Regulation of Serum Calcium and Phosphorus

Most (99%) of the body’s calcium exists as hydroxyapatite in bone, with the remaining 1% present in extracellular fluids. Serum calcium exists in three fractions: 50% to 55% is free (ionized) calcium; about 10% is complexed with low-molecular-weight anions; and 35% to 40% is bound to proteins, mainly albumin and, to a lesser extent, globulins. The calciotropic hormones calcitriol (the fully active form of vitamin D) and parathyroid hormone (PTH) act on their target organs, kidney, intestines, and bone to regulate mineral homeostasis (Figure 69-1). Phosphatonins such as FGF23 also play important regulatory roles in mineral metabolism and complement the actions of other calciotropic hormones; phosphatonins decrease renal phosphorus reabsorption while reducing synthesis of calcitriol and secretion of PTH.

Figure 69-1 Normal calcium and phosphate metabolism.

The principal source of vitamin D is the skin. High-energy ultraviolet B light penetrates the epidermis and cleaves 7-dehydrocholesterol to produce previtamin-D₃. Previtamin D₃ then undergoes a thermally induced isomerization to vitamin D₃ (cholecalciferol) that takes 2 to 3 days to reach completion. Therefore, after a single sunlight exposure, cutaneous synthesis of vitamin D₃ continues for many hours. It is not possible to generate too much vitamin D₃ in the skin because prolonged sunlight exposure activates a mechanism that converts excess previtamin D₃ and vitamin D₃ to biologically inert products. Vitamin D can also be obtained from the diet, from plant sources as ergocalciferol (vitamin D₂), and from animal sources as cholecalciferol (vitamin D₃). Both of these forms of vitamin D are fat soluble and are absorbed from the small intestine into the lymphatics. About 50% of the vitamin D in chylomicrons is transferred to the plasma, where it circulates tightly bound to proteins, principally vitamin D–binding protein (DBP, also termed Gc protein).

Additional enzymatic steps are required to produce the fully active vitamin D metabolite calcitriol (also termed 1,25(OH)₂D₃). Dietary and endogenously produced vitamin D undergoes 25-hydroxylation in the liver by the cytochrome P450 enzyme CYP2R1 to form 25(OH)D. Subsequently, 25-(OH)D₃ is directed to the kidney, where it is either converted to 24,25-dihydroxyvitamin D₃ (an inactive derivative) or to 1,25-dihydroxyvitamin D₃ (calcitriol). Activation to calcitriol requires hydroxylation by a 1α-hydroxylase enzyme (CYP 27B1) that is tightly regulated and is the rate-limiting step in the bioactivation of vitamin D: PTH increases production of calcitriol by stimulating CYP27B1 activity, and FGF23 decreases CYP27B1 activity.

PTH is synthesized as a pre-prohormone by parathyroid cells and processed to a mature 84-amino acid peptide (intact or whole PTH) that is stored in secretory granules. Extracellular ionized calcium is the principal regulator of PTH release and interacts with G protein–coupled calcium-sensing receptors that are expressed on the cell membrane. Low or decreasing concentrations of ionized calcium stimulate secretion of stored PTH within seconds and subsequently increase synthesis of new hormone. PTH acts directly on bone and kidney and indirectly on the intestine to increase the extracellular calcium concentration. After release into circulation, PTH has a half-life of only 6 to 8 minutes and is degraded rapidly to inactive (or less active) fragments by endopeptidases in the liver and kidney. PTH binds to receptors on the surface of target cells that are coupled via guanine–nucleotide binding (G) proteins to activation of adenylyl cyclase and phospholipase C, which increase intracellular concentrations of the second messengers cyclic AMP, inositol triphosphate, and calcium.

Acutely, PTH acts on bone to activate osteoclastic bone resorption, which releases calcium (and phosphorus) into the circulation within minutes. Chronically elevated levels of PTH increase the number of osteoblasts and osteoclasts and stimulate bone remodeling, which over time leads to decreased bone mass and osteoporosis.

In the kidney, PTH increases distal tubular reabsorption of calcium and decreases proximal tubular and thick ascending limb reabsorption of sodium, calcium, phosphate, and bicarbonate. PTH (and hypophosphatemia) stimulates renal 25(OH)D-1α-hydroxylase, which increases synthesis of 1,25(OH)₂D₃ and promotes intestinal absorption of calcium.

Whereas most extracellular phosphate is located in bone mineral in the form of hydroxyapatite, intracellular phosphate is in nucleotides and nucleic acids, phosphoproteins, and phospholipids. Therefore, phosphate’s important roles include maintenance of bone mineral, regulation of enzyme activity, and energy metabolism. Dietary phosphate is amply available and readily absorbed. Movement in and out of the bone mineral is regulated by PTH and 1,25(OH)₂D₃. In the kidney, PTH and phosphatonins (e.g., FGF23) inhibit phosphate transport by reducing membrane expression of Napi 2a and Napi 2c sodium-phosphate cotransporters in the proximal renal tubule cells.

Dynamics of Bone Homeostasis

Skeletal development is a complex process sensitive to the hormonal, mechanical, and nutritional milieu of the bone. The shape and structure of bones are modified and renovated by two processes, modeling and remodeling. Remodeling is the major process in adults and does not result in a change of the bone shape. This process takes place in the basic bone multicellular units where bone resorption by osteoclasts is tightly coupled to bone formation by osteoblasts. Old or damaged bone is repaired by remodeling. By contrast, modeling occurs only during development and growth of the skeleton and facilitates new bone formation at a location different from the site of bone resorption. Growth in the diameter of the cortical shaft is the result of bone formation at the outer (periosteal) surface and bone resorption at the inner (endosteal) surface.

Bone modeling and remodeling are regulated by a variety of factors such as biomechanical loading, hormonal balance, acid–base status, and drug exposures (Figure 69-2). Bone adapts its strength in response to the magnitude and direction of the forces to which it is subjected. Mechanical forces on the skeleton arise primarily from muscle contraction. This capacity of bone to respond to mechanical loading with increased bone size and strength is greatest during growth, especially during puberty and adolescence. Increased production of estrogen and testosterone in addition to increased pulsatile secretion of growth hormone are the hormonal hallmarks of puberty. These events act in an anabolic manner on bone to promote net bone formation.

Figure 69-2 Dynamics of bone homeostasis.

In patients with comorbid conditions such as anorexia, uncontrolled hyperthyroidism, malabsorption, or inflammatory disorders requiring long-term use of glucocorticoids, multiple competing factors may tip the balance of bone homeostasis in favor of net bone resorption. Adequate intake and absorption of dietary calcium, vitamin D, and amino acids are necessary to promote bone acquisition in children. Adequate intake of calcium for children varies by age and is related to pubertal, pregnancy, and lactation status.

Osteomalacia and Rickets

Osteomalacia is characterized by a defect in bone mineralization and occurs in both adults and children (Figure 69-3). By contrast, rickets represents a defect in mineralization of cartilage in the growth plate and therefore occurs only in children. Rickets and osteomalacia are classified as calcipenic or phosphopenic, depending on whether the defect in mineralization results from a primary deficiency of calcium and vitamin D or phosphorus. There are many forms of osteomalacia and rickets, both acquired and genetic, but the most common cause is nutritional deficiency of vitamin D. Other causes of vitamin D deficiency include chronic use of anticonvulsants, chronic kidney failure, hepatic disease, and malabsorption syndromes. Phosphopenic rickets can occur as a result of chronic use of medications that absorb phosphorus in the intestine or decreased renal phosphate reabsorption. The symptoms of osteomalacia may be subtle, with patients typically complaining of diffuse bone pain, proximal muscle weakness, and generalized fatigue. In children, rickets can cause growth failure and skeletal deformity. Over time, a waddling gait may result from the hip pain and thigh muscle atrophy. Biochemical abnormalities in patients with vitamin D deficiency include elevated serum levels of alkaline phosphatase and PTH, low serum phosphate, low or normal serum calcium, and low serum concentrations of 25(OH)D.

Figure 69-3 Childhood rickets and adult osteomalacia.

Nutritional Rickets

Nutritional rickets secondary to vitamin D deficiency is common throughout the world and reflects inadequate exposure to sunlight and poor intake of dietary vitamin D. Vitamin D deficiency is easily prevented, and the prevalence of this condition can be reduced by adequate nutritional intake of vitamin D or vitamin D–fortified foods (Figure 69-4). This form of rickets has a peak incidence between 3 and 18 months of age. Additional risk factors for vitamin D deficiency include dark skin, protracted exclusive breastfeeding, use of sunscreens or conservative clothing, fat malabsorption, use of anticonvulsants that induce hepatic P450 enzymes, marked prematurity, and lack of biliary secretions that may impair absorption of vitamin D and calcium. Mild to moderate vitamin D deficiency may be present for months before rickets is obvious on physical examination, and severe vitamin D deficiency may manifest as hypocalcemic seizures, growth failure, lethargy, irritability, and a predisposition to respiratory infections. Although relatively simple to prevent, vitamin D deficiency continues to be a significant problem worldwide, and vitamin D deficiency rickets continues to be a public health problem.

Figure 69-4 Nutritional-deficiency rickets and osteomalacia.

In 2008, the American Academy of Pediatrics issued revised guidelines regarding vitamin D supplementation in infants and children. The highlight of this revision was the recommendation that all infants and children, including adolescents, have a minimum daily intake of 400 IU of vitamin D₃ beginning the first few days of life and continuing through childhood. However, some patients may require more than 400 IU of vitamin D daily to maintain serum 25(OH)D levels that exceed 25 ng/mL, meeting the Institute of Medicine guideline for vitamin D sufficiency.

The treatment of vitamin D deficiency rickets requires supplementation with both vitamin D and calcium. In general, an older child or adult with vitamin D deficiency requires 300,000 to 500,000 IU of vitamin D to achieve normal vitamin D status, and a variety of therapeutic approaches can be used to achieve vitamin D replacement. Vitamin D may be prescribed as ergocalciferol or cholecalciferol (although cholecalciferol is preferred by many authorities) and administered orally on a once-daily or weekly schedule in low doses for several months. A daily dose of 2000 to 4000 IU is typically recommended, but daily doses of up to 10,000 IU appear to be safe. When compliance is a concern, it may be reasonable to replace vitamin D as “Stoss” therapy, a single one-time dose of 250,000 to 500,000 IU administered, either orally or by injection. To achieve optimal mineralization of the skeleton during vitamin D therapy, it is recommended that patients also receive additional oral calcium.

Genetic defects that impair vitamin D activation (vitamin D–dependent rickets type 1) or responsiveness (vitamin D–dependent rickets type 2) can masquerade as vitamin D deficiency, but serum concentrations of 25(OH)D will be normal.

Hypophosphatemic Rickets

Hypophosphatemia most commonly occurs as a result of impaired renal reabsorption of phosphate. Renal hypophosphatemia can be acquired (e.g., tumors that secrete excessive FGF23) or genetic.

X-Linked Hypophosphatemic Rickets

This X-linked, dominant disorder is caused by mutations in the PHEX gene that encodes a specialized metalloprotease enzyme (Figure 69-5). X-linked hypophosphatemic rickets (XLHR) is the most common form of genetic rickets, with an estimated prevalence of one in 15,000. Loss-of-function mutations in PHEX are associated with reduced degradation and clearance of FGF23; in turn, elevated circulating levels of FGF23 reduce expression of renal sodium–phosphate cotransporters and inhibit 1-α-hydroxylase activity. Patients with XLHR have normal serum levels of 1,25(OH)₂D₃, which are inappropriate in the context of hypophosphatemia. In general, males and females are similarly affected.

Figure 69-5 Vitamin D–resistant rickets and osteomalacia caused by proximal renal tubular defects (hypophosphatemic rachitic syndromes).

Hypophosphatemia occurs within the first 6 months of life, but the first indication of XLHR is usually reduced growth rate and short stature that begins during the first year of life and is often associated with delayed standing or walking. Nevertheless, it is common for the diagnosis of XLHR to be delayed until age 3 to 5 years of age. Older children may have a history of short stature with delayed dentition or multiple dental abscesses. Widened joint spaces, flaring at the knees, and bowing of the weight-bearing long bones may become apparent in children by 1 year of age. Osteomalacia persists after closure of the growth plates, and bone pain, skeletal deformity, and advanced osteoarthritis are common complications in adult patients. Remarkably, patients do not have muscle weakness even though serum phosphorus levels are low.

Optimal treatment requires administration of both 1,25(OH)₂D3 (calcitriol) and neutral phosphate salts; the goal is not to normalize the serum phosphorus level but to facilitate skeletal mineralization and normalization of serum alkaline phosphatase. Treatment must be closely monitored because inappropriate dosages of calcitriol or phosphate can hinder improvement or lead to either secondary hyperparathyroidism or hypercalciuria. The use of human recombinant growth hormone therapy to enhance growth velocity after the rickets is under adequate control is still experimental. Despite aggressive treatment, many patients require osteotomies to improve lower extremity alignment.

Autosomal Hypophosphatemic Rickets

The clinical and biochemical features of autosomal dominant (ADHR) and autosomal recessive (ARHR) hypophosphatemic rickets are very similar to those of XLHR. Some differences are worth noting, however. In contrast to XLDH rickets, ADHR shows incomplete penetrance, variable age at onset from childhood to adult, and often resolution during the second decade. Male-to-male transmission of hypophosphatemic rickets should alert the clinician to ADHR, which is caused by missense mutations within a specific region of the FGF23 gene at 12p13 that appear to inhibit degradation of FGF23. Patients with ARHR have loss of function mutations in the DMP1 or ENPP1 genes that lead to overproduction of FGF23 by osteocytes. Thus, serum levels of FGF23 are elevated in both ADHR and ARHR (and XLHR) but owing to different mechanisms. Management of ADHR and ARHR is similar to that for XLHR, consisting of phosphate and calcitriol.

Hereditary Hypophosphatemic Rickets with Hypercalciuria

Hereditary hypophosphatemic rickets with hypercalciuria (HHRH) is an autosomal recessive form of hypophosphatemic rickets that can be distinguished from the previously discussed forms of hypophosphatemic rickets by the presence of hypercalciuria. Circulating levels of FGF23 are suppressed in patients with HHRH, which stimulates production of 1,25(OH)₂D₃. Elevated serum 1,25(OH)₂D₃ decreases PTH secretion and increases bone resorption and intestinal absorption of calcium, thereby causing hypercalciuria and renal stone disease. HHRH is caused by loss of function mutations in the SLC34A3 gene encoding the type 2c sodium–phosphate cotransporter (NaPi-IIc) that is expressed in the proximal tubule. Therefore, loss of NaPi-IIc protein reduces the tubular reabsorption of phosphorus directly, and hypophosphatemia stimulates secretion of FGF23.

Fanconi Syndrome

Fanconi syndrome (FS) is associated with a variety of genetic defects (e.g., tyrosinemia) or can occur as a result of acute tubular necrosis, heavy metal and drug exposure, or protein malnutrition (Figure 69-6). Type 1 FS is the most common form and is the result of global tubular malfunction leading to urinary losses of bicarbonate, calciuria, phosphaturia, glycosuria, and proteinuria. Calcium losses in the urine cause secondary hyperparathyroidism; however, this increase in PTH cannot overcome the calcium and phosphate losses in the urine. Prolonged acidosis coupled with increased levels of PTH promoted bone resorption over time leads to rickets in children and osteomalacia in adults. Treatment consists of correcting any underlying primary disorder contributing to the development of FS, correction of acidosis, phosphate supplementation, and 1,25(OH)₂D₃ replacement.

Figure 69-6 Vitamin D–resistant rickets and osteomalacia caused by proximal and distal renal tubular defects.

Future Directions

The complex balance of calcium and phosphorus homeostasis is regulated on many levels to ensure adequate bone mineralization. The recent discovery of FGF23 and a growing number of similar phosphatonins now adds greater complexity to our understanding of the control of mineral metabolism and provides additional targets for development of novel therapies.