3186 PART 12 Endocrinology and Metabolism

(based on U.S. and Danish estimates). Symptoms of untreated hypocalcemia are shared by both types of hypoparathyroidism, although

the onset of hereditary hypoparathyroidism can be more gradual and

associated with other developmental defects. Basal ganglia calcification

and extrapyramidal syndromes are more common and earlier in onset

in hereditary hypoparathyroidism. Acquired hypoparathyroidism secondary to surgery in the neck is more common than hereditary hypoparathyroidism, but the frequency of surgically induced parathyroid

failure has diminished as a result of improved surgical techniques that

spare the parathyroid glands and increased use of nonsurgical therapy

for hyperthyroidism. PHP, an example of resistance to PTH action

rather than a failure of parathyroid gland production, may share several

features with hypoparathyroidism, including extraosseous calcification

and extrapyramidal manifestations such as choreoathetotic movements

and dystonia.

Papilledema, raised intracranial pressure, and lenticular cataracts

may occur in both hereditary and acquired hypoparathyroidism, as

do chronic changes in fingernails and hair, the latter usually reversible with treatment of hypocalcemia. Certain skin manifestations,

including alopecia and candidiasis, are characteristic of hereditary

hypoparathyroidism associated with autoimmune polyglandular failure (Chap. 388).

Hypocalcemia associated with hypomagnesemia is associated with

both deficient PTH release and impaired responsiveness to the hormone. Patients with hypocalcemia secondary to hypomagnesemia

have low levels of circulating PTH, indicative of diminished hormone

release despite a maximum physiologic stimulus by hypocalcemia.

Hypoparathyroidism can be due to hereditary or acquired causes or

acute but reversible gland dysfunction (hypomagnesemia).

GENETIC CAUSES Hereditary hypoparathyroidism can occur as an

isolated entity without other endocrine or dermatologic manifestations

or in association with other abnormalities (Chap. 388).

Hypoparathyroidism Associated with Other Abnormalities Hypoparathyroidism

associated with defective development of both the thymus and the

parathyroid glands is termed DiGeorge syndrome, or the velocardiofacial syndrome. Congenital cardiovascular, facial, and other developmental defects are present, and patients may die in early childhood

with severe infections, hypocalcemia and seizures, or cardiovascular

complications. Patients can survive into adulthood, and milder, incomplete forms may become manifest in childhood or adolescence. Most

cases are sporadic, but autosomal dominant forms involving microdeletions of chromosome 22q11.2 or point mutations in the transcription

factor TBX1 in that chromosomal region exist. Another autosomal

dominant developmental defect with hypoparathyroidism, deafness,

and renal dysplasia (HDR) is caused by mutations in the transcription

factor GATA3 (chromosome 10p14), which is important in embryonic

development and is expressed in developing kidney, ear structures, and

the parathyroids. Autosomal recessive disorders comprising hypoparathyroidism include Kenney-Caffey syndrome type 1, which also features

short stature, osteosclerosis, and thick cortical bones, and the related

Sanjad-Sakati syndrome, which also exhibits growth failure and other

dysmorphic features. Both syndromes involve mutations in a chaperone protein called TBCE (chromosome 1q42-q43), which is relevant

to tubulin function. FAM111A defects (chromosome 11q12.1) were

identified as the cause of Kenney-Caffey syndrome type 2.

Hypoparathyroidism that can occur in association with a complex

hereditary autoimmune syndrome involving failure of the adrenals,

the ovaries, the immune system, and the parathyroids in association

with recurrent mucocutaneous candidiasis, alopecia, vitiligo, and pernicious anemia is commonly referred to as polyglandular autoimmune

type 1 deficiency (Chap. 388). This disorder is caused by mutations in

the AIRE gene (chromosome 21q22.3). A stop codon mutation occurs

in many Finnish families with the disorder, while another mutation

(Y85C) is typically observed in Jews of Iraqi and Iranian descent.

Hypoparathyroidism is also seen in two disorders associated with

mitochondrial dysfunction and myopathy, one termed Kearns-Sayre

syndrome (KSS), with ophthalmoplegia and pigmentary retinopathy,

and the other termed MELAS syndrome (mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes). Mutations or deletions in

mitochondrial genes have been identified.

Isolated Hypoparathyroidism Several forms of hypoparathyroidism, each

rare in frequency, are seen as isolated defects; the genetic mechanisms

are varied. The inheritance includes autosomal dominant, autosomal

recessive, and X-linked modes.

PTH Mutations Three separate autosomal defects involving the prepro

sequence of PTH have been recognized. The dominant forms are

caused by point mutations in a critical region involved in intracellular transport of the hormone precursor. For example, an Arg for Cys

mutation interferes with processing of the precursor and is believed

to trigger an apoptotic cellular response, hence acting as a dominant

negative. The two recessive forms require both PTH alleles encoding

the prepro sequence to be mutated. Only one homozygous mutation

affecting the secreted PTH (Arg25>Cys25) has been described thus far

that leads to an autosomal recessive form of hypoparathyroidism. The

defect for an X-linked recessive form of hypoparathyroidism has been

localized to chromosome Xq26-q27, perhaps involving the SOX3 gene.

CaSR Mutations Abnormalities in the CaSR are detected in three distinctive hypocalcemic disorders. All are rare, but several different gain-offunction mutations have been found in one form of hypocalcemia

termed autosomal dominant hypocalcemic hypercalciuria (ADHH). The

receptor senses the ambient calcium level as excessive and suppresses

PTH secretion, leading to hypocalcemia. The hypocalcemia is aggravated by constitutive receptor activity in the renal tubule causing excretion of inappropriate amounts of calcium. Recognition of the syndrome

is important because efforts to treat the hypocalcemia with vitamin D

analogues and increased oral calcium exacerbate the already excessive

urinary calcium excretion (several grams or more per 24 h), leading to

irreversible renal damage from stones and ectopic calcification.

Other Causes of Isolated Hypoparathyroidism These include homozygous, inactivating mutations in the parathyroid-specific transcription factor

GCM2 or heterozygous point mutations in this protein, which have

a dominant-negative effect on the wild-type protein and thus lead to

an autosomal dominant form of hypoparathyroidism. Furthermore,

heterozygous mutations in Gα11, one of the two signaling proteins

downstream of the CaSR, have been identified as a cause of autosomal

dominant hypoparathyroidism. The Bartter syndrome is a group of

disorders associated with disturbances in electrolyte and acid-base

balance, sometimes with nephrocalcinosis and other features. Several

types of ion channels or transporters are involved. Curiously, Bartter

syndrome type V has electrolyte and pH disturbances but is caused

by a gain-of-function mutation in the CaSR. The defect may be more

TABLE 410-5 Functional Classification of Hypocalcemia (Excluding

Neonatal Conditions)

PTH Absent

Hereditary hypoparathyroidism Hypomagnesemia

Acquired hypoparathyroidism

PTH Ineffective

Chronic kidney disease Active vitamin D ineffective

Active vitamin D lacking Intestinal malabsorption

↓ Dietary intake or sunlight Vitamin D–dependent rickets type II

Defective metabolism:

Anticonvulsant therapy Pseudohypoparathyroidism

Vitamin D–dependent rickets type I Mutant, less active PTH

PTH Overwhelmed

Severe, acute hyperphosphatemia Osteitis fibrosa after

parathyroidectomy Tumor lysis

Acute kidney injury

Rhabdomyolysis

Abbreviation: PTH, parathyroid hormone.

3187 Disorders of the Parathyroid Gland and Calcium Homeostasis CHAPTER 410

severe than in ADHH and explains the additional features seen beyond

hypocalcemia and hypercalciuria. As with autoimmune disorders that

block the CaSR (discussed above under hypercalcemic conditions),

there are autoantibodies that at least transiently activate the CaSR,

leading to suppressed PTH secretion and hypocalcemia.

ACQUIRED HYPOPARATHYROIDISM Acquired chronic hypoparathyroidism is usually the result of inadvertent surgical removal of all the

parathyroid glands; in some instances, not all the tissue is removed, but

the remainder undergoes vascular supply compromise secondary to

fibrotic changes in the neck after surgery. In the past, the most frequent

cause of acquired hypoparathyroidism was surgery for hyperthyroidism. Hypoparathyroidism now usually occurs after surgery for hyperparathyroidism when the surgeon, facing the dilemma of removing too

little tissue and thus not curing the hyperparathyroidism, removes too

much. Parathyroid function may not be totally absent in all patients

with postoperative hypoparathyroidism.

Rare causes of acquired chronic hypoparathyroidism include radiation-induced damage subsequent to radioiodine therapy of hyperthyroidism and glandular damage in patients with hemochromatosis or

hemosiderosis after repeated blood transfusions. Infection may involve

one or more of the parathyroids but usually does not cause hypoparathyroidism because all four glands are rarely involved.

Transient hypoparathyroidism is frequent following surgery for

hyperparathyroidism. After a variable period of hypoparathyroidism,

normal parathyroid function may return due to hyperplasia or recovery of remaining tissue. Occasionally, recovery occurs months after

surgery.

TREATMENT

Acquired and Hereditary Hypoparathyroidism

Conventional treatment has involved replacement with vitamin

D and 1,25(OH)2

D (calcitriol) combined with a high oral calcium

intake. In most patients, blood calcium and phosphate levels are

maintained satisfactorily, but some patients show a tendency to

alternate between hypocalcemia and hypercalcemia, thus requiring

close monitoring of each patient. Compared to typical daily requirements in euparathyroid patients (200–1000 U/d), much higher

doses of vitamin D are needed for the treatment of hypoparathyroid patients (as much as 100-fold higher), which reflects the

reduced conversion of vitamin D to 1,25(OH)2

D. Thus, treatment

with 1,25(OH)2

D (0.5–1 μg/d of calcitriol) is frequently preferred,

particularly since calcitriol is cleared much more rapidly from the

circulation than vitamin D.

Oral calcium and vitamin D restore the overall calciumphosphate balance but do not reverse the lowered urinary calcium

reabsorption typical of hypoparathyroidism. Therefore, blood calcium levels should be maintained in these patients at the lower

end of the normal range in order to avoid excessive urinary calcium excretion; otherwise, nephrocalcinosis and kidney stones can

develop, and the risk of CKD is increased. Thiazide diuretics lower

urine calcium by as much as 100 mg/d in hypoparathyroid patients

on vitamin D, provided they are maintained on a low-sodium diet.

Use of thiazides seems to be of benefit in mitigating hypercalciuria

and easing the daily management of these patients.

Until recently, hypoparathyroidism has been the only endocrine

disorders not being treated with the missing hormone. After the

initial experimental use of PTH(1–34), the synthetic PTH fragment

used in treatment of osteoporosis, showed promise, full-length

PTH(1–84) has been shown to be effective and is now approved by

the U.S. Food and Drug Administration for therapy of hypoparathyroidism. Published reports illustrate its use substantially reduced

the requirements for supplemental calcium and active vitamin to

maintain serum calcium but did not prevent, throughout the day,

excessive urinary calcium losses.

HYPOMAGNESEMIA Severe hypomagnesemia (<0.4 mmol/L; <0.8 meq/L)

is associated with hypocalcemia (Chap. 409). Restoration of the

total-body magnesium deficit leads to rapid reversal of hypocalcemia.

There are at least two causes of the hypocalcemia—impaired PTH

secretion and reduced responsiveness to PTH. For further discussion

of causes and treatment of hypomagnesemia, see Chap. 409.

PTH levels are undetectable or inappropriately low in severe hypomagnesemia despite the stimulus of severe hypocalcemia, and acute

repletion of magnesium leads to a rapid increase in PTH level. Serum

phosphate levels are often not elevated, in contrast to the situation

with acquired or idiopathic hypoparathyroidism, probably because

phosphate deficiency is often seen in hypomagnesemia. In addition to

diminished PTH secretion, some patients with low calcium and magnesium levels show a blunted peripheral response to exogenous PTH

as documented by subnormal response in urinary phosphorus and

urinary cyclic AMP excretion.

TREATMENT

Hypomagnesemia

Repletion of magnesium cures the condition. Repletion should be

parenteral. Attention must be given to restoring the intracellular

deficit, which may be considerable. After IV magnesium administration, serum magnesium may return transiently to the normal

range, but unless replacement therapy is adequate, serum magnesium will again fall. If the cause of the hypomagnesemia is renal

magnesium wasting, magnesium may have to be given long-term

to prevent recurrence (Chap. 409).

PTH Ineffective PTH is ineffective when the PTHR1–signaling

protein complex is defective (as in the different forms of PHP, discussed below) or in CKD in which the calcium-elevating action of

PTH is impaired.

Typically, hypophosphatemia is more severe than hypocalcemia in

vitamin D deficiency states because the increased PTH levels, although

only partly effective in elevating blood calcium, are readily capable of

promoting urinary phosphate excretion.

PHP, on the other hand, has a pathophysiology that is different from

the other disorders of ineffective PTH action. PHP resembles hypoparathyroidism (in which PTH synthesis is deficient) and is manifested

by hypocalcemia and hyperphosphatemia yet elevated PTH levels. The

cause of the disorder is defective PTH-dependent activation of the

stimulatory G protein complex or the downstream effector protein

kinase A, resulting in failure of PTH to increase intracellular cyclic

AMP or to respond to elevated cyclic AMP levels (see below).

CKD Improved medical management of CKD allows many patients to

survive for decades and, hence, provides time enough to develop features of renal osteodystrophy, which must be controlled to avoid additional morbidity. Impaired production of 1,25(OH)2

D is a principal

factor that causes calcium deficiency, secondary hyperparathyroidism,

and bone disease; hyperphosphatemia, which lowers further blood calcium levels, typically occurs only in the later stages of the disease. Low

levels of 1,25(OH)2

D due to increased FGF23 production in bone (and

possibly other tissues) are critical in the development of hypocalcemia.

It is notable that FGF23 levels are often dramatically elevated in endstage kidney disease (ESKD). The uremic state also causes impairment

of intestinal absorption by mechanisms other than defects in vitamin

D metabolism. Nonetheless, treatment with supraphysiologic amounts

of vitamin D or calcitriol can correct impaired calcium absorption.

Increased FGF23 levels are seen already during the early CKD stages

and have been reported to correlate with kidney disease progression,

increased mortality, and left ventricular hypertrophy. Strategies involving different oral phosphate binders have therefore been pursued to

lower intestinal phosphate absorption early during the course of kidney

disease and to thereby lower FGF23 levels. However, these approaches

have been largely disappointing. Furthermore, there is concern as to

whether supplementation with activated vitamin D analogues increases

further the circulating FGF23 levels and their “off-target” effects in

CKD patients.

3188 PART 12 Endocrinology and Metabolism

TREATMENT

Chronic Kidney Disease

Therapy of CKD (Chap. 311) involves appropriate management of

patients prior to dialysis and adjustment of regimens once dialysis

is initiated. Attention should be paid to restriction of phosphate in

the diet; avoidance of aluminum-containing phosphate-binding

antacids; provision of an adequate calcium intake by mouth, usually 1–2 g/d; and supplementation with 0.25–1 μg/d calcitriol or

other activated forms of vitamin D. The aim of therapy is to restore

normal calcium balance to prevent osteomalacia and severe secondary hyperparathyroidism (it is usually recommended to maintain

PTH levels between 100 and 300 pg/mL) and, in light of evidence

of genetic changes and monoclonal outgrowths of parathyroid

glands in CKD patients, to prevent secondary hyperparathyroidism

from becoming autonomous hyperparathyroidism. Reduction of

hyperphosphatemia and restoration of normal intestinal calcium

absorption by calcitriol can improve blood calcium levels and

reduce the manifestations of secondary hyperparathyroidism. Since

adynamic bone disease can occur in association with low PTH levels, it is important to avoid excessive suppression of the parathyroid

glands while recognizing the beneficial effects of controlling the

secondary hyperparathyroidism. These patients should be closely

monitored with PTH assays that detect only the full-length or bioactive PTH(1–84) to ensure that inactive, inhibitory PTH fragments

are not measured. Use of oral phosphate-binding agents such as

sevelamer lower blood phosphate levels in ESKD, but their use in

earlier CKD stages does not seem to be beneficial in lowering blood

phosphate levels and to prevent the rise in FGF23.

VITAMIN D DEFICIENCY DUE TO INADEQUATE DIET AND/OR SUNLIGHT Vitamin D deficiency due to inadequate intake of dairy

products enriched with vitamin D, lack of vitamin supplementation,

and reduced sunlight exposure in the elderly, particularly during winter in northern latitudes, is more common in the United States than

previously recognized. Biopsies of bone in elderly patients with hip

fracture (documenting osteomalacia) and abnormal levels of vitamin

D metabolites, PTH, calcium, and phosphate indicate that vitamin D

deficiency may occur in as many as 25% of elderly patients, particularly

in northern latitudes in the United States. Concentrations of 25(OH)

D are low or low-normal in these patients. Quantitative histomorphometric analysis of bone biopsy specimens from such individuals reveals

widened osteoid seams consistent with osteomalacia (Chap. 409). PTH

hypersecretion compensates for the tendency for the blood calcium

to fall but also increases renal phosphate excretion and thus causes

osteomalacia.

Treatment involves adequate replacement with vitamin D and calcium until the deficiencies are corrected. Severe hypocalcemia rarely

occurs in moderately severe vitamin D deficiency of the elderly, but

vitamin D deficiency must be considered in the differential diagnosis

of mild hypocalcemia.

Mild hypocalcemia, secondary hyperparathyroidism, severe hypophosphatemia, and a variety of nutritional deficiencies occur with gastrointestinal diseases. Hepatocellular dysfunction can lead to reduction

in 25(OH)D levels, as in portal or biliary cirrhosis of the liver, and

malabsorption of vitamin D and its metabolites, including 1,25(OH)2

D,

may occur in a variety of bowel diseases, hereditary or acquired.

Hypocalcemia itself can lead to steatorrhea, due to deficient production of pancreatic enzymes and bile salts. Depending on the disorder,

vitamin D or its metabolites can be given parenterally, guaranteeing

adequate blood levels of active metabolites.

DEFECTIVE VITAMIN D METABOLISM • Anticonvulsant Therapy Anticonvulsant therapy with any of several agents induces acquired vitamin

D deficiency by increasing the conversion of vitamin D to inactive

compounds and/or causing resistance to its action. The more marginal

the vitamin D intake in the diet, the more likely that anticonvulsant

therapy will lead to abnormal mineral and bone metabolism.

Vitamin D–Dependent Rickets Type I Vitamin D–dependent rickets type I,

previously termed pseudo-vitamin D–resistant rickets, is caused by

homozygous or compound heterozygous mutations in the gene encoding 25(OH)D-1α-hydroxylase. It differs from true vitamin D–resistant

rickets (vitamin D–dependent rickets type II, see below) in that it is

typically less severe and the biochemical and radiographic abnormalities can be readily reversed with physiologic doses of the vitamin’s

active metabolite, 1,25(OH)2

D (Chap. 409). Clinical features include

hypocalcemia, often with tetany or convulsions; hypophosphatemia

due to secondary hyperparathyroidism; and thus, osteomalacia and

increased levels of alkaline phosphatase.

Vitamin D–Dependent Rickets Type II Vitamin D–dependent rickets type II

results from end-organ resistance to the active metabolite 1,25(OH)2

D.

The clinical features resemble those of the type I disorder and

include hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and rickets but also partial or total alopecia. Plasma levels

of 1,25(OH)2

D are elevated, in keeping with the refractoriness of the

end-organs. This disorder is caused by homozygous or compound

heterozygous mutations in the gene encoding the vitamin D receptor;

treatment requires regular, usually nocturnal calcium infusions, which

normalize PTH levels, thus reducing urinary phosphate excretion and

thereby improving rickets and thus growth, but do not restore hair

growth (Chap. 409).

PSEUDOHYPOPARATHYROIDISM PHP refers to a group of distinct

inherited disorders. Patients affected by PHP type Ia (PHP1A) develop

symptoms and signs of hypocalcemia in association with distinctive

skeletal and developmental defects, referred to as Albright’s hereditary

osteodystrophy (AHO). The hypocalcemia is due to a deficient PTH

response in the proximal renal tubules, probably leading to insufficient

1,25(OH)2

D production and thus impaired intestinal calcium absorption. Furthermore, PTH resistance in this portion of the kidney impairs

urinary phosphate excretion, thus leading to elevated serum phosphate

levels. Patients affected by PHP type Ib (PHP1B) also present with

hypocalcemia and hyperphosphatemia but less frequently with obvious AHO features. In response to the hypocalcemia observed in either

disorder, PTH levels increase, leading to parathyroid hyperplasia and,

in some cases, to autonomous PTH secretion. Studies, both clinical

and basic, have clarified some aspects of these disorders, including the

variable clinical spectrum, the pathophysiology, the genetic defects,

and their mode of inheritance.

A working classification of the various PHP forms is given in Table

410-6. The classification scheme is based on the signs of ineffective

PTH action (low calcium and high phosphate), low or normal urinary

cyclic AMP response to exogenous PTH, the presence or absence of

AHO, and assays to measure the concentration of the Gs

α subunit of

the adenylate cyclase enzyme. Using these criteria, there are four types:

PHP types Ia and Ib (PHP1A and PHP1B); pseudopseudohypoparathyroidism (PPHP), and PHP type II (PHP2). Another classification

has been proposed recently, which is being debated.

PHP1A and PHP1B Individuals with PHP type I (PHP1), the most common of the disorders, show deficient urinary cyclic AMP excretion in

response to administration of exogenous PTH. Patients with PHP1 are

divided into PHP1A and PHP1B. Patients with PHP1A show evidence

for AHO and reduced amounts of Gs

α protein/activity, as determined

in readily accessible tissues such as erythrocytes, lymphocytes, or

fibroblasts. Only some PHP1B patients show typically AHO features,

but they usually have normal Gs

α activity. PHP1C, sometimes listed

as a third form of PHP1, is really a variant of PHP1A, although the

mutant Gs

α shows normal activity in certain in vitro assays.

Most patients who have PHP1A reveal characteristic features of

AHO, which consist of short stature, early-onset obesity, round face,

obesity, skeletal anomalies (brachydactyly), intellectual impairment,

and/or heterotopic calcifications. Patients have low calcium and high

phosphate levels, as with true hypoparathyroidism. PTH levels, however, are elevated, reflecting resistance to hormone action. In addition,

hormonal resistance is observed at other Gs

α-coupled receptors, particularly at the TSH receptor, leading to elevated levels of this hormone.

3189 Disorders of the Parathyroid Gland and Calcium Homeostasis CHAPTER 410

Amorphous deposits of calcium and phosphate are found in the

basal ganglia. The typical shortening of metacarpal and metatarsal

bones is caused by premature closing of the epiphyses and is probably

a particularly sensitive sign of overall advanced skeletal maturation

resulting in adult short stature.

INHERITANCE AND GENETIC DEFECTS Multiple defects at the GNAS

locus have now been identified in PHP1A, PHP1B, and PPHP patients.

This gene, which is located on chromosome 20q13.3, encodes the

α-subunit of the stimulatory G protein (Gs

α), among other products

(see below). Mutations involving the GNAS exons encoding Gs

α, which

are the cause of PHP1A and PPHP, include abnormalities at splice

junctions, point mutations, insertions, and/or deletions that all result

in a Gs

α protein with defective function, resulting in a 50% reduction

of in vitro Gs

α activity in erythrocytes or other cells. While PHP1A is

caused by inactivating Gs

α mutations on the maternal allele, PPHP is

caused by the same or similar mutations on the paternal GNAS allele

(Fig. 410-7). The Gs

α transcript is biallelically expressed in most

tissues; however, expression from paternal allele is silenced through

as-of-yet-unknown mechanisms in some tissues, including proximal

renal tubules, thyroid, and pituitary. Consequently, inheritance of a

molecular defect involving the paternal exons encoding Gs

α has no

implications with regard to hormone function, while inactivating Gs

α

mutations involving the maternal GNAS allele lead to little or no Gs

α

protein in these tissues (Chap. 466). Thus, females affected by either

PHP1A or PPHP will have offspring with PHP1A, if these children

inherit the allele carrying the GNAS mutation; in contrast, if the

mutant allele is inherited from a male affected by either disorder, the

offspring will exhibit PPHP. However, patients affected by either disorder develop some but not all AHO features, making it likely that Gs

α

haploinsufficiency occurs during embryonic or postnatal development.

The complex mechanisms that control the GNAS gene contributed

particularly to challenges involved in unraveling the pathogenesis of

PHP1B. Analysis of families in which multiple members are affected

by PHP1B, as well as studies of the complex parent-specific methylation of four regions within the complex GNAS locus, revealed that the

autosomal dominant forms of PHP1B (AD-PHP1B) are caused either

by microdeletions, duplications, or inversions within or upstream of

the GNAS locus. These genetic mutations are associated with a loss of

DNA methylation at one or several loci on the maternal GNAS allele

(Table 410-6). These abnormalities in methylation silence maternal

Gs

α expression, thus leading in the proximal renal tubules—where Gs

α

appears to be expressed predominantly from the maternal allele—to

PTH resistance. While most cases of AD-PHP1B are by now resolved

at the molecular level, the genetic defect responsible for the sporadic

variant of PHP1B (sporPHP1B), the most frequent form of PHP1B,

remains to be defined, except for those sporPHP1B cases that are

caused by paternal uniparental isodisomy/heterodisomy of chromosome 20q (patUPD20q).

PHP1B patients, who rarely develop an AHO phenotype as severe

as in PHP1A, develop hypocalcemia and hyperphosphatemia caused

by PTH resistance and thus elevated PTH levels. The previously used

Ellsworth-Howard test to assess the presence or absence of hormone

resistance is used much less frequently, largely because of routinely

available sensitive PTH assays (Table 410-6). As for PHP1A, these

endocrine abnormalities become apparent only if disease-causing

mutations are inherited maternally. Bone responsiveness may be excessive rather than blunted in PHP1B (and in PHP1A) patients, based on

case reports that have emphasized an osteitis fibrosa–like pattern in

several PHP1B patients. Some patients present with PTH resistance in

the absence of AHO features and without GNAS methylation changes;

it remains unclear why this PHP variant readily resolves upon treatment with vitamin D supplements.

PHP2 refers to patients with hypocalcemia and hyperphosphatemia,

who have normal urinary cyclic AMP excretion, but an impaired urinary phosphaturic response to PTH. In one PHP2 variant, referred to as

acrodysostosis with hormonal resistance, patients have a heterozygous

TABLE 410-6 Classification of Pseudohypoparathyroidism (PHP) and Pseudopseudohypoparathyroidism (PPHP)

TYPE

HYPOCALCEMIA,

HYPERPHOSPHATEMIA

RESPONSE OF

URINARY CAMP TO

PTH SERUM PTH

GS

` SUBUNIT

DEFICIENCY AHO

RESISTANCE TO

HORMONES OTHER

THAN PTH

PHP1A Yes ↓ ↑ Yes Yes Yes

PPHP No Normal Normal Yes Yes No

PHP1B Yes ↓ ↑ No Yes (less frequently

and usually less

severe)

Yes (in some patients)

PHP2 Yes Normal ↑ No No No

Acrodysostosis due to

PRKAR1A mutations with

hormonal resistance

Yes Normal

(but ↓ phosphaturic

response)

↑ No Yes Yes

Abbreviations: ↓, decreased; ↑, increased; AHO, Albright’s hereditary osteodystrophy; cAMP, cyclic adenosine monophosphate; PTH, parathyroid hormone.

PTH

PHP-Ia

(+ AHO) Urinary

cyclic AMP/

phosphate

PTH

PPHP

(+ AHO)

FIGURE 410-7 Paternal imprinting of renal parathyroid hormone (PTH) resistance

(GNAS gene for Gs

` subunit) in pseudohypoparathyroidism (PHP1A and PHP1B).

An impaired excretion of urinary cyclic AMP and phosphate is observed in patients

with PHP type I. In the renal cortex, there is selective silencing of paternal Gs

α

expression; consequently, mutations involving the maternal GNAS exons encoding

Gs

α or loss of methylation at GNAS exon A/B leads to reduced or completely absent

Gs

α protein in this portion of the kidney. The disease becomes manifest only in

patients who inherit the defective gene from an obligate female carrier (left). If a

genetic defect involving GNAS exons encoding Gs

α is inherited from an obligate

male carrier of the mutation (PHP1A or PPHP patient), no biochemical abnormality

is encountered, and the administration of PTH causes an appropriate increase in

the urinary cyclic AMP and phosphate concentration (pseudoPHP [PPHP]; right).

Both patterns of inheritance lead to some but not all features of Albright’s hereditary

osteodystrophy (AHO), most likely because of haploinsufficiency; for example,

Gs

α protein derived from both parental GNAS alleles must be active for normal

bone development. Maternal inheritance of a mutation (deletion, duplication, or

inversion within or upstream of the GNAS locus) causes AD-PHP1B, while paternal

inheritance does not lead to any detectable abnormality.

3190 PART 12 Endocrinology and Metabolism

defect in the regulatory subunit of PKA (PRKAR1A) that mediates

the response to PTH distal to cyclic AMP production. Acrodysostosis

without or with only mild hormonal resistance can be caused by heterozygous mutations in the cyclic AMP–selective phosphodiesterase 4D.

In patients with one variant of acrodysostosis that is associated with

hypertension, it was shown to be caused by heterozygous phosphodiesterase 3A mutations.

The diagnosis of these hormone-resistant states can usually be

made when there is a positive family history for signs and symptoms

of hypocalcemia with or without AHO features. In both categories—

PHP1A and PHP1B—serum PTH levels are elevated, particularly

when patients start to experience hypocalcemia during childhood.

However, patients with PHP1B or PHP2 without skeletal findings

present only with hypocalcemia and high PTH levels, as evidence for

hormone resistance. In PHP1A and PHP1B, the response of urinary

cyclic AMP to the administration of exogenous PTH is blunted. The

diagnosis of PHP2, in the absence of acrodysostosis, is more complex,

and vitamin D deficiency must be excluded before such a diagnosis can

be entertained.

TREATMENT

Pseudohypoparathyroidism

Treatment of PHP is similar to that of hypoparathyroidism, except

that calcium and activated vitamin D analogues are usually given

at higher doses to maintain blood calcium levels within the normal range and PTH levels in the upper end of normal or slightly

elevated. Patients with PHP1 show no PTH resistance in the distal

tubules—hence, urinary calcium clearance is typically reduced, and

these individuals are not at risk of developing nephrocalcinosis, as

are patients with hypoparathyroidism, unless overtreatment occurs,

for example, after the completion of pubertal development and

skeletal mutation, when calcium and 1,25(OH)2

D treatment should

be reduced. Variability in response makes it necessary to establish

the optimal regimen for each patient.

PTH Overwhelmed Occasionally, loss of calcium from the ECF is

so severe that PTH cannot compensate. Such situations include acute

pancreatitis and severe, acute hyperphosphatemia, often in association

with renal failure, conditions in which there is rapid efflux of calcium

from the ECF. Severe hypocalcemia can occur quickly; PTH rises in

response to hypocalcemia but does not return blood calcium to normal.

SEVERE, ACUTE HYPERPHOSPHATEMIA Severe hyperphosphatemia

is associated with extensive tissue damage or cell destruction (Chap.

409). The combination of increased release of phosphate from muscle

and impaired ability to excrete phosphorus because of renal failure

causes moderate to severe hyperphosphatemia, the latter causing

calcium loss from the blood and mild to moderate hypocalcemia.

Hypocalcemia is usually reversed with tissue repair and restoration of

renal function as phosphorus and creatinine values return to normal.

There may even be a mild hypercalcemic period in the oliguric phase of

renal function recovery. This sequence, severe hypocalcemia followed

by mild hypercalcemia, reflects widespread deposition of calcium in

muscle and subsequent redistribution of some of the calcium to the

ECF after phosphate levels return to normal.

Other causes of hyperphosphatemia include hypothermia, massive hepatic failure, and hematologic malignancies, either because of

high cell turnover of malignancy or because of cell destruction by

chemotherapy.

TREATMENT

Severe, Acute Hyperphosphatemia

Treatment is directed toward lowering of blood phosphate by the

administration of phosphate-binding antacids or dialysis. Although

calcium replacement may be necessary if hypocalcemia is severe

and symptomatic, calcium administration during the hyperphosphatemic period tends to increase extraosseous calcium deposition

and aggravate tissue damage. The levels of 1,25(OH)2

D may be low

during the hyperphosphatemic phase and return to normal during

the oliguric phase of recovery.

OSTEITIS FIBROSA AFTER PARATHYROIDECTOMY Severe hypocalcemia after parathyroid surgery is rare now that osteitis fibrosa cystica

is an infrequent manifestation of hyperparathyroidism. When osteitis

fibrosa cystica is severe, however, bone mineral deficits can be large.

After parathyroidectomy, hypocalcemia can persist for days if calcium replacement is inadequate. Treatment may require parenteral

administration of calcium; addition of calcitriol and oral calcium supplementation is sometimes needed for weeks to a month or two until

bone defects are filled (which, of course, is of therapeutic benefit in the

skeleton), making it possible to discontinue parenteral calcium and/or

reduce the amount.

Differential Diagnosis Care must be taken to ensure that true

hypocalcemia is present; in addition, acute transient hypocalcemia can

be a manifestation of a variety of severe, acute illnesses, as discussed

above. Chronic hypocalcemia, however, can usually be ascribed to a few

disorders associated with absent or ineffective PTH. Important clinical

criteria include the duration of the illness, signs or symptoms of associated disorders, and the presence of features that suggest a hereditary

abnormality. A nutritional history can be helpful in recognizing a low

intake of vitamin D and calcium in the elderly, and a history of excessive alcohol intake may suggest magnesium deficiency.

Hypoparathyroidism and PHP are typically lifelong illnesses, usually

(but not always) appearing by adolescence; hence, a recent onset of

hypocalcemia in an adult is more likely due to nutritional deficiencies,

CKD, or intestinal disorders that result in deficient or ineffective vitamin D. Neck surgery, even long past, however, can be associated with

a delayed onset of postoperative hypoparathyroidism. A history of

seizure disorder raises the issue of anticonvulsive medication. Developmental defects may point to the diagnosis of PHP1A. Rickets and

a variety of neuromuscular syndromes and deformities may indicate

ineffective vitamin D action, either due to defects in vitamin D metabolism or to vitamin D deficiency.

A pattern of low calcium with high phosphorus in the absence of

renal failure or massive tissue destruction almost invariably means

hypoparathyroidism or PHP. A low calcium and low phosphorus pattern points to absent or ineffective vitamin D, thereby impairing the

action of PTH on calcium metabolism (but not phosphate clearance).

The relative ineffectiveness of PTH in calcium homeostasis in vitamin D deficiency, anticonvulsant therapy, gastrointestinal disorders,

and hereditary defects in vitamin D metabolism leads to secondary

hyperparathyroidism as a compensation. The excess PTH on renal

tubule phosphate transport accounts for renal phosphate wasting and

hypophosphatemia.

■ FURTHER READING

Bastepe M, Jüppner H: Pseudohypoparathyroidism, Albright’s hereditary osteodystrophy, and progressive osseous heteroplasia: Disorders

caused by inactivating GNAS mutations, in Endocrinology, 6th ed,

in Endocrinology, JL Jameson, LJ DeGroot (eds). Philadelphia, W.B.

Saunders Company, 2016.

Bilezikian JP et al: Guidelines for the management of asymptomatic

primary hyperparathyroidism: Summary statement from the fourth

international workshop. J Clin Endocrinol Metab 99:3561, 2014.

Thakker RV et al: Genetic disorders of calcium homeostasis caused

by abnormal regulation of parathyroid hormone secretion or responsiveness, in Endocrinology, 6th ed, in Endocrinology, JL Jameson, LJ DeGroot (eds). Philadelphia, W.B. Saunders Company,

2016.

3191Osteoporosis CHAPTER 411

Osteoporosis, a condition characterized by decreased bone strength,

is prevalent among postmenopausal women but also occurs in both

women and men as a function of age and with underlying conditions

or major risk factors associated with loss of bone mass. Its chief clinical manifestations are vertebral and hip fractures, although fractures

can occur at almost any skeletal site. Osteoporosis affects >10 million

individuals in the United States, but only a proportion are diagnosed

and treated.

DEFINITION

Osteoporosis is defined as a reduction in the strength of bone that

leads to an increased risk of fractures. Loss of bone tissue causes

deterioration in skeletal microarchitecture, and thus, the process of

bone loss causes a greater detriment to bone strength than might be

appreciated from the simple measure of bone “density.” The World

Health Organization (WHO) operationally defined osteoporosis as a

bone density that falls 2.5 standard deviations (SDs) or more below the

mean for young healthy adults of the same sex and race—also referred

to as a T-score of –2.5. Postmenopausal women at the lower end of the

young normal range (a T-score <–1.0) are defined as having low bone

density and may be at increased risk of osteoporosis. Although fracture

risk is lower in this group, >50% of fractures among postmenopausal

women, including hip fractures, occur in those with low bone density

as the numerical size of that population is larger than the group with

bone density osteoporosis. As a consequence, clinical assessment has

evolved to include an estimate of the risk of fracture, incorporating

bone mineral density (BMD) with age, gender, and other clinical

risk factors to allow a calculated 10-year risk of hip or major osteoporosis-related fracture. This has evolved into a second definition of

osteoporosis with cut points for intervention that are variable across

different geographies.

Osteoporosis-related fractures are defined as fractures of any bone

in adults that occur in the setting of trauma less than or equal to a fall

from standing height, with the exceptions of fingers, toes, face, and

skull. However, in individuals thought to be at risk of osteoporosis, any

traumatic fracture must be regarded as possibly indicative of an underlying skeletal problem, raising consideration of further evaluation.

EPIDEMIOLOGY

In the United States, as many as 10.8 million women and 2.5 million

men have osteoporosis (BMD T-score <–2.5 at lumbar spine, total

hip, or femoral neck). This does not include additional people who

present with an osteoporosis-related fracture but with low bone mass

(T-score <–1 to –2.5). It is estimated that 2 million osteoporosis-related

fractures occur each year in the United States at a cost of $19 billion,

a problem that will increase as the population ages with an estimate

of 3 million fractures and $25 billion in costs by 2025. The failure to

identify the first fracture and intervene is estimated to cost $6 billion to

Medicare alone for secondary fractures. About 40 million individuals

have low bone mass (T-score <–1 to –2.5) that potentially puts them

at increased of fracture and of developing osteoporosis. Osteoporosis

is mostly age related, as bone tissue is lost progressively. In women,

the loss of ovarian function at menopause (typically around age 50)

precipitates rapid bone loss such that most women meet the diagnostic

criterion for osteoporosis by age 70–80. As the population ages, the

number of individuals with osteoporosis and fractures rises. As many

of the fractures defined as related to osteoporosis occur in individuals

with low bone mass, identification of those at high risk of facture and

their evaluation and treatment have become important issues in clinical management.

The epidemiology of fractures follows the trend for loss of bone

density, with most fractures, especially those of the hip and vertebrae,

411 Osteoporosis

Robert Lindsay, Blossom Samuels

showing exponential increases with advancing age (Fig. 411-1). Lifetime osteoporotic fracture risk for a Caucasian woman who reaches

the age of 50 is ~50%, and corresponding risk for a 50-year-old man

is ~25%. Recent data suggest that fractures are increasing despite the

availability of effective medications. This may be related to the failure

to evaluate patients who fall into a high-risk group for underlying skeletal problems leading to fractures.

About 300,000 hip fractures occur each year in the United States,

almost all requiring hospital admission and emergency surgical intervention. The lifetime probability that a 50-year-old white individual

will have a hip fracture is 14% for women and 5% for men; the risk for

African Americans is about half of those rates, and the risk for Asians

and nonblack Hispanics appears similar to that for Caucasians. Surgical intervention for hip fractures is associated with a high incidence

of mortality and morbidity, with 20–25% of patients dying in the year

following the injury with higher mortality rates among males and

African Americans. About 30% of survivors require long-term care (at

least temporarily), and many never regaining the independence that

they had prior to the fracture.

There are ~500,000 symptomatic vertebral fractures per year in

the United States, but >1,000,000 vertebral fractures may actually

occur yearly since only about one-third are recognized clinically at the

time of the event. Many of these initially “silent” vertebral fractures

are identified incidentally during radiography for other purposes

(Fig. 411-2). Even when asymptomatic, these vertebral fractures are

a major sign of skeletal fragility and may carry the same predictive

value for subsequent fracture. Vertebral fractures rarely require hospitalization but are associated with long-term morbidity and an increase

in mortality. The occurrence of the first fracture increases the risk of

further fractures, especially in the first year after clinically evident fractures. The consequence is height loss (often of several inches), kyphosis, and secondary pain and discomfort related to altered biomechanics

of the back. Thoracic fractures can be associated with restrictive lung

disease, whereas lumbar fractures are associated with abdominal symptoms that include distention, early satiety, and constipation.

Approximately 400,000 wrist fractures occur in the United States

each year. Fractures of other bones (including ~150,000 pelvic fractures and >100,000 proximal humerus fractures) also occur with

osteoporosis. Although some fractures result from major trauma, the

threshold for fracture is reduced in osteoporotic bone (Fig. 411-3).

The occurrence of a traumatic fracture in someone at risk of osteoporosis in the skeleton necessitates evaluation for reduced bone mass

and, if appropriate, intervention to reduce future fracture risk. Fewer

than 10% of these patients are currently investigated for osteoporosis

within 6 months of a new fracture. In addition to reduced bone density

3000

Hip

Colles’

Vertebrae

2000

1000

35–39

Age group, year

Women

≥85

Incidence/100,000 person-year

FIGURE 411-1 Epidemiology of vertebral, hip, and Colles’ fractures with age.

(Reproduced with permission from C Cooper, LJ Melton 3rd: Epidemiology of

osteoporosis. Trends Endocrinol Metab 3:224, 1992.)

3192 PART 12 Endocrinology and Metabolism

with advancing age, there are a number of risk factors for fracture; the

common ones are summarized in Table 411-1. Prior fractures, a family

history of osteoporosis-related fractures (particularly hip fractures),

low body weight, cigarette consumption, and excessive alcohol consumption are all independent predictors of fracture. Chronic diseases

with inflammatory components that increase skeletal remodeling, such

as rheumatoid arthritis, increase the risk of osteoporosis, as do diseases

associated with malabsorption. Chronic diseases that increase the risk

of falling or frailty, including dementia, Parkinson’s disease, and multiple sclerosis, also increase fracture risk (Table 411-1). Many other risk

factors for osteoporosis have been described including air pollution,

triclosan, gastric bypass surgery, diabetes, cerebrovascular accidents,

dementia (including Alzheimer’s), the death of a spouse, and depression and its treatment, to name a few.

The increasing frailty with age is a potent risk factor for fracture, as

is sensory inattention (e.g., walking while looking at mobile phone).

In the United States and Europe, osteoporosis-related fractures are

more common among women than men, presumably due to a lower

peak bone mass as well as postmenopausal bone loss in women. However, this gender difference in bone density and age-related increase in

hip fractures is not as apparent in some other cultures, possibly due to

genetics, physical activity level, or diet.

Fractures are themselves risk factors for future fractures (Table 411-1).

Vertebral fractures increase the risk of other vertebral fractures as well

as fractures of the peripheral skeleton such as the hip and wrist. Wrist

fractures also increase the risk of vertebral and hip fractures. Among

individuals aged >50, any fracture except those of the fingers, toes, face,

and skull should be considered as potentially related to osteoporosis

regardless of the specific circumstances of the fracture. Osteoporotic

bone is more likely to fracture than is normal bone at any level of

trauma, and a fracture in a person aged >50 should trigger evaluation

for osteoporosis. This often does not occur since postfracture care is

fragmented. Recent attempts to coordinate care using a fracture liaison

health care provider to guide patients through the system and ensure

their evaluation and treatment for osteoporosis may improve care but

is more difficult to do in the open medical care systems in the United

States. In countries with single-payor systems, that approach does seem

to be effective, as is also the case in closed health care systems in the

United States.

The risk for future fracture after a first fracture is not linear. Highest

risk occurs within the first 2 years after the first fracture. A recent large

Medicare database study indicated that almost 20% of women will have

a second fracture within 2 years after the first. Risk diminishes to less

than half of that rate in the subsequent 3 years and declines to baseline

thereafter for most fracture types, although risk after a vertebral or hip

fracture may persist.

PATHOPHYSIOLOGY

■ BONE REMODELING

Osteoporosis results from bone loss due to age-related changes in bone

remodeling as well as extrinsic and intrinsic factors that exaggerate

this process. These changes may be superimposed on a low peak bone

mass. Consequently, understanding the bone remodeling process is

fundamental to understanding both the pathophysiology of osteoporosis (Chap. 409) and the effects of pharmacologic intervention.

During growth, the skeleton increases in size by linear growth and

by apposition of new bone tissue on the outer surfaces of the cortex

(Fig. 411-4). The latter process is called modeling, a process that also

allows the long bones to adapt in shape to the stresses placed on them.

Increased sex hormone production at puberty is required for skeletal

maturation, which reaches maximum mass and density in early adulthood. Recent data suggest that delayed puberty may be associated with

low bone mass that persists into adulthood. The sexual dimorphism in

skeletal size becomes obvious after puberty, although true bone density

remains similar between the sexes. Nutrition and lifestyle also play an

important role in growth, although genetic factors primarily determine

peak skeletal mass and density.

Numerous genes control skeletal growth, peak bone mass, and body

size, as well as skeletal structure and density. Heritability estimates of

50–80% for bone density and size have been derived on the basis of

twin studies. Though peak bone mass is often lower among individuals

with a family history of osteoporosis, association studies of candidate

genes (vitamin D receptors; type I collagen, estrogen receptors [ERs],

and interleukin 6 [IL-6]; and insulin-like growth factor I [IGF-I])

and bone mass, bone turnover, and fracture prevalence have been

inconsistent. Linkage studies suggest that a genetic locus on chromosome 11 is associated with high bone mass. Families with high bone

mass and without much apparent age-related bone loss have been

FIGURE 411-2 Lateral spine x-ray showing severe osteopenia and a severe wedgetype deformity (severe anterior compression).

Aging Menopause

Increased

 bone loss

Propensity

 to fall

Poor bone

 quality

Low peak

 bone mass

Other risk

 factors

Low bone

 density

Fractures

FIGURE 411-3 Factors leading to osteoporotic fractures.

TABLE 411-1 Risk Factors for Osteoporosis Fracture

NONMODIFIABLE POTENTIALLY MODIFIABLE

Personal history of fracture as an adult

History of fracture in first-degree

relative

Female gender

Advanced age

White race

Dementia

Current cigarette smoking

Estrogen deficiency

 Early menopause (<45 years) or

bilateral ovariectomy

 Prolonged premenstrual amenorrhea

(>1 year)

Poor nutrition especially low calcium

and vitamin D intake

Alcoholism

Impaired eyesight despite adequate

correction

Recurrent falls

Inadequate physical activity

Poor health/frailty

3193Osteoporosis CHAPTER 411

shown to have a point mutation in LRP5, a low-density lipoprotein

receptor–related protein. The role of this gene in the general population is not clear, although a nonfunctional mutation results in

osteoporosis-pseudoglioma syndrome, and LRP5 signaling appears to

be important in controlling bone formation. Genome-wide scans for

low bone mass suggest multiple genes are involved, many of which are

also implicated also in control of body size.

In adults, bone remodeling, not modeling, is the principal metabolic

skeletal process. Bone remodeling has two primary functions: (1) to

repair microdamage within the skeleton to maintain skeletal strength

and ensure the relative youth of the skeleton and (2) to supply calcium

when needed from the skeleton to maintain serum calcium. Remodeling may be activated by microdamage to bone as a result of excessive

or accumulated stress. Acute demands for calcium involve osteoclastmediated resorption as well as calcium transport by osteocytes. Chronic

demands for calcium can result in secondary hyperparathyroidism,

increased bone remodeling, and overall loss of bone tissue. Bone

remodeling occurs through well-coordinated activity of osteocytes,

osteoblasts, and osteoclasts. Osteocytes are the terminal-differentiated

cells derived from osteoblasts after incorporation into newly formed

bone tissue. Osteoblasts derive from mesenchymal cell lineage and

osteoclasts from monocyte/macrophage lineage. Remodeling sites are

discrete units with osteoclasts initiating the process by removal of bone

tissue and osteoblasts synthesizing new organic bone that becomes

gradually mineralized.

Bone remodeling also is regulated by multiple hormones, including

estrogens (in both genders), androgens, vitamin D, and parathyroid

hormone (PTH), as well as locally produced growth factors, such as

IGF-I, transforming growth factor β (TGF-β), PTH–related peptide

(PTHrP), interleukins (ILs), prostaglandins, and members of the

tumor necrosis factor (TNF) superfamily. These factors primarily modulate the rate at which new remodeling sites are activated, a process that

results initially in bone resorption by osteoclasts, followed by a period

of repair during which new bone tissue is synthesized by osteoblasts

(Chap. 409). The cytokine responsible for communication between the

osteoblasts, other marrow cells, and osteoclasts is receptor activator of

nuclear factor-κB (RANK) ligand (RANKL). RANKL, a member of the

TNF family, is secreted by osteocytes, osteoblasts, and certain cells of

the immune system. The osteoclast receptor for this protein is referred

to as RANK. Activation of RANK by RANKL is a final common

path in osteoclast development and activation. A humoral decoy for

RANKL, also secreted by osteoblasts, is referred to as osteoprotegerin

(Fig. 411-5). Modulation of osteoclast recruitment and activity appears

to be related to the interplay among these three factors. Additional

influences include nutrition (particularly calcium intake) and physical

activity level. RANKL production is in part regulated by the canonical

Wnt signaling pathway. Wnt activation through mechanical loading

or by hormonal or cytokine factors stimulates bone formation by

increasing formation and activity of osteoblasts and decreases RANKL

secretion, which inhibits production and activity of osteoclasts. Sclerostin, also an osteocyte protein, is a major inhibitor of Wnt activation and bone formation. Both the RANKL and Wnt pathways have

become major targets for pharmacologic treatment of osteoporosis (see

below).

In young adults, resorbed bone is replaced by an equal amount of

new bone tissue. Thus, the mass of the skeleton remains constant after

peak bone mass is achieved by the age of ~20 years. After age 30–45,

however, the resorption and formation processes become imbalanced,

and resorption exceeds formation. This imbalance may begin at different ages, varies at different skeletal sites, and becomes exaggerated

in women after menopause or any other cause of estrogen deficiency.

Excessive bone loss can be due to an increase in osteoclastic activity

and/or a decrease in osteoblastic activity. In addition, an increase in

remodeling activation frequency, and thus the number of remodeling

sites, can magnify the small imbalance seen at each remodeling unit.

Increased recruitment of bone remodeling sites produces a reversible

reduction in bone tissue but also can result in permanent loss of tissue and disrupted skeletal architecture, with the imbalance between

resorption and formation within each cycle. In trabecular bone, if

the osteoclasts penetrate trabeculae, they leave no template for new

bone formation to occur, and consequently, rapid bone loss ensues

and cancellous connectivity becomes impaired. A higher number

of remodeling sites increases the likelihood of this event. In cortical

bone, increased activation of remodeling creates more porous bone.

The effect of this increased porosity on cortical bone strength may be

modest if the overall diameter of the bone is not changed. However,

decreased apposition of new bone on the periosteal surface coupled

with increased endocortical resorption of bone decreases the biomechanical strength of long bones. Even a slight exaggeration in normal

bone loss increases the risk of osteoporosis-related fractures because

of the architectural changes that occur, and osteoporosis is largely

a disease of disordered skeletal architecture, although currently the

only clinical tool generally available (dual-energy x-ray absorptiometry [DXA]) measures mass (an estimate of the mineral in bone) not

architecture. Several tools are becoming available that may give more

BMU

Osteoclast

Osteoblasts

Osteoid

Preosteoclast

Preosteoblast

A

B

C

D

E

F

FIGURE 411-4 Mechanism of bone remodeling. The basic molecular unit (BMU)

moves along the trabecular surface at a rate of ~10 μm/d. The figure depicts

remodeling over ~120 days. A. Origination of BMU-lining cells contracts to expose

collagen and attract preosteoclasts. B. Osteoclasts fuse into multinucleated cells

that resorb a cavity. Mononuclear cells continue resorption, and preosteoblasts are

stimulated to proliferate. C. Osteoblasts align at bottom of cavity and start forming

osteoid (black). D. Osteoblasts continue formation and mineralization. Previous

osteoid starts to mineralize (horizontal lines). E. Osteoblasts begin to flatten. F.

Osteoblasts turn into lining cells; bone remodeling at initial surface (left of drawing)

is now complete, but BMU is still advancing (to the right). (Adapted with permission

from SM Ott, in JP Bilezikian, LG Raisz, GA Rodan: Principles of Bone Biology, vol.

18. San Diego, CA: Academic Press; 1996.)