Copyright 2009 Unique Global Possibilities Medical Pty Ltd A DOUBLE-BLIND, PLACEBO-CONTROLLED STUDY OF THE EFFECTS OF ALKALINE MAGNESIUM BICARBONATE SOLUTIONS ON ACID/BASE BALANCE, BONE METABOLISM AND CARDIOVASCULAR RISK FACTORS IN POSTMENOPAUSAL WOMEN Study Investigators R.O. Day 1, W.Liauw 2, L.M.R Tozer 3§ , P McElduff 3, R.J. Beckett 4, K.M.Williams 1 1 St Vincent’s Clinical Trials Centre, Department of Clinical Pharmacology and Toxicology and University of NSW, Sydney, 2010 2 Cancer Care Centre, St George Hospital, Gray St Kogarah NSW 2217 3 Datapharm Australia Pty Ltd, Drummoyne NSW 2047 4 Unique Global Possibilities Medical Pty Ltd, Sydney 2000 §Corresponding author ABSTRACT Background A number of health benefits including improvements in acid/base balance, bone metabolism, cardiovascular risk factors and longevity have been associated with the intake of alkaline mineral water. This study was designed to investigate the effects of the regular consumption of magnesium bicarbonate supplemented water compared to non supplemented water on selected biochemical parameters in healthy postmenopausal women. Methods In this double-blind, placebo-controlled, parallel-group, study 67 women were randomized to receive between 1500 and 1800 mL daily of magnesium bicarbonate supplemented spring water (650 mg/L bicarbonate, 120 mg/L magnesium, pH 8.3-8.5) (supplemented water group) or spring water without supplements (control water group) over 84 days. Over this period biomarkers of bone turnover (serum parathyroid hormone, 25-dihydroxyvitamin D, osteocalcin; urinary telopeptides and hydroxyproline), inflammation (erythrocyte sedimentation rate and C reactive protein) were measured together with measurements of safety by standard biochemistry, haematology and urine examinations. Results This study demonstrated overall that the daily consumption of 1.5 litres of water per se resulted in statistically significant increases in serum sodium, potassium and magnesium 11 June 2009 Page 1 Copyright 2009 Unique Global Possibilities Medical Pty Ltd concentrations. However the serum magnesium concentrations in subjects consuming the supplemented water were significantly increased at Day 84 over baseline (Day 0) compared to subjects in the control group (95% CI: 0.003 – 0.041 mmol/L; p=0.03). Another notable difference observed was a statistically significant trend for an increase in parathyroid hormone (PTH) concentrations with the consumption of non supplemented water, whereas the PTH concentrations remained stable when the magnesium bicarbonate supplemented water was consumed. These findings highlight the complexities of water and electrolyte balance in the body and suggest that regular ingestion of adequate water and magnesium bicarbonate supplemented water may assist in maintaining sodium and potassium mineral homeostasis, increased serum magnesium and stabilization of PTH. The possible health associated benefits warrant further clinical studies. TRIAL REGISTRATION ACTRN12609000863235 BACKGROUND Water is essential for hydration, yet needs vary according to environmental conditions, physical activity and individual metabolism. Both the World Health Organization (WHO) [1, 2] and the Australian National Health and Medical Research Council (NHMRC) [3] have established an Adequate Intake of fluid (water and other drinks) which for adults be at least two litres per day. There have long been claims related to the positive health benefits of drinking water. In addition, claims have been made for the health benefits of “hard water” (containing mineral salts such as calcium and magnesium) including reduction in the incidence of, and mortality from, cardiovascular disease [4, 5]. However, scientifically rigorous studies are needed to test these claims and to investigate possible mechanisms. Chronic, low-level, acidosis has been associated with the typical western diet [6-9] and, since the degree of acidosis increases with age, it has been postulated that acidosis may be associated with some of the diseases of aging [7]. In addition, clinical studies have reported that dietary bicarbonate supplementation significantly, positively impacts upon biomarkers of increased bone metabolism [10-12] and decreases urinary nitrogen loss that has been associated with the muscle and tissue wasting of aging [13]. Magnesium is present in the body in abundance in the cationic form and is a cofactor for numerous enzymes, including those involved in the metabolism of fats and carbohydrates and in the synthesis of protein and nucleic acids. About 50% of magnesium in the body resides in bone where it is directly involved in calcium and bone homeostasis [13, 14]. Low magnesium status has been associated with osteoporosis [15] and osteoarthritis [16] and affects the function of the parathyroid glands [17] where magnesium acts as an agonist at the calcium-sensing receptors [18]. Additionally, magnesium deficiency can worsen metabolic acidosis while dietary supplementation with magnesium and other alkaline minerals increases blood pH and can lead to improvements in the buffering 11 June 2009 Page 2 Copyright 2009 Unique Global Possibilities Medical Pty Ltd capacity of the blood [19, 20]. Low magnesium levels have been associated with endothelial dysfunction, vascular reactivity, raised C-reactive protein concentrations [21] and decreased insulin sensitivity [22]. Diseases associated with low magnesium status include Type II diabetes [23], hypertension [24], atherosclerosis, coronary heart disease and the metabolic syndrome [22, 24, 25]. Magnesium supplementation has been linked with suppression of bone turnover [26], improvements in lipid profile [27, 28] and reduction in blood pressure in magnesium deficient subjects [29]. Numerous epidemiological studies have reported that magnesium intake in the typical western diet is below the Recommended Daily Allowance (RDA) [17, 20-32]. This clinical study was conducted in order to investigate further some of the metabolic effects of regular ingestion of water supplemented with magnesium bicarbonate over a three month period. METHODS This was a randomised, double-blind, placebo-controlled, parallel-arm study conducted from 31 August 2005 to 3 November 2006. The study was approved by the St Vincent’s Hospital Human Research Ethics Committee. Ninety-one subjects attended the Clinical Trials Centre for screening for eligibility. All screened subjects were provided both oral and written information in plain language and consent was obtained before screening procedures began. Only post-menopausal subjects aged 50 -70 years and with BMI 20-35 kg/m 2 were eligible. Subjects were excluded if physical and mental health status, including laboratory abnormalities, indicated serious or chronic illness (LFTs, electrolytes, creatinine clearance <60 ml/min, haemoglobin < 10 g/L), if they were hypersensitive to magnesium, taking certain medications (antacids other than proton pump inhibitors or H 2 agonists, diuretics, calcium or magnesium supplements) or planned medication changes. Subjects using hormone replacement therapy (HRT) were to have been on a stable dose for at least one month prior to screening and continue this dose through the study. Subjects on special diets (including vegan, weight loss or high protein), those with a history of frequent use of magnesium based laxatives and substance abuse (including nicotine) were excluded. Of the 91 screened, 23 failed to satisfy the entry criteria and one was excluded due to poor venous access. The remaining 67 healthy, post-menopausal women were randomised in a 1:1 ratio to receive between 1500 and 1800 mL daily of magnesium bicarbonate supplemented spring water (650 mg/L bicarbonate, 120 mg/L magnesium, pH 8.3-8.5) (supplemented water group) or spring water without supplements (control water group) over three months (84 days). For those consuming the supplemented water this volume resulted in a daily dose of 975 – 1170 mg bicarbonate and 180 – 216 mg magnesium consistent with the recommended daily intake for these electrolytes. There was no bicarbonate and negligible amounts of magnesium (< 5mg/L) in the spring water given to the control group. Analysis of the spring water (control) was conducted by National Association of Testing Authorities (NATA) accredited (#1884) SONIC HEALTHCARE laboratory NSW. 11 June 2009 Page 3 Copyright 2009 Unique Global Possibilities Medical Pty Ltd Subjects were seen in the clinic at Baseline and at Days 14, 42 and 84. Blood and urine samples were collected at every visit to measure markers of bone turnover (PTH, 25- dihydroxyvitamin D and osteocalcin, telopeptides, hydroxyproline) and inflammation (erythrocyte sedimentation rate (ESR), and CRP. Visit examinations included blood pressure (supine and standing), serum fasting lipids, standard serum biochemistry and haematology, urinary and venous blood pH, mid-stream urine and 24 hour urine collection for measurement of concentration and excretion of calcium, phosphate, creatinine and free cortisol. Physical examination was performed and adverse event reports were elicited at each visit. All biochemical, haematology and urinanalysis testing was performed by NATA accredited (#2115) Institute of Laboratory Medicine (SydPath) St Vincent’s Hospital NSW. There were no directly comparable studies on which to base formal estimates of subject numbers required for this exploratory study. Consequently, broad guidance was obtained from studies examining the metabolic effects of magnesium supplementation [18, 45]. A sample