Tag Archives: negative

Phenytoin Lowers Vitamin D

Abstract

Bone health in young women with epilepsy after one year of antiepileptic drug monotherapy.

Antiepileptic drugs (AEDs) may have adverse effects on bone mineral density (BMD) and metabolism. We previously reported biochemical evidence of increased bone turnover in premenopausal women with epilepsy on phenytoin monotherapy compared with those on carbamazepine, lamotrigine, and valproate. We therefore hypothesized that rates of bone loss would be higher in young women treated with phenytoin.
Ninety-three premenopausal women with epilepsy receiving a single AED (carbamazepine, lamotrigine, phenytoin, or valproate) participated. Subjects completed nutritional and physical activity questionnaires. Biochemical indices of bone and mineral metabolism and BMD of the proximal femur and lumbar spine were measured at baseline and 1 year.
Participants reported high calcium intake (>1,000 mg/day) and were physically active. Significant loss (2.6%) was seen at the femoral neck in the phenytoin group. BMD remained stable in the other AED groups. Bone turnover markers and calciotropic hormones were unchanged after 1 year in all groups except for a significant decline in urine N-telopeptide in the phenytoin group. In women receiving phenytoin, lower serum 25-hydroxyvitamin D concentrations were associated with higher parathyroid hormone, bone alkaline phosphatase, and urine N-telopeptide levels, a biochemical pattern consistent with secondary hyperparathyroidism and increased remodeling.
In this study, young women treated with phenytoin had significant femoral neck bone loss over 1 year. In contrast, those treated with carbamazepine, lamotrigine, and valproate did not have detectable adverse effects on bone turnover or bone mineral density. These results raise concerns about the long-term effects of phenytoin monotherapy on bone in young women with epilepsy.

Pack AM, Morrell MJ, Randall A, McMahon DJ…
Neurology Apr 2008
PMID: 18443309

Phenytoin Associated with Increased Rate of Loss of Calcaneus Bone

Abstract

Antiepileptic drug use increases rates of bone loss in older women: a prospective study.

To test the hypothesis that older women with antiepileptic drug (AED) use have increased rates of bone loss. AED use was ascertained and calcaneal and hip bone mineral density (BMD) measured in a cohort of 9,704 elderly community-dwelling women enrolled in the Study of Osteoporotic Fractures, and they were followed prospectively for changes in BMD.
Current use of AED was assessed by interview, with verification of use from medication containers at baseline and follow-up examinations. Women were classified as continuous users, partial (intermittent) users, or nonusers. Rates of change in BMD were measured at the total hip and two subregions (average 4.4 years between examinations) and at the calcaneus (average 5.7 years between examinations).
After adjustment for confounders, the average rate of decline in total hip BMD steadily increased from -0.70%/year in nonusers to -0.87%/year in partial AED users to -1.16%/year in continuous AED users (p value for trend = 0.015). Higher rates of bone loss were also observed among continuous AED users at subregions of the hip and at the calcaneus. In particular, continuous phenytoin users had an adjusted 1.8-fold greater mean rate of loss at the calcaneus compared with nonusers of AED (-2.68 vs -1.46%/year; p < 0.001) and an adjusted 1.7-fold greater mean rate of loss at the total hip compared with nonusers of AED (-1.16 vs -0.70%/year; p = 0.069).
Continuous AED use in elderly women is associated with increased rates of bone loss at the calcaneus and hip. If unabated, the rate of hip bone loss among continuous AED users is sufficient to increase the risk of hip fracture by 29% over 5 years among women age 65 years and older.

Ensrud KE, Walczak TS, Blackwell T, Ensrud ER…
Neurology Jun 2004
PMID: 15184613

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

Abstract

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].

Review: Alkaline Diet is Not Supported by Evidence

Abstract

Causal assessment of dietary acid load and bone disease: a systematic review & meta-analysis applying Hill’s epidemiologic criteria for causality.

Modern diets have been suggested to increase systemic acid load and net acid excretion. In response, alkaline diets and products are marketed to avoid or counteract this acid, help the body regulate its pH to prevent and cure disease. The objective of this systematic review was to evaluate causal relationships between dietary acid load and osteoporosis using Hill’s criteria.
Systematic review and meta-analysis. We systematically searched published literature for randomized intervention trials, prospective cohort studies, and meta-analyses of the acid-ash or acid-base diet hypothesis with bone-related outcomes, in which the diet acid load was altered, or an alkaline diet or alkaline salts were provided, to healthy human adults. Cellular mechanism studies were also systematically examined.
Fifty-five of 238 studies met the inclusion criteria: 22 randomized interventions, 2 meta-analyses, and 11 prospective observational studies of bone health outcomes including: urine calcium excretion, calcium balance or retention, changes of bone mineral density, or fractures, among healthy adults in which acid and/or alkaline intakes were manipulated or observed through foods or supplements; and 19 in vitro cell studies which examined the hypothesized mechanism. Urine calcium excretion rates were consistent with osteoporosis development; however calcium balance studies did not demonstrate loss of whole body calcium with higher net acid excretion. Several weaknesses regarding the acid-ash hypothesis were uncovered: No intervention studies provided direct evidence of osteoporosis progression (fragility fractures, or bone strength as measured using biopsy). The supporting prospective cohort studies were not controlled regarding important osteoporosis risk factors including: weight loss during follow-up, family history of osteoporosis, baseline bone mineral density, and estrogen status. No study revealed a biologic mechanism functioning at physiological pH. Finally, randomized studies did not provide evidence for an adverse role of phosphate, milk, and grain foods in osteoporosis.
A causal association between dietary acid load and osteoporotic bone disease is not supported by evidence and there is no evidence that an alkaline diet is protective of bone health.

Fenton TR, Tough SC, Lyon AW, Eliasziw M…
Nutr J 2011
PMID: 21529374 | Free Full Text

 

Sodium Associated with Lower Bone Density in Young Women

Abstract

Higher urinary sodium, a proxy for intake, is associated with increased calcium excretion and lower hip bone density in healthy young women with lower calcium intakes.

We assessed 24-h urinary sodium (Na) and its relationship with urinary calcium (Ca) and areal bone mineral density (aBMD) at the whole body, lumbar spine and total hip in a cross-sectional study. 102 healthy non-obese women completed timed 24-h urine collections which were analyzed for Na and Ca. Dietary intakes were estimated using a validated food frequency questionnaire. Participants were grouped as those with lower vs. higher calcium intake by median split (506 mg/1000 kcal). Dietary Na intake correlated with 24-h urinary loss. Urinary Na correlated positively with urinary Ca for all participants (r = 0.29, p < 0.01) and among those with lower (r = 0.37, p < 0.01) but not higher calcium intakes (r = 0.19, p = 0.19). Urinary Na was inversely associated with hip aBMD for all participants (r = -0.21, p = 0.04) and among women with lower (r = -0.36, p < 0.01) but not higher (r = -0.05, p = 0.71) calcium intakes. Urinary Na also entered a regression equation for hip aBMD in women with lower Ca intakes, contributing 5.9% to explained variance. In conclusion, 24-h urinary Na (a proxy for intake) is associated with higher urinary Ca loss in young women and may affect aBMD, particularly in those with lower calcium intakes.

Bedford JL, Barr SI
Nutrients Nov 2011
PMID: 22254088 | Free Full Text

The potential implications of sodium-induced calciuria for bone are likely to be more serious in those with low calcium intakes, who may be unable to increase calcium absorption to fully compensate for increased urinary losses. For example, Heaney [3] noted that to offset the average urinary calcium loss of 1 mmol (40 mg) associated with an increased sodium intake of 100 mmol (2300 mg), gross calcium absorption efficiency would need to increase to 34% (from 25%) in those with intakes of 600 mg/day, and to about 50% (from 37%) in those with intakes of 300 mg/day-and that this may not be possible. However, at intakes of 1200 mg/day, absorption efficiency would only need to increase from to 23% (from 20%) [3]. Empirical support for the idea that high calcium intakes may protect against high sodium intakes is provided by the study of Ilich et al. [20]. In a 3-year prospective study, postmenopausal women were randomly assigned to maintain usual sodium intake of about 3000 mg/day or to reduce intake to 1500 mg/day. All women also received calcium supplements, and total calcium intake averaged over 1300 mg/day. Because compliance with the sodium intervention was not high, results were reported by tertile of observed urinary sodium excretion rather than by initial group assignment. No negative associations between urinary sodium and bone density were observed [20]. This suggests that, at least in postmenopausal women with high calcium intakes, sodium intake does not adversely affect bone.

DASH Diet and Sodium Reduction Improve Bone in Adults

Abstract

The DASH diet and sodium reduction improve markers of bone turnover and calcium metabolism in adults.

Dietary strategies to prevent and treat osteoporosis focus on increased intake of calcium and vitamin D. Modification of whole dietary patterns and sodium reduction may also be effective. We examined the effects of two dietary patterns and three sodium levels on bone and calcium metabolism in a randomized feeding study. A total of 186 adults, aged 23-76 y, participated. After a 2-wk run-in period, participants were assigned randomly to diets containing three levels of sodium (50, 100 and 150 mmol/d) to be consumed for 30 d in random order. Serum osteocalcin (OC), C-terminal telopeptide of type I collagen (CTX), fasting serum parathyroid hormone (PTH), urinary sodium, potassium, calcium and cAMP were measured at baseline and at the end of each sodium period. The Dietary Approaches to Stop Hypertension (DASH) diet reduced serum OC by 8-11% and CTX by 16-18% (both P < 0.001). Urinary calcium excretion did not differ between subjects that consumed the DASH and control diets. Reducing sodium from the high to the low level significantly decreased serum OC 0.6 microg/L in subjects that consumed the DASH diet, fasting serum PTH 2.66 ng/L in control subjects and urinary calcium 0.5 mmol/24 h in both groups. There were no consistent effects of the diets or sodium levels on urinary cAMP. In conclusion, the DASH diet significantly reduced bone turnover, which if sustained may improve bone mineral status. A reduced sodium intake reduced calcium excretion in both diet groups and serum OC in the DASH group. The DASH diet and reduced sodium intake may have complementary, beneficial effects on bone health.

Lin PH, Ginty F, Appel LJ, Aickin M…
J. Nutr. Oct 2003
PMID: 14519796 | Free Full Text

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

Abstract

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

 

Caffeine >330 mg/day Associated with Fractures in Swedish Women

Abstract

Coffee, tea and caffeine consumption in relation to osteoporotic fracture risk in a cohort of Swedish women.

Consumption of coffee and tea, and total intake of caffeine has been claimed to be associated with osteoporotic fracture risk. However, results of earlier studies lack consistency.
We examined this relation in a cohort of 31,527 Swedish women aged 40-76 years at baseline in 1988. The consumption of coffee, caffeinated tea and the intake of caffeine were estimated from a self-administered food frequency questionnaire (FFQ). Multivariate-adjusted hazards ratios (HRs) of fractures with 95% confidence intervals (95% CIs) were estimated by Cox proportional hazards models.
During a mean follow-up of 10.3 years, we observed 3,279 cases with osteoporotic fractures. The highest (>330 mg/day) compared with the lowest (<200 mg/day) quintile of caffeine intake was associated with a modestly increased risk of fracture: HR 1.20 (95% CI: 1.07-1.35). A high coffee consumption significantly increased the risk of fracture (p for trend 0.002), whereas tea drinking was not associated with risk. The increased risk of fracture with both a high caffeine intake and coffee consumption was confined to women with a low calcium intake (<700 mg/day): HR 1.33 (95% CI: 1.07-1.65) with > or =4 cups (600 ml)/day of coffee compared to <1 cup (150 ml)/day. The same comparison but risk estimated for women with a high propensity for fractures (> or =2 fracture types) revealed a HR of 1.88 (95% CI: 1.17-3.00).
In conclusion, our results indicate that a daily intake of 330 mg of caffeine, equivalent to 4 cups (600 ml) of coffee, or more may be associated with a modestly increased risk of osteoporotic fractures, especially in women with a low intake of calcium.

Hallström H, Wolk A, Glynn A, Michaëlsson K
Osteoporos Int 2006
PMID: 16758142

Coffee at ≥ 4 Cups Associated with Lower Bone Density, but Not Fractures

Abstract

Long-term coffee consumption in relation to fracture risk and bone mineral density in women.

High consumption of coffee has been suggested to reduce the risk of some late-onset diseases and death but also to contribute to the development of osteoporotic fractures. Results of previous fracture studies have been inconsistent, and a comprehensive study is needed. The longitudinal population-based Swedish Mammography Cohort, including 61,433 women born in 1914-1948, was followed up from 1987 through 2008. Coffee consumption was assessed with repeated food frequency questionnaires. During follow-up, 14,738 women experienced fracture of any type, and 3,871 had a hip fracture. In a subcohort (n = 5,022), bone density was measured and osteoporosis determined (n = 1,012). After multivariable adjustment, there was no evidence of a higher rate of any fracture (hazard ratio per 200 mL coffee = 0.99; 95% confidence interval: 0.98, 1.00) or hip fracture (hazard ratio per 200 mL coffee = 0.97, 95% confidence interval: 0.95, 1.00) with increasing coffee consumption. A high coffee intake (≥4 cups daily) versus a low intake (<1 cup daily) was associated with a 2%-4% lower bone density, depending on site (P < 0.001), but the odds ratio for osteoporosis was only 1.28 (95% confidence interval: 0.88, 1.87). Thus, high coffee consumption was associated with a small reduction in bone density that did not translate into an increased risk of fracture.

Hallström H, Byberg L, Glynn A, Lemming EW…
Am. J. Epidemiol. Sep 2013
PMID: 23880351

Caffeine with < 800mg Calcium May Accelerate Bone Loss

Abstract

Caffeine and bone loss in healthy postmenopausal women.

The effects of caffeine consumption on rates of change in bone mineral density (BMD) were examined in 205 healthy, nonsmoking, postmenopausal women. BMD of the spine and total body were measured by dual-energy x-ray absorptiometry, and dietary intakes by food-frequency questionnaire. Among women with calcium intakes above the median (744 mg/d), 1-y rates of bone change–adjusted for years since menopause, body mass index, physical activity, and baseline BMD–did not differ by caffeine intake. However, among women consuming less calcium, those with the highest caffeine intakes (> 450 mg/d) had significantly more bone loss (ANCOVA, P < 0.05) than did women consuming less caffeine (0-171 and 182-419 mg/d). Percent change in BMD by lowest to highest tertile of caffeine consumption was 0.26 +/- 2.74, 0.70 +/- 2.70, and -1.36 +/- 2.70 at the spine and -0.19 +/- 1.24, 0.23 +/- 1.23, and -0.68 +/- 1.25 at the total body. Daily consumption of caffeine in amounts equal to or greater than that obtained from about two to three servings of brewed coffee may accelerate bone loss from the spine and total body in women with calcium intakes below the recommended dietary allowance of 800 mg.

Harris SS, Dawson-Hughes B
Am. J. Clin. Nutr. Oct 1994
PMID: 8092093 | Free Full Text