Bone-loss drug triggers first case of drug-induced osteopetrosis

A drug used to treat bone loss associated with diseases such as osteoporosis has caused a child to develop an unhealthy, dense skeleton characteristic of osteopetrosis, or marble bone disease.

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 suggests that, in uncontrolled studies, these drugs are beneficial for many pediatric bone diseases and carry no significant side effects,” said lead investigator Michael P. Whyte, M.D. “But this case documents that excessive doses can result in osteopetrosis. 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, of pediatrics and of genetics and is the medical-scientific director of the Center for Metabolic Bone Disease and Molecular Research at Shriners Hospitals for Children.

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. 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, resulting in bones that are abnormally dense and, by encasing existing cartilage, are weaker and more susceptible to fractures.

Before referral, the boy in this study had been given increasing dosages of pamidronate (Aredia) from about age 8 to 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.

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 age 12, 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 distinguish individuals with osteopetrosis from those with other types of dense-bone disease by measuring blood levels of an enzyme called creatine kinase brain isoenzyme (BB-CK).

Although Steven Mumm, Ph.D., assistant professor 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 said. “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, when pamidronate leaves the skeleton, it can then redeposit and affect bone cells once again. Even after two years off pamidronate, this patient’s X-rays still look like those of a child with osteopetrosis.

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