OI Foundation Science Meeting, April 19, 2004 Mild Forms of OI: Molecular Basis, Natural History and Treatment
The fourth OI Foundation Scientific Meeting, Mild Forms Of Osteogenesis Imperfecta (OI) Molecular Basis, Natural History, and Treatment, was co-chaired by Peter H. Byers, MD and Michael Whyte, MD. This meeting focused on Type I (mild) OI. The meeting was sponsored by the National Institute of Arthritis and Musculoskeletal and Skin Diseases, the Office of Rare Diseases, and the Buchbinder Family, and was held in Chicago, IL, April 19, 2004. Nineteen investigators and clinicians participated in the meeting, along with nine observers, and two presenters who have mild OI.
This meeting generated unprecedented enthusiasm from families and adults living with mild OI. In preparation for the meeting, more than 100 people spent hours responding to a detailed survey. The results are shared here. Key topics for discussion were: social context, clinical aspects, and molecular basis, as well as preventative, genetic and drug therapies and treatments. The result is a better idea of where to focus our research efforts in the coming years, improved clinical knowledge, and progress toward our goal of better treatments, and a cure for all forms of osteogenesis imperfecta.
Peter Byers, M.D. opened the meeting with a description of mild OI as an invisible disorder that causes people to feel excluded from society and medical care. Socially, mild OI is different from the more severe types because it appears invisible and this also makes limitations difficult to understand. Therapy tends to look only at the more severe types of OI. The consistent, underlying factor of a positive outcome in chronic disability is the social network and parents. This meeting is designed to look not only at what we know, but at what we should know.
SOCIAL CONTEXT OF MILD OI
Amy Jackson, a medical resident who has mild OI, opened the meeting with her personal story which includes 50-60 fractures, pain in her back and knees, and occasional trouble walking (she uses a cane when necessary). Growing up, she played baseball, serving as a catcher or batter. She swam and walked. She was generally unable to run or jump. She chose to become a doctor and feels she is well equipped to help patients with chronic disorders. She worries about her scoliosis getting worse, joint problems, arthritis, weakness, and obtaining insurance.
The OI Foundation receives 7,000 inquiries each year from people with OI, families, medical professionals and service providers.
Inquiries about mild OI children focus on: child abuse allegations, schooling, bisphosphonates, medical management, exercise and sports. Inquiries from mild OI adults include: marriage and sex, genetics, pregnancy, caring for a child who is more severe than the parent(s), late diagnosis, knee, ankle and back problems, menopause, employment, and insurance.
Persistent misinformation includes: children with OI "grow out" of the disorder in their teens (resulting in risky behaviors such as smoking, drinking, etc.), focusing on fractures while ignoring joints and ligaments, "I don't need to exercise," "I don't need physical therapy after surgery or fracture."
Child Abuse Allegations and Mild OI About 15% of the total number of diagnostic tests are requested because of a child abuse allegation. About 6-11% of these tests result in a positive diagnosis. In most of these cases, a clinical diagnosis of OI has already been made.
Transition from Pediatric to Adult Models for Continuing Health Care The transition from pediatric health care should be a purposeful and planned movement to adult-based healthcare. Barriers to this transition include having received health care from the same institution for 21 years, parents, staff and young adults who are used to the parents making the health care decisions, and health care providers who forget to "switch" to the child when discussing health care.
In order to take charge of your own health care, you need knowledge and the ability to communicate your condition. Children age 6-12 should be encouraged to speak directly to the doctor with the parents assistance, and take part in making decisions. Teens age 13-18 should take full responsibility for making and remembering appointments, speaking with the doctor, and obtaining medications. Young adults age 19-21 should be able to identify care, determine how they will pay for it, and transfer medical records. The pediatrician should help the family and the patient review the patient's medical record and understand which parts are most important. Many teens go to college thinking they don't need any special medical attention. If a fracture occurs at school, everyone is unprepared.
CLINICAL ASPECTS OF MILD OI
Hearing Loss in Mild OI and its Treatment Hearing loss is most common in Type I OI, least common in Type IV. Although hearing loss most often begins in early adulthood, it may be present in childhood.
In a study of 143 patients with mild OI, OI-related hearing loss in at least one ear was found in 48% of the patients, hearing loss was found in 61% of the adults. The mean age at onset was 28 years (range was 8 months - 72 years). Twenty-six percent of the people with normal hearing thought they had hearing loss. Eleven and a half percent of those who had hearing loss didn't notice it. No clear correlation was found between clinical type of OI and hearing loss. The severity, occurrence, or type of hearing loss was not correlated with any clinical feature of OI.
Treatment for hearing loss includes: hearing aid (if loss is more than 30dB), or stapes surgery for more severe loss. Cochlear implants are more recent and less is known about them. In general, stapes surgery is safe and offers satisfying to excellent results. Laser-assisted stapedotomy might be the surgery of choice in middle ear surgery because of the risk of a thick, fixed or obliterated foot plate, and excessive bleeding.
Audiometry is recommended for children with OI if hearing difficulty is suspected. For a person without symptoms, a baseline test at 10 years of age and repeat tests every three years is recommended.
Musculoskeletal manifestations of Mild Osteogenesis Imperfecta in the Adult A 32-question voluntary, anonymous survey was distributed through the Osteogenesis Imperfecta Foundation web-site for 6 weeks. One hundred and eleven people with mild OI responded (78 Females, mean age 40.2 years; and 33 Males, mean age 42.1years, range 20-70). Peak height was 62.4" (65.6"M/61.1"F).
Seventy-four percent considered their OI mild, 23 percent moderate and 3 percent severe. Fracture number did not differ among these three groups and all fit the descriptive term mild. Ninety-one percent of sclera were blue or not white. Fifty-one percent of males considered bruising normal whereas 87.2 percent of females considered bruising abnormal. Fifty-one percent of males considered dental health normal whereas 87.2 percent of females considered dental health abnormal.
There were an average of 31 lifetime fractures per person; 27.6 percent (8.5 fractures per person) of these occurred after age 18. Forty-four percent received a diagnosis of "arthritis." Of those 66.7% reported osteoarthritis, 37.5% unknown, 6.25% fibromyalgia, 4.2% inflammatory arthritis. Pain and stiffness scores dominated at the low back, hips and knees. Eighty-three percent reported some impairment based on joint disability, 30-50% require some degree of assistance with ordinary activities of daily living; 5-15% require assistance with light physical and personal care tasks. Sixty-six percent reported hypermobility, 55.8 percent had prior joint dislocation and 38.9 percent prior tendon rupture. Instability dominated at the knees. Fifty-two percent reported some impairment based on ligament and tendon disability. Seventy percent reported that back pain was common, and slightly fewer people reported some impairment from back pain. Forty-seven percent reported scoliosis. Forty-four percent reported having a vertebral compression fracture. One person reported having vertebroplasty or kyphoplasty. No complications occurred with this procedure. Ninety-three percent rated physical health as good or excellent.
Skeletal Changes in Adults with Mild OI Treatment in OI Type I should be based on non-OI treatment. Rodding is appropriate for recurring breaks in one spot, or severe angulation. Compression fractures of the spine are not currently being treated with vertebroplasty because of concerns about additional fractures. Criteria for consideration of total joint replacement is severe disability with no other alternative, or degenerative progression based on x-ray. More typically, an alignment problem can be treated with an osteotomy to normalize.
Pregnancy in Mild OI A 1996 survey of women with mild OI showed that most have normal pregnancies. In 2002, a retrospective study of 100 women showed that half had mild-severe back pain. A 2001 study showed that the only reason to perform a C-section when the child has OI is if it is obstetrically necessary. There is a high incidence (37%) of breach presentations in mothers with OI. Mothers who had bisphosphonate treatment as children should be monitored during breast feeding because of the risk of calcium depletion.
MOLECULAR BASIS OF MILD OI
Familial Variability in Mild OI The Montreal Shriners Hospital for Children studied 132 children with mild OI and 36 parents with mild OI. Eighty-five percent had blue sclerae, 17% had DI. The children had lower BMD at the lumbar spine than the parents. Up to 18% of the variance between parents and children can be explained by common factors such as nutrition and exercise.
MEDICAL AND OTHER TREATMENTS OF MILD OI
Lessons from Osteoporosis With Osteoporosis, bone mass influences fracture risk. People with Mild OI are likely to encounter many of the same problems as people with osteoporosis. One of the most important ways to prevent fractures is to pay attention to body mechanics and safe exercise. Correct lifting, good posture, protecting the spine, strength training, keeping periods of bed rest brief (3-4 days), using a hard mattress, and lying on your side with hips and knees flexed can all contribute to decreased fracture risk. Because OI is a life long problem, the cautions about body mechanics pertain forever. Increase fracture risk occurs with smoking, too much sodium or caffeine.
Habilitation and Re-habilitation Because muscle strength correlates with ambulatory status, maintaining muscle mass is likely to support ambulation. Encourage participation in sport and leisure activity to promote self-esteem, fitness and well being.
Treatment in mild OI should focus on restoration of function, strengthening, use of gait aides, orthotics and adaptive equipment to maintain even balance.
An Approach to Treating Mild OI in Adolescents With Fractures Reasons to treat people with mild OI using drug therapy include: Increased risk of fractures due to sports injuries, lack of calcified cartilage, or psychosocial issues. Bisphosphonate treatment in mild adults showed no change after 1 year, small change after 2 years. Reasons not to treat include: no studies in mild OI with bisphosphonates, pregnancy risk is higher, no documentation of decreased fracture incidence resulting from treatment, and side effects such as weight gain and delayed fracture healing. Other therapeutic approaches focus on psychology, dentistry, social services, and audiology.
Bisphosphonates in Mild OI Criteria for treating mild OI children with bisphosphonates include, if their BMD is less than 2 Standard Deviations from the norm, or if BMD was progressively decreasing or stationary, or if they had bone pain, 3 or more fractures per year for two consecutive years and vertebral crush fractures. In 26 prepubertal children treated with bisphosphonates, BMD increased .6 from baseline during the first 12 months and .9 from baseline in the second 12 months. In the pubertal teens, BMD increases in the first 12 months were not significant, and BMD increases in the 2nd 12 months were .7. There was no significant increase in growth rates, but also no decrease.
Regarding whether bisphosphonate treatment is appropriate for mild OI, some doctors say yes because of the improved quality of life (decreased fracture rate, less pain, parents are less worried). Other doctors are still trying to assess through animal and human studies.
There is a concern that after 2-3 years of treatment the bone shows defective remodeling, it is more brittle, and strength decreases. Suggestions are to try smaller doses and increase the interval between doses. The conclusion is if you don't need bisphosphonates, don't use them.
Remaining questions about bisphosphonate treatment:
Does stopping the treatment sooner provide geometric gains without the matrix problems?
Is treating children to reach peak bone mass a realistic goal?
How to monitor the changes in bone remodeling rate with age
Evaluate surgical procedures in Type I
Rehabilitate for life, not just for a few years.
Promote bone formation
Can we maximize the effect of puberty?
Molecular Genetic Approaches to Treatment of Mild OI One way to look at OI is to view it as a failure of the osteoprogenitor lineage (the inability of a generation of cells to develop healthy bone). Bone disease may be caused by the ability of the lineage to respond (or not) to problems. In OI, the presence of a mutation makes cells become less efficient. In order to produce the normal amount of osteoblasts, OI bone compensates by making more precursor cells. This could result in cell fatigue and premature aging. Do bisphosphonates work by slowing this overproduction?
A protein called IGF-1 affects bone remodeling. It may be of use to improve remodeling or increase the amount of remodeling. When it is injected into one bone, it travels to the bones next to the original. If Type I cells could be re-engineered to produce more IGFP (precursor to IGF-1), this would create enough normal collagen to produce normal bones. A new mouse model is currently being prepared to study this hypothesis.