3209Paget’s Disease and Other Dysplasias of Bone CHAPTER 412

of glucocorticoid-induced osteoporosis (GCIO). Glucocorticoids are

used widely in the treatment of a variety of disorders, including chronic

lung disorders, rheumatoid arthritis and other connective tissue

diseases, and inflammatory bowel disease, and after transplantation.

Osteoporosis and related fractures are serious side effects of chronic

glucocorticoid therapy. Because the effects of glucocorticoids on the

skeleton are often superimposed on the consequences of aging and

menopause, it is not surprising that women and the elderly are most

frequently affected. The skeletal response to steroids is remarkably

heterogeneous, however, and even young, growing individuals treated

with glucocorticoids can present with fractures.

The risk of fractures depends on the dose and duration of glucocorticoid therapy, although recent data suggest that there may be no

completely safe dose. Bone loss is more rapid during the early months

of treatment, and trabecular bone is affected more severely than cortical bone. As a result, fractures have been shown to increase within

3 months of steroid treatment. There is an increase in fracture risk in

both the axial skeleton and the appendicular skeleton, including risk of

hip fracture. Bone loss can occur with any route of steroid administration, including high-dose inhaled glucocorticoids and intra-articular

injections. Alternate-day delivery does not appear to ameliorate the

skeletal effects of glucocorticoids.

■ PATHOPHYSIOLOGY

Glucocorticoids increase bone loss by multiple mechanisms, including (1) inhibition of osteoblast function and an increase in osteoblast

apoptosis, resulting in impaired synthesis of new bone; (2) stimulation of bone resorption, probably as a secondary effect; (3) impairment of the absorption of calcium across the intestine, probably by

a vitamin D–independent effect; (4) increase of urinary calcium loss

and perhaps induction of some degree of secondary hyperparathyroidism; (5) reduction of adrenal androgens and suppression of ovarian

and testicular secretion of estrogens and androgens; and (6) induction

of glucocorticoid myopathy, which may exacerbate effects on skeletal

and calcium homeostasis as well as increase the risk of falls.

■ EVALUATION OF THE PATIENT

Because of the prevalence of GCIO, it is important to evaluate the status of the skeleton in all patients starting or already receiving long-term

glucocorticoid therapy. Modifiable risk factors should be identified,

including those for falls. Examination should include testing of height

and muscle strength. Laboratory evaluation should include an assessment of 24-h urinary calcium. All patients on long-term (>3 months)

glucocorticoids should have measurement of bone mass at both the

spine and the hip using DXA. If only one skeletal site can be measured,

it is best to assess the spine in individuals <60 years and the hip in

those >60 years.

■ PREVENTION

Bone loss caused by glucocorticoids can be prevented, and the risk

of fractures significantly reduced. Strategies must include using the

lowest dose of glucocorticoid for disease management. Topical and

inhaled routes of administration are preferred, where appropriate. Risk

factor reduction is important, including smoking cessation, limitation

of alcohol consumption, and participation in weight-bearing and resistance exercise, when appropriate. All patients should receive an adequate calcium and vitamin D intake from the diet or from supplements.

TREATMENT

Glucocorticoid-Induced Osteoporosis

Several bisphosphonates (alendronate, risedronate, and zoledronic

acid) have been demonstrated in large clinical trials to reduce the

risk of fractures in patients being treated with glucocorticoids and

are FDA approved for the treatment of GCIO. Teriparatide is also

approved for treatment of GCIO. In one trial comparing teriparatide to alendronate, BMD increases were much greater and vertebral fracture risk reduction far more substantial with teriparatide

compared to alendronate. A study of denosumab indicates greater

efficacy of denosumab compared with risedronate for treatment

of GCIO. The American College of Rheumatology has published

guidelines for the management of GCIO.

■ FURTHER READING

Black DM, Rosen CJ: Postmenopausal osteoporosis. N Engl J Med

374:2096, 2016.

Black DM et al: Atypical femur fracture risk versus fragility fracture

prevention with bisphosphonates. N Engl J Med 383:743, 2020.

Compston J: Glucocorticoid-induced osteoporosis: An update. Endocrine 61:7, 2018.

Cosman F et al: Spine fracture prevalence in a nationally representative sample of US women and men aged >/=40 years: results from

the National Health and Nutrition Examination Survey (NHANES)

2013–2014. Osteoporos Int 28:2319, 2017.

Cosman F et al: Treatment sequence matters: Anabolic and antiresorptive therapy for osteoporosis. J Bone Miner Res 32:198, 2017.

Khosla S, Hofbauer LC: Osteoporosis treatment: Recent developments and ongoing challenges. Lancet Diabetes Endocrinol 5:898,

2017.

Reid IR: A broader strategy for osteoporosis interventions. Nat Rev

Endocrinol 16:333, 2020.

Roux C, Briot K: Imminent fracture risk. Osteoporos Int 28:1765,

2017.

PAGET’S DISEASE OF BONE

Paget’s disease is a localized bone-remodeling disorder that affects

widespread, noncontiguous areas of the skeleton. The pathologic process is initiated by overactive osteoclastic bone resorption followed by

a compensatory increase in osteoblastic new bone formation, resulting

in a structurally disorganized mosaic of woven and lamellar bone.

Pagetic bone is expanded, less compact, and more vascular; thus, it is

more susceptible to deformities and fractures. Although most patients

are asymptomatic, symptoms resulting directly from bony involvement

(bone pain, secondary arthritis, fractures) or secondarily from the

expansion of bone causing compression of surrounding neural tissue

are not uncommon.

Epidemiology There is a marked geographic variation in the

frequency of Paget’s disease, with high prevalence in Western Europe

(Great Britain, France, and Germany, but not Switzerland or Scandinavia)

and among those who have immigrated to Australia, New Zealand,

South Africa, and North and South America. The disease is rare in

native populations of the Americas, Africa, Asia, and the Middle East;

when it does occur, the affected subjects usually have evidence of

European ancestry, supporting the migration theory. For unclear reasons,

the prevalence and severity of Paget’s disease are decreasing, and the

age of diagnosis is increasing.

The prevalence is greater in males and increases with age. Autopsy

series reveal Paget’s disease in ~3% of those over age 40. Prevalence of

positive skeletal radiographs in patients aged >55 years is 2.5% for men

and 1.6% for women. Elevated alkaline phosphatase (ALP) levels in

asymptomatic patients have an age-adjusted incidence of 12.7 and 7 per

100,000 person-years in men and women, respectively.

Etiology The etiology of Paget’s disease of bone remains unknown,

but evidence supports both genetic and viral etiologies. A positive

412 Paget’s Disease and Other

Dysplasias of Bone

Rajesh K. Jain, Tamara J. Vokes

3210 PART 12 Endocrinology and Metabolism

family history is found in 15–25% of patients and, when present, raises

the prevalence of the disease seven- to tenfold among first-degree

relatives.

A clear genetic basis has been established for several rare familial

bone disorders that clinically and radiographically resemble Paget’s

disease but have more severe presentation and earlier onset. A homozygous deletion of the TNFRSF11B gene, which encodes osteoprotegrin

(Fig. 412-1), causes juvenile Paget’s disease, also known as familial

idiopathic hyperphosphatasia, a disorder characterized by uncontrolled

osteoclastic differentiation and resorption. Familial patterns of disease

in several large kindred are consistent with an autosomal dominant

pattern of inheritance with variable penetrance. Familial expansile

osteolysis, expansile skeletal hyperphosphatasia, and early-onset Paget’s

disease are associated with mutations in the TNFRSF11A gene, which

encodes RANK (receptor activator of nuclear factor-κB), a member of

the tumor necrosis factor superfamily critical for osteoclast differentiation (Fig. 412-1). A mutation in profilin 1, a small actin protein that

acts as a tumor suppressor, also causes early-onset Paget’s disease with

a predisposition for the development of osteosarcoma. Finally, mutations in the gene for valosin-containing protein cause a rare syndrome

with autosomal dominant inheritance and variable penetrance known

as inclusion body myopathy with Paget’s disease and frontotemporal

dementia (IBMPFD). The role of genetic factors is less clear in the

more common form of late-onset Paget’s disease. The most common

mutations identified in familial and sporadic cases of Paget’s disease

have been in the SQSTM1 gene (sequestasome-1 or p62 protein) in

the C-terminal ubiquitin-binding domain. The other candidate genes

include CSF1 (1p13), which encodes macrophage colony-stimulating

factor (M-CSF), a cytokine that is required for osteoclast differentiation; RIN3 (14q32), which encodes a guanine exchange factor called

Rab and Ras interactor 3; OPTN (10p13), which is involved in regulating nuclear factor (NF)-κB; TNFRSF11A (18q21), which encodes

Mesenchymal cell

Collagen

osteocalcin Osteoclast

Osteoclast

precursor

Osteoblasts

Osteoblasts

IGF-1

IGF-2

OPG

M-CSF

IL-1, IL-6

c-fms

+

RANK L

RANK

FIGURE 412-1 Diagram illustrating factors that promote differentiation and

function of osteoclasts and osteoblasts and the role of the RANK pathway. Stromal

bone marrow (mesenchymal) cells and differentiated osteoblasts produce multiple

growth factors and cytokines, including macrophage colony-stimulating factor

(M-CSF), to modulate osteoclastogenesis. RANKL (receptor activator of nuclear

factor-κB [NF-κB] ligand) is produced by osteoblast progenitors and mature

osteoblasts and can bind to a soluble decoy receptor known as osteoprotegerin

(OPG) to inhibit RANKL action. Alternatively, a cell-cell interaction between

osteoblast and osteoclast progenitors allows RANKL to bind to its membranebound receptor, RANK, thereby stimulating osteoclast differentiation and function.

RANK binds intracellular proteins called tumor necrosis factor receptor–associated

factors (TRAFs) that mediate receptor signaling through transcription factors such

as NF-κB. M-CSF binds to its receptor, c-fms, which is the cellular homologue of

the fms oncogene. See text for the potential role of these pathways in disorders

of osteoclast function such as Paget’s disease and osteopetrosis. IGF, insulin-like

growth factor; IL, interleukin.

receptor activator of NF-κB (RANK), a receptor that is essential for

osteoclast differentiation; and TM7SF4, which encodes dendritic

cell–specific transmembrane protein (DC-STAMP), a molecule that

is essential for fusion of the osteoclast. The phenotypic variability in

patients with SQSTM1 mutations suggests that additional factors, such

as other genetic influences or viral infection, may influence clinical

expression of the disease.

Several lines of evidence suggest that a viral infection may contribute to the clinical manifestations of Paget’s disease, including (1) the

presence of cytoplasmic and nuclear inclusions resembling paramyxoviruses (measles and respiratory syncytial virus) in pagetic osteoclasts

and (2) viral mRNA in precursor and mature osteoclasts. The viral

etiology is further supported by conversion of osteoclast precursors

to pagetic-like osteoclasts by vectors containing the measles virus

nucleocapsid or matrix genes. The decline in the incidence of Paget’s

disease coincides with the widespread vaccination against measles, also

consistent with the potential role of virus in the development of the disease. However, the viral etiology has been questioned by the inability to

culture a live virus from pagetic bone and by failure to clone the fulllength viral genes from material obtained from patients with Paget’s

disease. Furthermore, patients with Paget’s disease do not have higher

antibody levels against paramyxoviruses or measles as compared to

controls, nor do antibody levels correlate with disease severity in those

with Paget’s disease.

Pathophysiology The principal abnormality in Paget’s disease is

the increased number and activity of osteoclasts. Pagetic osteoclasts

are large, increased 10- to 100-fold in number, and have a greater number of nuclei (as many as 100 compared to 3–5 nuclei in the normal

osteoclast). The overactive osteoclasts may create a sevenfold increase

in resorptive surfaces and an erosion rate of 9 μg/d (normal is 1 μg/d).

Several causes for the increased number and activity of pagetic osteoclasts have been identified: (1) osteoclastic precursors are hypersensitive to 1,25(OH)2

D3

; (2) osteoclasts are hyperresponsive to RANK

ligand (RANKL), the osteoclast stimulatory factor that mediates the

effects of most osteotropic factors on osteoclast formation; (3) marrow

stromal cells from pagetic lesions have increased RANKL expression;

(4) osteoclast precursor recruitment is increased by interleukin (IL) 6,

which is increased in the blood of patients with active Paget’s disease

and is overexpressed in pagetic osteoclasts; (5) expression of the protooncogene c-fos, which increases osteoclastic activity, is increased; and

(6) the antiapoptotic oncogene Bcl-2 in pagetic bone is overexpressed.

Numerous osteoblasts are recruited to active resorption sites and produce large amounts of new bone matrix. As a result, bone turnover is

high, and bone mass is normal or increased, not reduced, unless there

is concomitant deficiency of calcium and/or vitamin D.

The characteristic feature of Paget’s disease is increased bone resorption accompanied by accelerated bone formation. An initial osteolytic

phase involves prominent bone resorption and marked hypervascularization. Radiographically, this manifests as an advancing lytic wedge,

or “blade of grass” lesion. The second phase is a period of very active

bone formation and resorption that replaces normal lamellar bone

with haphazard (woven) bone. Fibrous connective tissue may replace

normal bone marrow. In the final sclerotic phase, bone resorption

declines progressively and leads to a hard, dense, less vascular pagetic

or mosaic bone, which represents the so-called burned-out phase of

Paget’s disease. All three phases may be present at the same time at

different skeletal sites.

Clinical Manifestations Diagnosis is often made in asymptomatic patients because they have elevated ALP levels on routine blood

chemistry testing or an abnormality on a skeletal radiograph obtained

for another indication. The skeletal sites most commonly involved

are the pelvis, vertebral bodies, skull, femur, and tibia. Familial cases

with an early presentation often have numerous active sites of skeletal

involvement.

The most common presenting symptom is pain, which may result

from increased bony vascularity, expanding lytic lesions, fractures,

bowing, or other deformities. Bowing of the femur or tibia causes

3211Paget’s Disease and Other Dysplasias of Bone CHAPTER 412

gait abnormalities and abnormal mechanical stresses with secondary

osteoarthritis of the hip or knee joints. Long bone bowing also causes

extremity pain by stretching the muscles attached to the bone softened

by the pagetic process. Back pain results from enlarged pagetic vertebrae, vertebral compression fractures, spinal stenosis, degenerative

changes of the joints, and altered body mechanics with kyphosis and

forward tilt of the upper back. Rarely, spinal cord compression may

result from bone enlargement or from the vascular steal syndrome.

Skull involvement may cause headaches, symmetric or asymmetric

enlargement of the parietal or frontal bones (frontal bossing), and

increased head size. Cranial expansion may narrow cranial foramens

and cause neurologic complications including hearing loss from

cochlear nerve damage from temporal bone involvement, cranial nerve

palsies, and softening of the base of the skull (platybasia) with the risk

of brainstem compression. Pagetic involvement of the facial bones may

cause facial deformity; loss of teeth and other dental conditions; and,

rarely, airway compression.

Fractures are serious complications of Paget’s disease and usually

occur in long bones at areas of active or advancing lytic lesions. Common fracture sites are the femoral shaft and subtrochanteric regions.

Neoplasms arising from pagetic bone are rare (<0.5%). The incidence

of sarcoma appears to be decreasing, possibly because of earlier, more

effective treatment with potent antiresorptive agents. The majority of

tumors are osteosarcomas, which usually present with new pain in a

long-standing pagetic lesion. Osteoclast-rich benign giant cell tumors

may arise in areas adjacent to pagetic bone, and they respond to glucocorticoid therapy.

Cardiovascular complications may occur in patients with involvement of large (15–35%) portions of the skeleton and a high degree of

disease activity (ALP four times above normal). The extensive arteriovenous shunting and marked increases in blood flow through the

vascular pagetic bone lead to a high-output state and cardiac enlargement. However, high-output heart failure is relatively rare and usually

develops in patients with concomitant cardiac pathology. In addition,

calcific aortic stenosis and diffuse vascular calcifications have been

associated with Paget’s disease.

Diagnosis The diagnosis may be suggested on clinical examination

by the presence of an enlarged skull with frontal bossing, bowing of an

extremity, or short stature with simian posturing. An extremity with an

area of warmth and tenderness to palpation may suggest an underlying

pagetic lesion. Other findings include bony deformity of the pelvis,

skull, spine, and extremities; arthritic involvement of the joints adjacent to lesions; and leg-length discrepancy resulting from deformities

of the long bones.

Paget’s disease is usually diagnosed from radiologic and biochemical abnormalities. Radiographic findings typical of Paget’s disease

include enlargement or expansion of an entire bone or area of a long

bone, cortical thickening, coarsening of trabecular markings, and

typical lytic and sclerotic changes. Skull radiographs (Fig. 412-2)

reveal regions of “cotton wool,” or osteoporosis circumscripta, thickening of diploic areas, and enlargement and sclerosis of a portion or

all of one or more skull bones. Vertebral cortical thickening of the

superior and inferior end plates creates a “picture frame” vertebra.

Diffuse radiodense enlargement of a vertebra is referred to as “ivory

vertebra.” Pelvic radiographs may demonstrate disruption or fusion of

the sacroiliac joints; porotic and radiodense lesions of the ilium with

whorls of coarse trabeculation; thickened and sclerotic iliopectineal

line (brim sign); and softening with protrusio acetabuli, with axial

migration of the hips and functional flexion contracture. Radiographs

of long bones reveal bowing deformity and typical pagetic changes of

cortical thickening and expansion and areas of lucency and sclerosis

(Fig. 412-3). Radionuclide 99mTc bone scans are less specific but are

more sensitive than standard radiographs for identifying sites of active

skeletal lesions. Although computed tomography (CT) and magnetic

resonance imaging (MRI) studies are not necessary in most cases,

CT may be useful for the assessment of possible fracture, and MRI

is necessary to assess the possibility of sarcoma, giant cell tumor, or

FIGURE 412-2 A 48-year-old woman with Paget’s disease of the skull. Left. Lateral radiograph showing areas of both bone resorption and sclerosis. Right. 99mTc

hydroxymethylene diphosphonate (HDP) bone scan with anterior, posterior, and lateral views of the skull showing diffuse isotope uptake by the frontal, parietal, occipital,

and petrous bones.

FIGURE 412-3 Radiograph of a 73-year-old man with Paget’s disease of the right

proximal femur. Note the coarsening of the trabecular pattern with marked cortical

thickening and narrowing of the joint space consistent with osteoarthritis secondary

to pagetic deformity of the right femur.

3212 PART 12 Endocrinology and Metabolism

metastatic disease in pagetic bone. Definitive diagnosis of malignancy

often requires bone biopsy.

Biochemical evaluation is useful in the diagnosis and management

of Paget’s disease. The marked increase in bone turnover can be monitored using biochemical markers of bone formation and resorption.

The parallel rise in markers of bone formation and resorption confirms

the coupling of bone formation and resorption in Paget’s disease. The

degree of bone marker elevation reflects the extent and severity of the

disease. For most patients, serum total ALP remains the test of choice

both for diagnosis and assessing response to therapy. Occasionally, a

symptomatic patient with evidence of progression at a single site may

have a normal total ALP level but increased bone-specific ALP. For

unclear reasons, serum osteocalcin, another marker of bone formation,

is not always elevated and is not recommended for use in diagnosis or

management of Paget’s disease. In contrast, bone formation marker

P1NP does reflect the activity of the disease and can be used instead

of total ALP. Bone resorption markers (serum or urine N-telopeptide

or C-telopeptide measured in the blood or urine) are also elevated in

active Paget’s disease and decrease more rapidly in response to therapy

than does ALP.

Serum calcium and phosphate levels are normal in Paget’s disease.

Immobilization of a patient with active Paget’s disease may rarely cause

hypercalcemia and hypercalciuria and increase the risk for nephrolithiasis. However, the discovery of hypercalcemia, even in the presence of

immobilization, should prompt a search for another cause of hypercalcemia. In contrast, hypocalcemia or mild secondary hyperparathyroidism may develop in Paget’s patients with very active bone formation

and insufficient calcium and vitamin D intake, particularly during

bisphosphonate therapy when bone resorption is rapidly suppressed

and active bone formation continues. Therefore, adequate calcium

and vitamin D intake should be instituted prior to administration of

bisphosphonates.

TREATMENT

Paget’s Disease of Bone

The development of effective and potent pharmacologic agents

(Table 412-1) has changed the treatment philosophy from treating

only symptomatic patients to treating asymptomatic patients who

are at risk for complications. According to the Endocrine Society

Clinical Practice Guidelines published in 2014, pharmacologic

therapy is indicated for most patients with active Paget’s disease

who are at risk of complications. Treatment may be initiated to

control symptoms caused by metabolically active Paget’s disease

such as bone pain, fracture, headache, pain from pagetic radiculopathy or arthropathy, or neurologic complications; to decrease local

blood flow and minimize operative blood loss in patients who need

surgery at an active pagetic site; to reduce hypercalciuria that may

occur during immobilization; and to decrease the risk of complications when disease activity is high (elevated ALP) and when the

site of involvement involves weight-bearing bones, areas adjacent to

TABLE 412-1 Pharmacologic Agents Approved for Treatment of

Paget’s Disease

NAME

DOSE AND MODE OF

DELIVERY

NORMALIZATION

OF ALKALINE

PHOSPHATASE (ALP)

Zoledronic acid 5 mg IV over 15 min 90% of patients at 6 mo

Pamidronate 30 mg/d IV over 4 h on

3 days

~50% of patients

Risedronate 30 mg/d PO for 2 mo 73% of patients

Alendronate 40 mg/d PO for 6 mo 63% of patients

Tiludronate 800 mg/d PO for 3 mo 35% of patients

Etidronate 200–400 mg/d PO × 6 mo 15% of patients

Calcitonin (Miacalcin) 100 U SC daily for 6–18 mo

(may reduce to 50 U 3×

per week)

(Reduction of ALP by

up to 50%)

major joints, vertebral bodies, and the skull. Whether or not early

therapy prevents late complications remains to be determined.

Randomized studies from the United Kingdom showed no difference in bone pain, fracture rates, quality of life, and hearing loss

between patients who received pharmacologic therapy to control

symptoms (bone pain) and those receiving bisphosphonates to

normalize serum ALP. However, the conclusions of these studies

are debatable since the majority of subjects had already received

bisphosphonate therapy in the past, perhaps limiting generalizability, and because the bone deformities that occur with Paget’s

disease may take many years to manifest. It seems likely that the

restoration of normal bone architecture following suppression of

pagetic activity will prevent further deformities and complications.

Agents approved for treatment of Paget’s disease suppress the

very high rates of bone resorption and secondarily decrease the

high rates of bone formation (Table 412-1). As a result of decreasing

bone turnover, pagetic structural patterns, including areas of poorly

mineralized woven bone, are replaced by more normal cancellous

or lamellar bone. Reduced bone turnover can be documented by a

decline in serum formation markers (ALP and P1NP) and urine or

serum resorption markers (N-telopeptide, C-telopeptide).

Bisphosphonates are the mainstay of pharmacologic therapy of

Paget’s disease. Among them, zoledronic acid is currently recommended as the first choice, particularly for those who have severe

disease or need rapid normalization of bone turnover (neurologic

symptoms, severe bone pain due to a lytic lesion, risk of an impending fracture, or pretreatment prior to elective surgery in an area of

active disease). Zoledronic acid normalized bone turnover faster

and in a high proportion of patients (>90%) than oral bisphosphonates with the therapeutic effect persisting for months or even

years. It is given at a dose of 5 mg as an intravenous infusion over

20 min, although slower rates of infusion are recommended for

elderly or those with mild impairment of renal function. More significant renal impairment (glomerular filtration rate <35 mL/min)

is a contraindication for use of zoledronic acid due to higher risk of

further deterioration of renal function. About 20–25% of patients

experience a flulike syndrome after the first infusion, which can be

partly ameliorated by pretreatment with acetaminophen or nonsteroidal anti-inflammatory drugs (NSAIDs). Oral bisphosphonates,

alendronate and risedronate, can be used in subjects who have mild

disease or some degree of renal impairment. Oral bisphosphonates

should be taken first thing in the morning on an empty stomach,

followed by maintenance of upright posture with no food, drink, or

other medications for 30–60 min. The first clinically useful agent,

etidronate, is no longer used due to its low potency and higher risk

of inducing osteomalacia. The efficacy of different agents, based

on their ability to normalize or decrease ALP levels, is summarized

in Table 412-1, although the response rates are not comparable

because they are obtained from different studies.

The subcutaneous injectable form of salmon calcitonin is

approved for the treatment of Paget’s disease but is rarely used due

to its low potency and should be reserved for patients who either

do not tolerate bisphosphonates or have a contraindication to their

use. For patients with contraindication to bisphosphonates, another

alternative is denosumab, an antibody to RANKL, which has been

reported to result in reduction in ALP. However, it has not been

approved for this indication and has less complete and less durable

effect than bisphosphonates.

SCLEROSING BONE DISORDERS

■ OSTEOPETROSIS

Osteopetrosis refers to a group of disorders caused by severe impairment of osteoclast-mediated bone resorption. Other terms that are

often used include marble bone disease, which captures the solid x-ray

appearance of the involved skeleton, and Albers-Schonberg disease,

which refers to the milder, adult form of osteopetrosis also known

as autosomal dominant osteopetrosis type II. The major types of

3213Paget’s Disease and Other Dysplasias of Bone CHAPTER 412

osteopetrosis include malignant (severe, infantile, autosomal recessive)

osteopetrosis and benign (adult, autosomal dominant) osteopetrosis

types I and II. A rare autosomal recessive intermediate form has a more

benign prognosis. Autosomal recessive carbonic anhydrase (CA) II

deficiency produces osteopetrosis of intermediate severity associated

with renal tubular acidosis and cerebral calcification.

Etiology and Genetics Naturally occurring and gene-knockout

animal models with phenotypes similar to those of the human disorders

have been used to explore the genetic basis of osteopetrosis. The primary defect in osteopetrosis is the loss of osteoclastic bone resorption

and preservation of normal osteoblastic bone formation. Osteoprotegerin (OPG) is a soluble decoy receptor that binds osteoblast-derived

RANK ligand, which mediates osteoclast differentiation and activation

(Fig. 412-1). Transgenic mice that overexpress OPG develop osteopetrosis, presumably by blocking RANK ligand. Mice deficient in RANK

lack osteoclasts and develop severe osteopetrosis.

Recessive mutations of CA II prevent osteoclasts from generating an

acid environment in the clear zone between its ruffled border and the

adjacent mineral surface. Absence of CA II, therefore, impairs osteoclastic bone resorption. Other forms of human disease have less clear

genetic defects. About one-half of the patients with malignant infantile

osteopetrosis have a mutation in the TCIRG1 gene encoding the osteoclast-specific subunit of the vacuolar proton pump, which mediates the

acidification of the interface between bone mineral and the osteoclast

ruffled border. Mutations in the CLCN7 chloride channel gene cause

autosomal dominant osteopetrosis type II.

Clinical Presentation The incidence of autosomal recessive severe

(malignant) osteopetrosis ranges from 1 in 200,000 to 1 in 500,000 live

births. As bone and cartilage fail to undergo modeling, paralysis of one

or more cranial nerves may occur due to narrowing of the cranial foramens. Failure of skeletal modeling also results in inadequate marrow

space, leading to extramedullary hematopoiesis with hypersplenism

and pancytopenia. Hypocalcemia due to lack of osteoclastic bone

resorption may occur in infants and young children. The untreated

infantile disease is fatal, often before age 5.

Adult (benign) osteopetrosis is an autosomal dominant disease

that is usually diagnosed by the discovery of typical skeletal changes

in young adults who undergo radiologic evaluation of a fracture.

The prevalence is 1 in 100,000 to 1 in 500,000 adults. The course is

not always benign, because fractures may be accompanied by loss of

vision, deafness, psychomotor delay, mandibular osteomyelitis, and

other complications usually associated with the juvenile form. In some

kindred, nonpenetrance results in skip generations, while in other families, severely affected children are born into families with benign disease. The milder form of the disease does not usually require treatment.

Radiography Typically, there are generalized symmetric increases

in bone mass with thickening of both cortical and trabecular bone.

Diaphyses and metaphyses are broadened, and alternating sclerotic and

lucent bands may be seen in the iliac crests, at the ends of long bones,

and in vertebral bodies. The cranium is usually thickened, particularly

at the base of the skull, and the paranasal and mastoid sinuses are

underpneumatized.

Laboratory Findings The only significant laboratory findings

are elevated serum levels of osteoclast-derived tartrate-resistant acid

phosphatase (TRAP) and the brain isoenzyme of creatine kinase.

Serum calcium may be low in severe disease, and parathyroid hormone

and 1,25-dihydroxyvitamin D levels may be elevated in response to

hypocalcemia.

TREATMENT

Osteopetrosis

Allogeneic human leukocyte antigen (HLA)–identical bone marrow transplantation has been successful in some children. Following transplantation, the marrow contains progenitor cells and

normally functioning osteoclasts. With long-term follow-up after

transplantation, radiographic improvements, such as improvements

in Erlenmeyer flask deformities, are seen, although there is not

complete normalization. A cure is most likely when children are

transplanted before age 4. Marrow transplantation from nonidentical HLA-matched donors has a much higher failure rate. Limited

studies in small numbers of patients have suggested variable benefits

following treatment with interferon γ-1β, 1,25-dihydroxyvitamin D

(which stimulates osteoclasts directly), methylprednisolone, and a

low-calcium/high-phosphate diet.

Surgical intervention is indicated to decompress optic or auditory nerve compression. Orthopedic management is required for

the surgical treatment of fractures and their complications, including malunion and postfracture deformity.

■ PYKNODYSOSTOSIS

This is an autosomal recessive form of osteosclerosis that is believed

to have affected the French impressionist painter Henri de ToulouseLautrec. The molecular basis involves mutations in the gene that

encodes cathepsin K, a lysosomal metalloproteinase highly expressed

in osteoclasts and important for bone-matrix degradation. Osteoclasts

are present but do not function normally. Pyknodysostosis is a form of

short-limb dwarfism that presents with frequent fractures but usually a

normal life span. Clinical features include short stature; kyphoscoliosis

and deformities of the chest; high arched palate; proptosis; blue sclerae;

dysmorphic features including small face and chin, fronto-occipital

prominence, pointed beaked nose, large cranium, and obtuse mandibular angle; and small, square hands with hypoplastic nails. Radiographs

demonstrate a generalized increase in bone density, but in contrast to

osteopetrosis, the long bones are normally shaped. Separated cranial

sutures, including the persistent patency of the anterior fontanel, are

characteristic of the disorder. There may also be hypoplasia of the

sinuses, mandible, distal clavicles, and terminal phalanges. Persistence

of deciduous teeth and sclerosis of the calvarium and base of the skull

are also common. Histologic evaluation shows normal cortical bone

architecture with decreased osteoblastic and osteoclastic activities.

Serum chemistries are normal, and unlike osteopetrosis, there is no

anemia. There is no known treatment for this condition, and there are

no reports of attempted bone marrow transplant.

■ PROGRESSIVE DIAPHYSEAL DYSPLASIA

Also known as Camurati-Engelmann disease, progressive diaphyseal

dysplasia is an autosomal dominant disorder that is characterized

radiographically by diaphyseal hyperostosis and a symmetric thickening

and increased diameter of the endosteal and periosteal surfaces of the

diaphyses of the long bones, particularly the femur and tibia, and, less

often, the fibula, radius, and ulna. The genetic defect responsible for the

disease has been localized to the area of chromosome 19q13.2 encoding

tumor growth factor (TGF)-β1. The mutation promotes activation of

TGF-β1. The clinical severity is variable. The most common presenting symptoms are pain and tenderness of the involved areas, fatigue,

muscle wasting, and gait disturbance. The weakness may be mistaken

for muscular dystrophy. Characteristic body habitus includes thin limbs

with little muscle mass yet prominent and palpable bones and, when

the skull is involved, large head with prominent forehead and proptosis.

Patients may also display signs of cranial nerve palsies, hydrocephalus,

central hypogonadism, and Raynaud’s phenomenon. Radiographically,

patchy progressive endosteal and periosteal new bone formation is

observed along the diaphyses of the long bones. Bone scintigraphy

shows increased radiotracer uptake in involved areas.

Treatment with low-dose glucocorticoids relieves bone pain and

may reverse the abnormal bone formation. Intermittent bisphosphonate therapy has produced clinical improvement in a limited number of patients. Disease activity may also attenuate as patients enter

adulthood.

■ HYPEROSTOSIS CORTICALIS GENERALISATA

This is also known as van Buchem’s disease; it is an autosomal recessive

disorder characterized by endosteal hyperostosis in which osteosclerosis involves the skull, mandible, clavicles, and ribs. The major

3214 PART 12 Endocrinology and Metabolism

manifestations are due to narrowed cranial foramens with neural

compressions that may result in optic atrophy, facial paralysis, and

deafness. Adults may have an enlarged mandible. Serum ALP levels

may be elevated, which reflect the uncoupled bone remodeling with

high osteoblastic formation rates and low osteoclastic resorption. As

a result, there is increased accumulation of normal bone. Endosteal

hyperostosis with syndactyly, known as sclerosteosis, is a more severe

form. The genetic defects for both sclerosteosis and van Buchem’s disease have been associated with mutations in the SOST gene.

■ MELORHEOSTOSIS

Melorheostosis (Greek, “flowing hyperostosis”) may occur sporadically

or follow a pattern consistent with an autosomal recessive disorder. The

major manifestation is progressive linear hyperostosis in one or more

bones of one limb, usually a lower extremity. The name comes from the

radiographic appearance of the involved bone, which resembles melted

wax that has dripped down a candle. Symptoms appear during childhood as pain or stiffness in the area of sclerotic bone. There may be

associated ectopic soft tissue masses, composed of cartilage or osseous

tissue, and skin changes overlying the involved bone, consisting of

scleroderma-like areas and hypertrichosis. The disease does not progress in adults, but pain and stiffness may persist. Laboratory tests are

unremarkable. Somatic mutations in MAP2K1, which increases MEK1

activity downstream of the RAS pathway, and SMAD3, which upregulates the TGF-β/SMAD pathway, have been identified in affected bone

in patients with melorheostosis. There is no specific treatment. Surgical

interventions to correct contractures are often unsuccessful.

■ OSTEOPOIKILOSIS

The literal translation of osteopoikilosis is “spotted bones”; it is a

benign autosomal dominant condition in which numerous small,

variably shaped (usually round or oval) foci of bony sclerosis are seen

in the epiphyses and adjacent metaphyses. The lesions may involve any

bone except the skull, ribs, and vertebrae. They may be misidentified

as metastatic lesions. The main differentiating points are that bony

lesions of osteopoikilosis are stable over time and do not accumulate

radionucleotide on bone scanning. In some kindred, osteopoikilosis is

associated with connective tissue nevi known as dermatofibrosis lenticularis disseminata, also known as Buschke-Ollendorff syndrome. Most

cases are caused by mutations in LEMD3, which is involved with bone

morphogenetic protein (BMP) signaling. Histologic inspection reveals

thickened but otherwise normal trabeculae and islands of normal cortical bone. No treatment is indicated.

■ HEPATITIS C–ASSOCIATED OSTEOSCLEROSIS

Hepatitis C–associated osteosclerosis (HCAO) is a rare acquired diffuse osteosclerosis in adults with prior hepatitis C infection. After a

latent period of several years, patients develop diffuse appendicular

bone pain and a generalized increase in bone mass with elevated serum

ALP. Bone biopsy and histomorphometry reveal increased rates of

bone formation, decreased bone resorption with a marked decrease in

osteoclasts, and dense lamellar bone. One patient had increased serum

OPG levels, and bone biopsy showed large numbers of osteoblasts

positive for OPG and reduced osteoclast number. Empirical therapy

includes pain control, and there may be beneficial response to bisphosphonate. Long-term antiviral therapy may reverse the bone disease.

DISORDERS ASSOCIATED WITH

DEFECTIVE MINERALIZATION

■ HYPOPHOSPHATASIA

This is a rare inherited disorder that presents as rickets in infants and

children or osteomalacia in adults with paradoxically low serum levels

of ALP. The frequency of the severe neonatal and infantile forms is

about 1 in 100,000 live births in Canada, where the disease is most

common because of its high prevalence among Mennonites and Hutterites. It is rare in African Americans. The severity of the disease is

remarkably variable, ranging from intrauterine death associated with

profound skeletal hypomineralization at one extreme to premature

tooth loss as the only manifestation in some adults. Severe cases are

inherited in an autosomal recessive manner, but the genetic patterns

are less clear for the milder forms. The disease is caused by a deficiency

of tissue nonspecific (bone/liver/kidney) ALP (TNSALP), which,

although ubiquitous, results only in bone abnormalities. Protein levels

and functions of the other ALP isozymes (germ cell, intestinal, placental) are normal. Defective ALP permits accumulation of its major

naturally occurring substrates including phosphoethanolamine (PEA),

inorganic pyrophosphate (PPi), and pyridoxal 5′-phosphate (PLP). The

accumulation of PPi interferes with mineralization through its action

as a potent inhibitor of hydroxyapatite crystal growth.

Perinatal hypophosphatasia becomes manifest during pregnancy

and is often complicated by polyhydramnios and intrauterine death.

The infantile form becomes clinically apparent before the age of

6 months with failure to thrive, rachitic deformities, functional craniosynostosis despite widely open fontanels (which are actually hypomineralized areas of the calvarium), raised intracranial pressure, and flail

chest with predisposition to pneumonia. Hypercalcemia and hypercalciuria are common. This form has a mortality rate of ~50%. Prognosis

seems to improve for the children who survive infancy. Childhood

hypophosphatasia has variable clinical presentation. Premature loss of

deciduous teeth (before age 5) is the hallmark of the disease. Rickets

causes delayed walking with waddling gait, short stature, and dolichocephalic skull with frontal bossing. The disease often improves during

puberty but may recur in adult life. Adult hypophosphatasia presents

during middle age with painful, poorly healing metatarsal stress fractures or thigh pain due to femoral pseudofractures. Presentation may

be subtle with muscle pain or recurring headaches as the predominant

symptoms. It is important to recognize hypophosphatasia in adults

because treatment with bisphosphonates can result in increased rather

than decreased bone fragility.

Laboratory investigation reveals low ALP levels and normal or

elevated levels of serum calcium and phosphorus despite clinical and

radiologic evidence of rickets or osteomalacia. Serum parathyroid

hormone, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D levels

are normal. The elevation of PLP is specific for the disease and may

even be present in asymptomatic parents of severely affected children.

Because vitamin B6

 increases PLP levels, vitamin B6

 supplements

should be discontinued 1 week before testing. Clinical testing is available to detect loss-of-function mutation(s) within the ALPL gene that

encodes TNSALP.

In contrast to other forms of rickets and osteomalacia, calcium and

vitamin D supplementation should be avoided because they may aggravate hypercalcemia and hypercalciuria. A low-calcium diet, glucocorticoids, and calcitonin have been used in a small number of patients

with variable responses. Because fracture healing is poor, placement of

intramedullary rods is best for acute fracture repair and for prophylactic prevention of fractures. In 2015, asfotase alfa, a tissue-nonspecific

ALP was approved as enzyme replacement therapy for the perinatal/

infantile- and juvenile-onset forms. With 7 years of therapy, children

with perinatal/infantile forms showed sustained improvements in

mineralization, along with improvements in other features, such as

respiratory function and growth.

■ AXIAL OSTEOMALACIA

This is a rare disorder characterized by defective skeletal mineralization

despite normal serum calcium and phosphate levels. Clinically, the disorder presents in middle-aged or elderly men with chronic axial skeletal

discomfort. Cervical spine pain may also be present. Radiographic findings are mainly osteosclerosis due to coarsened trabecular patterns typical of osteomalacia. Spine, pelvis, and ribs are most commonly affected.

Histologic changes show defective mineralization and flat, inactive

osteoblasts. The primary defect appears to be an acquired defect in

osteoblast function. The course is benign, and there is no established

treatment. Calcium and vitamin D therapies are not effective.

■ FIBROGENESIS IMPERFECTA OSSIUM

This is a rare condition of unknown etiology. It presents in both sexes;

in middle age or later; and with progressive, intractable skeletal pain

3215Paget’s Disease and Other Dysplasias of Bone CHAPTER 412

and fractures; worsening immobilization; and a debilitating course.

The only biochemical abnormality is elevated ALP. Radiographic

evaluation reveals generalized osteomalacia, osteopenia, and occasional pseudofractures. Histologic features include a tangled pattern

of collagen fibrils with abundant osteoblasts and osteoclasts. Use of

growth hormone led to substantial short-term clinical improvement

in two adult patients, but long-term outcomes are unknown. No other

effective treatment is known. Spontaneous remission has been reported

in a small number of patients.

FIBROUS DYSPLASIA AND MCCUNEALBRIGHT SYNDROME

Fibrous dysplasia is a sporadic disorder characterized by the presence

of one (monostotic) or more (polyostotic) expanding fibrous skeletal

lesions composed of bone-forming mesenchyme. The association of

the polyostotic form with café au lait spots and hyperfunction of an

endocrine system such as pseudoprecocious puberty of ovarian origin

is known as McCune-Albright syndrome (MAS). A spectrum of the

phenotypes is caused by activating mutations in the GNAS1 gene,

which encodes the α subunit of the stimulatory G protein (Gs

α). As the

postzygotic mutations occur at different stages of early development,

the extent and type of tissue affected are variable and explain the mosaic

pattern of skin and bone changes. GTP binding activates the Gs

α regulatory protein and mutations in regions of Gs

α that selectively inhibit

GTPase activity, which results in constitutive stimulation of the cyclic

AMP–protein kinase A signal transduction pathway. Such mutations

of the Gs

α protein–coupled receptor may cause autonomous function

in bone (parathyroid hormone receptor); skin (melanocyte-stimulating

hormone receptor); and various endocrine glands including ovary

(follicle-stimulating hormone receptor), thyroid (thyroid-stimulating

hormone receptor), adrenal (adrenocorticotropic hormone receptor),

and pituitary (growth hormone–releasing hormone receptor). The skeletal lesions are composed largely of mesenchymal cells that do not differentiate into osteoblasts, resulting in the formation of imperfect bone.

In some areas of bone, fibroblast-like cells develop features of osteoblasts

in that they produce extracellular matrix that organizes into woven bone.

Calcification may occur in some areas. In other areas, cells have features

of chondrocytes and produce cartilage-like extracellular matrix.

Clinical Presentation Fibrous dysplasia occurs with equal frequency in both sexes, whereas MAS with precocious puberty is more

common (10:1) in girls. The monostotic form is the most common and

is usually diagnosed in patients between 20 and 30 years of age without

associated skin lesions. The polyostotic form typically manifests in

children <10 years old and may progress with age. Early-onset disease

is generally more severe. Lesions may become quiescent in puberty

and progress during pregnancy or with estrogen therapy. In polyostotic

fibrous dysplasia, the lesions most commonly involve the maxilla and

other craniofacial bones, ribs, and metaphyseal or diaphyseal portions

of the proximal femur or tibia. Expanding bone lesions may cause pain,

deformity, fractures, and nerve entrapment. Sarcomatous degeneration

involving the facial bones or femur is infrequent (<1%). The risk of

malignant transformation is increased by radiation, which has proven

to be ineffective treatment. In rare patients with widespread lesions,

renal phosphate wasting and hypophosphatemia may cause rickets or

osteomalacia. Hypophosphatemia may be due to production of a phosphaturic factor by the abnormal fibrous tissue.

MAS patients may have café au lait spots, which are flat, hyperpigmented skin lesions that have rough borders (“coast of Maine”) in contrast to the café au lait lesions of neurofibromatosis that have smooth

borders (“coast of California”). The most common endocrinopathy is

isosexual pseudoprecocious puberty in girls. Other less common endocrine disorders include thyrotoxicosis, Cushing’s syndrome, acromegaly, hyperparathyroidism, hyperprolactinemia, and pseudoprecocious

puberty in boys.

Radiographic Findings In long bones, the fibrous dysplastic

lesions are typically well-defined, radiolucent areas with thin cortices and a ground-glass appearance. Lesions may be lobulated with

trabeculated areas of radiolucency (Fig. 412-4). Involvement of facial

bones usually presents as radiodense lesions, which may create a leonine appearance (leontiasis osea). Expansile cranial lesions may narrow

foramens and cause optic lesions, reduce hearing, and create other

manifestations of cranial nerve compression.

Laboratory Results Serum ALP is occasionally elevated, but calcium,

parathyroid hormone, 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D levels are normal. Patients with extensive polyostotic lesions

may have hypophosphatemia, hyperphosphaturia, and osteomalacia.

The hypophosphatemia and phosphaturia are directly related to the

levels of fibroblast growth factor 23 (FGF23). Biochemical markers of

bone turnover may be elevated.

TREATMENT

Fibrous Dysplasia and MAS

Spontaneous healing of the lesions does not occur, and there is

no established effective treatment. Improvement in bone pain and

partial or complete resolution of radiographic lesions have been

reported after IV bisphosphonate therapy. Denosumab given every

3 months is effective in reducing bone turnover markers and could

be a therapeutic option in difficult cases. Surgical stabilization is

used to prevent pathologic fracture or destruction of a major joint

space and to relieve nerve root or cranial nerve compression or

sinus obstruction.

OTHER DYSPLASIAS OF BONE

AND CARTILAGE

■ PACHYDERMOPERIOSTOSIS

Pachydermoperiostosis, or hypertrophic osteoarthropathy (primary

or idiopathic), is an autosomal dominant disorder characterized by

periosteal new bone formation that involves the distal extremities. The

lesions present as clubbing of the digits and hyperhidrosis and thickening of the skin, primarily of the face and forehead. The changes usually

appear during adolescence, progress over the next decade, and then

become quiescent. During the active phase, progressive enlargement

FIGURE 412-4 Radiograph of a 16-year-old male with fibrous dysplasia of the right

proximal femur. Note the multiple cystic lesions, including the large lucent lesion

in the proximal midshaft with scalloping of the interior surface. The femoral neck

contains two lucent cystic lesions.