Vitamin D has receptors throughout many tissues and acts as both an endocrine as well as an autocrine/paracrine hormone. The endocrine properties have direct effects on bone and muscle tissue whereas the autocrine/paracrine pathways are involved in the immunologic system. 25(OH)D is converted into additional active metabolite 1,25(OH)₂D in renal tubules and monocyte cell lines. The synthesis of 1,25(OH)₂D is tightly regulated by serum PTH, calcium, and phosphorus such that it requires very high or very low 25(OH)D to change to serum 1,25(OH)₂D. This regulation is important because either high or low 1,25(OH)₂D can lead to either hypercalcemia or hypocalcemia. In syndromes of reduced 1,25(OH)₂D production, such as hypophosphatemic vitamin D–resistant rickets, oncogenic osteomalacia, or severe CKD, a secondary hyperparathyroidism develops, in part owing to hypocalcemia and in part owing to the direct effect(s) of 1,25(OH)₂D to regulate PTH synthesis. The biochemical abnormalities shown in Plate 3-15 lead to a syndrome that manifests all the histologic and radiographic findings of rickets and/or osteomalacia, as well as those of secondary hyperparathyroidism. In addition, the discovery of FGF-23 has led to a greater understanding of the interactions between the parathyroid gland, kidney, and bone. FGF-23, synthesized by the osteocyte, is a major regulator of renal phosphate reabsorption as well as PTH synthesis. Preliminary data suggest that FGF-23 also has effects on osteoid mineralization. FGF-23 increases early in CKD, much earlier than PTH, and is the peptide responsible for the phosphaturia and inhibition of 1,25(OH)₂D levels in the syndrome of oncogenic osteomalacia. The information presented in Plates 3-5 and 3-12 puts into perspective the links between bone/kidney/parathyroid glands that share common pathways in the pathophysiology of many, if not most, of the clinical conditions associated with osteomalacia.

As shown in the left half of Plate 3-15, other defects or conditions may result in a rachitic or an osteomalacic syndrome. For example, in a premature infant, the immature liver cannot adequately convert vitamin D to 25(OH)D. Chronic use of anticonvulsant medications may lead to a deficiency of 25(OH)D by interfering with the microsomal enzyme systems in the liver. Some nutritional disorders interfering with calcium absorption that may also lead to a similar syndrome are excessive dietary ingestion of phytate (in certain coarse cereals), oxalate (in spinach), citrate or phosphate, and an increased intake of aluminum salts (usually in the form of antacids) that can cause a phosphate deficiency. Any condition in which the gut wall is damaged (e.g., tuberculosis, celiac syndromes, sarcoidosis, presence of surgical shunts) or in which rapid transit of gastrointestinal contents occurs (e.g., biliary disease, postgastrectomy syndromes) may also cause a rachitic or an osteomalacic syndrome due to a deficiency of either calcium or vitamin D, or both.

VITAMIN D–RESISTANT RICKETS AND OSTEOMALACIA DUE TO PROXIMAL TUBULAR DEFECTS

In countries with vitamin D supplementation, genetic or acquired rachitic and osteomalacic syndromes (see Plate 3-16) that are resistant to high therapeutic doses of vitamin D are now more common than those associated with vitamin D deficiencies. Almost all of these syndromes are renal in origin and are associated with a narrow or broad reabsorptive defect in the renal tubule that leads to hypophosphatemia (thus, they are also known as hypophosphatemic vitamin D–resistant rickets, or phosphate diabetes).