OSTEOPETROSIS
DR, NANCY RUTO
MS/ACC/5801/22
FACILITATOR: DR ANJILA

INTRODUCTION
• The name osteopetrosis is derived from the Greek language. ‘Osteo’
means bone, and ‘petrosis,’ meaning stone. Therefore, the disease is
often referred to colloquially as “marble bone disease.”
• The name osteopetrosis encompasses a group of hereditary
metabolic bone diseases, all of which detrimentally affect bone
growth and remodeling leading to generalized osteosclerosis and the
potential of pathologic fractures, pancytopenia, and even cranial
neuropathies and hepatosplenomegaly in severe cases.

INTRODUCTION
• The disease was originally described by a radiologist in Germany, Dr.
Albers-Schonberg, in 1904.Bone with abnormally increased density is
the key radiographic finding. This increased density is secondary to
osteoclast dysfunction and leads to the affected bones being
abnormally brittle.

• Osteopetrosis is genetically and phenotypically heterogeneous,
ranging from lethal to relatively mild phenotypes. However, a
common hallmark of the disease is bone fragility despite the
increased bone mass.

INTRODUCTION
• Osteopetrosis-a rare hereditary bone disorder that presents in one of
three forms.
• There is a defect in bone resorption by osteoclasts
• Incidence:
1 in 300,000 births but is almost 10 times as high in Costa Rica

INTRODUCTION
• osteopetrosis could be categorized only on the basis of the clinical
aspects of the three primary types:
1. infantile, or “malignant,” osteopetrosis, inherited in an autosomal
recessive inheritance pattern
2. autosomal recessive osteopetrosis ( intermediate)
3. autosomal dominant osteopetrosis.

INTRODUCTION
• Bone is continuously remodelled to maintain its strength and
structural integrity.
• Remodelling is the result of an equilibrium between bone formation
performed by osteoblasts and bone resorption performed by
osteoclasts.
• In osteopetrosis this equilibrium is disturbed by a defect in the
osteoclastogenesis or by disfunction of osteoclasts.

MUTATIONS
• Three mutations cause defects in the acidification of bone.
-The most common of these, found in 50 to 60 percent of patients,
results in defects in the A3 subunit of the osteoclast vacuolar
H+–ATPase proton pump.
• The second most clinically significant mutation affects CLCN7, a gene
encoding an osteoclast-specific chloride channel. (10 -15 percent)
• Carbonic anhydrase II dysfunction is a feature of autosomal recessive
osteopetrosis but accounts for a small proportion
It should be noted that a substantial percentage of patients with
osteopetrosis have no identifiable gene defect

Etiology
• Genetic research has found this disease of osteoclastic dysfunction to
have an association with at least 8 gene mutations.
• Six of these eight genes are associated with a malignant, autosomal
recessive form of the disease.
• Loss of function mutations in TCIRG1, CLCN7, OSTM1, PLEKHM1, AND
SNX10 lead to an osteoclast rich version of autosomal recessive
osteopetrosis.

TYPES OF OSTEOPETROSIS
Osteopetrosis is divided into four types:
• malignant infantile osteopetrosis,
• intermediate osteopetrosis,
• autosomal osteopetrosis. (TYPE 1 /TYPE 2)
1. Malignant infantile osteopetrosis is usually diagnosed within the
first year of birth by bone sclerosis and bone marrow obliteration. This
type is very severe and usually results in death within a few years.
2. The intermediate type usually appears before the age of ten and
leads to recurrent pathologic fractures and cranial nerve compression.

3. Autosomal dominant osteopetrosis is usually mild and consists of
two sybtypes.
• Type I involves marked thickening of the cranial vault.
• Type II patients have predominantly sclerosis of the pelvis, the
vertebrae and the base of the skull.
• Type I and II patients may often be long-lasting asymptomatic, but will
eventually present with pathologic fractures, bone pain, and the
effects of cranial nerve compression.

• Intermediate autosomal recessive osteopetrosis is the result of a loss
of function mutation in CAII, the gene responsible for the production
of the carbonic anhydrase II protein.
• Autosomal dominant osteopetrosis is the result of the dysfunction of
chloride channel 7 secondary to a dominant-negative mutation of
CLCN7.

PATHOGENESIS
• Resorption occurs through acidification of the bony surface, which initiates dissolution
of the mineral matrix and secretion of enzymes that digest the organic component of
bone.
• In the cytoplasm of the osteoclast, carbonic anhydrase II forms carbonic acid (H2CO3)
from carbon dioxide (CO2) and water; the H2CO3 dissociates to bicarbonate (HCO2 ) and a
proton (H+).
• The protons are transported through the ruffled border into the resorption lacuna by a
vacuolar proton pump (H+–ATPase), generating a pH of 4 to 5 in the extracellular space
adjacent to bone.
• The electroneutrality of the ruffled membrane is preserved by a chloride-channel charge
coupled to the H+–ATPase.
• Acidification of this extracellular environment initiates the degradation of the mineral
component of bone, which is composed primarily of hydroxyapatite (Ca3(PO4)2)3•
Ca(OH)2). In the presence of protons, hydroxyapatite is degraded to calcium (Ca2+),
soluble inorganic phosphate (HPO4
2–), and water.

Epidemiology
• Fortunately, the autosomal recessive form of the disease has an
incidence far less than the autosomal dominant form.
• The autosomal recessive form occurs in approximately 1 out of every
250,000 births.
• Of note, in Costa Rica, the incidence has been found to be
significantly higher, with a rate of approximately 3.4 out of every
100,000 births.
• The autosomal dominant form of the disease occurs at an
approximate frequency of 1:20,000.

Pathophysiology
• Bone is in a dynamic state and is dependent upon a healthy balance
between osteoclast-mediated resorption and osteoblast-mediated
deposition.
• In osteopetrosis, defective osteoclast development or function leads
to a disruption in normal bone homeostasis.
• Osteoclasts that have defective proton pumps, chloride channels, or
carbonic anhydrase II proteins are unable to resorb bone effectively.
Consequently, the unorganized, overly dense bone that is prone to
fracture develops unchecked.

Pathophysiology
-The primary underlying mechanism involved in all forms of
osteopetrosis
is the failure of normal osteoclastic bone resorption.
-This results in dense, deformed sclerotic bones that show typical and
diagnostic patterns on radiograph.
“Bone within a bone”

Histopathology
• Histological evaluation of bone in a patient
with osteopetrosis will likely show empty
lacunae with plugged Haversian canals,
calcified cartilage dispersed within bony
trabeculae, and defective osteoclasts
that lack a clear zone and ruffled border.
• These clear zone and ruffled border structures are the trademark
findings in osteoclasts undergoing active resorption, and their
absence corresponds perfectly with the findings of osteopetrosis.

• Clinical presentation
Osteopetrosis tarda (benign osteopetrosis) /autosomal dominant
-usually detected by a family history of bone disease or
-as an incidental radiologic finding, and
-is asymptomatic in about 50 % of cases.
-About 40 percent of patients present with fractures related to brittle
osteopetrotic bones or with osteomyelitis, especially of the mandible

Clinical presentation
Osteopetrosis congenita
• Osteopetrosis congenita (malignant osteopetrosis)
• -presents in infancy
-associated with failure to thrive
-growth retardation.
-Proptosis,
-blindness,
-deafness
-hydrocephalus
Note
This form of osteopetrosis is very severe and usually results in death
by age two years.

Clinical presentation
Marble bone disease,( intermediate autosomal
recessive)
• Marble bone disease, the other infantile form of osteopetrosis, is not
characterized by bone marrow failure.
• Although survival rates are better for patients with marble bone
disease than for patients with osteopetrosis congenita, the
consequences of renal tubular acidosis may shorten life expectancy.
• Patients with marble bone disease are usually of
-short stature and present with
-intracranial calcifications,
-sensorineural hearing loss and
-psychomotor retardation

DENTAL
• Oral problems of osteopetrosis are delayed tooth eruption, absence
of some teeth, malformed teeth, enamel hypoplasia, disturbed
dentinogenesis, hypomineralisation of enamel and dentin, propensity
for tooth decay, defects of the periodontal membrane, thickened
lamina dura, mandibular protrusion, and the presence of odontomas.
Tooth removal should be limited as it may induce bone fractures and
osteomyelitis.

PRINCIPLE OF MANAGEMENT
• History
-a family history of bone disease or
-as an incidental radiologic finding,
-and is asymptomatic in about 50 percent of cases.
• About 40 percent of patients present with fractures, that is caused a
force that should cause
- mild but noticeable limp and knee pain on the right side.
-Recurrent infection, anemia , bleeding, progressive hearing loss.
-infantile osteopetros is diagnosed early in life. Failure to thrive and
growth retardation are symptoms

• Clinical examinations
-Examination unremarkable,
-moderate pain
-restriction ROM
-Sign and symptoms of fracture

• Differential diagnosis
-malignancies (leukemia AML.ALL),
-myeloproliferative diseases
-sickle cell disease.
-Osteoblastic metastases.
-Hypoparathyriodism
-Pseudohypoparathyrodism
-Pediatric Lead posioning

• Note
In rare instances patients survive into adulthood. They present with
-severe anemia,
-recurrent fractures,
-growth retardation,
-deafness,
-blindness and
-massive hepatosplenomegaly

• Laboratory
-CBC-Pancytopenia(thrombocytopenia, anemia, neutropenia).
-ESR
-CRP
-Urine analysis
-Sickling test/Hb Electrophoresis
-Blood culture
-BS for MPs
- Creatinine kinase isoform BB (CK-BB) - levels are increased due to
increased release from defective osteoclasts

• -Acid phosphatase - Increased due to increased release from
defective osteoclasts
-Parathyroid hormone (PTH) - Often is elevated (secondary
hyperparathyroidism

• Genetic screening
-Bone marrow aspiration and biopsy r/o AML,ALL
-Flow cytometry
-HLA typing for allogenic bone transplant
• If clinical and radiographic findings do not yield a diagnosis,
laboratory findings of increased creatinine kinase BB and tartrate-
resistant acid phosphatase can aid in diagnosis.
• Genetic testing can also be performed to evaluate for the presence of
the gene mutations associated with the condition

Radiography
• Radiologic features of osteopetrosis are usually diagnostic.
(sclerotic, “bone within a bone”)
show evidence of
-fractures or
-osteomyelitis.
-The entire skull is thickened and dense, especially at the base.
-Sinuses are small and underpneumatized.
• Vertebrae are extremely radiodense. They may show alternating
bands, known as the rugger-jersey sign

Evaluation
• Osteopetrosis is most frequently diagnosed based on the patient having
the typical clinical and radiographic findings of the disease.
• Radiographs will show diffuse osteosclerosis throughout the skeleton with
a “marble bone” appearance.
• There will generally be increased cortical thickness with associated
decreased medullary canal diameter. The “Erlenmeyer flask” deformity
can be found at the metaphyses of long bones, particularly at the proximal
humerus and the distal femur.
• A “bone-in-bone most frequently is noted in the bones of the spine or the
hand phalanges. “Rugger jersey spine” is another axial skeleton
radiographic finding that can occur secondary to excessive sclerosis of the
vertebral endplates.
• .

marble bone

“Erlenmeyer flask” deformity
decreased medullary canal diameter

• The long bones are usually shortened and frequently
exhibit a remodeling defect (the Erlenmeyer flask deformity)
characterized by loss of the normal metaphyseal flare.

Diagnosis
• Infantile:
• Serum calcium: May have hypocalcemia/ rickets if severe
• Often elevated PTH (secondary hyperparathyroidism)
• Elevated acid phosphatase: released from defective osteoclasts
• Elevated creatinine kinase isoform BB (CK-BB) - increased release from
defective osteoclasts
• Adult:
• Increased acid phosphatase and CK-BB - in type II disease
• Increased serum bone-specific alkaline phosphatase
• Radiography: Generalised sclerosis

Treatment / Management
• Management of patients with osteopetrosis must be tailored to the individual
patient.
• Treatment is predominantly supportive with no known cure, and
interprofessional care and surveillance are treatment mainstays.
• Fractures and arthritis associated with osteopetrosis are best managed by an
experienced orthopedic surgeon since fracture treatment, and arthroplasty in
these patients is frequently plagued by the following complications: non-union,
delayed union, and osteomyelitis.
• Nutritional support has also been used to improve growth and enhance patient
response to other treatment modalities
• Erythropoietin was found to correct anemia and thrombocytopenia in a patient
with osteopetrosis congenital
• Recombinant human interferon gamma

• Due to the frequency of cranial nerve compression neuropathies, most frequently of the
optic nerve, routine ophthalmologic evaluation is needed, and in some patients, surgical
decompression of the optic nerve may be required to preserve eyesight.
• Routine dental evaluation is needed in these patients to prevent the complications of
abscesses, cysts, and osteomyelitis that can occur more frequently in these patients due
to altered bone anatomy of the mandible .
• Bone marrow transplantation of hematopoietic stem cells (HSC) is reserved for the
malignant, autosomal recessive form of osteopetrosis due to the risk of rejection and
other possible complications
• Interferon-gamma 1b therapy has been used in some patients found unfit for bone
marrow transplantation or as bridging therapy until HSC therapy can be used. It shows
benefit in increasing immune function and bone resorption.
• High-dose calcitriol has also been used to attempt the stimulation of host osteoclasts.

•THANK YOU

• Development of Gene Therapy for Malignant Osteopetrosis:
https://www.med.lu.se/labmed/molecular_medicine_and_gene_therapy/r
esearch_groups/johan_richter
• Osteopetrosis: https://emedicine.medscape.com/article/123968-overview
• Tolar, J. et al. Osteopetrosis. New England Journal of Medicine.
https://www.nejm.org/doi/full/10.1056/NEJMra040952
• Osteopetrosis JEROME CAROLINO, M.D., JUAN A. PEREZ, M.D., and ANCA
POPA, M.D., Saint Mary Hospital, Hoboken, New Jersey
Am Fam Physician. 1998 Mar 15;57(6):1293-1296
mechanisms of disease Osteopetrosis Jakub Tolar, M.D., Ph.D., Steven L.
Teitelbaum, M.D., and Paul J. Orchard, M.D.
Medscape