Conventional management of osteogenesis imperfecta involves intensive physical rehabilitation, supplemented with orthopedic intervention as needed. Many parents and physicians place undue importance on the number of fractures sustained by children with OI. Fracture number may not be as important in judging the severity of the disorder as the degree of trauma needed to cause a fracture. In general, children with type III OI sustain fractures from more trivial trauma than those with type IV OI. In addition, they tend to have more fractures in arms and ribs than occur in type IV. Fractures, in addition to long bone deformity, can lead to significant physical handicap.

The goal of physical rehabilitation for children with OI is to promote and maintain optimal functioning in all aspects of life. This is best accomplished by a program combining early intervention, muscle strengthening and aerobic conditioning. Early intervention should include correct positioning of the infant. Proper head support to help avoid torticollis and neutral alignment of the femora are essential. [27] Custom molded seats can help with lower extremity alignment as well as head and spine positioning. [27] Gross motor skills are delayed in OI, mostly because of muscle weakness. This can be addressed with isotonic strengthening exercises of the deltoids and biceps in the upper extremity and the gluteus maximus and medius and trunk extensors in the lower extremity. Strengthening of these muscle groups will ensure that children are able to lift their limbs against gravity and transfer independently. [28]

In patients with potential, protected ambulation should be initiated as early as possible. This frequently requires a combination of surgical correction and physical therapy.

Individuals with OI should be under the care of an orthopedic surgeon with experience in the management of this disorder. Fractures should be evaluated with standard x-rays and should be managed with reduction and realignment, as needed, to prevent loss of function. Cast immobilization should be monitored to minimize any worsening of osteoporosis and muscle weakness. The decision to intervene surgically must take into account functional as well as skeletal status. Appropriate goals for surgery are to correct bowing to enhance ambulation potential and to interrupt a cycle of fracturing and refracturing. The classical surgical procedure was developed by Sofield and Millar, with multiple osteotomies, realignment of the long bone sections and fixation with intramedullary rods. Indications for this procedure include long bone angulation of greater than 40, functional valgus or varus deformity which interferes with gait, or more than two fractures in the same bone in a 6-month period. Both elongating (Bailey-Dubow) and non-elongating (Rush) rods are currently used for intramedullary fixation. Elongating rods have the advantage of extension with growth, but have a high rate of migration from OI bone. [29] Rush rods have less migration potential but need revision as the child outgrows them. In general, intramedullary rods induce significant cortical atrophy through mechanical unloading, especially in the diaphysis. The least stiff and smallest diameter rod possible should be utilized. Current intramedullary rodding procedures necessitate smaller incisions and, therefore, reduce pain and improve healing time after surgery. Recent developments in rodding for children with OI include the Fassier-Duval nail, an extendable rod with threaded ends which allow the rod to be anchored in the proximal and distal epiphyses. Recent data indicate that the complication rate is similar to Bailey-Dubow rods, but the reoperation rate is lower. According to a multicenter review of the FD rods, it is crucial that the rods are inserted properly. Further studies of the FD rod are needed [30].

Significant scoliosis is a feature of most type III and some type IV OI. Severe scoliosis does not correlate with number of collapsed vertebrae; however, it may be related to ligamentous laxity. Since resultant thoracic deformities can lead to pulmonary compromise, routine attention to the OI spine is warranted. [31] Scoliosis in OI does not respond to management with Milwaukee bracing. Spinal fusion with Harrington rod placement can provide stabilization and some correction to prevent pulmonary complications, but will not fully correct the curve. For best results, corrective surgery should occur when the curvature is less than 60.

Rarely, long-leg bracing may be indicated to provide support for weak muscles, control joint alignment and improve upright balance. Stabilizing the pelvic girdle and controlling the knees helps facilitate independent movement. Braces do not provide protection per se against fractures. Instead, bracing support promotes increased independent activity that may actually put the child at risk of incurring additional fractures. However, the advantages of increased independence and higher functional level tend to outweigh any increased fracture risk.

Recently, the potential of bisphosphonate treatment has caused great excitement in the OI patient community and has generated a rush to treatment. These drugs are synthetic analogs of pyrophosphate; their mechanism of action involves the inhibition of bone resorption. Bisphosphonates are deposited on the bone surface and are ingested by osteoclasts, inducing apoptosis. Because they inhibit bone resorption, these drugs have been used to treat malignancies with bony metastases, most commonly breast cancer. In this context, their ability to attenuate the need for major pain medications has been noted, although the duration of this effect was limited in controlled trials [32-34]. There is also extensive experience with these compounds in treatment of post-menopausal osteoporosis. Only limited knowledge about treatment of patients with structurally abnormal bone matrix has been gathered.

When used in patients with OI, bisphosphonates would presumably not affect the deposition of abnormal collagen into matrix. Thus, patients might have quantitatively more bone after treatment, but it would not be more structurally normal than before drug administration. Uncontrolled studies of pamidronate use in children and teenagers [35] and infants [36] with OI have been published. These studies reported increased BMD and vertebral height, as well as decreased fractures, less bone pain, and improved ambulation status. Anecdotal use of the drug has been widely associated with decreased bone pain, especially in the spine, and increased endurance. However, controlled trials [32-34], while they have demonstrated the expected increase in vertebral bone density and, more importantly, in vertebral height and area, have not shown an improvement in motor function, strength, or self-reported pain. Further trials are essential to determine if increased bone density is substantially due to retained mineralized cartilage, or if increased density correlates with increased brittleness. Also, these compounds may be helpful for the trabecular bone of the vertebral bodies, but not beneficial to the cortical bone of long bones. The major question regarding use of bisphosphonates for treatment of OI concerns the quality of the resulting bone. Is brittleness improved or worsened? To what extent is treated bone able to retain its flexibility while resisting load?

The use of growth hormone to ameliorate the cardinal feature of short stature in types III and IV OI is still under active investigation. Approximately half of the children studied to this point have achieved a sustained increase in linear growth of 50% or more over baseline growth rate. [37] Most responders (about 70%) had moderate type IV OI, and higher baseline PICP values. In addition, responders had increased bone formation and density. Trials of growth hormone in children with severe OI and short stature are therefore warranted in an effort to increase final adult stature and further explore the direct effect on bone. Patients who respond to growth hormone have increased BMD and improved bone histology (BV/TV).

Gene therapy of a dominant negative disorder such as osteogenesis imperfecta will not be amenable to the replacement approach being employed for recessive enzyme disorders. Dominant negative disorders are disorders of commission; the mutant protein is synthesized, secreted from the cell and incorporated into matrix, where it actively participates in weakening the structure.

Two potential approaches to gene therapy in OI are indicated by nature’s lessons in ameliorating the disorder. The first example is type I OI, in which individuals have a null allele, make half the normal amount of collagen, and have very mild disease. Approaches attempting to suppress expression of mutant collagen are modeled on this example. If expression of the mutant allele can be specifically suppressed, for example, by hammerhead ribozymes, the recipient will be biochemically transformed from type II, III or IV OI into type I. [38]

The second natural example is that of mosaic carriers, who have a substantial proportion of cells heterozygous for the collagen mutation but are clinically normal. They demonstrate that the presence of a substantial burden of mutant cells is possible before reaching the threshold of clinical disease. Approaches aimed at cell replacement by donated bone cell progenitors are modeled on this example. [39] Engraftment of only 1-2% of mesenchymal stem cells has been demonstrated after bone marrow transplant; therefore, this approach remains highly experimental. Studies of osteoblasts from mosaic carriers of type III and IV OI have shown that 40-75% of cells are mutant, setting the threshold for minimal symptoms at 30-40% normal cells [40].