Osteopetrosis Differential Diagnoses

Author: Robert Blank, MD, PhD; Chief Editor: George T Griffing, MD more...

Updated: Jan 23, 2012

What would you like to print?

Diagnostic Considerations

In the differential diagnosis, include conditions that can result in diffuse osteosclerosis. Such disorders may include congenital diseases (eg, pyknodysostosis, hypoparathyroidism, pseudohypoparathyroidism), chemical poisoning (eg, fluoride, lead, beryllium), malignancies (leukemia, myeloproliferative diseases), and sickle cell disease. Osteoblastic metastases should also be considered in the differential diagnosis.

Differential Diagnoses

Proceed to Workup

Contributor Information and Disclosures

Author

Robert Blank, MD, PhD Associate Professor, Section of Endocrinology, University of Wisconsin Medical School; Consulting Staff, William S Middleton Veterans Affairs Medical Center

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

Disclosure: Nothing to disclose.

Coauthor(s)

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, and American Diabetes Association

Disclosure: Merck Honoraria Speaking, research trials; Novo Nordisk Honoraria Speaking and teaching; Sanofi Honoraria Speaking and teaching; takeda Honoraria Speaking and teaching; Abbott Honoraria Speaking and teaching; Lilly Grant/research funds Research trials; Gilead Research Trials; Novartis Grant/research funds Research trials; Pfizer Grant/research funds Research trials; Roche Grant/research funds Research trials

Chief Editor

George T Griffing, MD Professor 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, American College of Medical Practice Executives, American College of Physician Executives, American College of Physicians, American Diabetes Association, American Federation for Medical Research, American Heart Association, Central Society for Clinical Research, Endocrine Society, International Society for Clinical Densitometry, and Southern Society for Clinical Investigation

Disclosure: Nothing to disclose.

Additional Contributors

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.

References

Stark Z, Savarirayan R. Osteopetrosis. Orphanet J Rare Dis. Feb 20 2009;4:5. [Medline]. [Full Text].
Albers-Schonberg H. Roentgenbilder einer seltenen Knochennerkrankung. Munch Med Wochenschr. 1904;51:365.
Beighton P, Hamersma H, Cremin BJ. Osteopetrosis in South Africa. The benign, lethal and intermediate forms. S Afr Med J. Apr 21 1979;55(17):659-65. [Medline].
Baron R. Anatomy and Ultrastructure of Bone. In: Favus MJ, ed. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. 4^th ed. Philadelphia, Pa: Lippincott, Williams, and Wilkins; 1999:3-10.
Plow EF, Qin J, Byzova T. Kindling the flame of integrin activation and function with kindlins. Curr Opin Hematol. Sep 2009;16(5):323-8. [Medline].
Teitelbaum SL. Bone resorption by osteoclasts. Science. Sep 1 2000;289(5484):1504-8. [Medline].
Tolar J, Teitelbaum SL, Orchard PJ. Osteopetrosis. N Engl J Med. Dec 30 2004;351(27):2839-49. [Medline].
Wada T, Nakashima T, Oliveira-dos-Santos AJ, et al. The molecular scaffold Gab2 is a crucial component of RANK signaling and osteoclastogenesis. Nat Med. Apr 2005;11(4):394-9. [Medline].
Pangrazio A, Cassani B, Guerrini MM, Crockett JC, Marrella V, Zammataro L, et al. RANK-dependent autosomal recessive osteopetrosis: characterisation of 5 new cases with novel mutations. J Bone Miner Res. Nov 9 2011;[Medline].
Van Wesenbeeck L, Cleiren E, Gram J, et al. Six novel missense mutations in the LDL receptor-related protein 5 (LRP5) gene in different conditions with an increased bone density. Am J Hum Genet. Mar 2003;72(3):763-71. [Medline].
Cleiren E, Benichou O, Van Hul E, et al. Albers-Schönberg disease (autosomal dominant osteopetrosis, type II) results from mutations in the ClCN7 chloride channel gene. Hum Mol Genet. Dec 1 2001;10(25):2861-7. [Medline].
Kornak U, Kasper D, Bosl MR, et al. Loss of the ClC-7 chloride channel leads to osteopetrosis in mice and man. Cell. Jan 26 2001;104(2):205-15. [Medline].
el-Tawil T, Stoker DJ. Benign osteopetrosis: a review of 42 cases showing two different patterns. Skeletal Radiol. Nov 1993;22(8):587-93. [Medline].
Fotiadou A, Arvaniti M, Kiriakou V, et al. Type II autosomal dominant osteopetrosis: radiological features in two families containing five members with asymptomatic and uncomplicated disease. Skeletal Radiol. Oct 2009;38(10):1015-21. [Medline].
Symposium on Osteopetrosis. Proceedings and abstracts of the First International Symposium on Osteopetrosis: biology and therapy. October 23-24, 2003. Bethesda, Maryland, USA. J Bone Miner Res. Aug 2004;19(8):1356-75. [Medline].
Key L, Carnes D, Cole S, et al. Treatment of congenital osteopetrosis with high-dose calcitriol. N Engl J Med. Feb 16 1984;310(7):409-15. [Medline].
Armstrong DG, Newfield JT, Gillespie R. Orthopedic management of osteopetrosis: results of a survey and review of the literature. J Pediatr Orthop. Jan-Feb 1999;19(1):122-32. [Medline].
Mazzolari E, Forino C, Razza A, et al. A single-center experience in 20 patients with infantile malignant osteopetrosis. Am J Hematol. Aug 2009;84(8):473-9. [Medline].
Martinez C, Polgreen LE, Defor TE, et al. Characterization and management of hypercalcemia following transplantation for osteopetrosis. Bone Marrow Transplant. Oct 5 2009;[Medline].
Key LL Jr, Rodriguiz RM, Willi SM, et al. Long-term treatment of osteopetrosis with recombinant human interferon gamma. N Engl J Med. Jun 15 1995;332(24):1594-9. [Medline].
Croke M, Ross FP, Korhonen M, Williams DA, Zou W, Teitelbaum SL. Rac deletion in osteoclasts causes severe osteopetrosis. J Cell Sci. Nov 15 2011;124:3811-21. [Medline]. [Full Text].

Table 1. Clinical Classification of Human Osteopetrosis

Characteristic	Adult onset	Infantile	Intermediate
Inheritance	Autosomal dominant	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 Csf1^opphenotype	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

View Table List

Read more about Osteopetrosis on Medscape