Risk of calcium oxalate nephrolithiasis in postmenopausal women supplemented with calcium or combined calcium and estrogen

Maturitas 41 (2002) 149– 156 www.elsevier.com/locate/maturitas

Risk of calcium oxalate nephrolithiasis in postmenopausal women supplemented with calcium or combined calcium and estrogen Somnuek Domrongkitchaiporn *, Boonsong Ongphiphadhanakul, Wasana Stitchantrakul, Sirinthorn Chansirikarn, Gobchai Puavilai, Rajata Rajatanavin Department of Medicine, Ramathibodi Hospital, Mahidol Uni6ersity, Rama 6, Bangkok 10400, Thailand Received 2 April 2001; received in revised form 13 August 2001; accepted 14 September 2001

Abstract Background: Recent studies showed that postmenopausal women lost less bone mass when supplemented with calcium or estrogen therapy. However, the safety of the treatments in terms of the risk of calcium oxalate stone formation is unknown. We therefore conducted this study to determine the alteration in calcium oxalate supersaturation after calcium supplement or after combined calcium and estrogen therapy in postmenopausal osteoporotic women. Methods: Fifty-six postmenopausal women were enrolled in this study. All subjects were more than 10 years postmenopausal with vertebral or femoral osteoporosis by bone mineral density criteria. They were randomly allocated to receive either 625 mg of calcium carbonate (250 mg of elemental calcium) at the end of a meal three times a day (group A, n=26) or calcium carbonate in the same manner plus 0.625 mg/day of conjugated equine estrogen and 5 mg medrogestone acetate from day 1–12 each month (group B, n= 30). The age (mean 9 S.E.M.) was 66.3 91.2 and 65.1 9 1.1 years, weight 54.1 91.2 and 55.3 92.1 kg, in group A and group B, respectively. Urine specimens (24-h) were collected at baseline and 3 months after treatment for the determination of calcium oxalate saturation by using Tiselius’s index (AP(CaOx)) and calcium/citrate ratio. Results: After 3 months of treatment, there was no significant alteration from baseline for urinary excretion of calcium, citrate and oxalate. Urinary phosphate excretion was significantly reduced (6.3 90.7 vs. 5.1 9 0.7 mmol/day for group A and 8.2 90.9 vs. 5.8 9 0.7 mmol/day for group B, PB 0.05), whereas net alkaline absorption was significantly elevated (10.1 9 3.6 vs. 20.1 94.4 meq/day for group A and 4.8 9 3.2 vs. 19.9 93.6 meq/day for group B, PB 0.05). Calcium/citrate ratio and AP(CaOx) determined at baseline were not different from the corresponding values after treatment in both groups; calcium/citrate: 10.1 9 3.1 vs. 10.1 92.5 for group A and 9.3 9 1.8 vs. 11.9 92.5 for group B and AP(CaOx): 1.1 9 0.1 vs. 1.3 90.2 for group A and 1.2 90.2 vs. 1.1 90.1 for group B. There were eight and nine patients with high AP(CaOx), or \2, at baseline and after treatment, respectively. Conclusions: Calcium supplement with a meal or combined calcium supplement and estrogen therapy is not associated with a significant increased risk of calcium oxalate stone formation in the majority of postmenopausal osteoporotic patients. Determination of urinary saturation * Corresponding author. Tel.: + 66-2-201-1391; fax: + 66-2-246-2123. E-mail address: [email protected] (S. Domrongkitchaiporn). 0378-5122/02/$ - see front matter © 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S 0 3 7 8 - 5 1 2 2 ( 0 1 ) 0 0 2 7 7 - 8

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for calcium oxalate after calcium and estrogen supplements, especially at the initial phase of treatment, may be helpful in the avoidance of nephrolithiasis. © 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Estrogen; Calcium supplement; Calcium oxalate; Nephrolithiasis; Osteoporosis; Supersaturation

1. Introduction Several regimens for the prevention of bone loss in postmenopausal osteoporotic women have been recommended, including calcium supplement, calcitriol, calcitonin, bisphosphonates and estrogen therapy. Recent studies showed that postmenopausal women lost less bone mass when supplemented with calcium [1,2] and the incidence of additional spine fractures was reduced in those with preexisting vertebral fractures [3]. However, there is concern about the safety of calcium supplement in osteoporosis, since it may cause hypercalciuria and may increase the risk of nephrolithiasis in otherwise healthy patients. Estrogen therapy may also affect calcium metabolism. Estrogen replacement increases circulating calcitriol levels [4] and may also increase intestinal calcium absorption independent of 1,25dihydroxyvitamin D3 [5,6]. These effects may induce or enhance hypercalciuria, causing a higher incidence of nephrolithiasis. Nephrolithiasis is a complex process, resulting from interactions among multiple factors. The increase in urinary calcium is not always associated with an increase in the risk of nephrolithiasis, if alterations in other relevant urinary constituents are in the opposite direction. Recent studies demonstrated that high dietary calcium intake was associated with a lower incidence of symptomatic stone disease [7,8]. This beneficial effect is presumably due in part to an increased binding of calcium with oxalate in the intestine, leading to decreased oxalate absorption and excretion. The decrease in urinary oxalate may counterbalance the effect of hypercalciuria on calcium oxalate stone formation. However, in Curhan’s study [7], an increased risk of calcium stone formation was demonstrated in a subgroup of population with calcium supplement. Estrogen therapy may also have a beneficial effect on the prevention of renal stone formation. A recent study demonstrated that estrogen de-

creased urinary oxalate excretion and kidney calcium oxalate crystal deposition [9]. Although there are a number of studies demonstrating the efficacy of calcium supplement and estrogen therapy in the treatment of postmenopausal osteoporosis, data concerning their safety with respect to the calcium nephrolithiasis formation is relatively scarce. Therefore, this study was undertaken to prospectively determine the effect of calcium supplement, with or without estrogen therapy, on the alteration in urinary supersaturation of calcium oxalate in Thai postmenopausal women with osteoporosis.

2. Subjects and methods Postmenopausal women (124) were recruited from the geriatric clinic of Ramathibodi Hospital. Only postmenopausal women with \ 10 years postmenopausal and osteoporosis, as defined by lumbar or femoral neck bone mineral density lower than − 2.5 S.D. from the mean of Thai young women, were enrolled in this study. All subjects did not smoke or drink and did not engage in regular strenuous exercise. The subjects consisted of 61 postmenopausal women and were randomly allocated to receive either calcium carbonate alone (group A) or combined calcium carbonate plus estrogen (group B), by means of a computer generated random number sequence. Subjects in group A were treated with 625 mg of calcium carbonate (or 250 mg of elemental calcium) at the end of a meal three times a day. In group B, the same dosage and time of calcium carbonate plus 0.625 mg/day of conjugated equine estrogen (Wyeth-Ayerst, USA) were given. The subjects allocated to group B also received 5 mg medrogestone acetate (Wyeth-Ayerst) for 12 days each month. Calcium carbonate or calcium carbonate plus estrogen were continued without change in the dosages for 3 months. All subjects

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were instructed and were emphasized to maintain their usual dietary habits throughout the study period. All subjects gave their written informed consents and the study was approved by the ethical committee of Ramathibodi Hospital. Three-day dietary records were kept. The total energy intake in this group of the population in the Bangkok Metropolitan area was 13939 54 kcal/day, carbohydrate 186.59 95.8 g/day, protein 50.9292.54 g/day (14.990.6% of total calories, 9.39 0.7% from animal and 5.49 0.3% from vegetable source), fat 49.09 2.6 g/day (31.991.02% of total calories, 13.89 0.9% from animal source and 18.19 1.1% from vegetable source). Sugar and crude fiber contents were 25.8391.87 and 4.7490.99 g/day, respectively. The calcium intake was 394.8920.9 mg/day. There was no change in dosages or types of other medications taken regularly by the subjects during the treatment phase. Patients who were taking medication that affected calcium balance, including vitamin D, hormones, diuretics and bisphosphonates, were excluded from this study. Compliance was assessed by tablet count. Single 24-h urine collections, using 10 g of boric acid as a preservative agent, at the baseline and at the end of the third month of treatment were obtained. There were 30 subjects in group A and 31 subjects in group B. All subjects tolerated the medication and complied with the study protocol. However, there were five subjects who failed to do complete urine collection. Therefore, only 26 subjects in group A and 30 subjects in group B completed the study protocol. The actual compliance rate was 91.8%. The mean age was 66.39 1.2 and 65.19 1.1 years, weight 54.191.2 and 55.39 2.1 kg in group A and group B, respectively. Urine volume and urine constituents, including sodium, potassium, calcium, magnesium, citrate, oxalate, phosphate and creatinine, were measured. Creatinine, sodium, potassium, chloride, calcium and phosphate were determined by autoanalyzer technique, magnesium by atomic absorption spectrometry, citrate by citrate lyase technique [10] and oxalate by HPLC technique [11]. For the oxalate assay, the inter-assay coefficients of variation averaged 4%, while the recovery of ox-

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alate averaged 93%. Risk of calcium oxalate stone formation was determined by using Tiselius’s index [12], where the ion-activity product was estimated by an index called AP(CaOx): AP(CaOx) index = A× Ca0.84 × Ox1.0 × Mg − 0.12 × Cit − 0.22 × V − 1.03 Urinary excretions of calcium (Ca), oxalate (Ox), magnesium (Mg) and citrate (Cit) were expressed in millimoles per collection period and urine volume (V) in liters. Factor A was 1.9, depending on the collection time of 24 h [12]. Calcium oxalate supersaturation value, calculated by the AP(CaOx) index, was highly and positively correlated (r=0.98) with those obtained by the Equil 2 program [13]. The correlation between the index and stone forming activity in calcium oxalate stone formers has been demonstrated [14–16]. It is clinically useful and has been recommended for a routine program of evaluation and follow-up of stone-forming patients [17]. Studies in normal subjects and stone formers indicate that when the AP(CaOx) index exceeds 2.0, crystallization can be anticipated [12]. AP(CaOx) were also derived from 56 non-stone forming normal females, who attended the renal clinic for living-related kidney donor evaluations, aged 36.79 1.8 years, weight 5391.0 kg. The 95% C.I. for AP(CaOx) of the non-stone forming female was 1.05–1.52. In this study, an AP(CaOx) of \ 2 was considered ‘high AP(CaOx)’. Hypercalciuria was defined as urinary calcium excretion \6 mmol/day. Net gastrointestinal alkaline absorption was estimated from urine constituents by the formula of Oh [18]: Net GI alkaline absorption = (urinary Na+ K+ Ca + Mg) − (urinary Cl+ 1.8P) Urinary excretion of sodium (Na), potassium (K), calcium (Ca), magnesium (Mg) and chloride (Cl) were expressed in milliequivalent/day, whereas phosphorus (P) in millimole per day.

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2.1. Statistical analysis

3. Results

Results were presented as group mean9 S.E.M. Values of urine constituents were presented as mmol/day. Differences of means between groups were assessed by paired and unpaired Student’s t-test as appropriate.  2-Test was applied to compare frequencies between two groups. Correlation between two independent variables was determined by Pearson’s correlation. A P value of B 0.05 was considered statistically significant.

All urinary constituents at baseline and after treatment for group A, group B and for the entire studied patients (combined group A and group B) are shown in Table 1. After treatment, the urinary calcium excretions were elevated, but the changes from baseline were not different in both groups. After treatment, the urinary calcium excretion tended to be greater in group A than in group B, but the difference was also not significant. There

Table 1 Urinary constituents at baseline and after treatment for group A and group B Urine (mmol/day)

Group A Baseline

Group B Treatment

Baseline

Total Treatment

Baseline

Treatment

Sodium P-value

61.596.5

72.89 8.2 0.22

73.5 9 9.1

84.1 911.9 0.52

66.2 95.7

77.8 9 7.5 0.24

Potassium P-value

17.5 92.5

19.8 9 2.3 0.34

18.1 92.9

21.7 9 2.6 0.36

17.8 9 2.8

20.6 9 1.7 0.19

3.49 0.5

2.8 9 0.3

2.9 9 0.3

2.8 9 0.3

Calcium P-value

2.890.4

Magnesium P-value

2.090.2

0.16

0.64 2.2 9 0.2

1.53 9 0.2

0.57

79.7 9 7.4 0.51

0.359 0.04

0.35 9 0.04 0.83

0.33 90.03

0.32 9 0.03 0.59

0.859 0.14

0.68 9 0.14

0.84 90.16 0.41

0.66 90.1

0.84 9 0.11 0.12

5.19 0.7

8.2 9 0.9

74.319 8.4 0.24

Oxalate P-value

0.319 0.02

0.299 0.03 0.52

Citrate P-value

0.65 90.11 0.1

Creatinine P-value

6.99 0.3

Volume (l) P-value

1.49 0.1

1.9 9 0.2 0.57

72.9 9 5.9

62.596.6

6.390.7

1.8 9 0.2

84.3 9 11.8 0.89

Chloride P-value

Phosphate P-value

1.6 9 0.2 0.81

82.03 9 9.2

3.1 9 0.3 0.17

0.02

5.8 9 0.7

7.3 9 4.6

7.9 90.3

7.3 9 0.3

0.01 6.4 9 0.3

7.6 90.4

0.21

0.36 1.29 0.1

1.5 9 0.1

0.2

5.5 9 0.5 B0.01 7.3 90.3 0.98

1.6 9 0.1

1.45 90.1

0.28

1.4 9 0.1 0.46

Alk. abs. P-value

10.109 3.6

20.19 4.4 0.01

4.8 93.2

19.9 9 3.6 B0.01

6.2 9 2.5

18.9 92.9 B0.01

Ca/citrate P-value

10.1 93.1

10.1 9 2.5 0.98

9.3 91.8

11.9 9 2.5 0.43

9.6 9 1.7

11.1 9 1.8 0.51

AP(CaOx) P-value

1.1 90.1

1.3 9 0.2

1.2 9 0.2

1.1 9 0.1

1.15 9 0.1

0.13

0.46

Comparisons were made between corresponding baseline and after treatment values.

1.2 9 0.1 0.65

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Fig. 1. Relationships of urinary excretion of calcium (a), oxalate (b), citrate (c), and AP(CaOx) (d) between baseline (B) and after treatment (T) values for individual patient in group A and group B.

was no increase in the number of hypercalciuric patients by both treatments, five patients at baseline and five patients after treatment. The urinary excretions of oxalate were decreased, whereas the urinary excretions of citrate were increased, but not significantly in both groups. The relationships between baseline and after treatment for urinary calcium, oxalate and citrate excretions of an individual patient in both groups are shown in Fig. 1(a– c), respectively. After treatment, the alkaline absorptions were elevated significantly above the baseline values in both groups, but there was no difference in alkaline absorption between the two groups. There were significant correlations between alkaline absorption and urinary excretion of citrate for the whole group of studied patients at base-

line (r= 0.3, PB 0.05) and after treatment (r= 0.4, PB 0.01). Urinary excretions of phosphate were significantly reduced in both groups by the treatments. There was no significant difference in calcium/citrate ratio and AP(CaOx) from baseline in both groups and between the two groups after the treatments. The relationship between baseline and after treatment values of AP(CaOx) is shown in Fig. 1(d). There was no significant increase in the number of patients with high AP(CaOx) at the end of the study. There were eight (14.3%) patients who had high AP(CaOx) at baseline, two from group A and six from group B. After treatment, nine (16.1%) patients developed high AP(CaOx) and eight (14.3%) patients, four from group A and four from group B, had normal basal AP(CaOx).

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4. Discussion Urinary tract stone formation is a complex process, resulting from interaction between multiple factors. An increase in urinary calcium excretion does not invariably result in an increased risk of calcium oxalate stone formation if there is also a concomitant increase in urinary stone inhibitor, for example urinary citrate. Calcium carbonate and estrogen therapy may simultaneously alter other urine constituents in addition to urinary calcium. Calcium carbonate supplement may provide more free calcium to combine with oxalate in gastrointestinal tract, resulting in less oxalate available for absorption and thereby reducing urinary oxalate excretion [19– 23]. These findings may explain the results of recent large epidemiological studies demonstrating that the incidence of kidney stones among women [7] and men [8] decreased in a population with higher dietary calcium intake. In our study, the total calcium intake during the study for osteoporosis patients, : 1200 mg/day, was somewhat lower than the recently recommended calcium intake for women aged \65 years [24]. The dosage of 750 mg/day of elemental calcium was selected in this study instead of 1000 mg/day or more due to the relatively low body weight in our osteoporosis patients compared to the Western population. We could not demonstrate significant alteration in the risk of calcium oxalate stone formation, determined by Tiselius’s index [12] after 3 months of treatment, either with calcium carbonate alone or with combined calcium carbonate and estrogen. Although there was a tendency towards higher urinary excretion of calcium after treatment in both groups, the differences were not significant. This was unlikely a result of complexation of supplemental calcium with intestinal oxalate, as the baseline urinary oxalate excretion was not elevated. The modest elevation in urinary calcium excretion after treatment was accompanied by a compensatory increase in urinary citrate, resulting in comparable values of baseline and after treatment calcium/citrate ratio. The increase in urinary citrate found in our subjects probably resulted from the absorption of carbonate, the anionic component of calcium carbonate

salt. This was supported by the significant correlation between net alkaline absorption and urinary citrate. It should be noted that the amount of citrate excretion in our subjects is less than the normal values reported in most studies from Western countries, ranging from 2 to 4 mmol/day [25]. The values of urinary citrate, measured by using the same technique, in normal Thai subjects reported by other groups were also within the range reported in our study [26,27]. The handling of specimens in our study was performed as described in a previous study in Western population [19]. Therefore, methodological error in the determination of urinary citrate is unlikely. There is no systematic approach to find out the cause of difference in urinary excretion of citrate between the Western population and our population so far. The difference in climate [27] and diet [28] may account for the difference. In contrast to other studies [19,22,23], an appreciable decline in urinary excretion of oxalate after calcium supplement was not found in our study. In the previous study [19,22], high calcium intake was provided to normal subjects with very high oxalate intake or gastrointestinal absorption and resulted in a significant reduction in urinary excretion of oxalate. The explanation for this was that the added calcium presumably formed an insoluble complex with the excess amount of oxalate in the intestine. The differences in findings between our study and the previous studies may result from the differences in the degree of oxalate load to the gastrointestinal tract. In our case, there was no hyperoxaluria at baseline. Therefore, the supplemental calcium had little or no role in further reduction in oxalate absorption. Therefore, the non-significant alteration in AP(CaOx) after calcium supplement in our study is less likely to be explained by the complexation of calcium with oxalate in the gastrointestinal tract. Apart from the dietary oxalate, supplemental calcium also acts as a phosphate binder, resulting in less intestinal phosphate absorption. The complexation of calcium with phosphate in the intestine may be an explanation for a significant decrease of urinary phosphate excretion after treatments in our study.

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Recent animal studies demonstrated that estrogen stimulated intestinal calcium absorption via estrogen receptor [4] or independent of 1,25-dihydroxyvitamin D3 level [5,6]. These findings suggest that concomitant estrogen therapy may further increase calcium absorption among patients who are receiving both estrogen and calcium supplement and may elevate the risk of calcium stone formation. However, estrogen therapy may also have beneficial effects on calcium oxalate stone prevention. Data from animal study suggest that estrogen decrease urinary oxalate excretion, plasma oxalate concentration and kidney calcium oxalate crystal deposition [9]. These findings may partly explain why nephrolithiasis is a predominantly male disease. However, the urinary excretions of calcium and oxalate after treatment in our patients who received both calcium carbonate and estrogen therapy were not different from those who received only calcium carbonate alone. The negative findings in our human study may result from either species difference or confounding effects of concomitant supplemental calcium to the effects of estrogen therapy on urinary constituents. In our study, medrogestone acetate was also prescribed to the subjects who received estrogen therapy. However, it is unlikely that medrogestone acetate had a significant effect on nephrolithiasis as there was no significant change in AP(CaOx) in this group. There is no study demonstrating the effect of progesterone on nephrolithiasis. The result of our study was contradictory to the findings from Curhan’s study on the effect supplemental calcium [7]. In Curhan’s study, supplemental calcium was associated with a 20% increased risk of kidney stones. The contradicting effects of supplemental calcium may result from the timing of the ingestion of supplemental calcium. In our study, all subjects were instructed to take calcium at the end of meals, whereas \70% of patients in Curhan’s study took supplemental calcium between meal or with meals whose oxalate content was probably low. The difference in the timing of calcium intake may be a cause of difference between these two studies. Although the sample size was relatively low in our study, there was little tendency to-

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ward a higher risk of calcium stone formation, as demonstrated by almost no change in the AP(CaOx) of both groups. Our treatment, however, is not totally risk free. Both treatments were still associated with some risk of calcium oxalate stone formation in a particular subgroup of patients. There were eight patients, who initially had no elevation in AP(CaOx), developed high AP(CaOx) after treatment. In order to avoid an inadvertent increase in the risk of calcium oxalate stone formation, determination of urinary saturation for calcium oxalate stone after calcium and estrogen supplements may be helpful, especially in the initial phase of treatment. For those with persistent elevated AP(CaOx) within the zone at risk, the treatment should be adjusted individually, or switched to other appropriate therapeutic regimens for osteoporosis. Although calcium or estrogen supplement is relatively safe, all osteoporosis women should not be treated without appropriated investigations to find out underlying diseases. In this geographic area, a very high incidence of renal tubular acidosis has been reported [29]. Renal tubular acidosis is more common in female and associates with low bone mass, recurrent renal stone and nephrocalcinosis [30], presumably resulted from longstanding metabolic acidosis. In this condition, complete correction of metabolic acidosis by alkaline therapy, e.g. potassium citrate, should be the first line of treatment to prevent further bone loss. In conclusion, calcium supplement with a meal alone or in combination with estrogen therapy in postmenopausal osteoporotic women is not associated with an elevated risk of calcium oxalate stone formation in the majority of patients. Determination of urinary saturation for calcium oxalate after calcium and estrogen supplements, especially at the initial phase of treatment, may be helpful in the avoidance of nephrolithiasis.

Acknowledgements This study was supported by a 1998 Ramathibodi Hospital Research Grant and the Thailand Research Fund.

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