Osteogenesis imperfecta (OI) is a genetic disorder characterized by fragile bones that break easily, leading to associated deformities. This condition results from an inability to produce either sufficient or normal quality type I collagen, an essential component of healthy bone.
The severity of OI varies considerably, with some children experiencing fractures in infancy and others in whom the disorder remains undetected until a series of fractures signals the need for evaluation. Infrequently, a patient reaches adulthood without being aware that they have a mild form of OI.
Although specialists in the field recognize that there may be even more variations of the disease than formerly recognized, currently, most OI diagnoses are categorized as one of the following types.
In addition to fractures, children with this condition may have ligamentous laxity (loose ligaments), muscle weakness, a tendency toward spinal curvature, and brittle teeth. Short stature - and in some cases severe growth retardation - is also a hallmark of OI.
However, other medical problems may also be present at birth or develop during childhood, including respiratory difficulties resulting from rib cage deformities and underdevelopment of the lungs. Some people with OI may experience hearing loss (usually in their 20’s) and/or tinted sclera (the whites of the eyes) due to the thinness of the sclera, which is composed of Type 1 collagen and allows the light to be reflected through the eye. The cornea is also thinner, which needs to be considered in patients who require eye surgery.
Because children with OI often have numerous medical needs, a number of specialists may be involved in their care. “A multidisciplinary approach offers the best chance for reducing the number of fractures the child experiences, addressing deformity, maximizing function, and improving quality of life,” says Daniel W. Green, MD, MS, FAAP, FACS, Associate Attending Orthopedic Surgeon at Hospital for Special Surgery (HSS).
At HSS, this means that orthopedists work as a team with pediatricians, pediatric physical therapists, genetic counselors, nurses, social workers and nutritionists. Much of this care is delivered through the Kathryn O. and Alan C. Greenberg Center for Skeletal Dysplasias under the direction of Cathleen L. Raggio, MD, Assistant Attending Orthopedic Surgeon at HSS and Co-Director of the Center, and Jessica G. Davis, MD, an Associate Attending Pediatrician at HSS and Co-Director of the Center and Director of the Division of Human Genetics at Weill Cornell Medical College.
“Fortunately, new advances in surgical technique and tools, combined with medication and physical therapy, are changing the course of this disease for many children,” Dr. Green says.
Leon Root, MD, attending orthopedic surgeon and former Chief of Pediatric Orthopedics at HSS, as well as a principal investigator in some of the first clinical studies of children with osteogenesis imperfecta, describes some of the early breakthroughs in the field. “Some of our initial attempts to strengthen the bone involved giving OI patients magnesium sulfate, which we thought might alter the action of an enzyme they produce that we thought to be part of the disease process. In doing so, we hoped to change the course of the disease.”
Other trials from this era involved hormone therapy, steroids, and high doses of vitamin C and calcium.
When these trials failed to yield any effective therapy, Dr. Root and his colleagues looked to surgical intervention, developing a procedure which involved segmenting the bone and inserting a long rod through the segments. “The rod acted as an internal strut, protecting the bone against fractures and allowing some children to walk for the first time,” Dr. Root says. Bone biopsies obtained during these early rodding surgeries also allowed orthopaedic surgeons to learn more about what constituted “normal” bone in OI patients and to gain a greater understanding about their collagen structure.
Despite the advances offered by rodding surgery, there were drawbacks as well. Children eventually outgrew the rods and fractures developed at the ends of the bone. “This meant that the procedure had to be repeated every few years,” explains Dr. Root. Since that time, more sophisticated, telescoping rods have been developed, helping surgeons obviate that problem. (see Surgical Treatment for OI, below.)
Although there is still no cure for osteogenesis imperfecta, many patients can now derive significant protection against fracture through drug therapy. “All individuals make osteoblasts, which are cells that build new bone, and osteoclasts, which are cells that are responsible for removing or breaking down bone,” explains Dr. Raggio (who, in addition to treating patients, conducts laboratory studies in OI.) “This process takes place throughout growth and, to a lesser extent, after a person reaches skeletal maturity. Patients with more severe forms of OI tend to have a very high turnover of bone.”
Bisphosphonates, drugs that were originally developed for the treatment of osteoporosis and certain cancers, slow down the rate at which osteoclasts take bone away, providing the patient with protective scaffolding, which is actually calcified cartilage, according to Dr. Raggio. (Because the action of the drug is related to turnover, bisphosphonates are not as helpful in mild cases of OI - in which turnover is slower - and in patients who have stopped growing.)
In patients who are appropriate candidates, therapy should be initiated as early as possible, Dr. Raggio says. Children as young as one to two months can receive IV infusions of a bisphosphonates in the hospital setting. As the child becomes older, the drug is administered orally, the bisphosphonate dose may be reduced, and the intervals between doses may become less frequent.
“Most children tolerate these drugs very well, but we do follow them carefully with the help of a pediatric endocrinologist,” (a physician who specializes in hormonal and metabolic disorders), says Dr. Green. The patient’s blood and urine are tested regularly for calcium phosphorus and the products of collagen. DEXA scans (a type of x-ray) which assess bone quality are taken every six months in young children and then annually when the child reaches three or four years of age.
Both Dr. Green and Dr. Raggio emphasize the need for an individualized approach with each patient. “Some patients may benefit from bisphosphonates therapy early on and may not do so later,” says Dr. Raggio. “In addition,” she continues, “we want to be watchful of the long-term effect on the bone.”
Owing to a careful selection process, most patients on bisphosphonates therapy at HSS do well. However, according to Dr. Green, in those less frequent cases where there is no improvement after a year, the drug is discontinued. Bisphosphonates have been shown to interfere with the normal healing process after a surgical osteotomy and therefore, bisphosphonate therapy needs to be discontinued prior to and after the surgery until it is established that the bone is healed.
Although orthopedic intervention for osteogenesis imperfecta can include bracing to help protect the patient during physical activity and physical therapy, surgery with intramedullary (in-bone) fixation to correct deformity offers the greatest long-term benefit and protection against future fracture.
Historically, orthopedists used rods of a fixed length to help fractures heal and avoid or correct deformity. However, as the child grew, he or she was at risk for fracturing the leg immediately below the rod. Today, pediatric orthopedists at HSS are using the Fassier-Duval Telescopic Intramedullary System, a relatively new form of instrumentation designed specifically for patients with OI who are still growing.
Fassier-Duval Telescopic Intramedullary System
Fassier-Duval rods are secured on the far end of each growth plate and telescope, or extend, as growth in the bone occurs. Following the initial placement, there is often no need for surgical adjustment while the child grows. The patient is therefore less likely to develop the type of fractures associated with older, non-telescoping rods, and may require fewer surgeries as well.
The development of the Fassier Duval nails have helped transform the nature of surgery, as these telescoping rods “grow” along with the child. “This can mean a reduction in the number of surgeries the child needs,” says Dr. Green.
This series of x-rays depicts the surgical progression addressing the needs of a growing child with OI. In the top left picture she was treated with intramedullary rods. However, as she outgrew these rods and approached the time of rapid growth, her rods were replaced with Fassier-Duval rods (bottom two x-rays). Fassier-Duval rods provide stability for the fragile bones, allow for correction of bowing, and grow (lengthen) as the child grows. [To follow her progress, begin with the top left image, followed by the upper right, lower left, and lower right. Click on each image to view a larger version.]
Regardless of the type of treatment they receive, maintaining or improving muscle and bone strength are goals for all children with osteogenesis imperfecta. But physical therapists also work closely with families of patients, especially those with newly diagnosed newborns. “Parents often need help in learning how to carry and handle their infants,” explains Frances Baratta-Ziska, PT, MS, who is a physical therapist at HSS. “We teach them how to safely allow the child to explore the environment, as well as to how to dress and change them in a way that protects them from fractures.”
As their young patients grow, Ms. Baratta-Ziska, and her colleague, Magda Oledzka, PT, Pediatric Section Manager in the Rehabilitation Department at HSS, help them continue to move safely and teach them about the importance of avoiding jarring movements, jerking, and twisting. “Because children with OI can fracture their limbs with everyday movement, our goal is to teach them ways to be active and develop skills in the safety of the PT setting, so they will feel more confident outside the hospital,” says Ms. Baratta-Ziska.
“Regardless of the level of mobility children with OI are able to achieve, we find that those who do best have been incorporated into family life, instead of family life revolving around them,” adds Ms. Oledzka. She cites the many creative ways families make adaptations to help the child with OI participate in a range of activities, including travel.
In addition to improving the quality of daily life, physical therapy is an especially important component of care following rodding surgery or other procedures resulting from fractures. “Muscle mass decreases in any person who is immobilized,” explains Ms. Baratta-Ziska, “so post-surgical therapy can be intensive. We see the patients two or three times a week and give them safe exercises to regain their strength.”
As OI patients reach adolescence there tends to be a reduction in fractures, although the reason for this is not yet clearly understood. However, new issues arise. “Teenagers and college-bound patients decide whether they want to continue with physical therapy,” says Ms. Baratta-Ziska. “Some opt to continue walking, while others find they can participate more easily at school and other activities by using a wheelchair.” In addition, she notes, some teenaged patients develop weight control issues. “Because weight gain may result in less movement and is hard on the joints, we often work with a nutritionist who works with the patients to make better food choices,” says Ms. Oledzka.
Genetic counseling also plays a key role in the treatment of osteogenesis imperfecta patients and their families at HSS, especially for the newly diagnosed.
“Parents of a new baby with OI come to us with many questions: ‘How did this happen and why? What are the chances that it will happen with another baby? Where do we go from here?’” says Erin Carter, MS, CGC, the clinical coordinator and genetic counselor at the HSS Kathryn O. and Alan C. Greenberg Center for Skeletal Dysplasias, who spends much of her time answering those questions and explaining the genetic origins of the disease.
“The majority of cases of OI are caused by autosomal dominant mutation in one of the genes that code for type I collagen,” she explains. “Usually, when no one else in the family has a history of OI, a spontaneous change, or mutation, occurred in the genes either in the sperm or in the egg before conception or shortly after (in the fertilized eggs). In the majority of these families, with no history of OI, who then have a child with OI, there is a negligible chance of having another child with the same thing.”
Occasionally, Ms. Carter says, she also encounters individuals with mild forms of OI who did not realize they had OI until their own child was diagnosed. Genetic counseling is also important to people who have OI who wish to become parents. “Individuals with OI who have a baby with a partner who does not have OI have a 50% chance of having a child with OI with each pregnancy," she says.
In addition to explaining the genetic background and implications of OI on family planning, Ms. Carter serves as research coordinator in a number of Dr. Raggio’s clinical trials and helps patients and families deal with insurance providers to obtain coverage for genetic testing.
“Fortunately, over the last ten years the prognosis for children with osteogenesis imperfecta has improved considerably,” says Dr. Green. “Through a combination of intramedullary fixation, timely surgical intervention, medication, and physical therapy, children now have the opportunity to achieve very good function. In some cases, this includes the ability to walk, which might not have been a possibility in the past.”
The future of OI treatment also continues to look promising. Dr. Raggio and her colleagues at HSS are presently conducting animal studies of a new class of drugs known as RANKL inhibitors. “Instead of rendering osteoclasts less effective, these drugs interfere with the formation of osteoclasts,” Dr. Raggio explains. She is also studying parathyroid hormone (PTH), a bone stimulator that may be useful in some adult patients with OI who are not good candidates for bisphosphonates therapy.
Taking the longer view, Dr. Root anticipates that stem cell therapy and gene manipulation may eventually lead to dramatic advances in OI treatment.
Read about Lauren Davidson, an HSS patient with osteogenesis imperfecta who went on to become a swimming medalist.
For more information on treatment of osteogenesis imperfecta at HSS, please call our Physician Referral Service at 1.877.606.1555.
Summary by Nancy Novick