Indapamine effects on hypercalciuria and bone mineral density

doi:10.21203/rs.3.rs-1751227/v1

Download PDF

Research Article

Indapamine effects on hypercalciuria and bone mineral density

https://doi.org/10.21203/rs.3.rs-1751227/v1

This work is licensed under a CC BY 4.0 License

Version 1

posted

You are reading this latest preprint version

Idiopathic hypercalciuria is associated to urinary stone formation and bone loss and should be treated not only to prevent kidney stone formation but also to prevent fragility fractures. Thiazide diuretics are traditionally used to control hypercalciuria. Indapamine, a sulfonamide thiazide diuretic, with some differences in structure is similar in its mechanisms of action such as its hypocalciuric effect, and bone density protection, with less adverse metabolic consequences than thiazides such as less hypokalemia and hypotension. We evaluated efficacy and adverse effects of Indapamine in 88 idiopathic hypercalciuric consecutive patients and those who reached normal calciuria in the first 9 months, were followed during two years. Changes in bone turn-over markers and bone density were evaluated. Since year one, there was a significant lowering of urine calcium to normal values in 77 patients, with no change in sodium excretion. There were changes in bone turn over markers and gains in bone mineral density according to the groups analyzed. In 25 hypercalciuric osteoporotic patients, there was a significant increment in lumbar spine bone density at year 2 of follow-up, (p<0.05). Those hypercalciuric osteoporotic stone former patients had a significant increase in femoral neck bone density since year one. Adverse effects were not significant, no changes found in blood pressure, glycaemia, cholesterol, serum uric acid, sodium and potassium. Two patients needed potassium supplementation for mild hypokalemia and did not stop Indapamine. In conclusion Indapamine is an effective alternative treatment to Idiopathic hypercalciuria, controlling calcium loss and bone density for at least two years.

Indapamine

Idiopathic hypercalciuria

renal hypercalciuric bone density loss

Idiopathic hypercalciuria (IH) is associated to urinary stone formation and bone loss. Our group defines Idiopathic hypercalciuria, as urinary calcium more than 220 mg/day in women and more than 300 mg/day in men or more than 4 mg/Kg [1].

Hypercalciuria should be treated not only to prevent kidney stone formation with its urinary tract complications but also to prevent fragility fractures [2,3,4].

Thiazide diuretics are traditionally used to control hypercalciuria by their known mechanisms of action inducing mild volume depletion, leading to a compensatory rise in the proximal reabsorption of sodium and calcium, and directly increasing calcium reabsorption in the distal tubule. Thiazide diuretics, which inhibit sodium-chloride cotransporter (NCC) in the distal convoluted tubule, are considered as the treatment of choice for idiopathic hypercalciuria due to their hypocalciuric effect [5].

Hye Ryoun et al. have suggested that calcium channel receptor TRPV5 has been directly implicated in the thiazide induced distal calcium reapsorption [6].

It is also well known that thiazides are related to adverse effects such us hypokalemia, fatigue, hypotension and metabolic disadvantages in cholesterol, uric acid and glycemic control, insulin resistance, hypomagnesemia and as a consequence of hypokalemia, reduced urine citrate excretion leading to increase in stone risk formation.

Indapamine, a sulfonamide thiazide diuretic, with some differences in structure is similar in its mechanisms of action such as its hypocalciuric effect, and bone mineral density protection, with less adverse consequences than thiazides such as less hypokalemia [7,8,9,10].

Although mostly used to treat blood hypertension it is becoming useful in the hypercalciuric patients as an alternative to prevent new renal stone events and bone loss.

The aim of our study was to evaluate efficacy and adverse effects of indapamine after one and two years of treatment in idiopathic hypercalciuric patients and changes in their bone mineral density.

This is a longitudinal study evaluating indamine fixed dose effects in urine calcium, bone mineral density, bone turn-over markers and adverse events. Idiopathic hypercalciuric consecutive patients, consulting our Metabolic Institution from 2008 to 2020 were included. Idiopathic hypercalciuria was defined as an excretion of urine calcium more than 220mg/day in women and 300mg/day in men. We included 88 hypercalciuric patients most of them women as our Institution is a referring center for bone metabolic diseases such as postmenopausal osteoporosis. To be included they had two samples with hyperalciuria in 24hs with their usual diet and a third sample with hypercalciuria measured after 4 day controlled diet containing per day total sodium 120 mmol, potassium 100 mmol, calcium 800–1000 mg and protein 1 g/kg.

Some patients had history of renal stone formation, defined as a stone spontaneously passed by urinary tract or surgically removed or confirmed by X-Ray, ultrasound scan or computed tomography. Other patients had osteoporosis defined in bone mineral density as a T score ≤-2.5 in lumbar spine (LS), femoral neck (FN) or total hip (TH).

Fasting morning venous blood samples were obtained before breakfast and analyzed for creatinine, calcium, phosphorus, 25 OH vitamin D (25 OHD), total alkaline phosphatase (ALP), bone-specific alkaline phosphatase (BAP),osteocalcin (bone GLA protein BGP), serum β crosslaps (CTX), glucose, total cholesterol, uric acid, and serum potassium. Three 24-hour urine samples were obtained from each patient to measure calcium, sodium and creatinine.

Methods

Serum and urine calcium were measured by ion-selective electrode (ISE) method using a Synchron CX3 automated analyzer (Beckman, Beckman Instruments Inc. Brea, California. USA). Normal values for total serum calcium: 8.8-10.5 mg/dl, urinary calcium: < 220 mg/ 24 h in women and <300mg/24h in men. Both blood and urine sodium and potassium were measured with automated analyzer CX3, normal values: serum sodium: 136 – 145 mEq/L, serum potassium: 3.5 – 5.1 mEq/L, urine sodium up to 150 mE/L and urine potassium 25-125 mEq/L. Creatinine (Jaffe kinetic method) and phosphate (UV) were measured using CCX Spectrum automated analyzer (Abbott Labs. USA). Normal values for serum creatinine: 0.6 – 1.1 mg/dl, and for phosphate: 2.7 - 4.5 mg/dl. Uric acid was analyzed by the uricase method, normal value: 2.5 – 6 mg/dl. Total alkaline phosphatase and its bone isoenzime (Kinetic method, normal value: 90-280 UI/L and 20-48% respectively). Serum β crosslaps (CTX): Electrochemoluminescence, normal value: 556 ± 226 pg/ml. 25 OH vitamin D Radioinmunoanalysis, normal value: 20-40 ng/ml. Osteocalcine (BGP): Electrocheoiluminescence, normal value for women: 11-4 ng/ml, men:14-42 ng/ml.

Bone mineral density (BMD) was assessed by Dual energy X-ray absorptiometry (DXA) using Lunar Prodigy densitometer (Lunar Corporation, General Electric, Madison, WI, USA) measured at the lumbar spine (LS), femoral neck ((FN) and total hip (TH). Bone densitometry was performed at baseline and during two year follow-up under Indapamide treatment, year 1 (Y1) and year 2 (Y2).

All patients were above 18 years of age, had confirmed idiopathic hypercalciuria with normal renal function (Cl Cre > 60 ml/min), parathyroid hormone (PTH) values and serum calcium were normal, and they were free from urinary tract infection. New stone formation or fracture events were not considered.

Exclusion criteria: We excluded patients under 18 years of age, patients with urine tract morphologic abnormalities and those taking drugs or suffering diseases that impair bone metabolism. Those who could not finish at least one year follow-up were also excluded.

All patients received IDP 1.5 mg/day slow release fixed dose. Vitamin D (ergocalciferol or cholecalciferol) was given weekly to correct insufficiency, and there were some osteoporotic patients receiving bisphosphonates.

All patients had blood pressure controls in each visit and were measured with their own medical doctors. Hypertension was present in 30% of the patients and received Losartan or Valsartan besides Indamine.

All the subjects signed an Informed Consent Form. The Informed consent form and the protocol were reviewed and approved by the Institutional Review Board of the Instituto de Diagnostico e Investigaciones Metabolicas

Statistical analysis

Mean and standard deviation were obtained. In all numeric statistical variables tests Kolmogorov-Smirnov or Shapiro Wilk were applied for normal values according to the sample size. Once null hypothesis was confirmed, we applied Factorial analysis of variance, ANOVA for parametric variables and Friedman test for non-parametric variables. We considered as significant change p value < 0.05.

From the total group, (n = 88 patients), there were 11 patients (12.5%) who did not control hypercalciuria within the third and ninth month of evaluation and were prescribed with thiazides. Follow-up was assessed in 77 patients under Indapamine.

Table 1 shows the characteristics of the studied population. As mentioned before there is a prevalence of women in the study group, but the proportion of women are similar in those stone formers and those osteoporotic. Body mass index (BMI) is less than 30 in all patients.

Table 1

Population characteristics (n = 77)
Age (years)	54 ± 11
BMI (Weight/Height²)	23,5 ± 4,6
Women (n/%)	71 (92,2)
Men (n/%)	6 (7,8)
Stone formers (n/%)	34 (44,1)
Osteoporosis (n/%)	33 (42,8)
Creat clear (ml/min)	87,5 ± 10,6
Creat clear: creatinine clearance

Table 2 shows IDP results in the total group at year one and two of follow-up. There was a significant lowering of urine calcium with no change in sodium excretion during follow-up. There was also a decrease in ALP, BGP and CTX in both periods, year one and two.

Table 2

Total group (n = 77) follow-up parameters Year 1 (Y1) and Year 2 (Y2)
Parameters	Mean/SD Basal (n = 77)	Mean/SD Y1 (n = 77)	p	Mean/SD Y2 (n = 69)	p
Calcemia (mg/dl)	9,6 ± 3,2	9,7 ± 0,3	NS	9,7 ± 0,4	NS
Phosphatemia (mg/dl)	4 ± 1	3,6 ± 0,5	NS	3,5 ± 0,4	NS
PTH (pg/ml)	44,1 ± 13,3	42,8 ± 14,6	NS	43,1 ± 18,9	NS
25 OHD (ng/ml)	30 ± 9,4	44,6 ± 14,6*	NS	37,5 ± 18,9	NS
Urine calcium (mg/24hs)	283 ± 63	189 ± 87	< 0.000	182 ± 70	< 0.000
Natriuria (mEq/24hs)	137 ± 58	131 ± 45	NS	128 ± 48,5	NS
ALP (UI/L)	145 ± 61	127 ± 55	< 0.01	121,2 ± 54	< 0.01
bALP (%)	24,7 ± 16,5	21 ± 21,7	NS	17 ± 14,4	0.008
BGP (ng/mL)	24,2 ± 10,2	21,4 ± 12,2	< 0.05	19, 7,2	< 0.01
CTX (pg/mL)	479 ± 262	321 ± 165	< 0.01	322 ± 167	< 0.01
Glycemia (mg/dl)	92,5 ± 10,5	95,3 ± 15,8	NS	96,3 ± 12,9	NS
Uricemia (mg/dl)	4,3 ± 1,0	4,6 ± 1,2	NS	4,6 ± 1	NS
Total Cholesterol (mg/dl)	205 ± 29,5	210 ± 40	NS	214 ± 1	NS
DXA Lumbar Spine	0,960 ± 0,146	0,932 ± 0,126	NS	0,946 ± 0,117	NS
T score Lumbar Spine	-1,8 ± 1,1	-1,9 ± 1,1	NS	-1,97 ± 0,9	NS
DXA Femoral Neck	0,790 ± 0,130	0,770 ± 0,46	NS	0,786 ± 0,09	NS
T score Femoral Neck	-1,5 ± 0,8	-1,6 ± 0,8	NS	-1,6 ± 0,7	NS
ALP: alkaline phosphatase, bALP: bone alkaline phosphatase, BGP: osteocalcin bone gla protein, CTX: Beta Cross laps, 25OHD: 25 vitamin D, Y1: year one of follow−up, Y2: year two of follow−up. DXA: Dual X ray absorptiometry

Table 3 shows results of 34 idiopathic hypercalciuric stone former patients, 28 women (32.6 ± 10.5 years) and 6 men (46.8 ± 12.4 years). After one year 25 patients achieved normal urine calcium and 23 of them continued with normal urine calcium in the second year. This group differs from the total group as no significant changes were found in bone turn-over markers (ALP, BGP, bALP and CTX).

Table 3 Biochemical parameters in idiopathic hypercalciuric and stone former patients, year 1 and year 2 of follow-up

Parameters	Mean/SD basal, n = 34	Mean/SD Y1 (n = 25)	p	Mean/SD Y2 (n = 23)	p
Calcemia (mg/dl)	9,6 ± 0,3	9,6 ± 0,2	NS	9,6 ± 0,4	NS
Phosphatemia (mg/dl)	3,5 ± 0,6	3,5 ± 0,5	NS	3,4 ± 0,5	NS
PTH (pg/ml)	39 ± 9,9	39,7 ± 6,4	NS	43 ± 10,8	NS
25 OHD (ng/ml)	27,1 ± 8,5	28,7 ± 9,3	NS	32 ± 8,4	NS
Urine calcium (mg/24h)	299 ± 65	189 ± 70	< 0.001	168 ± 76	< 0.001
Natriuria (mEq/24h)	166 ± 50	145 ± 52	NS	133 ± 50	NS
ALP (UI/L)	129 ± 58	143 ± 55	NS	140 ± 61	NS
bALP (%)	26,4 ± 17,5	24,5 ± 14,8	NS	24,5 ± 16,4	NS
BGP (ng/mL)	24,2 ± 10,2	24 ± 8,6	NS	19,3 ± 5,2	NS
CTX (pg/mL)	479 ± 277	358 ± 178	NS	333 ± 159	NS
Glycemia (mg/dl)	90,6 ± 7,3	92,2 ± 8	NS	96 ± 9,7	NS
Uricemia (mg/dl)	4,4 ± 1,2	4,8 ± 1,5	NS	4,4 ± 1,1	NS
Total Cholesterol (mg/dl)	198 ± 25	206 ± 31	NS	197 ± 30	NS
ALP: alkaline phosphatase, bALP: bone alkaline phosphatase, BGP: osteocalcin bone gla protein, CTX: Beta Cross laps, 25OHD: 25 vitamin D, Y1: year one of follow−up, Y2: year two of follow−up

Table 4 shows results in IH and osteoporotic patients. There were 33 women (54.9 ± 9.9 years) and 1 man (46.8 years). Urine calcium is in normal range at year one and also at the second year with a small but significant reduction in ALP and CTX with no changes in BGP nor in bALP.

Table 4Biochemical parameters in idiopathic hypercalciuric and osteporotic patients, year 1 and 2 of follow-up

Parameters	Mean/ SD basal n = 34	Mean/SD Y1 (n = 24)	p	Mean/SD Y2 (n = 19)	p
Calcemia (mg/dl)	9,5 ± 0,2	9,6 ± 0,2	NS	9,6 ± 0,2	NS
Phosphatemia (mg/dl)	3,8 ± 0,5	3,7 ± 0,7	NS	3,7 ± 0,4	NS
PTH (pg/ml)	44,4 ± 14,6	45,3 ± 15,3	NS	41,7 ± 23	NS
25 OHD (ng/ml)	29,8 ± 9,4	32,8 ± 12,9	NS	35,5 ± 10,3	NS
Urine calcium (mg/24h)	264 ± 65,1	180 ± 61	< 0.001	180 ± 74	< 0.001
Natriuria (mEq/24h)	114 ± 62	133 ± 36	NS	107 ± 43	NS
ALP (UI/L)	147 ± 46	129 ± 51	0.03	124 ± 43	0.03
bALP (%)	23,3 ± 14,2	15,1 ± 9,8	NS	15,1 ± 12,3	NS
BGP (ng/mL)	24,2 ± 9	22,7 ± 18	NS	17,4 ± 5,8	< 0.05
CTX (pg/mL)	426 ± 263	311 ± 181	< 0.05	297 ± 145	< 0.05
Glycemia (mg/dl)	90 ± 9,7	94 ± 6,8	NS	97 ± 11	NS
Uricemia (mg/dl)	4,3 ± 0,7	4,3 ± 0,7	NS	4,6 ± 1,3	NS
Total Cholesterol (mg/dl)	201 ± 36	215 ± 23	NS	220 ± 27	NS
ALP: alkaline phosphatase, bALP: bone alkaline phosphatase, BGP: osteocalcin bone gla protein, CTX: Beta Cross laps, 25OHD: 25 vitamin D, Y1: year one of follow−up, Y2: year two of follow−up

Patients with both conditions, stone forming and osteoporosis, (9 patients, 8 of them women, age 60,2 ± 7,2 years), achieved normal urine calcium and a reduction of bone turn-over markers, ALP, bALP and CTX both at year 1 and 2. (Table 5). No differences were seen in BGP.

Table 5 Biochemical parameters in IH patients with both conditions, stone-formers and osteoporotic patients, year 1 and 2 of follow-up

Parameters	Mean/SD basal	Mean/SD Y1 (n = 9)	p	Mean/SD Y2 (n = 8)	p
Calcemia (mg/dl)	9,37 ± 0,3	9,6 ± 0,5	NS	9,9 ± 0,2	NS
Phosphatemia (mg/dl)	3,9 ± 0,3	3,7 ± 0,4	NS	3,6 ± 0,4	NS
PTH (pg/ml)	55,1 ± 12,8	55,6 ± 12,7	NS	50,6 ± 13,4	NS
25 OHD (ng/ml)	25,8 ± 5,8	29 ± 12,5	NS	33 ± 7,4	NS
Urine calcium (mg/24h)	298 ± 54	167 ± 44	< 0.01	167 ± 42	< 0.01
Urine Sodium (mEq/24h)	127 ± 38	140 ± 40	NS	125 ± 40	NS
ALP (UI/L)	174 ± 72	136 ± 67	< 0.05	112 ± 61	< 0.05
bALP (%)	24,6 ± 16,5	17 ± 11	< 0.05	14,9 ± 11,5	< 0.05
BGP (ng/mL)	28,8 ± 13,1	19,4 ± 4,5	NS	18 ± 2,2	NS
CTX (pg/mL)	550 ± 304	303 ± 126	< 0.05	341 ± 66	< 0.05
Glycemia (mg/dl)	100 ± 2,8	98 ± 2,9	NS	95 ± 6	NS
Serum Uric Acid (mg/dl)	4,8 ± 1,6	5,5 ± 0 7	NS	5 ± 1,1	NS
Total Cholesterol (mg/dl)	192 ± 17	210 ± 22	NS	233 ± 27	NS
ALP: alkaline phosphatase, bALP: bone alkaline phosphatase, BGP: osteocalcin bone gla protein, CTX: Beta Cross laps, 25OHD: 25 vitamin D, Y1: year one of follow−up, Y2: year 2 of follow−up

Figure 1 shows results in BMD lumbar spine (DXA-LS) in IH and the three groups, IH-stone formers, IH-osteoporotic, IH-stone formers and osteoporotic. No significant changes in lumbar spine was found in stone formers (IH-SF), 15 women, (age: 47 ± 11years) and 5 men (age: 48 ± 10 years), and stone formers with osteoporosis (IH-SF-OS), 9 patients, (8 of them women, mean age: 60.2 ± 7.2 years). In IH with only osteoporosis (IH-OS), 24 women (age: 57.8 ± 7.5 years), there was a significant increment in lumbar spine bone mineral density at year 2 of follow-up, (p<0.05).

Figure 2 shows changes in BMD femoral neck (DXA-FN) in the three groups. No changes in stone formers, nor in osteoporotic groups. There was an increment in the group presenting both conditions that was significant in the first year and continued stable in year 2 of follow-up.

Many osteoporotic patients received bisphophonates that may account for changes in bone turn-over markers and BMD.

No significant changes in blood pressure nor hypotensive clinical events were reported.

No significant adverse events were seen. There were no changes in glycemia, serum uric acid and total cholesterol. Two patients needed potassium supplementation for serum potassium less than 3.5mEq/L, but they did not stop the indapamine treatment.

Two major concerns of idiopathic hipercalciuria are renal stone formation and its urinary tract complications as the third cause of renal pathology, as well as bone fragility [11-17].

Tannenbaum et al found 9.8% of IH in postmenopausal osteoporosis [18]. Our group found IH in 34.1% of 1000 patients with osteopenia or osteoporosis, (not published).

Idiopathic hypercalciuria is present in 40-60% of renal lithiasis [1,19,20] and is considered a risk factor for bone loss throughout life with fragility fractures increased risk [17,21,22]. Giannini and colleagues found that up to19% of postmenopausal women with osteoporosis, referred for the first time to their Metabolic Bone Diseases Unit, had hypercalciuria in their bone metabolic evaluation [23].

Thiazide diuretics and their analogs are commonly used for lowering calcium excretion in hypercalciuric, recurrent calcium stone formers [11]. Four randomized controlled trials (RCTs), which evaluated 408 patients over periods of 26 to 36 months, demonstrated significant reductions in recurrent kidney stones with thiazides and the thiazide analog, indapamide [12,13,14]. Thiazide administration along with dietary sodium restriction to maximize the hypocalciuric effect of thiazide is the treatment of choice in hypercalciuric, calcium stone-forming subjects. The incidence of thiazide diuretic adverse effects is about 30%, although adverse effects requiring discontinuation of the drug are rare [15]. Indapamine is a diuretic agent that was developed to be administered alone or combined for the treatment of hypertension [24,25] with similar effect as hydrochlorothiazide that has been reported in many studies to have 50% reduction in hypercalciuria even in patients followed for 3 years [7,26,27].

In our cohort of 88 IH patients we observed 12.5% non-responders that were prescribed other drug to control urine calcium. This lack of response percentage to indamine 1.5 mg fixed dose was also published by Martins et al. that found in a double blind randomized crossover protocol with indapamine 2.5 mg versus hydrochlorothiazide 50 mg a lack of response in the indapamine group of 16.6% after 3 months of treatment [28].

Significant reduction in hypercalciuria and no bone loss with few adverse events along 2 years under indamine 1.5mg/day, resulted in 77 patients participating in our study. We also observed a significant reduction in bone turn-over markers, (CTX, ALP, Bone ALP and BGP) different to Lalande et al. that reported that IDP, decreased bone resorption but increased bone formation without significant variation of PTH level in vivo, as assessed by bone histomorphometry [10].

Urine calcium in IH and stone forming patients was significantly reduced at first and second year of follow-up with no urine sodium changes nor bone turn-over markers changes in this group. Urine calcium had a 36.8% reduction at year one and 44% at year 2, similar to the 48% reported by Alonso et al in 12 IH stone forming patients followed for 18 months. Kadir et al. [27] reported similar reductions, 43% and 50% in IH patients with and without stone formation respectively [8].

Urine calcium also decreased significantly in 34 IH and osteoporotic patients, 32% reduction at both year 1 and 2 with a small reduction in ALP and CTX.

In a small group of 9 IH patients with both conditions stone formation and osteoporosis, there was a 44% reduction in urine calcium at both years of follow-up.

Bone densitometry showed no changes in lumbar spine and femoral neck in IH stone formers during the two year follow-up while IH osteoporotic patients had a significant increase in lumbar spine at year 2 of follow-up. Those IH with both conditions had an increase in femoral neck since year 1 that stayed stable at year 2.

Our 77 patients showed a significant reduction in urine calcium in all IH groups.

Bone turn-over markers changed with reduction in CTX (resorption) and in ALP and BGP (formation) different as it was observed in the experimental study with spontaneously hypertensive rats supplemented with sodium [29].

These changes were present in all IH and osteoporotic patients with or without renal stones. No changes were present in IH and stone formers.

The lack of changes in bone density in IH and stone formers suggests that IDP keeps stable bone mass by correcting urine calcium and increasing calcium balance [30].

There was a significant increase in lumbar spine at year 2 follow-up in IH and osteoporotic patients with small but not significant increase in femoral neck. In IH with both conditions the increase was seen in femoral neck since year 1 with a tendency of increase not significant in lumbar spine at year 2, but this group included low number of patients to withdraw evidence.

Changes in bone turn-over markers and bone density could be influenced by bisphosphonates. Giusti et al have demonstrated that combination of IDP and alendronate in IH has a superior result in controlling urine calcium and increasing bone density than alendronate alone [31].

Adverse effects were not significant, no changes in blood pressure, glycaemia, cholesterol, serum uric acid, sodium and potassium were found. Only 2 patients needed potassium supplementation for mild hypokalemia and did not stop IDP.

The limitations of our study is that women are superior in number, bisphosphonates were not excluded, and new stone or fracture events were not registered. Future prospective studies are needed. The strength is to show the use of an alternative diuretic that controls in the majority of cases urine calcium with very few adverse events.

In conclusion fixed dose of Indamine is an effective alternative treatment to Idiopathic Hypercalciuria, controlling urine calcium loss and bone mineral density for at least two years. Association with bisphosphonates not only controls urine calcium but has a positive effect in bone mass. No significant adverse events were present and only 12.5% of patients were prescribed other thiazide to treat urine calcium loss.

The authors have nothing to disclose, no conflicts of interests.

Acknowledgments

Not applicable.

Authors' contributions

Study concept and design: FRS

Acquisition of data: GS and PR

Results review and data analysis: FRS and PR.

Manuscript writing and review: FRS.

Manuscript style correction: PR.

Spivacow FR, del Valle EE, Negri AL, Fradinger E, Abib A, Rey Paula (2015) Biochemical diagnosis in 3040 kidney stone formers in Argentina. Urolithiasis 43:323–330. doi: 10.1007/s00240-015-0778-2.
Sakhaee K, Maalouf NM, Kumar R, Pasch A, Moe OW (2011) Nephrolithiasis associated bone disease: pathogenesis and treatment options Kidney Int 79 (4):393–403. doi: 10.1038/ki.2010.473
K. Aung, T. Htay (2011) Thiazide diuretics and the risk of hip fracture, Cochrane Database Syst. Rev (10) CD0051854.
X. Xiao, Y. Xu, Q. Wu (2018) Thiazide diuretic usage and risk of fracture: a meta-analysis of cohort studies, Osteoporos Int 29 (7):1515–1524. DOI: 10.1007/s00198-018-4486-9
Costanzo LS. Weiner IM (1974) On the hypocalciuric action of chlorothiazide. J Clin Invest 54:628–637. doi: 10.1172/JCI107800
Hye Ryoun Jang, Sejoong Kim, Nam Ju Heo, Jeong Hwan Lee, Hyo Sang Kim, Soren Nielsen et al (2009) Effects of Thiazide on the Expression of TRPV5. Calbindin-D28K and Sodium Transporters in Hypercalciuric Rats. J Korean Med Sci 24 (Suppl 1):S161-169. doi:10.3346/jkms.2009.24.S1.S161
Lemieux, G (1986) Treatment of idiopathic hypercalciuria with indapamide. CMAJ 135(2):119–121
Kadir Ceylan K, Cevat Topal, Reha Erkoc, Hayriye Sayarlioglu, Saban Can, Yuksel Yilmaz et al (2005) Effect of lndapamide on Urinary Calcium Excretion in Patients With and Without Urinary Stone Disease. Ann Pharmacother 39:1034–1038
Danielsen H., E.B., Pedersen, E.S (1984) Spencer. Department of Medicine C, Aarhus Kommunehospital, DK-8000 Aarhus C, Denmark. Effect of indapamide on the renin-aldosterone system, and urinary excretion of potassium and calcium in essential hypertension H Br J Clin Pharmac 18: 229–231. doi: 10.1111/j.1365-2125.1984.tb02458.x
Lalande A, Roux S, Annick Denne M, Stanley Er, Schiavi P, Guez D, De Vernejoul MC (2001) Indapamide, a thiazide-Like Diuretic, Decreases Bone Resorption in vitro J Bone Miner Res 16 (2):361–370. doi: 10.1359/jbmr.2001.16.2.361
Moe OW, Pearle MS, Sakhaee K (2011) Pharmacotherapy of urolithiasis: evidence from clinical trials Kidney Int 79:385–392. doi: 10.1038/ki.2010.389
Ettinger B, Citron JT, Livermore B, Dolman LI (1988) Chlorthalidone reduces calcium oxalate calculous recurrence but magnesium hydroxide does not J Urol 139:679–684. doi: 10.1016/s0022-5347(17)42599-7
Laerum E, Larsen S (1984) Thiazide prophylaxis of urolithiasis. A double-blind study in general practice Acta Med Scand 215:383–389
Ohkawa M, Tokunaga S, Nakashima T, Orito M, Hisazumi H (1992) Thiazide treatment for calcium urolithiasis in patients with idiopathic hypercalciuria Br J Urol 69:571–576. doi: 10.1111/j.1464-410x.1992.tb15624.x
Spivacow FR, Negri AL, del Valle EE (2013) Efecto a largo plazo de las tiazidas en la masa ósea de mujeres con nefrolitiasis por hipercalciuria Rev Nefrol Dial Transpl 33:180–187
Lauderdale DS, Thisted RA, Wen M, Favus MJ (2001) Bone mineral density and fracture among prevalent kidney stone cases in the Third National Health and Nutrition Examination Survey J Bone Miner Res 16:1893–1898. doi: 10.1359/jbmr.2001.16.10.1893
Zanchetta JR, Rodríguez G, Negri AL, del Valle E, Spivacow FR (1996) Bone mineral density in patients with hypercalciuric nephrolithiasis Nephron 73:557–560. doi: 10.1159/000189140
Tannenbaum C J, Schwartzman K, Wallenstein S, Lapinski R, Meier D, Luckey M (2002) Yield of Laboratory Testing to Identify Secondary Contributors to Osteoporosis in Otherwise Healthy Women J Clin Endocrinol Metabol 87(10):4431–4437. doi: 10.1210/jc.2002-020275
Lerolle N, Lantz B, Paillard F, Gattegno B, Flahault A, Ronco P, et al (2002) Risk factors for nephrolithiasis in patients with familial idiopathic hypercalciuria Am J Med 113 (2):99–103. doi: 10.1016/s0002-9343(02)01152-x
Frick KK, Bushinsky DA (2003) Molecular mechanisms of primary hypercalciuria J Am Soc Neph 14:1082–1095. doi: 10.1097/01.asn.0000062960.26868.17
Ryan CS, Petkov VI, Adler RA (2011) Osteoporosis in men: the value of laboratory testing Osteoporos Int 22:1845–1853. doi: 10.1007/s00198-010-1421-0
Pacifici R, Rothstein M, Rifas L, Lau KH, Baylink DJ, Avioli LV et al (1990) Increased monocyte interleukin-1 activity and decreased vertebral bone density in patients with fasting idiopathic hypercalciuria J Clin Endocrinol Metab 71:138–145. doi: 10.1210/jcem-71-1-138
Giannini S, Nobile M, Dalle Carbonare L, Lodetti MG, Sella S, Vittadello G et al (2003) Hypercalciuria is a common and important finding in postmenopausal women with osteoporosis Eur J Endocrinol 149:209–213. doi: 10.1530/eje.0.1490209
Milliez P, Tcherdakoff P (1975) Antihypertensive activity of a new agent, Indapamide: a double-blind study Curr Med Res Opin 3:9–15. doi: 10.1185/03007997509113638
Tzourio C, Anderson C, Chapman N, Woodward M, Neal B, MacMahon S, Chalmers J (2000) PROGRESS Collaborative Group. Ambulatory blood pressure profiles in patients treated with once-daily diltiazem extended-release or indapamide alone or in combination Am J Ther 7(3):177–184. doi: 10.1097/00045391-200007030-00005
Borghi L, Elia G, Trapassi MR, Melloni E, Amato F, Barbarese F, et al (1988) Acute effect of indapamide on urine calcium excretion in nephrolithiasis and human essential hypertension Pharmacology 36:348–355. doi: 10.1159/000138405
Alonso D, Pieras E, Pizá P, Grases F, Prieto RM (2012) Effects of short and long-term indapamide treatments on urinary calcium excretion in patients with calcium oxalate dihydrate urinary stone disease: A pilot study. Scand J Urol Nephrol 46: 97–101. doi: 10.3109/00365599.2011.644862
Martins MC, Meyers AM, Whalley NA, Margolius LP, Buys ME (1996) Indapamide (Natrilix): the agent of choice in the treatment of recurrent renal calculi associated with idiopathic hypercalciuria Br J Urol 78:176–180. doi: 10.1046/j.1464-410x.1996.00633.x
Lalande A, Roux C, Graulet AM, Schiavi P, De Vernejoul MC (1998) The Diuretic Indapamide Increases Bone Mass and Decreases Bone Resorption in Spontaneously Hypertensive Rats Supplemented with Sodium J Bone Miner Res (9):1444–1450. doi: 10.1359/jbmr.1998.13.9.1444
Middler S, Pak CY, Murad F, Bartter FC (1973) Thiazide diuretics and calcium metabolism Metabolism 22:139–146. doi: 10.1016/0026-0495(73)90264-3
Giusti A, Barone A, Pioli G, Girasole G, Siccardi V, Palummeri E, Bianchi G (2009) Alendronate and indapamide alone or in combination in the management of hypercalciuria associated with osteoporosis: a randomized controlled trial of two drugs and three treatments Nephrol Dial Transplant 24: 1472–1477. doi: 10.1093/ndt/gfn690

No competing interests reported.

Download PDF

Version 1

posted

You are reading this latest preprint version

Indapamine effects on hypercalciuria and bone mineral density

Status:

Version 1

Abstract

Figures

Introduction

Materials And Methods

Results

Discussion

Statements and Declarations

References

Additional Declarations

Status:

Version 1