Overview of Dystrophies Associated With Calcium, Phosphorus, and Vitamin D in Animals

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 that depend on the source of the minerals, intestinal pH, and dietary levels of calcium, phosphorus, iron, and fat, as well as on the concentration of activated vitamin D in the extracellular space. If the activated form of vitamin D₃ (calcitriol) is decreased, less calcium and phosphorus is absorbed from the digestive tract.

Vitamin D is obtained either through the diet or via endogenous synthesis when the skin is exposed to sunlight (UV radiation). To become metabolically effective, vitamin D must be converted to its active form through two consecutive hydroxylation steps by the liver and kidney.

The activated form of vitamin D₃ acts primarily on the GI tract to increase absorption of calcium and phosphorus; however, it also alters bone metabolism, thereby increasing the availability of elemental calcium and phosphorus. Through a negative feedback loop, increased calcitriol concentration in the blood also downregulates PTH secretion.

PTH secretion from the parathyroid glands occurs in response to a low circulating concentration of ionized calcium and is dependent on adequate availability of magnesium in the extracellular space. The target organs of PTH are the kidneys, bones, intestines, and, in ruminants, salivary glands.

In the kidneys, PTH promotes renal tubular absorption of calcium while hampering tubular reabsorption of phosphorus. PTH also triggers the synthesis in the kidney of 1alpha-hydroxylase, the enzyme that activates vitamin D. PTH also facilitates the mobilization of calcium and phosphorus from bone by stimulating the activity of osteoclasts in the bone.

In ruminants, PTH increases the salivary excretion of phosphorus in exchange for bicarbonate. In contrast, the effect of PTH on renal phosphorus excretion in these species appears to be negligible.

The effect of PTH on its target tissues, particularly bone, also depends on the acid-base balance. Metabolic acidosis enhances the effect; metabolic alkalosis seems to impair the effect on bone.

Apart from PTH, another substance that modulates the activation of vitamin D is fibroblast growth factor 23 (FGF-23), a phosphatonin that is synthesized in bone in response to an altered phosphorus balance. Osteocytes in bone upregulate FGF-23 synthesis with increased availability of phosphorus in the extracellular space, and they downregulate FGF-23 production in states of phosphorus depletion.

Increased FGF-23 levels lead to increased renal phosphorus excretion, together with hampered activation of vitamin D in the kidney. The opposite occurs with decreased FGF-23 production. FGF-23 thus represents a pathway through which vitamin D activation is regulated independently of PTH.

Specific bony lesions are associated with abnormalities in absolute or relative amounts of vitamin D, calcium, phosphorus, and PTH. A deficiency or excess in one element often causes secondary pathological changes due to feedback mechanisms, altered ratios, or concomitant metabolic deficiencies.

Specific disease syndromes can be classified as nutritional, metabolic, or genetic:

• Typical examples of nutritional osteodystrophies are rickets, osteomalacia, enzootic calcinosis, and hypervitaminosis D.

• Fibrous osteodystrophy and hyperparathyroidism are common metabolic osteodystrophies.

• Genetic osteodystrophies can be caused by defects in phosphate transporters or by genetic abnormalities in the hormonal regulation of phosphorus homeostasis. Examples of genetic defects associated with osteodystrophies include X-linked hypophosphatemia and hereditary hypophosphatemic rickets.