Study points way to potential new treatment for brittle bone disease
Patients with osteogenesis imperfecta (brittle bone disease) treated with teriparatide, a form of parathyroid hormone approved for treatment of women with osteoporosis, had stronger bones in the lower spine and the hip when compared to a group of similar patients who received placebo or an inactive medicine, said researchers from three academic institutions – Baylor College of Medicine, Oregon Health & Science University in Portland and the Kennedy Krieger Institute in Baltimore, Maryland, in a report that appears online in the Journal of Clinical Investigation.
“The treatment worked best in patients with a milder form of the disorder,” said Dr. Brendan Lee, professor of molecular and human genetics at Baylor and an author of the study. “We hope that larger studies using this drug will be undertaken to determine whether it can also reduce the risk of fracture.” He is also co-director of the Rolanette and Berdon Lawrence Bone Disease Program of Texas and a Howard Hughes Medical Institute investigator.
“Repurposing of drugs or discovering new indications for medications that already have FDA approval, is an efficient way of advancing therapies for rare disorders" said Dr. Sandesh CS Nagamani, assistant professor of Molecular and Human Genetics and the lead clinical investigator at Baylor for the study. “Our findings that anabolic bone therapy is likely to be more beneficial in patients with mild forms of osteogenesis imperfecta is an example for how well-controlled studies can help personalize therapy.” Nagamani is the director for Clinic and Metabolic Disorders of Bone and a member of the Rolanette and Berdon Lawrence Bone Disease Program of Texas.
Osteogenesis imperfecta is a genetic disorder in which the bones of those who have the problem are fragile and easily broken. The lifelong disease exists in several forms of varying severity. Those who benefited most from the drug in this study had type 1, a mild form of the disorder. It is estimated that between 25,000 and 50,000 people in the United States suffer from osteogenesis imperfecta.
In the study, 79 adults with osteogenesis imperfecta were randomly selected to be in one of two groups: the one that received the drug and those that received the placebo. The study lasted 18 months and neither patient nor physician knew who was receiving which medication. Teriparatide increased bone mineral density in the spine and hip in patients who received the drug. Those with type 1 osteogenesis imperfecta appeared to benefit more from the treatment than those with more severe forms of the disease (osteogenesis imperfecta types 3 and 4), raising important questions about how different genetic mutations found in the same gene can respond differently to medications.
Teriparatide differs from bisphosphonates, which are usually used in treating osteoporosis. Bisphosphonates prevent bone from being resorbed during the constant turnover process in which new bone is made and old bone is discarded. By contrast, teriparatide increases the rate of bone formation during this remodeling process. It, like most of the bisphosphonates, is approved by the U.S. Food and Drug Administration for treating osteoporosis.
Osteogenesis imperfecta, however, is a different disease. Bisphosphonates used in children with the disorder have resulted in reduced bone turnover, higher bone density and, in some studies, a lower fracture rate, said the authors in their study. However, only a few studies of those drugs have been carried out in adults with osteogenesis imperfecta. In those studies, the bone density seems to have increased but the fracture rate has not been reduced significantly.
First study of its kind
This is the largest controlled clinical trial ever performed in adult patients with the disorder. This is the first time a drug like teriparatide, a bone anabolic therapy that changes the way bone is remodeled, has been studied in this population.
The incidence of fracture as reported by the patient did not differ between the groups, though this may be due to the limited size of the study group in this rare disease. Because fracture patterns and frequencies show great variation from patient to patient, much larger numbers will be needed to test the effects on fracture frequency.
Others who took part in this study include: Mary A. Mullins and Sandesh C.S. Nagamani of Baylor; corresponding author Eric S. Orwoll, Sandra Veith, Ying Wang, Jodi Lapidus, Chaim Vanek and Jan L. Reeder, all of Oregon Health & Science University; Jay Shapiro of Kennedy Krieger Institute in Baltimore; and Tony M. Keaveny and David Lee of ON Diagnostics in Berkeley, California.
Funding for this work came from: The Osteogenesis Imperfecta Foundation; Eli Lilly and Co.; the Clinical and Translational Research Center of the Oregon Clinical and Translational Research Institute (NIH Grant UL1RR024140); the Baylor College of Medicine General Clinical Research Center (NIH RR00188); the Howard Hughes Medical Institute; the Osteogenesis Imperfecta Linked Clinical Research Center; the National Urea Cycle Disorders Foundation; and the Clinical Scientist Development Award from the Doris Duke Charitable Foundation.
Lee holds the Robert and Janice McNair Endowed Chair in Molecular and Human Genetics.