Osteogenesis imperfecta is a hereditary collagen disorder causing diffuse abnormal fragility of bone and is sometimes accompanied by sensorineural hearing loss, blue sclerae, dentinogenesis imperfecta, and joint hypermobility. Diagnosis is usually clinical. Treatment includes growth hormone for some types and bisphosphonates.
Alternative Names of Osteogenesis Imperfecta
Brittle bone disease
Brittle Bone Disease
Lobstein Disease (Type I)
Vrolik Disease (Type II)
Pathophysiology of Osteogenesis Imperfecta
can result from decreased collagen secretion & production of abnormal collagen
leads to insufficient osteoid production physeal osteoblasts cannot form sufficient osteoid
periosteal osteoblasts cannot form sufficient osteoid and therefore cannot remodel normally
90% have an identifiable genetic mutation of COL 1A1 and COL 1A2
causes abnormal collagen cross-linking via a glycine substitution in the procollagen molecule
autosomal dominant and autosomal recessive forms & milder autosomal dominant forms (Types I and IV) with severe autosomal recessive forms (Types II and III)
CRTAP and LEPRE1 genes associated with severe, lethal forms of OI not associated with a primary structural defect of type I collagen
bone fragility and fractures heal in normal fashion initially but the bone does not remodel & can lead to progressive bowing
codfish vertebrae (compression fx)
olecranon apophyseal avulsion fx
coxa vara (10%)
dysmorphic, triangle-shaped faces
hearing loss 50% of adults with OI may be conductive, sensorial and mixed
Type I collagen is the most important structural protein of bone, skin, tendon, dentin, sclera
Triple helix structure
two alpha-1 chains coded by genes COL1A1
one alpha-2 chain coded by gene COL1A2
triple helix structure is possible because of glycine at every 3rd amino acid residue genetic mutations alter triple helix by substitution of glycine with another amino acid
Types of Osteogenesis Imperfecta
This accounts for 60% of all cases.
Fractures can occur at any time from the perinatal period onwards.
There is a 7 x greater incidence of overall fracture rate than normal, with reduced vertebral bone mineral content in adults.
In childhood, fractures may be numerous but rarely lead to deformity.
Any type of fracture can occur and these become less frequent with age – most commonly affected are the lower limbs.
The skull shows multiple Wormian bones and the vault may overhang the base, causing basilar compression needing surgical correction.
When teeth are affected, some may be more affected than others. There is discoloration with enamel fracturing easily from the dentine, causing rapid erosion in both sets.
Blue sclerae is an important sign caused by scleral thinness allowing the pigmented coat of the choroid to become visible.
Frequently there is early arcus unrelated to hypercholesterolemia.
Cardiac effects are important; they include aortic incompetence, aortic root widening and mitral valve prolapse.
Often there is hypermobility of joints, with flat feet, hyper-extensible large joints, and dislocations.
Hearing can be affected by changes in the middle ear.
Most severe form.
Frequently lethal at or shortly after birth, often due to respiratory problems.
Numerous fractures and severe bone deformity.
Small stature with underdeveloped lungs.
Collagen improperly formed.
Bones fracture easily. Fractures often present at birth, and x-rays may reveal healed fractures that occurred before birth.
Sclera have a blue, purple, or gray tint.
Loose joints and poor muscle development in arms and legs.
Barrel-shaped rib cage.
Respiratory problems possible.
Bone deformity, often severe.
Brittle teeth possible.
Hearing loss possible.
Collagen improperly formed.
Between Type I and Type III in severity.
Bones fracture easily. Most fractures occur before puberty.
Shorter than average stature.
Sclera are white or near-white (i.e. normal in color).
Mild to moderate bone deformity.
The tendency toward spinal curvature.
Barrel-shaped rib cage.
Brittle teeth possible.
Hearing loss possible.
Collagen improperly formed.
By studying the appearance of OI bone under the microscope, investigators noticed that some people who are clinically within the Type IV group had a distinct pattern to their bone. When they reviewed the full medical history of these people, they found that groups had other features in common. They named these groups Types V and VI OI.
The mutations causing these forms of OI have not been identified, but people in these two groups do not have mutations in the type I collagen genes.
Clinically similar to Type IV in appearance and symptoms of OI.
A dense band seen on x-rays adjacent to the growth plate of the long bones.
Unusually large calluses (hypertrophic calluses) at the sites of fractures or surgical procedures. (A callus is an area of new bone that is laid down at the fracture site as part of the healing process.)
Calcification of the membrane between the radius and ulna (the bones of the forearm). This leads to restriction of forearm rotation.
Bone has a “mesh-like” appearance when viewed under the microscope.
Dominant inheritance pattern
Clinically similar to Type IV in appearance and symptoms of OI.
The alkaline phosphatase (an enzyme linked to bone formation) activity level is slightly elevated in OI Type VI. This can be determined by a blood test.
Bone has a distinctive “fish-scale” appearance when viewed under the microscope.
Diagnosed by bone biopsy.
Whether this form is inherited in a dominant or recessive manner is unknown, but researchers believe the mode of inheritance is most likely recessive.
Eight people with this type of OI have been identified.
The first described cases resemble Type IV OI in many aspects of appearance and symptoms.
In other instances the appearance and symptoms are similar to Type II lethal OI, except infants had white sclera, a small head and a round face.
Short humerus (arm bone) and short femur (upper leg bone)
Coxa vera is common (the acutely angled femur head affects the hip socket).
Results from recessive inheritance of a mutation to the CRTAP (cartilage-associated protein) gene. Partial function of CRTAP leads to moderate symptoms while total absence of CRTAP was lethal in all 4 identified cases.
Resembles lethal Type II or Type III OI in appearance and symptoms except that infants have white sclera.
Severe growth deficiency.
Extreme skeletal under mineralization.
Caused by a deficiency of P3H1 (Prolyl 3-hydroxylase 1) due to a mutation to the LEPRE1 gene.
Causes of Osteogenesis Imperfecta
Osteogenesis imperfecta is a genetic disorder that can be caused by inheritance from a parent with OI, or a random genetic mutation. The genetic disorder in most cases is passed from one of the parents to the child through autosomal dominant inheritance This type of inheritance is usually the cause for most people with type I or type IV OI. Random mutation of the COL1A1 or COL1A2 gene may also occur. These children have no family history of OI and tend to have either type II or type III osteogenesis imperfecta, which are more serious. The least common way that osteogenesis imperfecta is caused by autosomal recessive inheritance. This is when each cell has two copies of the mutated gene. This cause occurs by two people that are carriers of the mutated gene passing one copy each to a child. This cause usually results in a child with type III OI.
Constipation that may be caused due to pelvic asymetry in more serious forms of OI.
Difficulties swallowing solid foods in more serious forms of OI.
Heart valve problems such as aortic valve insufficiency, aortic aneurysm, mitral valve regurgitation, and mitral valve prolapse.
Restrictive pulmonary disorder is common in people with severe forms of OI.
Pulmonary complications due to rib fractures, weakness of the muscles in the chest wall, chronic bronchitis, pneumonia, asthma and heart valve disorders.
Basilar invagination of the base of the skull may occur in OI patients in the adult years and cause complications with the brain stem.
Kidney stones have at times been associated with osteogenesis imperfecta.
Patients with OI may have thin skin.
Excessive diaphoresis may be apparent.
Elevated serum pyrophoshate
Decreased platelet aggregation
Hearing loss/impairment is a common occurence in patients with OI. This can occur from deformity of the bony auditory structures.This can also be caused by a fracture of the stapes bone.
Sclera may be blue, purple, or grey tinted.
Vision loss can occur.
“It is a myth that patients with osteogenesis imperfecta feel less pain than patients without OI
Overall Symptoms of Brittle Bone Disease
People with OI experience frequent broken bones from infancy through puberty. The frequency typically decreases in the young adult years but may increase again later in life.
Respiratory problems including asthma are often seen. Other medical characteristics and issues include:
Bone deformity, and bone pain.
Low Bone Density.
Loose joints, ligament laxity and muscle weakness are common.
Distinctive features of the skull including late closing fontanels, and head circumference greater than average.
Hearing loss may begin in the early 20s and by middle age is present in more than 50% of people with OI.
Brittle teeth (called dentinogenesis imperfecta or DI) are seen in 50% of people who have OI
Respiratory problems including asthma; may be aggravated by chest wall deformity and/or spine deformity.
Vision problems including myopia and risk for retinal detachment
Skin hyperlaxity; easy bruising.
Basilar Invagination a serious neurological problem is seen in some people with the more severe forms of OI.
Skin, blood vessels and internal organs may be fragile.
The symptoms of brittle bone disease differ according to the type of the disease. Everyone with brittle bone disease has fragile bones, but the severity varies from person to person. Brittle bone disease has one or more of the following symptoms:
multiple broken bones
blue sclera, or a bluish color in the white of the eye
bowed legs and arms
kyphosis, or an abnormal outward curve of the upper spine
scoliosis, or an abnormal lateral curve of the spine
early hearing loss
Atrophy of muscles
Delayed developmental motor skills
Spinal and long bone deformities
The differential diagnosis for osteogenesis imperfecta can be grouped into stages of life that the differential diagnoses occur.
popcorn calcification: the metaphyses and epiphyses exhibit numerous scalloped radiolucent areas with sclerotic margins 1
zebra stripe sign: cyclic bisphosphonate treatment produces sclerotic growth recovery lines in the long bones
formation of pseudarthrosis at sites of healing fractures
The prenatal sonographic features are often useful in the type II (perinatal) and type III forms.
May show decreased calvarial ossification
this may result over visualisation of fetal brain detail
the skull may deform/compress with transducer pressure
May show evidence of fractures
long bones may appear shortened and/or angulated as a result
there may be a sonographic gap along the length of a long bone
rib may have a beaded appearance
there may be presence of polyhydramnios
While showing most of the plain film features, CT may also better demonstrate:
can be used to assess extent of basilar invagination
DNA blood test
DXA (dual-energy x-ray absorptiometry) scan: a painless, non-invasive scan that uses two different photon energies (x-ray beams) to measure soft tissue and bone. Currently, DXA is the most widely used way to measure bone mineral density.
dentinogenesis imperfecta: dental problems associated with osteogenesis imperfecta
Treatment of Osteogenesis Imperfecta
Medication – Medical bisphosphonates, given to the child either by mouth or intravenously, slow down bone resorption. In children with more severe osteogenesis imperfecta, bisphosphonate treatment often reduces the number of fractures and bone pain. These medications must be administered by properly trained doctors and require close monitoring.
Immobilization – Casting, bracing, or splinting fractures is necessary to keep the bones still and in line so that healing can occur.
Exercise – After a fracture, movement and weight bearing are encouraged as soon as the bone has healed. Specific exercises will increase mobility and decrease the risk of future fractures.
Early bracing indicated to decrease deformity and lessen fractures. Low-impact exercise, such as swimming and walking, can help strengthen bones and the muscles that support them. Exercise is part of a healthy lifestyle for every child.
The following medications have been not been proven to be effective for OI in controlled trials.
Current Pharmacological Treatment
Growth Hormone – This is used to improve bone metabolism and to improve growth for statural purposes.
Bisphosphonates – These are used to “promote bone mineral accretion while at the same time reducing bone turnover.
The goals of therapy are to reduce fracture rate, prevent long bone deformities, minimize chronic pain, and maximize functional capacity.[rx]
The main modalities of treatment can be grouped into medications, surgical intervention, physical therapy, and experimental therapies.[rx]
It is the mainstay of pharmacologic fracture prevention therapy for most forms of OI. Observational studies show that bisphosphonates for children reduced fracture frequency up to 100%.[rx] The long-term effects on structural outcomes such as scoliosis and basilar invagination are unclear. Optimal dose range, dosing interval, duration of treatment, and long-term efficacy and safety profile in treatment of OI are yet to be established.[rx]
Fourteen randomized controlled trials have been conducted which compared the following data:[rx] 6 – oral bisphosphonate to placebo, 3 – intravenous (IV) bisphosphonate to placebo, 1 – different doses of oral, 1 – different doses of IV, 1 – oral versus IV, and 2 – different IV (zoledronic vs. pamidronate).
For patients with all forms of OI, IV pamidronate is advised, except Type VI, in whom clinical benefits are likely to outweigh potential long-term risks (i.e., those with long bone deformities, vertebral compression fractures, and ≥3 fractures/year) Majority of information about the use of bisphosphonates in OI have come from uncontrolled studies of cyclical infusions of pamidronate in various regimens in children.[rx]
Reports have noted BMD, decreased fracture rate, and improved functional abilities, mobility, ambulation, and pain, without negative effects on fracture healing or growth rate in most studies, even when used in young children. Pamidronate is administered IV in cycles of 3 consecutive days at 2–4-month intervals with doses ranging from 0.5–1 mg/kg/day, depending on age, with a corresponding annual dose of 9 mg/kg. The smallest effective dose should be used, with careful monitoring of vertebral geometry, long-bone fractures, and BMD before initiating a new cycle of treatment.
Intravenous zoledronic acid
Safety and efficacy of zoledronic therapy was evaluated over 2 years, among 33 children with OI, showed a reduction in fracture rates, pain, and improvement in BMD and motor milestones of development and dose – 0.1 mg/kg ZA.[rx]
Pretreatment evaluation and monitoring
There are no written guidelines or protocols. Calcium and vitamin D intake are based on recommended dietary allowance for child’s age (700–1300 mg/day calcium and 400–600 IU vitamin D) should be supplemented before treatment is initiated if dietary intake is inadequate.
Indices of calcium homeostasis (e.g., calcium, phosphorous, and parathyroid hormone) and renal function test should be assessed before initiation of treatment and followed every 6–12 months. Calcium levels are to be assessed before each IV bisphosphonate infusion to assure that child is not hypocalcemic.
Orthopedic and other surgery
Management of fractures (with quick mobilization to prevent bone loss due to inactivity) and placement of intramedullary rods to prevent or correct long-bone deformities are advised. Telescoping rods is advised for patients older than >2 years who are actively growing. Those with severe scoliosis may benefit from surgery.
Physical and occupational therapy
Physical therapists are instrumental in designing physical activity program that minimizes fracture risk, ensuring mobilization to prevent contractures and bone loss from immobility.[rx] Occupational therapists can address impairments in activities of daily living secondary to upper or lower limb deformities.
In a single randomized trial, thirty prepubertal children with OI (Types I, III, and IV) were observed for 12 months during ongoing neridronate therapy and then randomized to recombinant growth hormone (GH) plus neridronate or neridronate alone. BMD and growth velocity were found to be significantly higher in the group that received GH compared with control group, but no differences were observed in the fracture risk.[rx]
Cell replacement therapies
A pilot study of allogeneic hematopoietic cell transplantation was performed in five children with OI; three children had successful engraftment, and in these 3, improvements in growth velocity and reduction in fracture rate were noted following transplantation.[rx] More clinical research is needed for exploring this modality.
It has been performed only in animal models by two techniques. Antisense therapy has been used to suppress or silence a particular mutant allele of Type I collagen gene and not interfere with expression of normal allele, and thus, a severe form has been potentially turned into mild form.[rx]
Gene targeting has been employed using patient’s mesenchymal stem cells. A preliminary study using adeno-associated virus vectors successfully disrupted mutated allele ex vivo in these cells and infusion into a mouse model resulted in bone formation.[rx]
Surgery may be recommended in cases of
Repeated fractures of the same bone
Fractures that do not heal properly
Bone deformity, such as scoliosis
realignment osteotomy with rod fixation (Sofield-Miller procedure)
Severe deformity to reduce fracture rates
Techniques include >nontelescopic devices (Rush rods, Williams rods >telescopic devices (Sheffield rod, Bailey-Dubow rod, Fassier-Duval rod)
Vital capacity drops to 40% of expected for a 60° curve
Observation >indications ,if curve is <45 °
Bracing is ineffective and not recommended because of fragility of ribs
For curves > 45 ° in mild forms and > 35 ° in severe forms
Challenging due to fragility of bones
Use allograft instead of iliac crest autograft due to paucity of bone
ASF only indicated in very young children to prevent crankshaft
Associated with a large blood loss
Decompression and posterior fusion
Indications >radiographic features of invagination and cord compression with physical exam findings of myelopathy
Techniques resection of bony compression via transoral approach
Treatments for preventing or correcting symptoms may include the following
Surgery to manage
Bowing of the bone
Scoliosis (sideways curvature)
Rodding (minimally-invasive procedure to insert a metal bar [Fassier Duval rod] the length of a long bone to stabilize it and prevent deformity)
Assistive devices, such as wheelchairs, braces and other custom equipment
Physical Therapy Management (current best evidence)
Physical therapy management for osteogenesis imperfecta can help prevent disuse atrophy of muscle and disuse loss of bone mass. It has also been found that physical therapy can strengthen muscles and even increase bone density in patients with OI.Physical therapy may also help cardiovascular fitness, mental alertness, improved sleep, weight control, ability to fight infection, decrease the chance of certain cancers, and improve activities of daily living. Physical therapy should begin as soon as the child begins to show signs of muscular weakness or motor skills are being accomplished later than other children of the same age.
Physical therapy intervention should include light resistance exercises to strengthen the hips and the core. A combination of hip extension, hip abduction, spinal musculature strengthening, and an aquatic exercise program twice a week has been found to increase the patient’s ability to achieve an upright position and ambulate. Positioning is important in the care of children with OI. Neutral positioning of the head, trunk, and extremities with the hips in extension is the correct positioning. In more severe cases the prone position should be avoided.
Physical therapy management may also include the selection and adaptation of ambulation devices that are safe and beneficial to the patients. Adaptive equipment, even powered wheelchairs, may be essential for the child to have as much independence as possible.
Get at least 15 minutes of sunshine twice weekly to help with vitamin D production. Get serum levels of 25-hydroxy Vitamin D checked. If low (ideal range is 40-50) take supplemental Vitamin D3 to increase blood levels.
Avoid cigarette smoking.
Seek alternatives to the use of steroid and other medications which can lead to osteoporosis.
Regular weight bearing exercise is essential for maintaining or building bone density. People with OI are encouraged to exercise as much as possible to promote muscle and bone strength, which can help prevent fractures.
Swimming is a good exercise choice for people with OI, as water has little risk of fracture. However, swimming does not increase bone density as much as weight-bearing exercise.
For those who are able, walking (with or without mobility aids) is an excellent exercise.
Consult your physician and/or physical therapist to discuss appropriate and safe exercise which is suited to your individual health and fitness needs.
Consume a healthy diet which includes lots of fruits, vegetables, legumes, nuts, seeds, beans, and fermented dairy products such as yogurt and kefir.
A diet high in vegetables promotes an optimal ratio of phosphorus to calcium.
Increase consumption of leafy green vegetables such as kale, collard greens, bok choy, parsley, mustard greens and escarole. These are excellent sources of calcium, magnesium, vitamin K and other nutrients which are essential for bone formation.
Other excellent sources of calcium are tofu (if it is produced with a calcium-based coagulant), chickpeas, black-eyed peas, other legumes, most nuts, sesame seeds and many grains (especially the grain amaranth).
Acidic foods such as lemon juice and vinegar help to absorb calcium.
Foods such as spinach, chard, beet greens, and chocolate contain oxalates, which may bind with calcium and prevent it from being absorbed.
Phytic acid found in wheat and oats will also bind with calcium and prevent it from being absorbed.
Decrease consumption of meat and dairy products. Meat and dairy increase urinary excretion (loss) of calcium.
Despite popular opinion, milk and dairy foods are not the best sources of absorbable calcium and should not be increased in the diet.
Avoid refined sugars. Diets high in sugar increase the loss of calcium in the urine.
Avoid the excessive use of sodium (table salt). Sodium increases the loss of calcium in the urine.
Avoid consumption of colas/sodas which contain excessive amounts of phosphorus and sugar. Excess phosphorus leads to increased loss of calcium and magnesium in the urine.
Avoid coffee consumption. Caffeine from coffee increases loss of calcium in the urine.
Caffeine from tea has not been shown to decrease bone density, but caffeine from coffee has.
Avoid excessive alcohol consumption.
Avoid the use of Tums, which have been actively promoted as a calcium supplement. Tums decrease the acidity of the stomach. However, stomach acid is necessary for the absorption of calcium.
Calcium & Vitamin D. Levels of calcium are often high in OI patients. Test calcium and vitamin D levels. Ensure optimal intake, but avoid overdosing.
Vitamin C. Incidence of fracturing drops with ongoing vitamin C ingestion.(Kurz and Eyring 1974)
Zinc. Zinc metabolism may be abnormal in OI.
Factors and cofactors necessary for collagen production: tyrosine, proline, lysine, Vitamin C, Zn, Cu, Mn, Fe
Other nutrients important for bone health: Magnesium, Vitamin K, boron, manganese
Chondroitin sulfate. Chondroitin sulfate is the major glycosaminoglycan (70-80% of total) both in normal and pathological bones, and its level was slightly less in the pathological bones. Glycosaminoglycans have been shown to participate in the formation of a functional supramolecular complex in extracellular matrices. Therefore, they may, in theory, be involved in bone fragility.
While not a common or accepted viewpoint, many of the signs and symptoms of OI have overlap with nutritional deficiencies.
Botanical (Herbal) Medicine
Catechin (from Uncaria Gambir) – Catechin has been shown to reduce fractures. There is also histological, electron microscopic, and biochemical evidence of improvement after treatment.(Cetta, Lenzi et al. 1977; Jones, Cummings et al. 1984) Catechin’s role in improving collagen defects in OI probably centers around its ability to
Herbal Remedies For Brittle Bone Disease
Drink Nettle Tea
Nettle is a rich green source of mineral calcium and protein when it is consumed in form of tea. Boron present in the nettles helps protect your bones effectively. Also, nettle tea provides adequate amount of silicon and iron to help maintain the bone strength. So it is advisable to drink nettle tea to boost your bone health.
Have Black Cohosh Extract Or Tincture
Consuming Black Cohosh extract offers protection to your bones, prevents them from weakening due to low estrogen levels, and helps improve yourestrogen levels substantially. You can have a teaspoon of Black Cohosh extract daily to boost your estrogen levels. Having tincture of this herb twice a day helps avoid fractures resulting due to the brittle bones.
Have Ginseng Tincture
Ginseng possesses high estrogen levels that help prevent erosion of the bone mass. It also aids to improve the health of OI and osteoarthritis patients. You can have ginseng tincture thrice every day. Even though you can have it at anytime of the day, it is advisable to have it before your meals.
Consume Turmeric Or Apply It On The Affected Area
Turmeric possesses various medicinal and anti-inflammatory properties that help treat brittle bone ailment effectively. Have a teaspoon of turmeric once in the morning to minimize the pain in your bones caused due to anxiety and stress. You can also add turmeric to your cooking. By adding a few drops of mustard oil to turmeric powder, you can prepare a remedial paste which you can apply on the affected region and massage it get relief.
Have Uncaria Gambir Extract
Uncaria Gambir is rich in catechin, a natural antioxidant that helps you have strong bones. Its extract can be an effective remedy to treat brittle bone disease. You can have the extract of this herb in liquid form or sun dried moist paste.
Homeopathy of Osteogenesis Imperfecta
A detailed homeopathic history may be taken to determine the most appropriate homeopathic remedy for a child.
Supplement Quality Is Important
Our intention when we use nutritional and botanical supplements is for these treatments to have a physiological effect and clinical benefit, meaning that they are effective and your health improves.
The quality of nutritional supplements in the general marketplace is suspect. In order to get the maximum benefit to your health, be sure you purchase the highest quality nutritional supplements.