Osteogenesis Imperfecta (OI) Treatment & Management

Because osteogenesis imperfecta (OI) is a genetic condition, it has no cure. For many years, surgical correction of deformities, physiotherapy, and the use of orthotic support and devices to assist mobility (eg, wheelchairs) were the primary means of treatment. ^[29] Subsequently, as a consequence of improved understanding of the molecular mechanisms of OI, medical treatments aimed at increasing bone mass and strength gained popularity, with surgery increasingly reserved for functional improvement. ^{[8, 9]}

Orthotics play a limited role in management of OI and are used to stabilize lax joints (eg, ankle and subtalar joints with ankle-foot orthoses [AFOs]) 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 remains a pillar of treatment for patients with OI, ^{[10, 7]} but it should be performed only if it is likely to improve function and only if the treatment goals are clear. Surgical interventions include intramedullary rod placement, surgery to manage basilar impression, and correction of scoliosis. Soft-tissue surgery is used in specific circumstances (eg, lower-limb contractures, particularly those of the Achilles tendon).

Skilled administration of anesthetics and awareness of the limitations of surgery are essential prerequisites. ^[30] Anesthetic-related problems may arise from in patients with relatively large heads and tongues and in those with short necks. Chest deformities may cause respiratory complications. On the operating table, fractures may arise as a result of the application of a blood pressure cuff or tourniquet, or they may occur during transfers. It is important to watch for hyperthermia and increased sweating.

Home visits and regular clinic assessments are necessary, particularly in the first few years of life. Postoperatively, close follow-up is vital to ensure fracture healing and restoration of function.

Bisphosphonates

Bisphosphonates (eg, pamidronate) are synthetic analogues 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. Their use in the treatment of OI is on off-label application.

Cyclic intravenous (IV) pamidronate is commonly given in a dosage of 7.5 mg/kg/y at 4- to 6-month intervals. ^{[31, 32]} Dosages have ranged from 4.5 to 9 mg/kg/y, depending on the protocol used. Cyclic administration of IV pamidronate reduces the incidence of fracture and increases bone mineral density (BMD), while reducing pain and increasing energy levels. ^[33] Current evidence does not support the use of oral bisphosphonates in patients with OI.

IV 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 BMD, decreasing bone pain, and significantly increasing height (especially with prolonged cyclic therapy up to 4 years). ^{[34, 35]} 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 OI, the indications for bisphosphonate therapy have yet to be evaluated.

Other bisphosphonates (eg, risedronate, alendronate, ^[36] and zoledronic acid) have been studied. Alendronate was found to decrease predicted material properties and to have detrimental effects on osteoblasts and bone formation in mice with OI. A study from China found that long-term (3 years) alendronate therapy significantly lowered the incidence of fractures, increased BMD in the lumbar spine and femoral neck, and reduced bone turnover biomarkers in children and adolescents with OI. ^[37]  Risedronate may have some effect in reducing fractures in patients with OI. ^[38]

In a retrospective chart review and analysis aimed at determining the safety and efficacy of pamidronate therapy in 18 children younger than 24 months who had OI (mean age at treatment, 12 months), Kusumi et al found that mean lumbar z score improved from –3.63 at baseline to –1.53 at 1 year and to 0.79 by study end, whereas fracture rate improved from 0.32 fractures/patient-month before treatment to 0.03 fractures/patient-month after treatment. ^[39] Height standard deviation score was conserved from baseline to study end.

Hald et al conducted a metanalysis of six placebo-controlled trials, involving 424 patients with 751 patient-years of follow-up, to determine the effects of bisphosphonate therapy on fracture risk for patients with OI. ^[40] They found that the proportion of patients who experienced a fracture was not significantly reduced by bisphosphonate therapy and concluded that the effects of bisphosphonates on fracture prevention in OI are inconclusive.

A Cochrane review concluded that whereas oral or IV bisphosphonates increase BMD in children and adults with OI, these agents do not differ significantly from each other in this respect, and they have not been clearly shown to decrease fractures consistently. ^[41]  The review did not demonstrate that bisphosphonates conclusively improve clinical status (eg, by reducing pain or improving growth and functional mobility) in people with OI.

A study by Garganta et al involving 22 children with OI found that cyclic IV bisphosphonate therapy transiently reduced pain and improved functional abilities, with pain relief occurring immediately after infusion and functional improvements seen 4 weeks later. ^[42] Both pain and physical functioning returned to pretreatment levels by time of the next infusion.

Other agents

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

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

A preclinical study demonstrated that inhibition of receptor activator of nuclear factor-kappaB ligand (RANKL) improves density and some geometric and biomechanical properties of the oim/oim mouse bone but does not decrease fracture incidence when compared with placebo. ^[43]

Bone marrow transplantation (BMT) has been advocated as a potential future therapeutic modality for OI. Transplantation of adult bone marrow in utero has been shown to decrease perinatal lethality in a murine model of OI.

Bone marrow contains both hematopoietic stem cells 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 for functional correction of the OI 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, both because of intrinsic difficulties (as illustrated by attempts to treat conditions such as cystic fibrosis) and because of the dominant negative mechanism of the disease. The success achieved in treating X-linked severe combined immunodeficiency disease (X-SCID) by means of gene therapy provides some hope that this approach may eventually be successful in conditions such as OI.

Painful bony deformities and recurrent fractures are typically treated with intramedullary stabilization with or without corrective osteotomies. In children with severe forms of OI (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 OI, rods (eg, extendable Sheffield rods or Bailey-Dubow rods), pins (eg, Rush pins), and wires (eg, Kirschner wires [K-wires]) are used rather than solid nails, plates, and screws; the latter are associated with increased fracture risk above and below the device and with poor fixation.

Rod placement is of particular use in the femur and is less commonly used in the tibia, humerus, and forearm. An experienced team can perform as many as four rod procedures in the long bones of the lower extremities in a single surgical session. Fractures heal normally in about 85% of patients with OI.

In the prebisphosphonate era, extendable rods were preferred to nonextendable ones in order to prevent bone bowing and bone growth beyond the end of the rod. Bailey-Dubow rods were complicated by a high incidence of mechanical failures (eg, migration and disconnection of T-parts); accordingly, Sheffield rods and the Fassier-Duval modification ^[44] are now more commonly used. The latter 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 (eg, tibiae and radii), nonextendable rods such as Rush pins and K-wires have most often been used. Complications of rod placement include breakage, rotational deformities, and migration. Extendable and nonextendable rods are associated with similar complications; however, the rate of repeat surgical intervention is lower with extendable rods than with nonextendable rods.

The use of a dual interlocking telescopic rod, in which both the sleeve and the obturator are anchored with interlocking pins, has been described for tibial stabilization in children with OI, ^[45]  with results comparable to or better than those seen with a single interlocking telescopic rod. Anchoring the sleeve at the proximal epiphysis appear to provide better anchorage and allow easier removal.

Surgery for basilar impression

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. A team of orthopedic surgeons and neurosurgeons is required. This procedure is reserved for cases with neurologic deficiencies.

Surgery for spinal deformities

Bracing is not effective in treating spinal deformities such as scoliosis and kyphosis, because 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 when the following two conditions are present:

• Acceptable bone quality
• Progressive scoliosis with curvature of more than 45° if OI is mild or more than 30-35° if OI is severe

Posterior spinal arthrodesis is the treatment of choice and is best performed with segmental instrumentation. Often, significant correction and stable fixation are not achieved. Pretreatment with pamidronate appears to improve the surgical outcome.

Nutritional evaluation and intervention are paramount to ensure appropriate intake of calcium, phosphorus, and vitamin D. Caloric management is important, particularly in adolescents and adults with severe forms of OI.

Physical therapy, in the form of comprehensive rehabilitation programs, should be directed toward improving joint mobility and developing muscle strength. ^[46] Physiotherapy has become more effective in the postbisphosphonate era because of the decrease in bone fragility and the improved prognosis for standing or walking. Strategies are age-dependent and are aimed at promoting gross motor development and maximizing functional independence. ^[17]

In early infancy, gentle handling of 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; 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. Weightbearing 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 OI.

Care of patients with OI is multidisciplinary. Team members may include an occupational therapist (OT), a physical therapist (PT), a nutritionist, an audiologist, an orthopedic surgeon, a neurosurgeon, a pneumologist, and a nephrologist, among others. Periodic evaluation and intervention by an OT, a PT, or both is warranted.

Genetic counseling should be offered to the parents of a child with OI who plan to have more children. During genetic counseling, the possibility of germline mosaicism must be discussed.