The principal causes of osteodystrophies are deficiencies or imbalances of dietary calcium, phosphorus, and vitamin D, as well as dysregulation of parathyroid hormone (PTH) activity. Their interrelationships are complex and not easily defined.
The primary source of calcium and phosphorus is the diet. These elements are absorbed in amounts depending on the source of the minerals, intestinal pH, and dietary levels of calcium, phosphorus, iron, and fat as well as the concentration of activated vitamin D in the extracellular space. If vitamin D or its activity is decreased, calcium and phosphorus absorption are reduced. Vitamin D is obtained either through the diet or by production when the skin is exposed to sunlight (ultraviolet radiation). To become metabolically effective, vitamin D must be converted to its active form through two consecutive hydroxylation steps by the liver and kidney. Vitamin D3 (cholecalciferol) acts primarily on the GI tract to increase absorption but also affects the bone, thereby increasing availability of elemental calcium. Through a negative feedback loop, it also contributes to the regulation of PTH secretion.
PTH secretion occurs in response to a low circulating ionized calcium concentration and depends on the availability of magnesium. The target organs of PTH are the kidneys, bones, and intestines. In the kidneys, PTH promotes renal tubular absorption of calcium while enhancing the renal excretion of phosphorus, as well as the activity of 1alpha-hydroxylase, the enzyme responsible for activation of vitamin D3 in the kidney. In the intestine, PTH promotes reabsorption of calcium. PTH also facilitates mobilization of calcium and phosphorus from bone, thereby allowing utilization of calcium from the osteoid matrix. In ruminants, PTH is thought to increase the salivary excretion of phosphorus in exchange for bicarbonate, whereas the effect on renal phosphorus excretion in these species appears to be negligible.
The activation of vitamin D has also been found to be regulated by fibroblast growth factor 23 (FGF23), a phosphatonin. FGF23 is synthesized by osteocytes and seems to respond to changes in the availability of phosphorus. Increased availability of phosphorus or hyperphosphatemia upregulate FGF23 secretion, whereas phosphorus depletion or hypophosphatemia reduces the production of FGF23. As far as this regulatory circuit is understood, increased FGF23 levels lead to increased renal phosphorus excretion together with hampered activation of vitamin D in the kidney, while the opposite occurs with decreased FGF23 synthesis. FGF23 thus seems to present a pathway through which the activation of vitamin D is regulated independently of PTH.
Specific bony lesions are associated with abnormalities in absolute or relative amounts of vitamin D, calcium, phosphorus, and PTH. Often, in addition to the deficiency or excess in one element, this also causes a secondary pathology due to feedback mechanisms, altered ratios, or concomitant metabolic deficiencies. Specific disease syndromes can be classified as nutritional, metabolic, or genetic in nature. Classic examples of nutritional osteodystrophies are rickets, osteomalacia, enzootic calcinosis, or hypervitaminosis D. Fibrous osteodystrophy and hyperparathyroidism are common metabolic osteodystrophies. Genetic osteodystrophies can be caused by defects in phosphate transporters or genetic abnormalities in the hormonal regulation of phosphorus homeostasis. Examples of genetic defects associated with osteodystrophies include X-linked hypophosphatemia and hereditary hypophosphatemic rickets.