Osteopetrosis !

Inherited "marble bone" disease: bones become very dense but brittle because they are not remodelled, which can crush nerves and crowd out the marrow.

Updated 2026-11-01

Structures involved

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Why it happens

What it is

A group of inherited disorders in which osteoclasts fail to resorb bone. Bone keeps being formed but is not remodelled, so the skeleton becomes dense yet brittle, marrow space shrinks and the skull foramina narrow. Severity ranges from a lethal infantile form to an adult form found by chance on X-ray.

Who gets it

The autosomal dominant adult form affects about 1 in 20,000 people and is the most common. The severe autosomal recessive infantile form affects roughly 1 in 250,000, and is more frequent where consanguineous marriage is common.

Causes

Autosomal dominant osteopetrosis (Albers-Schönberg disease): mostly CLCN7 variants
Autosomal recessive (infantile, "malignant") osteopetrosis: TCIRG1 variants in about half, also CLCN7, OSTM1, TNFSF11 (RANKL) and TNFRSF11A (RANK)
Carbonic anhydrase II deficiency: osteopetrosis with renal tubular acidosis and cerebral calcification
Intermediate forms with either inheritance pattern

Risk factors

Family history of osteopetrosis
Parental consanguinity (recessive forms)

Pathophysiology

Osteoclasts need acidification and chloride transport at the bone surface to dissolve mineral; when this fails, primary spongiosa and calcified cartilage persist. Bone becomes dense but poorly organised, so it fractures easily and heals slowly. Narrowed cranial foramina compress the optic, facial and auditory nerves. Loss of marrow space causes pancytopenia with extramedullary haematopoiesis in the liver and spleen. Calcium cannot be mobilised from bone, so infants may develop hypocalcaemia.

Classification

Autosomal recessive (severe, infantile)
Intermediate autosomal osteopetrosis
Autosomal dominant (adult, benign, Albers-Schönberg)
Carbonic anhydrase II deficiency

Symptoms and signs

Fractures after minor trauma; bone pain and hip osteoarthritis in adults
Vision loss, deafness and facial palsy from cranial nerve compression
Anaemia, bleeding and repeated infections from marrow failure (infantile form)
Enlarged liver and spleen, failure to thrive, short stature, macrocephaly
Dental problems and osteomyelitis of the jaw

Diagnosis

Clinical: Fractures, cranial nerve palsies and cytopenias in a child, or an incidental finding of dense bones in an adult; family history.
Tests: Full blood count and blood film (anaemia, thrombocytopenia, leucoerythroblastic picture); calcium, phosphate and PTH; acid phosphatase and creatine kinase BB may be raised. Genetic testing confirms the type. Eye examination and hearing tests.
Imaging: Radiographs show diffusely dense bones, "bone-in-bone" appearance, "sandwich" (rugger-jersey) vertebrae, club-shaped metaphyses and a thick skull base; CT or MRI of the skull assesses foramina and hydrocephalus.

Differential diagnosis

Pyknodysostosis
Paget disease of bone
Osteosclerotic bone metastases (prostate, breast)
Fluorosis and other toxic osteosclerosis
Myelofibrosis with osteosclerosis

Goal of treatment

In severe infantile forms, restore osteoclast function early with haematopoietic stem cell transplantation before vision is lost; in all forms, treat fractures, nerve compression, marrow failure and infections.

Treatment

Procedure: Haematopoietic stem cell transplantation for severe osteoclast-intrinsic recessive forms, because osteoclasts come from marrow precursors; it is not useful in RANKL-deficient forms.
Medical: Calcium and vitamin D management for hypocalcaemia; transfusions and treatment of infections; interferon gamma-1b has been used in selected patients.
Surgical: Fracture fixation (technically difficult because of hard, brittle bone); decompression of the optic canal in selected cases; joint replacement for hip arthritis.
Conservative: Careful dental care and oral hygiene to prevent jaw osteomyelitis.
Follow-up: Regular blood counts, vision and hearing checks, and growth monitoring in children.

Complications

Recurrent fractures and delayed healing
Blindness, deafness and facial nerve palsy
Pancytopenia with infections and bleeding
Osteomyelitis, especially of the mandible
Hypocalcaemia and hydrocephalus in infants

Prognosis

Untreated severe infantile osteopetrosis is usually fatal in early childhood; transplantation can cure the bone and marrow disease if done early, but vision already lost does not return. The adult dominant form usually allows a normal lifespan, with morbidity from fractures, arthritis and jaw infection.

Test yourself

Think of the answer, then tap the question to see it.

What cellular defect causes osteopetrosis?

Failure of osteoclast bone resorption (for example, defective acidification of the resorption pit).

Why does severe infantile osteopetrosis cause pancytopenia and hepatosplenomegaly?

Dense bone obliterates marrow space, so blood formation moves to the liver and spleen.

Why can stem cell transplantation cure the severe recessive form?

Osteoclasts derive from haematopoietic precursors, so donor marrow supplies working osteoclasts.

Which cranial nerves are typically compressed in osteopetrosis?

The optic (II), facial (VII) and vestibulocochlear (VIII) nerves, through narrowed foramina.

Which enzyme deficiency combines osteopetrosis with renal tubular acidosis and cerebral calcification?

Carbonic anhydrase II deficiency.

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Educational information, not medical advice. For any symptom, see a health professional.

Sources: Osteopetrosis: MedlinePlus Genetics (MedlinePlus Genetics (U.S. National Library of Medicine), 2025).

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