Table 3.
Interventional clinical trials based on the use of citrate supplements with primary or secondary outcomes related to bone health status.
| Reference | Study Design; Population | Intervention (Dose/Day) (I) Control (C) |
Other Supplements (Dose/Day) and/or Controlled Dietary Intake |
Follow Up and Outcomes | BTM Changes (Intragroup) | Changes in BTM and BMD Induced by Intervention (Intergroup) | Conclusion |
|---|---|---|---|---|---|---|---|
| Dawson-Hughes, 1990 [141] | RCT, controlled vs placebo, double-blind; ≥6 months postmenopausal women (early, <5 years: n = 67; late, >5 years: n = 169); age ≥ 65 years |
I 1: Ca citrate malate (500 mg Ca), n = 78 I 2: Ca carbonate (500 mg Ca), n = 78 C: Placebo (n = 80) |
Controlled Ca intake | Baseline, 18, 24, 36 months; BTM (BAP) and BMD |
I 1: 24 months ↓ BAP I 2: 24 months ↓ BAP C: 24 months ↓ BAP |
BTM I 1 vs. C: 36 months ↓ BAP, related to the Ca intake I 2 vs. C: 36 months ↓ BAP, related to the Ca intake BMD I 1 vs. C: 12, 24 months ↑ only in late postmenopause and Ca intake ≤400 mg/day I 2 vs C: ↓ in both groups |
Adequate Ca intake is essential in preventing postmenopausal bone loss; Ca citrate is more effective than Ca carbonate. |
| Dawson-Hughes, 1997 [142] | RCT, controlled vs. placebo, double-blind; healthy subjects living in a community (176 M/ 213 F); age ≥ 65 years |
I: Ca citrate malate (500 mg Ca) & Vit D3 (700 IU), n = 187 C: Placebo, n = 202 |
Controlled Ca intake | Baseline, 6, 12, 18, 24, 30, 36 months; BTM (OC, u-NTX) and BMD |
I: n.s C: n.s. |
BTM I vs. C: 36 months ↓ OC BMD I vs. C: 36 months ↑ |
Ca and vitamin D supplementation leads to a moderate reduction in bone loss and may substantially reduce the risk of nonvertebral fractures among elderly subjects who live in the community. |
| * Ruml, 1999 [143] | RCT, controlled vs. placebo; postmenopausal women (90% ≤5 years) | I: Ca citrate (800 mg Ca), n = 25 C: Placebo, n = 31 |
Baseline, 12, 24 months BTM (BAP, OC, u-NTX, u- OH proline) and BMD |
I: all BTMs are ↓, at unspecified time points | BMD I: 24 months, stable |
Ca citrate supplementation averted bone loss and stabilised bone density in early postmenopausal women. | |
| Sellmeyer, 2002 [144] | RCT, controlled vs. placebo, double-blind; ≥2 years postmenopausal women; age I: 65 ± 8 years; C: 63 ± 8 years |
I: K citrate (90 mmol), n = 26 C: Placebo, n = 26 |
Ca carbonate (500 mg); controlled salt intake | Baseline, 1 months; BTM (OC, u-NTX) |
I: n.s. C: 1 month ↓ OC, ↑ u-NTX |
BTM I vs. C: 1 month, ↓ u-NTX |
K citrate prevents increased bone resorption due to high salt intake. |
| Dawson-Hughes, 2002 [145] | RCT, controlled vs. placebo, double-blind; healthy subjects (161 M/ 181F); normal BMD; age ≥ 65 years |
I: Ca citrate malate (500 mg Ca), n = 158 C: Placebo, n = 184 |
Vitamin D3 (700 IU); controlled protein intake | Baseline, 18, 36 months; BTM (OC, u-NTX) and BMD |
I: 36 months ↓ u-NTX, related to the protein intake; C: n.s. |
BTM I vs C: 36 months, ↓ u-NTX BMD I vs C: 36 month, ↑ related to the protein intake |
BMD may be improved by increasing protein intake as long as an adequate intake of Ca and vitamin D is assumed. |
| Marangella, 2004 [146] | Controlled vs. untreated; postmenopausal women; T score: <−1.0; age: 43–72 years | I: K citrate 37-74 mEq (≈1 mEq/kg), n = 30 C: No treatment, n = 24 |
Controlled Ca intake | Baseline, 3 months BTM (BAP, OC, u-OH proline, u-DPD) |
I: 3 months ↓ OC, u-OH proline, u-DPD; C: 3 months ↑ OC |
not shown | K citrate decreases bone resorption thereby contrasting the potential adverse effects caused by chronic acidemia. The implication for the prevention and treatment of postmenopausal osteoporosis has to be confirmed. |
| Kenny, 2004 [147] | RCT, crossover, open label, 2 phases; 3 months/phase with a washout period of 2 weeks between phases; postmenopausal women; T score: <−1.0 and >−3.5; age: 73 ± 5 years |
I 1: Ca citrate (1000 mg Ca), n = 20; I 2: Ca carbonate (1000 mg Ca), n = 20 |
Vitamin D3 (900 IU); controlled Ca intake | Baseline, 1, 3 months (each phase) BTM (BAP, OC, NTX, u-CTX, u-NTX, u-DPD) |
I 1: 3 months ↓ NTX, u-CTX, u-NTX, u-DPD I 2: n.s |
Ca citrate inhibits bone resorption more than Ca carbonate. | |
| Sakhae, 2005 [139] | RCT, crossover, placebo controlled, double-blind, 4 phases; 2 weeks/phase with a washout period of 2 weeks between phases; postmenopausal women; age: 48–76 years |
I 1: K citrate (40 mEq), n = 18 I 2: Ca citrate (800 mg), n = 18 I 3: K citrate (40 mEq) and Ca citrate (800 mg), n = 18 C (1st phase): Placebo, n = 18 |
Rigid diet with fixed content of protein, Ca, P, Na, K and fluids | Baseline and at the end of each phase; BTM (BAP, CTX, OC, u-NTX, u-OH proline) |
I 1: n.s I 2: ↓ CTX, u-OH proline I 3: I: ↓ CTX, u-OH proline, u NTX |
I 3 vs I 1: ↓ u NTX | In postmenopausal women, combined treatment with K citrate and Ca citrate decreases bone resorption by providing an alkali load and increasing absorbed Ca. |
| Jehle, 2006 [148] | RCT, controlled; ≥5 years postmenopausal women; T score −1/−4; age: ≤70 years |
I: K citrate (30 mEq), n = 82 C: KCl (30 mmol), n = 79 |
Ca carbonate (500 mg), Vitamin D3 (400 IU); free, nonvegetarian diet | Baseline, 3, 6, 9, 12 months; BTM (BAP, CTX, OC, u-DPD, u-PD) and BMD |
I: 3 months, ↓ u-DPD, u-PD; 6 months, ↑ BAP and ↓ OC, u-DPD, u-PD; 9 months, ↓ u-DPD, u-PD; 12 months, ↑ BAP and ↓ OC, u-DPD, u-PD; C: 3 months, ↓ OC, u-DPD, u-PD; 6 months, ↑ BAP, u-DPD, u-PD and ↓ OC; 9 months, ↑ u-DPD, u-PD and ↓ OC; 12 months, ↑ BAP, u-DPD, u-PD and ↓ OC |
BTM I vs C: 3 months, ↓ u-DPD BMD I vs C: 12 months ↑ |
In postmenopausal women, bone mass can be increased significantly by K citrate. The effect on bone resorption seems to be unrelated to K intake. |
| Macdonald, 2008 [134] | RCT, controlled vs. placebo, double-blind for I1 e I2; ≥5 years postmenopausal women; age: 49–54 years | I 1: K citrate (55.5 mEq), n = 70 I 2: K citrate (18.5 mEq), n = 70 I 3: Diet (300 g fruit = 18.5 mEq alkali), n = 66 C: Placebo, n = 70 |
Food diary (free nonvegetarian diet) | Baseline, 3, 6, 12, 18, 24 months; BTM (CTX, P1NP, u-DPD) and BMD |
I 1: n.s. I 2: n.s. I 3: n.s. C: n.s |
BTM I 1, I 2, I 3 vs. C: n.s BMD I 1, I 2, I 3 vs. C: n.s |
In healthy postmenopausal women, neither K citrate at 18.5 or 55.6 mEq/d, nor 300 g self-selected fruit and vegetables influenced bone turnover or prevented BMD loss over 2 years. |
| Thomas, 2008 [149] | RCT, crossover, double-blind, 2 phases; postmenopausal women for 2 to 6 years; age: 50–60 years |
I 1: Ca carbonate (1000 mg Ca), n = 12 I 2: 2) Ca citrate (500 mg Ca), n = 13 |
Controlled Ca intake | Baseline, 7 days; BTM (CTX) |
I 1: 7 days, ↓ CTX I 2: 7 days, ↓ CTX |
Ca citrate is at least as effective as Ca carbonate in decreasing PTH and CTX cross-links, at half the dose. All changes are numerically superior after Ca citrate supplementation. | |
| Karp, 2009 [140] | RCT, controlled, 24 h study sessions; women of child-bearing age: 22–30 years | I 1: Ca carbonate (1000 mg Ca), n = 12 I 2: Ca citrate (Ca: 1000 mg; citrate: 3145 mg), n = 12 I 3: K citrate (K: 57 mEq; citrate: 3145 mg), n = 12 |
4-day diary to estimate food habits before starting the study session; the meals served during each study session were identical | Baseline, 2, 4, 6, 8, 20, 24 h; BTM (BAP, u-NTX) and BMD |
I 1: 24 h, ↓ u-NTX I 2: n.s I 3: 24 h, ↓ u-NTX |
K citrate supplementation decreases urinary Ca excretion and reduces bone resorption even when the diet is not acidogenic, and reduces the bone resorption marker despite low Ca intake. | |
| Jehle, 2013 [150] | RCT, controlled vs. placebo, double-blind; healthy subjects (79 M/122 F); T score > −2.5; age 65–80 years; women were past the perimenopausal peak turnover |
I: K citrate (60 mEq), n = 101 C: Placebo, n = 100 |
Ca carbonate (500 mg), Vitamin D3 (400 IU); free nonvegetarian diet | Baseline, 6, 12, 18, 24; BTM (BAP, P1NP, u-NTX) and BMD |
I: 6, 12 months, ↓ u-NTX; 18, 24 months, ↑ P1NP C: n.s. |
BTM I vs. C: 6 months, ↓ u-NTX BMD I vs. C: 12, 18, 24 months ↑ |
K citrate administered in a background of vitamin D and Ca supplementation is well tolerated and constitutes an inexpensive intervention to improve BMD and bone microarchitecture in healthy elderly people. |
| Moseley, 2013 [151] | RCT, controlled vs. placebo, double blind; healthy subjects (17 M/35 F); age ≥ 55 years; women were ≥5 years postmenopause |
I 1: K citrate (60 mmol), n = 17 I 2: K citrate (90 mmol), n = 17 C: Placebo, n = 18 |
Ca citrate (630 mg), Vitamin D3 (400 IU); controlled Ca, Na, P, protein, fat intake | Baseline, 6 months; BTM, (BAP, CTX) |
BTM I 1, I2 vs. C: 6 months, ↓ CTX |
K citrate decreases markers of bone resorption over 6 months, but a significant improvement in Ca balance is obtained with 90 mmol/day. This dose is well tolerated. | |
| Gregory, 2015 [152] | RCT, controlled vs. placebo, double-blind; ≥2 year postmenopausal women s; T score: <−1.0 > −2.5, or <−2.5 unable to take any other medication; age I: 65.1 ± 5.9 years; C: 66.1 ± 7.1 years |
I: K citrate (40 mEq), n = 42 C: Placebo, n = 41 |
Ca citrate (630 mg), Vitamin D3 (400 IU); free nonvegetarian diet | Baseline, 1, 3, 6, 12 months; BTM (BAP, OC, P1NP, u-NTX) and BMD |
I: 1 month, ↓ P1NP; 3, 6, 12 months, ↓ P1NP, u-NTX C. I: 6 months, ↓ P1NP u-NTX; 12 months, ↓ P1NP |
BTM I vs. C: n.s BMD I: 12 months, stable |
In postmenopausal osteopenia, K citrate improves the effect of supplementation with Ca citrate and Vitamin D, as proven by the more rapid decrease in BTM levels. |
| Granchi, 2018 [91] | RCT, controlled vs. placebo, double-blind; ≥5 years postmenopausal women; T score: <−1.0 and >−2.5; age I: 60.8 ± 1.0 years; C: 58.2 ± 1.1 years | I: K citrate (30 mEq), n = 20 C: Placebo, n = 20 |
Ca carbonate (500 mg), Vitamin D3 (400 IU); free nonvegetarian diet | Baseline, 3, 6 months; BTM (BAP, CTX, P1NP, TRAcP) |
I: 6 months, ↓ BAP, CTX C: 3, 6 months, ↓ BAP, CTX |
BTM I vs. C: 6 months ↓ BAP, CTX in subjects with low excretion of K and/or citrate, and/or low urine pH |
In postmenopausal osteopenia, K citrate improves the effects of supplementation with Ca carbonate and vitamin D, but only in women with low K and/or citrate excretion and/or low urine pH. |
C: control; I: Intervention; RCT: randomised clinical trial; K citrate: potassium citrate; Ca carbonate: calcium carbonate; Ca citrate: calcium citrate; KCl: potassium chloride; Na: sodium; P: phosporus; BMD: bone mineral density; BTM: bone turnover markers; n.a.: not applicable; n.s.: not significant; BAP: bone-specific alkaline phosphatase; BMD: bone mineral density; K: potassium; Ca: calcium; u-DPD: urinary deoxypyridinoline; u-PYR: urinary pyridinoline; u-OH proline: urinary hydroxyproline; OC: osteocalcin; P1NP: amino-terminal propeptide of type 1 procollagen; u-NTX: urinary N-telopeptide of collagen type 1; M: male; F: female; IU: International Units; PTH: parathyroid hormone; ↓ and ↑ show significant decreases and increases, respectively, according to the criteria indicated by the authors. * Partial data collected from the abstract.