Sample Chapter The Mosby Physiology Monograph Series Endocrine & Reproductive Physiology, 4e by White To Order Call SMS at +91-8527622422
n n 4 n n n n n CALCIUM AND PHOSPHATE HOMEOSTASIS n n n n n n n nO B J E C T I V E S1. Describe the structure and synthesis of PTH, the regula- 3. Discuss the roles of the GI tract, bone, and kidneys in tion of PTH secretion, and the nature of the PTH receptor. Ca2 þ/Pi homeostasis.2. Describe the structure and synthesis of 1,25-dihydroxyvita- 4. Discuss the actions of calcitonin, PTHrP, FGF23, and go- min D, the regulation of 1,25-dihydroxyvitamin D produc- nadal and steroid hormones on Ca2 þ/Pi metabolism. tion, and the receptor for 1,25-dihydroxyvitamin D. 5. Discuss the pathophysiology associated with imbal- ances in PTH and 1,25-dihydroxyvitamin D.C alcium (Ca2 þ) and phosphate (Pi) are es-sential to human life, playing important structuralroles in hard tissues (i.e., bones and teeth) and Two hormones, 1,25-dihydroxyvitamin D (also called calcitriol) and parathyroid hormone (PTH), regulate intestinal absorption of Ca2 þ and Pi andimportant regulatory roles in metabolic and sig- the release of Ca2 þ and Pi into the circulation afternaling pathways. The two primary sources of bone resorption. The primary processes for removalcirculating Ca2 þ and Pi are the diet and the skeleton of Ca2 þ and Pi from the blood are renal excretion(Fig. 4-1). and bone formation (see Fig. 4-1), and 1,25- dihydroxyvitamin D and PTH regulate these processes as well. Other hormones and paracrine growth factors also have clinical relevance to Ca2 þ and PiDietary calcium homeostasis.and phosphate GI tract Plasma calcium (10 mg/dL) Bone CALCIUM AND PHOSPHORUS ARE Plasma phosphate (4 mg/dL) IMPORTANT DIETARY ELEMENTS THAT PLAY MANY CRUCIAL ROLES Feces Kidneys IN CELLULAR PHYSIOLOGY Calcium is an essential dietary element. In addition to Urine getting calcium from the diet, humans contain a vast store (i.e., > 1 kg) of calcium in their bones, which can FIGURE 4-1 n Daily Ca2 þ and Pi fluxes. be called on to maintain normal circulating levels of 77
78 ENDOCRINE AND REPRODUCTIVE PHYSIOLOGY TABLE 4-1 muscle cell death) can result in hyperphosphatemia, Forms of Ca 2þ and Pi in Plasma which can then complex with Ca2 þ to cause acute hy- pocalcemia. Phosphate represents a key intracellular PROTEIN SIZE IONIZED BOUND COMPLEXED component. Indeed, it is the high-energy phosphateION (MG/DL) (%) (%) (%) bonds of adenosine triphosphate (ATP) that maintainCa2 þ* 10 50 45 5 life. Phosphorylation and dephosphorylation of pro-Pi 4 84 10 6 teins, lipids, second messengers, and cofactors represent key regulatory steps in numerous metabolic and*Ca2 þ is bound (i.e., complexed) to various anions in the plasma, signaling pathways, and phosphate also serves as theincluding HCO3À , citrate, Pi, and SO4À . Pi is complexed to variouscations, including Naþ and Kþ. backbone for nucleic acids.From Koeppen BM, Stanton BA: Renal Physiology, 4th ed., Philadelphia,2007, Mosby. PHYSIOLOGIC REGULATION OF CALCIUM AND PHOSPHATE:calcium in times of dietary restriction and during the PARATHYROID HORMONE ANDincreased demands of pregnancy and nursing. Circu- 1,25-DIHYDROXYVITAMIN Dlating calcium exists in three forms (Table 4-1): freeionized calcium (Ca2 þ), protein-bound calcium, PTH and 1,25-dihydroxyvitamin D represent the twoand calcium complexed with anions (e.g., phosphates, physiologically important hormones that are dedi-bicarbonate, citrate). The ionized form represents cated to the maintenance of normal blood Ca2 þ andabout 50% of circulating calcium, and because this Pi levels in humans. As such, they are referred to as aform is so critical to many cellular functions, Ca2 þ calciotropic hormones. The structure, synthesis, andlevels in both extracellular and intracellular compart- secretion of these two hormones and their receptorsments are tightly controlled (see Chapter 1 for discussion will be discussed here. In the following section, theof Ca2 þ-dependent signaling pathways). Circulating detailed actions of PTH and 1,25-dihydroxyvitaminCa2 þ is under direct hormonal control and is normally D on the three key sites of Ca2 þ/Pi homeostasismaintained in a relatively narrow range. Either too little (i.e., gut, bone, and kidney) will be discussed.of Ca2 þ (hypocalcemia; total serum Ca2 þ < 8.5 mg/dL[2.1 mM]) or too much Ca2 þ (hypercalcemia; total se- Parathyroid Hormonerum Ca2 þ > 10.5 mg/dL [2.6 mM]) in the blood can lead PTH is a key hormone that protects against a hypocal-to a broad range of pathophysiologic changes, including cemic challenge. The primary targets of PTH are boneneuromuscular dysfunction, central nervous system dys- and kidneys. PTH also functions in a positive feed-function, renal insufficiency, calcification of soft tissue, forward loop by stimulating 1,25-dihydroxyvitaminand skeletal pathologies. D production. Phosphorus is also an essential dietary element andis stored in large quantities in bone complexed with Parathyroid Glands The parathyroid glands developcalcium. In the blood, most phosphorus exists in the from the endodermal lining of the third and fourthionized form of phosphoric acid, which is called branchial pouches. They usually develop into fourinorganic phosphate (Pi). Most circulating Pi is in loosely organized glands: two superior and two infe-the free ionized form, but some Pi (< 20%) circulates rior parathyroid glands. The embryonic anlage ofas a protein-bound form or complexed with cations the parathyroids become associated with the caudal(see Table 4-1). Phosphorus also exists as pyrophos- migration of the thyroglossal duct, so the parathyroidphate (two Pi groups in a covalent linkage). Unlike glands usually become situated on the dorsal sideCa2 þ, phosphate is incorporated covalently as single of the right and left lobes of the thyroid glandor multiple phosphate groups into many molecules, (Fig. 4-2). The exact positions of the parathyroidand consequently, soft tissues contain about 10-fold glands are variable, and more than 10% of humansmore phosphate than Ca2 þ. This means that signifi- harbor a fifth parathyroid gland. The predominantcant tissue damage (e.g., crush injury with massive parenchymal cell type in the parathyroid gland is the
CALCIUM AND PHOSPHATE HOMEOSTASIS 79 tumors (i.e., primary hyperparathyroidism) can be derived from both principal and oxyphil cells. Structure, Synthesis, and Secretion of Parathyroid Superior Hormone Secreted PTH is an 84-amino acid polypep- thyroid artery Superior tide. PTH is synthesized as a preproPTH, which is parathyroid gland proteolytically processed to proPTH at the endoplas- Inferior mic reticulum, and then to PTH in the Golgi and Inferior thyroid artery parathyroid secretory vesicles. Unlike proinsulin, all intracellular gland proPTH is normally converted to PTH before secre- tion. PTH has a short half-life (< 5 minutes) because Thyrocervical it is proteolytically cleaved into biologically inactive trunk Left subclavian Right recurrent N-terminal and C-terminal fragments that are artery laryngeal nerve excreted by the kidney. The primary signal that stimulates PTH secretion is Left recurrent low circulating Ca2 þ levels (Fig. 4-3). The extracellular laryngeal nerve Ca2 þ concentration is sensed by the parathyroid prin- cipal cells through a Ca2 þ-sensing receptor (CaSR).FIGURE 4-2 n Anatomic position of the parathyroid glands. The CaSR is a member of the seven-transmembrane(Redrawn from Drake RL, Vogl W, Mitchell AWM: Gray’s G-protein-coupled receptor superfamily, which formsAnatomy for Students, Philadelphia, 2005, Elsevier.) disulfide-linked dimers in the membrane of chief cells of the parathyroid glands. The CaSR is also expressed in calcitonin-producing C cells, renal tubules, and sev-principal (also called chief) cell. These cells are the eral other tissues. In the parathyroid gland, increasingprimary endocrine cell of the gland. With age, a larger amounts of extracellular Ca2 þ bind to the CaSR andmitochondria-rich, eosinophilic cell type, the oxyphil activate incompletely understood downstream signal-cell, appears. Although the oxyphil cell is not normally ing pathways that repress PTH secretion. Thus, basalimportant to PTH secretion, PTH-overproducing PTH secretion (i.e., PTH secretion in the absence of Exocytosis Ca2+ yroid CaSR 1,25-Vitamin D FIGURE 4-3 n Regulation of Parath necell membra PTH PTH gene expression and PTH Gq+Gi secretion. The primary regulator of (–) CaSR PTH is extracellular Ca2 þ, which Downstream signaling is sensed by the Ca2 þ-sensing PTH pathway receptor (CaSR). The CaSR is a G- protein-coupled receptor (GPCR) linked to Gq and Gi, but the Pre-CaSR downstream signaling that inhibits pro-PTH (–) (–) PTH secretion and PTH gene CaSR mRNA PTH gene expression is poorly understood. Prepro-PTH CaSR gene 1,25-Dihydroxyvitamin D inhibits (+) PTH gene expression directly us PTH mRNA and indirectly by stimulating CaSR cle Nu gene expression.
80 ENDOCRINE AND REPRODUCTIVE PHYSIOLOGYCaSR signaling) is high but is inhibited by high extra- PTH production is also regulated at the level ofcellular Ca2 þ-CaSR binding and signaling. gene transcription (see Fig. 4-3). The preproPTH Although the CaSR binds to extracellular Ca2 þ gene is repressed by a calcium-response elementwith relatively low affinity, the CaSR is extremely sen- within the promoter of this gene. Thus, the signalingsitive to changes in extracellular Ca2 þ. A 0.1-mM drop pathway that is activated by Ca2 þ binding to thein blood Ca2 þ produces an increase in circulating CaSR ultimately leads to repression of prepro-PTH levels from basal (5% of maximum) to maximal PTH gene expression and PTH synthesis. The prepro-levels (Fig. 4-4). Thus, the CaSR regulates PTH out- PTH gene is also repressed by 1,25-dihydroxyvitaminput in response to subtle fluctuations in Ca2 þ on a D (acting through vitamin D–responsive elements, dis-minute-to-minute basis. It should be noted that the cussed later). The ability of 1,25-dihydroxyvitamin DCaSR is also stimulated by high levels of magnesium, to hold PTH gene expression in check is reinforced byso hypermagnesemia also inhibits PTH secretion. the coordinated up-regulation of CaSR gene expression by positive vitamin D–responsive elements in the pro- CLINICAL BOX 4-1 moter of the CaSR gene (see Fig. 4-3). Patients with familial benign hypocalciuric hypercal- Parathyroid Hormone Receptor The PTH receptor is a cemia (FBHH) or neonatal severe hyperparathyroid- ism are heterozygous or homozygous, respectively, for seven-transmembrane, G-protein-linked membrane inactivating mutations of the CaSR. In these patients, receptor. Because this receptor also binds PTHrP the CaSR fails to appropriately inhibit PTH secretion (see later), it is usually referred to as the PTH/PTHrP in response to high levels of blood calcium. The CaSR receptor. The PTH/PTHrP receptor is primarily also plays a direct role in Ca2 þ reabsorption at the coupled to a Gas signaling pathway that leads to kidney. The hypocalciuria (i.e., inappropriately low increased cyclic adenosine monophosphate (cAMP), Ca2 þ excretion in the face of high circulating Ca2 þ although it also is coupled to Gaq/11-phospholipase levels) in patients with FBHH is due to the lowered C–dependent pathways. The PTH/PTHrP receptor is ability of the CaSR to monitor blood calcium and re- expressed on osteoblasts in bone, and in the proximal spond by increasing urinary Ca2 þ excretion. and distal tubules of the kidney, as the receptor for the systemic actions of PTH. However, the PTH/PTHrP receptor is also expressed in many developing struc- tures in which PTHrP has an important paracrine 100 function.Serum PTH (% of maximum) Vitamin D Vitamin D is actually a prohormone that must undergo two successive hydroxylations to become the 50 active form, 1,25-dihydroxyvitamin D (Fig. 4-5). Vita- min D plays a critical role in Ca2 þ absorption, and to a lesser extent Pi absorption, by the small intestine. Vita- min D also regulates aspects of bone remodeling and renal reabsorption of Ca2 þ and Pi. 5 Structure, Synthesis, and Transport of Active Vitamin D Metabolites Vitamin D3 (D3; also called cholecal- 1.00 1.10 1.20 1.30 1.40 2+ ciferol) is synthesized by ultraviolet light (UV B) con- Free Ca in blood (mM) version of 7-dehydrocholesterol in the more basal 2þ FIGURE 4-4 n Ca /PTH secretion dose-response curve. layers of the skin (Fig. 4-6). UV radiation opens up
CALCIUM AND PHOSPHATE HOMEOSTASIS 81 21 22 24 26 20 23 25 18 12 17 27 11 13 16 19 C 14 D 15 7-Dehydrocholesterol 1 9 8 2 10 3 A 5 B 7 4 6 HO Skin Light 21 22 26 24 20 23 25 18 17 12 27 11 13 16 9 14 15 Cholecalciferol 8 (Vitamin D3) 7 6 5 CH2 4 10 3 A 1 2 HO Liver FIGURE 4-5 n Biosynthesis of 1,25- OH dihydroxyvitamin D dihydroxycho- lecalciferol. 25-Hydroxycholecalciferol (25-OHD3) CH2 HO Kidney OH OH OH CH2 CH2HO OH HO 1,25-(OH)2D3 24,25-(OH)2D3the B ring of cholesterol, generating pre–vitamin D3, (D2, also called ergocalciferol and also a secosteroid)which then undergoes a temperature-dependent is the form produced in plants. Vitamins D3 and to aisomerization into D3. Vitamin D3 is therefore referred lesser extent D2 are absorbed from the diet andto as a secosteroid, which is a class of steroids in which are equally effective after conversion into activeone of the cholesterol rings is opened. Vitamin D2 hydroxylated forms.
82 ENDOCRINE AND REPRODUCTIVE PHYSIOLOGY Basal keratinocyte 7-Dehydrocholesterol UV-B Enterocyte Vitamin D3 Caval Vit D-DBP Lymphatic and Dietary blood vitamin D3 Vit D- Vit D-chylomicron Vit DFIGURE 4-6 n Vitamin D metabolism. chylomicron andVitamin D can be synthesized in the vitamin D2skin keratinocyte or absorbed from Hepatocytethe gastrointestinal tract enterocyte. Vit D-DBP Vit DVitamin D is transported to the liver Portal bloodhepatocyte, where it is hydroxylated 25-Hydroxylaseat the 25 carbon. 25-HydroxyvitaminD is carried in the blood by vitamin 25-Hdroxyvitamin DD–binding protein (DBP) to the renalproximal tubules, where it is hydroxyl-ated at either the 1a position (activat- 25(OH)-Vit D– Peripheral blooding) or the 24 position (inactivating). DBPNote that 25-hydroxyvitamin D that Glomerular filtrateexits into the glomerular filtrate canbe recaptured by the apical mem- Megalin- 25(OH)-Vit D–brane protein, megalin, which binds DBP mediatedand internalizes DBP. endocytosis 24-Hydroxylase 25-Hydroxyvitamin D 24,25-Dihydroxyvitamin D 1α-Hydroxylase 24-Hydroxylase 1,25-Dihydroxyvitamin D 1,24,25-Trihydroxyvitamin D Renal tubule Biological effects at 1,25-Dihydroxyvitamin D gut, bone, kidney, etc. D3 is transported in the blood from the skin to the CLINICAL BOX 4-2 liver. Dietary D3 and D2 reach the liver directly The balance between UV-dependent, endogenously through transport in the portal circulation and indi- synthesized vitamin D3 and the absorption of dietary rectly through chylomicrons (see Fig. 4-6). In the forms of vitamin D becomes important in certain sit- liver, D2 and D3 are hydroxylated at the 25 carbon uations. Individuals with higher epidermal melanin position to yield 25-hydroxyvitamin D (at this junc- content and those who live in higher latitudes convert ture, no distinction will be made between D3 and D2 less 7-dehydrocholesterol into vitamin D3 and thus metabolites because they are equipotent). Hepatic are more dependent on dietary sources of vitamin vitamin D 25-hydroxylase is expressed at a relatively D. Dairy products are enriched in vitamin D3, but not all individuals tolerate or enjoy dairy products. constant and high level, so circulating levels of Institutionalized, sedentary elderly patients who stay 25-hydroxyvitamin D largely reflect the amount of indoors and avoid dairy products are particularly at precursor available for 25-hydroxylation. Because risk for developing vitamin D deficiency. the hydroxyl group at the 25 carbon position repre- sents the second hydroxyl group on the molecule,
CALCIUM AND PHOSPHATE HOMEOSTASIS 8325-hydroxyvitamin D is also referred to as calcifediol stimulate renal 1a-hydroxylase expression through(see Fig. 4-6). increased PTH levels, whereas elevated Ca2 þ inhibits 25-Hydroxyvitamin D is further hydroxylated 1a-hydroxylase activity directly through the CaSRin the mitochondria of the proximal tubules of the in the proximal tubule. A low-phosphate diet alsokidney at either the 1a carbon or 24 carbon position stimulates renal 1a-hydroxylase activity in a PTH-(see Figs. 4-5 and 4-6). The 1a-hydroxylase (also called independent manner. Some of the effect of a low-CYP1a in humans) generates 1,25-dihydroxyvitamin phosphate diet on renal 1a-hydroxylase activity isD (also called calcitriol), which is the most active dependent on a functional pituitary gland, whichform of vitamin D. Hydroxylation at the 24 position, may respond to hypophosphatemia by increasedgenerating 24,25-dihydroxyvitamin D and 1,24,25- growth hormone secretion (see Chapter 5).trihydroxyvitamin D, represents an inactivationpathway. Vitamin D Receptor 1,25-Dihydroxyvitamin D exerts Vitamin D and its metabolites circulate in the its actions primarily through binding to the nuclearblood primarily bound to vitamin D–binding protein vitamin D receptor (VDR). The VDR is a 50-kDa(DBP). DBP is a serum glycoprotein of about 60 kDa protein and is a member of the nuclear hormone re-that is related to the albumin gene family and is syn- ceptor superfamily, which also includes steroid andthesized by the liver. DBP binds more than 85% of thyroid hormone receptors and metabolic receptors25-hydroxyvitamin D and 1,25-dihydroxyvitamin D. such as the PPARs (see Chapter 1). The VDR is a tran-As a result of binding to other proteins, only 0.4% scription factor and binds to DNA sequences (vitaminof the active metabolite, 1,25-dihydroxyvitamin D, D–responsive elements) as a heterodimer with thecirculates as free steroid. DBP allows for the movement retinoid X receptor (RXR). Thus, a primary actionof the highly lipophilic molecules within the aqueous of 1,25-dihydroxyvitamin D is to regulate gene expres-environment of the blood. Studies using experimental sion in its target tissues, including the small intestine,mouse genetics indicate that DBP provides a reservoir bone, kidneys, and parathyroid gland.of vitamin D metabolites that protects against vitaminD deficiency. The bound fractions of vitamin D me-tabolites have a circulating half-life of several hours. SMALL INTESTINE, BONE, AND DBP may assist in the reuptake of the fraction KIDNEY DETERMINE CA2 1of 25-hydroxyvitamin D that passes through the AND PI LEVELSglomerular filter. DBP binds to 25-hydroxyvitaminD with high affinity, so a significant amount of 25- The general effects of PTH and 1,25-dihydroxyvitaminhydroxyvitamin D that enters the glomerular lumen D on Ca2 þ and Pi levels at the small intestine, bone,is complexed to DBP. The apical membranes of the kidneys, and parathyroid glands is summarized inproximal tubule cells express the protein, megalin, Table 4-2.which is a member of the low-density lipoprotein(LDL) receptor superfamily. Megalin functions to re-capture a broad range of proteins from the glomerular Handling of Ca2 1 and Pi by thefiltrate. Megalin binds DBP, some of which is com- Small Intestineplexed with 25-hydroxyvitamin D, and internalizes (Mosby Physiology Monograph Series cross reference:the complex through receptor-mediated endocytosis Chapter 12 in Gastrointestinal Physiology, Sixth Ed.,(see Fig. 4-6). LR Johnson) The renal 1a-hydroxylase represents a key target Dietary levels of calcium can vary, but in general,of regulation of vitamin D action (Fig. 4-7). First, North Americans consume about 1.5 kg of calciumthere exists a product feedback loop, in which per day. Of this, about 200 g is absorbed by the proxi-1,25-dihydroxyvitamin D inhibits 1a -hydroxylase ex- mal small intestine. Importantly, fractional absorptionpression and stimulates 24-hydroxylase expression. of calcium is stimulated by 1,25-dihydroxyvitamin D,Ca2 þ is also an important regulator of the renal 1a- so absorption can be made more efficient in the facehydroxylase. Low circulating levels of Ca2 þ indirectly of declining dietary calcium.
84 ENDOCRINE AND REPRODUCTIVE PHYSIOLOGY Renal capillary Ca2+ PTH 1,25(OH)2-Vit D 25(OH)-Vit D CaSR Epithelial cell of proximal tubule Gq/Gi Gs Ca2+ cAMP/PKA signaling signaling pathway? pathway 1,25(OH)2-Vit D (–) (+) (–) CYP1α gene 1α-HydroxylaseFIGURE 4-7 n Regulation of therenal CYP1a gene expressionby Ca2 þ and hormones. (+) 25(OH)-Vit D CYP24 gene 24-Hydroxylase Nucleus 25,25(OH)2-Vit D Megalin- mediated endocytosis Lumen of proximal tubule 25(OH)-Vit D–DBP Ca2 þ is absorbed from the duodenum and jejunum from the lumen of the gastrointestinal (GI) tract intoboth by a Ca2 þ- and hormone-regulated, active- the enterocyte, which is favored both by concentrationtransport transcellular route and by a passive, bulk-flow and electrochemical gradients, is facilitated by apicalparacellular route. Little is known about whether epithelial calcium channels, called TrpV5 and TrpV6.the paracellular route is regulated. However, significant Once inside, Ca2 þ ions bind to abundant cytoplasmicprogress has been made in our understanding of the proteins called calbindin-D, specifically calbindin-D9K,transcellular route (Fig. 4-8). Ca2 þ enters the transcel- in the human intestine. Calbindin-D9K serves to main-lular route by gaining access to the intestinal enterocytes tain the low cytoplasmic free Ca2 þ concentrations,through the apical membrane. The movement of Ca2 þ thus preserving the favorable lumen-to-enterocyte
CALCIUM AND PHOSPHATE HOMEOSTASIS 85 TABLE 4-2 Actions of Parathyroid Hormone and 1,25-Dihydroxyvitamin D on Ca2 þ/Pi Homeostasis PARATHYROID SMALL INTESTINE BONE KIDNEY GLANDPTH No direct action Promotes osteoblastic Stimulates 1a-hydroxylase No direct action growth and survival activity Regulates M-CSF, Stimulates Ca2 þ RANKL, and OPG reabsorption by distal production by osteoblast nephron by increasing Chronic high levels Inhibits Pi reabsorption by promote net Ca2 þ and proximal nephron (represses Pi release from bone NPT2a expression)1,25-Dihydroxyvitamin D Increases Ca2 þ Sensitizes osteoblasts Minimal actions on Directly inhibits PTH absorption by to PTH Ca2 þ reabsorption gene expression increasing TrpV channels, calbindin-D, and PMCA expression Marginally increases Pi Regulates osteoid Promotes Pi reabsorption by Directly stimulates absorption production and proximal nephron (stimulates CaSR gene calcification NPT2a expression) expression Luminal side Serosal side + Ca2 -Calbindin9k + TrpV + + Ca2 Ca2 Ca2 5 and 6 PMCA Calbindin9KFIGURE 4-8 n Intestinal absorption of Ca2 þ through the transcellular route. Ca2 þ enters through the Ca2 þ channel, TrpV 5or TrpV 6, in the luminal membrane of the enterocyte. Ca2 þ is then shuttled from the apical side of the cell to the basal sideby the carrier protein, calbindin-D9k. Ca2 þ is then actively transported out of the basolateral side by the plasma membraneCa2 þ ATPase (PMCA), and calbindin-D9K recycles. 1,25-Dihydroxyvitamin D increases the expression of all these proteinsin the gastrointestinal tract.concentration gradient during a meal. Calbindin-D9K D9K, and PMCA) involved in Ca2 þ uptake by the smallmay also play a role in apical-to-basolateral shuttling intestine. PTH affects Ca2 þ absorption at the gut in-of Ca2 þ. Ca2 þ is actively transported across the baso- directly by stimulating renal 1a-hydroxylase activity.lateral membrane, against an electrochemical and con- The fraction of phosphate absorbed by the jejunumcentration gradient, by the plasma membrane remains relatively constant at about 70% and is undercalcium ATPase (PMCA). The sodium-calcium minor hormonal control by 1,25-dihydroxyvitamin D.exchanger (NCX) may also contribute to the active The limiting process in transcellular Pi absorption istransport of Ca2 þ out of the enterocytes. 1,25- transport across the apical brush border, which is car-Dihydroxyvitamin D stimulates the expression of all ried out by an isoform (NPT2b) of the sodium-Piof the components (i.e., TrpV channels, calbindin- cotransporter, NPT2.
86 ENDOCRINE AND REPRODUCTIVE PHYSIOLOGYHandling of Ca2 1 and Pi by Bone Most of the bone (about 75%) is compact, corticalBone represents a massive and dynamic extracellular de- bone that makes up the outer surfaces of long and flatposit of proteins and minerals (mainly Ca2 þ and Pi). bones (Fig. 4-9). The inner core of bones is composedOnce maximal bone mass has been achieved in the of interconnecting spicules whose orientation be-adult, the skeleton is constantly remodeled through comes organized by stress forces. This bone is calledthe concerted activities of the resident bone cell types. cancellous (or trabecular) bone, and although itThe processes of bone accretion and bone resorption makes up only 25% of total bone mass, its surface areaare in balance in a healthy, physically active, and appro- is several-fold greater than that of cortical bone. Thepriately nourished individual. Of the about 1 kg of greater surface area means that trabecular bone iscalcium immobilized in bone, about 500 mg of Ca2 þ much more accessible to bone cells and thus more(i.e., 0.05% of skeletal calcium) is mobilized from and dynamic in its turnover.deposited into bone each day. However, the process of In the adult, bone remodeling involves the destruc-bone remodeling can be modulated to provide a net tion of preformed bone, with the release of Ca2 þ, Pi,gain or loss of Ca2 þ and Pi to the blood and is respon- and hydrolyzed fragments of the proteinaceous matrixsive to physical activity (or lack thereof), diet, age, and (called osteoid) into the blood; and new synthesis ofhormonal regulation. Because the integrity of bone is osteoid at the site of resorption, with subsequent cal-absolutely dependent on Ca2 þ and Pi, chronic dysregu- cification of the osteoid, primarily with Ca2 þ and Pi,lation of Ca2 þ and Pi levels, or of the hormones that reg- from the blood. Bone remodeling occurs continuallyulate Ca2 þ and Pi, leads to pathologic changes in bone. in about 2 million discrete sites involving subpopula- tions of bone cells, called basic multicellular units. The cells involved in bone remodeling fall into twoHistophysiology of Adult Bone major classes: cells that promote the formation of boneThe biogenesis, growth, and remodeling of bone is a (osteoblasts) and cells that promote the resorption ofcomplex process and will not be fully explained here. bone (osteoclasts). However, it should be emphasizedThe key features required to understand the role of that bone remodeling is a highly integrated process,adult bone in the hormonal regulation of calcium- and osteoblasts also play a primary role in the initia-phosphate metabolism are discussed next. tion and regulation of bone resorption (Fig. 4-10). Inner Periosteum circumferential Blood lamellae Haversian vessels system (osteon)FIGURE 4-9 n Diagram of a typical longbone shaft showing compact corticalbone around the perimeter andcancellous trabecular bone in thecenter. (From Stevens A, Lowe J: HumanHistology, 3rd ed., Philadelphia, 2005,Mosby.) Volkmann’s Trabecular canal Outer bone circumferential Interstitial bone Haversian lamellae lamellae canals
CALCIUM AND PHOSPHATE HOMEOSTASIS 87 C-FMS Monocyte/macrophage lineage preosteoclast M-CSF Differentiation Stromal cell RANK Osteoblast RANKL Preosteoclasts FIGURE 4-10 n Osteoblast regula- RANKL tion of osteoclast differentiation and function. OPG Release of Ca 2+ Fusion and activation and Pi into blood RANK Polykaryonic osteoclast H+ Hydrolytic enzymes Resorption cavity in boneOsteoblasts develop from mesodermally derived stro- the cell membrane of osteoblasts and as a solublemal cells that have the potential to differentiate into 31-kDa form. RANKL binds to its receptor, RANK,muscle, adipose, cartilage, and bone (i.e., osteoblasts) on osteoclast precursor membranes. RANK iscells. Several paracrine and endocrine factors modu- structurally related to the receptor for tumor ne-late the osteoblast differentiation program, which is crosis factor-a (TNF-a) and signals through NF-dependent on the expression of bone-specific tran- kB-related pathways to induce osteoclastogenesis.scription factors. For example, the transcription factor This process involves the clustering and fusion ofRunx2 is essential for osteoblast differentiation and several osteoclast precursors, giving rise to a fused,is mutated in patients with cleidocranial dysplasia, polykaryonic osteoclast. The perimeter of the oste-which is a congenital syndrome characterized by oclast membrane facing the bone adheres tightly tomultiple defects in bone formation. the bone, essentially sealing off the area of osteo- Osteoblasts express factors that induce osteo- clast-bone contact (see Fig. 4-10). The osteoclastclast differentiation from cells of the monocyte- cell membrane facing the bone transforms into amacrophage lineage and fully activate osteoclast ruffled border, from which enzymes (e.g., cathep-function (see Fig. 4-10). Osteoblasts release mono- sin K) and HCl are secreted. The acidic enzyme-cyte colony-stimulating factor (M-CSF), which is rich microenvironment proceeds to dissolve thea secreted cytokine that binds to its receptor, calcified crystals and ultimately hydrolyzes type Ic-Fms, on osteoclast precursor cells. M-CSF induces collagen and other osteoid components. After aboutthe earliest differentiating processes that lead to oste- 2 weeks, osteoclasts receive a different signal fromoclast precursors. M-CSF also acts in concert with neighboring osteoblasts. This signal is osteoprote-another factor, RANKL (named for receptor activa- gerin (OPG), which acts as a soluble decoy receptortor of NF-kB ligand), to promote osteoclastogenesis. for RANKL (see Fig. 4-10). Consequently, the pro-RANKL can exist as a 40- to 45-kDa protein on osteoclastic signal from osteoblasts is terminated.
88 ENDOCRINE AND REPRODUCTIVE PHYSIOLOGY During a reversal phase, osteoclasts are then As a calciotropic hormone, PTH is a primary endo-recruited to adjacent sites of bone, which extends the crine regulator of bone remodeling in adults. Theresorption cavity, also called the cutting cone, further PTH/PTHrP receptor is expressed on osteoblasts,into the bone. Alternatively, some osteoclasts may un- but not on osteoclasts. Therefore, PTH directly stim-dergo apoptosis. Adjacent osteoblasts migrate into the ulates osteoblastic activity and indirectly stimulatesresorbed area (now vacated by osteoclasts) and begin osteoclastic activity through osteoblast-derived para-to lay down osteoid. Some of the components in oste- crine factors (i.e., M-CSF, RANKL). Sustained elevatedoid (e.g., osteocalcin and alkaline phosphatase) pro- levels of PTH shift the balance to a relative increase inmote its calcification. This process removes Ca2 þ osteoclast activity, thereby increasing bone turnoverand Pi from the blood and deposits them first as and reducing bone density. In contrast, intermittentcalcium phosphate crystals. Later, bicarbonate and hy- administration of low doses of PTH promotes osteo-droxide ions are incorporated into the calcium phos- blast survival and bone anabolic functions, increasesphate to form hydroxyapatite crystals. The bone is bone density, and reduces the risk for fracture inlaid down in organized layers, called lamellae, starting humans. This is mediated, at least in part, by decreasedfrom the perimeter of the resorption cavity and pro- production of sclerostin (SOST) by osteocytes. SOSTgressing inward. In the fully repaired region, multiple is an inhibitor of bone formation that suppresses os-concentric lamellae surround a central haversian canal teoblast differentiation by inhibiting Wnt signalingor groove housing a nutritive capillary (see Fig. 4-9). in osteoblast progenitor cells. Loss-of-function muta-This area of bone accretion is also called the closing tions of the SOST gene in humans cause sclerosteosis,cone. As the osteoblasts become surrounded by and a disease characterized by excessive bone mass.entrapped within bone, they become osteocytes thatsit within small spaces, called haversian lacunae. Os-teocytes remain interconnected through cell processes CLINICAL BOX 4-4that run within canaliculi and form communicatingjunctions with adjacent cell processes. The new con- Regulation of bone remodeling by PTH requires nor-centric layers of bone, along with the interconnected mal levels of 1,25-dihydroxyvitamin D. In vitaminosteocytes and the central canal, are referred to collec- D–deficient individuals, the Ca2 þ-PTH secretion curvetively as an osteon. The exact function of osteocytes is is shifted to the right. Thus, normal Ca2 þ levels are less effective in suppressing PTH secretion, and ele-presently unclear, although evidence exists for a role of vated PTH levels and increased bone turnover result.osteocytes in the sensing of mechanical stress in bones. The vitamin D receptor is expressed in osteoblasts, and normal 1,25-dihydroxyvitamin D levels are also required for coordination of osteoid production with CLINICAL BOX 4-3 its calcification. In vitamin D–deficient individuals, The importance of the RANK/RANKL/osteoprote- osteoid is not properly calcified, and the bone is weak. gerin system is made evident by mutations in the In children, this leads to rickets, in which growth of human genes for RANK and osteoprotegerin that long bones is abnormal, and the weakened bones lead are associated with bone deformities. Loss of RANKL to bowing of extremities and collapse of the rib cage in mice causes osteopetrosis (i.e., excessive bone den- (see later). In adults, vitamin D deficiency leads to sity) because of the loss of osteoclasts. Conversely, osteomalacia, which is characterized by poorly loss of osteoprotegerin causes osteoporosis (reduced calcified osteoid associated with pain, increased risk bone density) because of a high number of overly for fracture, and vertebral collapse (see later). active osteoclasts. Furthermore, our current under- standing of bone regulation is based on how hormones, cytokines, and other factors alter the balance between Handling of Ca2 1 and Pi by the Kidneys RANKL and osteoprotegerin and on how they regulate the differentiation, survival, and apoptosis of osteo- (Mosby Physiology Monograph Series cross reference: blasts versus osteoclasts. Chapter 9 in Renal Physiology, Third Ed., BM Koep- pen and BA Stanton)
CALCIUM AND PHOSPHATE HOMEOSTASIS 89 The kidneys filter a large amount of Ca2 þ (about membranes of proximal renal tubule cells, thereby in-10 g) each day, but most of the filtered Ca2 þ is reab- creasing phosphate excretion (see Fig. 4-11). In con-sorbed by the nephron. Renal excretion typically trast, 1,25-dihydroxyvitamin D increases NPT2 geneaccounts for the loss of about 200 mg of Ca2 þ per day, expression in the proximal tubules.which is counterbalanced by net intestinal absorptionof about 200 mg/day. In the proximal tubule, mostof the Ca2 þ is reabsorbed by a passive, paracellular path- Integrated Physiologic Regulationway. As in the duodenum, transcellular Ca2 þ transport of Ca2 1/Pi Metabolism: Response ofalso exists and involves the constitutive expression of PTH and 1,25-Dihydroxyvitamin Dapical epithelial calcium channels (Trp-V5 and Trp- to a Hypocalcemic ChallengeV6), intracellular Ca2 þ-binding proteins (calbindins), The integrated response of PTH and 1,25-and active Ca2 þ extrusion (by PMCA and NCX) at dihydroxyvitamin D to a hypocalcemic challenge isthe basolateral membrane. Ca2 þ reabsorption in the shown in Figure 4-12. Low blood Ca2 þ, as detectedthick ascending limb (TAL) of the loop of Henle uses by the CaSR on the parathyroid chief cells, stimulatesboth paracellular and transcellular transport mecha- PTH secretion. In the kidney, PTH rapidly increasesnisms. Paracellular transport in the TAL is driven by Ca2 þ levels by increasing fractional reabsorption ofa lumen-positive electrical gradient established by the Ca2 þ in the distal renal tubules. The renal effects ofNa-K-2Cl transporter in the luminal membrane follow- PTH on Ca2 þ reabsorption are reinforced by Ca2 þing Kþ leakage back into the lumen. The CaSR is located levels as sensed by the CaSR and, to a lesser extent,in the basolateral membrane of TAL cells, and its activa- by 1,25-dihydroxyvitamin D. PTH also inhibits the ac-tion by high serum calcium inhibits the Na-K-2Cl sym- tivity of the sodium-dependent phosphate transporterporter and reduces paracellular Ca2 þ transport (Fig. 4- (NPT2), thereby increasing Pi excretion. The relative11). Clinically, inhibition of this transporter by loop di- loss of phosphate serves to increase free, ionizeduretics such as furosemide has been used to treat hyper- Ca2 þ in the blood. At the bone, PTH stimulates oste-calcemia. Transcellular Ca2 þ transport in the cortical oblasts to secrete RANKL, which, in turn, rapidlyportion of the TAL and the distal convoluted tubule oc- increases osteoclast activity, leading to increased bonecurs by an active transport process that is stimulated by resorption and the release of Ca2 þ and Pi into thePTH (see Fig. 4-11). Inhibition of the thiazide-sensitive blood.Naþ-ClÀ symporter in the luminal membrane of distal In a slower phase of the response to hypocalcemia,tubule cells enhances Ca2 þ reabsorption. Thiazide di- PTH and low Ca2 þ directly stimulate 1a-hydroxylaseuretics are therefore used to prevent renal calcium wast- (CYP1a) expression in the proximal renal tubule, therebying in idiopathic hypercalciuria. increasing 1,25-dihydroxyvitamin D levels. In the small As discussed earlier, intestinal absorption of intestine, 1,25-dihydroxyvitamin D supports adequatephosphate is largely proportional to the amount of Ca2 þ levels in the long term by stimulating Ca2 þ absorp-phosphate in the diet and is only slightly regulated tion. These effects occur over hours and days and in-by 1,25-dihydroxyvitamin D. This leaves the kidney volve increasing the expression of TrpV5 and TrpV6with an important role in the regulation of circulating calcium channels, calbindin-D9k, and PMCA. 1,25-phosphate levels. Phosphate is mostly reabsorbed by Dihydroxyvitamin D also stimulates osteoblast releasethe proximal convoluted tubule through a hormonally of RANKL, thereby amplifying the effect of PTH.regulated transcellular route. As in the small intestine, 1,25-Dihydroxyvitamin D and the CaSR play key rolesphosphate enters the apical surface of the proximal in negative feedback. Thus, elevated PTH stimulates 1,25-tubules in a rate-limiting manner through a dihydroxyvitamin D production, which then inhibits PTHsodium-phosphate cotransporter (NPT). In contrast gene expression directly, and indirectly by up regulatingto the NPT isoform expressed in the intestine the CaSR. 1,25-Dihydroxyvitamin D also represses renal(NPT2b), the kidney expresses an additional isoform, 1a-hydroxylase activity while increasing 24-hydroxylaseNPT2a, which is under strong hormonal regulation. activity. As blood Ca2 þ levels rise back to normal levels,PTH down regulates NPT2a expression on the apical they shut off PTH secretion and 1a-hydroxylase.
90 ENDOCRINE AND REPRODUCTIVE PHYSIOLOGY Ca2ϩ Transport Along the Nephron DT ~60% UF PT Ϫ9% 70% CCD TAL 1% 20% MCD 1% Transcellular: DCT (Cortical TAL) Blood Lumen Lumen Blood Paracellular: TAL Gs PTHFurosemide CaSR Ca2ϩ Ca2ϩ PTHR1 Naϩ TRPV5 Ca2ϩ2ClϪ Ca2ϩ PMCA Kϩ Kϩ Calbindin Naϩ Ca2ϩ ClϪ NCX1 3Naϩ Kϩ Claudin 16 Thiazide Ca2ϩ 2þFIGURE 4-11 n Handling of Ca by the distal nephron and proximal nephron (see text). Diagram of the nephron and thetransport pattern of Ca2 þ along the nephron. (From Koeppen BM, Stanton BA: Renal Physiology, 3rd ed., St. Louis, 2001, Mosby.Details of the Ca2 þ reabsorption by the TAL and DCT were drawn by Dr. John Harrison, University of Connecticut Health Center,Farmington, Conn.)Hormonal Regulation of Calcium and to show this effect. There are no definitive complica-Phosphate: Pharmacologic Regulators tions from calcitonin deficiency or excess in humans.Calcitonin The primary actions of calcitonin are on For this reason, it is unlikely that calcitonin has an im-bone and kidney. Calcitonin lowers serum calcium portant physiologic role in humans. Medical interestand phosphate levels, primarily by inhibiting bone in calcitonin stems from the fact that potent formsresorption, in many species of animals. However, of calcitonin can be used therapeutically in the treat-although human calcitonin can lower serum calcium ment of bone disorders. Calcitonin is also a useful his-and phosphate levels in humans, it takes high doses tochemical marker of medullary thyroid cancer.
CALCIUM AND PHOSPHATE HOMEOSTASIS 91 Negative feedback Rapid responses Slower responses (mins – hrs) (hr – days) Hypocalcemic Low blood challenge Ca2 + ↑ PTH ↑ CYP1α ↑ 1,25(OH)2-Vit D FIGURE 4-12 n Integrated response to a hypocalcemic challenge. ↑ Blood Ca2 + ↑ Bone Negative feedback turnover + ↑ Dietary Ca2 + ↑ Ca2 absorption by reabsorption small intestine and ↑ Pi excretion by kidneysParafollicular C Cells The cells that produce calcito- Calcitonin Receptor The calcitonin receptor is closelynin are called the parafollicular C cells. These cells related to the secretin and PTH/PTHrP receptors. It isare derived from the ultimobranchial bodies and a seven-transmembrane Gas-coupled receptor thatbecome incorporated and interspersed among the acts primarily through cAMP-dependent signalingthyroid follicles as the thyroglossal duct migrates pathways. In contrast to the PTH/PTHrP receptor,caudally. Parafollicular C cells do not invade the thy- the calcitonin receptor is expressed in osteoclasts.roid epithelium and thus are not in contact with the Calcitonin acts rapidly and directly on osteoclasts tofollicular colloid. suppress bone resorption. Paget disease is character- ized by excessive bone turnover that is driven by large,Structure, Synthesis, and Secretion of Calcitonin bizarre osteoclasts (see later). Because these osteoclastsCalcitonin is a 32-amino acid polypeptide. Because retain the calcitonin receptor, active forms of calcito-there is minimal species variation, calcitonins from nin can be used to suppress aberrant osteoclastic activ-other species are biologically active in humans. In fact, ity in patients with this disease.salmon calcitonin is about 20 times more potent in The calcitonin receptor is also expressed in thehumans than human calcitonin. Normal serum calci- nephron, where calcitonin inhibits phosphate and cal-tonin levels are about 10 to 50 pg/mL, and its half-life cium reabsorption.in circulation is less than 1 hour. Because the primarysite of inactivation is the kidney, serum calcitoninlevels are often elevated in renal failure. Alternative Hormonal Regulation of Calcium andsplicing of the calcitonin gene in other tissues can pro- Phosphate: Regulators Overexpressedduce calcitonin gene-related peptide (CGRP), which by Cancersis a potent vasodilator and positive cardiac inotrope. Parathyroid Hormone–Related Peptide Parathyroid The secretion of calcitonin is primarily regulated by hormone–related peptide (PTHrP) is a peptide para-the same CaSR that regulates PTH secretion. However, crine factor that shows limited structural similarity toelevated extracellular Ca2 þ levels stimulate the synthesis PTH but nevertheless binds to and signals throughand secretion of calcitonin. the PTH/PTHrP receptor. PTHrP is expressed in several
92 ENDOCRINE AND REPRODUCTIVE PHYSIOLOGYdeveloping tissues, including the growth plate of bones The 1a-hydroxylase enzyme is expressed by mono-and the mammary glands. PTHrP is not regulated by cytes and peripheral macrophages. In the autoimmunecirculating calcium and normally does not play a role disease of sarcoidosis, overactive macrophages pro-in Ca2 þ/Pi homeostasis in the adult. However, certain duce high levels of 1,25-dihydroxyvitamin D, resultingneoplasias can secrete high levels of PTHrP, which then in hypercalcemia.produces symptoms of hyperparathyroidism (see later). Regulation of Ca2 1/Pi Metabolism by CLINICAL BOX 4-5 Gonadal and Adrenal Steroid Hormones Fibroblast growth factor-23 (FGF23) is an approxi- Gonadal and adrenal steroid hormones have pro- mately 30-kDa peptide that is normally expressed by os- found effects on calcium and phosphate metabolism teocytes. It acts on proximal tubule cells of the kidney to and skeletal health. Estradiol-17b (E2; see Chapter 10) inhibit Pi reabsorption and promote phosphate excre- has a bone anabolic and calciotropic effect at several sites. tion. FGF23 is inactivated by a protease that cleaves E2 stimulates intestinal calcium absorption and renal FGF23 into N-terminal and C-terminal peptides. One tubular calcium reabsorption. E2 is also one of the most protease involved in FGF23 processing, although it is not a direct substrate, is PHEX (for phosphate- potent regulators of osteoblast and osteoclast function. regulating gene with homologies to endopeptidases Estrogen promotes survival of osteoblasts and apoptosis on the X chromosome). PHEX is mutated in X-linked of osteoclasts, thereby favoring bone formation over hypophosphatemia, characterized by renal phosphate resorption. In postmenopausal women, estrogen defi- wasting, rickets, osteomalacia, and inappropriate low- ciency results in an initial phase of rapid bone loss that normal levels of 1,25-dihydroxyvitamin D. lasts about 5 years, followed by a second phase of slower Current evidence indicates that when PHEX is bone loss. During the second phase, the individual is mutated, FGF23 levels increase and inhibit both chronically challenged with hypocalcemia because of in- phosphate reabsorption and 1a-hydroxylase in the prox- efficient calcium absorption and renal calcium wasting. imal renal tubules. Increased expression of FGF23 has This can result in secondary hyperparathyroidism, been linked to autosomal recessive hypophosphatemic which further exacerbates bone loss. Exercise, high levels rickets and tumor-induced rickets/osteomalacia. of dietary calcium with supplemental vitamin D, and hormonal replacement therapy can prevent postmeno-Regulation of Ca2 1/Pi Metabolism by pausal osteoporosis. Androgens also have bone anabolicImmune and Inflammatory Cells and calciotropic effects, although some of these effects are due to the peripheral conversion of testosterone toIt is interesting to note that the RANKL/RANK/ E2 (see Chapter 9).osteoprotegerin signaling system is similar to the TNF re- In contrast to gonadal steroids, the adrenal gluco-ceptor/NF-kB signaling pathways used in cells involved corticoids (e.g., cortisol) promote bone resorptionin the immune system and in inflammation. This link and renal calcium wasting and inhibit intestinal cal-is further stressed by the fact that activated T cells express cium absorption. Patients treated with high levels ofhigh levels of RANKL in response to stimulation by the a glucocorticoid (e.g., as an anti-inflammatory andcytokines, TNF-a, and several interleukins. Thus, inflam- immunosuppressive drug) can develop glucocorti-matory bone diseases (e.g., rheumatoid arthritis) are as- coid-induced osteoporosis.sociated with increased RANKL-to-osteoprotegerinratios in the vicinity of the inflammatory site, with sub-sequent erosions of bone and osteoporosis. PATHOLOGIC DISORDERS OF RANKL is also overproduced by cells associated CALCIUM AND PHOSPHATEwith several malignant bone diseases (e.g., multiple BALANCEmyeloma, skeletal metastatic breast cancer). As notedearlier, some malignant cells also overexpress PTHrP, Hyperparathyroidism (Primary)which induces RANKL expression in neighboring Primary hyperparathyroidism is caused by excessiveosteoblasts. Thus, several malignancies are associated production of PTH by the parathyroid glands. It is fre-with bone damage and hypercalcemia. quently caused by a single adenoma confined to one of
CALCIUM AND PHOSPHATE HOMEOSTASIS 93the parathyroid glands. A common cause of parathy- stones (nephrolithiasis) are common because hyper-roid adenoma is the overexpression of the PRAD1 gene calcemia eventually leads to hypercalciuria and(parathyroid adenomatosis gene), which encodes the increased phosphate clearance leads to phosphaturia.cell cycle regulator, cyclin D1. The high urinary calcium and phosphate concen- Patients with primary hyperparathyroidism have trations increase the tendency for precipitation of cal-high serum calcium levels and, in most cases, low se- cium-phosphate salts in the soft tissues of the kidney.rum phosphate levels. Hypercalcemia is a result of When serum calcium levels exceed about 13 mg/dLbone demineralization, increased GI calcium absorp- with a normal phosphate level, the calcium-phosphatetion (mediated by 1,25-dihydroxyvitamin D), and solubility product is exceeded. At this level, insolubleincreased renal calcium reabsorption. The major calcium-phosphate salts form, which results in calcifi-symptoms of the disorder are directly related to in- cation of soft tissues such as blood vessels, skin, lungs,creased bone resorption, hypercalcemia, and hypercal- and joints.ciuria (Fig. 4-13). High serum calcium levels decrease People with hyperparathyroidism have evidence ofneuromuscular excitability. People with hyperpara- increased bone turnover, such as elevated levels of se-thyroidism often show psychological disorders, partic- rum alkaline phosphatase and osteocalcin, which indi-ularly depression, that may be associated with cate high osteoblastic activity, and increased urinaryincreased serum calcium levels (Box 4-1). Other neu- hydroxyproline levels, which indicates high bonerologic symptoms include fatigue, mental confusion, resorptive activity. Hydroxyproline is an amino acidand at very high levels (> 15 mg/dL), coma. Hypercal- characteristically found in type I collagen. When thecemia can cause cardiac arrest. Hypercalcemia can collagen is degraded, urinary hydroxyproline excretionresult in peptic ulcer formation because calcium increases. Although hyperparathyroidism will eventu-increases gastrin secretion (see Chapter 2). Kidney ally cause osteoporosis (bone loss involving both A BFIGURE 4-13 n Primary hyperparathyroidism. A, Radiographs of middle and distal phalanges of index finger showsubperiosteal bone resorption of shafts and tip of distal phalanx. B, Second radiograph taken after bone had healedafter treatment by removal of parathyroid hematoma. (From Besser GM, Thorner MO: Clinical Endocrinology, London,1994, Mosby-Wolfe.)
94 ENDOCRINE AND REPRODUCTIVE PHYSIOLOGY n n n n n n n n n n decreasing fractional calcium reabsorption. Although BOX 4-1 fractional calcium reabsorption decreases, the urinary SYMPTOMS OF HYPERPARATHYROIDISM calcium level is generally low. Alkalosis occurs be- n Kidney stones cause bicarbonate excretion decreases; this further n Osteoporosis lowers the free calcium level in serum. Although n Gastrointestinal disturbances, peptic ulcers, nau- the serum calcium level is low, bone demineralization sea, constipation is usually not a problem because of the high serum n Muscle weakness, decreased muscle tone phosphate level. Hypocalcemia increases neuromus- n Depression, lethargy, fatigue, mental confusion cular excitability, increasing the possibility of tetany n Polyuria and even convulsions. Hypocalcemia alters cardiac n High serum phosphate concentration; low serum function. It can produce a first-degree heart block. calcium concentration The low serum calcium level decreases myocardial contractility. The most prominent symptom of hypoparathy- roidism is increased neuromuscular excitabilityosteoid and mineral), it is not necessarily the present- (Box 4-2). Low serum calcium concentrations decreaseing symptom. However, bone demineralization is the neuromuscular threshold. This can be manifestedapparent. These individuals frequently exhibit hyper- as repetitive responses to a single stimulus and as spon-chloremic acidosis. Some people with hyperparathy- taneous neuromuscular discharge. The increased neu-roidism have the bone disorder osteitis fibrosa romuscular excitability can result in tingling in thecystica, which is characterized by bone pain, multiple fingers or toes (paresthesia), muscle cramps, or evenbone cysts, a tendency for pathologic fractures of long tetany. Laryngeal spasms can be fatal. Sometimes thebones, and histologic abnormalities of the bone. serum calcium level is not low enough to produce overt tetany, but latent tetany can be demonstrated by inflat- ing a blood pressure cuff on the arm to a pressurePseudohypoparathyroidism greater than systolic pressure for 2 minutes. The resul-Pseudohypoparathyroidism is a rare familial disorder tant oxygen deficiency precipitates overt tetany ascharacterized by tissue resistance to PTH. In many in- demonstrated by carpal-pedal spasms. This is calledstances, the problem is thought to originate with the Trousseau sign (Fig. 4-14A). Another test is to tapPTH receptor. Often there is a decrease in levels of the facial nerve, which evokes facial muscle spasmsthe guanine nucleotide–binding protein, Gs. Individ- (Chvostek sign).uals with pseudohypoparathyroidism demonstrate in- Treatment of hypoparathyroidism is difficultcreased PTH secretion and low serum calcium levels, because of the lack of readily available effective hu-sometimes associated with congenital defects of the man PTH. The disorder is frequently treated with askeleton, including shortened metacarpal and meta-tarsal bones. n n n n n n n n n n BOX 4-2Hypoparathyroidism SYMPTOMS OF HYPOPARATHYROIDISMHypoparathyroidism is associated with low serum n Tetany, convulsions, paresthesias, muscle crampscalcium levels and high serum phosphate levels. n Decreased myocardial contractilityThe hypocalcemia results from both a PTH and a n First-degree heart block1,25-dihydroxyvitamin D deficiency. Consequently, n Central nervous system problems, including irrita-there is a decrease in bone calcium mobilization by bility and psychosisboth osteoclastic resorption and osteocytic osteolysis. n Intestinal malabsorptionBecause 1,25-dihydroxyvitamin D is deficient, GI n Low serum calcium concentration; high serumabsorption of calcium is impaired. The PTH defi- phosphate concentrationciency decreases renal calcium reabsorption, thereby
CALCIUM AND PHOSPHATE HOMEOSTASIS 95 high-calcium diet, vitamin D, and occasionally thia- zide diuretics to decrease renal calcium clearance. Thiazide diuretics increase calcium reabsorption in the thick ascending limb of the loop of Henle. Acute hypocalcemia can be treated with intravascular cal- cium gluconate infusion. Hypomagnesemia resulting from either severe malabsorption or chronic alcoholism can cause hy- A poparathyroidism. Hypomagnesemia impairs the se- cretion of PTH and decreases the biologic response to PTH. Vitamin D Deficiency Vitamin D deficiency produces hypocalcemia and hy- pomagnesemia and decreases GI absorption of cal- cium and phosphate. The drop in the serum calcium level stimulates PTH secretion, which stimu- lates renal phosphate clearance, thereby aggravating the serum phosphate loss. Because the level of the calcium-phosphate product in serum, and hence in body fluids, is low, bone mineralization is impaired, B C and demineralization is increased. This leads to oste- omalacia in adults or rickets in children. The second- ary elevation in PTH can produce osteoporosis. Rickets and osteomalacia are disorders in which bone mineralization is defective. Osteoid is formed, but it does not mineralize adequately. If the calcium- phosphate product level or the pH in bone fluid bath- ing the osteoid is low, demineralization rather than mineralization is favored. Rickets is caused by a vita- min D deficiency before skeletal maturation; it in- volves problems in not only the bone but also the cartilage of the growth plate (Fig. 4-14B and C). Oste- D omalacia is the term used when inadequate bone min-FIGURE 4-14 n A, Position of hand in hypocalcemic tetany. eralization occurs after skeletal growth is complete andB, Radiograph of left hand of 9-year-old boy with rickets the epiphyses have closed.caused by malnutrition. He would eat only potato chips. Allthe bony structures are osteopenic. Note widening of spacebetween provisional zone of calcification and epiphysis Paget Diseaseof left radius. C, After 2 months of force feedings, rickets Paget disease results in bone deformities. It is char-has subsided. Note decreased width of space between acterized by an increase in bone resorption followedprovisional zone of calcification and epiphysis of radius and by an increase in bone formation. The new bone isincreased bone calcification. D, Radiograph of skull ofpatient with Paget disease. Thickness of skull is increased, generally abnormal and often irregular. Serum alka-and sclerotic changes are seen scattered throughout skull, line phosphatase and osteocalcin levels are in-consistent with healing phase of Paget disease. (A from Hall creased, as are those of urinary hydroxyproline.R, Evered DC: Color Atlas of Endocrinology, 2nd ed., London, Pain, bone deformation, and bone weakness can1990, Mosby-Wolfe. B to D, Courtesy of Dr. C. Joe.) occur (Fig. 4-14D).
96 ENDOCRINE AND REPRODUCTIVE PHYSIOLOGYBone Problems of Renal Failure (RenalOsteodystrophy) 5000Approximately 0.9 g, or more than 50% of dietaryphosphate, is normally lost in the urine in a day. Con-sequently, the kidney serves as the major excretory 3000route for phosphate. As renal function, and hence Serum PTH (μEg/mL)phosphate clearance, decreases, the serum phosphate 1000concentration rises. The increase in serum phosphateconcentration will lower serum calcium levels byexceeding the solubility product and hence increasing 600calcium-phosphate precipitation. A drop in the serumcalcium level is an effective stimulus for PTH, andserum PTH levels also rise (Fig. 4-15). In addition, 400vitamin D activation by 1a-hydroxylase occurs inthe renal proximal tubules. In kidney failure,vitamin D activation is impaired, which decreases 200GI absorption of calcium and phosphate. This resultsin a further drop in the serum calcium level and aggra-vates the preexisting problem with excess PTH secre- 0tion. The result is to stimulate bone resorption and 3 4 5 6 7 8 9 10 11 12demineralization. As bone demineralization occurs, Serum phosphate (mg/dL)it aggravates the hyperphosphatemia because the renal FIGURE 4-15 n Relationship between serum parathormonemechanisms of counteracting the hyperphosphatemia (PTH) level and serum phosphate level in patientsare now defective. with renal failure. (Redrawn from Bordier PF, Marie PF, Figure 4-16 shows the effect of renal impairment on Arnaud CD: Evolution of renal osteodystrophy: Correlation ofphosphate, calcium, vitamin D, and PTH. bone histomorphometry and serum mineral and immunoreactive parathyroid hormone values before and after treatment with calcium carbonate or 25-hydroxycholecalciferol. Kidney Int 7 [Suppl 2]:102, 1975.). Renal destruction Increased phosphate retention Decreased vitamin D activationFIGURE 4-16 n The physiologic basis Increased serum phosphateof bone loss in renal failure. GI, Decreased GI calcium andgastrointestinal; PTH, parathyroid phosphate absorptionhormone. Decreased serum calcium Increased PTH secretion Increased bone resorption