Tag Archives: prospective

Milk Increases Risk of Fracture in Women


Milk, dietary calcium, and bone fractures in women: a 12-year prospective study.

This study examined whether higher intakes of milk and other calcium-rich foods during adult years can reduce the risk of osteoporotic fractures.
This was a 12-year prospective study among 77761 women, aged 34 through 59 years in 1980, who had never used calcium supplements. Dietary intake was assessed with a food-frequency questionnaire in 1980, 1984, and 1986. Fractures of the proximal femur (n = 133) and distal radius (n = 1046) from low or moderate trauma were self-reported on biennial questionnaires.
We found no evidence that higher intakes of milk or calcium from food sources reduce fracture incidence. Women who drank two or more glasses of milk per day had relative risks of 1.45 for hip fracture (95% confidence interval [CI] = 0.87, 2.43) and 1.05 for forearm fracture (95% CI = 0.88, 1.25) when compared with women consuming one glass or less per week. Likewise, higher intakes of total dietary calcium or calcium from dairy foods were not associated with decreased risk of hip or forearm fracture.
These data do not support the hypothesis that higher consumption of milk or other food sources of calcium by adult women protects against hip or forearm fractures.

Feskanich D, Willett WC, Stampfer MJ, Colditz GA
Am J Public Health Jun 1997
PMID: 9224182 | Free Full Text

Bisphosphonates Reduce Mortality in Women


Osteoporosis medication and reduced mortality risk in elderly women and men.

Osteoporotic fractures are associated with premature mortality. Antiresorptive treatment reduces refracture but mortality reduction is unclear.
The objective of the study was to examine the effect of osteoporosis treatment [bisphosphonates (BP), hormone therapy (HT), and calcium ± vitamin D only (CaD)] on mortality risk.
This was a prospective cohort study (April 1989 to May 2007).
The study was conducted with community-dwelling elderly (aged 60+ yr) subjects in Dubbo, a semiurban city, Australia.
Subjects included 1223 and 819 women and men in the Dubbo Osteoporosis Epidemiology Study.
Mortality according to treatment group was recorded.
There were 325 (BP, n = 106; HT, n = 77; CaD, n = 142) women and 37 men (BP, n = 15; CaD, n = 22) on treatment. In women, mortality rates were lower with BP 0.8/100 person-years (0.4, 1.4) and HT 1.2/100 person-years (0.7, 2.1) but not CaD 3.2/100 person-years (2.5, 4.1) vs. no treatment 3.5/100 person-years (3.1, 3.8). Accounting for age, fracture occurrence, comorbidities, quadriceps strength, and bone mineral density, mortality risk remained lower for women on BP [hazard ratio (HR) 0.3 (0.2, 0.6)] but not HT [HR 0.8 (0.4, 1.8)]. For 429 women with fractures, mortality risk was still reduced in the BP group [adjusted HR 0.3 (0.2, 0.7)], not accounted for by a reduction in subsequent fractures. In men, lower mortality rates were observed with BP but not CaD [BP 1.0/100 person-years (0.3, 3.9) and CaD 3.1/100 person-years (1.5, 6.6) vs. no treatment 4.3/100 person-years (3.9, 4.8)]. After adjustment, mortality was similar, although not significant [HR 0.5 (0.1, 2.0)].
Osteoporosis therapy appears to reduce mortality risk in women and possibly men.

Center JR, Bliuc D, Nguyen ND, Nguyen TV…
J. Clin. Endocrinol. Metab. Apr 2011
PMID: 21289270

Vitamin K Intake Not Associated with Fracture in Chinese Men and Women


No association between dietary vitamin K intake and fracture risk in chinese community-dwelling older men and women: a prospective study.

Data on the association between dietary vitamin K intake and fracture risk are limited among Chinese. This study examined such an association in community-dwelling elderly in Hong Kong. We present data from 2,944 subjects (1,605 men, 1,339 women) who participated in a prospective cohort study. Baseline dietary intakes of energy, protein, calcium, vitamin D, and vitamin K were assessed using a food-frequency questionnaire. Data on incident hip fracture and nonvertebral fracture during a median of 6.9 follow-up years were collected from a hospital database. Cox regression analyses were performed with adjustments for age, education attainment, smoking status, alcohol use, body mass index, hip bone mineral density, physical activity, use of calcium supplement, and energy-adjusted nutrient intakes. There were 29 (1.8 %) men and 19 (1.4 %) women with incident hip fractures and 97 (6.0 %) men and 88 (6.6 %) women with nonvertebral fractures. The median (interquartile range) of dietary vitamin K intake was 241.8 (157.5-360.8) and 238.9 (162.4-343.6) μg/day in men and women, respectively. Similar dietary vitamin K intakes were observed between subjects with hip or nonvertebral fractures and subjects without hip or nonvertebral fractures. In both men and women, dietary vitamin K intake was not associated with fracture risks at all measured sites in either crude or adjusted models. In Chinese community-dwelling elderly, hip or nonvertebral fracture risk was not associated with dietary vitamin K intake. The high dietary vitamin K intake of the studied group may have limited the ability to detect the association between vitamin K intake and fracture risk.

Chan R, Leung J, Woo J
Calcif. Tissue Int. May 2012
PMID: 22451220

Low Vitamin K1, but Not K2, Associated with Hip Fracture


Intake of vitamin K1 and K2 and risk of hip fractures: The Hordaland Health Study.

Evidence of the effect of vitamin K on bone health is conflicting. The aim was to investigate the association between intake of vitamins K1 and K2 and subsequent risk of hip fracture in a general population sample, as well as potential effect modification by apolipoprotein E gene (APOE) status by presence of the E4 allele.
1238 men and 1569 women 71-75 years of age were included in the community-based Hordaland Health Study 1997-1999 in Western Norway. Information on hip fracture was obtained from hospitalizations in the region from enrolment until 31 December 2009. Information on intake of vitamins K1 and K2 collected at baseline was used as potential predictors of hip fracture in Cox proportional hazards regression analyses.
Participants in the lowest compared to the highest quartile of vitamin K1 intake had increased risk of suffering a hip fracture (hazard ratio (HR)=1.57 [95% CI 1.09, 2.26]). Vitamin K2 intake was not associated with hip fracture. Presence of APOE4-allele did not increase the risk of hip fracture, nor was there any effect modification with vitamin K1 in relation to risk of hip fracture.
A low intake of vitamin K1, but not K2, was associated with an increased risk of hip fractures.

Apalset EM, Gjesdal CG, Eide GE, Tell GS
Bone Nov 2011
PMID: 21839190

Vitamin K1 and Vitamin D are Independently and Synergistically Associated with Lower Hip Fracture in Elderly


Vitamin K1 and 25(OH)D are independently and synergistically associated with a risk for hip fracture in an elderly population: A case control study.

The incidence of hip fractures in Oslo is among the highest in the world. Vitamin D, as well as vitamin K, may play an important role in bone metabolism. We examined if vitamin K1 and 25(OH)D were associated with an increased risk of hip fracture, and whether the possible synergistic effect of these two micronutrients is mediated through bone turnover markers.
Blood was drawn for vitamin K1, 25(OH)D, and the bone turnover marker osteocalcin upon admission for hip fracture and in healthy controls.
Vitamin K1 and 25(OH)D were independently associated with a risk of hip fracture. The adjusted odds ratio (95% CI) per ng/ml increase in vitamin K1 was 0.07 (0.02-0.32), and that per nmol/L increase in 25(OH)D was 0.96 (0.95-0.98). There was a significant interaction between 25(OH)D and vitamin K1 (p < 0.001), and a significant correlation between total osteocalcin and vitamin K1 and 25(OH)D (rho = 0.18, p = 0.01; rho = 0.20, p = 0.01, respectively).
Vitamin K1 and 25(OH)D are lower in hip fracture patients compared with controls. Vitamin K1 and 25(OH)D are independently and synergistically associated with the risk of hip fracture when adjusting for confounders. Intervention studies should include both vitamins.

Torbergsen AC, Watne LO, Wyller TB, Frihagen F…
Clin Nutr Jan 2014
PMID: 24559841

Lowering Sodium Increases the Effect of Calcium to Reduce Bone Loss in 124 Postmenopausal Women


A longitudinal study of the effect of sodium and calcium intakes on regional bone density in postmenopausal women.

The influence of urinary sodium excretion and dietary calcium intake was examined in a 2-y longitudinal study of bone density in 124 women postmenopausal for > 10 y. Analysis of bone density changes showed that urinary sodium excretion was negatively correlated with changes in bone density at the intertrochanteric and total hip sites. Multiple-regression analysis of dietary calcium intake and urine sodium excretion on the change in bone density showed that both dietary calcium and urinary sodium excretion were significant determinants of the change in bone mass over 2 y at the hip and ankle sites. These data suggest that an effect of reducing bone loss equivalent to that achieved by a daily dietary increase of 891 mg (22 mmol) Ca can also be achieved by halving daily sodium excretion. No bone loss occurred at the total hip site at a calcium intake of 1768 mg/d (44 mmol/d) or a urine sodium excretion of 2110 mg/d (92 mmol/d). We report a significant effect of sodium excretion on bone loss in this population.

Devine A, Criddle RA, Dick IM, Kerr DA…
Am. J. Clin. Nutr. Oct 1995
PMID: 7572702 | Free Full Text

Risk Factors for Hip Fracture in 9,516 White Women


Risk factors for hip fracture in white women. Study of Osteoporotic Fractures Research Group.

Many risk factors for hip fractures have been suggested but have not been evaluated in a comprehensive prospective study.
We assessed potential risk factors, including bone mass, in 9516 white women 65 years of age or older who had had no previous hip fracture. We then followed these women at 4-month intervals for an average of 4.1 years to determine the frequency of hip fracture. All reports of hip fractures were validated by review of x-ray films.
During the follow-up period, 192 women had first hip fractures not due to motor vehicle accidents. In multivariable age-adjusted analyses, a maternal history of hip fracture doubled the risk of hip fracture (relative risk, 2.0; 95 percent confidence interval, 1.4 to 2.9), and the increase in risk remained significant after adjustment for bone density. Women who had gained weight since the age of 25 had a lower risk. The risk was higher among women who had previous fractures of any type after the age of 50, were tall at the age of 25, rated their own health as fair or poor, had previous hyperthyroidism, had been treated with long-acting benzodiazepines or anticonvulsant drugs, ingested greater amounts of caffeine, or spent four hours a day or less on their feet. Examination findings associated with an increased risk included the inability to rise from a chair without using one’s arms, poor depth perception, poor contrast sensitivity, and tachycardia at rest. Low calcaneal bone density was also an independent risk factor. The incidence of hip fracture ranged from 1.1 (95 percent confidence interval, 0.5 to 1.6) per 1,000 woman-years among women with no more than two risk factors and normal calcaneal bone density for their age to 27 (95 percent confidence interval, 20 to 34) per 1,000 woman-years among those with five or more risk factors and bone density in the lowest third for their age.
Women with multiple risk factors and low bone density have an especially high risk of hip fracture. Maintaining body weight, walking for exercise, avoiding long-acting benzodiazepines, minimizing caffeine intake, and treating impaired visual function are among the steps that may decrease the risk.

Cummings SR, Nevitt MC, Browner WS, Stone K…
N. Engl. J. Med. Mar 1995
PMID: 7862179 | Free Full Text

Flavonoids Associated with Increased Bone Density in Women


Associations between dietary flavonoid intakes and bone health in a Scottish population.

Flavonoids are bioactive polyphenols found particularly in fruit and vegetables, but little is known about their role in bone health in humans. The aim of this observational study was to investigate whether dietary flavonoid intake was associated with bone mineral density (BMD) and bone resorption in a large group of perimenopausal Scottish women. Over 3000 women completed a food frequency questionnaire as part of an osteoporosis screening study. The diets were analyzed for flavonoid intake using a food composition database. BMD was measured at the femoral neck (FN) and lumbar spine (LS) by dual-energy X-ray absorptiometry (DXA). Free pyridinoline (PYD) and deoxypyridinoline (DPD) were measured by high-performance liquid chromatography (HPLC) in second early morning fasted urine samples. The mean flavonoid intake of the diet was 307 ±199 mg/d. The catechin family contributed the most to flavonoid intakes (55%), and the flavones the least (<1%). Associations were found between energy-adjusted total flavonoid intakes and BMD at the FN and LS (FN r = 0.054, LS r = 0.036, p ≤ .05). Annual percent change in BMD was associated with intakes of procyanidins and catechins (p ≤ .05), and flavanones were negatively associated with bone-resorption markers (PYD r = -0.049, DPD r = -0.057, p ≤ .001). These associations were still seen after adjusting for confounders. It is concluded that dietary flavonoid intakes are associated with BMD, supporting the evidence from animal and cellular studies.

Hardcastle AC, Aucott L, Reid DM, Macdonald HM
J. Bone Miner. Res. May 2011
PMID: 21541996

Urine pH or Acid Excretion Doesn’t Predict Bone Density or Fractures


Low urine pH and acid excretion do not predict bone fractures or the loss of bone mineral density: a prospective cohort study.

The acid-ash hypothesis, the alkaline diet, and related products are marketed to the general public. Websites, lay literature, and direct mail marketing encourage people to measure their urine pH to assess their health status and their risk of osteoporosis. The objectives of this study were to determine whether 1) low urine pH, or 2) acid excretion in urine [sulfate + chloride + 1.8x phosphate + organic acids] minus [sodium + potassium + 2x calcium + 2x magnesium mEq] in fasting morning urine predict: a) fragility fractures; and b) five-year change of bone mineral density (BMD) in adults.
Design: Cohort study: the prospective population-based Canadian Multicentre Osteoporosis Study. Multiple logistic regression was used to examine associations between acid excretion (urine pH and urine acid excretion) in fasting morning with the incidence of fractures (6804 person years). Multiple linear regression was used to examine associations between acid excretion with changes in BMD over 5-years at three sites: lumbar spine, femoral neck, and total hip (n = 651). Potential confounders controlled included: age, gender, family history of osteoporosis, physical activity, smoking, calcium intake, vitamin D status, estrogen status, medications, renal function, urine creatinine, body mass index, and change of body mass index.
There were no associations between either urine pH or acid excretion and either the incidence of fractures or change of BMD after adjustment for confounders.
Urine pH and urine acid excretion do not predict osteoporosis risk.

Fenton TR, Eliasziw M, Tough SC, Lyon AW…
BMC Musculoskelet Disord 2010
PMID: 20459740 | Free Full Text

The evidence to support the acid-ash hypothesis of osteoporosis predominantly comes from studies using changes in urine calcium as the outcome [6,8-12,46], some prospective observational studies [16,18,19,47] and one randomized trial [13]. Although one randomized trial has supported the hypothesis [13], another did not [40]. The randomized trial [13] supporting the hypothesis did not use concealment of allocation, a study quality indicator for randomized studies that is important to avoid bias during the randomization process [48]. Without concealment of allocation, investigators can influence the allocation of individuals into the treatment groups, invalidating the randomization. Trials that do not have concealed allocation can overestimate effectiveness of a therapy [49]. The more recent randomized trial, that concealed allocation, did not reveal any protective effect of either potassium citrate or increased fruit and vegetable consumption on change in BMD [14].

Three previous prospective cohort studies of the hypothesis reported some protective associations between fruit and vegetable, potassium, and/or vitamin C intakes and bone health [16,18,19], and thus may support the hypothesis, while two more recent cohort studies do not support it [50,51]. One of the positive reporting studies did not see a significant protective association for potassium once potential confounders were controlled [16]. Further, it is possible that the associations in agreement with the hypothesis in the cohort studies were due to uncontrolled confounding by estrogen status [19], baseline BMD [16,19], change of weight status during follow-up [18], and/or vitamin D status [16,18,19,47].

Further, three recent meta-analyses of the acid-ash hypothesis do not support the hypothesis. First, a meta-analysis of calcium balance studies, restricted to studies of superior methodology, revealed no association between net acid excretion and calcium balance, in spite of the strong relationship between net acid excretion and urinary calcium [52]. A systematic review and meta-analysis of the effect of protein intake on bone health revealed a small beneficial effect of protein supplementation on lumbar spine BMD in randomized placebo-controlled trials [53]. Further, the acid-ash hypothesis predicts higher phosphate intakes would be associated with increased urinary calcium and lower calcium balance, but this was not supported by a third recent meta-analysis [54].

ACE Inhibitors, But Not ARBs, Marginally Increase Bone Loss in Men


Does the use of ACE inhibitors or angiotensin receptor blockers affect bone loss in older men?

In a prospective cohort study of 5,995 older American men (MrOS), users of angiotensin-converting enzyme (ACE) inhibitors had a small but significant increase in bone loss at the hip over 4 years after adjustment for confounders. Use of angiotensin II AT1 receptor blockers (ARB) was not significantly associated with bone loss.
Experimental evidence suggests that angiotensin II promotes bone loss by its effects on osteoblasts. It is therefore plausible that ACE inhibitor and ARB may reduce rates of bone loss. The objective of this study is to examine the independent effects of ACE inhibitor and ARB on bone loss in older men.
Out of 5,995 American men (87.2%) aged ≥65 years, 5,229 were followed up for an average of 4.6 years in a prospective six-center cohort study-The Osteoporotic Fractures in Men Study (MrOS). Bone mineral densities (BMD) at total hip, femoral neck, and trochanter were measured by Hologic densitometer (QDR 4500) at baseline and year 4.
Out of 3,494 eligible subjects with complete data, 1,166 and 433 subjects reported use of ACE inhibitors and ARBs, respectively. When compared with nonusers, continuous use of ACE inhibitors was associated with a small (0.004 g/cm(2)) but significant increase in the average rate of BMD loss at total hip and trochanter over 4 years after adjustment for confounders. Use of ARB was not significantly associated with bone loss.
Use of ACE inhibitors but not ARB may marginally increase bone loss in older men.

Kwok T, Leung J, Zhang YF, Bauer D…
Osteoporos Int Aug 2012
PMID: 22080379