Dietary calcium and vitamin D intake in relation to osteoporotic fracture risk

The etiologic role of dietary calcium and vitamin D intake in primary prevention of osteoporotic fractures is uncertain, despite considerable research efforts. With the aim to examine these associations with an improved precision, we used data from a large population-based prospective cohort study in central Sweden. We estimated nutrient intake from a self-administered food-frequency questionnaire filled in by 60,689 women, aged 40–74 years at baseline during 1987–1990. During follow-up, we observed 3986 women with a fracture at any site and 1535 with a hip fracture. Rate ratio of fractures (RR) and 95% CI were estimated using Cox proportional hazards models. We found no dose–response association between dietary calcium intake and fracture risk. The age-adjusted RR of hip fracture was 1.01 (95% CI 0.96–1.06) per 300 mg calcium/day and the corresponding risk of any osteoporotic fracture was 0.99 (95% CI 0.96–1.03). Furthermore, women with an estimated calcium intake below 400 mg/day and those with a calcium intake higher than 1200 mg/day both had a similar age-adjusted hip fracture risk as those with intermediate calcium intakes: RR 1.07 (95% CI 0.92–1.24) and RR 1.00 (95% CI 0.79–1.27), respectively. Vitamin D intake was not associated with fracture risk. Furthermore, women in the highest quintiles compared to the lowest quintiles of both calcium and vitamin D intake had an age-adjusted RR of 1.02 for all fractures (95% CI 0.88–1.17). Dietary calcium or vitamin D intakes estimated at middle and older age do not seem to be of major importance for the primary prevention of osteoporotic fractures in women.     

Dietary B vitamin intake and risk of hip fracture: the Singapore Chinese Health Study

Summary

This prospective cohort study that comprehensively examined effects of different B vitamins in an Asian population showed an inverse relationship between dietary intake of pyridoxine and hip fracture risk in elderly women. These findings suggest that maintaining sufficient pyridoxine intake may be beneficial in preserving bone health in postmenopausal women.

Introduction

B vitamins have recently been investigated for their possible roles in maintaining bone health. Incidence of osteoporotic hip fracture has been rising in Asia, but epidemiological data on dietary B vitamins and risk of osteoporotic fractures are sparse. We aimed to examine the association between dietary intakes of B vitamins (thiamin, riboflavin, niacin, pyridoxine, folate, and cobalamin) and hip fracture risk among elderly Chinese in Singapore.

Methods

The current study was conducted in the Singapore Chinese Health Study, which is a population-based cohort prospective study that enrolled a total of 63,257 men and women aged 45–74 years between 1993 and 1998. Dietary intakes of B vitamins were derived from a validated food frequency questionnaire and the Singapore Food Composition Database.

Results

After a mean follow-up period of 13.8 years, 1,630 hip fracture incident cases were identified. A statistically significant inverse relationship between dietary pyridoxine intake and hip fracture risk was observed among women (p for trend?=?0.002) but not among men. Compared to women in the lowest quartile intake (0.37–0.61 mg/1,000 kcal/day), women in the highest quartile intake (0.78–1.76 mg/1,000 kcal/day) had a 22 % reduction in hip fracture risk (hazard ratio 0.78, 95 % confidence interval 0.66–0.93). Dietary intakes of the other B vitamins of interest were not related to hip fracture risk.

Conclusions

Our findings suggest that maintaining adequate intake of pyridoxine may prevent osteoporotic fractures among elderly women.     

Epidemiology and prevention of osteoporosis in urbanized Asian populations

The incidence rate of hip fracture in Hong Kong in 1989 was calculated from hospital admission data and the census population. The incidence rate has increased 3-fold since 1966 to reach 9 per 1000 in men and 13 per 1000 in women 80 years and over. The age-adjusted rate was comparable to that in Singapore but higher than that in Japan. A case-control study was conducted on 280 women and 120 men with hip fracture and 800 controls. The relative risk for hip fracture increased with a low calcium intake, being 2.9 (95% confidence interval 1.9 to 4.6) in the lowest quartile. The relative risk for hip fracture was also significantly increased in subjects who did not perform load-bearing activity every day. Osteoporosis may be prevented by an adequate calcium intake and load-bearing activity in urbanized Asian populations.     

Protective Effects of Dietary Carotenoids on Risk of Hip Fracture in Men: The Singapore Chinese Health Study

Experimental and epidemiologic data suggest that carotenoids in vegetables and fruits may benefit bone health due to their antioxidant properties. The relationship between dietary total and specific carotenoids, as well as vegetables and fruits, and risk of hip fracture was examined among Chinese in Singapore. We used data from the Singapore Chinese Health Study, a prospective cohort of 63,257 men and women who were of ages 45 to 74 years between 1993 and 1998. At recruitment, subjects were interviewed on lifestyle factors and medical history. Usual diet was measured using a validated food frequency questionnaire. During a mean follow‐up of 9.9 years, we identified 1630 hip fracture incident cases. Among men, consumption of vegetables was associated with lower hip fracture risk. Similarly, dietary total carotenoids and specific carotenoids, α‐carotene, β‐carotene, and lutein/zeaxanthin were inversely associated with hip fracture risk. Compared to men in the lowest quartile of nutrient density, men in the highest quartile had statistically significant 26% to 39% risk reduction (all p for trend <0.05). When stratified by body mass index (BMI), the greatest protective effects of total vegetables and carotenoids were found in men with BMI <20 kg/m² (p for trend ≤0.004). There was no association between dietary carotenoids or vegetables/fruits and hip fracture risk among women. This study suggests that adequate intake of vegetables may reduce risk of osteoporotic fractures among elderly men and that the antioxidant effects of carotenoids may counteract the mechanism of osteoporosis related to leanness. © 2014 American Society for Bone and Mineral Research.     

A case-control study of hip fracture: evaluation of selected dietary variables and teenage physical activity

Recent diet, teenage physical activity and teenage calcium consumption were examined as risk factors for hip fracture in a case-control study. Cases were 161 white women admitted to one of 30 participating hospitals with a first hip fracture. Controls included 168 white women from general and orthopedic surgical services frequency-matched to cases by age group and hospital. Information on exposure to possible risk factors was obtained by in-person interview. No association was found between recent intake of calcium, phosphorus, protein, vitamin C or caffeine and hip fracture. Also, teenage calcium intake and milk drinking were not related to hip fracture risk. Recreational activities in adolescence and early adulthood appeared to afford protection against hip fracture. The highest quartile of recreational activity (4 times/week) was associated with an odds ratio of 0.24 (95% confidence interval 0.08–0.75) relative to the lowest quartile (<1 time/week).     

The effects of high potassium consumption on bone mineral density in a prospective cohort study of elderly postmenopausal women

Summary  Few studies have investigated the long-term effects of potassium intake on BMD. In a cohort of 266 elderly women, we found that baseline potassium intake as reflected by 24-hour urine potassium excretion had positive association with BMD measured at 1 and/or 5 years later, suggesting a role of dietary potassium on osteoporosis prevention. Introduction  High dietary potassium intake has been suggested to be beneficial for bone structure, but few studies have investigated the long-term effects of potassium intake on BMD in elderly women. We examined the relationship between potassium intake as reflected by 24-hour urine potassium excretion and bone density in a cohort of elderly women. Methods  The study subjects were 266 elderly postmenopausal women aged 70–80 years. Twenty-four-hour urinary potassium excretion was determined at baseline. At one year hip DXA BMD was measured, at 5 years hip and total body DXA BMD and distal radius and tibia pQCT vBMD were measured. The effects of potassium were evaluated by ANCOVA according to the quartile of baseline urinary potassium excretion. Results  After adjustment for confounding factors, subjects in the highest quartile of urinary potassium excretion had significantly higher total hip BMD at 1 (5%) and 5 years (6%), and significantly higher total body BMD (4%) and 4% distal tibia total (7%) and trabecular vBMD (11%) at 5 years than those in the lowest quartile. Conclusions  Potassium intake shows positive association with bone density in elderly women, suggesting that increasing consumption of food rich in potassium may play a role in osteoporosis prevention.     

Soy protein consumption and bone mass in early postmenopausal Chinese women

Recent interest has been shown in the potential beneficial effects of phytoestrogens on bone health. As the early years of menopause are a period of rapid bone loss, and the risk for osteoporosis increases substantially, the habitual intake of soy protein and isoflavones may play a role in the retardation of bone loss. This paper reports the results of the baseline cross-sectional analysis of the association between dietary soy protein intake and bone mineral density/content in a population-based study of Chinese women. The sample comprised 454 healthy Chinese women (mean age 55.1±3.57) within the first 12 years of postmenopause. We estimated the dietary intake of soy protein and isoflavones, and other key nutrients, including dietary protein and calcium, using the quantitative food frequency method. Bone mineral density (BMD) and content (BMC) at the spine, hip and total body were measured with a dual energy X-ray densitometer (Hologic 4500A). Soy protein consumption was categorized as quartiles of intake, and related to BMD values at the spine and hip, and BMC of total body. Stratified analyses were carried out among women within or at least 4 years postmenopausal. We observed few differences in BMD/BMC values among the intake quartiles in women within the first 4 years of menopause. However, among the later postmenopausal women, we noted a dose-response relationship with increasing higher BMD values at the trochanter, intertrochanter as well as the total hip and total body with increasing soy protein intake quartiles (P<0.05 from tests for trend). The BMD values differed by about 4–8% between the first and fourth soy protein intake quartiles. Though women from the fourth intake quartile had a 2.9% higher BMD value compared with those from the first intake quartile, the difference was not statistically significant. Stepwise multiple linear regression analyses showed the association between soy intake quartiles and hip BMD as well as total body BMC values remained after adjusting for body weight, which was retained in the final model. Analyses based on soy isoflavones content yielded similar results. This study demonstrated that, among women after the initial few years postmenopausal, soy protein/isoflavones intake had a modest but significant association with hip BMD as well as total body BMC. The effects of soy protein and soy isoflavones on bone health should be further explored in populations with habitual dietary soy intake.     

A meta-analysis of milk intake and fracture risk: low utility for case finding

A low intake of calcium is widely considered to be a risk factor for future fracture. The aim of this study was to quantify this risk on an international basis and to explore the effect of age, gender and bone mineral density (BMD) on this risk. We studied 39,563 men and women (69% female) from six prospectively studied cohorts comprising EVOS/EPOS, CaMos, DOES, the Rotterdam study, the Sheffield study and a cohort from Gothenburg. Cohorts were followed for 152,000 person-years. The effect of calcium intake as judged by the intake of milk on the risk of any fracture, any osteoporotic fracture and hip fracture alone was examined using a Poisson model for each sex from each cohort. Covariates examined were age and BMD. The results of the different studies were merged by using the weighted -coefficients. A low intake of calcium (less than 1 glass of milk daily) was not associated with a significantly increased risk of any fracture, osteoporotic fracture or hip fracture. There was no difference in risk ratio between men and women. When both sexes were combined there was a small but non-significant increase in the risk of osteoporotic and of hip fracture. There was also a small increase in the risk of an osteoporotic fracture with age which was significant at the age of 80 years (RR=1.15; 95% CI=1.02–1.30) and above. The association was no longer significant after adjustment for BMD. No significant relationship was observed by age for low milk intake and hip fracture risk. We conclude that a self-reported low intake of milk is not associated with any marked increase in fracture risk and that the use of this risk indicator is of little or no value in case-finding strategies.     

Low serum concentrations of alpha-tocopherol are associated with increased risk of hip fracture. A NOREPOS study

Summary

We investigated the risk of hip fracture according to circulating alpha-tocopherol, a plant-derived substance with antioxidant properties, in community-dwelling older Norwegians. We found a linear increasing risk of hip fracture with lower serum alpha-tocopherol concentrations, with a 51 % higher risk in the lowest compared to the highest quartile.

Introduction

Oxidative stress is a suggested contributing cause of osteoporosis and fractures. Vitamin E (α-tocopherol) has potent antioxidant properties in humans. The relationship between circulating α-tocopherol and fracture risk is not established. The aim of this study was to investigate the association between serum α-tocopherol concentrations and risk of hip fracture during up to 11 years of follow-up.

Methods

We performed a case-cohort analysis among 21,774 men and women aged 65–79 years who participated in four community-based health studies in Norway 1994–2001. Serum α-tocopherol concentrations at baseline were determined in 1,168 men and women who subsequently suffered hip fractures (median follow-up 8.2 years) and in a random sample (n?=?1,434) from the same cohort. Cox proportional hazard regression adapted for gender-stratified case-cohort data was performed.

Results

Median (25, 75 percentile) serum α-tocopherol was 30.0 (22.6, 38.3) μmol/L, and it showed a linear inverse association with hip fracture: hazard ratio (HR) 1.11 (95 % confidence interval (CI) 1.04–1.20) per 10-μmol/L decrease in serum α-tocopherol, adjusted for gender and study center. The lowest compared to the highest quartile conferred an HR of 1.51 (95 % CI 1.17–1.95), adjusted for gender and study center. Adjustment for smoking, month of blood sample, BMI, education, physical inactivity, self-rated health, and serum 25-hydroxyvitamin D (25(OH)D) yielded similar results. Taking serum total cholesterol concentration into account attenuated the association somewhat: HR of hip fracture was 1.37 (95 % CI 1.05–1.77) in first versus fourth quartile of serum α-tocopherol/total cholesterol ratio.

Conclusions

Low serum concentrations of α-tocopherol were associated with increased risk of hip fracture in older Norwegians.     

Vitamin A intake and the risk of hip fracture in postmenopausal women: the Iowa Women’s Health Study

Excessive intake of vitamin A is postulated to have a detrimental effect on bone by inducing osteoporosis. This may lead to an increased risk of fracture, particularly in persons who are already at risk of osteoporosis. However, few studies have specifically examined the association of vitamin A intake through diet and supplement use, with fractures in a cohort of older, community-dwelling women. We prospectively followed a cohort of 34,703 postmenopausal women from the Iowa Womens Health Study to determine if high levels of vitamin A and retinol intake through food and supplement use were associated with an increased risk of hip or all fractures. A semiquantitative food frequency questionnaire was used to obtain the participants baseline vitamin A and retinol intake. Participants were followed for a mean duration of 9.5 years for incident self-reported hip and nonhip fractures. After multivariate adjustment, it was revealed that users of supplements containing vitamin A had a 1.18-fold increased risk of incident hip fracture (n=525) compared with nonusers (95% CI, 0.99 to 1.41), but there was no evidence of an increased risk of all fractures (n=6,502) among supplement users. There was also no evidence of a dose-response relationship in hip fracture risk with increasing amounts of vitamin A or retinol from supplements. Furthermore, our results showed no association between vitamin A or retinol intake from food and supplements, or food only, and the risk of hip or all fractures. In conclusion, we found little evidence of an increased risk of hip or all fractures with higher intakes of vitamin A or retinol among a cohort of older, postmenopausal women.     

Serum estradiol and sex hormone-binding globulin and the risk of hip fracture in elderly women: the EPIDOS study.

It has been suggested that low serum 17beta-estradiol (E2) and sex hormone-binding globulin (SHBG) may predict hip fracture in postmenopausal women. We have investigated the predictive value of serum E2 and SHBG concentrations and urinary deoxypyridinoline (D-Pyr) and type I collagen breakdown products (CTX) in a large prospective cohort of 7,598 healthy elderly ambulatory women (EPIDOS study), aged 75 years or more. We performed a nested case control study, by matching 212 patients with incident hip fracture with 636 controls. Mean follow-up was 3.3 years (maximum, 4.9 years). Women having serum E2 below the limit of detection (3 pg/ml), that is, 2% of the population, were not at higher risk, with a relative hazard (RH) of 1.59 (95% CI = 0.45-5.55). Women having serum E2 below 5, 6, 7, or 8 pg/ml, in the lowest quartile, or below the median had no increased risk of hip fracture. In contrast, women having serum E2 in the highest quartile (i.e., > or = 10 pg/ml) were protected, with an RH of 0.66 (0.44-0.98) that did not remain significant after adjustment for weight (RH = 0.71 [0.47-1.06]). High serum SHBG values with different cut-offs tended to be associated with an increased risk of hip fracture. Women in the highest quartile had an RH of 2.5 (1.37-4.61), compared with those in the lowest quartile, that decreased markedly after adjustment for body weight (1.61 [0.99 -2.62]). The highest quartile of the ratio E2/SHBG, which is an index of free E2, was associated with a lower hip fracture risk (RH = 0.6 [0.4-0.91]) that was no longer significant after adjustment for weight. In contrast, urinary D-Pyr and CTX, when elevated above the upper limit of premenopausal values, were predictive of hip fracture, with an RH of 2.07 (1.49-2.9) and 1.67 (1.19-2.32), respectively, even after adjustment for body weight, serum E2, and SHBG. We conclude that in healthy elderly French women over 75 years of age, serum E2 and E2/SHBG in the highest quartile are associated with a lower risk of hip fracture and that this association is explained by a higher body weight. In addition, serum levels of E2 and SHBG do not account for the increased risk of hip fracture associated with high levels of bone resorption markers.     

Independent predictors of all osteoporosis-related fractures among healthy Saudi postmenopausal women: the CEOR Study

This study was designed to identify independent predictors of all osteoporosis-related fractures (ORFs) among healthy Saudi postmenopausal women. We prospectively followed a cohort of 707 healthy postmenopausal women (mean age, 61.3±7.2 years) for 5.2±1.3 years. Data were collected on demographic characteristics, medical history, personal and family history of fractures, lifestyle factors, daily calcium intake, vitamin D supplementation, and physical activity score. Anthropometric parameters, total fractures (30.01 per 1000 women/year), special physical performance tests, bone turnover markers, hormone levels, and bone mineral density (BMD) measurements were performed. The final model consisted of seven independent predictors of ORFs: [lowest quartile (Q(1)) vs highest quartile (Q(4))] physical activity score (Q(1) vs Q(4): ≤12.61 vs ≥15.38); relative risk estimate [RR], 2.87; (95% confidence interval [CI]: 1.88-4.38); age≥60 years vs age<60 years (RR=2.43; 95% CI: 1.49-3.95); hand grip strength (Q(1) vs Q(4): ≤13.88 vs ≥17.28 kg) (RR=1.88; 95% CI: 1.15-3.05); BMD total hip (Q(1) vs Q(4): ≤0.784 vs 0.973 g/cm(2)) (RR=1.86; 95% CI: 1.26-2.75); dietary calcium intake (Q(1) vs Q(4): ≤391 vs ≥648 mg/day) (RR=1.66; 95% CI: 1.08-2.53); serum 25(OH)D (Q(1) vs Q(4): ≤17.9 vs ≥45.1 nmol/L) (RR=1.63; 95% CI: 1.06-2.51); and past year history of falls (RR=1.61; 95% CI: 1.06-2.48). Compared with having none (41.9% of women), having three or more clinical risk factors (4.8% of women) increased fracture risk by more than 4-fold, independent of BMD. Having three or more risk factors and being in the lowest tertile of T-score of [total hip/lumbar spine (L1-L4)] was associated with a 14.2-fold greater risk than having no risk factors and being in the highest T-score tertile. Several clinical risk factors were independently associated with all ORFs in healthy Saudi postmenopausal women. The combination of multiple clinical risk factors and low BMD is a very powerful indicator of fracture risk.     

Homocysteine and fracture risk in postmenopausal women: the OFELY study

Summary Homocysteine has recently been described as an independent risk factor for osteoporotic fractures in the elderly. We prospectively followed 671 postmenopausal women belonging to the OFELY study, mean age 62 years, during a mean follow-up of 10 years. After adjustment for age, there was no significant relation between the plasma level of homocysteine and the subsequent risk of fracture. Introduction Plasma homocysteine increases with age. Recent studies have described homocysteine as an independent risk factor for osteoporotic fractures in elderly. We investigated the role of plasma homocysteine in the subsequent risk of fractures in healthy ambulatory postmenopausal women. Methods Homocysteine was measured at baseline in 671 postmenopausal women from the OFELY cohort (mean age 62.2 ± 9 years). Incident clinical fractures were recorded during annual follow-up and vertebral fractures were evaluated with radiographs every four years. A cox proportional hazards model based on time to first fracture was used to calculate hazard ratios for quartiles of homocysteine values. Results Mean homocysteine was 10.6 ± 3.4 μmol/l, increasing with age. After adjustment for age, homocysteine was significantly associated with physical activity, calcium intake, serum albumin and serum creatinine but not with bone turnover markers and bone mineral density. During a mean follow-up of 10 years, 183 fractures occurred among 134 women. After adjustment for age, the overall relative risk of fracture for each 1 SD increment of homocysteine was 1.03 (95%CI 0.87–1.31). Fracture risk was higher in women with homocysteine in the highest quartile without adjustment but no longer after adjustment for age. Conclusions Homocysteine is not an independent risk factor of osteoporotic fractures in healthy postmenopausal women from the OFELY cohort with a broad age range.     

Long‐Term Low Intake of Dietary Calcium and Fracture Risk in Older Adults With Plant‐Based Diet: A Longitudinal Study From the China Health and Nutrition Survey

The aim of this longitudinal study was to investigate long‐term associations between low dietary calcium intake and fracture risk in older adults with plant‐based diet. Data of self‐reported first fracture events of any type from 6210 Chinese men and women, aged 50 years or older and free from fracture at baseline, in a subcohort based on the China Health and Nutrition Survey (CHNS), were analyzed. Diet was repeatedly assessed by a combination of three consecutive 24‐hour individual dietary recalls and a weighing and measuring of household food inventory in each round. The older men and women habitually ingested mean (SD) of 415 (147) mg/d and 373 (140) mg/d of calcium from plant‐based diet, respectively. During a median follow‐up of 7.0 years, 127 men (4.34%) and 232 women (7.06%) experienced first fracture events. The crude rates were 4.88, 2.55, and 6.83 per 1000 person‐years at risk for men, and 6.72, 7.10, and 11.0 per 1000 person‐years at risk for women in the lowest, third, and highest quintile of dietary calcium intake. In nonlinear regressions, an increased risk of fracture was associated with dietary calcium intake more than 778 mg/d (multivariable adjusted hazard ratio [HR] 2.10, 95% confidence interval [CI] 1.00–4.41) or lower than 275 mg/d (1.74, 95% CI 1.00–3.01) for men and more than 651 mg/d for women (1.54, 95% CI 1.00–2.38). A nonsignificant trend of increase in fracture risk was found below 248 mg/d (1.00, 95% CI 0.67–1.50) in women using restricted cubic spline Cox regression. A relatively low fracture risk is observed in men with dietary calcium intakes of 275 to 780 mg/d and in women with intakes of 250 to 650 mg/d, and higher intakes may have no further benefit for fracture prevention. The patterns of dietary calcium with fracture risk are U‐shaped in men and possibly in women. © 2016 American Society for Bone and Mineral Research.     

A prospective study of thyroid function,bone loss,and fractures in older men: The MrOS study

Excess thyroid hormone is associated with increased bone loss and fracture risk in older women, but few data exist for men. We sought to determine if thyroid function is independently associated with bone loss and fracture risk in older men. Data were analyzed from the Osteoporotic Fractures in Men (MrOS) study, a cohort of community‐dwelling U.S. men aged 65 years and older. Using a case‐cohort design, fasting baseline serum archived at ?80°C was assayed for thyroid‐stimulating hormone (thyrotropin) (TSH) and free thyroxine (FT4) in 397 men with confirmed nonspine fracture, including 157 hip fractures, and 1420 randomly selected men without fracture. TSH and FT4 were analyzed as continuous variables and as thyroid function categories (subclinical hyperthyroid, euthyroid, and subclinical hypothyroid). Hip dual‐energy X‐ray absorptiometry (DXA) (Hologic QDR4500) was measured at baseline and after a mean follow‐up of 4.6 years. Incident nonspine fractures were centrally adjudicated. Bone loss was evaluated with multivariate regression methods and fractures risk was evaluated using hazard models that accounted for the case‐cohort sampling, adjusted for age, clinic‐site, body mass index (BMI), race, physical activity, corticosteroid use, smoking, alcohol intake, and thyroid medication use. In fully adjusted analyses, TSH was not associated with risk of nonspine fracture (relative hazard [RH] 0.92 per SD decrease in TSH; 95% confidence interval [CI], 0.74–1.14), but was significantly associated with risk of hip fracture (RH 1.31; 95% CI, 1.01–1.71), which persisted among normal range TSH values (RH 1.21; 95% CI, 1.00–1.47). There was no association between TSH or FT4 and bone loss, and fracture risk did not differ significantly by thyroid function category. We conclude that although neither TSH nor FT4 are associated with bone loss, lower serum TSH may be associated with an increased risk of hip fractures in older men. © 2013 American Society for Bone and Mineral Research.     

Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study.

The mechanisms leading to increased bone loss and skeletal fragility in women with postmenopausal osteoporosis are still poorly understood. Increased bone resorption, low serum estradiol and high serum sex-hormone-binding globulin (SHBG) recently have been reported as predictors of vertebral and hip fractures in elderly women. In a cohort of healthy untreated younger postmenopausal women aged 50-89 years (mean, 64 years), we compared baseline levels of bone markers and endogenous hormones in 55 women who subsequently had a fracture (20 vertebral and 35 peripheral fractures) with levels in the 380 women who did not fracture during a mean 5 years of follow-up. Women with levels in the highest quartile of four bone resorption markers including urinary-free deoxypyridinoline (D-Pyr), urinary type I collagen N-telopeptides (NTX), and urinary and serum type I collagen C-telopeptides (CTX) had about a 2-fold increased risk of fractures compared with women with levels in the three lowest quartiles with relative risk (RR) and 95% CI of 1.8 (1.0-3.4) for free D-Pyr, 1.7 (0.9-3.2) for urinary NTX, 2.3 (1.3-4.1) for urinary CTX, and 2.1 (1.2-3.8) for serum CTX. Serum levels of bone alkaline phosphatase (BAP) in the highest quartile were associated with an RR of fracture of 2.4 (1.3-4.2). Women with serum levels of estradiol and dehydroepiandrosterone (DHEA) sulfate in the lowest quartile had an RR of fracture of 2.2 (1.2-4.0) and 2.1 (1.2-3.8), respectively. Increased levels of SHBG and intact parathyroid hormone (PTH) were moderately associated with an increased risk of fracture. Similar results were obtained when the analysis was restricted to symptomatic vertebral and nonvertebral fractures. Adjustment of biochemical markers by hormone levels did not significantly alter the results. Women with both high bone resorption markers and low estradiol (or low DHEA sulfate) had a higher risk of fracture with RRs of 3.0-3.3 (p < 0.001). After adjustment for bone mineral density (BMD) of the hip, spine, radius, or total body, bone markers and hormones were still predictive of fracture risk with similar RRs. We conclude that high levels of some biochemical markers of bone turnover, low serum estradiol, low DHEA sulfate, high SHBG, and high PTH are associated with increased risk of osteoporotic fracture in postmenopausal women, independently of each other and of BMD. The mechanism by which some postmenopausal women have an increased rate of bone turnover leading to an increased risk of fracture remains to be elucidated.     

Association of serum fibroblast growth factor 23 (FGF23) and incident fractures in older men: The Osteoporotic Fractures in Men (MrOS) study

Normal mineral metabolism is critical for skeletal integrity, and recently serum fibroblast growth factor 23 (FGF23) levels were found to be directly related to overall fracture risk in elderly Swedish men. To confirm this association, we performed a prospective case‐cohort study to understand the relation of FGF23 and fracture risk in older white men enrolled in the Osteoporotic Fractures in Men (MrOS) study. In the cohort of 5994 men attending the baseline MrOS examination, we evaluated a subgroup of 387 men with incident nonvertebral fracture including 73 hip fractures and a sample of 1385 men randomly selected from the cohort with baseline mineral and calcium hormone measurements. FGF23 was measured in baseline serum samples by ELISA (Millipore, Billerica, MA, USA). Modified Cox proportional hazards models that account for case‐cohort study design were used to estimate the relative hazards (RH) of fracture in men across quartiles of FGF23. Subjects were also stratified by renal function, and RH per strata was estimated in men with the highest quartile of FGF23 compared with quartiles 3, 2, and 1. Overall, there was no difference in risk of nonspine or hip fracture by baseline FGF23. However, associations differed by strata of eGFR_CrCy. Among men with eGFR_CrCys <60 mL/min/1.73 m² (n = 73/313 nonspine fractures), the RH in the highest quartile of FGF23 compared with the rest was 2.02 (95% confidence interval [CI] 1.07–3.79), but in men with eGFR_CrCy, >60 mL/min/1.73 m² (304/1370 fractures) the RH was 0.91 (95% CI 0.66–1.25) after adjustment for age, clinic site, body mass index, race, total hip bone mineral density, vitamin D, parathyroid hormone, alcohol use, physical activity, fracture history, and serum phosphorus. Serum FGF23 levels are not associated with incident fractures in elderly men overall. However, higher levels of serum FGF23 are associated with fracture risk in those with poor renal function. © 2013 American Society for Bone and Mineral Research.     

Dietary protein intake and risk of osteoporotic hip fracture in elderly residents of Utah.

The role of protein intake in osteoporosis is unclear. In a case-control study in Utah (n = 2501), increasing level of protein intake was associated with a decreased risk of hip fracture in men and women 50-69 years of age but not in those 70-89 years of age. Protein intake may be important for optimal bone health. INTRODUCTION: Protein is an important component of bone, but the role of dietary protein intake in osteoporosis and fracture risk remains controversial. MATERIAL AND METHODS: The role of dietary protein intake in osteoporotic hip fracture was evaluated in a statewide case-control study in Utah. Patients, 50-89 years of age, with hip fracture (cases) were ascertained through surveillance of 18 Utah hospitals during 1997-2001. Age- and gender-matched controls were randomly selected. Participants were interviewed in their place of residence, and diet was assessed using a picture-sort food frequency questionnaire previously reported to give a useful measure of usual dietary intake in the elderly Utah population. The association between protein intake and risk of hip fracture was examined across quartiles of protein intake and stratified by age group for 1167 cases (831 women, 336 men) and 1334 controls (885 women, 449 men). RESULTS: In logistic regression analyses that controlled for gender, body mass index, smoking status, alcohol use, calcium, vitamin D, potassium, physical activity, and estrogen use in women, the odds ratios (OR) of hip fracture decreased across increasing quartiles of total protein intake for participants 50-69 years of age (OR: 1.0 [reference]; 0.51 [95% CI: 0.30-0.87]; 0.53 [0.31-0.89]; 0.35 [0.21-0.59]; p < 0.001). No similar associations were observed among participants 70-89 years of age. Results from analyses stratified by low and high calcium and potassium intake did not differ appreciably from the results presented above. CONCLUSION: Higher total protein intake was associated with a reduced risk of hip fracture in men and women 50-69 years of age but not in men and women 70-89 years of age. The association between dietary protein intake and risk of hip fracture may be modified by age. Our study supports the hypothesis that adequate dietary protein is important for optimal bone health in the elderly 50-69 years of age.     

Are effects of MTHFR (C677T) genotype on BMD confined to women with low folate and riboflavin intake? Analysis of food records from the Danish osteoporosis prevention study

We have previously found BMD and fracture risk to be significantly associated with the MTHFR (C677T) polymorphism in healthy postmenopausal women in the first years after menopause. Since then, other cohort studies have suggested that sufficient intake of riboflavin and/or folate may have the potential to prevent development of low BMD in women with the TT genotype. This could to some extent explain why this polymorphism is associated with low BMD or fracture in some study populations and not in others. It would also indicate that fractures associated with the TT genotype could be preventable by vitamin B supplementation. We have, therefore, reviewed baseline food record data from our original study to determine if BMD and fracture associations with the MTHFR genotype depended on the intake of folate, riboflavin, or other members of the vitamin B complex, associated with homocysteine metabolism. We analyzed genotype, BMD, and dietary records from 1700 healthy postmenopausal women who participated in the DOPS study. For the assessment of fracture risk, we used longitudinal observations from 854 women in the control group who remained compliant with their initial allocation of no treatment. Riboflavin intake was significantly correlated with femoral neck (FN) BMD in women with the TT genotype (r = 0.24, P < 0.01). FN and lumbar spine (LS) BMD were only associated with the MTHFR genotype in the lowest quartile of riboflavin intake. At the FN, similar threshold effects were shown for folate, vitamin B12, and vitamin B6. Among these vitamin B complex members, stepwise regression analysis identified riboflavin as the only significant predictor of FN BMD in the TT genotype. In conclusion, we confirm reports that BMD in the MTHFR TT genotype is only significantly reduced in the lowest quartile of riboflavin, B12, B6, and folate intake, at least at the time of menopause. Vitamin B supplementation would only be expected to benefit BMD in about 2% of the population, i.e., those with the TT genotype and low vitamin B intake.     

An 18-year prospective study of dietary calcium and bone mineral density in the hip

The object of this study was to determine whether a single 24-hour diet recall of calcium intake obtained an average of 18 years previously would predict bone mineral density (BMD) in the hip in older men and women. A prospective population-based cohort study was done in Rancho Bernardo, California. Between 1973 and 1975, a 24-hour diet recall was obtained in 140 men and 220 women aged 45 and older by a trained interviewer using food models and containers. Responses were coded by the Nutrition Coordinating Center, University of Minnesota. Between 1988 and 1991, BMD in the femoral neck, trochanter, and intertrochanter was measured using dual-energy x-ray absorptiometry. Results showed that age-adjusted mean BMD levels increased significantly with increasing tertile of calcium intake at all hip sites in women, with the most striking difference at the femoral neck. These associations persisted after adjustment for body mass index, smoking, exercise, alcohol intake, use of estrogen replacement therapy, and number of years postmenopausal. No significant trends were seen for men at any hip site. It is concluded that low dietary calcium predicts low BMD in older women independent of other major determinants of BMD.