Whole-grain intake, incident hip fracture, and presumed frailty in the Iowa Women’s Health Study

Abstract

Whole cereal grain foods are high in phytate, a calcium chelator, and could increase risk of hip fracture. We investigated baseline whole grain intake and incident hip fracture. We followed 29,192 women who, at baseline in 1986 were aged 55–69 y, free of diabetes, reported plausible energy intake of 600–5000 kcal/d, and reported no fracture since age 35 y. Hip fracture (n=746) was self-reported in 5 questionnaires through 2004. Of 1451 hip fractures identified passively by Medicare linkage through Dec 31, 2004 (Medicare hip fracture), 507 had also been self-reported. Whole grain intake was inversely related to Medicare hip fracture (p_trend=0.02), but was unrelated to self-reported hip fracture (p_trend=0.27). The hazard ratio in highest to lowest quintile of whole grain intake for incident Medicare only hip fracture (n=944) was 0.68 (95% confidence interval 0.56, 0.84) after adjustment for age, energy intake, education, body mass index, waist to hip ratio, farm residence, physical activity, estrogen use, smoking, alcohol use, history of cancer and other dietary variables. Medicare only cases may have failed to self-report due to severe illness; hazard ratio for total mortality after hip fracture was 2.92 (2.37,3.59) for Medicare only cases vs Medicare-confirmed self-reported cases. In conclusion, in this cohort, an inverse association of whole grain intake with hip fracture was explained by ascertainment bias. Whole grain intake may increase ability to respond to a questionnaire and self-report hip fracture and could reflect less undocumented frailty.

Whole cereal grain consumption is thought to have health benefits such as protecting against coronary heart disease and diabetes^(1–7). Accordingly, the 2005 US Dietary Guidelines recommend that at least half of the recommended 6–11 grain servings/day comprise whole grain foods⁽⁸⁾. However, one potential concern is whether the phytic acid in whole grain foods might lead to an increased risk of hip fracture by reducing the bioavailability of dietary minerals^(9–16), in particular co-ingested calcium. Thus, increased whole grain consumption could have an adverse effect on bone metabolism⁽¹³⁾ potentially increasing risk for fracture⁽¹⁴⁾.

Most studies concerned with this phenomenon have been either in vitro⁽¹¹⁾ or short term human feeding studies which measure calcium-binding or biomarkers of bone turnover^(15,16). Findings from balance studies^{(10, 17)} have been inconsistent, possibly due to imprecise measurements of calcium absorption. Human feeding studies^(13,14,16) have suggested a lack of association between whole grain food intake and markers of bone turnover or density, however these studies have been limited by small sample size, short duration of the intervention, and other study design limitations.

In this study, we evaluated the association between whole grain intake and risk of incident hip fracture in a large, prospective cohort study of women, most of whom were post-menopausal. Based on the literature to date, we hypothesized no effect of whole grain or phytic acid intake on incident hip fracture risk. We actually observed an inverse association with hip fracture that was not self-reported. We therefore explored the characteristics of women who did not report their hip fracture and considered the possibility that those hip fractures might be associated with a frail condition.

Subjects and methods

Subjects

The Iowa Women’s Health Study was originally designed to study dietary and lifestyle factors and cancer incidence. In 1986, 99,826 Iowa women aged 55–69 were randomly sampled from the 1985 Iowa Department of Transportation driver’s license list and sent a questionnaire; 41,836 women (42%) participated, as previously described⁽¹⁷⁾. On average, non-responders had a 0.4 kg/m² higher mean BMI, were 3 months younger, more likely to live in rural counties, and had a slightly lower mean income compared to responders⁽¹⁷⁾. From the participating Iowa women’s cohort (N=41,836), the present analysis was carried out with (n=29,192) women. We followed women for self-reported hip fracture in 5 questionnaires. We excluded women whose baseline questionnaire self-reported diabetes (n=3007), energy intake outside a reasonable range (600–5000 kcal/day) (n=3102), a self-reported fracture between age 35 and baseline (n=5863) or had missing data on variables used in the multivariate adjusted model of the analysis (n=916); exclusions were not mutually exclusive. We additionally linked the women to the Centers for Medicare and Medicaid Services (CMS) database (Medicare records) to identify hip fractures that had not been self-reported. Some women had no CMS record, so that the final sample size for the outcome variable hip fracture identified by CMS linkage was 28,706. About 98% of women were ever enrolled in Medicare.

Data Collection

The 1986 baseline questionnaire included questions on variables possibly relevant to hip fracture (demographic: age, weight, height, farm residence, educational level; lifestyle factors: smoking, alcohol consumption, hormone replacement therapy (HRT), and physical activity; medical conditions: cancer other than skin cancer). A tape measure was included with the questionnaire; waist and hip measurements obtained following instructions and with the help of a friend, and waist to hip ratio (WHR) computed. Also included was a 127-item semi-quantitative food frequency questionnaire, adapted from the Nurses’ Health Study, developed and validated within a subgroup of nurses of the Boston area aged 34–59⁽¹⁸⁾ and tested for reliability in 1988 within a subset of this study’s cohort of 44 women giving several 24-hour recalls⁽¹⁹⁾. The women indicated their average dietary intake in servings per week over the past year from nine categories (never or less than once per month, 1–3 per month, 1 per week, 2–4 per week, 1 per day, 2–3 per day, 4–5 per day, 6+ per day) for the listed food items, disregarding seasonal variations in intake for fruit and vegetables.

The composite measure of whole grain intake (servings per week), has been well documented previously and was the sum of servings per week consumed for each of dark bread, cold breakfast cereal, brown rice, popcorn, wheat germ, bran, cooked oatmeal, and other grains (i.e. bulgar, kasha, and couscous)⁽²⁰⁾. Further, the women were asked for the brand of their most commonly eaten breakfast cereal which was counted as being whole grain if ≥25% of its weight was from whole grain or bran⁽²¹⁾. Energy intake, phytic acid, and dietary calcium were calculated using the Harvard Nutrient Database⁽¹⁸⁾.

Five mailed follow up questionnaires were collected in 1987, 1989, 1992, 1997, and 2004, with response rates of 91%, 89%, 83%, 79%, and 69%. Included were queries whether since the last survey date they had suffered a fracture (broken bone) which required treatment by a doctor, and if so whether it was a hip fracture. For hip fractures reported in the 1987 and 1989 followup questionnaires, detailed validation questionnaires were sent by Munger et al.⁽²¹⁾ Of 75 detailed questionnaires returned, 66 (88.0%) confirmed their original brief report of hip fracture, errors being attributed to incorrectly marking the followup questionnaire or mistaking sprains or other pains for fractures. The hip fracture diagnosis was confirmed in all 44 cases in which the physician responded to a separate inquiry.

In the present study, hip fracture was self-reported by 746 women. CMS data linkage identified 1451 hip fractures (all acute care hospitalizations from 1986–2004 with an International Classification of Diseases 9 code of 820.XX in any of the 10 discharge diagnosis fields). Of the 746 self-report hip fractures, 507 also had a CMS report. No CMS hip fracture was found in 233 self-report cases, 6 self-report cases had no CMS record, and 944 hip fractures were found by CMS linkage only. Among those with hip fracture age at least 65 years (the age of Medicare eligibility for most people), 1379 were identified by CMS linkage and 662 were self-reported, of which 496 also had a CMS report. Unconfirmed self-report hip fracture may be partly errant reporting. If 88% of self-reports are correct⁽²¹⁾, about 90 of 746 would not actually be hip fractures, and these 90 would constitute 38% of the 239 not confirmed by CMS linkage. Unconfirmed self-report could also be attributed to age ineligibility for Medicare or treatment not captured by CMS (in a Health Maintenance Organization or outside of Medicare).

For self-reported hip fracture, total person-years at risk was computed from the time of the baseline questionnaire in 1986 until (a) the midpoint between the dates of the follow up questionnaire first reporting a hip fracture and the questionnaire preceding it, (b) the date of death through December 31, 2004, or (c) the date of the last survey completed prior to December 31, 2004. For CMS-identified hip fracture, total person-years at risk was computed similarly, except that the start of follow-up was the date of first Medicare enrollment and ended at the date of death or first Medicare disenrollment. Deaths were identified through the Iowa State Health Registry and the National Death Index.

Statistical Analysis

All data analyses were carried out with SAS software (version 9.2; SAS Institute Inc., Cary, NC). Proportional hazards regression analysis was used to compare hip fracture risk across quintiles of whole grain, with the lowest intake as the reference category. The p-value for risk trend was computed from a parallel regression analysis in which whole grain was used as a continuous variable. Covariates in the fully adjusted model were age (continuous), energy intake (continuous), education, body mass index (BMI), BMI², WHR, living on a farm (yes/no), physical activity (low, moderate, high), HRT (yes, no/not currently), smoking (current, past, never), alcohol (g/day), total dairy (servings/week), legumes (servings/week), fish and seafood (servings/week), fruit (servings/week), vegetables (servings/week), and history of cancer at baseline (yes/no). Relative hazards with their respective 95% confidence intervals were presented. Parallel analyses were carried out with phytic acid or the ratio of phytic acid to calcium intake as the predictor variable.

Results

As previously reported^(3,6,22,23), compared with women who rarely ate whole grain foods, habitual whole grain food consumers had an otherwise healthy life style, including lower BMI, lower refined grain intake, higher fruit and vegetable intake, higher education, less smoking, more estrogen and multivitamin use, and were more likely to live on a farm. As hypothesized, we found no significant difference in risk of incident self-reported hip fracture across quintiles of whole cereal grain intake among the 29,192 Iowa women, whether in the minimally adjusted or the multivariable adjusted model (Table 1A). In contrast, and contrary to our hypothesis, risk of incident hip fracture identified by CMS decreased across quintiles of whole cereal grain intake among the 28,706 Iowa women ever enrolled in Medicare, in both the minimally adjusted (p_trend = 0.003) and the multivariable adjusted model (p_trend = 0.02, Table 1B). The difference in findings between analyses from the two case ascertainment sources is more apparent in analysis of risk of incident hip fracture identified only by CMS, decreased strongly across quintiles of whole cereal grain intake (p_trend <0.001, Table 1C). The lack of association of whole grain intake with self-reported hip fracture (Table 1A) was also found in self-reported cases that were confirmed in CMS linkage (Table 1D).

Table 1.

Adjusted hazard ratios (95% CI) for incident self-reported hip fractures across quintiles of whole grain intake (servings/week) among women aged 55–69 at baseline, Iowa Women’s Health Study, 1986–2004

		Quintiles of Total Whole Grain
		Q1	Q2	Q3	Q4	Q5	P for trend
Servings/week		(0–3.5)	(4–7)	(7.5–10.5)	(10.84–18.5)	(19+)
Mean (SD)		1.8±1.1	5.6±1.1	8.8±1.0	14.5±2.5	25.7±7.5
A. Self-reported hip fracture
Number at risk	29,192	5477	5740	6060	6171	5744
Cases	746	131	143	152	168	152
Person-Years	407,571	72,952	79,467	85,725	87,271	82,157
Minimally-adjusted (95% CI)*		1	1.00 (0.79, 1.27)	0.95 (0.75, 1.20)	1.01 (0.81, 1.26)	0.99 (0.78, 1.26)	0.62
Multivariable-adjusted (95% CI)†		1	1.08 (0.85, 1.38)	1.04 (0.82, 1.32)	1.12 (0.89, 1.43)	1.11 (0.86, 1.42	0.27
B. Hip fracture identified by Medicare linkage
Number at risk	28,706	5357	5634	5968	6079	5668
Cases	1451	295	279	308	307	262
Person-Years	382,285	68,705	73,793	79,932	82,693	77,162
Minimally-adjusted (95% CI)*		1	0.74 (0.62, 0.87)	0.81 (0.69, 0.95)	0.86 (0.73, 1.00)	0.87 (0.74, 1.02)	0.003
Multivariable-adjusted (95% CI)†		1	0.93 (0.79, 1.09)	0.93 (0.79, 1.09)	0.88 (0.74, 1.04)	0.81 (0.68, 0.96)	0.02
C. Hip fracture identified only by Medicare linkage
Number at risk	28,706	5357	5634	5968	6079	5668
Cases	944	209	182	208	194	151
Minimally-adjusted (95% CI)*		1	0.79 (0.65, 0.97)	0.81 (0.67, 0.98)	0.71 (0.58, 0.86)	0.59 (0.48, 0.73)	<.0001
Multivariable-adjusted (95% CI)†		1	0.85 (0.69, 1.04)	0.89 (0.73, 1.08)	0.78 (0.63, 0.95)	0.66 (0.53, 0.82)	<0.001
D. Hip fracture identified by self-report and by Medicare linkage
Number at risk	28,706	5357	5634	5968	6079	5668
Cases	507	86	97	100	113	111
Minimally-adjusted (95% CI)*		1	1.05 (0.79,1.41)	0.97 (0.73, 1.30)	1.08 (0.81, 1.43)	1.12 (0.84, 1.50)	0.17
Multivariable-adjusted (95% CI)†		1	1.12 (0.83, 1.50)	1.03 (0.77, 1.39)	1.13 (0.84, 1.51)	1.18 (0.87, 1.59)	0.16

^*Adjusted for age (continuous), and energy intake (continuous)

^†Adjusted for age (continuous), energy intake (continuous), education, BMI, BMI², WHR, living on a farm (yes/no), physical activity (low, moderate, high), HRT (yes, no/not currently), smoking (current, past, never), alcohol (g/day), total dairy (servings/week), legumes (servings/week), fish and seafood (servings/week), fruit (servings/week), vegetables (servings/week), and cancer at baseline (yes/no).

Additional analyses focused on the influence of case ascertainment method. First, polychotomous logistic regression in the multivariable adjusted model found that the prediction coefficients for whole grain differed significantly for self-reported vs, CMS only cases (p = 0.0003). Second, within those who self-reported hip fracture (n=746) or were CMS only cases (n=944), 56% were CMS only cases. In the multivariable model using linear regression, the case ascertainment source was CMS only was 62% in the lowest whole grain intake quintile, decreasing progressively to 49% in the highest quintile.

Severe illness may have been involved in failure to self-report in CMS only cases. Self-reported hip fractures not reported by CMS occurred at average age 69.8±7.1 years, compared to 74.8±5.2 years in self-report cases also identified by CMS and 76.3±7.2 years in cases identified only be CMS. Death was much more frequent after a CMS only hip fracture than after CMS-confirmed self-reported hip fracture (23% vs 48% through the end of follow-up). The hazard ratio for total mortality after hip fracture was 2.92 (2.37, 3.59) for CMS only cases vs those that were also self-reported, with multivariable adjustment as in Table 1. Furthermore, those alive at the end of 2004 with CMS only hip fracture were by far the least likely to respond to the questionnaire in 2004 (Table 2).

Table 2.

Percent responding to the questionnaire in 2004 among 21,770 women alive at the end of 2004

	Number alive	Number responding	Percent responding	z	p
Never had hip fracture	21,023	15,242	73%
Self-report hip fracture through 1997 (in the first 4 followup questionnaires)	252	174	69%	−1.26	0.21
CMS only hip fracture prior to the end of 1997	55	22	40%	−4.89	<1*10−06
CMS only hip fracture between 1998 and 2004	440	108	25%	−19.93	<1*10−87

The z statistic compares the proportion responding in the given row to those who never had a hip fracture, with corresponding 2-sided p-value. Omitted are 321 women alive at the end of 2004 who self-reported their first hip fracture on the 2004 questionnaire.

Proportional hazards regression models (not shown) substituting phytic acid intake (correlation with whole grain food intake = 0.64) agreed with the lack of association of whole grain with self-reported hip fracture. Phytic acid, like whole grain food, was inversely associated with CMS-identified hip fracture (p = 0.04). Phytic acid lost significance in a model that also contained whole grain food intake, while whole grain food intake remained strongly inversely associated with CMS-identified hip fracture (p=0.002) in this model. In contrast, the ratio of phytic acid to calcium intake, which had a correlation with whole grain food intake of 0.20, did not show a significant association with incident hip fracture, whether self-reported or identified by CMS only.

Discussion

During 18 years of followup of women initially aged 55–69 years, whole grain food intake showed an inverse relationship to incident CMS hip fracture (n=1451, p_trend=0.02), but was unrelated to self-reported incident hip fracture (n=746, p_trend=0.27). However, we did see a strong inverse association of whole grain food intake and incident hip fracture identified only through CMS linkage. It is unlikely that whole grain intake is causally related to risk of hip fracture since it is unrelated in a substantial subset of 507 CMS-confirmed, self-reported hip fracture. Our interpretion is therefore that the overall inverse association is the result of ascertainment bias. The CMS only hip fractures were associated with severe illness, as illustrated by accelerated death rate and failure to respond to the 2004 questionnaire. Thus it is reasonable to speculate that many women whose hip fracture was identified only by CMS record linkage exhibited signs of frailty, although we do not have specific data to verify this assumption.

Self-reported hip fracture was partially validated in that it was generally identified in CMS records, however more hip fractures were identified by CMS only than by self-report. In order to self-report hip fracture, a questionnaire must be sent after the hip fracture occurs, reach the subject, and the respondent must be in sufficiently good health to complete and return the survey. Many CMS only cases (women who did not self-report their hip fracture) may well have been incapacitated long after the event.

Although phytate in whole grain could have adverse effects on bone health, such an effect was not apparent in our data. A balance study found negative net calcium effects in subjects consuming a whole grain product⁽¹⁷⁾, but another study did not⁽¹⁰. The inconclusive findings of balance studies have been attributed to imprecise measurements of calcium absorption⁽¹²⁾. Weaver et al.⁽¹²⁾, within a series of randomized crossover experiments, created calcium-labeled wheat which allowed them to measure calcium absorption more precisely. They concluded that calcium absorption was similar from wheat products as from milk, although phytate-rich bran does interfere with co-ingested calcium absorption⁽¹²⁾.

In a study of 19 healthy young women (mean age: 25.7 ± 3.9 years), Zittermann et al. found no difference in serum biomarkers of bone turnover between the high wheat bran fiber (15g/d) and low wheat bran fiber (1g/d) supplementation groups⁽¹⁶⁾. Similarly, in a study of healthy individuals in southern India, Harinarayan et al. found no difference in PTH levels between 205 participants living in rural areas consuming high phytate/calcium diets and 943 participants living in urban areas consuming low phytate/calcium diets, although both groups had low dietary calcium intake and were vitamin D deficient⁽¹³⁾. Whole grain foods provide benefit to the consumer beyond the additive effects of its individual consituents⁽⁹⁾, which could explain why negative net calcium balance studies remain incongruent with serum biomarkers of bone turnover.

Our conclusion that there is no association between whole grain food intake and risk of future hip fracture is consistent with a randomized trial⁽¹⁴⁾. There, no adverse effect was seen of 2–3 years of wheat bran supplementation (124 people assigned to eat 13.5 g/d of wheat bran fiber supplement, delivered as loops, shredded cereal, or bars, and 113 people assigned to eat 2 g/d of the wheat bran fiber) on forearm bone mineral density was seen in a sample of men and women aged 40–80 years.

Much of the beneficial effect of whole grain foods on other health outcomes has been attributed to its multifaceted constitution of dietary fiber, antioxidants, phytochemicals, and other bioactive compounds (lignans, phytosterols, unsaturated fatty acids, anti-nutrients), which are thought to act together to provide protective health benefits to the consumer⁽²⁾. Protease inhibitors, phytic acid, phenolics and saponins have been shown to reduce the risk of cancer of the colon and breast in animals. Phytic acid, lectins, phenolics, amylase inhibitors and saponins have also been shown to lower the plasma glucose, insulin and/or plasma cholesterol and triacylglycerols levels⁽⁹⁾. The synergistic effect of the individual constituents within the whole grain has yet to be explained, but suggest that studies focusing on isolated constituents are to be interpreted with caution.

A limitation of this study is its observational nature, because residual confounding is always a possibility. Although we have adjusted for lifestyle characteristics and other aspects of diet than whole grain food intake, it remains possible that the whole grain intake is a marker for aspects of healthy lifestyle and diet which we did not measure. We were not able to exclude hip fracture due to causes other than osteoporosis, such as traumatic injuries. The study is strictly generalizable only to older women. Strengths include the size and long follow-up. The whole grain food intake variable data collected for this cohort appears to be valid in that it has been shown to be associated with several different chronic disease outcomes^{(1,3,6,22,23)}.

We conclude that in this cohort the inverse association of whole grain intake with hip fracture reflected case ascertainment bias. It is of substantial methodological interest that correlates of self-reported hip fracture differ greatly from those of hip fracture identified by CMS fracture, as has been noted in the Iowa Women’s Health Study data⁽²⁴⁾. It is likely that whole grain intake has a role of whole grain food intake in limiting risk of future frailty. However, because we did not specifically assess frailty, this possibility is stated as a hypothesis for future study.