Potassium citrate prevents increased osteoclastogenesis resulting from acidic conditions: Implication for the treatment of postmenopausal bone loss

Abstract

The extracellular acidic milieu in bones results in activation of osteoclasts (OC) and inhibition of osteoblasts (OB) causing a net loss of calcium from the skeleton and the deterioration of bone microarchitecture. Alkalinization through supplementation with potassium citrate (K citrate) has been proposed to limit the osteopenia progression, even though its pharmacological activity in bone microenvironment is not well defined. We evaluated if K citrate was able to prevent the adverse effects that acidic milieu induces on bone cells. OC and OB were maintained in neutral (pH 7.4) versus acidic (pH 6.9) culture medium, and treated with different K citrate concentrations. We evaluated the OC differentiation at seven days, by counting of multinucleated cells expressing tartrate-resistant acid phosphatase, and the activity of mature OC at 14 days, by quantifying of collagen degradation. To evaluate the effects on OB, we analyzed proliferation, mineralization, and expression of bone-related genes. We found that the low pH increased OC differentiation and activity and decreased OB function. The osteoclastogenesis was also promoted by RANKL concentrations ineffective at pH 7.4. Non-cytotoxic K citrate concentrations were not sufficient to steadily neutralize the acidic medium, but a) inhibited the osteoclastogenesis, the collagen degradation, and the expression of genes involved in RANKL-mediated OC differentiation, b) enhanced OB proliferation and alkaline phosphatase expression, whereas it did not affect the in vitro mineralization, and c) were effective also in OC cultures resistant to alendronate, i.e. the positive control of osteoclastogenesis inhibition. In conclusion, K citrate prevents the increase in OC activity induced by the acidic microenvironment, and the effect does not depend exclusively on its alkalizing capacity. These data provide the biological basis for the use of K citrate in preventing the osteopenia progression resulting from low-grade acidosis.

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

“…For instance, potassium citrate (K citrate) is an alkaline compound used to increase urinary pH and prevent the precipitation of solutes in the urinary tract [ 26 ]. Previous in vitro studies demonstrated that K citrate is capable of preventing the adverse biological effects which a low extracellular pH induces on human bone cells [ 27 ]. A recent meta-analysis has shown that the daily administration of alkalizing supplements, including K citrate, for a time span ranging from 6 months to 2 years, led to a significant reduction in acid and calcium excretion, and a reduction in bone resorption, thus, suggesting a potential benefit to bone health [ 25 ].…”

Low bone mineral density is a potential risk factor for symptom onset and related with hypocitraturia in urolithiasis patients: a single-center retrospective cohort study

“…Citrate is considered to decrease with acidosis under circumstances of increasing bone resorption; therefore, patients with urolithiasis with osteopenia or osteoporosis tend to have hypocitraturia [ 24 , 31 ]. In fact, some papers indicated that potassium citrate treatment reversed low BMD [ 32 , 33 ]. Such evidence suggests that awareness of urinary citrate levels is essential for evaluating stone development risk factors, including BMD.…”

Low Bone Mineral Density is a Potential Risk Factor for Symptom Onset and Related with Hypocitraturia in Urolithiasis Patients: A Single-Center Retrospective Cohort Study

“…Citrate is considered to decrease with acidosis under circumstances of increasing bone resorption; therefore, patients with urolithiasis with osteopenia or osteoporosis tend to have hypocitraturia [23,30]. In fact, some papers indicated that potassium citrate treatment reversed low BMD [31,32]. Such evidence suggests that awareness of urinary citrate levels is essential for evaluating stone development risk factors, including BMD.…”