Osteogenesis Imperfecta Treatment & Management

Until recently, surgical correction of deformities, physiotherapy, and the use of orthotic support and devices to assist mobility (eg, wheelchairs) were the primary means of treatment for osteogenesis imperfecta.^[14] With the more recent understanding of the molecular mechanisms of the disease, medical treatment to increase bone mass and strength are gaining popularity, and surgery is reserved for functional improvement.^{[15, 16]}

Bisphosphonates, particularly pamidronate, are synthetic analogs of pyrophosphate that inhibit osteoclast-mediated bone resorption on the endosteal surface of bone by binding to hydroxyapatite. As a result, unopposed osteoblastic new bone formation on the periosteal surface results in an increase in cortical thickness. Cyclic intravenous pamidronate is given in a dose of 7.5 mg/kg/y at 4- to 6-month intervals.

Intravenous pamidronate is effective in babies and can be used to relieve pain in severe cases. Good evidence suggests that bisphosphonate therapy may significantly improve the natural history of type III and type IV disease, particularly by decreasing the rate of fracture, increasing bone mineral density, decreasing bone pain, and significantly increasing height (especially with prolonged cyclic therapy up to 4 y). In some cases, crumpled femurs and flattened vertebrae may assume more normal shapes and cortical thickness.

Adverse effects of pamidronate include an acute febrile reaction, mild hypocalcemia, leukopenia, a transient increase in bone pain, and scleritis with or without anterior uveitis. With milder forms of osteogenesis imperfecta, the indications for bisphosphonate therapy have yet to be evaluated. Other bisphosphonates, such as risedronate, alendronate, and zoledronic acid, are also being assessed.

Growth hormone is known to act on the growth plate and also stimulate osteoblast function, possibly via insulinlike growth factor-1 (IGF-1) and IGF–binding protein-3 (IGFBP-3). Growth hormone may be beneficial in patients with a quantitative collagen defect, but its role in the management of osteogenesis imperfecta has not been clearly defined.

Teriparatide (Forteo) is a recombinant human form of parathyroid hormone that increases the number and activity of osteoblasts. The US Food and Drug Administration (FDA) has approved teriparatide for use in osteoporosis, but because of the potential risk of osteosarcoma induction (as seen in preclinical studies in rats), teriparatide has not been approved by the FDA for use in children and adolescents. The potential use of this drug for the treatment of osteogenesis imperfecta has not been defined.

Bone marrow transplantation (BMT) has been advocated as a potential future therapeutic modality in osteogenesis imperfecta. Bone marrow contains both hematopoietic and mesenchymal stem cells (MSCs), the latter being the precursors of osteoblasts. Because there are very few MSCs in the average human bone marrow graft, approaches involving expansion of the number of MSCs in ex vivo cultures with subsequent infusion into the recipient have been advocated.

Such cell therapies usually result in somatic mosaicism, where normal and abnormal osteoblasts exist in the same body. Unfortunately, a higher proportion of engrafted normal cells is required to achieve the level of normal osteoblasts necessary to functionally correct the osteogenesis imperfecta phenotype. Furthermore, the use of immunosuppressive agents to prevent graft rejection and graft versus host reaction can itself damage bone. Future approaches include the autografting of genetically modified mutant osteoblasts, whereby the mutant collagen gene is inactivated. These therapies are several years away from clinical reality.

Gene therapy is being explored in animal models, but major obstacles remain because of intrinsic difficulties (as evidenced in attempts to treat conditions such as cystic fibrosis) and because of the dominant negative mechanism of the disease. The recent success in treating X-linked severe combined immunodeficiency disease (X-SCID) by using gene therapy provides some hope that this approach may eventually be successful in conditions such as osteogenesis imperfecta.

Orthotics play a limited role in osteogenesis imperfecta and are used to stabilize lax joints (eg, ankle and subtalar joints with ankle-foot orthoses) and to prevent progressive deformities and fractures. It is more important to provide walking aids, specialized wheelchairs, and home adaptation devices to help improve the patient's mobility and function.

Surgery should be performed only if it is likely to improve function and only if the treatment goals are clear. Skilled administration of anesthetics and awareness of the limitations of surgery are essential prerequisites.^[17]

Soft tissue surgery is used in specific circumstances (eg, lower-limb contractures, particularly those of the Achilles tendon).

Painful bony deformity and recurrent fractures are typically treated with intramedullary stabilization with or without corrective osteotomies. In children with severe forms of osteogenesis imperfecta (eg, type III), rodding of lower extremities is performed to correct deformities and provide preventive protection around the time of first attempts at standing. Osteotomies should be simple, preferably single, and performed under direct vision with maximum care and gentle handling of tissues.

Because the bone is soft in osteogenesis imperfecta, rods (eg, extendable Sheffield rods, Bailey-Dubow rods), pins (eg, Rush pins), and wires (eg, Kirschner wires) are used rather than solid nails, plates, and screws (the latter being prone to increased fracture risk above and below the device and poor fixation). Rod placement is of particular use in the femur and is less commonly used in the tibia, humerus, and forearm.

Extendable rods were preferred over nonextendable rods in the prebisphosphonate era to prevent the bowing of bone and growth of bone beyond the end of the rod. Bailey-Dubow rods were complicated by a high incidence of mechanical failures, such as migration and disconnection of T-parts; therefore, Sheffield rods and the Fassier-Duval modification are now in use instead. The latter modification also has the advantage of being inserted through the greater trochanter (as in adult fixations), thus avoiding the need for a knee arthrotomy in femoral surgery.

With the decreased fragility of bone exposed to bisphosphonate, the future role of extendable rods is unclear. In long bones, such as tibiae and radii, nonextendable rods such as Rush pins and Kirschner wires are most often used. Complications of rod placement include breakage, rotational deformities, and migration; and extendable to nonextendable rods are associated with similar complications. However, the rate of reintervention is lower with extendable rods than with nonextendable rods.

Bracing is ineffective in treating spinal deformities such as scoliosis and kyphosis, given that the rib cage is too fragile to transfer the brace pressure to the vertebral column. Moreover, the external pressure may worsen the chest deformities. Surgery is indicated if the bone quality is acceptable and progressive scoliosis with more than 45° curvature is present in mild forms of osteogenesis imperfecta or more than 30-35° curvature is present in severe forms of osteogenesis imperfecta. Posterior spinal arthrodesis is the treatment of choice and is best performed with segmental instrumentation. Often, significant correction and stable fixation is not achieved.

Basilar invagination may result in long tract signs and respiratory depression from direct compression of the brainstem and the upper cervical and cranial nerves. It is best treated with decompression and stabilization of the craniocervical junction.

Physiotherapy, in the form of comprehensive rehabilitation programs, has become more effective in the postbisphosphonate era because of the decrease in bone fragility and better prognosis for standing or walking. Strategies are age-dependent and are aimed at promoting gross motor development and maximizing functional independence.^[18]

In early infancy, gentle handling of the babies by parents is encouraged to prevent fractures, with frequent positional changes advised to prevent occipital flattening, torticollis, and frog-leg positioning of the hips.

When the infant is crawling, upper-limb mobility is promoted, as this is vital for future transfers. Exercises can include propelling a wheelchair or ambulating with walking aids.

When the child starts to stand, walking is encouraged, both as exercise and as a primary or secondary means of mobility. Weight bearing is promoted in the pool, on tricycles, and with walkers. Prone positioning is used to prevent hip flexion contractures; this is aided by strengthening of hip extensors and quadriceps. Bisphosphonates have significantly improved the walking ability of children with severe forms of the disease.