![Blue sclerae](https://upload.wikimedia.org/wikipedia/commons/4/4c/Blue_sclerae.jpg)
Osteogenesis imperfecta (;
OI), colloquially known as brittle bone disease, is a group of
genetic disorders
A genetic disorder is a health problem caused by one or more abnormalities in the genome. It can be caused by a mutation in a single gene (monogenic) or multiple genes (polygenic) or by a chromosomal abnormality. Although polygenic disorders ...
that all result in
bone
A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, ...
s that
break
Break or Breaks or The Break may refer to:
Time off from duties
* Recess (break), time in which a group of people is temporarily dismissed from its duties
* Break (work), time off during a shift/recess
** Coffee break, a short mid-morning res ...
easily.
The range of symptoms—on the
skeleton as well as on the body's other
organs
In biology, an organ is a collection of tissues joined in a structural unit to serve a common function. In the hierarchy of life, an organ lies between tissue and an organ system. Tissues are formed from same type cells to act together in a f ...
—may be mild to severe.
Symptoms found in various types of OI include
whites of the eye (sclerae) that are blue instead,
short stature
Short stature refers to a height of a human which is below typical. Whether a person is considered short depends on the context. Because of the lack of preciseness, there is often disagreement about the degree of shortness that should be called ' ...
,
loose joints,
hearing loss
Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spoken ...
, breathing problems
and problems with the teeth (
dentinogenesis imperfecta
Dentinogenesis imperfecta (DI) is a genetic disorder of tooth development. It is inherited in an autosomal dominant pattern, as a result of mutations on chromosome 4q21, in the dentine sialophosphoprotein gene (DSPP). It is one of the most frequen ...
).
Potentially life-threatening
complications, all of which become more common in more severe OI, include: tearing (
dissection) of the major
arteries
An artery (plural arteries) () is a blood vessel in humans and most animals that takes blood away from the heart to one or more parts of the body (tissues, lungs, brain etc.). Most arteries carry oxygenated blood; the two exceptions are the pu ...
, such as
the aorta;
pulmonary valve insufficiency secondary to distortion of the
ribcage
The rib cage, as an enclosure that comprises the ribs, vertebral column and sternum in the thorax of most vertebrates, protects vital organs such as the heart, lungs and great vessels.
The sternum, together known as the thoracic cage, is a sem ...
;
and
basilar invagination.
The underlying mechanism is usually a problem with
connective tissue due to a lack of, or poorly formed,
type I collagen
Type I collagen is the most abundant collagen of the human body. It forms large, eosinophilic fibers known as collagen fibers.
It is present in scar tissue, the end product when tissue heals by repair, as well as tendons, ligaments, the endomy ...
.
In more than 90% of cases, OI occurs due to
mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA replication, DNA or viral repl ...
s in the ''
COL1A1
Collagen, type I, alpha 1, also known as alpha-1 type I collagen, is a protein that in humans is encoded by the gene. ''COL1A1'' encodes the major component of type I collagen, the fibrillar collagen found in most connective tissues, including c ...
'' or ''
COL1A2
Collagen alpha-2(I) chain is a protein that in humans is encoded by the ''COL1A2'' gene.
This gene encodes one of the chains for type I collagen, the fibrillar collagen found in most connective tissues. Mutations in this gene are associated with o ...
'' genes. These mutations may be
inherited from a person's parents in an
autosomal dominant manner but may also occur spontaneously (''
de novo'').
There are four
clinically defined types: type I, the least severe; type IV, moderately severe; type III, severe and progressively deforming; and type II,
perinatally lethal.
, 19 different genes are known to cause the 21 documented genetically defined types of OI, many of which are extremely rare and have only been documented in a few individuals.
Diagnosis is often based on symptoms and may be confirmed by collagen
biopsy
A biopsy is a medical test commonly performed by a surgeon, interventional radiologist, or an interventional cardiologist. The process involves extraction of sample cells or tissues for examination to determine the presence or extent of a dise ...
or
DNA sequencing.
Although there is no cure,
most cases of OI do not have a major effect on life expectancy,
death during childhood from it is rare,
and many adults with OI can achieve a significant degree of
autonomy despite
disability
Disability is the experience of any condition that makes it more difficult for a person to do certain activities or have equitable access within a given society. Disabilities may be cognitive, developmental, intellectual, mental, physical, ...
.
Maintaining a
healthy lifestyle
Health promotion is, as stated in the 1986 World Health Organization (WHO) Ottawa Charter for Health Promotion, the "process of enabling people to increase control over, and to improve their health."
Scope
The WHO's 1986 Ottawa Charter for Hea ...
by
exercising
Exercise is a body activity that enhances or maintains physical fitness and overall health and wellness.
It is performed for various reasons, to aid growth and improve strength, develop muscles and the cardiovascular system, hone athleti ...
, eating a balanced diet sufficient in
vitamin D
Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group are vitamin D3 (c ...
and
calcium
Calcium is a chemical element with the symbol Ca and atomic number 20. As an alkaline earth metal, calcium is a reactive metal that forms a dark oxide-nitride layer when exposed to air. Its physical and chemical properties are most similar t ...
, and avoiding
smoking can help prevent fractures.
Genetic counseling may be sought by those with OI to prevent their children from inheriting the disorder from them.
Treatment may include acute care of broken bones,
pain medication
An analgesic drug, also called simply an analgesic (American English), analgaesic (British English), pain reliever, or painkiller, is any member of the group of drugs used to achieve relief from pain (that is, analgesia or pain management). It ...
,
physical therapy,
mobility aids
A mobility aid is a device designed to assist walking or otherwise improve the mobility of people with a mobility impairment.
There are various walking aids which can help people with impaired ability to walk, and wheelchairs or mobility scoot ...
such as
leg braces
Orthotics ( el, Ορθός, translit=ortho, lit=to straighten, to align) is a medical specialty that focuses on the design and application of orthoses, or braces. An is "an externally applied device used to influence the structural and functio ...
and
wheelchairs
A wheelchair is a chair with wheels, used when walking is difficult or impossible due to illness, injury, problems related to old age, or disability. These can include spinal cord injuries (paraplegia, hemiplegia, and quadriplegia), cerebral pa ...
,
vitamin D supplementation, and, especially in childhood,
rodding surgery.
Rodding is an implantation of metal
intramedullary rods along the
long bones
The long bones are those that are longer than they are wide. They are one of five types of bones: long, short, flat, irregular and sesamoid. Long bones, especially the femur and tibia, are subjected to most of the load during daily activities a ...
(such as the
femur
The femur (; ), or thigh bone, is the proximal bone of the hindlimb in tetrapod vertebrates. The head of the femur articulates with the acetabulum in the pelvic bone forming the hip joint, while the distal part of the femur articulates wit ...
) in an attempt to strengthen them.
Medical research also supports the use of medications of the
bisphosphonate
Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis. They are called bisphosphonates because they ...
class, such as
pamidronate
Pamidronic acid or pamidronate disodium or APD (marketed as Aredia among others), is a nitrogen-containing bisphosphonate used to prevent osteoporosis.
It was patented in 1971 and approved for medical use in 1987.
Medical uses
It is used to pre ...
, to increase
bone density
Bone density, or bone mineral density, is the amount of bone mineral in bone tissue. The concept is of mass of mineral per volume of bone (relating to density in the physics sense), although clinically it is measured by proxy according to optic ...
. Bisphosphonates are especially effective in children,
however it is unclear if they either increase
quality of life
Quality of life (QOL) is defined by the World Health Organization as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards ...
or decrease the rate of fracture incidence.
OI affects only about one in 15,000 to 20,000 people, making it a
rare genetic disease.
[ Outcomes depend on the genetic cause of the disorder (its type). Type I (the least severe) is the most common, with other types comprising a minority of cases.] Moderate-to-severe OI primarily affects mobility; if rodding surgery is performed during childhood, some of those with more severe types of OI may gain the ability to walk. The condition has been described since ancient history. The Latinate
Latin (, or , ) is a classical language belonging to the Italic branch of the Indo-European languages. Latin was originally a dialect spoken in the lower Tiber area (then known as Latium) around present-day Rome, but through the power of the ...
term ''osteogenesis imperfecta'' was coined by Dutch anatomist Willem Vrolik
Willem Vrolik (29 April 1801 – 22 December 1863) was a Dutch anatomist and pathologist who was a native of Amsterdam. He was a pioneer in the field of vertebrate teratology.
He studied medicine at the University of Utrecht, and furthered hi ...
in 1849; translated literally, it means "imperfect bone formation".
__TOC__
Signs and symptoms
Orthopedic
The main symptom of osteogenesis imperfecta is fragile, low mineral density bones; all types of OI have some bone involvement. In moderate and especially severe OI, the long bones may be bowed, sometimes extremely so. The weakness of the bones causes them to fracture easily; a study in Pakistan found an average of 5.8 fractures per year in untreated children. Fractures typically occur much less after puberty
Puberty is the process of physical changes through which a child's body matures into an adult body capable of sexual reproduction. It is initiated by hormonal signals from the brain to the gonads: the ovaries in a girl, the testes in a bo ...
, but begin to increase again in women after menopause
Menopause, also known as the climacteric, is the time in women's lives when menstrual periods stop permanently, and they are no longer able to bear children. Menopause usually occurs between the age of 47 and 54. Medical professionals often ...
and in men between the ages of 60 and 80.
Joint hypermobility
Hypermobility, also known as double-jointedness, describes joints that stretch farther than normal. For example, some hypermobile people can bend their thumbs backwards to their wrists, bend their knee joints backwards, put their leg behind the h ...
is also a common sign of OI, thought to be because the affected genes are the same as those that cause some types of Ehlers–Danlos syndrome. [One OI mutation also causes combined Ehler–Danlos syndrome: "OIEDS1". ( Cabral, ''et al.'' 2005, Rasmussen 2020)]
Otologic
By the age of 50, about 50% of adults with OI experience significant hearing loss
Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spoken ...
, much earlier as compared to the general population. Hearing loss in OI may or may not be associated with visible deformities of the ossicles and inner ear. Hearing loss frequently begins during the second, third, and fourth decades of life, and may be conductive
In physics and electrical engineering, a conductor is an object or type of material that allows the flow of charge (electric current) in one or more directions. Materials made of metal are common electrical conductors. Electric current is gene ...
, sensorineural
Sensorineural hearing loss (SNHL) is a type of hearing loss in which the root cause lies in the inner ear or sensory organ (cochlea and associated structures) or the vestibulocochlear nerve ( cranial nerve VIII). SNHL accounts for about 90% of r ...
, or a combination of both ("mixed"). If hearing loss does not occur by age 50, it is significantly less likely to occur in the years afterwards. Mixed hearing loss is most common among those with OI of all age groups, while conductive hearing loss is most likely to affect older people, with sensorineural hearing loss most likely to affect children.
Although relatively rare, OI-related hearing loss can also begin in childhood; in a study of forty-five children aged four to sixteen, two were found to be affected, aged 11 and 15. In a different 2008 study, the hearing of 41 people with OI was checked. The results showed that 88% of those over 20 years of age had some form of hearing loss, while only 38% of those under 20 did.
Hearing loss is most common in type I OI; it is less common in types III and IV. Other parts of the inner ear may also be affected by OI. causing balance
Balance or balancing may refer to:
Common meanings
* Balance (ability) in biomechanics
* Balance (accounting)
* Balance or weighing scale
* Balance as in equality or equilibrium
Arts and entertainment Film
* ''Balance'' (1983 film), a Bulgaria ...
issues; however, only small studies have found links between vertigo
Vertigo is a condition where a person has the sensation of movement or of surrounding objects moving when they are not. Often it feels like a spinning or swaying movement. This may be associated with nausea, vomiting, sweating, or difficulties w ...
and OI. OI may worsen the outcome of medical treatments which correct hearing loss.
Besides OI's association with sensorineural hearing loss, OI is associated with a number of neurological abnormalities, usually involving the central nervous system
The central nervous system (CNS) is the part of the nervous system consisting primarily of the brain and spinal cord. The CNS is so named because the brain integrates the received information and coordinates and influences the activity of all p ...
, due to deformities
A deformity, dysmorphism, or dysmorphic feature is a major abnormality of an organism that makes a part of the body appear or function differently than how it is supposed to.
Causes
Deformity can be caused by a variety of factors:
*Arthritis an ...
in the skeletal structures surrounding it. Neurological complications, especially basilar invagination, may adversely affect life expectancy. In OI, this is most often due to upwards migration of the dens, a feature of the C2 vertebra. Neurosurgery
Neurosurgery or neurological surgery, known in common parlance as brain surgery, is the medical specialty concerned with the surgical treatment of disorders which affect any portion of the nervous system including the brain, spinal cord and pe ...
may be needed to correct severe abnormalities when they risk the patient's life or cause either great suffering or intolerable neurological deficits.
Systemic
As its biological causes have been more precisely determined, it has become more widely recognized that while the primary disease process of OI happens in the bones, the most common types of OI—those caused by type I collagen gene mutations—affect virtually all of the human body's organs
In biology, an organ is a collection of tissues joined in a structural unit to serve a common function. In the hierarchy of life, an organ lies between tissue and an organ system. Tissues are formed from same type cells to act together in a f ...
in some way.
Type I collagen is present throughout the circulatory
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
and respiratory systems
The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animals and plants. The anatomy and physiology that make this happen varies grea ...
: from the ventricles of the heart itself, to the heart valves
A heart valve is a one-way valve that allows blood to flow in one direction through the chambers of the heart. Four valves are usually present in a mammalian heart and together they determine the pathway of blood flow through the heart. A heart v ...
, to the vasculature
The blood circulatory system is a system of organs that includes the heart, blood vessels, and blood which is circulated throughout the entire body of a human or other vertebrate. It includes the cardiovascular system, or vascular system, tha ...
, it is an integral part of the connective tissue of the lungs
The lungs are the primary organs of the respiratory system in humans and most other animals, including some snails and a small number of fish. In mammals and most other vertebrates, two lungs are located near the backbone on either side ...
. As such, cardiovascular complications, among them aortic insufficiency
Aortic regurgitation (AR), also known as aortic insufficiency (AI), is the leaking of the aortic valve of the heart that causes blood to flow in the reverse direction during ventricular diastole, from the aorta into the left ventricle. As a conseq ...
, aortic aneurysm, and arterial dissections, are sometimes comorbid
In medicine, comorbidity - from Latin morbus ("sickness"), co ("together"), -ity (as if - several sicknesses together) - is the presence of one or more additional conditions often co-occurring (that is, concomitant or concurrent) with a primary ...
with OI, but not as frequently as they are comorbid with Marfan syndrome.
Respiratory illnesses are a major cause of death in OI. The most obvious source of respiratory problems in OI is pulmonary insufficiency
Pulmonary (or pulmonic) insufficiency (or incompetence, or regurgitation) is a condition in which the pulmonary valve is incompetent and allows backflow from the pulmonary artery to the right ventricle of the heart during diastole. While a small ...
caused by problems in the architecture of the thoracic wall
The thoracic wall or chest wall is the boundary of the thoracic cavity.
Structure
The bony skeletal part of the thoracic wall is the rib cage, and the rest is made up of muscle, skin, and fasciae.
The chest wall has 10 layers, namely (from sup ...
. However, respiratory tract infections
Respiratory tract infections (RTIs) are infectious diseases involving the respiratory tract. An infection of this type usually is further classified as an upper respiratory tract infection (URI or URTI) or a lower respiratory tract infection (LRI ...
, such as pneumonia
Pneumonia is an inflammatory condition of the lung primarily affecting the small air sacs known as alveoli. Symptoms typically include some combination of productive or dry cough, chest pain, fever, and difficulty breathing. The severi ...
, are also more fatal among those with OI than the general population. Those with more severe ribcage
The rib cage, as an enclosure that comprises the ribs, vertebral column and sternum in the thorax of most vertebrates, protects vital organs such as the heart, lungs and great vessels.
The sternum, together known as the thoracic cage, is a sem ...
deformities were found to have worse lung restriction in a small-scale 2012 study involving 22 Italian patients with OI types III and IV, plus 26 non-affected controls.
OI—especially its severe form type III—also has effects on the gastrointestinal system. It was found to be associated with recurrent abdominal pain and chronic constipation
Constipation is a bowel dysfunction that makes bowel movements infrequent or hard to pass. The stool is often hard and dry. Other symptoms may include abdominal pain, bloating, and feeling as if one has not completely passed the bowel movement ...
in two studies on patients affected by OI. Chronic constipation is especially common, and is thought to be aggravated by an asymmetric pelvis ( acetabular protrusion). Especially in childhood, OI-associated constipation may cause a feeling of fullness and associated food refusal, leading to malnutrition
Malnutrition occurs when an organism gets too few or too many nutrients, resulting in health problems. Specifically, it is "a deficiency, excess, or imbalance of energy, protein and other nutrients" which adversely affects the body's tissues ...
.
Classification
There are two typing systems for OI in modern use. The first, created by David Sillence in 1979, classifies patients into four types, or syndromes, according to their clinical presentation
In a physical examination, medical examination, or clinical examination, a medical practitioner examines a patient for any possible medical signs or symptoms of a medical condition. It generally consists of a series of questions about the patie ...
, without taking into account the genetic cause of their disease. The second system expands on the Sillence model, but assigns new numbered types genetically as they are found. Therefore, people with OI can be described as having both a ''clinical'' type and a ''genetic'' type, which may or may not be equivalent.
Type I is the most common, and 90% of cases result from mutations to either ''COL1A1
Collagen, type I, alpha 1, also known as alpha-1 type I collagen, is a protein that in humans is encoded by the gene. ''COL1A1'' encodes the major component of type I collagen, the fibrillar collagen found in most connective tissues, including c ...
'' or ''COL1A2
Collagen alpha-2(I) chain is a protein that in humans is encoded by the ''COL1A2'' gene.
This gene encodes one of the chains for type I collagen, the fibrillar collagen found in most connective tissues. Mutations in this gene are associated with o ...
''. Symptoms vary a lot between types, as well as vary from person to person, even in the same family.
As of 2021, 21 types of OI have been defined:
Sillence types
Sillence's four types have both a clinical and a genetic meaning; the descriptions below are clinical and can be applied to several genetic types of OI. When used to refer to a genetic as well as a clinical type, it indicates that the clinical symptoms are indeed caused by mutations in the ''COL1A1'' or ''COL1A2'' genes which are inherited in an autosomal dominant fashion.
Type
Collagen is of normal quality but is produced in insufficient quantities. Bones fracture more easily than in the general public, but not as easily as more severe types of OI; there might be scoliosis, albeit mild compared to OI types III and IV, with a lower Cobb angle
The Cobb angle is a measurement of bending disorders of the vertebral column such as scoliosis and traumatic deformities.
Definition and method
It is defined as the greatest angle at a particular region of the vertebral column, when measured from ...
; the joints may be loose; blue sclerae may be apparent; hearing loss is likely to occur; and there might be a slight decrease in height. Because cases exist missing one or more of these symptoms, OI type I in some cases goes undetected into adulthood.
Some further split type I into types I–A and I–B, defined as being distinguished by the absence (I–A) or presence (I–B) of dentinogenesis imperfecta
Dentinogenesis imperfecta (DI) is a genetic disorder of tooth development. It is inherited in an autosomal dominant pattern, as a result of mutations on chromosome 4q21, in the dentine sialophosphoprotein gene (DSPP). It is one of the most frequen ...
(opalescent teeth). People with type I generally have a normal lifespan.
Type
Collagen is fatally defective at its C-terminus. Most cases result in death shortly after birth, or within the first year of life, due to respiratory failure
Respiratory failure results from inadequate gas exchange by the respiratory system, meaning that the arterial oxygen, carbon dioxide, or both cannot be kept at normal levels. A drop in the oxygen carried in the blood is known as hypoxemia; a rise ...
. Another common cause of death is intracranial bleeds from skull fractures present at, or sustained during or shortly after, birth. In many cases, the newborn already has multiple broken bones at the time of birth. Type II infants also exhibit severe respiratory
The respiratory system (also respiratory apparatus, ventilatory system) is a biological system consisting of specific organs and structures used for gas exchange in animals and plants. The anatomy and physiology that make this happen varies gre ...
problems, and have severely deformed bones. Sixty percent of infants die less than 24 hours after being born, and survival after the first year is extremely unlikely and normally requires mechanical ventilation
Mechanical ventilation, assisted ventilation or intermittent mandatory ventilation (IMV), is the medical term for using a machine called a ventilator to fully or partially provide artificial ventilation. Mechanical ventilation helps move a ...
. In the rare cases of infants who survive their first year of life, severe developmental and motor delays are seen; neither of two infants studied in 2019, both aged around two years, had achieved head control, and both required a ventilator to breathe.
Type II is also known as the "lethal perinatal
Prenatal development () includes the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal devel ...
" form of OI, and is not compatible with survival into adulthood. Due to similarly severely deformed bones, sometimes infants with severe type III are wrongly initially classified as type II; once long-term survival is shown, they are considered as having type III instead.
Type
Collagen quantity is sufficient, but is not of a high enough quality. Clinical differentiation between types III and IV is not always simple, and is further confounded by the fact that an untreated adult with type IV may have worse symptoms than a treated adult with type III; features only found in type III are its progressively deforming nature and the presence of a face with a "triangular" appearance. Another differentiating factor between type III and IV is blue sclerae; in type III, infants commonly have blue sclerae that gradually turn white with age, but blue sclerae are not commonly seen in type IV, although they are seen in 10% of cases.
OI type III causes osteopenic bones that fracture very easily, sometimes even ''in utero'', often leading to hundreds of fractures during a lifetime; early scoliosis that progresses until puberty; dwarfism (a final adult height frequently less than ); loose joints; and possible respiratory problems due to low rib cage
The rib cage, as an enclosure that comprises the ribs, vertebral column and sternum in the thorax of most vertebrates, protects vital organs such as the heart, lungs and great vessels.
The sternum, together known as the thoracic cage, is a sem ...
volume causing low lung volumes
Lung volumes and lung capacities refer to the volume of air in the lungs at different phases of the respiratory cycle.
The average total lung capacity of an adult human male is about 6 litres of air.
Tidal breathing is normal, resting breath ...
.
Due to the severity of the issues with the bones, neurological and seizure disorders
Epilepsy is a group of non-communicable neurological disorders characterized by recurrent epileptic seizures. Epileptic seizures can vary from brief and nearly undetectable periods to long periods of vigorous shaking due to abnormal electrical ...
are more likely to develop in type III. Basilar invagination, which puts pressure on the brainstem, may cause or contribute to early death; surgical treatment of it is more complex in OI cases.
Type
Collagen quantity is sufficient, but is not of a high enough quality. Type IV is for cases of variable severity, which do not fit into either types III or I. While one of Sillence's required characteristics for type IV was having normal sclerae, modern classification allows even those with blue sclerae to fit the criteria for type IV if they meet the other clinical requirements of the type.
In type IV, bone deformity can be mild to severe, bones fracture easily (especially before puberty), dwarfism is common, vertebral collapse and scoliosis are evident, and hearing loss is possible, although uncommon. Type IV OI is mostly defined in contrast to type III and type I, being the clinical classification for patients somewhere in the middle ground between the two. As such, type IV OI is often termed "variable" OI, with the severity of even those in the same family (so, with the same genetic mutation) differing.
Prepubertal bone fracture rates are another way of clinically assessing type IV OI—those with it tend to have fracture rates of ≈1 per year, compared to ≈3 per year for severe OI (type III).
As in type I, some further split type IV into types IV–A and IV–B, defined again by the absence (IV–A) or presence (IV–B) of dentinogenesis imperfecta
Dentinogenesis imperfecta (DI) is a genetic disorder of tooth development. It is inherited in an autosomal dominant pattern, as a result of mutations on chromosome 4q21, in the dentine sialophosphoprotein gene (DSPP). It is one of the most frequen ...
.
Genetically defined types (types –)
As of 2020, fifteen types of OI are defined genetically:
* Type – Having the same clinical features as type IV, it can be clinically distinguished by observing a "mesh-like" appearance to a bone biopsy A bone biopsy is a procedure in which a small bone sample is removed from the outer layers of bone for examination, unlike a bone marrow biopsy, which involves the innermost part of the bone. The bone biopsy sample retains the architecture of bone w ...
under a microscope. Type V can be further distinguished from other types of OI by the "V triad": an opaque band (visible on X-ray) adjacent to the growth plates
The epiphyseal plate (or epiphysial plate, physis, or growth plate) is a hyaline cartilage plate in the metaphysis at each end of a long bone. It is the part of a long bone where new bone growth takes place; that is, the whole bone is alive, with ...
; hypertrophic
Hypertrophy is the increase in the volume of an organ or tissue due to the enlargement of its component cells. It is distinguished from hyperplasia, in which the cells remain approximately the same size but increase in number.Updated by Linda J. ...
calluses
A callus is an area of thickened and sometimes hardened skin that forms as a response to repeated friction, pressure, or other irritation. Since repeated contact is required, calluses are most often found on the feet and hands, but they may o ...
(abnormally large masses of bony repair tissue) which form at fracture sites during the healing process; and calcification of the interosseous membrane of the forearm
The interosseous membrane of the forearm (rarely middle or intermediate radioulnar joint) is a fibrous sheet that connects the interosseous margins of the radius and the ulna. It is the main part of the radio-ulnar syndesmosis, a fibrous joint be ...
, which may make it difficult to turn the wrist. Other features of this condition may include pulled elbow, and, as in other types of OI, long bone bowing and hearing loss. Cases of this type are caused by mutations in the '' IFITM5'' gene on chromosome 11
Chromosome 11 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome. Chromosome 11 spans about 135 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the tot ...
p15.5. The separation of type V from type IV OI, its clinical type, was initially suggested even before its genetic cause was known, by Glorieux ''et al''. in 2000. Type V is relatively common compared to other genetically defined types of OI—4% of OI patients at the genetics department of the Brazilian Hospital de Clínicas de Porto Alegre were found to have it.
* Type – With the same clinical features as type III, it is distinguished by bones which have an appearance similar to that seen in osteomalacia
Osteomalacia is a disease characterized by the softening of the bones caused by impaired bone metabolism primarily due to inadequate levels of available phosphate, calcium, and vitamin D, or because of resorption of calcium. The impairment of bon ...
. Type VI is caused by a loss-of-function mutation
In biology, a mutation is an alteration in the nucleic acid sequence of the genome of an organism, virus, or extrachromosomal DNA. Viral genomes contain either DNA or RNA. Mutations result from errors during DNA or viral replication, mitos ...
in the '' SERPINF1'' gene on chromosome 17
Chromosome 17 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 17 spans more than 83 million base pairs (the building material of DNA) and represents between 2.5 and 3% of the total D ...
p13.3.
* Type – OI caused by a mutation in the gene '' CRTAP'' on chromosome 3
Chromosome 3 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 3 spans almost 200 million base pairs (the building material of DNA) and represents about 6.5 percent of the total DNA in ...
p22.3; clinically similar to OI types II and III, depending on affected individual. Type VII was the first recessive OI type confirmed, initially found among First Nations
First Nations or first peoples may refer to:
* Indigenous peoples, for ethnic groups who are the earliest known inhabitants of an area.
Indigenous groups
*First Nations is commonly used to describe some Indigenous groups including:
**First Natio ...
people in Quebec
Quebec ( ; )According to the Canadian government, ''Québec'' (with the acute accent) is the official name in Canadian French and ''Quebec'' (without the accent) is the province's official name in Canadian English is one of the thirtee ...
.
* Type – OI caused by a mutation in the gene '' LEPRE1'' on chromosome 1
Chromosome 1 is the designation for the largest human chromosome. Humans have two copies of chromosome 1, as they do with all of the autosomes, which are the non- sex chromosomes. Chromosome 1 spans about 249 million nucleotide base pairs, which ...
p34.2; clinically similar to OI types II and III, depending on affected individual.
* Type – OI caused by homozygous or compound heterozygous mutation in the ''PPIB
Peptidyl-prolyl cis-trans isomerase B is an enzyme that is encoded by the ''PPIB'' gene. As a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family, this protein catalyzes the cis-trans isomerization of proline imidic peptide bonds, w ...
'' gene on chromosome 15
Chromosome 15 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 15 spans about 102 million base pairs (the building material of DNA) and represents between 3% and 3.5% of the total DN ...
q22.31.
* Type – OI caused by homozygous mutation in the '' SERPINH1'' gene on chromosome 11q13.
* Type – OI caused by mutations in ''FKBP10
FK506-binding protein 10 is a protein that in humans is encoded by the ''FKBP10'' gene.
The protein encoded by this gene belongs to the FKBP-type peptidyl-prolyl cis/trans isomerase family. It is located in endoplasmic reticulum and acts as mol ...
'' on chromosome 17q21. The mutations cause a decrease in secretion of trimeric procollagen molecules. Other mutations in this gene can cause autosomal recessive Bruck syndrome, which is similar to OI.
* Type – OI caused by a frameshift mutation in '' SP7'' on chromosome 12
Chromosome 12 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 12 spans about 133 million base pairs (the building material of DNA) and represents between 4 and 4.5 percent of the to ...
q13.13. This mutation causes bone deformities, fractures, and delayed tooth eruption
Tooth eruption is a process in tooth development in which the teeth enter the mouth and become visible. It is currently believed that the periodontal ligament plays an important role in tooth eruption. The first human teeth to appear, the deciduo ...
.
* Type – OI caused by a mutation in the bone morphogenetic protein 1 (''BMP1'') gene on chromosome 8
Chromosome 8 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 8 spans about 145 million base pairs (the building material of DNA) and represents between 4.5 and 5.0% of the total DNA ...
p21.3. This mutation causes recurrent fractures, high bone mass, and hypermobile joints.
* Type – OI caused by mutations in the '' TMEM38B'' gene on chromosome 9
Chromosome 9 is one of the 23 pairs of chromosomes in humans. Humans normally have two copies of this chromosome, as they normally do with all chromosomes. Chromosome 9 spans about 138 million base pairs of nucleic acids (the building blocks of D ...
q31.2. This mutation causes recurrent fractures and osteopenia
Osteopenia, known as "low bone mass" or "low bone density", is a condition in which bone mineral density is low. Because their bones are weaker, people with osteopenia may have a higher risk of fractures, and some people may go on to develop osteop ...
, although the disease trajectory is highly variable.
* Type – OI caused by homozygous or compound heterozygous mutations in the ''WNT1'' gene on chromosome 12q13.12. It is autosomal recessive.
* Type – OI caused by mutations in the ''CREB3L1
CAMP responsive element binding protein 3 like 1 is a responsive element binding protein that in humans is encoded by the CREB3L1 gene.
Function
The protein encoded by this gene is normally found in the membrane of the endoplasmic reticulum (ER ...
'' gene on chromosome 11p11.2. The homozygous mutation causes prenatal onset of recurrent fractures of the ribs and long bones, demineralization, decreased ossification of the skull, and blue sclerae; it is clinically type II or type III. Family members who are heterozygous for OI XVI may have recurrent fractures, osteopenia and blue sclerae.
* Type – OI caused by homozygous mutation in the ''SPARC
SPARC (Scalable Processor Architecture) is a reduced instruction set computer (RISC) instruction set architecture originally developed by Sun Microsystems. Its design was strongly influenced by the experimental Berkeley RISC system develope ...
'' gene on chromosome 5
Chromosome 5 is one of the 23 pairs of chromosomes in humans. People normally have two copies of this chromosome. Chromosome 5 spans about 181 million base pairs (the building blocks of DNA) and represents almost 6% of the total DNA in cells. C ...
q33, causing a defect in the protein osteonectin
Osteonectin (ON) also known as secreted protein acidic and rich in cysteine (SPARC) or basement-membrane protein 40 (BM-40) is a protein that in humans is encoded by the ''SPARC'' gene.
Osteonectin is a glycoprotein in the bone that binds calciu ...
, which leads to severe disease characterized by generalized platyspondyly
Congenital vertebral anomalies are a collection of malformations of the spine. Most, around 85%, are not clinically significant, but they can cause compression of the spinal cord by deforming the vertebral canal or causing instability. This condi ...
, dependence on a wheelchair, and recurrent fractures.
* Type – OI caused by homozygous mutation in the '' FAM46A'' gene on chromosome 6q14.1. Characterized by congenital bowing of the long bones, Wormian bones
Wormian bones, also known as intrasutural bones or sutural bones, are extra bone pieces that can occur within a suture (joint) in the skull. These are irregular isolated bones that can appear in addition to the usual centres of ossification of the ...
, blue sclerae, vertebral collapse, and multiple fractures in the first years of life.
*Type – OI caused by hemizygous mutation in the '' MBTPS2'' gene on chromosome X
The X chromosome is one of the two sex-determining chromosomes (allosomes) in many organisms, including mammals (the other is the Y chromosome), and is found in both males and females. It is a part of the XY sex-determination system and XO sex ...
p22.12. Thus far, OI type XIX is the only known type of OI with an X-linked recessive
X-linked recessive inheritance is a mode of inheritance in which a mutation in a gene on the X chromosome causes the phenotype to be always expressed in males (who are necessarily homozygous for the gene mutation because they have one X and one Y ...
pattern of inheritance, making it the only type that is more common in males than females. OI type XIX disrupts regulated intramembrane proteolysis Intramembrane proteases (IMPs), also known as intramembrane-cleaving proteases (I-CLiPs), are enzymes that have the property of cleaving transmembrane domains of integral membrane proteins. All known intramembrane proteases are themselves integral m ...
, which is critical for healthy bone formation.
*Type – OI caused by homozygous mutation in the '' MESD'' gene on chromosome 15q25.1. Initial studies of type XX indicate that it may cause global developmental delay
Global developmental delay is an umbrella term used when children are significantly delayed in their cognitive and physical development. It can be diagnosed when a child is delayed in one or more milestones, categorised into motor skills, speech ...
, a first among OI types. OI type XX disrupts the Wnt signaling pathway
The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling ...
, which is thought to have a role in bone development.
*Type – OI caused by homozygous mutation in the ''KDELR2
ER lumen protein retaining receptor 2 is a protein that in humans is encoded by the ''KDELR2'' gene.
Retention of resident soluble proteins in the lumen of the endoplasmic reticulum (ER) is achieved in both yeast and animal cells by their continua ...
'' gene on chromosome 7
Chromosome 7 is one of the 23 pairs of chromosomes in humans, who normally have two copies of this chromosome. Chromosome 7 spans about 159 million base pairs (the building material of DNA) and represents between 5 and 5.5 percent of the total D ...
p22.1. Causes disease clinically similar to types II and III, thought to be related to inability of chaperone protein HP47 to unbind from collagen type I, as to do so it needs to bind to the missing ER lumen protein retaining receptor 2 protein encoded by ''KDELR2''.
Given the rapid rate of type discovery, it is extremely likely that there are other genes associated with OI that have yet to be reported.
Genetics
Osteogenesis imperfecta is a group of genetic disorders, all of which cause bone fragility. OI has high genetic heterogeneity Genetic heterogeneity occurs through the production of single or similar phenotypes through different genetic mechanisms. There are two types of genetic heterogeneity: allelic heterogeneity, which occurs when a similar phenotype is produced by diffe ...
, that is, many different genetic mutations lead to the same or similar sets of observable symptoms (phenotypes
In genetics, the phenotype () is the set of observable characteristics or phenotypic trait, traits of an organism. The term covers the organism's morphology (biology), morphology or physical form and structure, its Developmental biology, dev ...
).
The main causes for developing the disorder are a result of mutations in the ''COL1A1'' and/or ''COL1A2'' genes which are jointly responsible for the production of collagen type I
Type I collagen is the most abundant collagen of the human body. It forms large, eosinophilic fibers known as collagen fibers.
It is present in scar tissue, the end product when tissue heals by repair, as well as tendons, ligaments, the endo ...
. Approximately 90% of people with OI are heterozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
for mutations in either the ''COL1A1'' or ''COL1A2'' genes. There are several biological factors that are results of the dominant form of OI. These factors include: intracellular stress; abnormal tissue mineralization; abnormal cell to cell interactions; abnormal cell- matrix interactions; a compromised cell matrix structure; and, abnormal interaction between non-collagenous proteins and collagen.
Previous research lead to the belief that OI was an autosomal dominant disorder with few other variations in genomes. However, with the lowering of the cost of DNA sequencing in the wake of 2003's Human Genome Project, autosomal recessive forms of the disorder have been identified. Recessive forms of OI relate heavily to defects in the collagen chaperones responsible for production of procollagen
Collagen () is the main structural protein in the extracellular matrix found in the body's various connective tissues. As the main component of connective tissue, it is the most abundant protein in mammals, making up from 25% to 35% of the whole ...
and the assembly of the related proteins. Examples of collagen chaperones that are defective in patients with recessive forms of OI include chaperone HSP47 ( Cole-Carpenter syndrome) and FKBP65. Mutations in these chaperones result in an improper folding
Fold, folding or foldable may refer to:
Arts, entertainment, and media
* ''Fold'' (album), the debut release by Australian rock band Epicure
* Fold (poker), in the game of poker, to discard one's hand and forfeit interest in the current pot
*Abov ...
pattern in the collagen 1 proteins which causes the recessive form of the disorder. There are three significant types of OI that are a result of mutations in the collagen prolyl 3-hydroxylation complex (components CRTAP, P3H1, and CyPB). These components are responsible for the modification of collagen α1(l)Pro986. Mutations in other genes such as ''SP7'', ''SERPINF1'', '' TMEM38B'' and ''BMP1'' can also lead to irregularly formed proteins and enzymes that result in other recessive types of osteogenesis imperfecta.
Defects in the proteins pigment epithelium-derived factor (PEDF) and bone-restricted interferon-induced transmembrane protein (BRIL) are the causes of type V and VI osteogenesis imperfecta. Defects in these proteins lead to defective bone mineralization which causes the characteristic brittle bones of osteogenesis imperfecta. A single point mutation in the 5′ untranslated region (5′ UTR) of the ''IFITM5'' gene, which encodes BRIL, is linked directly to OI type V.
In the rare case of type XIX, first discovered in 2016, OI is inherited as an X-linked genetic disorder, with its detrimental effects resulting ultimately from a mutation in the gene '' MBTPS2.'' Genetic research is ongoing, and it is uncertain when all the genetic causes of OI will be identified, as the number of genes that need to be tested to rule out the disorder continue to increase.
In a study of 37 families, a 1.3% chance was found that OI recurs in multiple siblings born to two unaffected parents—this is a much higher rate than would be expected if all such recurrences were ''de novo''. The cause is genetic mosaicism; that is, some of, or most of, the germ cells
Germ or germs may refer to:
Science
* Germ (microorganism), an informal word for a pathogen
* Germ cell, cell that gives rise to the gametes of an organism that reproduces sexually
* Germ layer, a primary layer of cells that forms during embryo ...
of one parent have a dominant form of OI, but not enough of their somatic cells
A somatic cell (from Ancient Greek σῶμα ''sôma'', meaning "body"), or vegetal cell, is any biological cell forming the body of a multicellular organism other than a gamete, germ cell, gametocyte or undifferentiated stem cell. Such cells compo ...
do to cause symptoms or obvious disability in the parent—the parent's different cells have two (or more) sets of slightly different DNA. It has been clinically observed that ≈5–10% of cases of OI types II and III are attributable to genetic mosaicism.
Pathophysiology
People with OI are either born with defective connective tissue, born without the ability to make it in sufficient quantities, or, in the rarest genetic types, born with deficiencies in other aspects of bone formation
Ossification (also called osteogenesis or bone mineralization) in bone remodeling is the process of laying down new bone material by cells named osteoblasts. It is synonymous with bone tissue formation. There are two processes resulting in th ...
such as chaperone proteins, the Wnt signaling pathway
The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling ...
, the BRIL protein, et cetera. In type I the collagen's structure itself is normal, it is just its quantity that is low. Types II, III and IV are usually, but not always, related to a deficiency of type I collagen
Type I collagen is the most abundant collagen of the human body. It forms large, eosinophilic fibers known as collagen fibers.
It is present in scar tissue, the end product when tissue heals by repair, as well as tendons, ligaments, the endomy ...
. One possible deficiency arises from an amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha a ...
substitution of glycine
Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid ( carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinog ...
to a bulkier amino acid, such as alanine
Alanine (symbol Ala or A), or α-alanine, is an α-amino acid that is used in the biosynthesis of proteins. It contains an amine group and a carboxylic acid group, both attached to the central carbon atom which also carries a methyl group side ...
, in the collagen protein's triple helix
In the fields of geometry and biochemistry, a triple helix (plural triple helices) is a set of three congruent geometrical helices with the same axis, differing by a translation along the axis. This means that each of the helices keeps the same ...
structure. The larger amino acid side-chains lead to steric effects that creates a bulge in the collagen complex
Complex commonly refers to:
* Complexity, the behaviour of a system whose components interact in multiple ways so possible interactions are difficult to describe
** Complex system, a system composed of many components which may interact with each ...
, which in turn influences both the molecular nanomechanics and the interaction between molecules, which are both compromised. Depending on both the location of the substitution and the amino acid being used instead, different effects are seen which account for the type diversity in OI despite the same two collagen genes being responsible for most cases. Replacements of glycine with serine or cysteine are seen less often in fatal type II OI, while replacements with valine
Valine (symbol Val or V) is an α-amino acid that is used in the biosynthesis of proteins. It contains an α- amino group (which is in the protonated −NH3+ form under biological conditions), an α- carboxylic acid group (which is in the deprotona ...
, aspartic acid, glutamic acid, or arginine are seen more often.
At a larger scale, the relationship between the collagen fibrils and hydroxyapatite crystals to form bone is altered, causing brittleness. Bone fractures occur because the stress state within collagen fibrils is altered at the locations of mutations, where locally larger shear forces
In solid mechanics, shearing forces are unaligned forces acting on one part of a Rigid body, body in a specific direction, and another part of the body in the opposite direction. When the forces are collinear (aligned with each other), they ...
lead to rapid failure of fibrils even at moderate loads because the homogeneous stress state normally found in healthy collagen fibrils is lost. OI is therefore a multi-scale phenomenon, where defects at the smallest levels of tissues (genetic, nano, micro) domino
Dominoes is a family of tile-based games played with gaming pieces, commonly known as dominoes. Each domino is a rectangular tile, usually with a line dividing its face into two square ''ends''. Each end is marked with a number of spots (also c ...
to affect the macro level of tissues.
Diagnosis
Diagnosis is typically based on medical imaging, including plain X-rays
An X-ray, or, much less commonly, X-radiation, is a penetrating form of high-energy electromagnetic radiation. Most X-rays have a wavelength ranging from 10 picometers to 10 nanometers, corresponding to frequencies in the range 30&nbs ...
, and symptoms. In severe OI, signs on medical imaging include abnormalities in all extremities and in the spine. As X-rays are often insensitive to the comparatively smaller bone density loss associated with type I OI, DEXA scans may be needed.
An OI diagnosis can be confirmed through DNA or collagen protein analysis
Proteomics is the large-scale study of proteins. Proteins are vital parts of living organisms, with many functions such as the formation of structural fibers of muscle tissue, enzymatic digestion of food, or synthesis and replication of DNA. In ...
, but in many cases, the occurrence of bone fractures with little trauma and the presence of other clinical features such as blue sclerae are sufficient for a diagnosis. A skin biopsy
Skin biopsy is a biopsy technique in which a skin lesion is removed to be sent to a pathologist to render a microscopic diagnosis. It is usually done under local anesthetic in a physician's office, and results are often available in 4 to 10 days. ...
can be performed to determine the structure and quantity of type I collagen. While DNA testing can confirm the diagnosis, it cannot absolutely exclude it because not all mutations causing OI are yet known and/or tested for. OI type II is often diagnosed by ultrasound during pregnancy, where already multiple fractures and other characteristic features may be visible. Relative to control, OI cortical bone
A bone is a rigid organ that constitutes part of the skeleton in most vertebrate animals. Bones protect the various other organs of the body, produce red and white blood cells, store minerals, provide structure and support for the body, and ...
shows increased porosity, canal diameter, and connectivity in micro-computed tomography. OI can also be detected before birth by using an ''in vitro'' genetic testing technique such as amniocentresis.
Genetic testing
In order to determine whether osteogenesis imperfecta is present, genetic sequencing of the most common problematic genes, ''COL1A1'', ''COL1A2'', and ''IFITM5'', may be done; if no mutation is found yet OI is still suspected, the other 10+ genes known to cause OI may be tested. Duplication and deletion testing is also suggested to parents who suspect their child has OI. The presence of frameshift mutations caused by duplications and deletions is generally the cause of increased severity of disease.
Differential diagnosis
An important differential diagnosis of OI is child abuse, as both may present to a clinician with multiple fractures in various stages of healing. Differentiating them can be difficult, especially when no other characteristic features of OI are present. This can become an issue in court; in the United States, several child abuse cases were resolved with a finding that osteogenesis imperfecta was the true cause of a child's fractures, leading to lawsuits seeking redress such as ''Alice Velasquez, et al. v. United States''.
Other differential diagnoses include rickets
Rickets is a condition that results in weak or soft bones in children, and is caused by either dietary deficiency or genetic causes. Symptoms include bowed legs, stunted growth, bone pain, large forehead, and trouble sleeping. Complications ma ...
and osteomalacia
Osteomalacia is a disease characterized by the softening of the bones caused by impaired bone metabolism primarily due to inadequate levels of available phosphate, calcium, and vitamin D, or because of resorption of calcium. The impairment of bon ...
, both caused by malnutrition
Malnutrition occurs when an organism gets too few or too many nutrients, resulting in health problems. Specifically, it is "a deficiency, excess, or imbalance of energy, protein and other nutrients" which adversely affects the body's tissues ...
, as well as rare skeletal syndromes such as Bruck syndrome, hypophosphatasia
Hypophosphatasia (; also called deficiency of alkaline phosphatase, phosphoethanolaminuria, or Rathbun's syndrome; sometimes abbreviated HPP) is a rare, and sometimes fatal, inherited metabolic bone disease. Clinical symptoms are heterogeneous, ...
, geroderma osteodysplasticum, and Ehlers–Danlos syndrome. Various forms of osteoporosis, such as iatrogenic
Iatrogenesis is the causation of a disease, a harmful complication, or other ill effect by any medical activity, including diagnosis, intervention, error, or negligence. "Iatrogenic", ''Merriam-Webster.com'', Merriam-Webster, Inc., accessed 27 ...
osteoporosis, idiopathic juvenile osteoporosis, disuse osteoporosis and exercise-related osteoporosis should also be considered as explanations when OI is suspected.
Treatment
There is no cure for osteogenesis imperfecta.[ Maintaining a healthy lifestyle by exercising and avoiding smoking can help prevent fractures.] Treatment may include care of broken bones, pain medication, physical therapy, mobility aids such as braces or wheelchairs, and surgery.
Judging the success or failure of treatment can be difficult in OI patients, as decreased bone fracture rates may just be coincidental. While these rates are often used in medical studies to judge treatment efficacy, a Norwegian study of fifteen people with OI emphasized that they feel doctors should consider the whole patient and not just fracture rates.
Acute bone fracture care
Bone fractures are treated in individuals with osteogenesis imperfecta in much the same way as they are treated in the general population—OI bone heals at the same rate as non-OI bone. A greater emphasis is placed on using lightweight materials to immobilize the fracture, as in moderate or severe types of OI, using heavy casts, such as hip spica casts, can cause fractures at the bones at the boundaries of the cast, as well as generalized osteopenia
Osteopenia, known as "low bone mass" or "low bone density", is a condition in which bone mineral density is low. Because their bones are weaker, people with osteopenia may have a higher risk of fractures, and some people may go on to develop osteop ...
. The lightweight cast or splint is then replaced with a removable orthosis
Orthotics ( el, Ορθός, translit=ortho, lit=to straighten, to align) is a medical specialty that focuses on the design and application of orthoses, or braces. An is "an externally applied device used to influence the structural and functio ...
after a few weeks and once evidence of union is seen on X-ray. In order to prevent a nonunion
Nonunion is permanent failure of healing following a broken bone unless intervention (such as surgery) is performed. A fracture with nonunion generally forms a structural resemblance to a fibrous joint, and is therefore often called a "false j ...
or malunion
A malunion is when a fractured bone does not heal properly. Some ways that it shows is by having the bone being twisted, shorter, or bent. Malunions can occur by having the bones improperly aligned when immobilized, having the cast taken off to ...
, all fractures should be immobilized, even if the fracture seems trivial (microfracture
Fracture mechanics is the field of mechanics concerned with the study of the propagation of cracks in materials. It uses methods of analytical solid mechanics to calculate the driving force on a crack and those of experimental solid mechanics t ...
), as people with OI are at greater risk of nonunion.
Bone infection
An infection is the invasion of tissues by pathogens, their multiplication, and the reaction of host tissues to the infectious agent and the toxins they produce. An infectious disease, also known as a transmissible disease or communicable dis ...
s secondary to fractures are treated as and when they occur with the appropriate antibiotics
An antibiotic is a type of antimicrobial substance active against bacteria. It is the most important type of antibacterial agent for fighting bacterial infections, and antibiotic medications are widely used in the treatment and prevention o ...
and antiseptics
An antiseptic (from Greek ἀντί ''anti'', "against" and σηπτικός ''sēptikos'', "putrefactive") is an antimicrobial substance or compound that is applied to living tissue/skin to reduce the possibility of infection, sepsis, or putre ...
, as in the general population.
Medications
Bisphosphonates
In 1998, an initial observational trial demonstrated the effectiveness of intravenous pamidronate
Pamidronic acid or pamidronate disodium or APD (marketed as Aredia among others), is a nitrogen-containing bisphosphonate used to prevent osteoporosis.
It was patented in 1971 and approved for medical use in 1987.
Medical uses
It is used to pre ...
, a bisphosphonate
Bisphosphonates are a class of drugs that prevent the loss of bone density, used to treat osteoporosis and similar diseases. They are the most commonly prescribed drugs used to treat osteoporosis. They are called bisphosphonates because they ...
which had previously been used in adults to treat osteoporosis. In severe OI, this trial showed that pamidronate reduced bone pain, prevented new vertebral fractures, reshaped previously fractured vertebral bodies, and reduced the number of long-bone fractures.
Although oral bisphosphonates are more convenient and cheaper, they are not absorbed as well, and intravenous bisphosphonates are generally more effective, although this is under study. Some studies have found oral and intravenous bisphosphonates, such as oral alendronate
Alendronic acid, sold under the brand name Fosamax among others, is a bisphosphonate medication used to treat osteoporosis and Paget's disease of bone. It is taken by mouth. Use is often recommended together with vitamin D, calcium supplementati ...
and intravenous pamidronate, equivalent. In a 2013 double-blind trial of children with mild OI, oral risedronate
Risedronic acid, often used as its sodium salt risedronate sodium, is a bisphosphonate. It slows down the cells which break down bone. It's used to treat or prevent osteoporosis, and treat Paget's disease of bone. It is taken by mouth.
It was pa ...
increased bone mineral densities, and reduced nonvertebral fractures. However, it did not decrease new vertebral fractures. A ''Cochrane'' review in 2016 concluded that though bisphosphonates seem to improve bone mineral density, it is uncertain whether this leads either to a reduction in bone fractures
A bone fracture (abbreviated FRX or Fx, Fx, or #) is a medical condition in which there is a partial or complete break in the continuity of any bone in the body. In more severe cases, the bone may be broken into several fragments, known as a '' ...
or improvement in the quality of life
Quality of life (QOL) is defined by the World Health Organization as "an individual's perception of their position in life in the context of the culture and value systems in which they live and in relation to their goals, expectations, standards ...
of individuals with osteogenesis imperfecta.[ Even in trials with as many as 125 children, no causal link has been found between bisphosphonates and decreased fracture rates; placebo controlled trials were also unable to prove that they brought about increased strength, motor control or lower pain levels.]
Bisphosphonates are not as effective at increasing the bone mineral density of adults.
Nutritional supplements
OI is a genetic disorder and is not caused by insufficient intake of any vitamin or mineral; supplementation cannot cure OI. With that said, people with OI tend to be severely deficient in vitamin D
Vitamin D is a group of fat-soluble secosteroids responsible for increasing intestinal absorption of calcium, magnesium, and phosphate, and many other biological effects. In humans, the most important compounds in this group are vitamin D3 (c ...
at much higher rates than the general population, and the cause of this is not well understood. The severity of the deficiency and the likelihood of its occurrence is thought to be related to severity of OI. Vitamin D supplementation may be recommended, at least until levels of 25(OH)D3 in blood return to normal. Below normal levels of vitamin D are also concerning as they may decrease the benefit of bisphosphanates.
Surgery
A surgery of any type inherently carries more risks when done on a patient who has (especially moderate to severe) OI. Skeletal deformities and dentinogenesis imperfecta may hinder access to the airway. Use of, and weaning
Weaning is the process of gradually introducing an infant human or another mammal to what will be its adult diet while withdrawing the supply of its mother's milk.
The process takes place only in mammals, as only mammals produce milk. The infan ...
off of, mechanical ventilation
Mechanical ventilation, assisted ventilation or intermittent mandatory ventilation (IMV), is the medical term for using a machine called a ventilator to fully or partially provide artificial ventilation. Mechanical ventilation helps move a ...
is also more challenging to carry out on patients with OI. During the procedure itself or the healing process, defective OI collagen may lead to bleeding diatheses.
The safety of anesthesia is also of more concern among patients with OI, with anesthetic complications 5.6x more likely to occur when the patient has OI type III. A unique concern of anesthesia in OI is perioperative
The perioperative period is the time period of a patient's surgical procedure. It commonly includes ward admission, anesthesia, surgery, and recovery. Perioperative may refer to the three phases of surgery: preoperative, intraoperative, and posto ...
fracture—fractures sustained due to patient transfer and airway access techniques that, while routine when a patient's bones are strong, may cause injury with brittle OI bones. As an example, due to a 1972 report of a humerus fracture from a sphygmomanometer
A sphygmomanometer ( ), a blood pressure monitor, or blood pressure gauge, is a device used to measure blood pressure, composed of an inflatable cuff to collapse and then release the artery under the cuff in a controlled manner, and a mercury ...
cuff sustained in an OI patient during surgery, blood pressure monitoring protocols are often modified for patients with OI, with neonatal
An infant or baby is the very young offspring of human beings. ''Infant'' (from the Latin word ''infans'', meaning 'unable to speak' or 'speechless') is a formal or specialised synonym for the common term ''baby''. The terms may also be used to ...
size cuffs and machine settings being used even in adults; further, the least deformed of the patient's limbs is preferred to receive the cuff.
Rodding
Metal rods can be surgically
Surgery ''cheirourgikē'' (composed of χείρ, "hand", and ἔργον, "work"), via la, chirurgiae, meaning "hand work". is a medical specialty that uses operative manual and instrumental techniques on a person to investigate or treat a pa ...
inserted in the long bones to improve strength, a procedure developed by Harold A. Sofield when he was Chief of Staff at Chicago's Shriners Hospitals for Children
Shriners Children's is a network of non-profit medical facilities across North America. Children with orthopaedic conditions, burns, spinal cord injuries, and cleft lip and palate are eligible for care and receive all services in a family-center ...
, a hospital that offers orthopedic care and surgery to children regardless of their family's ability to pay. Large numbers of children with OI came to Shriners, and Sofield experimented with various methods to strengthen their bones. In 1959, with Edward A. , Sofield wrote a seminal article describing a three-part surgery that seemed radical at the time: precisely breaking the bones ("fragmentation"), putting the resulting bone fragments in a straight line ("realignment"), then placing metal rods into the intramedullary
The medullary cavity (''medulla'', innermost part) is the central cavity of bone shafts where red bone marrow and/or yellow bone marrow (adipose tissue) is stored; hence, the medullary cavity is also known as the marrow cavity.
Located in the m ...
canals of the long bones to stabilize and strengthen them ("rod fixation"). His treatment proved useful for increasing the mobility of people with OI, and it has been adopted throughout the world—it became standard surgical treatment for severe OI by 1979, in which year David Sillence found that ≈ of the patients he surveyed with OI type III had undergone at least one rodding surgery.
Rodding surgery is often done with the hope that it will offer a path to ambulation, walking
Walking (also known as ambulation) is one of the main gaits of terrestrial locomotion among legged animals. Walking is typically slower than running and other gaits. Walking is defined by an ' inverted pendulum' gait in which the body vaults ...
, to patients with moderate or severe OI. A 2020 review in '' The Journal of Bone and Joint Surgery'' (''JB&JS'') found it remains broadly popular: ≈ of people with OI types III and IV (severe OI) have undergone some form of rodding surgery in their lives, at a mean age of and years respectively; one possible explanation for a tendency towards earlier intervention in type III is that one half of affected children could not walk at all without the surgery, as their limbs were more bowed, so surgery was sought sooner.
In those with type III OI who had undergone rodding surgery, 79.5% had the femurs and tibias of both legs rodded. The most common form of rods used are intramedullary (IM) rods, some of which, such as the Fassier–Duval IM rod, are telescoping, meaning that they are designed to grow as the child grows, in an attempt to avoid the necessity of revision surgeries. Telescoping IM rods are widely used, and the common Fassier–Duval IM rod is designed to be used to rod the femur, tibia, and humerus. The surgery involves breaking the long bones in between one and three (or more) places, then fixing the rod alongside the bone to keep it straight.
While telescoping IM rods are intended to grow along with both the femur and tibia in developing children; surgeons have a preference to use non-telescoping IM rods, such as Rush rods, in the tibia, which grows less comparatively—the ''JB&JS'' review found that while 69.7% of femurs were treated with telescoping IM rods, only 36.9% of tibiae were.
While the review in the ''JB&JS'' was able to correlate receiving rodding surgery with greater mobility across all types of OI, in patients with type IV, the surgery did not decrease the incidence of broken bones as compared to non-rodded patients—while type IV patients with rodded tibiae experienced 0.93 tibia fractures per year, patients with natural tibiae experienced only 0.81. However, in patients with type III, rodding surgery decreased the average number of tibia fractures per year from 0.84 to 0.57.
Spinal
Spinal fusion
Spinal fusion, also called spondylodesis or spondylosyndesis, is a neurosurgical or orthopedic surgical technique that joins two or more vertebrae. This procedure can be performed at any level in the spine (cervical, thoracic, or lumbar) and pre ...
can be performed either as a preventative measure or to correct existing scoliosis, although the inherent fragility of OI bone makes this operation more complex in OI patients than it does with patients who have adolescent idiopathic
An idiopathic disease is any disease with an unknown cause or mechanism of apparent spontaneous origin. From Greek ἴδιος ''idios'' "one's own" and πάθος ''pathos'' "suffering", ''idiopathy'' means approximately "a disease of its own kin ...
scoliosis, but normal bone density. Despite the risks, however, three Nemours–duPont orthopedic surgeons who specialize in surgical intervention for osteogenesis imperfecta recommend operating if the curve is greater than 50° after a child is past peak height velocity, as the spine's curve can continue to worsen even into adulthood.
Due to the risk involved, the same surgeons recommend that surgery for basilar impressions and basilar invaginations should only be carried out if the pressure being exerted on the spinal cord
The spinal cord is a long, thin, tubular structure made up of nervous tissue, which extends from the medulla oblongata in the brainstem to the lumbar region of the vertebral column (backbone). The backbone encloses the central canal of the sp ...
and brain stem
The brainstem (or brain stem) is the posterior stalk-like part of the brain that connects the cerebrum with the spinal cord. In the human brain the brainstem is composed of the midbrain, the pons, and the medulla oblongata. The midbrain is co ...
is causing actual neurological symptoms. Once basilar invagination has become symptomatic, only surgery can halt or reverse the progression of neurological deficits.
Physical therapy
Physical therapy is generally recommended, however individualized protocols are required due to the variability of OI. Physical therapy is used to strengthen muscles, improve motility
Motility is the ability of an organism to move independently, using metabolic energy.
Definitions
Motility, the ability of an organism to move independently, using metabolic energy, can be contrasted with sessility, the state of organisms th ...
, improve flexibility
Stiffness is the extent to which an object resists deformation in response to an applied force.
The complementary concept is flexibility or pliability: the more flexible an object is, the less stiff it is.
Calculations
The stiffness, k, of a bo ...
, and help with weight maintenance, although it must be done in a gentle manner to minimize the risk of bone fracture. In people with OI, exercise often involves water aerobics
Water aerobics (waterobics, aquarobics, aquatic fitness, aquafitness, aquafit) is the performance of aerobic exercise in water such as in a swimming pool. It is done mostly vertically and without swimming typically in waist deep or deeper water. W ...
, light resistance exercises, and walking, if the patient is able. However, even in patients with mild OI, contact sports
Contact sports are sports that emphasize or require physical contact between players. Some sports, such as mixed martial arts, are scored on impacting an opponent, while others, including rugby football, gridiron football and Australian rules foot ...
, as well as activities likely to put unnecessary stress on the joints, such as jumping
Jumping or leaping is a form of locomotion or movement in which an organism or non-living (e.g., robotics, robotic) mechanical system propels itself through the air along a ballistic trajectory. Jumping can be distinguished from running, gallo ...
, are contraindicated due to the risks they pose.
Individuals with more limited mobility are encouraged to change positions regularly throughout the day; people who sit in a wheelchair most or all of the day are recommended to get out of it every two hours, as a form of exercise, to decrease stiffness, and to prevent pressure ulcers.
Individuals with moderate to severe OI, who require assistive mobility devices and adapted vehicles, face significant barriers to access wheelchair-accessible
Accessibility is the design of products, devices, services, vehicles, or environments so as to be usable by people with disabilities. The concept of accessible design and practice of accessible development ensures both "direct access" (i.e ...
pools or gyms—they either may not have any in their area, nor the means to get there. Obesity
Obesity is a medical condition, sometimes considered a disease, in which excess body fat has accumulated to such an extent that it may negatively affect health. People are classified as obese when their body mass index (BMI)—a person's ...
may be more likely to present among those with severe OI, (especially after the age of 20,) and can, in some, cause further declines in mobility.
Tilt table
A tilt table test (TTT), occasionally called upright tilt testing (UTT), is a medical procedure often used to diagnose dysautonomia or syncope. Patients with symptoms of dizziness or lightheadedness, with or without a loss of consciousness ( f ...
whole body vibration may also be done to increase the mobility of long-term immobilized ( bedridden) patients with OI; in at least two cases it helped bedridden children to be able to sit upright.
Teeth
More than 1 in 2 people with OI also have dentinogenesis imperfecta (DI)—a congenital abnormality in the formation of dentin, one of the four major components of the human tooth. Dental treatment may pose as a challenge as a result of the various deformities, skeletal and dental, due to OI. Children with OI should go for a dental check-up as soon as their teeth erupt; this may minimize tooth structure loss as a result of abnormal dentine, and they should be monitored regularly to preserve their teeth and oral health.
Many people with OI are treated with bisphosphonates, and there are several possible related complications with dental procedures, for example, medication-related osteonecrosis of the jaw (MRONJ). However, no report of bisphosphonate-related MRONJ in either a child or adult with OI was found in a 2016 ''Cochrane'' review of the safety and efficacy of bisphosphonates for OI.
In development
Monoclonal antibodies
Monoclonal antibodies have long been considered for OI, but as of 2021, such therapy has not been approved for OI, neither in the European Union nor in the United States. Thus, it is unclear whether they are safe or effective. Among the monoclonal antibodies that have been studied are romosozumab
Romosozumab, sold under the brand name Evenity, is a medication used to treat osteoporosis. It has been found to decrease the risk of fractures of the spine.
Common side effect include headache, joint pain, and pain at the site of injection. ...
(targets sclerostin
Sclerostin is a protein that in humans is encoded by the ''SOST'' gene.
Sclerostin is a secreted glycoprotein with a C-terminal cysteine knot-like (CTCK) domain and sequence similarity to the DAN (differential screening-selected gene aberrative ...
, by Amgen
Amgen Inc. (formerly Applied Molecular Genetics Inc.) is an American multinational biopharmaceutical company headquartered in Thousand Oaks, California. One of the world's largest independent biotechnology companies, Amgen was established in T ...
), fresolimumab (TGF-β
Transforming growth factor beta (TGF-β) is a multifunctional cytokine belonging to the transforming growth factor superfamily that includes three different mammalian isoforms (TGF-β 1 to 3, HGNC symbols TGFB1, TGFB2, TGFB3) and many other sign ...
, Sanofi
Sanofi S.A. is a French multinational pharmaceutical and healthcare company headquartered in Paris, France. Originally, the corporation was established in 1973 and merged with Synthélabo in 1999 to form Sanofi-Synthélabo. In 2004, Sanofi-Syn ...
), blosozumab (sclerostin, Lilly), and setrusumab (sclerostin, begun by Novartis
Novartis AG is a Swiss-American multinational pharmaceutical corporation based in Basel, Switzerland and
Cambridge, Massachusetts, United States (global research).name="novartis.com">https://www.novartis.com/research-development/research-loc ...
).
Setrusumab, formerly known as BPS-804, is a monoclonal antibody that targets sclerostin
Sclerostin is a protein that in humans is encoded by the ''SOST'' gene.
Sclerostin is a secreted glycoprotein with a C-terminal cysteine knot-like (CTCK) domain and sequence similarity to the DAN (differential screening-selected gene aberrative ...
, and has been studied in OI specifically more than any of the others. In the body, sclerostin binds to the LRP5
Low-density lipoprotein receptor-related protein 5 is a protein that in humans is encoded by the ''LRP5'' gene. LRP5 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway. Mutations in LRP5 can le ...
and LRP6
Low-density lipoprotein receptor-related protein 6 is a protein that in humans is encoded by the ''LRP6'' gene. LRP6 is a key component of the LRP5/LRP6/Frizzled co-receptor group that is involved in canonical Wnt pathway.
Structure
LRP6 is a t ...
receptors, resulting in inhibition of the Wnt signaling pathway
The Wnt signaling pathways are a group of signal transduction pathways which begin with proteins that pass signals into a cell through cell surface receptors. The name Wnt is a portmanteau created from the names Wingless and Int-1. Wnt signaling ...
. This decreases bone formation, and is not a problem when a person has healthy bones. It is thought, though, that decreasing the concentration of sclerostin in the body may lead to the formation of more bone, and that is the premise as to why monoclonal antibodies that reduce the concentrations of naturally occurring sclerostin may help strengthen OI bone. While setrusumab was first developed at the pharmaceutical company Novartis, Novartis sold its rights to patent the drug to Mereo Biopharma in 2015, who has continued its development in conjunction with Ultragenyx
Ultragenyx is an American biopharmaceutical company involved in the Research and Development of novel products for treatment of rare and ultra-rare genetic diseases for which there are typically no approved treatments and high unmet medical need ...
. In 2019, Mereo announced that it had concluded collecting data for its phase II-B trial of setrusumab; the study was completed on 12 November 2020. Despite the trial data failing to show improvements in bone density on QCT scans, its primary goal, there were improvements on DXA
Dual-energy X-ray absorptiometry (DXA, or DEXA) is a means of measuring bone mineral density (BMD) using spectral imaging. Two X-ray beams, with different energy levels, are aimed at the patient's bones. When soft tissue absorption is subtracted ...
scans. In a September 2020 press release, Mereo said it was seeking to do a phase III trial
The phases of clinical research are the stages in which scientists conduct experiments with a health intervention to obtain sufficient evidence for a process considered effective as a medical treatment. For drug development, the clinical phases ...
in 2021, and had received a Rare Pediatric Disease (RPD) designation from the US Food and Drug Administration
The United States Food and Drug Administration (FDA or US FDA) is a List of United States federal agencies, federal agency of the United States Department of Health and Human Services, Department of Health and Human Services. The FDA is respon ...
(FDA).
Romosozumab
Romosozumab, sold under the brand name Evenity, is a medication used to treat osteoporosis. It has been found to decrease the risk of fractures of the spine.
Common side effect include headache, joint pain, and pain at the site of injection. ...
, which also is a monoclonal antibody targeting sclerostin, is an approved drug in the US and EU for the treatment of osteoporosis. The pharmaceutical industry analyst Evercore
Evercore Inc., formerly known as Evercore Partners, is a global independent investment banking advisory firm founded in 1995 by Roger Altman, David Offensend, and Austin Beutner. The firm has advised on over $4.7 trillion of merger, acquisition, a ...
has remarked that "it could wipe out setrusumab's economics
Economics () is the social science that studies the production, distribution, and consumption of goods and services.
Economics focuses on the behaviour and interactions of economic agents and how economies work. Microeconomics analyzes ...
", as romosozumab is priced more cheaply than a drug for a rare disease would be, claiming that it will be "vital" to Ultragenyx's profit margins to prove its setrusumab is more efficacious than romosozumab for OI. A clinical trial evaluating romosozumab's efficacy in OI began in September 2020 and as of September 2021 is ongoing. Ultragenyx predicts that its phase 2/3 trials for setrusumab will be completed in 2026.
Prevention
As a genetic disorder, the mainstay of twenty-first century prevention of osteogenesis imperfecta is based on preventing affected individuals from being born in the first place. Genetic counseling can help patients and their families determine what types of screening, if any, are right for their situation. Patients can consider preimplantation genetic diagnosis
Preimplantation genetic diagnosis (PGD or PIGD) is the genetic profiling of embryos prior to implantation (as a form of embryo profiling), and sometimes even of oocytes prior to fertilization. PGD is considered in a similar fashion to prenatal ...
after in vitro fertilization
In vitro fertilisation (IVF) is a process of fertilisation where an egg is combined with sperm in vitro ("in glass"). The process involves monitoring and stimulating an individual's ovulatory process, removing an ovum or ova (egg or eggs) f ...
to select fertilized embryos which are not affected. Common mutations which cause OI may be caught by exome sequencing
Exome sequencing, also known as whole exome sequencing (WES), is a genomic technique for sequencing all of the protein-coding regions of genes in a genome (known as the exome). It consists of two steps: the first step is to select only the subs ...
and whole genome sequencing
Whole genome sequencing (WGS), also known as full genome sequencing, complete genome sequencing, or entire genome sequencing, is the process of determining the entirety, or nearly the entirety, of the DNA sequence of an organism's genome at a ...
. If a pregnancy is already in progress, the procedure of amniocentesis
Amniocentesis is a medical procedure used primarily in the prenatal diagnosis of genetic conditions. It has other uses such as in the assessment of infection and fetal lung maturity. Prenatal diagnostic testing, which includes amniocentesis, is n ...
may be undergone to see if the fetus is affected. If affected, it is up to the family to consider whether or not they want to terminate the pregnancy and try again—raising questions of medical ethics and a woman's right to choose.
Without intervention, patients with the most common mutations causing osteogenesis imperfecta have a 50% chance per gestation of passing on the disorder, as these mutations are inherited in an autosomal dominant pattern of Mendelian inheritance
Mendelian inheritance (also known as Mendelism) is a type of biological inheritance following the principles originally proposed by Gregor Mendel in 1865 and 1866, re-discovered in 1900 by Hugo de Vries and Carl Correns, and later popularize ...
. Those with the rare autosomal recessive forms of OI have a 25% chance of passing on the disorder. Genetic testing of the affected members of the family can be used to determine which inheritance pattern applies.
As OI type I may be difficult to detect in a newborn child, the cord blood
Cord blood (umbilical cord blood) is blood that remains in the placenta and in the attached umbilical cord after childbirth. Cord blood is collected because it contains stem cells, which can be used to treat hematopoietic and genetic disorders s ...
of the child can be tested to determine if it has been passed on if the family has already rejected the more invasive genetic screening methods. In more severe cases, the diagnosis may be able to be done via ultrasound, especially if OI is already a possibility. An ethical concern with prenatal screening for OI often arises when parents inquire as to how severely affected their child will be—such questions are as yet difficult to answer conclusively.
If a non-affected person has already had a child with OI, there is a greater likelihood (although still quite remote), that their future children will have OI due to genetic mosaicism.
The disability rights
The disability rights movement is a global social movement that seeks to secure equal opportunities and equal rights for all people with disabilities.
It is made up of organizations of disability activists, also known as disability advocat ...
critique of prenatal screening for OI, held by some bioethicists
Bioethics is both a field of study and professional practice, interested in ethical issues related to health (primarily focused on the human, but also increasingly includes animal ethics), including those emerging from advances in biology, med ...
and some affected individuals, negatively compares it to eugenics
Eugenics ( ; ) is a fringe set of beliefs and practices that aim to improve the genetic quality of a human population. Historically, eugenicists have attempted to alter human gene pools by excluding people and groups judged to be inferior o ...
, with even those not opposed to abortion opposing selective abortions on the ethical ground that their existence betrays the belief that the lives of those with OI are "less worth living ndless valuable".
Prognosis
The prognosis of osteogenesis imperfecta depends entirely on its type (see ).
Life expectancy
In the mild form of the disorder, type I, the life expectancy
Life expectancy is a statistical measure of the average time an organism is expected to live, based on the year of its birth, current age, and other demographic factors like sex. The most commonly used measure is life expectancy at birth ...
of patients is near that of the general population. In type II, however, patients only very rarely live past the age of two, and typically die in their first weeks of life. Assessment of the life expectancy of patients with types III and IV is more complicated, as lifestyle choices can cause fatally traumatic injuries that would not have otherwise occurred, or not been fatal in the general population. Life expectancy in type IV OI is thought to be close to normal, but in type III it is lower than in the general population.
A 2016 study of data in Denmark's found that across all types of OI, all-cause mortality
Mortality rate, or death rate, is a measure of the number of deaths (in general, or due to a specific cause) in a particular population, scaled to the size of that population, per unit of time. Mortality rate is typically expressed in units of de ...
was three times higher, leading to a loss of around seven years in females and nine years in males. A 1996 study published in the '' British Medical Journal'' found that mortality in type III OI is significantly higher, with many patients dying in their 20's, 30's, and 40's; patients who survive to the age of 10 were further found to have longer life expectancy than newborns.
Mobility
People with mild (type I) OI as adults need few pieces of adaptive equipment
Adaptive equipment are devices that are used to assist bathing, dressing, grooming, toileting, and feeding are self-care activities that are including in the spectrum of activities of daily living (ADLs). Jennifer McLaughlin Maly a P.T./ D.P.T. i ...
, although in infancy they reach motor milestones at a significant delay compared to the general population.
With adaptive equipment such as crutches
A crutch is a mobility aid that transfers weight from the legs to the upper body. It is often used by people who cannot use their legs to support their weight, for reasons ranging from short-term injuries to lifelong disabilities.
History
Crutc ...
, motorized wheelchair
A motorized wheelchair, powerchair, electric wheelchair or electric-powered wheelchair (EPW) is a wheelchair that is propelled by means of an electric motor (usually using differential steering) rather than manual power. Motorized wheelchairs ...
s, splints, reach extenders, and/or modifications to the home, many individuals with moderate to severe OI can achieve or maintain a significant degree of independence
Independence is a condition of a person, nation, country, or state in which residents and population, or some portion thereof, exercise self-government, and usually sovereignty, over its territory. The opposite of independence is the statu ...
. With treatment and physical therapy, the maximum levels of mobility are expected to be unassisted community walking for type I, household or exercise walking for type III, and household or community walking for type IV; due to the variability of OI between individuals, mobility achieved varies and may be below this expected maximum.
Epidemiology
In the United States, the incidence of osteogenesis imperfecta is estimated to be one per 20,000 live births. An estimated 20,000 to 50,000 people are affected by OI in the United States.
The most common types are I, II, III, and IV, while the rest are very rare. Type I is the most common and has been reported to be around three times more common than type II. The prevalence of types III and IV is less certain. In a 1989 study in Denmark, type I was found to comprise 71% of cases and type II 12% of cases, with other types comprising the other 17%. In a 2015 study in Sweden, type I was nearly six times more common than type III and nearly four times more common than type IV.
Most people with OI receive it from a parent, but in many cases, it is a brand new (''de novo'' or "sporadic") mutation in a family. Among a study of patients with survivable types of OI, OI type III is most often ''de novo'' (85%), followed by type IV (50%) and type I (34%).
Some populations can have a higher incidence of OI than would be otherwise expected if they have a larger than average number of carriers of the recessive forms of the disease.
History
The condition, or types of it, has had various other names over the years and in different nations; " osteogenesis
Genesis may refer to:
Bible
* Book of Genesis, the first book of the biblical scriptures of both Judaism and Christianity, describing the creation of the Earth and of mankind
* Genesis creation narrative, the first several chapters of the Book of ...
imperfecta" has, however, been the most widely accepted name for the condition since the late 20th century. Among some of the most common alternatives are " fragilitas ossium"; "Ekman–Lobstein syndrome", and "Vrolik syndrome", both eponyms
An eponym is a person, a place, or a thing after whom or which someone or something is, or is believed to be, named. The adjectives which are derived from the word eponym include ''eponymous'' and ''eponymic''.
Usage of the word
The term ''epon ...
; and, the colloquialism, "brittle bone disease".
Earliest recorded cases
OI has been identified in an ancient Egyptian infant mummified
A mummy is a dead human or an animal whose soft tissues and organs have been preserved by either intentional or accidental exposure to chemicals, extreme cold, very low humidity, or lack of air, so that the recovered body does not decay furt ...
in around 1000 BC, originally dismissed by archaeologists as containing the remains of a monkey. The Norse king Ivar the Boneless
Ivar the Boneless ( non, Ívarr hinn Beinlausi ; died c. 873), also known as Ivar Ragnarsson, was a Viking leader who invaded England and Ireland. According to the ''Tale of Ragnar Lodbrok'', he was the son of Ragnar Loðbrok and his wife Asl ...
, who lived , is speculated to have had OI as well.
Nicolas de Malebranche is oft credited as being the first person to describe the physical characteristics of OI in his 1688 book , in which he describes a man who has had his "bones broken in the places a murderer's would be" all his life. His confident description of the pathology
Pathology is the study of the causes and effects of disease or injury. The word ''pathology'' also refers to the study of disease in general, incorporating a wide range of biology research fields and medical practices. However, when used in ...
of the disorder, however, which creates what he termed «» ("monstrous children"), is scientifically void—he wrote that it was due to the mother's antepartum
Prenatal development () includes the development of the embryo and of the fetus during a viviparous animal's gestation. Prenatal development starts with fertilization, in the germinal stage of embryonic development, and continues in fetal devel ...
viewership of a public execution
A public execution is a form of capital punishment which "members of the general public may voluntarily attend." This definition excludes the presence of only a small number of witnesses called upon to assure executive accountability. The purpose ...
by breaking wheel
The breaking wheel or execution wheel, also known as the Wheel of Catherine or simply the Wheel, was a torture method used for public execution primarily in Europe from antiquity through the Middle Ages into the early modern period by breakin ...
.
The earliest modern scientific studies of OI began in 1788 by Olof Jakob Ekman, who described the condition, which he termed "osteomalacia
Osteomalacia is a disease characterized by the softening of the bones caused by impaired bone metabolism primarily due to inadequate levels of available phosphate, calcium, and vitamin D, or because of resorption of calcium. The impairment of bon ...
congenital", in his doctoral thesis
A thesis ( : theses), or dissertation (abbreviated diss.), is a document submitted in support of candidature for an academic degree or professional qualification presenting the author's research and findings.International Standard ISO 7144: ...
and mentioned cases of it going back to 1678, all in the same family, through three generations. Ekman's description of the condition mentioned dwarfism, bone fragility, and bowing of the long bones. In 1831, Edmund Axmann gave a detailed description of it in himself and his two brothers, being the first to mention blue sclerae as a characteristic sign of OI. Jean Lobstein first described the mild form of the condition, today known as type I, in 1833, calling it "osteo psathyrosis idiopathic
An idiopathic disease is any disease with an unknown cause or mechanism of apparent spontaneous origin. From Greek ἴδιος ''idios'' "one's own" and πάθος ''pathos'' "suffering", ''idiopathy'' means approximately "a disease of its own kin ...
a".
It was not until 1912 that hearing loss
Hearing loss is a partial or total inability to hear. Hearing loss may be present at birth or acquired at any time afterwards. Hearing loss may occur in one or both ears. In children, hearing problems can affect the ability to acquire spoken ...
was positively recognized as a symptom of OI, first mentioned in a brief paper by the English physician Charles Allen Adair-Dighton.
Of the term
Willem Vrolik
Willem Vrolik (29 April 1801 – 22 December 1863) was a Dutch anatomist and pathologist who was a native of Amsterdam. He was a pioneer in the field of vertebrate teratology.
He studied medicine at the University of Utrecht, and furthered hi ...
, a Dutch anatomist
Anatomy () is the branch of biology concerned with the study of the structure of organisms and their parts. Anatomy is a branch of natural science that deals with the structural organization of living things. It is an old science, having it ...
who was also curator
A curator (from la, cura, meaning "to take care") is a manager or overseer. When working with cultural organizations, a curator is typically a "collections curator" or an "exhibitions curator", and has multifaceted tasks dependent on the parti ...
of the "Museum Vrolikianum", which made him privy to many specimens of bodies having birth defects
A birth defect, also known as a congenital disorder, is an abnormal condition that is present at birth regardless of its cause. Birth defects may result in disabilities that may be physical, intellectual, or developmental. The disabilities can ...
, coined the term "osteogenesis imperfecta" in his bilingual Latin
Latin (, or , ) is a classical language belonging to the Italic branch of the Indo-European languages. Latin was originally a dialect spoken in the lower Tiber area (then known as Latium) around present-day Rome, but through the power of the ...
and Dutch language
Dutch ( ) is a West Germanic language spoken by about 25 million people as a first language and 5 million as a second language. It is the third most widely spoken Germanic language
The Germanic languages are a branch of the Indo-Europea ...
book on teratology
Teratology is the study of abnormalities of physiological development in organisms during their life span. It is a sub-discipline in medical genetics which focuses on the classification of congenital abnormalities in dysmorphology. The relate ...
, ''Illustrations of Human and Mammalian Embryogenesis'', first published in 1849.
Included is a description of the remains of an infant who had what is now known as perinatally fatal OI type II (as verified in a 1998 re-examination of the remains by Baljet ''et al.''). The remains were first given to Vrolik's father, who could not make sense of them. Vrolik described poorly mineralized bones, bowed long bones, and fractures in various states of healing. Vrolik correctly determined that what he termed OI in the infant was not caused by secondary rickets
Rickets is a condition that results in weak or soft bones in children, and is caused by either dietary deficiency or genetic causes. Symptoms include bowed legs, stunted growth, bone pain, large forehead, and trouble sleeping. Complications ma ...
, but a congenital abnomality causing primary osteopenia
Osteopenia, known as "low bone mass" or "low bone density", is a condition in which bone mineral density is low. Because their bones are weaker, people with osteopenia may have a higher risk of fractures, and some people may go on to develop osteop ...
; he theorized this was due to a lack of "intrinsic generative energy".
Of its classification
Classification of OI has also evolved as scientific understanding of it has improved. Before the advent of modern genetic testing, OI was classified in two broad groups: ''osteogenesis imperfecta congenita'', and ''osteogenesis imperfecta tarda'', a division first proposed by the German physician
A physician (American English), medical practitioner (Commonwealth English), medical doctor, or simply doctor, is a health professional who practices medicine, which is concerned with promoting, maintaining or restoring health through th ...
E. Looser in 1906. ''Congenita'' was used to describe the modern clinical types II, III, and some cases of IV, where upon birth the condition was obvious, either due to bowing of the limbs or due to fractures sustained ''in utero''. ''Tarda'' was used to classify the modern OI type I and some cases of type IV, where the inherent fragility of the bones did not become clear until long after birth. The idea that these "late" and "prenatal" forms were manifestations of the same disorder was first proposed in 1897 by Martin Benno Schmidt; by the 1950s this fact was well accepted.
The modern system of four types (I, II, III, IV), meanwhile, were introduced in a paper by David Sillence, Alison Senn, and David Danks in the ''Journal of Medical Genetics
The ''Journal of Medical Genetics'' is a monthly peer-reviewed medical journal covering all aspects of medical genetics, including reviews of and opinion on the latest developments. It was established in 1964 and is published by the BMJ Group. The ...
'' in 1979, and have since become standard terms among doctors, patients, and researchers. The modern genetic types, (those with numbers greater than IV,) have come into use as more and more recessively inherited forms of OI have been discovered since the discovery of the first one by Roy Morello ''et al.'' in 2006. In 2010, the International Nomenclature Group for Constitutional Disorders of the Skeleton (INCDS) "freed" the Sillence types from molecular reference, acquiescing to their new clinical-first role in the wake of what was to them a "surprising" increase in the number of genetic causes of OI.
Writing for the '' Annual Review of Genetics'' in 2012, Drs. Peter Byers and Shawna M. Pyott lamented how the expansion of the number of types to include genetic types has created a system that " grew like Topsy". They suggest that it may indeed be impossible to create a system which is useful for clinicians and which accurately describes the genetic cause of a person's OI, with attempts always prioritizing one use at the expense of the other.
Society and culture
Much medical research has been done into the causes of osteogenesis imperfecta, benefiting not only those with OI but medicine more broadly; in the ten years between 2006 and 2016, the many discoveries of non-collagen related recessive gene mutations, which still led in those who have them to the clinical signs of OI, led to numerous breakthroughs in medical understanding of the process of healthy bone development.
Other animals
In dogs, OI is an autosomal recessive condition, meaning that dogs with two copies of the allele will be affected. Many breed organizations and veterinarians offer OI tests to tell if a dog is a carrier of OI. Dogs who are heterozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
for OI should only be bred to non-carriers. Homozygous
Zygosity (the noun, zygote, is from the Greek "yoked," from "yoke") () is the degree to which both copies of a chromosome or gene have the same genetic sequence. In other words, it is the degree of similarity of the alleles in an organism.
Mo ...
carriers should never be bred, unless it is to a non-carrier.
Naturally occurring mutations causing OI have been found in Golden Retrievers
The Golden Retriever is a Scottish breed of retriever dog of medium size. It is characterised by a gentle and affectionate nature and a striking golden coat. It is commonly kept as a pet and is among the most frequently registered breeds ...
, Dachshunds
The dachshund ( or ; German: "badger dog"), also known as the wiener dog, badger dog, and sausage dog, is a short-legged, long-bodied, hound-type dog breed. The dog may be smooth-haired, wire-haired, or long-haired, and comes in a variety of c ...
, and Beagles
The beagle is a breed of small scent hound, similar in appearance to the much larger foxhound. The beagle was developed primarily for hunting hare, known as beagling. Possessing a great sense of smell and superior tracking instincts, the b ...
. OI has also been identified in zebrafish
The zebrafish (''Danio rerio'') is a freshwater fish belonging to the minnow family (Cyprinidae) of the order Cypriniformes. Native to South Asia, it is a popular aquarium fish, frequently sold under the trade name zebra danio (and thus often ca ...
and mice.
Although dogs, mice, fish, and humans are not genetically identical, some of these animal models
A model organism (often shortened to model) is a non-human species that is extensively studied to understand particular biological phenomena, with the expectation that discoveries made in the model organism will provide insight into the working ...
have been officially recognized to represent the varying types of OI in humans. For example, homozygous ''oim''/''oim'' mice experience spontaneous bone fractures, small body size, and kyphosis, making them a model of OI type III. Meanwhile, heterozygous ''oim''/+ mice appear normal but have bones which are quite a bit weaker than wild mice, making them a model for OI type I. As in human OI, the location on the gene which is mutated affects the severity of resulting disease—the G859C ''Col1a1'' mouse is a model for OI type II as affected mice all die in the perinatal period.
Animal testing
Animal testing, also known as animal experimentation, animal research, and ''in vivo'' testing, is the use of non-human animals in experiments that seek to control the variables that affect the behavior or biological system under study. This ...
on identified animal models may lead to human therapies for OI.
Explanatory notes
References
External links
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{{DEFAULTSORT:Osteogenesis Imperfecta
Abnormalities of dermal fibrous and elastic tissue
Skeletal disorders
Collagen disease
Rare diseases
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