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Osteopetrosis Workup

  • Author: Robert Blank, MD, PhD; Chief Editor: George T Griffing, MD  more...
Updated: Dec 17, 2014

Approach Considerations

Laboratory findings in infantile osteopetrosis include the following:

  • Serum calcium - Generally reflects oral intake; hypocalcemia can occur and cause rickets if it is severe enough
  • Parathyroid hormone (PTH) - Often is elevated (secondary hyperparathyroidism)
  • Acid phosphatase - Increased due to increased release from defective osteoclasts
  • Creatinine kinase isoform BB (CK-BB) - levels are increased due to increased release from defective osteoclasts

Laboratory findings in adult osteopetrosis include the following:

  • Acid phosphatase and CK-BB - Concentrations are often increased in type II disease
  • Serum bone-specific alkaline phosphatase - Values may also be increased in various types of the disease

Genetic screening

In addition to the routine laboratory investigations listed above, mutation screening of appropriate candidate genes should be undertaken in patients whose presentation corresponds to any of the known genetic lesions. Knowledge of the molecular basis of the osteopetrosis allows clinicians to provide informed genetic counseling and, in some cases, to choose appropriate therapy.


Bone biopsy is not essential for diagnosis, because radiographs usually are diagnostic. Histomorphometric studies of bone may be useful to predict the likelihood that BMT will succeed. Patients with crowded bone marrow are less likely than others to respond to a transplant.

Histologic findings

Failure of osteoclasts to resorb skeletal tissue is the pathognomonic feature of true osteopetrosis. Remnants of mineralized primary spongiosa are seen as islands of calcified cartilage within mature bone. Woven bone is commonly seen. Osteoclasts can be increased, normal, or decreased in number.

Histologic analysis has revealed that type I adult-onset osteopetrosis is not a genuine form of osteopetrosis, because it lacks the characteristic findings.



Radiologic features of osteopetrosis are usually diagnostic. Because osteopetrosis encompasses a heterogeneous group of disorders, findings differ according on the variant.[17]

Patients usually have generalized osteosclerosis. Bones may be uniformly sclerotic, but alternating sclerotic and lucent bands may be noted in iliac wings and near the ends of long bones. The bones may be clublike or may have the appearance of a bone within bone (endobone). Radiographs may also 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 (see Table 3).

Differentiating type 1 from type 2 adult osteopetrosis

Two types of adult osteopetrosis are identified on the basis of radiographs. Typing the patient's disease may be important in predicting a fracture pattern, because type II disease appears to increase the risk of fracture (see Table 3). Radiographic characteristics of type I and type II disease are as follows:

  • Type I disease - Sclerosis of the skull mainly affects the vault with marked thickening; the spine does not show much sclerosis.
  • Type II disease - Sclerosis is found mainly in the base of the skull; the spine always has the rugger-jersey appearance, and the pelvis always shows subcristal sclerosis; transverse banding of metaphysis is common in patients with type II disease but not in patients with type I disease (this finding confirms type II disease, but its absence does not necessarily indicate type I disease)
Contributor Information and Disclosures

Robert Blank, MD, PhD Professor of Medicine, Cell Biology, and Physiology, Chief, Division of Endocrinology, Metabolism, and Clinical Nutrition, Director, TOPS Obesity Center, Medical College of Wisconsin; Staff Physician, Clement J Zablocki Veterans Affairs Medical Center

Robert Blank, MD, PhD is a member of the following medical societies: Alpha Omega Alpha, American Society of Human Genetics, Central Society for Clinical and Translational Research, International Bone and Mineral Society, International Society for Clinical Densitometry, American College of Physicians, American Society for Bone and Mineral Research, Endocrine Society

Disclosure: Serve(d) as a director, officer, partner, employee, advisor, consultant or trustee for: Bristol-Myers Squibb.


Anuj Bhargava, MD, MBA Adjunct Assistant Professor, Drake College of Pharmacy; Co-Director, Diabetes Institute, Mercy Medical Center; President, Iowa Diabetes and Endocrinology Research Center; President, My Diabetes Home, LLC

Anuj Bhargava, MD, MBA is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians-American Society of Internal Medicine, American Diabetes Association

Disclosure: Received honoraria from Merck for speaking, research trials; Received honoraria from Novo Nordisk for speaking and teaching; Received honoraria from Sanofi for speaking and teaching; Received honoraria from takeda for speaking and teaching; Received honoraria from Abbott for speaking and teaching; Received grant/research funds from Lilly for research trials; Received grant/research funds from Gilead for research trials; Received grant/research funds from Novartis for research trials; Received gr.

Chief Editor

George T Griffing, MD Professor Emeritus of Medicine, St Louis University School of Medicine

George T Griffing, MD is a member of the following medical societies: American Association for the Advancement of Science, International Society for Clinical Densitometry, Southern Society for Clinical Investigation, American College of Medical Practice Executives, American Association for Physician Leadership, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical and Translational Research, Endocrine Society

Disclosure: Nothing to disclose.


Romesh Khardori, MD, PhD, FACP Former Professor, Department of Medicine, Former Chief, Division of Endocrinology, Metabolism, and Molecular Medicine, Southern Illinois University School of Medicine

Romesh Khardori, MD, PhD, FACP is a member of the following medical societies: American Association of Clinical Endocrinologists, American College of Physicians, American Diabetes Association, and Endocrine Society

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Stanley Wallach, MD Executive Director, American College of Nutrition; Clinical Professor, Department of Medicine, New York University School of Medicine

Stanley Wallach, MD is a member of the following medical societies: American College of Nutrition, American Society for Bone and Mineral Research, American Society for Clinical Investigation, American Society for Clinical Nutrition, American Society for Nutritional Sciences, Association of American Physicians, and Endocrine Society

Disclosure: Nothing to disclose.

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Table 1. Clinical Classification of Human Osteopetrosis
Characteristic Adult onset Infantile Intermediate
Inheritance Autosomal dominant[3] Autosomal recessive Autosomal recessive
Bone marrow failure None Severe None
Prognosis Good Poor Poor
Diagnosis Often diagnosed incidentally Usually diagnosed before age 1y Not applicable
Table 2. Molecular Lesions Leading to Osteopetrosis in the Mouse
Gene Protein Lesion Phenotype Human Equivalent Key References
Csf1 M-CSF Naturally occurring op allele (frame shift) Reduced size, short limbs, domed skull, absence of teeth, poor hearing, poor fertility, extramedullary hematopoiesis, rescued by administration of M-CSF None known Yoshida et al, 1990
Csf1r M-CSF receptor Targeted disruption in exon 3 Reduced size, short limbs, domed skull, absence of teeth, poor fertility, extramedullary hematopoiesis, slightly more severe than Csf1opphenotype None known Dai et al, 2002
Tnfsf11 RANKL Targeted disruptions Osteopetrosis, failure of lymph nodes to develop None known Kong et al, 1999; Kim et al, 2000
Tnfrsf11a RANK Targeted disruptions Osteopetrosis, failure of lymph nodes to develop Duplications in exon 1 found in Paget disease and in familial expansile osteolysis Li et al, 2000
Ostm1 Osteopetrosis-associated transmembrane protein 1 Naturally occurring deletion Abnormal coat color, short lifespan, chondrodysplasia, failure of tooth eruption, osteopetrosis Infantile malignant osteopetrosis Chalhoub et al, 2003
Acp5 Tartrate resistant acid phosphatase (acid phosphatase 5) Targeted disruption Chondrodysplasia, osteopetrosis None known Hayman et al, 1996
Car2 Carbonic anhydrase II N -ethyl-N -nitrosourea (ENU) mutagenesis No skeletal phenotype in mouse, renal tubular acidosis, growth retardation Osteopetrosis with renal tubular acidosis Lewis et al, 1988
Clcn7 Chloride channel 7 Targeted disruptions Chondrodysplasia, osteopetrosis, failure of tooth eruption, optic atrophy, retinal degeneration, premature death Autosomal dominant type 2 osteopetrosis, autosomal recessive osteopetrosis Kornak et al, 2001; Cleiren et al, 2001
Ctsk Cathepsin K Targeted disruption Osteopetrosis with increased osteoclast surface Pycnodysostosis Saftig et al, 1998; Kiviranta et al, 2005
Gab2 Grb2 -associated binder 2 Targeted disruption Osteopetrosis, defective osteoclast maturation None known Wada et al, 2005
Mitf Micro-ophthalmia–associated transcription factor Spontaneous mutations, ENU mutagenesis, radiation mutagenesis, targeted disruption, untargeted insertional mutagenesis Pigmentation failure, failure of tooth eruption, osteopetrosis, microphthalmia, infertility in both sexes Waardenburg syndrome, type 2a; Tietz syndrome, ocular albinism with sensorineural deafness Hodgkinson et al, 1993; Steingrimsson et al, 1994
Src c-SRC Targeted disruption Osteopetrosis, failure of tooth eruption, premature death, reduced body size, female infertility, poor nursing None known Soriano et al, 1991
Tcirg1 116-kD subunit of vacuolar proton pump Spontaneous deletion, targeted disruption Osteopetrosis, failure of tooth eruption, chondrodysplasia, small size, premature death Autosomal recessive osteopetrosis Li et al, 1999; Scimeca et al, 2000; Frattini et al, 2000
Traf6 Tumor necrosis factor (TNF)-receptor–associated factor 6 Targeted disruptions Osteopetrosis, failure of tooth eruption, decreased body size, premature death, impaired maturation of dendritic cells None known Naito et al, 1999; Lomaga et al, 1999; Kobayashi et al, 2003
Table 3. Types of Adult Osteopetrosis
Characteristic Type I Type II
Skull sclerosis Marked sclerosis mainly of the vault Sclerosis mainly of the base
Spine Does not show much sclerosis Shows the rugger-jersey appearance
Pelvis No endobones Shows endobones in the pelvis
Transverse banding of metaphysis Absent May or may not be present
Risk of fracture Low High
Serum acid phosphatase Normal Very high
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