MECHANISM OF VALPROATE BONE LOSS

August 10, 2010 — A molecular mechanism may finally explain the bone loss side effect that often accompanies the long-term use of valproate, a drug commonly used to treat epilepsy, bipolar disorder, and spinal muscular atrophy (SMA), according to results of a new study.

In fact, the researchers found that valproate reduced the formation of "2 key proteins important for bone strength" — decreasing the production of collagen by 60% and levels of osteonectin by 28% in patients with SMA.

"Our proteomic study has revealed that treatment of cultured cells with valproate causes reduced production of both collagen, the main protein in bone, and osteonectin, which is required for maintenance of bone mass," write lead investigator Glenn Morris, PhD, from the RJAH Orthopedic Hospital in Shropshire, United Kingdom, and colleagues.

They note that this is an especially important finding for those with SMA, a rare genetic disease that causes loss of muscle control and movement.

"SMA patients may already suffer bone weakness as a result of SMN1 gene deletion, so further bone loss would [certainly] be undesirable," write the study authors.

The study was published online June 22 in the Journal of Proteome Research.

Bone Loss Common, but Why?

Valproate was first introduced more than 40 years ago to prevent seizures in patients with epilepsy. Today, it is also commonly prescribed to treat several mood disorders, migraine headache, and SMA.

Although it is commonly known that bone loss can occur as a possible side effect after long-term use of this drug, the reason has been "a long-standing mystery," write the researchers.

So for this study, they sought to answer the question by examining more than 2000 cellular proteins of patients with SMA. "Using iTRAQ labeling technology, followed by 2-dimensional liquid chromatography and mass spectrometry analysis, a quantitative comparison of the proteome of an SMA cell line, with and without valproate treatment, was performed," the study authors report.

Clinical Problem Answered

Results showed that although most detectable proteins were unchanged after treatment with valproate, procollagen I peptides were decreased by 60% (P = .00002).

"[This] decrease in procollagen I suggests that the effect of valproate is on collagen production in the fibroblasts rather than collagen matrix turnover," explain the study authors.

Production of collagen VI was also "substantially and significantly down-regulated by valproate treatment of cultured cells."

Further, levels of osteonectin, a collagen-binding glycoprotein, were also decreased by 28% (P = .0007).

"In conclusion, our study suggests a novel molecular explanation for a long-recognized clinical problem," the study authors summarize.

The study authors have disclosed no relevant financial relationships.

J Proteome Res. Published online June 22, 2010.