The boy had been given a bisphosphonate compound to treat weak, painful bones. This is the first reported case of drug-induced osteopetrosis, which typically is a genetic disorder.
"The medical literature on bisphosphonates suggests that, in uncontrolled studies, these drugs are beneficial for many pediatric bone diseases and carry no significant side effects," says lead investigator Michael P. Whyte, M.D. "But this case documents that excessive doses can result in osteopetrosis, leading to fractures. Our findings emphasize that it is essential to carefully monitor this type of medication, especially when given to children."
Whyte is a professor of medicine, pediatrics and genetics at Washington University School of Medicine in St. Louis and medical-scientific director of the Center for Metabolic Bone Disease and Molecular Research at Shriners Hospitals for Children, St. Louis. The case report appears in the July 31 issue of The New England Journal of Medicine.
Even in adulthood, healthy bones reflect a constant balance between skeletal formation and breakdown, both of which occur throughout the skeleton and near cartilage growth plates in children. A key part of this process during childhood is replacement of cartilage by bone, which occurs as bones lengthen during growth.
In diseases such as osteoporosis, bone typically is broken down faster than it is made. In contrast, osteopetrosis results when bone is made faster than it is broken down. Bones become denser but, by encasing existing cartilage, become weaker and more susceptible to fractures.
Before referral, Whyte's patient had been given increasing dosages of pamidronate (Aredia®) from about age 8 to age 10 in an effort to treat his mysteriously painful bones. This potent bisphosphonate drug blocks skeletal breakdown and is increasingly being used to treat children with several bone conditions, including the genetic form of osteoporosis, called osteogenesis imperfecta.
After two years on high doses of this drug regimen, the patient developed abnormally dense and misshapen bones. The drug eventually was discontinued but the pain remained unexplained. Eighteen months later, at 12 years of age, the boy was referred to Whyte for evaluation, at which point he was diagnosed with acquired osteopetrosis.
In 1996, Whyte and his colleagues reported a way to help diagnose osteopetrosis by measuring blood levels of an enzyme called creatine kinase brain isoenzyme (BB-CK). In addition to being present in the brain, BB-CK normally is found in osteoclasts, skeletal cells that break down bone. It is not, however, normally found in the blood. But when osteoclasts become sick during osteopetrosis, the enzyme seems to escape and leak into the bloodstream. Testing blood levels of BB-CK therefore helps distinguish individuals with osteopetrosis from those with other types of dense-bone disease.
Although Steven Mumm, Ph.D., assistant professor of medicine at the School of Medicine, found that the boy in this study lacked genetic abnormalities that can lead to osteopetrosis or several other heritable bone diseases, the patient's blood did have detectable levels of BB-CK and elevated amounts of another enzyme called acid phosphatase, which also accumulates in the bloodstream during osteopetrosis.
These findings, combined with bone biopsy specimens showing encased cartilage and skeletal changes seen on X-rays, documented that the boy had developed osteopetrosis.
"In light of our findings, the diagnosis of osteopetrosis is unequivocal, and the development of the disease matches perfectly with the time course of his pamidronate therapy," Whyte says. "The question now is how long his marble bone disease will persist now that he is off this drug."
According to co-investigator Deborah Wenkert, M.D., staff pediatric rheumatologist at Shriners Hospitals for Children, St. Louis, when pamidronate leaves the skeleton, it can then redeposit and affect bone cells once again. Even after two years off pamidronate, this one patient's X-rays still look like those of a child with osteopetrosis. "It's generally thought that increasing bone density in a symptomatic thin-bone disease is a good idea," Whyte says. "But this case shows that excessive doses of a bone anti-resorptive drug can cause osteopetrosis in people not genetically predisposed to the disease. If their use is not closely monitored, we may see more cases of bisphosphonate-induced osteopetrosis."
Whyte MP, Wenkert D, Clements KL, McAlister WH, Mumm S. Bisphosphonate-induced osteopetrosis. The New England Journal of Medicine, pp. 457-463, July 31, 2003.
Funding from the Shriners Hospitals for Children, the Clark and Mildred Cox Inherited Metabolic Bone Disease Research Fund, Hypophosphatasia Research Fund and the Barnes-Jewish Hospital Foundation supported this research.
The full-time and volunteer faculty of Washington University School of Medicine are the physicians and surgeons of Barnes-Jewish and St. Louis Children's hospitals and many of the medical staff at Shriners Hospitals for Children, St. Louis. The School of Medicine is one of the leading medical research, teaching and patient-care institutions in the nation. Through its affiliations with Barnes-Jewish and St. Louis Children's hospitals, the School of Medicine is linked to BJC HealthCare.
Journal
New England Journal of Medicine