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Chapter 72

L. Lyndon Key, Jr.* and William L. Ries
Department of Pediatrics, General Clinical Research Center, Medical University of South Carolina, Charleston, South Carolina

INTRODUCTION high rate of adverse events and to prepare a plan for each
patients needs (Burt et al., 1999).
Osteopetrosis results from a reduction in bone resorption An understanding of osteopetrosis in humans has been
relative to bone formation, leading to an accumulation intertwined with the description and creation of a vari-
of excessive amounts of bone. The relative decrease in ety of animal mutations in osteoclastic function (Seifert
resorption is a consequence of inadequate osteoclastic et al., 1993). Although the precise genetic defect in most
bone resorption. Karsdal et al. (2007) have demonstrated patients remains to be established (one exception being the
that osteoclasts, although unable to resorb bone owing to deficiency in carbonic anhydrase type II Fathallah et al.,
an inability to acidify the ruffled border, are still capable 1994; Whyte, 1993a), the animal models have contributed
of stimulating osteoblastic bone formation. del Fattore substantially to the understanding of osteoclastic function
et al. (2006) examined 49 patients with osteopetrosis. and dysfunction. The osteoclast biology learned from these
Bone formation was increased beyond a normal level. mutants has led to a variety of treatment strategies that
This suggested that a coupling factor was being produced, have been used in patients with osteopetrosis. An under-
increasing osteoblastic bone formation. Although a spe- standing of the genetic basis of the animal mutations has
cific coupling factor(s) has not been defined, Karsdal et al. generated a list of candidate genes that may prove to be the
proposed that IGF1, TGF-, BMP-2, IL-7, and IL-6 could basis for discovering the genetic defects in humans.
be factors that result in the excessive stimulation. These
imbalances lead to a thickening of the cortical region and
a decrease in the size of the medullary space in the long CLINICAL DESCRIPTION
bones, with sclerosis of the base of the skull (Elster et al.,
1992a,b) and vertebral bodies. There are a number of seri- Classically, osteopetrosis has been divided into a fatal
ous consequences resulting from the excessive accumula- infantile malignant form, AlbersSchnberg disease, and a
tion of bone. A reduced marrow space results in decrease milder adult form of osteopetrosis with long-term survival
in hematopoiesis, even to the point of complete bone (Grodum et al., 1995; Key, 1987; Shapiro, 1993; Whyte,
marrow failure. Extramedullary hematopoiesis occurs 1993b). Recently, a variety of intermediate forms have been
but is unable to compensate for the reduction in medul- described. Without knowledge of the genetic defect explain-
lary blood cell production. A decrease in the caliber of the ing the osteoclastic dysfunction, it has been difficult to
cranial nerve and vascular canals leads to nerve compres- delineate the mechanisms of these different forms (Table I).
sion and vascular compromise. Dense, poorly vascularized
bones are subject to fracture and, being vascularized, are
predisposed to necrosis and infection. An increased risk Severe
of morbidity and mortality during anesthesia is present in A variety of presentations of osteopetrosis have been seen
children with osteopetrosis. The increase risk in children in infancy. In general, patients have had sporadic forms
with osteopetrosis is primarily related to airway and respi- that appear to have an autosomal recessive inheritance.
ratory factors; however, anemia, hypocalcemia, and airway Although the severe, malignant form predominates, milder
reactivity have all been noted during anesthesia for surgical forms and autosomal dominant inheritance patterns have
procedures. Anesthesia management needs to consider the also been observed in individuals diagnosed in the neo-
natal period (Manusov et al., 1993; Whyte, 1993b). In the
*Corresponding author: L. Lyndon Key, Jr., Department of Pediatrics, absence of a known genetic defect in osteoclastic func-
General Clinical Research Center, Medical University of South Carolina, tion, histomorphometric and clinical parameters have been
Charleston, SC 29425 established to describe the degree of severity.

Principles of Bone Biology, 3rd Edition

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TABLE I Genetic Defects Identified in Human and Animal Osteopetrotic Syndromes

Genetic defects Animal Human disease Mechanism Function References

Severe TCIRG1 T-cell osteosclerosis severe infantile loss of encodes a3 Kornak et al.
immunoregulatory 1 mouse malignant function subunit of the (2001)
vacuolar ATPase,
proton pump
ClCN-7 chloride channel 7 ClCN-7/ infantile milder loss of encodes the Li et al.
mouse (mi/mi bone disease, but function chloride channel (1999)
mouse) Mitf neurodegeneration (ClC-7)
OSTM1 osteopetrosis- gray lethal severe infantile loss of possible protein Ramirez et al.
associated mouse malignant function degradation (2004)
transmembrane decreasing
protein 1 protein transport
Intermediate ClCN-7 chloride channel 7 (ADO)II loss of encodes the Waguespack
function chloride channel et al. (2003)
LRP5 low-density (ADO)I gain of putatively Van
lipoprotein receptor- function upregulates an Wesenbeeck
related protein 5 osteoblastic et al. (2003)
gene function
PLEKHM1 plekstrin homology incisor absent intermediate loss of trafficking acidic Van
domain-containing rat osteopetrosis function vesicles in Wesenbeeck
family M (with RUN osteoclasts et al. (2007)
domain) member 1
Mild CA II carbonic anyhydrase II mild osteopetrosis loss of proton Fathallah
with cerebral function production et al. (1994)
calcification and

Patients with osteopetrosis presenting at birth or in early A subgroup of patients has an extremely malignant
infancy are usually referred to as having the severe, malig- form of the disease. In a group of 33 patients reported
nant form. The implication is that these patients will have by Gerritsen et al., eight patients had hematological and
severe sequelae and will die during the first decade of life. visual impairment before 3 months of age (Gerritsen et al.,
This has been the justification for using treatment modalities, 1994a). All eight of these patients died before the age of
such as bone marrow transplantation, that carry a high risk 12 months. Hematological impairment before 6 months
of mortality and morbidity (Gerritsen et al., 1994b; Key and of life is prognostic of a markedly reduced survival rate;
Ries 1993; Schroeder et al., 1992). Patients with this form are however, visual impairment alone does not correlate with
characterized by a diffusely sclerotic skeleton with little or no an early fatal outcome.
bone marrow space evident, even at birth (Fig. 1) (Gerritsen Cytological evidence of large osteoclasts with increased
et al., 1994a). In addition, there is evidence of a severe defect numbers of nuclei and a markedly increased amount of ruf-
in bone resorption, leading to the presence of the bone-in- fled border membrane correlates with a poor prognosis for
bone appearance on radiographs (Fig. 2) and in cartilaginous cure with bone marrow transplantation (Schroeder et al.,
islands within mineralized bone on histology (Fig. 3). 1992; Shapiro et al., 1988). Although there is no exact
However, some patients with this phenotype will not explanation for the reduced success in cure by transplanta-
have a fatal outcome. Indeed, up to 30% of patients diag- tion, the defect in bone resorption in these patients could be
nosed with severe, malignant osteopetrosis are still alive at explained if the osteoclast itself were normal but some other
age 6 years, with rare patients surviving into the second or aspect of the bone rendered it less resorbable. Thus, histo-
third decade (Gerritsen et al., 1994a). Although the qual- logical and electron microscopic analysis of osteoclasts is
ity of life is reported to be poor, up to half of the surviv- recommended before a transplantation is undertaken.
ing patients, despite a variety of skeletal and neurological Another form of osteopetrosis that has not responded
impairments, have normal intelligence and are capable of to any therapeutic modality is associated with a neuro-
attending school (Charles and Key, 1998). degenerative disease (Whyte, 1993b). In some patients, a

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Chapter | 72 Osteopetrosis 1563

frequently demonstrate severe manifestation of diffuse scle-

rotic bone in this form of the disorder, quite similar to those
seen in the malignant form (Fig. 4). These patients tend to
have fractures toward the end of the first decade and fre-
quently have repetitive fractures with very minor trauma.
Infections of the bone can be difficult to eradicate, especially
if the mandible is involved. Most patients survive into adult-
hood. Although anemia and hepatosplenomegaly are rare, at
least one patient developed anemia and thrombocytopenia
so severe that he was transfusion dependent. His anemia and
thrombocytopenia were eliminated by splenectomy.
A subgroup of patients with the intermediate form
of osteopetrosis has a carbonic anhydrase II deficiency
(Fathal-lah et al., 1994; Whyte, 1993a). These patients
have a hyperchloremic metabolic acidosis. Several differ-
ent mutations have been described in the 50 cases diag-
nosed. Patients tend to have delayed development with a
reduction in intelligence as adults, short stature, fractures,
cranial nerve compression, dental malocclusion, and cere-
bral calcifications. Patients usually have no defects in
hematological function and no increased risk of infection.

Some patients with severe radiographic abnormalities and
with anemia have had severely sclerotic bone early, which
resolves without specific therapy (Monaghan et al., 1991;
Whyte, 1993b; L. L. Key, personal observation). Although
long-term follow-up is not available in these patients, no
FIGURE 1 The skeleton, both the long bones and the pelvis, is shown known sequelae resulted from the condition. The patients
to be sclerotic in this radiograph of a 5-day-old infant with anemia and had no visual impairment, but did have anemia and throm-
optic nerve compression. Patients with this severe presentation have a
100% chance of death before age 1 year, if untreated. Note that no intra-
bocytopenia. In one patient (personal experience), there
medullary space is seen in the long bones or the pelvis. was a history of acetazolamide administration. Whereas
osteopetrosis has not been widely associated with acet-
neuronal storage disease has been suggested by cytoplas- azolamide administration, the existence of osteopetrosis
mic inclusions. In most patients, seizures, poor neurologi- with naturally occurring mutations in carbonic anhydrase
cal development, abnormalities in the cerebral cortex seen suggests that the therapy may be related to the osteoclas-
on magnetic resonance imaging, and early development of tic dysfunction. In both cases, the resolution in the bone
central apnea characterize this specific presentation. No disease was apparent early (within 1 month). In addition,
therapy that has been tried in these patients (bone mar- patients with other milder sclerosing bony dysplasias are
row transplantation, calcitriol, or interferon-) has resulted frequently considered to have osteopetrosis in infancy. A
in any significant improvement of the disease. It is likely classic case is seen in the natural history of severe cranio-
that even when the bony disease can be reversed (as has metaphyseal dysplasia where early radiographs are nearly
occurred by using each of the modalities), the underlying indistinguishable from osteopetrosis (Fig. 5); however,
neurological disorder remains unaffected. Death usually there is no involvement of the vertebral bodies.
occurs before 2 years of age.
In general, patients with the adult forms of the disease have
The intermediate form of osteopetrosis is frequently silent a family history suggesting an autosomal dominant inheri-
at birth with few or no obvious clinical abnormalities (Key, tance pattern (Whyte, 1993b). Anemia is not a common
1987; Whyte, 1993b). Some cases are diagnosed in infancy, manifestation; however, fractures and cranial nerve dys-
when suspected, suggesting that the defect is present at a function are frequently observed (Bollerslev and Mosekilde,
subclinical level even from birth. Of interest, the radiographs 1993; Bollerslev et al., 1994). When defects have been

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FIGURE 2 This radiograph shows a phalangeal bone, obtained at autopsy from a 7-year-old with malignant osteopetrosis treated with calcitriol. Note the
presence of the original bony template (endobone, between the arrows) which was present at birth and never remodeled. The radiograph shows the presence
of mineralized bone that has been laid down outside of this original bone/cartilage template without the underlying template having been resorbed.

FIGURE 3 The pathognomonic feature of osteopetrosis at the histological level is the presence of unresorbed cartilage (denoted at C). Around the car-
tilage, a highly cellular, embryonic bone (designated as B) has been laid down. This combination of nonresorbed cartilage and poorly formed bone is the
microscopic feature that results in the macroscopic appearance seen in the bone-in-bone appearance on radiographs (see Fig. 2). The bar denotes 80.

sought for in infancy, radiographic abnormalities have been presence of an autosomal dominant disorder. In each of
found that define the presence of the disease and portend these cases, the children were diagnosed with the malig-
the onset of symptoms in later life. nant form of the disease owing to anemia and cranial nerve
dysfunction presenting in infancy. In one patient, there was
a history of severe infections and failure to thrive. Family
Severe members in each case had survived into the fifth and sixth
We have observed two patients who presented with severe decade (Fig. 6). In each case, the parent transmitting the
neonatal disease that had a family history suggestive of the disease was unaffected.

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Chapter | 72 Osteopetrosis 1565

R FIGURE 5 This radiograph of a 1 month old with craniometaphyseal

dysplasia demonstrates sclerotic long bones with little marrow space seen
in the diaphyses. It should be noted that there is already some clearing of
the bone in the distal metaphyseal region of both femurs (arrows, which
FIGURE 4 A radiograph of the long bones of a 6-year-old with an inter- had been sclerotic at birth).
mediate form of osteopetrosis shows the presence of some intramedullary
space (denoted as I). The deformities of modeling result in bowing and
thickening of the shaft and metaphyseal regions of the bone. Note a frac-
ture, which was clinically not apparent, is present in the left tibia (arrow). vault. There is diffusely sclerotic bone in the spine and pel-
vis. Cranial nerve compression is common in type I. There
are few abnormalities seen in the remodeling of bony tra-
beculae. Indeed, the strength of bone in type I is increased
compared with normal. Thus, pathological fractures are
Mild rarely observed.
The benign adult form of osteopetrosis is frequently Radiographs from patients with type II disease dem-
silent until later in life (Bollerslev and Mosekidle, 1993; onstrate massive sclerosis of the base of the skull, hyper-
Whyte, 1993b). Two distinct subtypes have been described sclerotic endplates of the vertebrae resulting in the rugger
based on radiographic appearance, symptoms, and bio- jersey spine, and subcristal sclerotic bands diagnostic
chemical characteristics. Each of these subtypes has been of endobones. Bone turnover is decreased, leading to a
inherited in a variety of kindreds. Each subtype has a dis- reduction in bone tensile strength and resulting in frequent
tinct natural history, resulting in differing symptomatic fractures. In type II, creatine phosphokinase, especially the
presentations. Both types have universally sclerotic bones, BB isoenzyme, is increased. Histomorphometric analysis
primarily involving the axial skeleton. Little or no mod- shows a defect in trabecular remodeling, resulting in bone
eling defects are seen in the long bones. Both types have that had not been replaced, yielding weakness.
been observed in some children in the identified families. In summary, the adult forms of osteopetrosis are usu-
Approximately 40% of patients with the adult form of ally diagnosed symptomatically in the second decade.
osteopetrosis are symptom-free regardless of type. Anemia These disorders rarely significantly alter hematopoiesis.
is rare in either type. Bone pain is common to both types. Defects in type I disease result in cranial nerve compres-
Type I is characterized radiographically, by massive sion, but fractures are rare. In type II disease, fractures are
sclerosis of the skull with increased thickness of the cranial common, but nerve compression is rare.

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Genetic Defects
The search for genetic abnormalities that result in osteo-
petrosis has recently identified two genetic defects that are
related to the osteopetrotic condition. In the first report of a
gene localization based on linkage analysis, van Hul et al.
reported an 8.5-cM region on chromosome 1p21 that is
associated with the autosomal dominant adult form, type
II (van Hul et al., 1997). Although this region was chosen
for study because of the presence of the CSF-1 gene, a pre-
cise defect has not been identified. Indeed, a survey of 20
patients with osteopetrosis found no evidence of defects in
Unaffected carrier the c-src, c-fos, c-cbl, and MITF (human equivalent of the
mi/mi) genes (Yang et al., 1998).
FIGURE 6 This is the family tree of two patients with adult forms of
osteopetrosis. The presentation of these patients was severe enough (sclerosis
Two studies have identified precise mutations in a sub-
of the long bones in one, anemia, sclerosis of the long bones, and blindness unit of the V-type H-ATPase protein, OC116 (Kornak
in the second) to result in an initial diagnosis of the severe malignant form. et al., 2000; Frattini et al., 2000). Numerous genetic defects
have been reported (see Table I). All of these patients
appear to have a classic severe osteopetrosis with severe
PATHOPHYSIOLOGY osteosclerosis, hematological failure secondary to reduced
bone marrow space, and visual impairment in all but one
Osteoclast Dysfunction patient. A history of consanguinity was a common theme
Although animal models and a few patients have been for four patients.
found with a profoundly reduced number of osteoclasts, Functionally, the defect causes the absence of the
defective function rather than a reduction of formation a3-subunit, OC116, of the V-type proton pump that is
appears to be the primary pathogenesis (Key and Ries, present along the ruffled border and responsible for acid-
1993). This holds true for malignant, intermediate, and ification next to the bone surface. In the absence of this acid-
benign forms. In the malignant form, there is the pos- ification, calcium cannot be removed from the surface of the
sibility of replacing the defective cell and curing the dis- bone. Of interest, a knockout animal has been described (Li
ease with bone marrow transplantation. However, defects et al., 1999), providing the first example of an animal model
in the osteoclasts environment have also been suspected predicting a human osteopetrotic genetic defect (the details
and may be the explanation for the greater-than-predicted of animal model are presented later). This makes the exist-
rate of failure in bone marrow transplantation therapy ing animal models even more exciting as a repository of
in this disorder (Gerritsen et al., 1994a; Key, 1987). defects that may potentially explain human disease.
However, to date, no patient has been definitively diag-
nosed with the one clear-cut stromal defect, a defect in
producing macrophage colony-stimulating factor (M-CSF)
seen in the op/op (osteopetrotic) mouse model (Key et al.,
1995a). One patient was reported with a decreased level of
M-CSF after a failed transplantation; however, no data A variety of animal models for osteopetrosis have been
were available before the immunomodulation necessary for explored. The M-CSF deficiency in the op/op mouse
the transplantation. seems to be the most clearly related defect (Begg et al.,
A defect in white blood cell and osteoclastic superoxide 1993; Lowe et al., 1993; Marks et al., 1992; Nilsson
production has been documented in the majority of patients and Bertoncello, 1994; Philippart et al., 1993; Wiktor-
with osteopetrosis (Key and Ries, 1993). Although the Jedrezejczak et al., 1994); however, replacing the M-CSF
defect in superoxide generation in osteoclasts may repre- with exogenous cytokine does not result in a complete
sent a more generalized decrease in the ability of the osteo- remission (Sundquist et al., 1995). Several possible explana-
clast to resorb bone, therapy with interferon--1b, designed tions have been suggested. The timing of the administration
to increase superoxide production, increases white blood may not be the most advantageous (Hofstetter et al., 1995;
cell superoxide production, thereby reducing infections, and Lee et al., 1994; Sundquist et al., 1995). Alternatively,
increases bone resorption, enhancing hematopoiesis and there may be other related factors that must interact. One
enlarging cranial nerve foramina. The result is a reduction of the most plausible ideas is that, in addition to circulat-
in the need for intravenous antibiotics and transfusions and ing levels of M-CSF, there is also the need for membrane-
in a deceleration of cranial nerve damage. The net result is bound M-CSF (Stanley et al., 1994) on the osteoblast or
an improved survival with reduced morbidity. embedded in the bone surface (Ohtsuki et al., 1995) to be

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Chapter | 72 Osteopetrosis 1567

presented to the osteoclast or its precursors. A less clear- The most well studied of these mutants is the c-src
cut defect, but a role demonstrated for M-CSF therapy in knockout mutation (Boyce et al., 1993; Lowe et al., 1993).
improving the phenotypic abnormalities in the tl/tl (tooth- In this mutation, the c-src tyrosine kinase is defective and
less) rat (Aharinejad et al., 1995; Marks et al., 1993) has yields a mutant with osteoclasts lacking ruffled borders.
suggested some involvement with the M-CSF production or This appears to result from the lack of production of phos-
the M-CSF receptor in the genesis of this mutant phenotype phorylated proteins necessary to allow fusion of the mem-
as well. To date the precise defect has not been reported. brane of endosomes with the cellular membrane within
Thus, animals or humans with few macrophages and osteo- the sealed attachment of the osteoclast to bone. The result
clasts may be found to have a defect in M-CSF production is an inactive cell with none of the machinery present at
or response. the osteoclast-bone interface necessary to resorb bone.
In the mi/mi mouse (microphthalmic), there is a defect The precise mechanism is not well understood and seems
in the production of a transcription factor (Steingrmsson to be more complex than originally thought.
et al., 1994). This has led to the possibility that a variety In the c-fos knockout mutation (Jacento, 1995;
of defects, all related to the presence of a defective tran- Grigoriadis et al., 1994; Johnson et al., 1992; Wang et al.,
scription factor, could exist in the osteoclast and/or in other 1992), there are few mature osteoclasts formed and there is
cells as well. One suggested defect is a decrease in the c-kit a reduction in the number of osteoclasts and an increase in
receptor production, which is necessary for stimulation of the number of macrophages. Thus, it appears that c-fos is
tyrosine kinase activity with the stem-cell factor (Ebi et al., related to the osteoclast lineages switch point, which
1992). Stem-cell factor and M-CSF activate similar recep- determines whether the progenitor moves in the direction
tor populations, c-kit and c-fims, which are quite similar in of the osteoclast or the macrophage (Jacento, 1995).
their binding regions. There are also data suggesting that The knockout of PU.1 (Tondravi et al., 1997), an ETS-
possibly there is a defect in the ability of mi/mi stromal domain transcription factor essential for the development
cells, failing to support osteoclastic function (Key, 1987) of myeloid and B-lymphoid cells, is thought to regulate
or possibly even inhibiting osteoclastic function in vitro. the c-fms receptor (receptor for CSF-1). A mutation in this
Both M-CSF and/or interferon- have been shown to gene results in a nearly complete absence of osteoclasts,
improve the defect in the mi/mi mouse (Key et al., 1995a). resulting in severe osteopetrosis. Bone marrow transplanta-
Because these cytokines are not deficient in these animals, tion with PU.1 competent stem cells rescued the animals,
the studies suggest that these therapies circumvent the completely reversing the defects. No human correlate has
specific defects rather than reversing the defects directly. been found. Knocking out the gene for cathepsin K gen-
Similar effects of these cytokines have been observed in erated an additional osteopetrotic mouse model (Saftig
patients with osteopetrosis where defects are unknown and et al., 1998; Gowen et al., 1999). This mutant was found
not directly related to deficiencies in cytokine production to have dense bones with a reduction in bone marrow
or response elements. space, and extramedullary hematopoiesis. Although these
animals shared features of osteopetrosis, it was noted that
the defective bone resorption varied from bone to bone.
Recently, a similar mutation was identified in humans with
Perhaps the greatest interest has been in the analysis of pycnodysostosis, a disorder resembling osteopetrosis, but
man-made knockout mutations that have been found to having osteoacrolysis, poor fusion of the sagittal suture,
yield an osteopetrotic phenotype. The effects of a targeted micrognathia, and a predisposition for fracture (Ho et al.,
disruption of Atp6i, a gene encoding a subunit of the vacu- 1999). The osteoclastic defect appears to be an inability of
olar pump in the C57BL/6J inbred mouse strain, have been the osteoclast to degrade matrix, although removal of cal-
described (Li et al., 1999). The mutant animals resulting cium appears to be normal. Thus, it is likely that some of
from this mutation have extremely dense bones with car- the knockout mutations may be genes responsible for other
tilaginous islands, reduced marrow space (decreased by sclerosing bony dysplasias. It appears that mutations result-
80% in the long bones), absent tooth eruption, decreased ing in osteopetrosis are those that completely inactivate the
growth, and severely deformed bones. The condition was osteoclastic bone resorption by either leading to a failure to
lethal in all animals by the fifth week. These animals generate the osteoclast itself or the failure to form the ruf-
appear to be quite similar to the patients described with fled border. This suggests that there is some redundancy
defects in the TCIRG1 gene of the human vacuolar pro- of function in the osteoclasts bone-resorbing process such
ton pump described by Frattini et al. (2000) and Kornak that knocking out a single enzyme system does not com-
et al. (2000). The results of this animal mutation prove that pletely inactivate bone resorption.
a defect in the proton pump can cause osteopetrosis, con- At the present time, knockout mutations have been
firming the speculation that the genetic mutations in the much more important in understanding osteoclastic func-
vacuolar pump documented in humans is responsible for tion than in explaining the human osteopetrotic condition.
the associated osteopetrotic phenotype. However, these studies do provide a variety of candidate

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genes and are beginning to suggest genetic defects that will In transplantations where the graft is obtained from HLA
allow us to diagnose certain types of osteopetrosis. haploidentical (mismatched) relatives, the engraftment and
survival rates for transplants are only 15%. Given the
natural history of a survival of almost 30% for the malig-
Avian Osteopetrosis (Increased Osteoblastic nant form of osteopetrosis as a whole, this is considered
Function) by most transplantation experts to be an unacceptable rate
of failure. However, it should be noted that in the 15% of
Osteopetrosis has been described in the chicken and patients where transplantations have been successful, cures
appears to result from infection with the avian leuko- have been achieved. The great hope for the future is trans-
sis virus. This sclerosing condition is characterized by an plants with matched unrelated donors and possibly, cord
increase in bone formation by infected osteoblasts (Smith blood stem cells. (Information on cord blood transplan-
and Ivanyi, 1980) with normal osteoclastic function. Avian tation in children was communicated personally by M.
osteopetrosis, although similar to the sclerosis seen in a Klemperer, St. Petersberg, FL.) With the advent of DNA
variety of human diseases, has not been shown to occur in typing to ensure the adequacy of the matches, success rates
humans with one possible exception. In transient osteo- of 80% are being achieved in most diseases. However,
petrosis, Ozsoylu and Besim have suggested that the success rates of only 40% have been found in osteope-
etiology may be bony sclerosis secondary to excessive trosis. The exact reason for this discrepancy is not clear at
osteoblastic function (Ozsoylu and Besim, 1992). this time. The possibility that cord blood or placental trans-
plants may improve chances for engraftments is just begin-
ning to be explored. Nonetheless, at present, in the absence
THERAPY OF HUMAN DISEASE of a matched sibling donor, survival can be expected to be
well below 50%.
Even with the marked advances in understanding the osteo-
clastic defects that could result in osteopetrosis, we are still
left today with the need to treat somewhat blindly in trying to Other Therapies
combat this disorder. Transplantation has been the mainstay
Many families have found that transplantation carries an
of treatment; however, somewhat disappointing results and,
unacceptable risk, and thus, there has been a search for
at present, the lack of available donors have made it difficult
alternative therapies. The use of high-dose calcitriol has
to rely on transplantation as the sole therapy for this disease.
been tried in a large number of children with some period
Thus, a variety of other therapies have been attempted with
of stabilization, and in some instances, a cure (Key and
some success. Because the mortality associated with failed
Ries, 1993; van Lie Peters et al., 1993). Nonetheless, long-
transplantations is high, other treatment alternatives and/or
term cures have been achieved in 25% of patients treated.
stopgap measures remain important despite the inability
Interferon- has been used as a treatment of osteope-
of these therapies to completely cure the condition in most
trosis (Key et al., 1995b; Kubo et al., 1993). The intent of
patients. These therapies may be the sole therapy of the
the therapy was to enhance the production of oxygen radi-
patient or may result in a milder course of the disease while
cals by white blood cell phagocytes as a means of fight-
awaiting a definitive cure.
ing off life-threatening infections. In addition, therapy
with interferon--1b along with calcitriol increases both
bone remodeling and the amount of bone marrow space
Transplantation in patients (Fig. 7 and Fig. 8). To determine whether
Despite the fact that, at present, transplantation is avail- interferon--1b (1.5 g/kg/dose subcutaneously, three
able in only 50% of children with osteopetrosis and is times per week, Actimmune, Intermune Pharmaceuticals,
successful in 45% of patients who receive grafts; the Inc., Palo Alto, CA) plus calcitriol (1 g/kg/day orally) or
allure of this therapy is that a successful transplantation calcitriol alone is effective in delaying the time to treat-
yields a nearly complete cure (Gerritsen et al., 1994b). If ment failure, 16 patients with congenital osteopetrosis
this cure can be obtained before there are too many physi- were recruited from all over the world to participate in a
cal disabilities, children with osteopetrosis tend to grow randomized, controlled trial. Patients were randomized in
and develop normally. In transplantations where the donor a 2:1 ratio onto interferon--1b plus calcitriol or calcitriol
graft is harvested from young siblings who have a favor- alone, respectively. The drug was administered subcutane-
able HLA match, there appears to be 70%, or slightly ously to patients three times a week. The patients receiving
greater, survival. Despite the fact that not all engraftments interferon--1b plus calcitriol had their first evidence of
are maintained, even the retention of a small number of failure at a mean of 452 days compared with those on cal-
donor cells seems to correct the defect significantly and citriol alone, who failed at 130 days (P 0.016). Only 10%
stave off recurrence of symptomatic disease. However, of the patients treated with interferon--1b experienced
beyond this group, the success rate is less favorable. a serious infection compared with 67% of the patients on

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Chapter | 72 Osteopetrosis 1569

FIGURE 7 Bone biopsies from age 11 and 29 months in a patient with severe infantile osteopetrosis. (Top) Contains a 1-m Epon-embedded section
obtained from the patient at 11 months of age, prior to therapy with interferon--1b and calcitriol. Coarse trabecular bone (denoted as B) with carti-
laginous streaks (denoted as C) is evident. Lacunae are absent even though osteoclasts (arrows) adjoin the bone surface. Bone marrow cells are absent
from this section. (Bottom) A 5-m-thick methyl-methacrylate-embedded section obtained by biopsy of the same patient after 18 months of therapy. A
combination of mineralized coarse trabecular bone and porous cortical bone (designated by B) lined with numerous osteoclasts (open arrows) with
brush borders and adjoining lacunae (arrowheads) is visible. Islands and streaks of cartilaginous tissue are absent. Bar 40 m.

calcitriol alone (P 0.0001). In limited data, biopsies prognostic information to be provided to the parent or
obtained from patients treated with interferon--1b had a patient, improving decision making concerning the appro-
50% reduction in bone mass; while no reduction was seen priate therapy. The genetics of osteopetrosis has become
in one patient treated with calcitriol alone. The size of both clearer with the discovery of the etiology of the autoso-
the optic nerve foramina and auditory canals increased mal recessive disorders (severe) is related to defects in
in subjects treated with interferon--1b, but not in those acid production and possibly, an increased bone forma-
treated with calcitriol only. tion. A defect in the osteopetrosis associated transmem-
brane protein 1, previously described in the grey lethal
SUMMARY mouse (Ramirez et al., 2004) and in human patients with
severe infantile osteopetrosis. Additional knowledge has
In summary, significant progress has been made in clas- been gained in understanding the milder forms. ADO II,
sifying osteopetrosis. There are at least three major cat- the predominant type of the Adult or mild osteopetrosis,
egories (malignant, intermediate, and mild) of the disease appears to be related primarily to chloride channel defects
with a variety of subtypes. This classification allows (Waguespack et al., 2003). Cases of intermediate severity

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1570 Part | II Molecular Mechanisms of Metabolic Bone Disease

FIGURE 8 f0080999Tc-labeled sulfur colloid bone marrow scans are shown from the same patient whose biopsies are shown in Fig. 7. The initial
scan (left) shows abnormal uptake of label in the long bones of the lower extremities. Areas with little or no radionuclide are seen in the diaphyses with
the uptake of the radionuclide being primarily concentrated to the subepiphyseal regions. (Right) After interferon -1b therapy, there is an increase in
the amount of radionuclide labeling and there are no longer any discreet areas with reduced uptake.

also result from mutations in low-density lipoprotein day) could provide an excellent regimen. As in the past,
receptor-related protein 5 (van Wesenbeeck et al., 2003) this very interesting family of disorders continues to lead
and Plekstrin Homology Domain-containing Family M 1 the way in developing our understanding of osteoclastic
(PLEKHM 1) (van Wesenbeeck et al., 2007). Finally, treat- function., and now appears to be important in our under-
ment is largely still directed toward enhancing osteoclastic standing of formationresorption coupling.
function in general rather than correcting specific defects.
Based on the work of Karsdal et al. (2007) and del Fattore
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