[Focus: Drug-related osteonecrosis of the jaw]. / Les médicaments inducteurs d'ostéchimionécroses des maxillaires.

Antiresorptives and antiangiogenics are treatments that have proven effective in oncology and the treatment of osteoporosis and they are increasingly prescribed. The care of these patients requires collaboration between the prescriber and the oral health professional to establish an optimized treatment plan. Therapeutic education of the patient is essential for him to understand the issues of good oral health and the adverse effects that can be caused by these treatments. The management is essentially based on the individual benefit/risk balance resulting from the general, local and inherent of the molecule risk factors. Management of drug-related osteonecrosis of the jaw should be as early as possible.

Pharmacist Theodor Salzer (1833-1900) and the discovery of bisphosphonates.

Herbert Fleisch, the father of the therapeutic use of bisphosphonates in modern medicine, repeatedly stated in his numerous reviews that bisphosphonates were first synthesized 1865 in Germany by the Russian chemist Menschutkin. He was wrong on two counts. Had Menschutkin synthesized bisphosphonates, as he was a student of Wurtz at the time of the "synthesis", the birthplace of the substances would have been France and not Germany; but he did not. By reacting phosphorous acid with acetyl-chloride he obtained derivatives of pyro-phosphorous and pyro-phosphoric acids (P-O-P backbone) and not bisphosphonates (P-C-P backbone). The discovery of the first bisphosphonate occurred indeed in Germany but some thirty years later and not without some drama. First 1894 the pharmacist Theodor Salzer (1833-1900) described an impurity contained in commercially available phosphoric acid but failed to identify it as acetodiphosphoric acid, a bisphosphonate. 1896, an undergraduate student, Hans von Baeyer working in Munich at the Royal Academy of Sciences in the chemical laboratory of his father Adolf (the 1905 Nobel Prize laureate and discoverer of the barbiturates) synthesized an unknown substance which his famous father summarily rejected as some "Dreck" or impurity. Only due to the tenacity of young Hans work on the matter was continued and the paper describing the synthesis published a year later. The correctness of the chemical structure of the compound as assumed by von Baeyer (and his Ph.D. supervisor Hofmann) was confirmed 1901 by Heidepriem, a Ph.D. student of Hofmann. This short report attempts to shed some light on the life of the lesser known pharmacists and chemists involved in the synthesis of the first bisphosphonate, focusing on Salzer, Heidepriem and von Baeyer.

Bisphosphonate-related osteonecrosis of the jaw (BRONJ): initial discovery and subsequent development.

The efficacy of bisphosphonates in controlling skeletally related events in cancer patients and fractures in osteoporotic patients coupled with a relatively low level of toxicity and adverse events resulted in a widespread use of these medications in oncology and general internal medicine. However, in early 2001 a relationship had been established between these medications and a new disease entity characterized by necrosis of bone that was isolated to the jaws. This paper will present the chronology of events that led to the discovery of this new complication now known as bisphosphonate-related osteonecrosis of the jaw and review the reaction of professional organizations, the pharmaceutical industry, and government regulators.

Historical perspectives on the clinical development of bisphosphonates in the treatment of bone diseases.

Bisphosphonates (formerly termed diphosphonates) were first synthesized in the late 1800s; however, their clinical use has been relatively recent. The bisphosphonates' affinity for hydroxyapatite crystal surface led Procter and Gamble to test these compounds in dental, then medical applications. With key input from university researchers, this led to the medical use of the first bisphosphonate, etidronate disodium in 1968 to treat a young patient with myositis ossificans progressiva. Further clinical research led to widespread medical application for the bisphosphonate class including use as a diagnostic in radionuclide bone imaging agents, treatment of osteoporosis, Paget's disease of bone, hypercalcemia of malignancy and metastatic bone disease. The historical development of bisphosphonates provides an excellent example of how observations and knowledge obtained at the basic science level were applied and successfully tested in the clinic. The end result of these efforts has provided health care professionals with diagnostic and therapeutic tools to improve the lives of patients.