Potassium Citrate Supplementation Decreases the Biochemical Markers of Bone Loss in a Group of Osteopenic Women: The Results of a Randomized, Double-Blind, Placebo-Controlled Pilot Study

Abstract

The relationship involving acid-base imbalance, mineral metabolism and bone health status has previously been reported but the efficacy of the alkalizing supplementation in targeting acid overload and preventing bone loss has not yet been fully elucidated. In this randomized, double-blind, placebo-controlled study, the hypothesis that potassium citrate (K citrate) modifies bone turnover in women with postmenopausal osteopenia was tested. Three hundred and ten women were screened; 40 women met the inclusion criteria and were randomly assigned to the treatment or the placebo group. They were treated with K citrate (30 mEq day-1) or a placebo in addition to calcium carbonate (500 mg day-1) and vitamin D (400 IU day-1). At baseline and time points of 3 and 6 months, serum indicators of renal function, electrolytes, calciotropic hormones, serum bone turnover markers (BTMs), tartrate-resistant acid phosphatase 5b (TRACP5b), carboxy-terminal telopeptide of type I collagen (CTX), bone alkaline phosphatase (BAP), procollagen type 1 N terminal propeptide (PINP)), and urine pH, electrolytes, and citrate were measured. The follow-up was completed by 17/20 patients in the "K citrate" group and 18/20 patients in the "placebo" group. At baseline, 90% of the patients exhibited low potassium excretion in 24 h urine samples, and 85% of cases had at least one urine parameter associated with low-grade acidosis (low pH, low citrate excretion). After treatment, CTX and BAP decreased significantly in both groups, but subjects with evidence of low-grade acidosis gained significant benefits from the treatment compared to the placebo. In patients with low 24h-citrate excretion at baseline, a 30% mean decrease in BAP and CTX was observed at 6 months. A significant reduction was also evident when low citrate (BAP: -25%; CTX: -35%) and a low pH (BAP: -25%; CTX: -30%) were found in fasting-morning urine. In conclusion, our results suggested that K citrate supplementation improved the beneficial effects of calcium and vitamin D in osteopenic women with a documented potassium and citrate deficit, and a metabolic profile consistent with low-grade acidosis.

Keywords: acid-base; bone remodeling; bone turnover markers; osteopenia; potassium citrate; urolithiasis.

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1

CONSORT flow diagram.

Figure 2

Changes in urine (u) parameters according to treatment group. The line-graphs highlight the changes observed in both fasting-morning urine (A,C,E) and 24 h urine (B,D,F,G). Data are expressed as mean plus or minus the standard error of the mean (mean ± SEM) of the variations over time calculated in each subject as [(concentration at time point × concentration at baseline−1) − 1], with the baseline = 0. Symbols indicate the statistically significant differences over time (paired t test; * = p < 0.05 vs. Baseline); the symbol in square brackets indicates a statistically significant difference between groups at the time point highlighted by the arrow (unpaired t test; * = p < 0.05).

Figure 3

Bone turnover marker (BTM) changes (%) according to treatment group. The data regarding bone alkaline phosphatase (BAP) (A), carboxy-terminal telopeptide of type I collagen (CTX) (B), procollagen type 1 N terminal propeptide (PINP) (C) and tartrate-resistant acid phosphatase 5b (TRACP5b) (D) are expressed as mean ± SEM of the changes calculated in each subject as [(BTM concentration at the time point × BTM concentration at baseline−1) − 1] × 100, where the baseline is 0. Symbols indicate the statistically significant values obtained from the paired t test. K citrate group: * = p < 0.05 vs. Baseline; ** = p < 0.005 vs. Baseline; † = p < 0.05 vs. 3 months. Placebo group: § = p < 0.05 vs. Baseline; §§ = p < 0.005 vs. Baseline; ∇∇ = p < 0.005 vs. 3 months.

Figure 4

BAP changes (%) in the subgroups of patients with signs of low-grade acidosis at baseline. The BAP changes were analyzed in women who exhibited low urinary (u) pH in fasting-morning urine (A: n = 14), and low citrate excretion in both fasting-morning urine (B: n = 25) and 24 h urine (C:n = 23; D: n = 13). Data are expressed as mean ± SEM of the BAP change calculated in each subject as described in Figure 3. The symbols indicate the statistically significant values obtained with the paired t test. K citrate group: * = p < 0.05 vs. Baseline; ** = p < 0.005 vs. Baseline; † = p < 0.05 vs. 3 months; †† = p < 0.005 vs. 3 months. Placebo group: § = p< 0.05 vs. Baseline; ∇ = p < 0.05 vs. 3 months.

Figure 5

CTX changes (%) in subgroups of patients with signs of low-grade acidosis at baseline. The CTX changes were analyzed in the women who exhibited low urinary (u) pH in fasting-morning urine (A: n = 14), and low citrate excretion in both fasting-morning urine (B: n = 25) and 24 h urine (C: n = 23; D: n = 13). Data are expressed as mean ± SEM of the CTX change calculated in each subject as described in Figure 3. The symbols indicate the statistically significant values obtained with the paired t test. K citrate group: * = p < 0.05 vs. Baseline; † = p < 0.05 vs. 3 months. Placebo group: § = p < 0.05 vs. Baseline; ∇ = p < 0.05 vs. 3 months.

Figure 6

BTM changes in the last three-month period of treatment. Data are expressed as mean ± SEM of the changes calculated in each subject as [(BTM concentration at 6 months × BTM concentration at 3 months−1) − 1] × 100, where the 3-month value is 0. The bars represent the variation in CTX (A), BAP (B), and PINP (C) in all patients and subgroups who completed the follow-up. All patients: n = 35. Number of patients with altered parameters in fasting-morning urine: n = 13, pH <5.5; n = 20, citrate <3.3 mol L−1; n = 32, low citrate and/or pH. Number of patients with altered parameters in 24 h urine: n = 20, citrate <3.3 mol day−1; n = 11, citrate/creatinine <0.3 mol mol−1; n = 32, citrate and/or pH. The significant differences between K citrate and the placebo are highlighted by p values < 0.05 over the bars.

Figure 6

BTM changes in the last three-month period of treatment. Data are expressed as mean ± SEM of the changes calculated in each subject as [(BTM concentration at 6 months × BTM concentration at 3 months−1) − 1] × 100, where the 3-month value is 0. The bars represent the variation in CTX (A), BAP (B), and PINP (C) in all patients and subgroups who completed the follow-up. All patients: n = 35. Number of patients with altered parameters in fasting-morning urine: n = 13, pH <5.5; n = 20, citrate <3.3 mol L−1; n = 32, low citrate and/or pH. Number of patients with altered parameters in 24 h urine: n = 20, citrate <3.3 mol day−1; n = 11, citrate/creatinine <0.3 mol mol−1; n = 32, citrate and/or pH. The significant differences between K citrate and the placebo are highlighted by p values < 0.05 over the bars.

Figure 7

Diagram showing some of the mechanisms that explain the relationship between diminished citrate excretion and bone loss in postmenopausal women. Estrogen deficiency promotes the activity of multicellular units (BRUs) containing osteoclasts (OCs) and osteoblasts (OBs) which, in sequence, resorb old bone and form new bone. The “net bone loss” depends on the increased bone resorption by OCs which exceed the new bone formation since osteogenic precursors (MSCs) are destined to differentiate into adipocytes, and the number and function of OBs are decreased. Bone resorption should favor the availability of citrate embedded in the bone matrix (green topic), but the lower production and the higher consumption (yellow topics) cause a “net citrate loss”.