The efficacy of calcium supplementation alone in elderly Thai women over a 2-year period: a randomized controlled trial

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1 Osteoporos Int () 4: DOI.7/s ORIGINAL ARTICLE The efficacy of calcium supplementation alone in elderly Thai women over a -year period: a randomized controlled trial R. Rajatanavin & L. Chailurkit & S. Saetung & A. Thakkinstian & H. Nimitphong Received: 8 October /Accepted: 8 March /Published online: 7 May # International Osteoporosis Foundation and National Osteoporosis Foundation Abstract Summary Supplementation with elemental calcium 5 mg/ day alone for years is able to decrease bone turnover and is effective in retarding bone loss at lumbar spine and slowing bone loss at femoral neck in elderly Thai women who had low dietary calcium intake. Introduction Most elderly Thais have a total dietary calcium intake of less than the recommended amount. The aim of the study was to investigate the effect of calcium supplementation on bone mineral density and biochemical indices of bone remodeling in Thai postmenopausal women. Methods Four hundred and four healthy postmenopausal women 6 years old or older without osteoporosis were recruited and conducted in a randomized, double-blinded, placebo-controlled trial. They were randomly given elementary calcium 5 mg/day or placebo for years. Dietary calcium intake was calculated from the nutrient compositional analysis of the -day food records. Serum 5 hydroxyvitamin D was measured by radioimmunoassay and bone turnover markers were determined by electrochemiluminescence immunoassay. Results The age of the subjects was 65.8±4.4 years. All baseline characteristics of the subjects in the calciumsupplemented group and the placebo group were not statistically different. At the end of the study, significant decreases in serum C-terminal telopeptide of type I collagen and serum total procollagen type I amino terminal propeptide in the calciumsupplemented group were observed, while there was no change in the placebo group. In addition, plasma parathyroid hormone decreased, although not significantly, only in the calcium-supplemented group. Percent changes from baseline of lumbar spine (L L4) bone mineral density increased.76 % in the calcium-supplemented group and.87 % in the placebo group, whereas the percent changes from baseline of femoral neck decreased. % in the calcium-supplemented group and.9 % in the placebo group. Conclusions supplementation is necessary for the decrease of bone turnover and prevention of bone loss in Thai elderly women. Keywords Bone mineral density. supplementation. Dietary calcium intake. Elderly women R. Rajatanavin : L. Chailurkit () : S. Saetung : H. Nimitphong Division of Endocrinology and Metabolism, Department of Medicine, Faculty of Medicine, Ramathibodi Hospital, Rama 6 Rd., Rajthevi, Bangkok 4, Thailand laor.cha@mahidol.ac.th R. Rajatanavin rajata.raj@mahidol.ac.th S. Saetung ssaetung@hotmail.com H. Nimitphong hataikarnn@hotmail.com A. Thakkinstian Section for Clinical Epidemiology and Biostatistics, Faculty of Medicine, Ramathibodi Hospital, Bangkok 4, Thailand ammarin.tha@mahidol.ac.th Introduction is an essential nutrient for bone health throughout life. It is important for attaining peak bone mass and for preventing and treating osteoporosis. Osteoporosis is much more common in elderly postmenopausal women because they experience loss of the beneficial effects of estrogen on the stimulation of intestinal calcium absorption and reduction of renal calcium excretion [] as well as an increase in bone turnover rate []. The dietary calcium requirement increases with aging. Some randomized controlled trials have shown that calcium supplements could prevent bone loss and reduce osteoporosis in subjects with calcium deficiency and in elderly women [ 6]. In addition, a meta-analysis has shown that calcium supplementation

2 87 Osteoporos Int () 4: significantly reduced fracture risk at various skeletal sites by % in postmenopausal women [7]. However, it is still debatable whether or not calcium supplementation can reduce osteoporotic fractures. Previous studies have shown that dietary calcium intake in the elderly Thai population is low (9± 47 mg/day [8]; 6±88 mg/day [9]; 6 49 mg/day []). Although the recommendation of an adequate intake of calcium for Caucasians was approximately,, mg/day for older adults [], it might not be appropriate for older Thais. The effects of calcium supplementation on bone mineral density may vary according to dietary calcium intake []. Increasing calcium beyond a certain point may not provide further benefits to bone []. In addition, the value of supplementation of calcium intake in the prevention of osteoporosis remains uncertain [4, 5]. Therefore, the purpose of the current study was to determine the efficacy of years of 5 mg calcium supplementation in healthy elderly women 6 years old or older by assessing the bone mineral density and the biochemical indexes of calcium homeostasis. Methods Subjects Seven hundred and two physically active healthy postmenopausal women 6 years old or older were recruited by public advertisements. Medical history taking and physical examination were performed in each individual. The exclusion criteria were a history of metastatic or non-osteoporotic metabolic disease; history of kidney stone within the previous 5 years; vertebral fractures (confirmed by radiographs of the thoracolumbar spine at the beginning of the study) ; thyroid or parathyroid disease; the use of calcium or vitamin D supplementation within the previous months; the use of hormone replacement therapy (such as estrogen, SERMs, or testosterone) or any medication influencing bone metabolism (such as bisphosphonate) within the previous 6 months; and the use in the last year of any glucocorticoid, anticonvulsant medication, or fluoride. Women with lumbar spine (L L4) bone mineral density (BMD) less than or equal to.5 SD were also excluded. On the basis of these criteria, 44 women were included in the study. In a double-blind fashion, subjects were randomly divided into two equally sized groups using computer-generated random numbers. Their allocation remained concealed until the final medical examination. Subjects were assigned either to receive 5 mg of elemental calcium in the form of calcium carbonate or similar-looking placebo tablets, taken once daily after the evening meal for years. All the tablets were provided by the British Dispensary (L.P.) Co., Ltd. (Samutprakarn, Thailand). Subjects were told to avoid any other calcium supplementation. Demographic data such as age, sex, reproductive history, and other lifestyle information including alcohol consumption, smoking, and exercise habits were obtained through an interview. Body mass index (BMI) was calculated as weight in kilograms divided by the square of height in meters. All subjects were evaluated at baseline and the same measurements were repeated every 6 months over a -year period. Their medical history and clinical side effects which occurred during the study were recorded. Compliance was assessed by tablet counts at each visit. The study was approved by the Ethics Committee of Ramathibodi Hospital, and written informed consent was obtained from each participant before entering the study. Dietary calcium intake A -day food record was obtained on each subject at baseline, and this was repeated at -month intervals throughout the study. All food records were analyzed for nutrient intake using the INMUCAL software, which was developed by the Institute of Nutrition, Mahidol University, Bangkok, Thailand [6]. Biochemical measurement Blood and 4-h urine samples were collected at baseline and at and years of the study. Blood samples were taken between 8 and AM after overnight fasting. Serum calcium, creatinine, inorganic phosphorus, alkaline phosphatase, and urinary calcium and creatinine were analyzed on an automated biochemical analyzer (Dimension RxL, Dadebehring Co. Ltd., USA). Urinary calcium was expressed as a ratio with urinary creatinine. Serum 5-hydroxyvitamin D [5(OH)D] was measured by radioimmunoassay (DiaSorin Inc., Stillwater, MN) with an intra-assay precision of 8.9 %. Plasma intact parathyroid hormone (PTH), serum C- terminal telopeptide of type I collagen (CTx) and serum total procollagen type I amino terminal propeptide (PINP) levels were determined by electrochemiluminescence immunoassay on an Elecsys analzer (Roche Diagnostic GmbH, Mannheim, Germany). The assays have intra-assay precisions of.6, 5.4, and.8 %, respectively. Bone mineral density BMD at the lumbar spine (L L4) and femoral neck was measured using dual-energy X-ray absorptiometry (Lunar Corp., Madison, WI) at baseline and at 6-month intervals over a -year period. Quality assurance was maintained by daily calibration and the use of one

3 Osteoporos Int () 4: phantom. The precision error in BMD was calculated as root mean square (RMS) averages of the standard deviations of repeated measurements. The RMS values of the lumbar spine (L L4) and femoral neck were.7 and. g/cm, respectively. Statistical analysis Results are presented as the mean±sd, unless otherwise indicated. The two groups were compared at baseline to evaluate the success of randomization using unpaired Student s t test. The χ test was used to analyze differences in non-continuous variables between both regimens. Changes in each parameter are represented as percent change from baseline. Repeated measures ANOVA or paired Student s t test was used to compare changes in the variables over time with each treatment. Unpaired Student s t test or Mann Whitney U test was used to analyze changes at each time point between groups. All tests were two-tailed. Statistical significance was assigned at a p<.5 for all analyses. The programs of the SPSS were used for all analyses. Results Baseline characteristics and compliance During the course of the study, there were 5 dropouts in the placebo group and 6 dropouts in the calcium supplementation group. The remaining 4 women (78 in the calcium supplementation group and 65 in the placebo group) completed the -year study. The age of the subjects was 65.8±4.4 years (range, 6 85 years). Dietary calcium intake was 75.6±5.5 mg/day. Serum 5(OH)D was 68.±6. nmol/l. The mean (±SD) compliance of pill taking (by tablet count at each visit) during the -year study period was 89.4±4.8 % in the calcium group and 88.7±7.9 % in the placebo group. At study entry, there were no significant differences between the two groups with regard to clinical characteristics, biochemical parameters, and BMD levels (Table ). The prevalence values of vitamin D insufficiencywerefoundtobe.9and6.%inthecalcium supplementation group and. and 67. % in the placebo group when using a 5(OH)D threshold of 5 Table Baseline clinical and biochemical characteristics and BMD of elderly women in the calcium supplementation and placebo groups Results are the mean±sd or median (range) Characteristics (n=78) (n=65) p value Age (years) 66.± ±4..4 Age at first menstruation (years) 5.±6.6 5.± Age at menopause (years) 49.± ±8..7 BMI (kg/m ) 5.±.5 5.6±.5. No. of Alcohol consumption No. of smokers.48 Sun exposure (h/day), n (%) < > 4 9 Exercise, n (%) Regular 87.6 Sometime No 8 Dietary calcium intake (mg/day) 4. (94.5,4.) 5.6 (5.8,49.).4 Serum calcium (mmol/l).4±..4±..55 Serum inorganic phosphorus (mmol/l).±..±..594 Serum alkaline phosphatase (U/L) 85.± ±.5.55 Serum creatinine (μmol/l) 7.8±7.8 7.±.7. Plasma PTH (pmol/l) 4.7±.9 4.5±.5. Serum 5(OH)D (nmol/l) 69.7±5. 69.±6.5.8 Serum CTx-I (ng/ml).4±..4±.7.95 Serum PINP (ng/ml) 5.±. 5.± Urinary calcium/urinary creatinine.5 (.8.4).46 (.5.99).6 Lumbar spine L L4 BMD (g/cm ).±..±.4.9 Femoral neck BMD (g/cm ).79±..8±..76

4 874 Osteoporos Int () 4: and 75 nmol/l, respectively. Overall,. and 64. % of the subjects had 5(OH)D <5 and 75 nmol/l, respectively. Dietary calcium intake The mean usual calcium intake of the elderly women in the study was 76±8 (SD)mg/day. Almost all subjects (4 in 4 women, 99.4 %) had an average daily calcium intake lower than the current recommendation (, mg/day), and only.8 % (n=) met the recommended dietary reference intake for Thais (8 mg/day). However, the mean daily dietary calcium intake assessed before the beginning of calcium supplementation was similar between groups (Fig. ). According to the treatment assignment, the mean dietary calcium intake in the calcium-treated group was higher than that in the placebo group at subsequent visits up to years. At the end of the study, the mean dietary calcium intakes in the calcium-treated group and the placebo group were 87.± 4.4 and.±47. mg, respectively. homeostasis and biochemical markers of bone turnover At years, serum calcium was increased in both calciumtreated and placebo groups. But the change in serum calcium in the calcium-treated group was significantly higher than in the placebo group (Fig. ). When a comparison was made of the plasma PTH value at years with baseline, there was a non-significant decrease in the plasma PTH of the calcium-treated group, while there was a non-significant increase in the plasma PTH in the placebo group (Fig. ). However, the PTH value of subjects in the calcium-treated group was significantly lower than in the placebo group at the end of the study (p<.). No changes in serum 5(OH)D levels were observed in both calcium group (69.7±5. vs. 68.6±5. nmol/l) and in the placebo group intake (mg/day) Months after enrollment 89 Fig. Total daily calcium intake over years. Values are the mean± SE. Treatment, time, and treatment time interactions were significant (p<.) percent change from baseline at year Serum calcium Plasma PTH calcium placebo Fig. Effect of calcium supplementation on changes in serum calcium and plasma PTH from baseline to years. Values are the mean±se. p<.5 (vs. placebo) (69.±6.5 vs. 68.±4.7 nmol/l). In addition, there was no inverse relationship between change from baseline in serum 5(OH)D and change from baseline in plasma PTH (r=.7, p=.4). Bone turnover markers in the placebo group did not change overtime (Fig. ). On the other hand, both CTx-I and PINP of subjects in the calcium-treated group significantly decreased from baseline (Fig. ). Serum CTx-I % change from baseline Serum PNP % change from baseline Months after enrollment Fig. Percentage change (mean±se) relative to baseline in serum CTx-I and PINP. Treatment, time, and treatment time interactions were significant at each marker (p<.)

5 Osteoporos Int () 4: Bone mineral density There was no significant change in lumbar spine (L L4) BMD in the placebo group, but it increased significantly in the calcium supplementation group (p<.5; Fig. 4). Femoral neck BMD in the calcium-treated group did not change over time, but a significant decline was found in the placebo group (p<.5). Therefore, subjects in the calcium-treated group had higher lumbar spine (L L4) and femoral neck BMDs than subjects in the placebo group (p<.; Fig. 4). To account for the probable interaction between BMD and time since menopause, further analyses were performed every years by the time of menopause ( years, years, and > years). At years of menopause, there was no significant difference between the calcium-treated group and the placebo group in the percent changes from baseline of lumbar spine (L L4; Fig. 5) and femoral neck (Fig. 6)BMD at any time point during the study. However, at more than years of menopause, the calcium-treated group had greater accretion of lumbar spine (L L4) and femoral neck BMD than did the control group (Figs. 5 and 6). Adverse effects The most common adverse effects of calcium are constipation, bloating, cramps, and gas. However, the adverse effects in the calcium supplementation group were not significantly Lumbar spine (L-L4) BMD Percent change from baseline Femoral neck BMD Percent change from baseline months after enrollment Fig. 4 Percentage change (mean±se) relative to baseline in lumbar spine (L L4) and femoral neck BMD. p<. (vs. placebo) Percent change from baseline of lumbar spine (L-L4) BMD Menopause years Menopause - years Menopause > years (n =8) (n = 6) ( n = 8) (n = 9) (n = 4) (n = 7) Fig. 5 Percentage change (mean±se) relative to baseline in lumbar spine (L L4) BMD according to time since menopause. p<. (vs. placebo) Percent change from baseline of femoral neck BMD Menopause years Menopause - years Menopause > years (n =8) (n =6) (n = 8) (n = 9) (n = 4) (n = 7) Fig. 6 Percentage change (mean±se) relative to baseline in femoral neck BMD according to time since menopause. p<. (vs. placebo)

6 876 Osteoporos Int () 4: different from the placebo group (Table ). Elemental calcium supplement for 5 mg/day did not cause hypercalciurea. We found similar levels of 4-h urinary calcium/creatinine ratio in both the calcium supplementation and control groups [.5 ( ) vs..47 (.9 5.4)]. Nonetheless, we also noticed inadequacy of urinary collection in some subjects. Discussion The present study showed the beneficial effects of calcium supplementation on bone. We demonstrated that calcium supplementation of at least 5 mg/day for years in healthy elderly women without osteoporosis or previous osteoporotic fractures modestly increased BMD at lumbar spine, slowed down bone loss at femoral neck, and reduced bone turnover markers. The Institute of Medicine recommends calcium intakes of, mg/day for elderly women []. Even with lower calcium intake than suggested in the recommendation (total calcium intake=87.±4.4 mg in the calcium-treated group), we still noticed the benefit of calcium supplement to bone health. Our findings are consistent with previous reports that calcium supplement might be crucial in people who have low calcium intake at baseline [4, 7]. Our findings are consistent with data from other interventional studies using calcium supplementation as a primary preventive therapy, maintaining bone mineral density, in postmenopausal women. Therefore, calcium supplementation has a protective effect on postmenopausal bone loss; maintaining bone mineral content provides important opportunities for the prevention of osteoporosis and fractures. The effect of calcium supplementation on bone mass in postmenopausal women may be modified by many factors, including the level of dietary of calcium intake, age, genetics, ethnicity, and vitamin D status. supplements have been observed to be most effective in those women in whom the baseline calcium intake was low, the mean age was high, and there was clinical evidence of osteoporosis [4,,, 5]. Our study confirmed the effectiveness of calcium supplement Table Frequency of adverse events between groups (n=78) Constipation Bloating 4 5 Constipation and bloating Bloating and chest tightness Nausea 5 Dizziness Dyspepsia Urticaria Nonspecific 6 Total 7 7 (n=65) in maintaining bone mass in low-calcium-intake subjects. The subjects in our study had daily calcium intakes <4 mg, consistent with previous reports of 4 5 mg of daily calcium intake in Thais [8 ]. The application is the same when we cannot increase the total calcium intake up to,, mg/day according to the standard recommendation []; adding 5 mg of calcium supplement might be of benefit in maintaining bone health in Thai postmenopausal women. Further studies are needed to explore whether increasing the total calcium intake to,, mg/day has additional benefits in maintaining bone health. Studies about the effectiveness of calcium supplement in other groups of Thais, such as in males or younger females, are also warranted. The average calcium intake of elderly Thai women was about a quarter of the current recommended value by the Institute of Medicine of the National Academies []. More than 99 % of the women in the study have less dietary calcium than the recommended level of, mg/day, and only.8 % consumed dietary calcium at the level of 8 mg/day. This is mainly due to the eating habit with limited food source of high calcium, and milk drinking is an uncommon eating habit in the Thai population. The results were consistent with previous studies in other Asian countries where milk is not part of the traditional diet [8 ], confirming that a low dietary calcium intake persists in the Asian population. In addition, we found a lower prevalence of vitamin D deficiency/insufficiency in our subjects when compared with other countries in the same latitude;. and 64. % of subjects had 5(OH)D <5 and 75 nmol/l, respectively. This may imply for the better calcium absorption and maximize the benefit of calcium in maintaining bone health even if the total daily calcium intake is lower than, mg. Studies of direct calcium absorption are needed to confirm this hypothesis. In addition, we found a greater percentage of increased BMD in subjects who were in menopause for more than years in the calcium supplementation group when compared with the control group. On the other hand, such difference was not detected in subjects who were in menopause for < years. Our data correspond to a previous study in which calcium supplementation in the elderly revealed a lesser reduction in BMD and thus a greater reduction in fracture risk when compared with younger age []. In conclusion, supplementation with elemental calcium 5 mg/day alone is able to decrease bone turnover and is effective in retarding bone loss at the lumbar spine and slowing bone loss at the femoral neck in elderly Thai women who had low dietary calcium intake. Dietary calcium augmentation should be recommended as a strategic option in helping to prevent early postmenopausal bone loss. Acknowledgments This study was supported by the Thailand Research Fund and National Health Foundation. Conflicts of interest None.

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