| Acid-base balance, dentinogenesis and dental caries: Experimental studies in rats | ||
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The main constituents of bone are type I collagen in the organic matrix and hydroxyapatite in the inorganic matrix. The mineral in the skeleton is being turned over throughout life. Calcium in bone turns over at a rate of 100% per year in infants and 18% per year in adults. Osteoblasts produce bone by secreting collagen that forms the matrix which then calcifies. Osteoclasts are responsible of resorption: they erode and phagocytose bone. One turnover cycle, in which one cavity is resorbed and filled again, is relatively slow: approximately eight months. (Green & Kleeman 1991)
Inactive osteoblasts flatten out over the bone surfaces (Fig 1.). They make a partial membrane, which separates the so-called bone fluid (which is in contact with the hydroxyapatites) from the extracellular fluid of the adjacent tissues (Green & Kleeman 1991). The fast regulation of serum calcium occurs across this quiescent surface area (Parfitt 1987). Inside the bone canaliculi, osteocytes are involved in this process (Talmage & Grubb 1977). The tiny hydroxyapatite crystals present an enormous surface area in the bone (100-200 square meters per gram of bone). Also, the bone is relatively well vascularized. This structure allows a rapid mobilization of the bone calcium. (Green & Kleeman 1991, Ganong 1991)
Acid-base balance has an effect on bone turnover, especially on the rates of bone resorption and calcium mobilization. Bone mineral participates in the defense against acid-base disturbances, especially against metabolic acidosis (Lemann et al. 1966, Green & Kleeman 1991). The role of the bone mineral is important in the acid-base disorders, as no appreciable change in the intestinal calcium absorption occurs (Bichara et al. 1990).
In the mammalian body, mainly three hormones regulate the calcium metabolism and the bone turnover. 1,25-dihydroxycholecalciferol (vitamin D derivative) increases calcium absorption from the intestine and, indirectly, from bone. Parathyroid hormone mobilizes calcium from the bone and increases the urinary phosphate excretion. Calcitonin inhibits bone resorption (Ganong 1981). Used as drugs, these hormones are also capable of inducing acid-base disorders. Calcitonin administration (Escanero et al. 1991) and vitamin D excess (Bichara et al. 1990) have been reported to cause metabolic alkalosis.
In mammals, the endogenous metabolism produces acids, mostly originating from the proteins in the diet. The extracellular fluid bicarbonate buffers in part these acids, causing a decrease of bicarbonate in blood and thus a fall in systemic pH. Fall in pH is buffered by other buffers in the body, including the mineral phases of bone (Bushinsky 1995). Bone contains large buffer stores, specifically salts of phosphate and carbonate (Rhoades & Tanner 1995). In the process of skeletal buffering, calcium is released from the bone mineral (Bushinsky et al. 1983).
If the acids are produced in great amounts or their excretion is impaired, the result is the loss of bone. The kidneys react to the additional calcium in plasma by increasing calcium excretion (hypercalcinuria). As there is no change in the intestinal calcium absorption, the net result is a decrease in the amount of calcium in the body (Breslau et al. 1988).
The change in the total mineral content of the bone is marked in severe acidosis (Lemann Jr et al. 1966, Green & Kleeman 1991). The effect of acidosis on the bone is much greater in young mammals than in adults (first described by Jaffe et al. 1932). In adult subjects, there is less bone buffering due to the lower proportion of bone water and exchangable mineral surface (Burton 1992). However, even a mild acid loading may lead over the years to osteoporosis (Sebastian et al. 1994). This kind of a mild acid loading may be caused by, for example, the high-protein diet.
In the bone the cell-mediated calcium release is the most important and sensitive mechanism of response to metabolic acidosis (Bushinsky 1989, Goldhaber & Rabadjija 1987). To a lesser extent, low pH also promotes physicochemical mineral solubility, which does not depend on the cells (Bushinsky & Lechleider 1987). In addition to stimulating osteoclastic function, metabolic acidosis also inhibits osteoblastic bone formation by slowing down collagen synthesis (Krieger et al. 1992, Whiting & Draper 1981).
In vitro, a decrease in the bone collagen synthesis and diminished alkaline phosphatase activity occur in calvariae in metabolic acidosis, both indicating a suppression of osteoblastic function (Krieger et al. 1992). The genes critical to osteoblastic function are altered by pH. In a group of the immediate early response genes (c-fos, egr-1, junB, c-jun, junD), metabolic acidosis (pH 6.8) leads to a reduction in egr-1 stimulation, while metabolic alkalosis (pH 7.6) stimulates it. RNA for type 1 collagen reacts in the same way to both acidosis and alkalosis. Increasing or decreasing external pH by 0.2 units causes a significant change in the egr-1 stimulation. Thus, small changes in systemic pH may have a significant effect on the expression of certain genes important for the osteoblastic function. (Frick et al. 1997)
The activity of osteoclastic enzymes in cultured calvariae is enhanced in metabolic acidosis (Krieger et al. 1992). Stimulation of the osteoclastic beta-glucuronidase release has been reported (Bushinsky & Nilsson 1995).
Parathyroid hormone has similar effects as acidosis on the bone. It also induces the cell-mediated bone resorption, suppresses the osteoblastic collagen synthesis and stimulates the osteoclastic beta-glucuronidase release. In vitro, additive effects of metabolic acidosis and hyperparatyroidism on the net calcium efflux and the bone cell function have been reported (Bushinsky & Nilsson 1995)
Respiratory acidosis seems to cause mainly similar, but not as profound changes in the calcium metabolism as metabolic acidosis. Alterations in the surface ion composition in the cultured bone in metabolic, but not in respiratory acidosis, have been reported (Chabala et al. 1991). There is proton influx into the bone during metabolic acidosis, but not during respiratory acidosis (Bushinsky 1988), and calcium efflux from the bone during metabolic acidosis is greater than during respiratory acidosis in vitro (Bushinsky 1989). In the cultured bone, the alterations in the ion composition in respiratory acidosis are much less severe than in metabolic acidosis (Chabala et al. 1991). In vivo, respiratory acidosis does not appreciably increase the urine calcium excretion, although there is an increase in the serum calcium concentration (Lau et al. 1987).
Metabolic alkalosis causes an influx of calcium into the bone, but the effect is not as strong as the opposite effect of metabolic acidosis (Bushinsky et al. 1983). Also, metabolic alkalosis results in hypocalcinuria and thus a retention of calcium, while there is no change in the intestinal calcium absorption (Bichara et al. 1990).
Neutralization of the daily metabolic acid load with base decreases calcium excretion (Bushinsky 1996). In clinical studies, patients with a negative calcium balance have been treated successfully with sodium bicarbonate (Lutz 1984) and potassium bicarbonate (Sebastian et al. 1994).
In vitro, both mild (pH 7.5) and severe (pH 7.6) metabolic alkalosis cause a progressive decrease in the calcium efflux from the bone. The calcium efflux is inversely correlated with medium pH: the higher the medium bicarbonate, the less calcium efflux from the bone (Bushinsky 1996). Also in several clinical studies metabolic alkalosis has decreased bone resorption and even increased bone formation (Breslau et al. 1988, Licata et al. 1981, Schuette et al. 1980).
Metabolic alkalosis decreases bone calcium efflux by stimulating the osteoblasts and suppressing the osteoclasts (Bushinsky 1996). Alkalosis may alter the function of both the osteoblasts and the osteoclasts to a similar degree or it may modify the function of one cell type which then alters the function of the other. These mechanisms are not yet clear.
Alkalosis causes a decrease in the release of osteoclastic enzyme beta-glucuronidase, which has an important role in the bone resorption (Bushinsky 1996). Also, the osteoblastic collagen synthesis is induced. The genes important for the osteoblastic function have been found to react in metabolic alkalosis. In vitro, the osteoblastic early response gene egr-1 and RNA for the type 1 collagen are stimulated resulting in induction of the odontoblast collagen synthesis (Frick et al. 1997). There is an inverse correlation between the effects of metabolic alkalosis on osteoclastic enzyme release and osteoblastic collagen synthesis (Bushinsky 1996).
In the process of resorption, the osteoclasts secrete protons between themselves and the bone mineral. To prevent intracellular alkalinity, the osteoclasts must excrete the bicarbonate generated for every hydrogen ion secreted. In metabolic alkalosis, the increased concentration of the bicarbonate in the extracellular fluid may suppress the osteoclastic hydrogen ion secretion. (Bushinsky 1996)
If the osteoclastic activity is inhibited by calcitonin, the influx and efflux of calcium are still, although in lesser extent, correlated with the concentration of bicarbonate. This indicates that the alterations in the bicarbonate concentration have also a non-osteoclast-mediated effect on the bone. It remains unknown whether metabolic alkalosis also affects the physicochemical mineral dissolution in addition to its effects on the cell-mediated calcium flux. (Bushinsky 1996)
Data relating to the alkali loads and the respiratory changes are scarce (Green and Kleeman 1991). No reports concerning respiratory alkalosis and the bone seem to have been published.