Calcium and phosphate: a duet of ions playing for bone health

The acquisition and maintenance of bone mass and strength are influenced by environmental factors, including physical activity and nutrition. Among micronutrients, calcium (Ca) and inorganic (i) phosphate (P) are the two main constituents of hydroxyapatite, the bone mineral that strengthens the mechanical resistance of the organic matrix. Bone contains about 99% and 80% of the body's entire supply of Ca and P, respectively. The Ca/P mass ratio in bone is 2.2, which is similar to that measured in human milk. The initial step of Ca-Pi crystal nucleation takes place within matrix vesicles that bud from the plasma membrane of osteogenic cells and migrate into the extracellular skeletal compartment. They are endowed with a transport system that accumulates Pi inside the matrix vesicles, followed by the influx of Ca ions. This process leads to the formation of hydroxyapatite crystal and its subsequent association with the organic matrix collagen fibrils. In addition to this structural role, both Ca and Pi positively influence the activity of bone-forming and bone-resorbing cells. Pi plays a role in the maturation of osteocytes, the most abundant cells in bone. Osteocytes are implicated in bone mineralization and systemic Pi homeostasis. They produce fibroblast growth factor-23, a hormonal regulator of renal Pi reabsorption and 1,25-dihydroxy vitamin D production. This relationship is in keeping with the concept proposed several decades ago of a bone-kidney link in Pi homeostasis. In contrast to their tight association in bone formation and resorption, Ca and Pi renal reabsorption processes are independent from each other, driven by distinct molecular machineries. The distinct renal control is related to the different extraskeletal functions that Ca and Pi play in cellular metabolism. At both the renal and the intestinal levels, interactions of Ca and Pi have been documented that have important implications in the acquisition and maintenance of bone health, as well as in osteoporosis management. In the kidney, increased Pi intake enhances Ca reabsorption and Ca balance. During growth and adulthood, administration of Ca-Pi in a ratio close to that of dairy products leads to positive effects on bone health. In contrast, when separately ingested as pharmaceutical salt supplements, thus inducing large differences between Ca and Pi concentrations in the intestinal lumen, they might have adverse effects on bone health. In osteoporotic patients treated with anabolic agents, a Ca-Pi supplement appears to be preferable to carbonate or citrate Ca salt. In conclusion, Ca and Pi constitute a key duo for appropriate bone mineral acquisition and maintenance throughout life. Outside the skeleton, their essential but distinct physiological functions are controlled by specific transporters and hormonal systems that also serve to secure the appropriate supply of Ca and Pi for bone health. Key teaching points: Bone contains about 99% and 80% of the body's supply of Ca and P, respectively, as hydroxyapatite and has a Ca/P mass ratio of about 2.2, close to that measured in human milk. The first step of Ca-Pi crystal nucleation takes place within matrix vesicles that bud from the plasma membrane of osteogenic cells. In addition to their structural role, both Ca and Pi influence bone-forming and bone-resorbing cells. There is a bone-kidney link in Pi homeostasis in which fibroblast growth factor-23, a molecule produced by osteocytes, appears to play a pivotal role. In contrast to their tight association during bone formation and resorption, both intestinal and renal Ca and Pi processes are independent of each other. Observational and interventional studies suggest that Ca-Pi salt or dairy products can exert positive effects on bone acquisition and maintenance.