3157Bone and Mineral Metabolism in Health and Disease CHAPTER 409

of type 2 diabetes. Metformin also reduces the incidence of diabetes, although the effect is less pronounced than that of lifestyle

intervention.

INSULIN RESISTANCE (SEE ALSO CHAP. 404)

Several drug classes (biguanides, thiazolidinediones [TZDs])

increase insulin sensitivity. Because insulin resistance is the primary pathophysiologic mechanism for the metabolic syndrome,

representative drugs in these classes reduce its prevalence. Both

metformin and TZDs enhance insulin action in the liver and

suppress endogenous glucose production. TZDs, but not metformin, also improve insulin-mediated glucose uptake in muscle and

adipose tissue. In a meta-analysis of nine trials involving 12,026

participants, the TZD pioglitazone versus placebo was associated

with reduction in ASCVD events in patients with insulin resistance

(metabolic syndrome), prediabetes and type 2 diabetes. However,

adverse effects including weight gain, bone fracture, and congestive

heart failure with/or without edema were seen. Benefit of TZDs has

been seen in patients with NAFLD, and with metformin in women

with polycystic ovary syndrome, and both drug classes have been

shown to reduce markers of inflammation.

■ FURTHER READING

Alberti KG et al: Harmonizing the metabolic syndrome: A joint

interim statement of the International Diabetes Federation Task

Force on Epidemiology and Prevention; National Heart, Lung, and

Blood Institute; American Heart Association; World Heart Federation; International Atherosclerosis Society; and International Association for the Study of Obesity. Circulation 120:1640, 2009.

Brown AE, Walker M: Genetics of insulin resistance and the metabolic syndrome. Curr Cardiol Rep 18:75, 2016.

Eckel RH et al: The metabolic syndrome. Lancet 365:1415, 2005.

Genser L et al: Obesity, type 2 diabetes, and the metabolic syndrome:

Pathophysiologic relationships and guidelines for surgical intervention. Surg Clin North Am 96:681, 2016.

Lechner K et al: High-risk atherosclerosis and metabolic phenotype:

The roles of ectopic adiposity, atherogenic dyslipidemia, and inflammation. Metab Syndr Relat Disord 18:176, 2020.

Lim S, Eckel RH: Pharmacological treatment and therapeutic perspective of metabolic syndrome. Rev Endocr Metab Disord 15:329, 2014.

Neeland IJ et al: Visceral and ectopic fat, atherosclerosis, and cardiometabolic disease: A position statement. Lancet Diabetes Endocrinol 7:715, 2019.

Section 4 Disorders of Bone and Mineral

Metabolism

409 Bone and Mineral

Metabolism in Health

and Disease

F. Richard Bringhurst, Henry M.

Kronenberg, Eva S. Liu

BONE STRUCTURE AND METABOLISM

Bone is a dynamic tissue that is remodeled constantly throughout life.

The arrangement of compact and cancellous bone provides strength

and density suitable for both mobility and protection. Compact or

cortical bone forms the roughly cylindrical shell of long bones; cancellous or trabecular bone forms the plate-like meshwork that internally

supports the cortical shell. In addition, bone provides a reservoir for

calcium, magnesium, phosphorus, sodium, and other ions necessary

for homeostatic functions. Bone also 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. Remodeling of bone is accomplished by two distinct cell types:

osteoblasts produce bone matrix, and osteoclasts resorb the matrix.

The activities of these cells are coordinated by osteocytes, long-lived

regulatory cells embedded within bone matrix.

The extracellular components of bone consist of a solid mineral

phase in close association with an organic matrix, of which 90–95% is

type I collagen (Chap. 413). The noncollagenous portion of the organic

matrix is heterogeneous and contains serum proteins such as albumin as well as many locally produced proteins, whose functions are

incompletely understood. Those proteins include cell attachment/signaling proteins such as thrombospondin, osteopontin, and fibronectin;

calcium-binding proteins such as matrix gla protein and osteocalcin;

and proteoglycans such as biglycan and decorin. Some of the proteins

organize collagen fibrils; others influence mineralization and binding

of the mineral phase to the matrix.

The mineral phase is made up of calcium and phosphate and is best

characterized as a poorly crystalline hydroxyapatite. The mineral phase

of bone is deposited initially in intimate relation to the collagen fibrils

and is found in specific locations in the “holes” between the collagen

fibrils. This architectural arrangement of mineral and matrix results

in a two-phase material well suited to withstand mechanical stresses.

The organization of collagen influences the amount and type of mineral phase formed in bone. Although the primary structures of type I

collagen in skin and bone tissues are similar, there are differences in

posttranslational modifications and distribution of intermolecular

cross-links. The holes in the packing structure of the collagen are larger

in mineralized collagen of bone and dentin than in unmineralized

collagens such as those in tendon. Single amino acid substitutions in

the helical portion of either the α1 (COL1A1) or α2 (COL1A2) chains

of type I collagen disrupt the organization of bone in the disease, osteogenesis imperfecta. The severe skeletal fragility associated with this

group of disorders highlights the importance of the fibrillar matrix in

the structure of bone (Chap. 413).

Osteoblasts synthesize and secrete the organic matrix and regulate its mineralization. They are derived 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 then is

mineralized, the cell may become an osteocyte, still connected with

its nutrient supply through a series of canaliculi. Osteocytes account

for the vast majority of the cells in bone. They are thought to be

the mechanosensors in bone that communicate signals to surface

osteoblasts and osteoclasts and their progenitors through the canalicular network and thereby serve as master regulators of bone formation

and resorption. Remarkably, osteocytes also secrete fibroblast growth

factor 23 (FGF23), a major hormonal regulator of phosphate metabolism (see below). Mineralization of the matrix, both in trabecular

bone and in osteones of compact cortical bone (Haversian systems),

begins soon after the matrix is secreted (primary mineralization) but

is not completed for several weeks or even longer (secondary mineralization). Although this mineralization takes advantage of the high

concentrations of calcium and phosphate, already near saturation in

serum, mineralization is a carefully regulated process that is dependent on the activity of osteoblast-derived alkaline phosphatase, which

probably works by hydrolyzing inhibitors of mineralization, such as

pyrophosphate.

Genetic studies in humans and mice have identified several key

genes that control osteoblast development. Runx2 is a transcription

factor expressed specifically in chondrocyte (cartilage cells) and

osteoblast progenitors as well as in hypertrophic chondrocytes and

mature osteoblasts. Runx2 regulates the expression of several important osteoblast proteins, including osterix (another transcription factor

needed for osteoblast maturation), osteopontin, bone sialoprotein,

type I collagen, osteocalcin, and receptor-activator of nuclear factor

(NF)-κB (RANK) ligand. Runx2 expression is regulated in part by bone

morphogenic proteins (BMPs). Runx2-deficient mice are devoid of

3158 PART 12 Endocrinology and Metabolism

osteoblasts, whereas mice with a deletion of only one allele (Runx2 +/–)

exhibit a delay in formation of the clavicles and some cranial bones.

The latter abnormalities are similar to those in the human disorder cleidocranial dysplasia, which is also caused by heterozygous inactivating

mutations in Runx2.

The paracrine signaling molecule, Indian hedgehog (Ihh), also plays

a critical role in osteoblast development, as evidenced by Ihh-deficient

mice that lack osteoblasts in the type of bone formed on a cartilage

mold (endochondral ossification). Signals originating from members

of the wnt (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) family of paracrine factors

are also important for osteoblast proliferation and differentiation.

Osteocytes regulate osteoblasts partly by secreting a potent inhibitor

of wnt signaling called sclerostin. Numerous other growth-regulatory

factors affect osteoblast function, including the three closely related

transforming growth factor βs, fibroblast growth factors (FGFs) 2

and 18, platelet-derived growth factor, and insulin-like growth factors

(IGFs) I and II. Hormones such as parathyroid hormone (PTH) and

1,25-dihydroxyvitamin D [1,25(OH)2

D] activate receptors expressed

by osteoblasts to assure mineral homeostasis and influence a variety

of bone cell functions. Osteoclasts that resorb bone (see below) also

regulate osteoblasts by releasing growth factors from bone matrix and

by synthesizing proteins that can directly regulate osteoblastogenesis.

Resorption of bone is carried out mainly by osteoclasts, multinucleated cells that are formed by fusion of cells derived from the common

precursor of macrophages and osteoclasts. Thus, these cells derive

from the hematopoietic lineage, quite different from the mesenchymal

lineage cells that become osteoblasts. Multiple factors that regulate

osteoclast development have been identified (Fig. 409-1B). Factors

produced by osteocytes, osteoblasts, and marrow stromal cells allow

cells of the osteoblast lineage to control osteoclast development and

Mesenchymal

osteoblast

progenitor

Osteoblast

precursor

Collagen (I)

Alkaline phosphatase

Osteocalcin, osteopontin

Bone sialoprotein

c-src+

β3 integrin+

PYK2 kinase+

Cathepsin K+

TRAF+

Carbonic anhydrase II+

Runx 2

Hematopoietic

osteoclast

progenitor

M-CSF

BMPs PTH, Vit D, IGFs,

BMPs, Wnts

Osteoclast

precursor

Active

osteoblast

Mononuclear

osteoclast

Quiescent

osteoclast

Active

osteoclast

PU-1+ c-fos+

NKκB+

TRAF+

Commitment

RANK Ligand

Differentiation

M-CSF

RANK Ligand

IL-1, IL-6

Fusion

RANK Ligand

IL-1

A

B

FIGURE 409-1 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 depicted below the arrows. BMPs, bone

morphogenic proteins; IGFs, insulin-like growth factors; IL-1, interleukin 1; IL-6, interleukin 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. (Modified

with permission from T Suda et al: Modulation of osteoclast differentiation and function by the new members of the tumor necrosis factor receptor and ligand families.

Endocr Rev 20:345, 1999.)

activity. Macrophage colony-stimulating factor (M-CSF) plays a critical

role during several steps in the pathway and ultimately leads to fusion

of osteoclast progenitor cells to form multinucleated, active osteoclasts.

RANK ligand, a member of the tumor necrosis factor (TNF) family,

is expressed on the surface of osteocytes, osteoblasts, and stromal

fibroblasts. In a process involving cell-cell interactions, RANK ligand

binds to the RANK receptor on osteoclast progenitors, stimulating

osteoclast differentiation and activation. Alternatively, a soluble decoy

receptor, referred to as osteoprotegerin, can bind RANK ligand and

inhibit osteoclast differentiation. Several growth factors and cytokines

(including interleukins 1, 6, and 11; TNF; and interferon γ) modulate

osteoclast differentiation and function. Most hormones that influence

osteoclast function do not target these cells directly but instead target

cells of the osteoblast lineage to increase production of M-CSF and

RANK. Both PTH and 1,25(OH)2

D increase osteoclast number and

activity by this indirect mechanism. Calcitonin, in contrast, binds to its

receptor on the basal surface of osteoclasts and directly inhibits osteoclast function. Estradiol has multiple cellular targets in bone, including

osteoclasts, immune cells, and osteoblasts; actions on all these cells

serve to decrease osteoclast number and decreased bone resorption.

Osteoclast-mediated resorption of bone takes place in scalloped

spaces (Howship’s lacunae) where the osteoclasts are attached through

a specific αvβ3 integrin to components of the bone matrix such as

osteopontin. The osteoclast forms a tight seal to the underlying matrix

and secretes protons, chloride, and proteinases into a confined space

that has been likened to an extracellular lysosome. The active osteoclast

surface forms a ruffled border that contains a specialized proton pump

ATPase that secretes acid that 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

adjacent to the ruffled border by proteases, such as cathepsin K, that

act at low pH.

3159Bone and Mineral Metabolism in Health and Disease CHAPTER 409

In the embryo and the growing child, bone develops mostly by

replacing previously calcified cartilage (endochondral bone formation)

with subsequent remodeling or, in a few bones, is formed without a

cartilage matrix (intramembranous bone formation). During endochondral bone formation, chondrocytes proliferate, secrete and mineralize a matrix, enlarge (hypertrophy), and then die, enlarging bone

and providing the matrix and factors that stimulate endochondral

bone formation. This program is regulated by both local factors such

as IGF-I and -II, Ihh, parathyroid hormone–related peptide (PTHrP),

BMPs, and FGFs and by systemic hormones such as growth hormone,

glucocorticoids, and estrogen. Some hypertrophic chondrocytes do

not die but, instead, through still poorly understood steps, can become

osteoblasts and bone stromal cells.

New bone, whether formed in infants or in adults during repair,

has a relatively high ratio of cells to matrix and is characterized by

coarse fiber bundles of collagen that are interlaced and randomly

dispersed (woven bone). In adults, the more mature bone is organized with fiber bundles regularly arranged in parallel or concentric

sheets (lamellar bone). In long bones, deposition of lamellar bone in

a concentric arrangement around blood vessels forms the Haversian

systems. Growth in length of bones is dependent on proliferation of

cartilage cells and the endochondral sequence at the growth plate.

Growth in width and thickness is accomplished by formation of bone

at the periosteal surface and by resorption at the endosteal surface,

with the rate of formation exceeding 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. Even in

adults, however, remodeling of bone (within Haversian systems as

well as along the surfaces of trabecular bone) continues throughout

life. In adults, ~4% of the surface of trabecular bone (such as iliac

crest) is involved in active resorption, whereas 10–15% of trabecular

surfaces are covered with osteoid, unmineralized new bone formed by

osteoblasts. Radioisotope studies indicate that as much as 18% of the

total skeletal calcium is deposited and removed each year. Thus, bone

is an active metabolizing tissue that requires an intact blood supply.

The cycle of bone resorption and formation is a highly orchestrated

process, directed by osteocytes and carried out by the basic multicellular unit, which is composed of a group of osteoclasts and osteoblasts

(Fig. 409-2).

The response of bone to fractures, infection, and interruption of

blood supply and to expanding lesions is relatively limited. Dead bone

must be resorbed, and new bone must be formed, a process carried

out in association with growth of new blood vessels into the involved

area. In injuries that disrupt the organization of the tissue, such as a

fracture, in which apposition of fragments is poor or when motion

exists at the fracture site, progenitor stromal cells recapitulate the

endochondral bone formation of early development and form cartilage

that is replaced by bone and, variably, fibrous tissue. When 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.

Remodeling of bone occurs along lines of force generated by

mechanical stress. The signals from these mechanical stresses are

sensed by osteocytes, which transmit signals to osteoclasts and

osteoblasts or their precursors. One such signal made by osteocytes is

sclerostin, an inhibitor of wnt signaling. Mechanical forces suppress

sclerostin production and thus increase bone formation by osteoblasts.

Expanding lesions in bone such as tumors induce resorption at the

surface in contact with the tumor by producing ligands such as PTHrP

that stimulate osteoclast differentiation and function. Thus, bone

plasticity reflects the interaction of cells with each other and with the

environment.

Measurement of the products of osteoblast and osteoclast activity can assist in the diagnosis and management of bone diseases.

Osteoblast activity can be assessed by measuring serum bone-specific

alkaline phosphatase. Similarly, osteocalcin, a protein secreted from

osteoblasts, is made virtually only by osteoblasts. Measurement of an

amino-terminal fragment of procollagen I is also an effective index of

bone formation. Osteoclast activity can be assessed by measurement of

products of collagen degradation. Collagen molecules are covalently

linked to each other in the extracellular matrix through the formation

of hydroxypyridinium cross-links (Chap. 413). After digestion by

osteoclasts, these cross-linked peptides can be measured both in urine

and in blood.

CALCIUM METABOLISM

Over 99% of the 1–2 kg of calcium present normally in the adult

human body resides in the skeleton, where it provides mechanical stability and serves as a reservoir sometimes needed to maintain extracellular fluid (ECF) calcium concentration (Fig. 409-3). Skeletal calcium

accretion first becomes significant during the third trimester of fetal

life, accelerates throughout childhood and adolescence, reaches a peak

in early adulthood, and gradually declines thereafter at rates that rarely

exceed 1–2% per year. These slow changes in total skeletal calcium content contrast with relatively high daily rates of closely matched fluxes of

calcium into and out of bone (~250–500 mg each), a process mediated

by coupled osteoblastic and osteoclastic activity. Another 0.5–1% of

skeletal calcium is freely exchangeable (e.g., in chemical equilibrium)

with that in the ECF.

The concentration of ionized calcium in the ECF must be maintained within a narrow range because of the critical role calcium plays

in a wide array of cellular functions, especially those involved in neuromuscular activity, secretion, and signal transduction. Intracellular

cytosolic free calcium levels are ~100 nmol/L and are 10,000-fold lower

than ionized calcium concentration in

the blood and ECF (1.1–1.3 mmol/L).

Cytosolic calcium does not play the

structural role played by extracellular

calcium; instead, it serves a signaling

function. The steep chemical gradient

of calcium from outside to inside the

cell promotes rapid calcium influx

through various membrane calcium

channels that can be activated by hormones, metabolites, or neurotransmitters, swiftly changing cellular function.

In blood, total calcium concentration is

normally 2.2–2.6 mM (8.5–10.5 mg/dL),

of which ~50% is ionized. The remainder

is bound ionically to negatively charged

proteins (predominantly albumin and

immunoglobulins) or loosely complexed

with phosphate, citrate, sulfate, or other

anions. Alterations in serum protein concentrations directly affect the total blood

calcium concentration even if the ionized

~3 weeks ~3 months

Osteoid

Osteoclast

precursor

Osteocyte

Osteoclast Active osteoclast

Osteoblast

precursors Bone

remodeling

unit

Osteoblast

Lining cells

Activation

Resorption

Bone formation Mineralization

Cement

 line

Reversal

Resting

 bone

 surface

FIGURE 409-2 Schematic representation of bone remodeling. The cycle of bone remodeling is carried out by the

basic multicellular unit (BMU), which consists of a group of osteoclasts and osteoblasts. In cortical bone, the BMUs

tunnel through the tissue, whereas in cancellous bone, they move across the trabecular surface. The process of

bone remodeling is initiated by the recruitment of osteoclast precursors, perhaps to sites of microdamage. These

precursors fuse to form multinucleated, active osteoclasts that mediate bone resorption. Osteoclasts adhere to bone

and subsequently remove it by acidification and proteolytic digestion. As the BMU advances, osteoclasts leave the

resorption site and osteoblasts, derived from marrow precursors and previously inactive bone lining cells, move in

to cover the excavated area and begin the process of new bone formation by secreting osteoid, which eventually is

mineralized into new bone. After osteoid mineralization, osteoblasts flatten and form a layer of lining cells over new

bone, become osteocytes, or die.

3160 PART 12 Endocrinology and Metabolism

calcium concentration remains normal. An algorithm to correct for protein changes adjusts the total serum calcium (in mg/dL) upward by 0.8

times the deficit in serum albumin (g/dL) or by 0.5 times the deficit

in serum immunoglobulin (in g/dL). Such corrections provide only

rough approximations of actual free calcium concentrations, however,

and may be misleading, particularly during acute illness. Acidosis also

alters ionized calcium by reducing its association with proteins. The

best practice is to measure blood ionized calcium directly by a method

that employs calcium-selective electrodes in acute settings during

which calcium abnormalities might occur.

Control of the ionized calcium concentration in the ECF ordinarily

is accomplished by adjusting the rates of calcium movement across

intestinal and renal epithelia and into and out of bone. These adjustments are mediated mainly via changes in blood levels of the hormones PTH and 1,25(OH)2

D. Acting via binding to calcium-sensing

receptors (CaSRs) on the surface of parathyroid cells, blood ionized

calcium suppresses PTH secretion by reducing levels of PTH mRNA

and promoting the cleavage of PTH to inactive peptides. Also, ionized

calcium indirectly affects PTH secretion by lowering 1,25(OH)2

D

production. This active vitamin D metabolite inhibits PTH production by an incompletely understood mechanism of negative feedback

(Chap. 410).

Normal dietary calcium intake in the United States varies widely,

ranging from 10 to 37 mmol/d (400–1500 mg/d). A National Academy

of Medicine (formerly, Institute of Medicine) analysis recommends

a daily allowance of 25–30 mmol (1000–1200 mg) for most adults.

Intestinal absorption of ingested calcium involves both active (transcellular) and passive (paracellular) mechanisms. Passive calcium

absorption is nonsaturable and approximates 5% of daily calcium

intake, whereas active absorption involves apical calcium entry via specific ion channels (TRPV5 in the kidney and TRPV6 in the intestine),

whose expression is controlled principally by 1,25(OH)2

D. This active

transport mechanism normally accounts for absorption of 20–70%

of dietary calcium. Active calcium transport occurs mainly in the

proximal small bowel (duodenum and proximal jejunum), although

some active calcium absorption occurs in most segments of the small

intestine. Optimal rates of calcium absorption require gastric acid.

This is especially true for weakly dissociable calcium supplements such

as calcium carbonate. In fact, large boluses of calcium carbonate are

poorly absorbed because of their neutralizing effect on gastric acid.

In achlorhydric subjects and for those taking drugs that inhibit gastric

acid secretion, supplements should be taken with meals to optimize

their absorption. Use of calcium citrate may be preferable in these circumstances. Calcium absorption may also 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 levels of calcium intake, synthesis of 1,25(OH)2

D is reduced; this

decreases the rate of active intestinal calcium 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 and is not regulated by calciotropic hormones.

The feedback-controlled hormonal regulation of intestinal absorptive efficiency results in a relatively constant daily net calcium absorption of ~5–10 mmol/d (200–400 mg/d) despite large changes in daily

dietary calcium intake. This daily load of absorbed calcium is excreted

by the kidneys in a manner that is also tightly regulated by the concentration of ionized calcium in the blood. Approximately 8–10 g/d

of calcium is filtered by the glomeruli, of which only 2–3% appears in

the urine. Most filtered calcium (65%) is reabsorbed in the proximal

tubules via a passive, paracellular route that is coupled to concomitant

NaCl reabsorption and not specifically regulated. The cortical thick

ascending limb of Henle’s loop (cTAL) reabsorbs roughly another 20%

of filtered calcium, also via a paracellular mechanism. Calcium reabsorption in the cTAL requires a tight-junctional protein called paracellin-1 and is inhibited by increased blood concentrations of calcium or

magnesium, acting via the CaSR, which is highly expressed on basolateral membranes in this nephron segment. Operation of the renal CaSR

provides a mechanism, independent of those engaged directly by PTH

or 1,25(OH)2

D, by which serum ionized calcium can control renal

calcium reabsorption. Finally, ~10% of filtered calcium is reabsorbed

in the distal convoluted tubules (DCTs) by a transcellular mechanism.

Calcium enters the luminal surface of the cell through specific apical

calcium channels (TRPV5), whose number is regulated. It then moves

across the cell in association with a specific calcium-binding protein

(calbindin-D28k) that buffers cytosolic calcium concentrations from

the large mass of transported calcium. Ca2+-ATPases and Na+/Ca2+

exchangers actively extrude calcium across the basolateral surface and

thereby maintain the transcellular calcium gradient. All these processes

are stimulated directly or indirectly by PTH. The DCT is also the site of

action of thiazide diuretics, which lower urinary calcium excretion by

inducing sodium depletion and thereby augmenting proximal calcium

reabsorption. Conversely, dietary sodium loads, or increased distal

sodium delivery caused by loop diuretics or saline infusion, induce

calciuresis.

The homeostatic mechanisms that normally maintain a constant

serum ionized calcium concentration may fail at extremes of calcium

intake or when the hormonal systems or organs involved are compromised. Thus, even with maximal activity of the vitamin D–dependent intestinal active transport system, sustained calcium intakes

<5 mmol/d (<200 mg/d) cannot provide enough net calcium absorption to replace obligate losses via the intestine, the kidney, sweat,

and other secretions. In this case, increased blood levels of PTH and

1,25(OH)2

D activate osteoclastic bone resorption to obtain needed

calcium from bone, which leads to progressive bone loss and negative

calcium balance. Increased PTH and 1,25(OH)2

D also enhance renal

calcium reabsorption, and 1,25(OH)2

D enhances calcium absorption

in the gut. At very high calcium 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 calcium reabsorption. This can cause severe hypercalciuria,

nephrocalcinosis, progressive renal failure, and hypercalcemia (e.g.,

“milk-alkali syndrome”). Deficiency or excess of PTH or vitamin D,

intestinal disease, and renal failure represent other commonly encountered challenges to normal calcium homeostasis (Chap. 410).

PHOSPHORUS METABOLISM

Although 85% of the ~600 g of body phosphorus is present in bone

mineral, phosphorus is also a major intracellular constituent both as

the free anion(s) and as a component of numerous organophosphate

compounds, including structural proteins, enzymes, transcription

Kidney

Bone

ECF

1–2 g

Intestine

1000–2000 g

0.25–0.5 g

0.25–0.5 g

0.15–.3 g

0.3–1 g

0.4–1.5 g

8–10 g 7.9–9.7 g

0.25–0.5 g

0.1–0.2 g

FIGURE 409-3 Calcium homeostasis. Schematic illustration of calcium content of

extracellular fluid (ECF) and bone as well as of diet and feces; magnitude of calcium

flux per day as calculated by various methods is shown at sites of transport in

intestine, kidney, and bone. Ranges of values shown are approximate and were

chosen to illustrate certain points discussed in the text. In conditions of calcium

balance, rates of calcium release from and uptake into bone are equal.

3161Bone and Mineral Metabolism in Health and Disease CHAPTER 409

factors, carbohydrate and lipid intermediates, high-energy stores (ATP

[adenosine triphosphate], creatine phosphate), and nucleic acids.

Unlike calcium, phosphorus exists intracellularly at concentrations

close to those present in ECF (e.g., 1–2 mmol/L). In cells and in the

ECF, phosphorus exists in several forms, predominantly as H2

PO4

–

 or

NaHPO4

–

, with perhaps 10% as HPO4

2–. This mixture of anions will

be referred to here as “phosphate.” In serum, ~12% of phosphorus is

bound to proteins. Concentrations of phosphates in blood and ECF

generally are expressed in terms of elemental phosphorus, with the

normal range in adults being 0.75–1.45 mmol/L (2.5–4.5 mg/dL).

Because the volume of the intracellular fluid compartment is twice that

of the ECF, measurements of ECF phosphate may not accurately reflect

phosphate availability within cells that follows even modest shifts of

phosphate from one compartment to the other.

Phosphate is widely available in foods and is absorbed efficiently

(65%) by the small intestine even in the absence of vitamin D. However, phosphate absorptive efficiency may be enhanced (to 85–90%) via

active transport mechanisms that are stimulated by 1,25(OH)2

D. These

mechanisms involve activation of Na+/PO4

2– co-transporters, such as

Npt2b, that move phosphate into intestinal cells against an unfavorable

electrochemical gradient. Daily net intestinal phosphate absorption

varies widely with the composition of the diet but is generally in the

range of 500–1000 mg/d. Phosphate absorption can be inhibited by

large doses of calcium salts or by sevelamer hydrochloride (Renagel),

strategies commonly used to control levels of serum phosphate in

renal failure. Aluminum hydroxide antacids also reduce phosphate

absorption but are used less commonly because of the potential for

aluminum toxicity. Low serum phosphate stimulates renal proximal

tubular synthesis of 1,25(OH)2

D, perhaps by suppressing blood levels

of FGF23 (see below).

Serum phosphate levels vary by as much as 50% on a normal day.

This reflects the effect of food intake but also an underlying circadian

rhythm that produces a nadir between 7 and 10 a.m. Carbohydrate

administration, especially as IV dextrose solutions in fasting subjects,

can decrease serum phosphate by >0.7 mmol/L (2 mg/dL) during

treatment of ketoacidosis or during metabolic or respiratory alkalosis.

Because of this wide variation in serum phosphate, it is best to perform

measurements in the basal, fasting state.

Control of serum phosphate is determined mainly by the rate of

renal tubular reabsorption of the filtered load, which is ~4–6 g/d.

Because intestinal phosphate absorption is highly efficient, urinary

excretion is not constant but varies directly with dietary intake. The

fractional excretion of phosphate (ratio of phosphate to creatinine

clearance) is generally in the range of 10–15%. The proximal tubule is

the principal site at which renal phosphate reabsorption is regulated.

This is accomplished by changes in the levels of apical expression and

activity of specific Na+/PO4

2– co-transporters (NaPi-2a and NaPi-2c) in

the proximal tubule. Levels of these transporters at the apical surface of

these cells are reduced rapidly by PTH, a major hormonal regulator of

renal phosphate excretion. FGF23 can impair phosphate reabsorption

dramatically by a similar mechanism. Activating FGF23 mutations

cause the rare disorder autosomal dominant hypophosphatemic rickets

(ADHR). In contrast to PTH, FGF23 also leads to reduced synthesis of

1,25(OH)2

D, which may worsen the resulting hypophosphatemia by

lowering intestinal phosphate absorption. Renal reabsorption of phosphate is responsive to changes in dietary intake such that experimental

dietary phosphate restriction leads to a dramatic lowering of urinary

phosphate within hours, preceding any decline in serum phosphate

(e.g., filtered load). This physiologic renal adaptation to changes in

dietary phosphate availability occurs independently of PTH and may

be mediated in part by changes in levels of serum FGF23. Findings

in FGF23-knockout mice suggest that FGF23 normally acts to lower

blood phosphate and 1,25(OH)2

D levels. In turn, elevation of blood

phosphate increases blood levels of FGF23.

Renal phosphate reabsorption is impaired by hypocalcemia, hypomagnesemia, and severe hypophosphatemia. Phosphate clearance is

enhanced by ECF volume expansion and impaired by dehydration.

Phosphate retention is an important pathophysiologic feature of renal

insufficiency (Chap. 311).

■ HYPOPHOSPHATEMIA

Causes Hypophosphatemia can occur by one or more of three

primary mechanisms: (1) inadequate intestinal phosphate absorption,

(2) excessive renal phosphate excretion, and (3) rapid redistribution of

phosphate from the ECF into bone or soft tissue (Table 409-1). Because

phosphate is so abundant in foods, inadequate intestinal absorption is

almost never observed now that aluminum hydroxide antacids, which

bind phosphate in the gut, are no longer widely used. Fasting or starvation, however, may result in depletion of body phosphate and predispose to subsequent hypophosphatemia during refeeding, especially if

this is accomplished with IV glucose alone.

Chronic hypophosphatemia usually signifies the presence of a persistent renal tubular phosphate-wasting disorder. Excessive activation

of PTH/PTHrP receptors in the proximal tubule as a result of primary

or secondary hyperparathyroidism or because of the PTHrP-mediated

hypercalcemia syndrome in malignancy (Chap. 410) is among the

more common causes of renal hypophosphatemia. Familial hypocalciuric hypercalcemia and Jansen’s chondrodystrophy are rare examples of

genetic disorders in this category (Chap. 410).

Several genetic and acquired diseases cause PTH/PTHrP receptor-independent tubular phosphate wasting with associated rickets and

osteomalacia. All these diseases manifest severe hypophosphatemia;

renal phosphate wasting, sometimes accompanied by aminoaciduria;

inappropriately low blood levels of 1,25(OH)2

D; low-normal serum

levels of calcium; and evidence of impaired cartilage or bone mineralization. Analysis of these diseases led to the discovery of the hormone

FGF23, which is an important physiologic regulator of phosphate

metabolism. FGF23 decreases phosphate reabsorption in the proximal

tubule and also suppresses the 1α-hydroxylase responsible for synthesis

of 1,25(OH)2

D. FGF23 is synthesized by cells of the osteoblast lineage,

primarily osteocytes. High-phosphate diets increase FGF23 levels, and

low-phosphate diets decrease them. ADHR was the first disease linked

to abnormalities in FGF23. ADHR results from activating mutations

in the gene that encodes FGF23. These mutations alter a cleavage site

that ordinarily allows for inactivation of intact FGF23. Several other

genetic disorders feature elevated FGF23 and hypophosphatemia. The

most common of these is X-linked hypophosphatemic rickets (XLH),

which results from inactivating mutations in an endopeptidase termed

PHEX (phosphate-regulating gene with homologies to endopeptidases

on the X chromosome) that is expressed most abundantly on the surface of osteocytes and mature osteoblasts. Patients with XLH usually

have high FGF23 levels, and ablation of the FGF23 gene reverses the

hypophosphatemia found in the mouse version of XLH. How inactivation of PHEX leads to increased levels of FGF23 has not been determined. Two rare autosomal recessive hypophosphatemic syndromes

associated with elevated FGF23 are due to inactivating mutations of

dentin matrix protein 1 (DMP1) and ectonucleotide pyrophosphatase/

phosphodiesterase 1 (ENPP1), respectively, both of which normally are

highly expressed in bone and presumably regulate FGF23 production.

An unusual hypophosphatemic disorder, tumor-induced osteomalacia

(TIO), is an acquired disorder in which tumors, usually of mesenchymal origin and generally histologically benign, secrete FGF23 that

induces renal phosphate wasting. The hypophosphatemic syndrome

resolves completely within hours to days after successful resection of

the responsible tumor. Such tumors typically express large amounts

of FGF23 mRNA, and patients with TIO usually exhibit elevations of

FGF23 in their blood.

Dent’s disease is an X-linked recessive disorder caused by inactivating mutations in CLCN5, a chloride transporter expressed in

endosomes of the proximal tubule; features include hypercalciuria,

hypophosphatemia, and recurrent kidney stones. Renal phosphate

wasting is common among poorly controlled diabetic patients and

alcoholics, who therefore are at risk for iatrogenic hypophosphatemia

when treated with insulin or IV glucose, respectively. Diuretics and

certain other drugs and toxins can cause defective renal tubular phosphate reabsorption (Table 409-1).

In hospitalized patients, hypophosphatemia is often attributable to

massive redistribution of phosphate from the ECF into cells. Insulin

3162 PART 12 Endocrinology and Metabolism

TABLE 409-1 Causes of Hypophosphatemia

I. Reduced renal tubular phosphate reabsorption

A. PTH/PTHrP-dependent

1. Primary hyperparathyroidism

2. Secondary hyperparathyroidism

a. Vitamin D deficiency/resistance

b. Calcium starvation/malabsorption

c. Bartter’s syndrome

d. Autosomal recessive renal hypercalciuria with hypomagnesemia

3. PTHrP-dependent hypercalcemia of malignancy

4. Familial hypocalciuric hypercalcemia

B. PTH/PTHrP-independent

1. Excess FGF23 or other “phosphatonins”

a. X-linked hypophosphatemic rickets (XLH)

b. Autosomal recessive hypophosphatemia (ARHP)

c. Autosomal recessive hypophosphatemic rickets (ARHR) (DMP1,

ENPP1 deficiency)

d. Tumor-induced osteomalacia syndrome (TIO)

e. McCune-Albright syndrome (fibrous dysplasia)

f. Epidermal nevus syndrome

2. Intrinsic renal disease

a. Fanconi’s syndrome(s)

b. Cystinosis

c. Wilson’s disease

d. NaPi-2a or NaPi-2c mutations

3. Other systemic disorders

a. Poorly controlled diabetes mellitus

b. Alcoholism

c. Hyperaldosteronism

d. Hypomagnesemia

e. Amyloidosis

f. Hemolytic-uremic syndrome

g. Renal transplantation or partial liver resection

h. Rewarming or induced hyperthermia

4. Drugs or toxins

a. Ethanol

b. Acetazolamide, other diuretics

c. High-dose estrogens or glucocorticoids

d. Heavy metals (lead, cadmium, saccharated ferric oxide)

e. Toluene, N-methyl formamide

f. Cisplatin, ifosfamide, foscarnet, rapamycin

II. Impaired intestinal phosphate absorption

A. Aluminum-containing antacids

B. Sevelamer

III. Shifts of extracellular phosphate into cells

A. Intravenous glucose

B. Insulin therapy for prolonged hyperglycemia or diabetic ketoacidosis

C. Catecholamines (epinephrine, dopamine, albuterol)

D. Acute respiratory alkalosis

E. Gram-negative sepsis, toxic shock syndrome

F. Recovery from starvation or acidosis

G. Rapid cellular proliferation

1. Leukemic blast crisis

2. Intensive erythropoietin, other growth factor therapy

IV. Accelerated net bone formation

A. After parathyroidectomy

B. Treatment of vitamin D deficiency, Paget’s disease

C. Osteoblastic metastases

Abbreviations: PTH, parathyroid hormone; PTHrP, parathyroid hormone–related

peptide.

therapy for diabetic ketoacidosis is a paradigm for this phenomenon, in which the severity of the hypophosphatemia is related to the

extent of antecedent depletion of phosphate and other electrolytes

(Chap. 404). The hypophosphatemia is usually greatest at a point

many hours after initiation of insulin therapy and is difficult to predict

from baseline measurements of serum phosphate at the time of presentation, when prerenal azotemia can obscure significant phosphate

depletion. Other factors that may contribute to such acute redistributive hypophosphatemia include antecedent starvation or malnutrition,

administration of IV glucose without other nutrients, elevated blood

catecholamines (endogenous or exogenous), respiratory alkalosis, and

recovery from metabolic acidosis.

Hypophosphatemia also can occur transiently (over weeks to

months) during the phase of accelerated net bone formation that follows parathyroidectomy for severe primary hyperparathyroidism or

during treatment of vitamin D deficiency or lytic Paget’s disease. This is

usually most prominent in patients who preoperatively have evidence

of high bone turnover (e.g., high serum levels of alkaline phosphatase).

Osteoblastic metastases can also lead to this syndrome.

Clinical and Laboratory Findings The clinical manifestations of

severe hypophosphatemia reflect a generalized defect in cellular energy

metabolism because of ATP depletion, a shift from oxidative phosphorylation toward glycolysis, and associated tissue or organ dysfunction.

Acute, severe hypophosphatemia occurs mainly or exclusively in hospitalized patients with underlying serious medical or surgical illness and

preexisting phosphate depletion due to excessive urinary losses, severe

malabsorption, or malnutrition. Chronic hypophosphatemia tends to

be less severe, with a clinical presentation dominated by musculoskeletal complaints such as bone pain, osteomalacia, pseudofractures, and

proximal muscle weakness or, in children, rickets and short stature.

Neuromuscular manifestations of severe hypophosphatemia are

variable but may include muscle weakness, lethargy, confusion, disorientation, hallucinations, dysarthria, dysphagia, oculomotor palsies,

anisocoria, nystagmus, ataxia, cerebellar tremor, ballismus, hyporeflexia, impaired sphincter control, distal sensory deficits, paresthesia,

hyperesthesia, generalized or Guillain-Barré–like ascending paralysis,

seizures, coma, and even death. Serious sequelae such as paralysis,

confusion, and seizures are likely only at phosphate concentrations

<0.25 mmol/L (<0.8 mg/dL). Rhabdomyolysis may develop during

rapidly progressive hypophosphatemia. The diagnosis of hypophosphatemia-induced rhabdomyolysis may be overlooked, as up to 30%

of patients with acute hypophosphatemia (<0.7 mM) have creatine

phosphokinase elevations that peak 1–2 days after the nadir in serum

phosphate, when the release of phosphate from injured myocytes may

have led to a near normalization of circulating levels of phosphate.

Respiratory failure and cardiac dysfunction, which are reversible

with phosphate treatment, may occur at serum phosphate levels of

0.5–0.8 mmol/L (1.5–2.5 mg/dL). Renal tubular defects, including

tubular acidosis, glycosuria, and impaired reabsorption of sodium and

calcium, may occur. Hematologic abnormalities correlate with reductions in intracellular ATP and 2,3-diphosphoglycerate and may include

erythrocyte microspherocytosis and hemolysis; impaired oxyhemoglobin dissociation; defective leukocyte chemotaxis, phagocytosis, and

bacterial killing; and platelet dysfunction with spontaneous gastrointestinal hemorrhage.

TREATMENT

Hypophosphatemia

Severe hypophosphatemia (<0.75 mmol/L [<2 mg/dL]), particularly

in the setting of underlying phosphate depletion, constitutes a dangerous electrolyte abnormality that should be corrected promptly.

Unfortunately, the cumulative deficit in body phosphate cannot be

predicted directly from knowledge of the circulating level of phosphate, and therapy must be approached empirically. The threshold

for IV phosphate therapy and consequently the dose of phosphate to

be administered should reflect consideration of renal function, the

likely severity and duration of the underlying phosphate depletion,

3163Bone and Mineral Metabolism in Health and Disease CHAPTER 409

and the presence and severity of symptoms consistent with those

of hypophosphatemia. In adults, phosphate may be safely administered IV as neutral mixtures of sodium or potassium phosphate

salts at initial doses of 0.2–0.8 mmol/kg of elemental phosphorus

over 6 h (e.g., 10–50 mmol over 6 h), with doses >20 mmol/6 h

reserved for those who have serum levels <0.5 mmol/L (1.5 mg/dL)

and normal renal function. A suggested approach is presented in

Table 409-2. Serum levels of phosphate and calcium must be monitored closely (every 6–12 h) throughout treatment. It is necessary to

avoid a serum calcium-phosphorus product >50 mg2

/dL2

 to reduce

the risk of heterotopic calcification. Hypocalcemia, if present,

should be corrected before administering IV phosphate. Less severe

hypophosphatemia, in the range of 0.5–0.8 mmol/L (1.5–2.5 mg/

dL), usually can be treated with oral phosphate in divided doses of

750–2000 mg/d as elemental phosphorus; higher doses can cause

bloating and diarrhea.

Management of chronic hypophosphatemia requires knowledge

of the cause(s) of the disorder. Hypophosphatemia related to the

secondary hyperparathyroidism of vitamin D deficiency usually

responds to treatment with vitamin D and calcium alone. XLH,

ADHR, TIO, and related renal tubular disorders usually are managed with divided oral doses of phosphate, often with calcium and

1,25(OH)2

D supplements to bypass the block in renal 1,25(OH)2

D

synthesis and prevent secondary hyperparathyroidism caused by

suppression of ECF calcium levels. Care must be taken to be sure

that oral calcium and phosphate are not administered at the same

time, to avoid precipitation before absorption. Thiazide diuretics

may be used to prevent nephrocalcinosis in patients who are managed this way. Complete normalization of hypophosphatemia is

generally not possible in these conditions. Burosumab, a human

monoclonal antibody that inhibits FGF23, has been approved for

the treatment of XLH. It corrects hypophosphatemia, improves

bone pain, and heals fractures in both adults and children.

Optimal therapy for TIO is extirpation of the responsible tumor,

which may be localized by radiographic skeletal survey or bone

scan (many are located in bone) or by radionuclide scanning

using sestamibi or labeled octreotide. Successful treatment of TIOinduced hypophosphatemia with octreotide has been reported in a

small number of patients. Burosumab treatment, originally used for

XLH, also shows promise as a treatment for TIO.

■ HYPERPHOSPHATEMIA

Causes When the filtered load of phosphate and glomerular filtration rate (GFR) are normal, control of serum phosphate levels is

achieved by adjusting the rate at which phosphate is reabsorbed by

the proximal tubular NaPi-2 co-transporters. The principal hormonal

regulators of NaPi-2 activity are PTH and FGF23. Hyperphosphatemia,

defined in adults as a fasting serum phosphate concentration >1.8

mmol/L (5.5 mg/dL), usually results from impaired glomerular filtration, hypoparathyroidism, excessive delivery of phosphate into the ECF

(from bone, gut, or parenteral phosphate therapy), or a combination of

these factors (Table 409-3). The upper limit of normal serum phosphate concentrations is higher in children and neonates (2.4 mmol/L

[7 mg/dL]). It is useful to distinguish hyperphosphatemia caused by

impaired renal phosphate excretion from that which results from

excessive delivery of phosphate into the ECF (Table 409-3).

In chronic renal insufficiency, reduced GFR leads to phosphate

retention. Hyperphosphatemia in turn further impairs renal synthesis

of 1,25(OH)2

D, increases FGF23 levels, and stimulates PTH secretion

and parathyroid gland hypertrophy both directly and indirectly (by

lowering blood ionized calcium levels). Thus, hyperphosphatemia is

a major cause of the secondary hyperparathyroidism of renal failure

and must be addressed early in the course of the disease (Chaps. 311

and 410).

Hypoparathyroidism leads to hyperphosphatemia via increased

expression of NaPi-2 co-transporters in the proximal tubule. Hypoparathyroidism, or parathyroid suppression, has multiple potential

causes, including autoimmune disease; developmental, surgical, or

radiation-induced absence of functional parathyroid tissue; vitamin D

intoxication or other causes of PTH-independent hypercalcemia; cellular PTH resistance (pseudohypoparathyroidism or hypomagnesemia);

infiltrative disorders such as Wilson’s disease and hemochromatosis;

and impaired PTH secretion caused by hypermagnesemia, severe

hypomagnesemia, or activating mutations in the CaSR. Hypocalcemia

may also contribute directly to impaired phosphate clearance, as calcium infusion can induce phosphaturia in hypoparathyroid subjects.

Increased tubular phosphate reabsorption also occurs in acromegaly,

during heparin administration, and in tumoral calcinosis. Tumoral

TABLE 409-2 Intravenous Therapy for Hypophosphatemia

CONSIDER

Likely severity of underlying phosphate depletion

Concurrent parenteral glucose administration

Presence of neuromuscular, cardiopulmonary, or hematologic complications of

hypophosphatemia

Renal function (reduce dose by 50% if serum creatinine >220 μmol/L [>2.5 mg/dL])

Serum calcium level (correct hypocalcemia first; reduce dose by 50% in

hypercalcemia)

Guidelines

SERUM PHOSPHORUS,

MM (MG/DL)

RATE OF

INFUSION,

MMOL/H DURATION, H

TOTAL

ADMINISTERED,

MMOL

<0.8 (<2.5) 2 6 12

<0.5 (<1.5) 4 6 24

<0.3 (<1) 8 6 48

Note: Rates shown are calculated for a 70-kg person; levels of serum calcium

and phosphorus must be measured every 6–12 h during therapy; infusions can

be repeated to achieve stable serum phosphorus levels >0.8 mmol/L (>2.5 mg/dL);

most formulations available in the United States provide 3 mmol/mL of sodium or

potassium phosphate.

TABLE 409-3 Causes of Hyperphosphatemia

I. Impaired renal phosphate excretion

A. Renal insufficiency

B. Hypoparathyroidism

1. Developmental

2. Autoimmune

3. After neck surgery or radiation

4. Activating mutations of the calcium-sensing receptor

C. Parathyroid suppression

1. Parathyroid-independent hypercalcemia

a. Vitamin D or vitamin A intoxication

b. Sarcoidosis, other granulomatous diseases

c. Immobilization, osteolytic metastases

d. Milk-alkali syndrome

2. Severe hypermagnesemia or hypomagnesemia

D. Pseudohypoparathyroidism

E. Acromegaly

F. Tumoral calcinosis

G. Heparin therapy

II. Massive extracellular fluid phosphate loads

A. Rapid administration of exogenous phosphate (intravenous, oral, rectal)

B. Extensive cellular injury or necrosis

1. Crush injuries

2. Rhabdomyolysis

3. Hyperthermia

4. Fulminant hepatitis

5. Cytotoxic therapy

6. Severe hemolytic anemia

C. Transcellular phosphate shifts

1. Metabolic acidosis

2. Respiratory acidosis