A study conducted at the Montreal Shriners Hospital for Children promises new hope for children born with osteogenesis imperfecta. The results of the study, which examined the use of pamidronate in children with OI, were published in the Oct. 1, 1998, issue of the New England Journal of Medicine.
For more current information on bisphosphonates, how they work, and why they're important, see the Foundation's fact sheet: Questions & Answers about Bisphosphonates.
The OI Foundation wrote the following special report in 1998 explaining the study and its results:
Montreal Study Advances Potential Drug Treatment for Children with OI
On October 1, 1998, the New England Journal of Medicine published an article by a team of physicians from the Montreal Shriners Hospital for Children. The article discussed results of a five-year study involving the use of a drug called pamidronate to treat children with severe osteogenesis imperfecta. The research suggests that, for most of the 30 children who participated in the study, pamidronate helped increase bone mineral content, reduce fractures, increase mobility, and decrease bone pain.
Though other drugs (such as fluoride and calcitonin) have been studied as potential treatments for OI, none of them have ever proven successful. The Montreal study shows promise for treating OI with pamidronate and other bisphosphonates (see definitions below). More research is needed to determine whether these drugs will become an established treatment for OI.
Bone Metabolism and the Effects of Bisphosphonate Drugs
Pamidronate is one of several drugs known as bisphosphonates. Pamidronate is given intravenously (by vein), whereas alendronate (another bisphosphonate drug) is given in pill form. (Fosamax® is the brand name for alendronate pills used to treat postmenopausal osteoporosis.) Pamidronate and alendronate both inhibit bone resorption (breakdown)--the natural, ongoing process of bone being destroyed by osteoclasts.
Previous studies of OI bone have suggested that abnormal activity of osteoclasts and osteoblasts (the cells that form new bone) contribute to the bone's fragility. In normal bone, the osteoblasts are producing new, healthy bone to replace the older bone that is resorbed by the osteoclasts. This is one of the body's natural processes to get rid of tissue that no longer functions well. In OI, imperfect bone is more susceptible to the osteoclasts, so OI bone is resorbed more quickly than normal bone. Meanwhile, the osteoblasts are producing new bone--but that bone is also imperfect, and abnormal collagen causes the osteoblasts to become less efficient and produce less bone. This combination of imperfect bone cells, increased bone resorption, and decreased bone formation leads to the fragile bones that are characteristic of OI. (For more information, see the OI Foundation's fact sheet on Understanding the Structure of OI Bone, available at www.oif.org or by calling 800-981-2663.)
The researchers at Montreal Shriners Hospital sought to determine if pamidronate, by slowing down bone resorption, could strengthen the skeleton in children with OI, thus decreasing fractures and increasing mobility.
Results of the Montreal Pamidronate Study
Between October 1992 and December 1997, the Montreal Shriners Hospital researchers administered pamidronate intravenously to 30 children, 3 to 16 years old, with severe osteogenesis imperfecta. Nine of the children had Type III OI, nine had Type IV, and the remaining 12 children had an unclassified type, but had features similar to Type IV. All but five of the children had moderate to severe restrictions on their ambulation.
In each treatment cycle, the children received pamidronate by slow intravenous infusion over a four-hour period on each of three successive days. At the beginning of the study, the children received the medication every six months, then it was increased to every four months.
Each time the children went to the Montreal Shriners Hospital for the treatment, the researchers recorded information on their growth and development, bone density, and mobility and ambulation. Significant findings of the study are as follows:
Before the treatment, all of the children had low z scores (the measurement used to quantify bone density). During treatment, the mean (average) bone density of the group increased by 41.9 percent per year. The z scores of three participants reached the normal bone density range.
X-rays were used to examine changes in the spine and long bones. During the treatment, no new crush fractures of the spinal vertebrae were found. Instead, an increase in the height of individual vertebrae was noticed, as was an increase in the vertebral coronal ("crown") area.
The cortex (outer portion) of the long bones increased. In 26 (90%) of 29 patients, the cortical width increased by an average of 27 percent per year. (In children without OI, cortical width usually increases about 10 percent per year.)
In 10 prepubertal children, their average pre-treatment growth rate was maintained. In 11 children undergoing puberty, the average growth rate during treatment increased slightly compared with the average pre-treatment growth rate.
There was a marked reduction in chronic bone pain reported by many of the children one to six weeks after the treatment began, with only an occasional recurrence of pain in the days preceding a treatment cycle.
The researchers used a scoring system to measure the children's mobility: 0=confined to bed or wheelchair; 1=able to walk with aids, but not functionally mobile; 2=able to walk in the household, with or without aids; 3=able to walk short distances, with or without aids; and 4=able to walk independently. Ambulation scores improved in 16 (53%) of the children: six children gained one grade, five gained two grades, one gained three grades, and four progressed from grade 0 or 1 to grade 4 (independent walking). In the other 14 children (47%), no change in grade was noticed.
The incidence of fractures decreased, from an average of 2.3 per year before treatment to 0.6 per year during treatment. Before treatment, three children (10%) had gone two years without fractures. During treatment (which lasted an average of 2.1 years), nine children (30%) had no fractures. The treatment did not appear to affect fracture healing.
The only side effect during treatment was a mild, drug-related fever in 26 (87%) of the children on the second day of the first treatment. This reaction did not recur during subsequent treatments.
What Do These Results Mean?
The researchers provide evidence for reduced bone resorption and increased bone mass in 30 children with severe osteogenesis imperfecta through intravenous doses of pamidronate. The results varied among the 30 children, but overall, many of the children gained greater bone density, reported reduced bone pain, gained mobility, and had fewer fractures during the treatment.
The researchers examined some other possible explanations for the improvements in the OI bone. They concluded, however, that the increased bone density was likely due to the pamidronate. They also concluded that the increase in bone cortical width could have resulted, in part, from the children's improved mobility (the strain of muscles against bone stimulates bone formation). Part of the growth increase could have been due to increases in the size of spinal vertebrae.
The Montreal investigation was an observational study. The group studied was not large, and both the patients and the researchers had full knowledge of the treatment. The investigators were aware that there was no control group of similar patients with which to compare the group of children being treated. (See article on controlled clinical trials). As the study's authors state, "We cannot exclude the possibility that there was a placebo effect, particularly with respect to the relief of bone pain and the improvement in ambulation." In other words, it is possible that full knowledge of the treatment, and the hope that it would succeed, caused the patients to attribute any and all progress to the treatment. Patients could have experienced relief of symptoms because of factors unrelated to the treatment.
Despite these cautions concerning study interpretation, the research is a welcome step in medical treatment for OI. The researchers concluded that "the consistency of the clinical, biochemical, and radiologic findings suggests that the changes resulted from the administration of pamidronate. This medical therapy does not stand alone: it should be considered part of a coordinated, multidisciplinary approach to the treatment of children with osteogenesis imperfecta, including timely corrective surgery, physiotherapy, and occupational therapy."
Does this study mean that physicians will immediately begin prescribing pamidronate to children with OI? Not necessarily. A great deal more research must be done to confirm the safety and efficacy of pamidronate for children with OI. Additional studies must determine the long-term effects of this therapy on bone, and on children's health.
Before the U.S. Food and Drug Administration (FDA) will approve use of a drug, they typically require controlled clinical trials to show that the drug is effective, and to prove that the benefits of the drug outweigh any risks to those using the drug. Bisphosphonates are one of many types of medications that have been approved for use in treating certain disorders in adults, but have not been approved for pediatric use. The FDA is committed to doing more to test drugs for use in children. Currently, alendronate has been FDA-approved for use by adults in preventing or treating postmenopausal osteoporosis, but not specifically for treatment of OI in either adults or children. Pamidronate has not been approved for adult or pediatric use for OI.