1. Bone structure and cells: osteoblasts, osteoclasts and osteocytes, the organic matrix and the mineral phase (Figure 409-1)
2. Bone remodeling (Figure 409-2)
3. Calcium homeostasis (Figure 409-3)
4. Phosphate metabolism: hypophosphatemia (Tables 409-1 and 409-2) and hyperphosphatemia (Table 409-3)
5. Magnesium metabolism: hypomagnesemia (Table 409-4), hypermagnesemia (Table 409-5) and their treatment
6. Vitamin D: synthesis and activation (Figure 409-4) and the hormonal control loop (Figure 409-5)
7. Causes of impaired vitamin D action (Table 409-6) and treatment

1. Bone structure and cells: osteoblasts, osteoclasts and osteocytes, the organic matrix and the mineral phase (Figure 409-1)
2. Bone remodeling (Figure 409-2)
3. Calcium homeostasis (Figure 409-3)
4. Phosphate metabolism: hypophosphatemia (Tables 409-1 and 409-2) and hyperphosphatemia (Table 409-3)
5. Magnesium metabolism: hypomagnesemia (Table 409-4), hypermagnesemia (Table 409-5) and their treatment
6. Vitamin D: synthesis and activation (Figure 409-4) and the hormonal control loop (Figure 409-5)
7. Causes of impaired vitamin D action (Table 409-6) and treatment

Chapter 409: Bone and Mineral Metabolism in Health and Disease

A. COMPLETE EXTRACTION

1. Functions and general features of bone

• Bone is a reservoir for calcium, magnesium, phosphorus, sodium and other ions necessary for homeostatic functions.
• Bone hosts and regulates hematopoiesis by providing niches for hematopoietic cell proliferation and differentiation.
• The skeleton is highly vascular and receives ~10% of the cardiac output.
• Two distinct cell types remodel bone:
  • Osteoblasts produce bone matrix.
  • Osteoclasts resorb the matrix.
• Osteocytes coordinate the activities of these cells. They are long-lived regulatory cells embedded within bone matrix.

2. Bone matrix (extracellular components)

• The extracellular components are a solid mineral phase in close association with an organic matrix.
• Of the organic matrix, 90-95% is type I collagen.
• The noncollagenous portion of the organic matrix is heterogeneous. It contains serum proteins such as albumin, and many locally produced proteins whose functions are incompletely understood.
• The locally produced proteins include:
  • Cell attachment/signaling proteins: thrombospondin, osteopontin, fibronectin.
  • Calcium-binding proteins: matrix gla protein, osteocalcin.
  • Proteoglycans: biglycan, decorin.
• Some of these proteins organize collagen fibrils. Others influence mineralization and binding of the mineral phase to the matrix.

3. Mineral phase

• It is made up of calcium and phosphate.
• It is best characterized as a poorly crystalline hydroxyapatite.
• It is deposited initially in intimate relation to the collagen fibrils. It is found in specific locations in the "holes" between the collagen fibrils.
• This arrangement of mineral and matrix gives a two-phase material well suited to withstand mechanical stresses.

4. Collagen organization and osteogenesis imperfecta

• The organization of collagen influences the amount and type of mineral phase formed in bone.
• The primary structures of type I collagen in skin and bone are similar. They differ in posttranslational modifications and in the distribution of intermolecular cross-links.
• The holes in the packing structure of collagen are larger in mineralized collagen (bone and dentin) than in unmineralized collagens such as tendon.
• Single amino acid substitutions in the helical portion of either the α1 (COL1A1) or α2 (COL1A2) chain of type I collagen disrupt the organization of bone in osteogenesis imperfecta.
• The severe skeletal fragility in this group of disorders highlights the importance of the fibrillar matrix in bone structure (Chap. 413).

5. Osteoblasts and osteocytes

• Osteoblasts synthesize and secrete the organic matrix and regulate its mineralization.
• They derive from cells of mesenchymal origin (Fig. 409-1A).
• Active osteoblasts are found on the surface of newly forming bone.
• As an osteoblast secretes matrix, which is then mineralized, the cell may become an osteocyte. The osteocyte stays connected to its nutrient supply through a series of canaliculi.
• Osteocytes account for the vast majority of the cells in bone.
• Osteocytes are thought to be the mechanosensors in bone. They communicate signals to surface osteoblasts, osteoclasts and their progenitors through the canalicular network. They thereby serve as master regulators of bone formation and resorption.
• Osteocytes secrete fibroblast growth factor 23 (FGF23), a major hormonal regulator of phosphate metabolism.

6. Mineralization

• It occurs in trabecular bone and in osteones of compact cortical bone (Haversian systems).
• Primary mineralization begins soon after the matrix is secreted.
• It is not completed for several weeks or even longer (secondary mineralization).
• Mineralization takes advantage of the high concentrations of calcium and phosphate, already near saturation in serum.
• It is a carefully regulated process. It depends on the activity of osteoblast-derived alkaline phosphatase, which probably works by hydrolyzing inhibitors of mineralization such as pyrophosphate.

7. Genes and factors controlling osteoblast development

• Runx2
  • It is a transcription factor expressed specifically in chondrocyte (cartilage cell) and osteoblast progenitors, in hypertrophic chondrocytes and in mature osteoblasts.
  • It regulates expression of several important osteoblast proteins:
    • Osterix, another transcription factor needed for osteoblast maturation.
    • Osteopontin.
    • Bone sialoprotein.
    • Type I collagen.
    • Osteocalcin.
    • RANK ligand.
  • Its expression is regulated in part by bone morphogenic proteins (BMPs).
  • Runx2-deficient mice are devoid of osteoblasts.
  • Mice with a deletion of only one allele (Runx2 +/-) show a delay in formation of the clavicles and some cranial bones.
  • These abnormalities are similar to the human disorder cleidocranial dysplasia, which is caused by heterozygous inactivating mutations in Runx2.
• Indian hedgehog (Ihh)
  • It is a paracrine signaling molecule with a critical role in osteoblast development.
  • Ihh-deficient mice lack osteoblasts in the type of bone formed on a cartilage mold (endochondral ossification).
• wnt family
  • Signals from members of the wnt family of paracrine factors are important for osteoblast proliferation and differentiation.
  • wnt is an amalgam of "wingless" (the Drosophila developmental gene) and "int-1" (an analogous mammalian gene activated by integration of a mouse tumor viral genome nearby).
• Sclerostin
  • Osteocytes regulate osteoblasts partly by secreting sclerostin, a potent inhibitor of wnt signaling.
• Other growth-regulatory factors affecting osteoblast function
  • The three closely related transforming growth factor βs.
  • Fibroblast growth factors (FGFs) 2 and 18.
  • Platelet-derived growth factor.
  • Insulin-like growth factors (IGFs) I and II.
• Hormones
  • PTH and 1,25-dihydroxyvitamin D [1,25(OH)2D] activate receptors expressed by osteoblasts. This assures mineral homeostasis and influences a variety of bone cell functions.
• Osteoclasts regulate osteoblasts
  • They release growth factors from bone matrix.
  • They synthesize proteins that can directly regulate osteoblastogenesis.

8. Osteoclasts

• They carry out resorption of bone mainly.
• They are multinucleated cells formed by fusion of cells derived from the common precursor of macrophages and osteoclasts.
• They derive from the hematopoietic lineage, quite different from the mesenchymal lineage of osteoblasts.
• Factors produced by osteocytes, osteoblasts and marrow stromal cells allow cells of the osteoblast lineage to control osteoclast development and activity (Fig. 409-1B).
• M-CSF (macrophage colony-stimulating factor)
  • It plays a critical role during several steps in the pathway.
  • It ultimately leads to fusion of osteoclast progenitor cells to form multinucleated, active osteoclasts.
• RANK ligand
  • It is a member of the tumor necrosis factor (TNF) family.
  • It is expressed on the surface of osteocytes, osteoblasts and stromal fibroblasts.
  • Through cell-cell interactions, it binds the RANK receptor on osteoclast progenitors. This stimulates osteoclast differentiation and activation.
• Osteoprotegerin
  • It is a soluble decoy receptor.
  • It binds RANK ligand and inhibits osteoclast differentiation.
• Cytokines
  • Interleukins 1, 6 and 11, TNF and interferon γ modulate osteoclast differentiation and function.
• Hormones acting on osteoclasts
  • Most hormones that influence osteoclast function do not target these cells directly. They target cells of the osteoblast lineage to increase production of M-CSF and RANK.
  • PTH and 1,25(OH)2D both increase osteoclast number and activity by this indirect mechanism.
  • Calcitonin binds to its receptor on the basal surface of osteoclasts and directly inhibits osteoclast function.
  • Estradiol has multiple cellular targets in bone: osteoclasts, immune cells and osteoblasts. Its actions on all these cells decrease osteoclast number and decrease bone resorption.
• Mechanism of resorption
  • It takes place in scalloped spaces (Howship's lacunae).
  • The osteoclasts attach through a specific αvβ3 integrin to bone matrix components such as osteopontin.
  • The osteoclast forms a tight seal to the underlying matrix. It secretes protons, chloride and proteinases into a confined space, likened to an extracellular lysosome.
  • The active osteoclast surface forms a ruffled border. The ruffled border contains a specialized proton pump ATPase that secretes acid, which solubilizes the mineral phase.
  • Carbonic anhydrase (type II isoenzyme) within the osteoclast generates the needed protons.
  • The bone matrix is resorbed in the acid environment next to the ruffled border by proteases such as cathepsin K, which act at low pH.

9. Figure 409-1 legend (osteoblast and osteoclast pathways)

• The figure shows pathways regulating development of (A) osteoblasts and (B) osteoclasts.
• Hormones, cytokines and growth factors that control cell proliferation and differentiation are shown above the arrows.
• Transcription factors and other markers specific for various stages of development are shown below the arrows.
• (A) Osteoblast lineage: mesenchymal osteoblast progenitor → osteoblast precursor → active osteoblast.
  • Factors above the arrows: BMPs, Wnts; PTH, Vit D, IGFs.
  • Markers: Runx2; collagen (I), alkaline phosphatase, osteocalcin, osteopontin, bone sialoprotein.
• (B) Osteoclast lineage: hematopoietic osteoclast progenitor → osteoclast precursor → mononuclear osteoclast → (fusion) → quiescent osteoclast → active osteoclast.
  • Factors above the arrows: M-CSF, RANK ligand, IL-1, IL-6.
  • Markers: PU-1+, c-fos+, NFκB+, TRAF+; later c-src+, β3 integrin+, PYK2 kinase+, cathepsin K+, TRAF+, carbonic anhydrase II+.
• Abbreviations in the legend:
  • BMPs: bone morphogenic proteins.
  • IGFs: insulin-like growth factors.
  • IL-1, IL-6: interleukins 1 and 6.
  • M-CSF: macrophage colony-stimulating factor.
  • NFκB: nuclear factor-κB.
  • PTH: parathyroid hormone.
  • PU-1: a monocyte- and B lymphocyte-specific ets family transcription factor.
  • RANK ligand: receptor activator of NFκB ligand.
  • Runx2: Runt-related transcription factor 2.
  • TRAF: tumor necrosis factor receptor-associated factor.
  • Vit D: vitamin D.
  • wnts: wingless-type mouse mammary tumor virus integration site.

10. Bone formation (embryo, child, adult)

• In the embryo and growing child, bone develops mostly by replacing previously calcified cartilage (endochondral bone formation), with subsequent remodeling.
• In a few bones, bone forms without a cartilage matrix (intramembranous bone formation).
• During endochondral bone formation, chondrocytes proliferate, secrete and mineralize a matrix, enlarge (hypertrophy) and then die. This enlarges bone and provides the matrix and factors that stimulate endochondral bone formation.
• The program is regulated by:
  • Local factors: IGF-I and -II, Ihh, parathyroid hormone-related peptide (PTHrP), BMPs, FGFs.
  • Systemic hormones: growth hormone, glucocorticoids, estrogen.
• Some hypertrophic chondrocytes do not die. Through still poorly understood steps, they can become osteoblasts and bone stromal cells.

11. Woven versus lamellar bone

• New bone, whether formed in infants or in adults during repair, has a relatively high ratio of cells to matrix. It has coarse fiber bundles of collagen that are interlaced and randomly dispersed (woven bone).
• In adults, more mature bone has fiber bundles regularly arranged in parallel or concentric sheets (lamellar bone).
• In long bones, lamellar bone deposited concentrically around blood vessels forms the Haversian systems.

12. Bone growth

• Growth in length depends on proliferation of cartilage cells and the endochondral sequence at the growth plate.
• Growth in width and thickness occurs by bone formation at the periosteal surface and resorption at the endosteal surface. The rate of formation exceeds that of resorption.
• In adults, after the growth plates of cartilage close through the actions of estrogen, growth in length and endochondral bone formation cease.
• Remodeling continues throughout life, within Haversian systems and along the surfaces of trabecular bone.
• In adults, ~4% of the surface of trabecular bone (such as iliac crest) is involved in active resorption.
• 10-15% of trabecular surfaces are covered with osteoid, which is unmineralized new bone formed by osteoblasts.
• Radioisotope studies indicate that as much as 18% of total skeletal calcium is deposited and removed each year.
• Bone is an active metabolizing tissue that requires an intact blood supply.
• The cycle of bone resorption and formation is highly orchestrated. It is directed by osteocytes and carried out by the basic multicellular unit (BMU), a group of osteoclasts and osteoblasts (Fig. 409-2).

13. Response of bone to injury

• The response of bone to fractures, infection, interruption of blood supply and expanding lesions is relatively limited.
• Dead bone must be resorbed and new bone must be formed. This occurs together with growth of new blood vessels into the involved area.
• If tissue organization is disrupted (for example a fracture with poor apposition of fragments, or motion at the fracture site):
  • Progenitor stromal cells recapitulate the endochondral bone formation of early development.
  • They form cartilage that is replaced by bone and, variably, fibrous tissue.
• If there is good apposition with fixation and little motion at the fracture site, repair occurs predominantly by formation of new bone without other mediating tissue.

14. Mechanical stress and remodeling

• Remodeling occurs along lines of force generated by mechanical stress.
• Osteocytes sense the signals from mechanical stress and transmit signals to osteoclasts and osteoblasts or their precursors.
• One such signal is sclerostin, an inhibitor of wnt signaling.
• Mechanical forces suppress sclerostin production. This increases bone formation by osteoblasts.
• Expanding lesions in bone, such as tumors, induce resorption at the surface in contact with the tumor. They do this by producing ligands such as PTHrP that stimulate osteoclast differentiation and function.
• Bone plasticity reflects the interaction of cells with each other and with the environment.

15. Markers of bone turnover

• Measuring the products of osteoblast and osteoclast activity can assist in the diagnosis and management of bone diseases.
• Osteoblast activity (bone formation)
  • Serum bone-specific alkaline phosphatase.
  • Osteocalcin, a protein secreted from osteoblasts and made virtually only by osteoblasts.
  • An amino-terminal fragment of procollagen I, which is also an effective index of bone formation.
• Osteoclast activity (resorption)
  • Products of collagen degradation.
  • Collagen molecules are covalently linked to each other in the extracellular matrix through hydroxypyridinium cross-links (Chap. 413).
  • After digestion by osteoclasts, these cross-linked peptides can be measured in urine and in blood.

16. Figure 409-2 legend (bone remodeling)

• The figure is a schematic of bone remodeling.
• The cycle is carried out by the basic multicellular unit (BMU), a group of osteoclasts and osteoblasts.
• In cortical bone the BMUs tunnel through the tissue. In cancellous bone they move across the trabecular surface.
• Remodeling is initiated by recruitment of osteoclast precursors, perhaps to sites of microdamage.
• The precursors fuse to form multinucleated, active osteoclasts that mediate bone resorption.
• Osteoclasts adhere to bone and remove it by acidification and proteolytic digestion.
• As the BMU advances, osteoclasts leave the resorption site. Osteoblasts move in to cover the excavated area and begin new bone formation by secreting osteoid, which is eventually mineralized into new bone. These osteoblasts derive from marrow precursors and previously inactive bone lining cells.
• After osteoid mineralization, osteoblasts flatten and form a layer of lining cells over new bone, become osteocytes, or die.
• Stages labeled on the figure: resting bone surface → activation → resorption → reversal (cement line) → bone formation (osteoid) → mineralization.
• Time labels on the figure: ~3 weeks and ~3 months.

B. HIGH-YIELD NEET SS POINTS (this section)

1. Matrix: type I collagen makes up 90-95% of the organic matrix. The mineral is poorly crystalline hydroxyapatite, deposited in the "holes" between collagen fibrils.
2. Osteogenesis imperfecta: a single amino acid substitution in the helical portion of COL1A1 (α1) or COL1A2 (α2) of type I collagen disrupts bone organization and causes severe skeletal fragility.
3. Cell origin: osteoblasts are mesenchymal. Osteoclasts are hematopoietic (macrophage/osteoclast common precursor).
4. Osteocytes:
   • They are the most numerous cells in bone and are the mechanosensors.
   • They are master regulators of formation and resorption.
   • They secrete FGF23 (a major regulator of phosphate metabolism) and sclerostin (a wnt inhibitor).
5. Mechanical loading suppresses sclerostin, which increases bone formation.
6. Mineralization:
   • Primary mineralization starts soon after matrix secretion. Secondary mineralization takes weeks or longer.
   • It depends on osteoblast alkaline phosphatase, which probably hydrolyzes the inhibitor pyrophosphate.
7. Runx2:
   • It is the key osteoblast transcription factor. It acts upstream of osterix (needed for osteoblast maturation), osteopontin, bone sialoprotein, type I collagen, osteocalcin and RANK ligand.
   • Runx2 -/- mice have no osteoblasts.
   • Heterozygous inactivating Runx2 mutations cause cleidocranial dysplasia, with delayed clavicle and cranial bone formation.
8. Ihh is needed for osteoblasts in endochondral ossification. wnt signals promote osteoblast proliferation and differentiation.
9. Osteoclast lineage factors:
   • M-CSF drives fusion of progenitors into multinucleated osteoclasts.
   • RANK ligand (a TNF family member on osteocytes, osteoblasts and stromal fibroblasts) binds RANK on progenitors.
   • Osteoprotegerin is the soluble decoy receptor that binds RANK ligand and inhibits osteoclast differentiation.
10. Indirect action on osteoclasts: PTH and 1,25(OH)2D act on osteoblast lineage cells to raise M-CSF and RANK, which increases osteoclast number and activity.
11. Calcitonin acts directly on a receptor on the basal surface of osteoclasts and inhibits them.
12. Estradiol decreases osteoclast number and resorption by acting on osteoclasts, immune cells and osteoblasts.
13. Resorption machinery:

• It occurs in Howship's lacunae.
• Attachment is through αvβ3 integrin to osteopontin.
• The ruffled border has a proton pump ATPase.
• Carbonic anhydrase type II generates the protons.
• Cathepsin K degrades matrix at low pH.

1. Osteoclast markers in Fig. 409-1B: c-src, β3 integrin, PYK2 kinase, cathepsin K, TRAF, carbonic anhydrase II. PU-1, c-fos and NFκB appear in earlier stages.
2. Endochondral versus intramembranous:

• Endochondral replaces calcified cartilage.
• Intramembranous forms without a cartilage matrix.
• Chondrocyte hypertrophy is followed by death, but some hypertrophic chondrocytes become osteoblasts and stromal cells.
• Regulators are IGF-I/II, Ihh, PTHrP, BMPs, FGFs, growth hormone, glucocorticoids and estrogen.

1. Woven bone is coarse, randomly interlaced and highly cellular (new bone, repair). Lamellar bone is parallel or concentric (mature). Lamellar bone laid concentrically around vessels forms Haversian systems.
2. Growth:

• Length growth comes from the growth plate (endochondral).
• Width growth comes from periosteal formation plus endosteal resorption, with formation exceeding resorption.
• Growth plates close through the action of estrogen.

1. Adult turnover numbers:

• ~4% of trabecular surface is in active resorption.
• 10-15% of trabecular surface is covered with osteoid.
• As much as 18% of total skeletal calcium is turned over per year.

1. Fracture healing:

• Poor apposition or motion gives an endochondral pathway, with cartilage replaced by bone and variably fibrous tissue.
• Good apposition with fixation and little motion gives direct new bone formation.

1. Tumor-induced bone resorption occurs through PTHrP, which stimulates osteoclast differentiation and function.
2. Bone turnover markers:

• Formation markers: bone-specific alkaline phosphatase, osteocalcin (virtually only from osteoblasts), amino-terminal fragment of procollagen I.
• Resorption markers: collagen degradation products. These are hydroxypyridinium cross-linked peptides, measured in urine and blood.

1. Remodeling unit (BMU):

• It is a group of osteoclasts and osteoblasts, directed by osteocytes.
• The sequence is activation → resorption → reversal → formation → mineralization.
• Resorption is by acidification and proteolysis. Osteoblasts come from marrow precursors and inactive bone lining cells.
• In cortical bone the BMUs tunnel. In cancellous bone they move across the trabecular surface.
• After mineralization, osteoblasts become lining cells or osteocytes, or die.

• Calcium metabolism (Fig. 409-3).
• Phosphate: hypophosphatemia (Tables 409-1 and 409-2) and hyperphosphatemia (Table 409-3).
• Magnesium (Tables 409-4 and 409-5).
• Vitamin D (Figs. 409-4 and 409-5, Table 409-6).

Chapter 409: Part 2, Calcium Metabolism (PDF pages 3-4)

A. COMPLETE EXTRACTION

1. Body calcium distribution and skeletal calcium

• Over 99% of the 1-2 kg of calcium in the normal adult human body resides in the skeleton.
• The skeleton provides mechanical stability. It also serves as a reservoir, sometimes needed to maintain extracellular fluid (ECF) calcium concentration (Fig. 409-3).
• Skeletal calcium accretion:
  • It first becomes significant during the third trimester of fetal life.
  • It accelerates throughout childhood and adolescence.
  • It reaches a peak in early adulthood.
  • It then declines gradually, at rates that rarely exceed 1-2% per year.
• These slow changes in total skeletal calcium contrast with relatively high daily fluxes of calcium into and out of bone. The fluxes are closely matched, ~250-500 mg each, and are mediated by coupled osteoblastic and osteoclastic activity.
• Another 0.5-1% of skeletal calcium is freely exchangeable (in chemical equilibrium) with ECF calcium.

2. Ionized and cytosolic calcium

• ECF ionized calcium must be kept within a narrow range because calcium has a critical role in a wide array of cellular functions. Neuromuscular activity, secretion and signal transduction are especially dependent on it.
• Intracellular cytosolic free calcium is ~100 nmol/L. This is 10,000-fold lower than the ionized calcium in blood and ECF (1.1-1.3 mmol/L).
• Cytosolic calcium does not play the structural role of extracellular calcium. It serves a signaling function.
• The steep chemical gradient from outside to inside the cell promotes rapid calcium influx through various membrane calcium channels. Hormones, metabolites or neurotransmitters can activate these channels, swiftly changing cellular function.

3. Blood calcium

• Total blood calcium is normally 2.2-2.6 mM (8.5-10.5 mg/dL). About 50% is ionized.
• The remainder is:
  • Bound ionically to negatively charged proteins, predominantly albumin and immunoglobulins.
  • Loosely complexed with phosphate, citrate, sulfate or other anions.
• Changes in serum protein concentration directly affect total blood calcium even if ionized calcium remains normal.
• Correction algorithm for protein changes:
  • Adjust total serum calcium (mg/dL) upward by 0.8 times the deficit in serum albumin (g/dL).
  • Or adjust it upward by 0.5 times the deficit in serum immunoglobulin (g/dL).
  • These corrections give only rough approximations of actual free calcium and may be misleading, particularly during acute illness.
• Acidosis alters ionized calcium by reducing its association with proteins.
• Best practice: measure blood ionized calcium directly, using calcium-selective electrodes, in acute settings in which calcium abnormalities might occur.

4. Control of ECF ionized calcium

• Control is ordinarily accomplished by adjusting the rates of calcium movement across intestinal and renal epithelia and into and out of bone.
• The adjustments are mediated mainly by changes in blood levels of PTH and 1,25(OH)2D.
• Blood ionized calcium acts by binding calcium-sensing receptors (CaSRs) on the surface of parathyroid cells. This suppresses PTH secretion by:
  • Reducing levels of PTH mRNA.
  • Promoting cleavage of PTH to inactive peptides.
• Ionized calcium also affects PTH secretion indirectly by lowering 1,25(OH)2D production.
• 1,25(OH)2D inhibits PTH production by negative feedback, through an incompletely understood mechanism (Chap. 410).

5. Dietary calcium and intestinal absorption

• Dietary calcium intake in the United States varies widely, from 10 to 37 mmol/d (400-1500 mg/d).
• The National Academy of Medicine (formerly the Institute of Medicine) recommends a daily allowance of 25-30 mmol (1000-1200 mg) for most adults.
• Intestinal absorption involves two mechanisms:
  • Passive (paracellular):
    • It is nonsaturable.
    • It approximates 5% of daily calcium intake.
  • Active (transcellular):
    • It involves apical calcium entry via specific ion channels. TRPV5 is in the kidney and TRPV6 is in the intestine.
    • Their expression is controlled principally by 1,25(OH)2D.
    • It normally accounts for absorption of 20-70% of dietary calcium.
    • It occurs mainly in the proximal small bowel (duodenum and proximal jejunum). Some active absorption occurs in most segments of the small intestine.
• Gastric acid:
  • Optimal calcium absorption requires gastric acid.
  • This is especially true for weakly dissociable supplements such as calcium carbonate.
  • Large boluses of calcium carbonate are poorly absorbed because they neutralize gastric acid.
  • In achlorhydric subjects and in those taking drugs that inhibit gastric acid secretion, supplements should be taken with meals to optimize absorption.
  • Calcium citrate may be preferable in these circumstances.
• Absorption may be blunted in disease states such as pancreatic or biliary insufficiency, in which ingested calcium remains bound to unabsorbed fatty acids or other food constituents.
• At high calcium intake, synthesis of 1,25(OH)2D is reduced, which decreases active intestinal absorption. The opposite occurs with dietary calcium restriction.
• Some calcium, ~2.5-5 mmol/d (100-200 mg/d), is excreted as an obligate component of intestinal secretions. It is not regulated by calciotropic hormones.
• Feedback-controlled hormonal regulation of intestinal absorptive efficiency produces a relatively constant daily net calcium absorption of ~5-10 mmol/d (200-400 mg/d) despite large changes in intake.

6. Renal handling of calcium

• The absorbed daily calcium load is excreted by the kidneys. Excretion is tightly regulated by the blood ionized calcium concentration.
• Approximately 8-10 g/d of calcium is filtered by the glomeruli. Only 2-3% appears in the urine.
• Proximal tubule:
  • ~65% of filtered calcium is reabsorbed here.
  • The route is passive and paracellular, coupled to NaCl reabsorption.
  • It is not specifically regulated.
• Cortical thick ascending limb of Henle's loop (cTAL):
  • It reabsorbs roughly another 20% of filtered calcium, also paracellularly.
  • Reabsorption requires the tight-junction protein paracellin-1.
  • It is inhibited by increased blood concentrations of calcium or magnesium, acting via the CaSR. The CaSR is highly expressed on basolateral membranes in this segment.
  • The renal CaSR lets serum ionized calcium control renal calcium reabsorption by a mechanism independent of those engaged directly by PTH or 1,25(OH)2D.
• Distal convoluted tubule (DCT):
  • ~10% of filtered calcium is reabsorbed here, by a transcellular mechanism.
  • Calcium enters the luminal surface through apical calcium channels (TRPV5), whose number is regulated.
  • It crosses the cell bound to the calcium-binding protein calbindin-D28k, which buffers cytosolic calcium concentrations against the large mass of transported calcium.
  • Ca2+-ATPases and Na+/Ca2+ exchangers extrude calcium across the basolateral surface. This maintains the transcellular gradient.
  • All these processes are stimulated directly or indirectly by PTH.
• Diuretics and sodium:
  • The DCT is the site of action of thiazide diuretics. They lower urinary calcium excretion by inducing sodium depletion, which augments proximal calcium reabsorption.
  • Dietary sodium loads, or increased distal sodium delivery from loop diuretics or saline infusion, induce calciuresis.

7. Failure of calcium homeostasis

• The homeostatic mechanisms may fail at extremes of calcium intake, or when the hormonal systems or organs involved are compromised.
• Low intake:
  • Even with maximal activity of the vitamin D-dependent active intestinal transport system, sustained intake <5 mmol/d (<200 mg/d) cannot provide enough net absorption to replace obligate losses via the intestine, kidney, sweat and other secretions.
  • Increased PTH and 1,25(OH)2D then activate osteoclastic bone resorption to obtain calcium from bone. This leads to progressive bone loss and negative calcium balance.
  • Increased PTH and 1,25(OH)2D also enhance renal calcium reabsorption.
  • 1,25(OH)2D also enhances gut calcium absorption.
• Very high intake:
  • At intakes >100 mmol/d (>4 g/d), passive intestinal absorption continues to deliver calcium into the ECF despite maximally downregulated intestinal active transport and renal tubular reabsorption.
  • This can cause severe hypercalciuria, nephrocalcinosis, progressive renal failure and hypercalcemia (e.g., "milk-alkali syndrome").
• Other common challenges to calcium homeostasis are deficiency or excess of PTH or vitamin D, intestinal disease and renal failure (Chap. 410).

8. Figure 409-3 legend (calcium homeostasis)

• The figure is a schematic of the calcium content of ECF and bone, and of diet and feces.
• It shows the magnitude of daily calcium flux, as calculated by various methods, at the sites of transport in intestine, kidney and bone.
• The ranges are approximate. They were chosen to illustrate points discussed in the text.
• In conditions of calcium balance, the rates of calcium release from bone and uptake into bone are equal.
• Values printed on the figure (the PDF text does not label which value belongs to which arrow):
  • Bone: 1000-2000 g.
  • ECF: 1-2 g.
  • Flux values: 0.25-0.5 g; 0.25-0.5 g; 0.15-0.3 g; 0.3-1 g; 0.4-1.5 g; 0.1-0.2 g.
  • Renal filtered load and urine: 8-10 g and 7.9-9.7 g.

B. HIGH-YIELD NEET SS POINTS (Calcium)

1. Distribution:

   • 99% of the 1-2 kg of body calcium is in the skeleton.

   • 0.5-1% of skeletal calcium is freely exchangeable with the ECF.
   • Skeletal accretion starts in the third trimester, peaks in early adulthood, and then declines by no more than 1-2% per year.
2. Bone fluxes: ~250-500 mg/day go in and out, matched by coupled osteoblast and osteoclast activity. In balance, release equals uptake.
3. Concentrations:
   • Cytosolic free Ca is ~100 nmol/L. This is 10,000-fold lower than ECF ionized Ca (1.1-1.3 mmol/L). Cytosolic Ca is a signaling ion.
   • Total serum Ca is 2.2-2.6 mM (8.5-10.5 mg/dL), with ~50% ionized.
4. Binding: the bound fraction is mostly on albumin and immunoglobulins. The rest is complexed with phosphate, citrate and sulfate.
5. Correction formula:
   • Add 0.8 × albumin deficit (g/dL) to total Ca (mg/dL).
   • Or add 0.5 × immunoglobulin deficit (g/dL).
   • The correction is only approximate and may mislead in acute illness.
   • Best practice is direct ionized calcium by calcium-selective electrode in acute settings.
6. Acidosis reduces calcium-protein binding, which alters the ionized fraction.
7. CaSR on parathyroid cells: ionized Ca lowers PTH mRNA, promotes cleavage of PTH to inactive peptides, and lowers 1,25(OH)2D, which indirectly lowers PTH. 1,25(OH)2D exerts negative feedback on PTH.
8. Recommended allowance: 25-30 mmol (1000-1200 mg) per day.
9. Absorption:
   • Passive absorption is paracellular and nonsaturable, about 5% of intake.
   • Active absorption is transcellular via TRPV6 (gut) and TRPV5 (kidney), under 1,25(OH)2D control. It accounts for 20-70% of dietary Ca and occurs mainly in the duodenum and proximal jejunum.
10. Calcium carbonate needs gastric acid. Large boluses are poorly absorbed.
    • In achlorhydria or on acid-suppressing drugs, give it with meals.
    • Calcium citrate may be preferable.
11. Malabsorption: pancreatic or biliary insufficiency impairs Ca absorption because Ca binds unabsorbed fatty acids.
12. Adaptation: high intake lowers 1,25(OH)2D synthesis and so lowers active absorption. Restriction does the opposite. Net absorption stays at ~5-10 mmol/d (200-400 mg/d).
13. Obligate intestinal secretory loss is 2.5-5 mmol/d (100-200 mg/d) and is not regulated by calciotropic hormones.
14. Renal handling (8-10 g/d filtered, 2-3% excreted):
    • Proximal tubule: ~65%, passive, paracellular, coupled to NaCl, not specifically regulated.
    • cTAL: ~20%, paracellular, needs paracellin-1, inhibited by high Ca or Mg through the basolateral CaSR. This is a PTH-independent mechanism.
    • DCT: ~10%, transcellular via TRPV5 → calbindin-D28k → basolateral Ca2+-ATPase and Na+/Ca2+ exchanger, stimulated by PTH.
15. Diuretics:
    • Thiazides act at the DCT. They lower urine Ca by sodium depletion, which augments proximal Ca reabsorption.
    • Loop diuretics, saline infusion and sodium loads cause calciuresis.
16. Intake <5 mmol/d (<200 mg/d) gives negative Ca balance. Raised PTH and 1,25(OH)2D drive osteoclastic resorption, which leads to bone loss.
17. Intake >100 mmol/d (>4 g/d) causes severe hypercalciuria, nephrocalcinosis, progressive renal failure and hypercalcemia (milk-alkali syndrome), because passive absorption continues.