Vitamin D and/or calcium deficiency leads to a decrease in the level of ionized calcium (Ca²⁺), resulting in an increase in PTH. PTH increases tubular reabsorption of calcium to correct the serum calcium into the normal range. However, in severe calcium and vitamin D deficiency, the serum calcium is below normal. In addition, PTH causes phosphorus loss via the urine, resulting in a decrease in serum HPO₄^2–. An inadequate calcium-phosphorus product (Ca⁺² × HPO₄^2–) leads to a defect in bone mineralization that causes rickets in children and osteomalacia in adults. There are various inherited and acquired disorders that can disrupt calcium and phosphorus metabolism that can also result in defective mineralization of the skeleton. There are 3 inherited syndromes that cause vitamin D resistance. Vitamin D–dependent rickets type 1 (DDR-1) is due to a mutation of the 1-OHase. A mutation of the VDR gene results in an ineffective recognition of 1,25(OH)₂D, causing DDR-2. A genetic defect that results in the overproduction of hormone response element–binding protein (HRBP) eliminates the interaction of 1,25(OH)₂D with its VDR, resulting in DDR-3. There are also inherited and acquired disorders that cause severe hypophosphatemia and decrease renal production of 1,25(OH)₂D. The acquired disorders X-linked hypophosphatemic rickets (XLH) and autosomal dominant hypophosphatemic rickets (ADHR) are caused by the increased production or decreased destruction, respectively, of phosphatonins that include FGF23. Tumor-induced osteomalacia (TIO) is caused by the tumor’s production of FGF23, which results in phosphaturia and a decrease in the renal production of 1,25(OH)₂D.