Osteopetrosis

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Adult-onset osteopetrosis (Albers-Schönberg Disease)
X-ray of the pelvis of a patient with osteopetrosis, adult onset form (Albers-Schönberg disease). Note the dense appearance.
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Osteopetrosis, literally "stone bone", also known as marble bone disease or Albers-Schönberg disease, is an extremely rare

inherited disorder whereby the bones harden, becoming denser, in contrast to more prevalent conditions like osteoporosis, in which the bones become less dense and more brittle, or osteomalacia, in which the bones soften. Osteopetrosis can cause bones to dissolve and break.[1]

It is one of the hereditary causes of

osteoclasts and their inability to resorb bone. Although human osteopetrosis is a heterogeneous disorder encompassing different molecular lesions and a range of clinical features, all forms share a single pathogenic nexus in the osteoclast. The exact molecular defects or location of the mutations taking place are unknown.[3] Osteopetrosis was first described in 1903, by German radiologist Albers-Schönberg
.

Signs and symptoms

A 17-year-old male with osteopetrosis: Typical cranial deformity and thoracic scoliosis

Despite this excess bone formation, people with osteopetrosis tend to have bones that are more brittle than normal. Mild osteopetrosis may cause no symptoms, and present no problems.[4]

The metabolism of calcium, phosphate, hormones, and Vitamin D

However, serious forms can result in the following:[4]

Comparison of bone pathology
Condition 		Calcium Phosphate Alkaline phosphatase Parathyroid hormone Comments
Osteopenia unaffected unaffected normal unaffected decreased bone mass
Osteopetrosis unaffected unaffected elevated unaffected [citation needed] thick dense bones also known as marble bone
Osteomalacia and rickets decreased decreased elevated elevated soft bones
Osteitis fibrosa cystica elevated decreased elevated elevated brown tumors
Paget's disease of bone unaffected unaffected variable (depending on stage of disease) unaffected abnormal bone architecture

Malignant infantile osteopetrosis

Main article: Malignant infantile osteopetrosis

Autosomal recessive osteopetrosis (ARO), also known as malignant infantile osteopetrosis or infantile malignant osteopetrosis (IMO), is a rare type of skeletal dysplasia characterized by a distinct radiographic pattern of overall increased density of the bones with fundamental involvement of the medullary portion. Infantile osteopetrosis typically manifests in infancy. Diagnosis is principally based on clinical and radiographic evaluation, confirmed by gene analysis where applicable.

Erlenmeyer flask deformity type 2 which is characterized by the absence of normal diaphysial metaphysical modeling of the distal femora with abnormal radiographic appearance of trabecular bone and alternating radiolucent metaphyseal bands.[5]

The precise and early diagnosis of infantile osteopetrosis is important for management of complications, genetic counselling, and timely institution of appropriate treatment, namely hematopoietic stem cell transplantation (HSCT), which offers a satisfactory treatment modality for a considerable percentage of infantile osteopetrosis.[6] Amelioration of radiographic bone lesions after HSCT in infantile osteopetrosis has been proposed as an important indicator of success of the therapy. A few publications with limited study participants have demonstrated the resolution of skeletal radiographic pathology following HSCT.[7][8]

Adult osteopetrosis

Autosomal dominant osteopetrosis (ADO) is also known as

Albers-Schonberg disease. Most do not know they have this disorder because most individuals do not show any symptoms. However, the ones that do show symptoms will typically have a curvature of the spine (scoliosis
), and multiple bone fractures. There are two types of adult osteopetrosis based on the basis of radiographic, biochemical, and clinical features.

Characteristic Type I Type II
Skull Sclerosis Marked sclerosis mainly of the vault Sclerosis mainly of the base
Spine Does not show signs of sclerosis Shows the sandwich appearance[9]
Pelvis No endobones Shows endobones in the pelvis
Risk of Fracture Low High
Serum Acid Phosphate Normal Very high

Many patients will have bone pains. The defects are very common and include neuropathies due to cranial nerve entrapment, osteoarthritis, and carpal tunnel syndrome. About 40% of patients will experience recurrent fractures of their bones. 10% of patients will have osteomyelitis of the mandible.

Causes

The various types of osteopetrosis are caused by genetic changes (mutations) in one of at least ten genes. There is nothing a parent can do before, during or after a pregnancy to cause osteopetrosis in a child.[4]

The genes associated with osteopetrosis are involved in the development and/or function of osteoclasts, cells that break down bone tissue when old bone is being replaced by new bone (bone remodeling). This process is necessary to keep bones strong and healthy. Mutations in these genes can lead to abnormal osteoclasts, or having too few osteoclasts. If this happens, old bone cannot be broken down as new bone is formed, so bones become too dense and prone to breaking.[4]

  • Mutations in the
    autosomal recessive
    osteopetrosis (the most severe form), and all known cases of intermediate autosomal osteopetrosis.
  • Mutations in the
    autosomal recessive
    osteopetrosis.
  • Mutations in the
    X-linked
    osteopetrosis.
  • Mutations in other genes are less common causes of osteopetrosis.
  • In about 30% percent of affected people, the cause is unknown.[citation needed]

Normally, bone growth is a balance between osteoblasts (cells that create bone tissue) and osteoclasts (cells that destroy bone tissue). Those with osteopetrosis have a deficiency of osteoclasts, meaning too little bone is being resorbed, resulting in too much bone being created.

Gene variation

Name
OMIM
 Gene
OPTA1 607634 LRP5 receptor
OPTA2 166600 CLCN7 chloride channel
OPTB1 259700 TCIRG1 ATPase
OPTB2 259710 RANKL
OPTB3 259730 CA2 (renal tubular acidosis)
OPTB4 611490 CLCN7 chloride channel
OPTB5 259720 OSTM1 ubiquitin ligase
OPTB6 611497 PLEKHM1 adapter protein
OPTB7 612301
TNFRSF11A
 (RANK receptor)

Mechanisms

Normal bone growth is achieved by a balance between bone formation by

osteoclasts.[10] In osteopetrosis, the number of osteoclasts may be reduced, normal, or increased. Most importantly, osteoclast dysfunction mediates the pathogenesis of this disease.[11]

Osteopetrosis is caused by underlying mutations that interfere with the acidification of the osteoclast resorption pit, for example due to a deficiency of the

calcium hydroxyapatite from the bone matrix. As bone resorption fails while bone formation continues, excessive bone is formed.[13]

Mutations in at least nine genes cause the various types of osteopetrosis. Mutations in the

X-linked type of osteopetrosis, OL-EDA-ID, results from mutations in the IKBKG gene. In about 30 percent of all cases of osteopetrosis, the cause of the condition is unknown.[14]

The genes associated with osteopetrosis are involved in the formation, development, and function of specialized cells called osteoclasts. These cells break down bone tissue during bone remodeling, a normal process in which old bone is removed and new bone is created to replace it. Bones are constantly being remodeled, and the process is carefully controlled to ensure that bones stay strong and healthy.[14]

Mutations in any of the genes associated with osteopetrosis lead to abnormal or missing osteoclasts. Without functional osteoclasts, old bone is not broken down as new bone is formed. As a result, bones throughout the skeleton become unusually dense. The bones are also structurally abnormal, making them prone to fracture. These problems with bone remodeling underlie all of the major features of osteopetrosis.[14]

Protein TNFSF 11(RANKL)

Diagnosis

The differential diagnosis of osteopetrosis includes other disorders that produce

skeletal dysplasias.[5] Besides, the differential diagnosis includes acquired conditions that induce osteosclerosis such as osteosclerotic metastasis notably carcinomas of the prostate gland and breast, Paget's disease of bone, myelofibrosis (primary disorder or secondary to intoxication or malignancy), Erdheim-Chester disease, osteosclerosing types of osteomyelitis, sickle cell disease, hypervitaminosis D, and hypoparathyroidism.[15]

Treatment

It was the first genetic disease treated with hematopoietic stem cell transplantation (osteoclasts are derived from hematopoietic precursors).[citation needed] There is no cure, although curative therapy with bone marrow transplantion is being investigated in clinical trials. It is believed the healthy marrow will provide cells from which osteoclasts will develop.[4] If complications occur in children, patients can be treated with vitamin D. Gamma interferon has also been shown to be effective, and it can be associated to vitamin D. Erythropoetin has been used to treat any associated anemia. Corticosteroids may alleviate both the anemia and stimulate bone resorption. Fractures and osteomyelitis can be treated as usual.[4] Treatment for osteopetrosis depends on the specific symptoms present and the severity in each person. Therefore, treatment options must be evaluated on an individual basis. Nutritional support is important to improve growth and it also enhances responsiveness to other treatment options. A calcium-deficient diet has been beneficial for some affected people.[4]

Treatment is necessary for the infantile form:[4]

  • Vitamin D (calcitriol) appears to stimulate dormant osteoclasts, which stimulates bone resorption
  • Gamma interferon can have long-term benefits. It improves white blood cell function (leading to fewer infections), decreases bone volume, and increases bone marrow volume.
  • Erythropoietin can be used for anemia, and corticosteroids can be used for anemia and to stimulate bone resorption.

Bone marrow transplantation (BMT) improves some cases of severe, infantile osteopetrosis associated with bone marrow failure, and offers the best chance of longer-term survival for individuals with this type.[4]

In pediatric (childhood) osteopetrosis, surgery is sometimes needed because of fractures. Adult osteopetrosis typically does not require treatment, but complications of the condition may require intervention. Surgery may be needed for aesthetic or functional reasons (such as multiple fractures, deformity, and loss of function), or for severe degenerative joint disease.[4]

Prognosis

The long-term-outlook for people with osteopetrosis depends on the subtype and the severity of the condition in each person. The severe infantile forms of osteopetrosis are associated with shortened life expectancy, with most untreated children not surviving past their first decade.

Bone marrow transplantation seems to have cured some infants with early-onset disease. However, the long-term prognosis after transplantation is unknown. For those with onset in childhood or adolescence, the effect of the condition depends on the specific symptoms (including how fragile the bones are and how much pain is present). Life expectancy in the adult-onset forms is normal.[16]

Prevalence

Approximately eight to 40 children are born in the United States each year with the malignant infantile type of osteopetrosis. One in every 100,000 to 500,000 individuals is born with this form of osteopetrosis. Higher rates have been found in Denmark and Costa Rica. Males and females are affected in equal numbers.[17]

The adult type of osteopetrosis affects about 1,250 individuals in the United States. One in every 200,000 individuals is affected by the adult type of osteopetrosis. Higher rates have been found in Brazil. Males and females are affected in equal numbers.[17]

Osteopetrosis affects one newborn out of every 20,000 to 250,000[18] worldwide, but the odds are much higher in the Russian region of Chuvashia (1 of every 3,500–4,000 newborns) due to genetic traits of the Chuvash people.[19][20]

Recent research

Recent research demonstrated that the systematic administration of RANKL for one month to Rankl(-/-) mice, which closely resemble the human disease, significantly improved the bone phenotype and has beneficial effects on bone marrow, spleen and thymus; major adverse effects arise only when mice are clearly overtreated. Overall, it provided evidence that the pharmacological administration of RANKL represents the appropriate treatment option for RANKL-deficient ARO patients, to be validated in a pilot clinical trial.[21]

Interferon gamma-1b is FDA-approved to delay the time to disease progression in patients with severe, malignant osteopetrosis.[22]

Notable cases

References

  1. ^ "Marble Bone Disease: A Review of Osteopetrosis and Its Oral Health Implications for Dentists". Cda-adc.ca. Retrieved 2013-10-17.
  2. PMID 18028760
    .
  3. PMID 19232111
    .
  4. ^ a b c d e f g h i j "Albers-Schonberg disease — CheckOrphan". www.checkorphan.org. 31 December 2014. Retrieved 2017-12-13.
  5. ^
    PMID 28326337.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  6. PMID 26012570.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  7. doi:10.1016/j.ejrnm.2016.12.013.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  8. S2CID 11287381.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  9. ^ Niknejad, Mohammadtaghi. "Sandwich vertebral body | Radiology Reference Article | Radiopaedia.org". Radiopaedia.
  10. ISBN 9780124160156
    .
  11. PMID 22499339
    . Retrieved August 19, 2016.
  12. ^ Askmyr MK et al.: Towards a better understanding and new therapeutics of osteopetrosis. Br J Haematol 140:597, 208
  13. ^ Robbins Basic Pathology by Kumar, Abbas, Fausto, and Mitchell, 8th edition
  14. ^ a b c Reference, Genetics Home. "osteopetrosis". Genetics Home Reference. Retrieved 2017-12-13.
  15. PMID 22084176.{{cite journal}}: CS1 maint: multiple names: authors list (link
    )
  16. ^ "Osteopetrosis | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". rarediseases.info.nih.gov. Archived from the original on 2017-12-13. Retrieved 2017-12-13.
  17. ^ a b "Osteopetrosis - NORD (National Organization for Rare Disorders)". NORD (National Organization for Rare Disorders). Retrieved 2017-12-13.
  18. ^ "Osteopetrosis: MedlinePlus Genetics". medlineplus.gov.
  19. ^ "Остеопетроз рецессивный (мраморная болезнь костей) - ДНК-диагностика - Центр Молекулярной Генетики". www.dnalab.ru.
  20. ^ Медицинская генетика Чувашии Archived February 1, 2016, at the Wayback Machine
  21. PMID 22836362
    .
  22. ^ "List of FDA Orphan Drugs | Genetic and Rare Diseases Information Center (GARD) – an NCATS Program". Archived from the original on 2021-11-23. Retrieved 2021-09-01.
  23. ^ Maddan, Heather (2007-09-23). "Marin County artist Laurel Burch dead at 61 of rare bone disease". The San Francisco Chronicle. Retrieved 2007-12-23.

Bibliography

External links

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