There cannot be many fields of product development that are subject to more regulation and supervision than pharmaceutics. New drugs undergo careful chemical assessments of potential toxicity before they are ever tested in biological systems such as cell cultures or laboratory animals. Most candidate substances never make it to any trials in healthy volunteers or patients with a particular target condition because initial screening procedures have identified a risk of toxicity. Clinically important side effects of those drugs which have survived the screening stage are expected to reveal themselves in double-blind randomised controlled trials (RCT) in which drug effects (and side effects) are compared with those of placebo. Given that these trials are usually of short duration even if they are designed to test the effectiveness of treatments intended for long-term use (including antiepileptic drugs), pharmaceutical companies have to continue monitoring for rarer side-effects or those that take longer to develop even after a drug has been licenced for use in patients.
While all this may offer some reassurance to individuals using medications, the story of valproate (VPA) is shows just how long it takes to discover the full side-effect profile of a drug and to understand the mechanisms causing these side-effects. As recounted in my editor’s choice paper from the current issue of Seizure (1), the antiepileptic properties of VPA were first discovered in 1963, although it took until 1978 for the drug to gain FDA approval. Since then VPA has become a key part of the epileptological toolbox. It continues to be the most effective drug for generalised and clinically unclassifiable epilepsies and rarely aggravates seizure disorders. Whereas the risk of side effects such as tremor, hair-loss, weight gain, hepatotoxicity and pancreatitis was identified early on, it took until 1995 before initial reports of the adverse effects of VPA on bone health were published (2). Although the teratogenic potential of valproate was initially suggested in 1983 (3), it took a similar length of time for knowledge about the relatively high risk of teratogenicity associated with valproate to emerge.
The very comprehensive review article by Dimitris Pitetzis et al. shows that we have found out a lot more about the effects of VPA on bone health since then (1). It is now clear that VPA can contribute to osteoporosis in adults and to reduced bone growth in children through a range of mechanisms. These mechanisms include decreased osteoblast proliferation, altered collagen synthesis, induction of vitamin D catabolism and endocrine effects. The fact that we now understand these mechanisms better will hopefully help with the development of strategies to prevent the adverse effects of VPA treatment on bone health and of molecules retaining the antiepileptic properties of valproate but avoiding its adverse effects on bones.
(1) Pitetzis D, Spilioti M, Yovos J, Maria P. The effect of VPA on bone: From clinical studies to cell cultures- the molecular mechanisms revisited. Seizure 2017; 48, 36-43.
(2) Sheth RD, Wesolowski CA, Jacob JC, Penney S, Hobbs GR, Riggs JE, Bodensteiner JB. Effect of carbamazepine and valproate on bone mineral density. J Pediatr, 1995. 127: 256-62.
(3) Koch S, Göpfert-Geyer I, Jäger-Roman E, Jakob S, Huth H, Hartmann A, Rating D, Helge H. [Anti-epileptic agents during pregnancy. A prospective study on the course of pregnancy, malformations and child development] (in German). Dtsch Med Wochenschr 1983;108: 250–7.