LCT 13910 C/T polymorphism, serum calcium, and bone mineral density in postmenopausal women

Summary  LCT 13910 CC genotype is associated with lactose intolerance, a condition often resulting in reduced milk intake. Women with the CC genotype were found to have decreased serum calcium and reduced bone mineral density. Introduction  The CC genotype of the 13910 C/T polymorphism of the LCT gene is linked to lactose intolerance and low calcium intake. Methods  We studied 595 postmenopausal women, including 267 osteoporotic, 200 osteopenic, and 128 healthy subjects. Genotyping, osteodensitometry, and laboratory measurements were carried out. Results  Frequency of aversion to milk consumption was 20% for CC genotype and 10% for TT + TC genotypes (p = 0.03). The albumin-adjusted serum calcium was 2.325 ± 0.09 mmol/L for CC genotype and 2.360 ± 0.16 mmol/L for TT + TC genotypes (p = 0.031). Bone mineral density (BMD; Z score) was lower in the CC than TT + TC genotypes, respectively, at the radius (0.105 ± 1.42 vs 0.406 ± 1.32; p = 0.038), at the total hip (−0.471 ± 1.08 vs −0.170 ± 1.09; p = 0.041), and at the Ward’s triangle (−0.334 ± 0.87 vs −0.123 ± 0.82; p = 0.044). Conclusion  LCT 13910 C/T polymorphism is associated with decreased serum calcium level and lower BMD in postmenopausal women. Péter Lakatos and Gábor Speer contributed equally to this work.     

Molecularly Defined Lactose Malabsorption,Peak Bone Mass and Bone Turnover Rate in Young Finnish Men

Lactose malabsorption (LM; adult-type hypolactasia), an autosomal recessive condition, results from the down-regulation of the activity of lactase enzyme in the intestinal wall. In previous studies the effect of LM on bone mass, bone turnover rate, development of osteoporosis and osteoporotic fractures has remained controversial. We have recently identified a single nucleotide polymorphism (SNP), a C to T change residing 13910 base pairs upstream of the lactase (LCT) gene at chromosome 2q21-22, which shows complete association with lactase persistence, with the C/C_–13910 genotype defining LM and the genotypes C/T_–13910 and T/T_–13910 lactase persistence. The present study was undertaken to examine the relationship of the C/T_–13910 polymorphism to peak bone mass, bone turnover rate, and stress fractures among young Finnish men. The study population comprised 234 young men, aged 18.3 to 20.6 years, 184 men were recruits of the Finnish Army, and 50 were men of similar age who had postponed their military service for reasons not related to health. Bone mineral content (BMC), density (BMD), and scan area were measured in the lumbar spine and upper femur by dual-energy X-ray absorptiometry (DXA). Blood was sampled for genotyping of the C/T_–13910 polymorphism and determination of serum 25-hydroxyvitamin D (25OHD), intact parathyroid hormone (iPTH), type I procollagen aminoterminal propeptide (PINP), and tartrate-resistant acid phosphatase 5b (TRACP5b). Second-void urine samples were collected for the determination of type I collagen aminoterminal telopeptide (NTX). The prevalence of the C/C_–13910-genotype of these young adults did not differ significantly from the corresponding population prevalence of C/C_–13910 (17.1% vs 18.1%) among Finnish blood donors. Fifteen recruits of the army experienced a stress fracture; 3 of them (20%) had the C/C_–13910-genotype. Calcium intake was similar for the three genotypes as were the unadjusted BMCs, scan areas, and BMDs at different measurement sites. The adjustments for age, height, weight, smoking, alcohol consumption, and physical exercise in the multiple regression analysis did not reveal any significant relationships between the lactase genotypes and BMDs at lumbar (P = 0.16), femoral neck (P = 0.99) or total hip (P = 0.96) sites. Serum 25OHD, iPTH, and bone marker levels were similar for the C/C_–13910 C/T_–13910 and T/T_–13910 genotypes. In summary, in young Finnish men, molecularly defined lactose malabsorption does not alter bone turnover rate and impair the acquisition of peak bone mass. Moreover, the C/C_–13910 genotype does not seem to be a risk factor for stress fractures in army recruits.N. Enattah and V.-V. Välimäki equally contributed to the study.     

Lactase Gene C/T?13910 Polymorphism, Calcium Intake, and pQCT Bone Traits in Finnish Adults

Genetic lactase nonpersistence may influence calcium intake and thereby bone health. We investigated in the Cardiovascular Risk in Young Finn Study whether young adults aged 31-46?years with the C/C(-13910) genotype are more susceptible to reduced bone phenotypes, low-energy fractures, and low calcium intake than subjects with other lactase genotypes. We also analyzed the gene-environment interactions on bone with calcium intake and physical activity. Peripheral quantitative computed tomography bone traits were measured from the distal and shaft sites of the radius and tibia. The total number of those subjects whose nondominant forearm was measured and the lactase genotype was defined was 1551. Information on diet, lifestyle factors, and fractures was collected with questionnaires. The mean intake of calcium was the lowest in men with the C/C(-13910) genotype (P?=?0.001). Men with the T/T(-13910) genotype had ~3% higher trabecular density at the distal radius and distal tibia compared to other lactase genotypes (P?=?0.03 and 0.02, respectively). In women, we found no evidence of the gene effect at the radius and tibia. No major interactions of the C/T(-13910) polymorphism with calcium intake or physical activity on bone phenotypes were found in either sex. In conclusion, the C/T(-13910) polymorphism was associated with trabecular density at the distal radius and tibia in men. These differences may be due to the differences in calcium intake between the lactase genotypes.     

Adult-type hypolactasia and calcium availability: decreased calcium intake or impaired calcium absorption?

Summary Adult-type hypolactasia, as mediated by a widespread genetic predisposition, not only reduces calcium intake but also calcium absorption in the presence of high amounts of lactose and may, therefore, promote osteoporosis. A lactose-reduced diet and lactose-free calcium supplements may reverse this imbalance. Introduction and hypothesis Adult-type hypolactasia (HL) defined by the LCT_(−13910) polymorphism may reduce calcium intake by reducing dairy consumption and, therefore, promote osteoporosis. This study aimed to evaluate whether lactose also decreases intestinal calcium absorption in subjects with HL and whether lactose-reduced diet and lactose-free calcium supplementation as recommended could maintain bone mineral density (BMD). Methods Based on LCT genotyping, 73 postmenopausal women with and without HL underwent a conventional H₂ breath test with a concomitant oral strontium absorption test lasting 150 minutes, which closely reflects intestinal calcium absorption. In addition, we compared bone-specific laboratory parameters, lumbar and femoral BMD, and spinal radiographs to a similar bone assessment 5 years earlier. Results LCT genotyping and functional lactose malabsorption tests were highly correlated. Dairy product consumption was reduced by 80% in HL individuals. During concomitant lactose application, mean strontium absorption was blunted by 54% in HL subjects after 150 minutes (1272 ± 629 μg/L vs. 2020 ± 1130 μg/L in lactose tolerant subjects, p = 0.001). Nevertheless, BMD in HL subjects remained stable with lactose-free calcium supplements during the observation period. Conclusion Both decreased calcium intake as well as lactose-associated impaired calcium absorption may predispose subjects with HL to osteoporosis. Lactose-free calcium supplementation may help to maintain BMD in HL subjects.     

The T‐13910C polymorphism in the lactase phlorizin hydrolase gene is associated with differences in serum calcium levels and calcium intake

The C‐variant of a T‐13910C polymorphism (rs4988235; NT_022135.15:g.25316568G > A) upstream of the lactase phlorizin hydrolase (LPH) gene causes lactose intolerance. Association studies with differences in bone parameters and fracture risk have been inconclusive. The objective of this study was to examine the association of LPH rs4988235 with body height and bone parameters and calcium homeostasis in two elderly populations of Dutch Caucasians and assess interaction with vitamin D receptor (VDR) polymorphisms. Genotyping of LPH and VDR polymorphisms was performed in 6367 individuals from the Rotterdam Study and 844 from the Longitudinal Aging Study Amsterdam (LASA). Associations with age, height, weight, bone mineral density (BMD), skeletal morphometric parameters and serum vitamin D and calcium levels, and dietary calcium intake were assessed using ANOVA or analysis of covariance, and allele dose effect was assessed using linear regression analysis. Fracture risk was analyzed using Cox's proportional hazard regression analysis. Associations with body height (p = 2.7 × 10^?8) and vertebral area (p = .048) found in the Rotterdam Study were explained by population stratification, as assessed by principal‐component analyses, and disappeared after additional adjustments. No associations with femoral neck or lumbar spine BMD or with fracture risk were detected. Calcium intake and serum ionized serum calcium were significantly lower in C‐homozygotes (p = 9.2 × 10^?7, p = .02, respectively). For none of the parameters studied was interaction between the T‐13910C polymorphism and VDR block 5 haplotype 1 observed. We show that the C allele of the T‐13910C polymorphism causing lactose intolerance is associated with lower dietary calcium intake and serum calcium levels but not with BMD or fractures. The associations observed with height and vertebral area were the result of population stratification. This demonstrates the impact of population stratification and urges researchers to carefully take this into account in genetic associations, in particular, in dietary intake–related phenotypes, of which LPH and lactose intolerance are a strong example. © 2010 American Society for Bone and Mineral Research     

Milk, rather than other foods, is associated with vertebral bone mass and circulating IGF-1 in female adolescents

Summary  Low calcium intake hampers bone mineral acquisition in adolescent girls. This study explores dietary calcium sources and nutrients possibly associated with vertebral mass. Milk intake is not influenced by genetic variants of the lactase gene and is positively associated with serum IGF-1 and with lumbar vertebrae mineral content and density. Introduction  Low calcium intake hampers bone mineral acquisition during adolescence. We identified calcium sources and nutrients possibly associated with lumbar bone mineralization and calcium metabolism in adolescent girls and evaluated the possible influence of a genetic polymorphic trait associated with adult-type hypolactasia. Methods  Lumbar bone mineral content (BMC), bone mineral density (BMD), and area, circulating IGF-1, markers of bone metabolism, and −13910 LCT (lactase gene) polymorphism; and intakes of milk, dairy products, calcium, phosphorus, magnesium, proteins, and energy were evaluated in 192 healthy adolescent girls. Results  After menarche, BMC, BMD, serum IGF-1, and serum PTH were tightly associated with milk consumption, but not with other calcium sources. All four parameters were also associated with phosphorus, magnesium, protein, and energy from milk, but not from other sources. Girls with milk intakes below 55 mL/day have significantly lower BMD, BMC, and IGF-1 and higher PTH compared to girls consuming over 260 mL/day. Neither BMC, BMD, calcium intakes, nor milk consumption were associated with −13910 LCT polymorphism. Conclusions  Milk consumption, preferably to other calcium sources, is associated with lumbar BMC and BMD in postmenarcheal girls. Aside from being a major source of calcium, milk provides phosphates, magnesium, proteins, and as yet unidentified nutrients likely to favor bone health.     

Interactions of interleukin-6 promoter polymorphisms with dietary and lifestyle factors and their association with bone mass in men and women from the Framingham Osteoporosis Study.

Lifestyle and dietary factors may influence the association of IL-6 polymorphisms with bone mass. In 1574 unrelated men and women from the Framingham Offspring Cohort, we observed significant hip BMD differences between IL-6 -174 genotypes only in older women, those without estrogens, and those with a poor calcium intake. Hence, association of IL-6 polymorphisms with BMD may be limited to discrete population subgroups. INTRODUCTION: Interleukin (IL)-6 plays a central role in the pathogenesis of osteoporosis. Two functional variants in the IL-6 promoter have previously been associated with IL-6 expression, bone resorption levels, and BMD in late postmenopausal women, but results were conflicting in different populations. We hypothesized that the association between IL-6 promoter alleles and BMD may be affected by interactions with lifestyle and dietary factors known to influence bone turnover. MATERIALS AND METHODS: Among the Offspring Cohort of the Framingham Heart Study, 1574 unrelated men and women were genotyped for IL-6 -572 and -174 alleles. Interaction analyses with years since menopause, estrogen status, physical activity, smoking, dietary calcium, vitamin D, and alcohol intake were based on BMD measurements at the hip. RESULTS AND CONCLUSIONS: In models that considered only the main effects of IL-6 polymorphisms, no significant association with BMD was observed in either gender. In contrast, p values (0.003-0.096 by ANOVA) suggestive of an interaction between IL-6 -174 genotypes and years since menopause, estrogen status, dietary calcium, and vitamin D intake were observed in women (n = 819). In turn, BMD was significantly lower with genotype -174 GG compared with CC, and intermediate with GC, in women who were more than 15 years past menopause and in those without estrogens or with calcium intake <940 mg/day. In estrogen-deficient women with poor calcium intake, BMD differences between genotypes CC and GG were 10.2% at femoral neck (p = 0.012), 12.0% at trochanter (p = 0.012), and 16.8% at Ward's area (p = 0.0014). In contrast, no such interactions were observed in men (n = 755). In conclusion, IL-6 genetic variation was prominently associated with hip BMD in late postmenopausal women, those without estrogen replacement therapy, and those with inadequate calcium intake. In contrast, IL-6 polymorphisms are unlikely to be significant determinants of bone mass in other women or men.     

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.     

Analysis of Three Functional Polymorphisms in Relation to Osteoporosis Phenotypes: Replication in a Spanish Cohort

Osteoporosis is a complex disease involving many putative genetic factors. Association analysis of functional SNPs in candidate genes is an important tool for their identification. However, this approach is affected by limited power, population stratification, and other drawbacks that lead to discordant results. Replication in independent cohorts is essential. We performed association analyses of three functional polymorphisms previously associated with bone phenotypes—namely, Ala222Val in MTHFR, Ile1062Val in LRP6, and −13910C>T in LCT—in a cohort of 944 postmenopausal Spanish women, all of them with lumbar spine (LS) bone mineral density (BMD) data and most with femoral neck (FN) BMD and fracture data. We found significant differences between genotypes only for the MTHFR polymorphism and vertebral factures, with an OR of 2.27 (95% CI 1.17–4.38) for the TT vs. CC/CT genotypes, P = 0.018. We present genotype and allele frequency data for LCT −13910C>T for a Spanish population, where the T allele (conferring lactase persistence) has a frequency of 38.6%. Genotype frequencies were consistent with observed clines in Europe and with the prevalence of lactase nonpersistence. The LCT −13910C>T polymorphism was significantly associated with height and weight, such that T allele carriers were 0.88 cm taller (95% CI 0.08–1.59 cm, P = 0.032, adjusted by age) than CC individuals and TT homozygotes were 1.91 kg heavier than CC/CT individuals (95% CI 0.11–3.71 kg, P = 0.038, adjusted by age). In conclusion, no significant association was observed between the studied polymorphisms and LS BMD or FN BMD in postmenopausal Spanish women, and only MTHFR Ala222Val was associated with vertebral fractures.     

Milk supplementation of the diet of postmenopausal Chinese women on a low calcium intake retards bone loss.

The Chinese diet is low in calcium (less than 500 mg/day on average), and previous observational studies have suggested an association between a low calcium intake and risk of hip and vertebral fracture. In this study, we randomly assigned 200 postmenopausal Chinese women (age range, 55-59 years) to receive 50 g of milk powder containing 800 mg of calcium per day or to a control group. The following are the mean percentage changes (and SEs) in height and bone mineral density (BMD) over 24 months: for height, -0.1 +/- 0.2 cm in the milk supplementation group and -0.2 +/- 0.1 cm in the control group; for BMD at the total hip, -0.06 +/- 0.22% in the milk supplementation group and -0.88 +/- 0.26% in the control group; for BMD at the spine (L1-L4), -0.56 +/- 0.29% in the milk supplementation group and -1.5 +/- 0.29% in the control group; for total body BMD, -0.32 +/- 0.16% in the milk supplementation group and -1.2 +/- 0.19% in the control group (p < 0.05 by analysis of covariance [ANCOVA] for repeated measures for height and BMD at all sites). The milk supplementation group had less loss in terms of both height and BMD than the control group (p < 0.05 by ANCOVA for repeated measures). Serum parathyroid hormone (PTH) concentration was lower and serum 25-hyroxyvitamin D [25(OH)D] level was higher in the milk supplementation group than the control group at 12 months (p < 0.05 by paired t-test). We conclude that supplementing the diet of postmenopausal Chinese women with high calcium milk powder retards bone loss.     

Physical activity and calcium consumption are important determinants of lower limb bone mass in older women.

A population-based study of 1363 older women showed that the 24% who achieved high physical activity and dietary calcium intakes had a 5.1% higher hip BMD than those who did not, supporting the concept that lifestyle factors play an important role in the maintenance of lower extremity bone mass in older women. INTRODUCTION: Although there is general agreement that increased dietary calcium consumption and exercise can slow bone loss in older women, the amount required to have this effect in an older population remains uncertain. This study was devised to examine the effects of calcium consumption (CC) and physical activity (PA) (lifestyle management) on bone mass in an older female population. MATERIALS AND METHODS: Using a cross-sectional study design, a population-based sample of older women (mean age, 75 +/- 3 years) had hip and heel bone mass measured using DXA (Hologic 4500A; n = 1076) and quantitative ultrasound (QUS, Lunar Achilles; n = 1363), respectively. CC and PA were measured by a validated habitual food frequency and activity questionnaire, respectively. Dose-response effects of PA and CC on bone mass were examined using ANOVA. RESULTS AND CONCLUSIONS: Division of the PA and CC into tertiles best described the dose-response effects. After adjustment for CC, age, weight, alcohol consumption, and cigarette smoking, high PA compared with medium or low PA was associated with higher hip BMD and heel QUS (total hip BMD, 3.1%; p < 0.001; QUS stiffness, 2.7%; p = 0.002). After adjustment for PA and covariates, high or medium CC compared with low CC was associated with higher total hip BMD (1.8%; p = 0.027), with no effect at the QUS heel site. PA and CC were dichotomized at the cut-points for effects on BMD. The combination of high PA and CC, achieved by 24% of the population, was associated with a total hip BMD that was 5.1% higher (34% of SD) than those individuals in the low PA and CC group. Stiffness was 3.6% (23% of SD) higher in the high PA and CC group than in the low PA and CC group. If the whole population undertook and achieved a high PA and high CC lifestyle, the population risk of hip fractures may be expected to be reduced by about 17% in this age group as a result of beneficial effects on the musculoskeletal system.     

Calcium and vitamin D intake influence bone mass,but not short-term fracture risk,in Caucasian postmenopausal women from the National Osteoporosis Risk Assessment (NORA) study

Summary The impact of calcium and vitamin D intake on bone density and one-year fracture risk was assessed in 76,507 postmenopausal Caucasian women. Adequate calcium with or without vitamin D significantly reduced the odds of osteoporosis but not the risk of fracture in these Caucasian women. Introduction Calcium and vitamin D intake may be important for bone health; however, studies have produced mixed results. Methods The impact of calcium and vitamin D intake on bone mineral density (BMD) and one-year fracture incidence was assessed in 76,507 postmenopausal Caucasian women who completed a dietary questionnaire that included childhood, adult, and current consumption of dairy products. Current vitamin D intake was calculated from milk, fish, supplements and sunlight exposure. BMD was measured at the forearm, finger or heel. Approximately 3 years later, 36,209 participants returned a questionnaire about new fractures. The impact of calcium and vitamin D on risk of osteoporosis and fracture was evaluated by logistic regression adjusted for multiple covariates. Results Higher lifetime calcium intake was associated with reduced odds of osteoporosis (peripheral BMD T-score ≤−2.5; OR = 0.80; 95% CI 0.72, 0.88), as was a higher current calcium (OR = 0.75; (0.68, 0.82)) or vitamin D intake (OR = 0.73; 95% CI 0.0.66, 0.81). Women reported 2,205 new osteoporosis-related fractures. The 3-year risk of any fracture combined or separately was not associated with intake of calcium or vitamin D. Conclusions Thus, higher calcium and vitamin D intakes significantly reduced the odds of osteoporosis but not the 3-year risk of fracture in these Caucasian women. Sources of support: This work was supported by grant AG1406701 from the National Institute on Aging. The National Osteoporosis Risk Assessment (NORA) was funded and managed by Merck & Co Inc.     

Predictors and relationships of serum 25 hydroxyvitamin D concentration with bone turnover markers, bone mineral density, and vitamin D receptor genotype in Emirati women

OBJECTIVES: To determine factors influencing serum 25 hydroxyvitamin D (25OHD) concentration and relationships between serum 25OHD concentration, bone turnover markers, bone mineral density (BMD), and vitamin D receptor (VDR) genotype in Emirati women. METHODS: Serum 25OHD, parathyroid hormone (PTH), osteocalcin (OC), vitamin D binding protein (VDBP), and urinary deoxypyrdinoline (UDPD) concentrations and VDR genotype were determined in Emirati women volunteers who were participating in a study aiming at establishing a reference database for BMD. RESULTS: Serum 25OHD concentration in the 259 women volunteers was 25.3 +/- 10.8 nmol/l (mean +/- SD), and all had vitamin D deficiency (25OHD <80 nmol/l). Mean serum 25OHD was highest in April (29.2 +/- 13.0 nmol/l), which marks the end of the short and cooler winter season, and lowest in August (18.2 +/- 5.9 nmol/l). No significant difference in 25OHD concentration was noted among Emirati women wearing different dress styles, but the mean serum 25OHD was significantly lower in comparison with non-Arab Caucasian women volunteers who dressed in a Western style (P < 0.001). Serum 25OHD correlated positively with age (r = 0.2), number of pregnancies (r = 0.16), dietary vitamin D intake (r = 0.15), serum calcium (r = 0.14), phosphorus (r = 0.14), VDBP (r = 0.15), and urinary calcium/creatinine (r = 0.2), and inversely with PTH (r = -0.22), OC (r = -0.13), and UDPD/creatinine (r = -0.15); P < 0.05 for all correlations. Multiple linear regression analysis showed that age, dietary vitamin D intake, multivitamin intake, and cooler season were independent positive predictors of serum 25OHD concentration (R(2) = 0.18). The frequencies of VDR genotypes were 36% GG, 44.1% AG, and 19.9% AA. Allele frequencies were 58% for G allele and 42% for A allele and were in Hardy-Weinberg equilibrium (x(2) = 1.44; P > 0.1). There was no statistically significant influence of VDR genotype on bone turnover or BMD. CONCLUSIONS: Vitamin D deficiency is highly prevalent in Emirati women and appears largely attributable to insufficient sunlight exposure. It is associated with increased bone turnover. VDR genotype does not appear to influence bone turnover markers or BMD in Emirati women.     

Differences between lactase deficient and non-lactase deficient women with spinal osteoporosis

Both osteoporosis and lactase deficiency are seen commonly in the United States. Since the latter may lead to avoidance of calcium sources and may exacerbate the bone disease in populations at risk, we studied lactose tolerance and histomorphometrically analyzed undecalcified transiliac bone biopsies in a consecutive group of postmenopausal women with the osteoporotic spinal compression fracture syndrome. Oral lactose tolerance tests prior to the biopsy clearly separated two groups. Sixty-five percent had abnormal test results. The bone biopsies in the lactase deficient group showed more osteoid volume and osteoid seam widths on examined trabecular bone. Analysis of tetracycline-labeled bone revealed significant increases in both single, double, combined single and double tetracycline labels, and the percent osteoid labeled with tetracycline. There was no difference in the calcification rates. These findings indicate different mineralization activity in lactase deficient patients, possibly reflecting their lower dietary calcium intake.     

Overweight postmenopausal women lose bone with moderate weight reduction and 1 g/day calcium intake.

Overweight postmenopausal women may be more susceptible to bone loss with weight reduction than previously studied obese women. The influence of energy restriction and Ca intake on BMD was assessed in 66 individuals. Weight reduction resulted in bone loss at several sites in women consuming 1 g Ca/day and was mitigated with higher calcium intake at 1.7 g/day. INTRODUCTION: Bone loss is associated with weight loss in obese postmenopausal women and can be prevented with calcium (Ca) supplementation. However, because bone loss caused by weight loss may be greater in overweight than obese women, it is not clear whether Ca supplementation is also beneficial in overweight women. MATERIALS AND METHODS: We assessed the influence of caloric restriction at two levels of Ca intake on BMD and BMC in 66 overweight postmenopausal women (age, 61 +/- 6 years; body mass index, 27.0 +/- 1.8 kg/m2). Subjects completed either a 6-month energy-restricted diet (WL, n = 47) and lost 9.3 +/- 3.9 % weight or maintained weight (WM; 1 g Ca/day, n = 19). Participants in the WL group were randomly assigned to either normal (1 g/day; WL NL-Ca) or high (1.7 g/day; WL Hi-Ca) Ca intake. Regional BMD and BMC were measured at baseline and after 6 months. RESULTS: During normal Ca intake, trochanter BMD and BMC and total spine BMD were decreased more in WL than WM women (p < 0.05). The WL NL-Ca group lost more trochanter BMD (-4.2 +/- 4.1%) and BMC (-4.8 +/- 7.1%) than the WL Hi-Ca group (-1.4 +/- 5.6% and -1.1 +/- 8.1%, respectively; p < 0.05). There were no significant changes in BMD or BMC at the femoral neck in any group. Weight loss correlated with trochanter BMD loss (r = 0.687, p < 0.001) in the WL NL-Ca group. CONCLUSION: Despite an intake of 1 g Ca/day, bone loss occurred at some sites because of weight loss. Calcium intake of 1.7 g/day will minimize bone loss during weight loss in postmenopausal overweight women.     

Relationship among VDR (BsmI and FokI), COLIA1, and CTR polymorphisms with bone mass,bone turnover markers,and sex hormones in men

Osteoporosis is a disease characterized by low bone mineral density (BMD) and up to 80% of its variance is under genetic control. Although osteoporosis is more frequent in women, one-third of hip fractures also occur in men. Much information on genetic factors and bone density has been obtained in women, but only a few studies have been performed in osteoporotic men. We have evaluated the relationship between polymorphisms for several candidate genes such as vitamin D receptor (VDR), collagen type Ia1 (COLIA1), and calcitonin receptor (CTR) in a sample of unrelated Italian men (n = 253, mean age 58.41 +/- 15.64 SD). We found no significant differences in BMD when subjects were stratified for their VDR (BsmI and FokI) and COLIA1 genotypes. BMD both at the lumbar spine and at the femoral neck were associated with polymorphism of CTR gene. The CC genotype of CTR gene had the lowest BMD value (P <0.05 and P <0.01 at the spine and hip, respectively) and its prevalence was significantly over-represented in the subgroup of men with prior hip or vertebral fracture as compared with controls (P = 0.004% c2 = 11.10). The men with the CC genotype also showed significantly lower body mass index (BMI), serum sex hormone binding globulin (SHBG), estradiol, total alkaline phosphatase-(total AP) and bone alkaline phosphatase (bone AP) levels and significantly higher free androgen index (FAI). In conclusion, the polymorphism of CTR gene but not VDR and COLIA1 is associated with osteoporosis incidence and the levels of alkaline phosphatase and estradiol. The lower BMD in CC genotype is apparently associated in males with depressed bone formation and lower estradiol levels.     

Interleukin-6 gene polymorphism is related to bone mineral density during and after puberty in healthy white males: a cross-sectional and longitudinal study.

Bone mineral density (BMD) is under strong genetic control and is the major determinant of fracture risk. The cytokine interleukin-6 (IL-6) is an important regulator of bone metabolism and is involved in mediating the effects of androgens and estrogens on bone. Recently, a G/C polymorphism in position -174 of the IL-6 gene promoter was found. We investigated this genetic polymorphism in relation to BMD during late puberty and to peak bone mass, in healthy white males. We identified the IL-6 genotypes (GG, GC, and CC) in 90 boys, age 16.9 +/- 0.3 years (mean +/- SD), using polymerase chain reaction (PCR). BMD (g/cm2) at the femoral neck, lumbar spine, and total body was measured using dual energy X-ray absorptiometry. The volumetric BMD (vBMD; mg/cm3) of the lumbar spine was estimated. Differences in BMD in relation to the genotypes were calculated using analysis of variance (ANOVA). Subjects with the CC genotype had 7.9% higher BMD of the femoral neck (p = 0.03), 7.0% higher BMD of the lumbar spine (p < 0.05), and 7.6% higher vBMD of the lumbar spine (p = 0.04), compared with their GG counterparts. Using multiple regression, the IL-6 genotypes were independently related to total body BMD (CC > GG; p = 0.03), humerus BMD (CC > GG; p < 0.05), neck BMD (CC > GG; p = 0.01), spine BMD (CC > GG; p = 0.01), and spine vBMD (CC > GG; p = 0.008). At age 19.3 +/- 0.7 years (mean +/- SD; 88 men) the IL-6 genotypes were still independent predictors for total body BMD (CC > GG; p = 0.03), humerus BMD (CC > GG; p = 0.03), spine BMD (CC > GG; p = 0.02), and spine vBMD (CC > GG; p = 0.003), while the IL-6 genotypes were not related to the increase in bone density seen after 2 years. We have shown that polymorphism of the IL-6 gene is an independent predictor of BMD during late puberty and of peak bone mass in healthy white men.     

Assessment of age and risk factors on bone density and bone turnover in healthy premenopausal women

The influence of age and risk factors on bone density and bone turnover was evaluated in 249 healthy premenopausal women. Risk factors were assessed by standardized questionnaires and included reproductive history and lifestyle factors (intake of calcium and vitamin D supplements, consumption of caffeine, smoking habits and physical activity). Bone mineral density (BMD) measurements were obtained in the distal forearm, the lumbar spine and the proximal femur. Bone turnover were assessed by plasma bone Gla proteins (pBGP) and fasting urinary hydroxyproline corrected for creatinine (fUHPr/Cr). Peak bone density seems to be achieved before the age of 30 years, whereafter we found no appreciable bone loss at any skeletal site. Accordingly, the levels of pBGP and fUHPr/Cr were increased before the age of 30, whereafter the values stabilized at a lower level. A dairy calcium intake above 660 mg/day significantly increased BMD in the spine and proximal femur by 3%–5%. Physical activity alone had no influence on BMD, but in combination with calcium intake an additive effect was observed. Women who had an active lifestyle (corresponding to at least 1 h of daily walking) and a dairy calcium intake above 660 mg/day had a 3%–7% increase in BMD compared with more sedentary women with a calcium intake below this limit. Vitamin D supplements, caffeine, smoking and reproductive history did not consistently influence BMD or bone turnover. Only pBGP was selectively reduced by smoking and current use of oral contraceptives, respectively. We conclude that there is no appreciable change in BMD before the menopause once skeletal maturity has been reached. Dietary calcium intake increases peak bone density and this positive effect can be potentiated by an active lifestyle. Other putative risk factors had no influence on premenopausal BMD.     

Effect of dietary protein on bone loss in elderly men and women: the Framingham Osteoporosis Study.

Few studies have evaluated protein intake and bone loss in elders. Excess protein may be associated with negative calcium balance, whereas low protein intake has been associated with fracture. We examined the relation between baseline dietary protein and subsequent 4-year change in bone mineral density (BMD) for 391 women and 224 men from the population-based Framingham Osteoporosis Study. BMD (g/cm2) was assessed in 1988-1989 and in 1992-1993 at the femur, spine, and radius. Usual dietary protein intake was determined using a semiquantitative food frequency questionnaire (FFQ) and expressed as percent of energy from protein intake. BMD loss over 4 years was regressed on percent protein intake, simultaneously adjusting for other baseline factors: age, weight, height, weight change, total energy intake, smoking, alcohol intake, caffeine, physical activity, calcium intake, and, for women, current estrogen use. Effects of animal protein on bone loss also were examined. Mean age at baseline (+/-SD) of 615 participants was 75 years (+/-4.4; range, 68-91 years). Mean protein intake was 68 g/day (+/-24.0; range, 14-175 g/day), and mean percent of energy from protein was 16% (+/-3.4; range, 7-30%). Proportional protein intakes were similar for men and women. Lower protein intake was significantly related to bone loss at femoral and spine sites (p < or = 0.04) with effects similar to 10 lb of weight. Persons in the lowest quartile of protein intake showed the greatest bone loss. Similar to the overall protein effect, lower percent animal protein also was significantly related to bone loss at femoral and spine BMD sites (all p < 0.01) but not the radial shaft (p = 0.23). Even after controlling for known confounders including weight loss, women and men with relatively lower protein intake had increased bone loss, suggesting that protein intake is important in maintaining bone or minimizing bone loss in elderly persons. Further, higher intake of animal protein does not appear to affect the skeleton adversely in this elderly population.     

Relation between vitamin D insufficiency, bone density, and bone metabolism in healthy postmenopausal women.

Although only few postmenopausal women exhibit biochemical signs of hypovitaminosis D, vitamin D insufficiency has been shown to have adverse effects on bone metabolism and could be an important risk factor for osteoporosis and fracture. We determined serum levels of 25-hydroxyvitamin D [25(OH)D], intact parathyroid hormone (iPTH), bone turnover markers, dietary calcium intake, and bone mineral density (BMD; measured by dual X-ray absorptiometry) in 161 consecutive ambulatory women, healthy except for osteoporosis, referred to a bone metabolic unit. The prevalence of vitamin D insufficiency [25(OH)D < or = 15 ng/ml] was 39.1%. 25(OH)D was lower in the osteoporotic subjects (15.7 +/- 5.3 ng/ml vs. 21.8 +/- 9.7 ng/ml; p < 0.001). After controlling for all other variables, lumbar spine (LS) BMD was found to be significantly associated with 25(OH)D, body mass index (BMI), and years after menopause (YSM) (R2 = 0.253; p < 0.001). For femoral neck (FN), significant independent predictors of BMD were YSM, BMI, iPTH, and 25(OH)D (R2 = 0.368; p < 0.001). The probability of meeting osteoporosis densitometric criteria was higher in the vitamin D insufficiency group (odds ratio [OR], 4.17, 1.83-9.48) after adjusting by YSM, BMI, iPTH, and dietary calcium intake. Our study shows that vitamin D insufficiency in an otherwise healthy postmenopausal population is a common risk factor for osteoporosis associated with increased bone remodeling and low bone mass.