Efficacy of Potassium Citrate in the Treatment of Postmenopausal Osteopenia

Bone tissue carries out some of the important metabolic functions, including the regulation of acid-base balance. In order to buffer the systemic acidosis, the skeleton acts as a "ion exchange column" modifying the composition of the mineral portion, i.e. the hydroxyapatite. There is a linear correlation between elimination of calcium and acidosis: the higher is the acidosis, the higher will be the loss of calcium from bones. In vitro experiments showed that acidosis also directly influences the cellular component of bone by increasing the osteoclast activity and inhibiting the production of the mineralized matrix by osteoblast. Since the low pH is a risk factor that accelerates the bone loss, the use of alkalizing compounds could prevent the osteopenia or support the conventional therapy of the osteoporosis.

KCitr is an alkaline compound which may be used in metabolic acidosis. Potassium is an alkaline metal that plays a pivotal role in the function of all living cells. Citric acid is a key molecule of the Krebs cycle, and it is abundant in bone where exhibits a stabilizing function. Although clinical data regarding the KCitr effectiveness on calcium metabolism are encouraging, it is still unclear whether the beneficial effects are due exclusively to the buffering function or whether KCitr may affect the bone cells activity. The purpose of this study is to evaluate the effects of KCitr on bone metabolism. We hypothesize that administration of potassium citrate to postmenopausal women with osteopenia will delay (or will prevent) the weakening of bone mass.

Postmenopausal women with osteopenia (T score between -1.0 and -2.5) and no history of fracture will be randomized to assume KCitr ate or placebo, daily for six months. Primary outcomes will be evaluated by measuring markers of bone turnover, which will be measured at baseline (before treatment), in the mid-term (3 months) and at the end (6 months).

• Potassium citrate (Dietary supplement): Kcitr 3.064 milligrams daily in two tablets by mouth (1.032 milligrams every 12 hours)
• Placebo (Dietary supplement): Excipients: 3.064 milligrams daily in two tablets by mouth (1.032 milligrams every 12 hours)
• Vitamin D3 (Dietary supplement), also known as Cholecalciferol: 400 IU/die Vitamin D3 daily by mouth
• Calcium carbonate (Dietary supplement): 500 mg/die calcium carbonate daily by mouth

Primary outcomes

• Changes in Serum Level of Carboxyterminal Cross-linked Telopeptide of Type I Collagen (CTX); Over Time, i.e. Baseline, 3 Months, 6 Months. [Baseline (T0), 3 months (T3) 6 months (T6)]: Carboxyterminal cross-linked telopeptide of type I collagen (CTX) is a degradation product of the type I collagen; it is considered as a marker of bone resorption. The concentration of CTX (µg/L) will be measured at T0, T3, and T6 on serum samples (fasting morning samples) using commercially available reagents and following the manufacturer's protocol. At the end of the study, the results will be aggregated as mean ± standard of the mean, median and min-max range. Data will be statistically analyzed in order to compare the activity of Potassium citrate versus Placebo (unpaired analysis) and to evaluate the effect of Potassium Citrate and Placebo over time (paired analysis). Differences will be considered to be statistically significant for p-value <0.05.
• Changes in Serum Levels of "Tartrate-resistant Acid Phosphatase 5b Isoenzyme" (TRAcP5b) Over Time, i.e. Baseline, 3 Months, 6 Months. [Baseline (T0), 3 months (T3) 6 months (T6)]: Tartrate-resistant acid phosphatase 5b isoenzyme" (TRAcP5b) is a specific product of osteoclasts; it is considered as a marker of bone resorption. The concentration of TRAcP5B (U/L) will be measured at T0, T3, and T6 on serum samples (fasting morning samples) using commercially available reagents and following the manufacturer's protocol. At the end of the study, the results will be aggregated as mean ± standard of the mean, median and min-max range. Data will be statistically analyzed in order to compare the activity of Potassium Citrate versus Placebo (unpaired analysis) and to evaluate the effect of Potassium Citrate and Placebo over time (paired analysis). Differences will be considered to be statistically significant for p-value <0.05.
• Changes in Serum Levels of "N-terminal Propeptide of Type I Procollagen" (P1NP) Over Time, i.e. Baseline, 3 Months, 6 Months. [Baseline (T0), 3 months (T3) 6 months (T6)]: N-terminal propeptide of type I procollagen" (P1NP) is a product of the conversion of procollagen to collagen; it is considered as a marker of bone formation. The concentration of P1NP (pg/L) will be measured at T0, T3, and T6 on serum samples (fasting morning samples) using commercially available reagents and following the manufacturer's protocol. At the end of the study, the results will be aggregated as mean ± standard of the mean, median and min-max range. Data will be statistically analyzed in order to compare the activity of Potassium citrate versus Placebo (unpaired analysis) and to evaluate the effect of Potassium Citrate and Placebo over time (paired analysis). Differences will be considered to be statistically significant for p-value <0.05.
• Changes in Serum Levels of "Bone-specific Alkaline Phosphatase" (BAP) Over Time, i.e. Baseline, 3 Months, 6 Months. [Baseline (T0), 3 months (T3) 6 months (T6)]: Bone-specific alkaline phosphatase (BAP) is a specific product of osteoblasts; it is considered as a marker of bone formation. The concentration of BAP (µg/L) will be measured at T0, T3, and T6 on serum samples (fasting morning samples) using commercially available reagents and following the manufacturer's protocol. At the end of the study, the results will be aggregated as mean ± standard of the mean, median and min-max range. Data will be statistically analyzed in order to compare the activity of Potassium citrate versus Placebo (unpaired analysis) and to evaluate the effect of Potassium Citrate and Placebo over time (paired analysis). Differences will be considered to be statistically significant for p-value <0.05.

Sex: Female

Inclusion Criteria:

* Postmenopausal women, more than 5 years post menopause
* Osteopenia (T-score < -1 and > -2.5)
* Low risk of fracture (FRAX: < 20 major osteoporotic; < 3 hip fracture)

Exclusion Criteria:

* Hyperkalemia
* Renal insufficiency
* Nephrolithiasis
* Use of potassium sparing diuretics
* Use of potassium supplements
* Use of therapies influencing bone metabolism (e.g. corticosteroids, thiazide diuretics, aromatase inhibitors, estrogens)
* Use of protonic pump inhibitors
* Current or recent use of bisphosphonates (stopped less than three years prior to the start of the study)
* Gastrointestinal disorders that hamper nutrient absorption;
* Mental or psychiatric disorders that preclude the possibility of correctly adhering to the protocol

Participant flow

Outcome results

• Changes in Serum Level of Carboxyterminal Cross-linked Telopeptide of Type I Collagen (CTX); Over Time, i.e. Baseline, 3 Months, 6 Months. (Primary), Mean, µg/L: Treatment Group, Potassium Citrate 0.64 +/- 0.08; Control Group, Placebo 0.64 +/- 0.05 (p 0.172)
• Changes in Serum Levels of "Tartrate-resistant Acid Phosphatase 5b Isoenzyme" (TRAcP5b) Over Time, i.e. Baseline, 3 Months, 6 Months. (Primary), Mean, U/L: Treatment Group, Potassium Citrate 2.35 +/- 0.20; Control Group, Placebo 2.64 +/- 0.22 (p 0.954)
• Changes in Serum Levels of "N-terminal Propeptide of Type I Procollagen" (P1NP) Over Time, i.e. Baseline, 3 Months, 6 Months. (Primary), Mean, pg/L: Treatment Group, Potassium Citrate 17.45 +/- 1.48; Control Group, Placebo 18.82 +/- 1.73 (p 0.213)
• Changes in Serum Levels of "Bone-specific Alkaline Phosphatase" (BAP) Over Time, i.e. Baseline, 3 Months, 6 Months. (Primary), Mean, µg/L: Treatment Group, Potassium Citrate 21.89 +/- 1.67; Control Group, Placebo 20.36 +/- 1.17 (p 0.094)

Adverse events

Time frame: Adverse events were recorded at 3 months and 6 months

Other adverse events by term

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• Jehle S, Hulter HN, Krapf R. Effect of potassium citrate on bone density, microarchitecture, and fracture risk in healthy older adults without osteoporosis: a randomized controlled trial. J Clin Endocrinol Metab. 2013 Jan;98(1):207-17. doi: 10.1210/jc.2012-3099. Epub 2012 Nov 15. PMID 23162100
• Results publication: Granchi D, Caudarella R, Ripamonti C, Spinnato P, Bazzocchi A, Massa A, Baldini N. 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. Nutrients. 2018 Sep 12;10(9):1293. doi: 10.3390/nu10091293. PMID 30213095

• Study Protocol and Statistical Analysis Plan (PDF, 2016-03-09)

• Nicola Baldini, MD, Prof., Principal investigator, Istituto Ortopedico Rizzoli