Osteogenesis Imperfecta

Therapeutics for Patients with Osteogenesis Imperfecta

The hallmark of osteogenesis imperfecta is bone fragility with fractures occurring with minimal to moderate trauma. Treatment depends mainly on the severity of the disease, with the primary goal being to minimize fractures and maximize function. Current therapeutics for the syndrome are discussed below.

1. Orthopedic Management

The principles for management of osteogenesis imperfecta are to maximize function and minimize fracture occurrence.

As mentioned earlier, treatment plans are designed to correct the existing deformities and to avoid future deformities by combining state of the art fracture care with prophylactic management of brittle bones using internal supports and external orthotic devices.

A multidisciplinary approach, including the orthopedic surgeon, pediatrician, physical therapist, and social worker, can maximize the independent function of the child, provide education to the family, and improve the patient’s social integration.

The level of maximum function varies depending on the severity of the disease and age of the patient. Thus the extent of operative and nonoperative treatment required also varies from patient to patient.

In younger children, fractures occur due to falls because of lack of coordination and adequate postural strength. As a child matures, the incidence of fractures decreases, but other complications of osteogenesis imperfecta Opens in new window begin to manifest themselves, such as scoliosis or hearing loss.

It has been reported that patients with type III Opens in new window and IV osteogenesis imperfecta Opens in new window require the greatest amount of care (Bleck 1981). With adequate treatment, most patients with osteogenesis imperfecta can have a normal life expectancy and lead very productive lives. Usually they can attend regular schools, enjoy a wide range of career and lifestyle choices, and experience fulfilling relationships.

Treatment starts early in life, ranging from basic concepts, such as instructions for proper handling and transfer, to complex operative procedures.

Rehabilitation medicine has an important role in the treatment plan for patients with ambulation potential.

• It provides strength and conditioning of both the upper and lower extremities.
• It also assists in developing adequate head and trunk control.

With the coordination of a physical therapy team, improved muscle strength allows for ambulation. This is accomplished by using such modalities as

• hydrotherapy,
• passive and active range of motion, and
• aerobic exercises (Gerber, Bionde, and Wentrob 1990).

Increased stresses on the long bones of the lower extremities increase bone density. Repetitive fracturing and casting, particularly of the lower extremities, immobilizes the limb, causing disuse atrophy.

Therefore, a strengthening program must start as soon as fracture healing occurs. Joint instability and malalignment from ligament laxity may require orthoses for ambulation.

Lightweight knee-ankle-foot orthoses (KAFOs) restore proper alignment for normal ambulation. Bracing for spinal deformities has been used with limited success, although there is restricted application in patients with preexisting chest wall deformities and fragile rib cage.

Surgical management can be used for either fracture repair or limb deformity. The correct age for operative intervention is around 5 to 7 years of age.

Until that age, closed treatment of fractures is the most widely accepted means of treatment. After that time, surgical correction of severe deformities that interfere with a patient’s functional status may be used.

Such interventions include

• osteoclasis,
• intramedullary nailing, and
• osteotomies,
• or a combination of these techniques.

Elongating intramedullary rods have also been used with similar results to use of nonelongating rods (Porat et al. 1991).

2. Systematic Therapy

In addition to orthopedic management, systematic therapy has been attempted, but has met with little success.

Some examples of these agents include calcium, fluoride, calcitonin, anabolic steroids, and magnesium. Because the incidence of fractures decreases after puberty, sex hormones have been used, but have been of no benefit.

Drugs which were initially indicated for osteoporosis Opens in new window have also been investigated. Calcitonin, an osteoclastic inhibitor, has been used in osteoporosis to increase total bone mass.

No study, however, has shown any clinical improvement in fracture occurrence with the administration of calcitonin. Recently, however, the use of bisphosphonates in children with osteogenesis imperfecta Opens in new window has produced some beneficial effects.

Bisphosphonates, which are compounds that inhibit osteoclastic activity, have been used in the treatment of Paget’s disease Opens in new window. Treatment is aimed at reducing bone resorption, which has been found by histomorphometric and biochemical studies to be abnormally high.

Bembi et al. (1998) reported a clear clinical response with bisphosphonate over a 22- to 29-month treatment period, with a striking reduction in the frequency of new fractures.

They also observed an effect on bone density; no notable adverse effects during therapy were observed.

In another study, a 2-yerar treatment with pamidronate showed a marked reduction in bone pain in as early as 1 week in addition to a reduction in the incidence of fractures (Glorieux et al. 1998). Decreased osteoclastic activity was indicated by a reduction in serum levels of calcium, phosphate, and alkaline phosphatase.

Radiographc evidence of increased bone density above normal age-related increases was noted over the 2-year treatment period as measured by X-ray absorptiometry.

Other radiographc evidence of increased bone density included increased vertebral body height, formation of dense lines, and increased cortical width.

Although bone density appeared to improve, no biomechanical analysis was performed to demonstrate enhanced structural integrity.

These studies show promising possibilities for the use of systemic therapy in the treatment plan for osteogenesis imperfecta; however, since osteogenesis imperfecta is a genetic disease, systemic therapy is far from providing a cure.

3. Stem Cell Therapy

Although the treatment options available for osteogenesis imperfecta patients have improved their lifestyle, there is still no cure for osteogenesis imperfecta Opens in new window.

Gene therapy and novel approaches using stem cells harvested from bone marrow to replace cells synthesizing defective molecules in the affected individuals are currently being investigated.

Most osteogenesis imperfect mutations result from point mutations that substitute the conserved glycine with a charged amino acid or an amino acid with a bulky side chain that destabilizes the triple helix.

These types of mutations lead to a dominant negative situation in which abnormal α chains are synthesized and then associate with normal chains. Consequently, either a decrease in the amount of type I collagen present in the extracellular matrix or a formation of abnormal collagen fibrils occurs, followed by abnormal mineralization.

Stem cell therapy is currently being investigated for dominant negative mutations. In this approach, normal cells from a normal individual are used to replace the mutant cells of an individual with osteogenesis imperfecta, the object being that enough normal cells will be supplied and that the supplied cells will synthesize sufficient normal matrix to have an effect on tissue function.

Bone marrow has been shown to contain cells with the potential to differentiate into osteoblasts. The aim here is to isolate cells from the bone marrow and then transplant them into the affected individual.

The stem cells of hemapoietic lineage can self renew: through transplantation of bone marrow into an osteopetrotic patient, a defect in bone resorption due to the failure of osteoclasts to resorb bone, has previously been demonstrated (Cocia et al. 1980).

Since osteoclasts are believed to be derived from the cells of the hemopoietic lineage, bone marrow transplantation has been shown to reverse the defects in these patients.

The treatment here for osteogenesis imperfect is, therefore, based on the same premise: there are stem cells in bone marrow that will give rise to osteoblasts in vivo once the cells are transplanted into an individual with osteogenesis imperfecta.