Treatment algorithm

Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups: see disclaimer

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all patients

1st line – multidisciplinary team management

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1st line – 

multidisciplinary team management

Optimal care of individuals with OI should take a multidisciplinary approach, which may involve numerous specialties including clinical genetics, endocrinology, orthopaedics, physiatry, physical and occupational therapy, dentistry, audiology and otorhinolaryngology, pain management, cardiology, and pulmonology.

The overall goals of treatment are to:[1]

  • Institute measures to prevent fractures

  • Increase areal bone mineral density

  • Promptly treat fractures to prevent bone deformities

  • Appropriately manage pain

  • Improve functional outcomes

  • Optimise hearing

  • Improve oral and dental health

  • Prevent extraskeletal complications

  • Provide appropriate genetic counselling.

Refer patients with skeletal deformities (such as bowing of legs or spinal abnormalities) to orthopaedic surgeons as a part of multidisciplinary management, who may provide non-operative or surgical interventions.[1]

Referral to a pain management specialist may be required in patients with chronic pain symptoms.

Refer to a pulmonologist and/or cardiologist who may perform surveillance for pulmonary and cardiac health, based on OI severity and the presence of cardiopulmonary symptoms.[45]

Note that cardiopulmonary involvement can be significant, and respiratory failure is the main cause of premature death in patients with OI.[45] Cardiopulmonary surveillance options may include:​

  • Forced vital capacity (FVC), FEV₁/FVC, and pulse oximetry​[45]

    • In children, perform at age 7 years or above or when the child is capable of performing the test. Key 4OI consensus recommendations for lung function guidance in OI suggest to repeat these tests following the transition to adult care for mild OI, and to repeat annually for severe OI.[45] The authors of this topic, however, recommend a less frequent follow-up for severe OI (every 1-2 years). If required, seek specialist input on the most appropriate follow-up frequency for your individual patient.

    • In adult patients, if FVC, FEV₁/FVC, and pulse oximetry are within normal values and in the absence of pulmonary symptoms, Key 4OI recommends to reassess every 5 years for mild OI and annually for severe OI.[45] The authors of this topic, however, recommend a less frequent follow-up for severe OI (every 1-2 years). If required, seek specialist input on the most appropriate follow-up frequency for your individual patient.

  • Advanced testing (chest radiograph) and measurement of outcomes (e.g., peak cough flow, forced expiratory flow at 25%-75% of the vital capacity, diffusing capacity, total lung capacity, residual volume/total lung capacity, and expiratory reserve volume).[45]

  • Echocardiography in patients with severe OI and those with clinical features of cardiovascular disease.[45]

Refer patients to a dentist with expertise in treating dentinogenesis imperfecta and malocclusions for regular (e.g., every 6 months) review.

  • The overall goals are to maintain good oral health and assist with developing a functional bite.

  • The treating dentist should be informed if the patient is taking a bisphosphonate before starting treatment owing to the risk of osteonecrosis of the jaw.

It is recommended, based on experience in practice, that:

  • Baseline audiology evaluation is performed in all patients at diagnosis; the frequency of further audiological evaluations should be based on the severity of hearing loss, with particular consideration given to the impact of hearing loss on quality of life for the patient.

  • Hearing evaluation is performed in children with OI before they start school and repeated every 3 years; annual evaluation should be carried out if abnormalities in hearing are detected.

    • Children with issues with speech, recurrent ear infections, or whose parents suspect a hearing loss should have a formal audiological assessment regardless of age.

  • Adults with reported hearing loss should have annual testing and follow-up appointments similar to the schedule for children.

    • If hearing loss is identified, regular ENT/audiology follow-up is recommended, with further review if hearing changes.

    • Adults experiencing tinnitus or symptoms of hearing loss should also have an audiological assessment to determine if hearing loss is conductive or sensorineural.

The use of hearing aids may be considered in patients of all age groups with hearing loss as a first-line intervention, as many patients are well compensated by hearing aids.[5]

Surgical procedures such as stapedectomy or cochlear implant may be considered in people with severe, conductive progressive hearing loss in whom hearing aids are ineffective.[85]

  • Note that complications of stapedectomy include dizziness, change in taste, and potential worsening of hearing loss.

  • A cochlear implant may provide partial restoration of hearing in patients with sensorineural hearing loss; complications include dizziness and facial nerve injury.

Plus – lifestyle modifications

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Plus – 

lifestyle modifications

Treatment recommended for ALL patients in selected patient group

Provide family members, carers, and healthcare providers with information regarding safe handling techniques.[27]

  • The overall goals are to be gentle, avoid undue pressure on a single area, and avoid sudden and rapid movements.

Encourage patients to be as physically active as possible.[27]

  • Physical activity improves muscle strength, bone health, and joint mobility.

  • Bear in mind, however, that patients with OI should avoid physical activities that are associated with increased risk of falls/fractures such as contact sports, skiing, and skating.

Advise patients to avoid smoking and excessive alcohol consumption (where relevant).

Avoid the use of medications that adversely affect bone metabolism, such as corticosteroids, wherever possible.

Encourage adequate calcium and vitamin D intake in all patients, with testing and supplementation as required, to ensure the recommended daily intake of calcium and vitamin D is achieved.[65]

Encourage the use of orthotics, braces, and other assistive devices that may decrease pain and increase mobility.[27]

  • For individuals with limited mobility, assistive devices are pivotal to achieve independence for daily activities.[27]

Consider the use of ambulation aids as appropriate for the individual patient.[27]

  • Most children with mild OI are able to walk in the community independently.[27]

  • Those with moderate OI are typically able to walk with or without ambulation devices and may benefit from a lightweight manual wheelchair for safety during longer, unpredictable distances or during periods of frequent fractures, or surgeries.[27]

  • Children with severe OI will tend to primarily use wheeled mobility, but may ambulate very short distances; encourage these children to walk even very short distances (therapeutic ambulation).[27]

Provide all patients with OI advice regarding ear protection (such as use of ear plugs or ear muffs in situations where environmental noise may be high, and controlling volume on devices that send sound directly to the ear) to defer or minimise hearing loss wherever possible.

Advise all patients with moderate to severe OI to have pneumococcal vaccination and annual influenza vaccination, as individuals with severe OI typically have compromised lung function. Note that many countries including the US and UK offer all children influenza and pneumococcal vaccinations as a part of routine childhood vaccination schedules.

Consider – analgesia

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Consider – 

analgesia

Additional treatment recommended for SOME patients in selected patient group

Consider the use of analgesia to relieve chronic pain and optimise functional mobility. Chronic pain is commonly prevalent in all OI types, affecting mobility, and interfering with activities of daily living.

Patients with OI have reported the use of analgesia, massage therapy, physiotherapy, and transcutaneous nerve stimulators for management of pain. Most patients typically need more than one strategy or medication for management of pain.[36]

Primary options for analgesia include paracetamol, and non-steroidal anti-inflammatory drugs (NSAIDs) such as ibuprofen. Note that there are no controlled studies assessing comparative efficacy and safety of different NSAIDs in individuals with OI.

  • When using analgesics for treatment of pain, a dose appropriate for the patient's body size should be used.

  • As is true for the treatment of any condition associated with chronic pain, the duration of therapy should be limited to prevent adverse effects associated with long-term use of analgesia. Long-term use of NSAIDs, for example, can be associated with gastrointestinal adverse effects (bleeding, perforation, or ulceration), cardiovascular thrombotic events, and renal disease. Use the lowest effective dose for the shortest effective treatment duration.

  • Opioids should ideally be avoided wherever possible due to their potential for addiction and abuse.

Referral to a pain management specialist may be required (for example, if symptoms are not managed effectively by analgesia, or worsen).

Primary options

paracetamol: children: consult specialist for guidance on dose; adults: 500-1000 mg orally every 4-6 hours when required, maximum 4000 mg/day

OR

ibuprofen: children ≥6 months of age: 5-10 mg/kg orally every 6-8 hours when required, maximum 40 mg/kg/day; adults: 200-400 mg orally every 4-6 hours when required, maximum 2400 mg/day

Consider – bisphosphonate

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Consider – 

bisphosphonate

Additional treatment recommended for SOME patients in selected patient group

The use of bisphosphonates is recommended in some children and adults with OI.[61][68][69][70][71][72][73][74]​ Although widely used in patients with OI, there is no consensus that bisphosphonates reduce fracture risk in children or adults.

Treatment should be initiated and managed under the guidance of specialists with experience in the use of bisphosphonates in line with local protocols. Strength, formulation, and duration of bisphosphonate therapy is dependent on numerous factors including severity of OI, bone mineral density, and the stage of growth, and should be individualised to the patient.[68]

Commonly used options include intravenous bisphosphonates (e.g., zoledronic acid, pamidronate) and oral bisphosphonates (e.g., alendronic acid, risedronate). Many centres prefer using intravenous rather than oral bisphosphonates due to improved adherence rates, reduced incidence of gastrointestinal adverse effects, and to avoid the requirement of remaining upright for 30 minutes following oral dosing.[61]

Indications for intravenous bisphosphonates in children and adolescents include:[68]

  • severe OI (e.g., type III)

  • vertebral compression fractures

  • two or more long-bone fractures per year.

In children, oral bisphosphonates should only be considered for those with mild to moderate OI in the absence of vertebral compression fractures.[68]

In adults, candidates for bisphosphonate therapy should be determined according to local protocols.

Although increased bone mass density as a result of bisphosphonate therapy is unlikely to have an effect on the underlying defective type I collagen in OI, an increase in bone mass density may lead to decreased fracture rates in those with OI.[66]

There are sparse data evaluating bisphosphonates in patients with OI. Results are inconsistent; available evidence should be interpreted with caution given the heterogeneity of OI and variability in clinical study designs.[66][75]

  • In children with OI, bisphosphonates have been shown in some studies to have beneficial effects on areal and volumetric bone mineral density, quality of life, fracture incidence, and progression of scoliosis.[35][62][76][77][78][79]

  • In systematic studies of the utility of bisphosphonates in adults with OI, some show bisphosphonates to decrease bone resorption and increase bone mineral density.[61][69][70][71][72][73][74]

  • Intravenous bisphosphonates have been shown in some studies to decrease pain in OI.[66][67]

Common adverse effects associated with bisphosphonate use include gastrointestinal discomfort (in patients on oral therapy) and acute influenza-like illness (in patients on intravenous therapy).

  • In the general population, there is an increased risk for osteonecrosis of the jaw with long-term bisphosphonate use, most commonly associated with patients receiving intravenous bisphosphonate treatment who have poor dental hygiene or following dental extractions/dental implants.[80] Bisphosphonate therapy in the general population has also been associated with higher risk of atypical femur fracture (AFF).[81] Note that there are no data available for these adverse events occurring in children with OI treated with bisphosphonates; one systematic review of literature did not show any evidence for increased risk for osteonecrosis of the jaw in children and adolescents treated with bisphosphonates.[82]

  • Intravenous bisphosphonates may cause renal toxicity and should be used with caution in patients with renal impairment.

  • Hypocalcaemia is also a potential adverse effect of intravenous bisphosphonate therapy and supplementation may be required in the days following treatment.[83][84]​​ Zoledronic acid is contraindicated in patients with hypocalcaemia.

Oral bisphosphonates should be taken 30 minutes before first food, drink, and medication for the day. The patient should avoid lying down for 30 minutes after.

The use of bisphosphonates for OI is off-label. Limited data are available to guide dosing, and dose regimens are variable.

Primary options

zoledronic acid: children ≥1 year of age: 0.05 mg/kg intravenously every 6 months, maximum 5 mg/dose; adults: 5 mg intravenously every 12-24 months

OR

alendronic acid: children ≥2 years of age and <40 kg body weight: 5 mg orally once daily; children ≥2 years of age and ≥40 kg body weight: 10 mg orally once daily; adults: 10 mg orally once daily, or 70 mg once weekly

OR

risedronate sodium: children <30 kg body weight: 2.5 mg orally (immediate-release) once daily; children ≥30 kg body weight: 5 mg orally (immediate-release) once daily; adults: 5 mg orally (immediate-release) once daily, or 35 mg once weekly, or 150 mg once monthly

OR

pamidronate disodium: children and adults: consult specialist for guidance on dose

Plus – orthopaedic referral and surgery

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with fracture
Plus – 

orthopaedic referral and surgery

Treatment recommended for ALL patients in selected patient group

Refer all patients with OI with a fracture to an orthopaedic surgeon with expertise in managing individuals with OI.[1]

  • Intramedullary rodding with telescoping rods remains one of the mainstays of internal fixation for long bones. Nonunions and malunions can be more commonly observed in individuals with severe forms of OI.

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Please note that formulations/routes and doses may differ between drug names and brands, drug formularies, or locations. Treatment recommendations are specific to patient groups. See disclaimer

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