Scientific Opinion on the substantiation of health claims related to sodium
and potassium salts of citric acid and maintenance of normal bone (ID 330)
pursuant to Article 13(1) of Regulation (EC) No 1924/2006[sup]1[/sup]
EFSA Panel on Dietetic Products, Nutrition and Allergies (NDA)2, 3
European Food Safety Authority (EFSA), Parma, Italy
Słowa kluczowe:
Sodium citrate
bone
health claims
potassium citrate
1. Charakterystyka żywności / składnika
The food constituent that is the subject of the health claim is “citrates as Na-, K-, Ca, Mg-salts”.
In the context of the information provided, the Panel assumes that the food constituents that are the subject of the health claim are calcium, magnesium, sodium and potassium salts of citric acid.
A claim on calcium (including calcium salts of citric acid) and maintenance of normal bone, and a claim on magnesium (including magnesium salts of citric acid) and maintenance of normal bone, have already been assessed with favourable outcomes (EFSA Panel on Dietetic Products Nutrition and Allergies (NDA), 2009, 2010).
This opinion refers to sodium and potassium salts of citric acid.
Potassium and sodium salts of citric acid are soluble in water and occur naturally in foods, particularly in fruits.
Sodium citrate (includes mono-, di- and tricitrate, E331) and potassium citrate (includes mono- and tricitrate, E332) are authorised for addition to foods for technological purposes. Potassium and sodium salts of citric acid are also authorised for addition to foods and for use in food supplements (Annex II of the Regulation (EC) No 1925/20066, Annex II of Directive 2002/46/EC7 and Regulation (EC) No 1333/20088). This evaluation applies to potassium and sodium salts of citric acid naturally present in foods, and those forms authorised for addition to foods and for use in food supplements (Annex II of the Regulation (EC) No 1925/2006, Annex II of Directive 2002/46/EC and Regulation (EC) No 1333/2008).
The Panel considers that the food constituents, potassium and sodium salts of citric acid, which are the subject of the health claim, are sufficiently characterised.
3. Naukowe uzasadnienia wpływu na zdrowie człowieka - Utrzymanie prawidłowego stanu kości
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Utrzymanie prawidłowego stanu kości
Among the references provided for the scientific substantiation of the claim were narrative reviews on for example acid-base homeostasis and dietary potential renal acid load (PRAL) on various chronic diseases, including osteoporosis, or on the influence of dietary PRAL and/or net endogenous acid production (NEAP) on urine pH and renal excretion of minerals, acids and/or bases, which did not include original data that could be used for the scientific substantiation of the claim. A number of references referred to food constituents (e.g. carbonates and/or bicarbonates) other than the citrate salts of sodium and potassium or reported on health outcomes (e.g. back pain and rheumatoid arthritis) other than bone mineral density (BMD). One reference was not available to the Panel after every effort was made to retrieve it. The Panel considers that no conclusions can be drawn from these references for the scientific substantiation of the claim.
Three human intervention studies assessed the effects of potassium citrate on urinary calcium excretion and markers of bone turnover (Marangella et al., 2004; Sakhaee et al., 2005; Sellmeyer et al., 2002).
In two of the studies the intervention lasted less than three months (Sakhaee et al., 2005; Sellmeyer et al., 2002, two and four weeks, respectively). The Panel considers that no conclusions can be drawn from these short-term studies with respect to the effect of potassium citrate on markers of bone turnover.
Marangella et al. (2004) performed a controlled non-randomised trial of potassium citrate administration for three months in 30 post-menopausal women (age 58±8.1 years) with BMD T-scores (femoral neck or lumbar spine) less than -1. Twenty-four age-matched women who did not differ from the study group in BMD or urine/serum biochemistry served as controls. Lumbar and femoral BMD were measured by dual-energy X-ray absorptiometry (DXA) at baseline. Markers of bone turnover were measured at the beginning and end of the study. The Panel notes that in this non-randomised, controlled intervention, no direct comparisons between the intervention and control groups are reported for the relevant outcomes, and considers that no conclusions can be drawn from this study for the scientific substantiation of the claim.
In a double-blind, placebo-controlled trial (Jehle et al., 2006), 181 non-vegetarian healthy post-menopausal women (age 58.6±4.8 years) with low bone mass (T-score -1 to -4) were randomised to consume orally either 30 mEq potassium citrate or 30 mEq potassium chloride (control) daily for a period of 12 months while consuming their usual diet. All subjects received a supplement of 500 mg calcium and 10 µg vitamin D. BMD of the lumbar spine and the hip was assessed by DXA twice at baseline (one week apart at all sites), and at three, six, nine and 12 months for spine and hip regions. BMD of the distal radius and the whole body was assessed at baseline, and after six and 12 months. Blood was collected at baseline and at six and 12 months, and morning fasting urine samples were collected at baseline, and after three, six, nine and 12 months. A total of 161 women completed the trial (n=82 in the potassium citrate group), and 20 dropped out before month 12 (7 in the potassium citrate group), mostly because of gastro-intestinal complaints. The primary endpoint was the intergroup difference in mean percentage change in BMD at lumbar vertebrae L2 through L4 at
month 12. Statistical analyses were performed in the population of completers only. Post-hoc power calculations for this endpoint, using SD values of 3.8 % reported elsewhere and a two-sided α of 0.05, showed that the study had a 90 % power to detect a 2 % intergroup difference with a sample size of 161. It is unclear why the actual SD values obtained in this study were not used for this post-hoc power calculation. Intergroup comparisons were tested by the nonparametric Kruskal-Wallis test. Within-group differences were tested using the nonparametric Wilcoxon rank sum test. The Panel notes that repeated measures at different time points were not considered appropriately in the statistical analyses. BMD at the lumbar spine significantly increased in the potassium citrate group (by 0.89±0.30 %) whilst it significantly decreased in the potassium chloride group (by -0.98±0.38 %). The intergroup difference was 1.87±0.5 % (p<0.001). Similar significant differences between groups were observed for the total hip BMD (1.98±0.51 %; p <0.001) and femoral neck BMD (1.39±0.48 %; p<0.001), but not for the distal radius or total body BMD. Markers for bone formation behaved discordantly but similarly in both groups: bone specific alkaline phosphatase significantly increased and serum osteocalcin significantly decreased. Changes in the urinary markers of bone resorption, deoxypyridinoline (DPD) and pyridinoline (PYR), were not significantly different between groups, except for a significant decrease in DPD at month 3 in the potassium citrate group compared to the potassium chloride group only. No significant differences between groups were observed for changes in beta C-terminal telopeptide of type 1 collagen (CTX), another marker for bone resorption. Potassium citrate significantly decreased renal calcium excretion and increased citrate excretion as well as net acid excretion (NAE; 35±8 mmol/day in the potassium chloride group vs. 6±9 mmol/day in the potassium citrate group). NAE was significantly and negatively correlated with the percentage change in lumbar BMD at 12 months. The Panel notes that this study, which had some methodological limitations (i.e. statistical analyses were performed in the sample of completers only, repeated measures at different time points were not considered), showed an effect of potassium citrate compared to potassium chloride on BMD in the lumbar spine at 12 months. The Panel also notes that no consistent differences in bone turnover markers were observed between groups throughout the study.
In a double-blind, placebo-controlled trial (Macdonald et al., 2008), 276 non-vegetarian, healthy post-menopausal women (55-65 years) were randomised to consume orally a high dose of potassium citrate (55.5 mEq/day, n=70), a low dose of potassium citrate (18.5 mEq/day, n=70), placebo (unspecified, n=70) or 300 g additional fruits and vegetables/day (n=66) for two years. BMD was measured at the spine and the hip at baseline and at two years by the same radiographer using a DXA scanner. Two-hour urine samples (collected early in the morning in the fasted state) and blood samples (collected non-fasted at the same time of day) were taken at baseline and at 3, 6, 12, 18, and 24 months, for the determination of markers of bone turnover (serum N-terminal propeptide of type 1 collagen (P1NP), CTX, and urine free deoxypyridinoline cross links (fDPD)). A sample size of 42
subjects per group was estimated to detect a difference of 2.5 4 % BMD (80 % power, p=0.05) between the intervention and placebo groups, assuming an annual BMD loss of 0.75 % in the placebo group, and allowing an annual increase in spine BMD of 0.5 % to be detected in the treatment arms. Statistical analyses were carried out on an intention-to-treat basis, and on a per-protocol basis for women with > 80 % compliance. Compliance was estimated at each 3-month visit by capsule count for the potassium citrate and placebo groups and by dietary reporting for the fruit and vegetable arm. No significant differences in BMD at any site were observed between the intervention and placebo groups in the intention-to-treat or per-protocol analyses. Adjustment for weight, height, age, and social deprivation category did not change the outcome. Repeated-measures ANOVA on an intention-to-treat basis comparing baseline and last visit only (n=260) showed no significant visit x treatment interaction for serum P1NP or CTX. Similarly, for fDPD/Cr (n=258) there was no difference between groups. Repeated-measures ANOVA for the bone marker data that were available for every visit (n=202) also showed no visit x treatment interaction for serum P1NP, CTX, or urinary fDPD/Cr. The outcome was the same when the analysis was repeated with the exclusion of non-compliers or women who were on blood pressure–lowering medication. The Panel notes that this two-year, adequately powered, study did not show an effect of either low (18.5 mEq/day) or high
(55.5 mEq/day) doses of potassium citrate on BMD or markers of bone turnover in post-menopausal women.
The Panel notes that one human intervention study with some limitations showed an effect of potassium citrate administered at doses of 30 mEq/day for one year on BMD in the lumbar spine in osteopenic post-menopausal women, whereas another adequately powered human intervention study without such limitations showed no effect of potassium citrate at doses of either 18.5 or 55.5 mEq/day administered for two years on BMD at any site. The Panel also notes that no consistent effect of potassium citrate on markers of bone turnover was observed in either of the studies.
No studies which investigated the effects of sodium citrate on either BMD or markers of bone turnover were provided.
In weighing the evidence, the Panel took into account that the results from the two human intervention studies provided which investigated the effects of potassium citrate on BMD in post-menopausal women are conflicting, and that the adequately powered intervention study of longer duration using a higher dose of potassium citrate did not show an effect on BMD.
The Panel concludes that a cause and effect relationship has not been established between the dietary intake of potassium or sodium salts of citric acid and maintenance of normal bone.