Chances are that you or a family member are taking a medication to reverse or improve Osteoporosis – a condition of poor bone density. The most common class of treatment is the Biphosphonates for which Fosamax is a prime example. The purpose of this article is not to discuss the clinical uses of this drug, but rather to review the history of Biphosphonate development by several Jewish scientists and physicians. I will specifically focus on “The Stumble” effect – that moment when a basic observation is recognized for its greater relevance, as with Alexander Fleming’s work with Penicillium molds or the story of Isaac Newton and the apple.
“Stumble” is not meant to imply a lack of awareness but, to the contrary, the sudden insight of a connection between apparently unrelated concepts. In this context, the story of the clinical uses of Biphosphonates may be more akin to a serendipitous revelation – the enlightening discovery of something important that was not deliberately sought.
In 1897 in Germany, two Jews – Baeyer and Hofmann - first synthesized Biphosphonates for medical use, but for 63 years this compound sat idle on chemists’ shelves receiving scant attention. In the 1930’s, phosphates were recognized as crystal inhibiting substances.
A few years later, L. Rothstein accidently added phosphate to an irrigation system which prevented blockage by inhibiting crystal formation which led to derivatives for scale prevention. In 1960, it was used for water softening and prevention of deposits in plumbing. Procter and Gamble then bought it for detergent research.
Three more Jews working in Berne, Switzerland demonstrated that soft tissue calcifications could be prevented by the intravenous injection of polyphosphates. The major clinical break through, however, occurred in 1968 when a child with severe calcification of his respiratory muscles leading to inability to breathe was treated with Etidronate (a bisphosphonate) and surprisingly recovered. This led to the use of this class of drugs in the treatment of metabolic bone disease. The child survived and grew into adulthood – testimony to a fortuitous juxtaposition of basic science, clinical skill, and recognition of potential benefit – in other word, an informed “Stumble”.
Is what has been said so far a contradiction? Biphosphonates inhibit calcification and inhibit bone resorption, therefore, how can they increase bone density? Paradoxically, these medications have two distinct biologic effects. At high doses, there is inhibition of calcification, whereas at lower doses, there is inhibition of bone resorption. This latter effect proves beneficial in osteoporosis which led to a new understanding of bone formation: bone requires reshaping for optimal mechanical function. This process is initiated by recruiting ‘cleaning’ cells (osteoclasts) which leads to bone resorption followed by ‘building’ cells (osteoblasts) that lead to new bone synthesis. Biphosphonates exert their major biologic action on bone resorption through inhibition of osteoclasts.
The history of the Biphosphonates – from detergents to pipe cleaners to pharmaceutical agents – demonstrates with remarkable clarity that the application of these associations requires perseverance and sound scientific judgment. At the same time, we are witness to Jewish researchers and scientists and physicians who unknown to each other are now inextricably linked in helping prevent fractures, deformities and in some cases- death.