total fat and skeletal muscle mass. RESULTS: We studied 344 men (age, 23-90 years) and 276 women (age, 21-93 years; 166 postmenopausal) not on hormone replacement or oral contraceptives. In both men and women, IGF-I and IGFBP-3 levels fell with advancing age, whereas IGFBP-2 levels tended to rise with age. There was an inverse association of IGFBP-2 with BMD at most skeletal sites in men and both premenopausal and postmenopausal women, whereas lower IGF-I and IGFBP-3 were associated with lower BMD in men and postmenopausal women only. Lower IGF-II was associated with lower BMD in men only. There were no associations between IGFBP-1 and BMD in either sex. After adjustment for age, in most cases, we found no further associations between IGF-I, IGF-II, or IGFBP-3 and BMD. In contrast, after age adjustment, higher IGFBP-2 remained a predictor of lower BMD in men and postmenopausal women at all sites except for the lateral spine (for men: r = -0.21, -0.20, and -0.19, all p < 0.001; and for postmenopausal women: r = -0.34, -0.24, and -0.25, all p < 0.01, for the total hip, midshaft, and ultradistal radius, respectively). IGFBP-2 remained an independent negative predictor of BMD in men, postmenopausal women, and all women combined after additional adjustment for bioavailable sex steroids, but not at all sites after adjustment for SHBG and muscle mass. In premenopausal women, IGFBP-2 had similar associations as seen in postmenopausal women, but they were weaker and not statistically robust. CONCLUSIONS: Among the IGF/IGFBPs in our study, IGFBP-2 was a key negative predictor of BMD among men and women, particularly postmenopausal women. Our findings suggest a potential role of the IGF/IGFBP system in regulating bone loss in aging men and women and identify a previously under-recognized, potentially deleterious role for IGFBP-2, a known inhibitor of IGF action that increases with age in both sexes. Whether the action of the IGF/IGFBP system on bone metabolism is mediated partly through its effects on muscle mass or SHBG deserves further study.     

How Do Reproductive and Lifestyle Factors Influence Bone Density in Distal and Ultradistal Radius of Early Postmenopausal Women? The Nord-Trøndelag Health Survey, Norway

In a population-based health survey, densitometry was performed at the distal and ultradistal radius with single-energy X-ray absorptiometry. Bone mineral density (BMD) data and self-reported reproductive and lifestyle data from 1652 randomly selected peri- and postmenopausal women aged 50–59 years were analyzed. A total of 893 (54.1%) postmenopausal women reported no prior use of hormone replacement therapy (HRT) and constituted the principal group of study. These women were more frequently smokers, consumed less alcohol, more coffee and had made less use of oral contraceptives (OC) than women in the HRT group. The strongest association with both distal and ultradistal radius bone densities was found for age, weight, time since menopause and a history of bilateral oophorectomy. Among reproductive factors, nulliparous women had lower BMD than parous women; however, no linear relationship was found between parity and bone density. A weak, positive relationship was found for OC and BMD in bivariate, but not in multivariate analyses. A history of hysterectomy was positively associated with BMD, stronger at the ultradistal than distal radius. A positive relationship between alcohol consumption and BMD was found at the ultradistal radius. Present or prior smokers had lower BMD than never smokers. In the multivariate model, interaction between pack-years of smoking and daily coffee intake was observed at the distal radius, and both factors had a stronger negative influence on distal than ultradistal radius bone density. In perimenopausal women, most reproductive and lifestyle risk factors found to be associated with BMD of the radius may be explained by different levels of estrogen. Received: 3 April 2000 / Accepted: 12 October 2000