History of etidronate.

Etidronate is a non-nitrogen-containing bisphosphonate. Because it binds with calcium and inhibits crystal formation and dissolution, it was considered by Procter & Gamble as an additive to toothpaste (to prevent build-up of tartar) and detergent (to bind calcium and increase sudsing in "hard" water). The first clinical use (1968) was for fibrodysplasia ossificans progressiva. The first approved clinical use (1977) was for treatment of Paget's disease of bone. Other approved indications are hypercalcemia of malignancy and heterotopic ossification, with a host of off-label uses (including fibrous dysplasia, periodontal disease, multiple myeloma, neuropathic arthropathy, pulmonary microlithiasis, diabetic retinopathy, bone metastases, melorheostosis, urinary stone disease, periodontal disease, etc.). Unique among bisphosphonates, etidronate (oral therapy) results in hyperphosphatemia, increased tubular reabsorption of phosphorus and increased levels of 1,25-dihydroxyvitamin D. The dose that reduces bone resorption is close to the dose that impairs mineralization; prolonged high-dose use can result in osteomalacia and bone fractures. Intermittent cyclic etidronate for osteoporosis resulted in favorable changes in bone density and histomorphometry (no mineralization defect) as well as a decrease in vertebral fracture rates in postmenopausal women with osteoporosis. Later studies showed similar effects in men with osteoporosis and patients with glucocorticoid-induced osteoporosis. Although its use for osteoporosis has given way to newer bisphosphonates and other agents, because of its unique properties, it remains the bisphosphonate of choice for treatment of heterotopic ossification.

Historical perspectives on advertising and the meme that personal oral hygiene prevents dental caries.

The consensus of a leading scientific panel in 1930 was that oral hygiene products could not prevent dental caries. Their view was that dental caries prevention required the proper mineralisation of teeth and that vitamin D could achieve this goal. Over a hundred subsequent controlled trials, conducted over seven decades, largely confirmed that this scientific panel had made the right decisions. They had, in 1930, when it comes to dental caries, correctly endorsed vitamin D products as dental caries prophylactics and oral hygiene products as cosmetics. And yet, despite this consistent scientific evidence for close to a century, an opposing conventional wisdom emerged which thrives to this day: oral hygiene habits (without fluoride) protect the teeth from dental caries, and vitamin D plays no role in dental caries prevention. This historical analysis explores whether persistent advertising can deeply engrain memes on dental caries prevention which conflict with controlled trial results. The question is raised whether professional organisations, with a dependence on advertising revenues, can become complicit in amplifying advertised health claims which are inconsistent with the principles of evidence-based medicine.

8th Pieter van Keep Memorial Lecture. Estrogen and bone: have we completed a full circle?

Estrogen therapy was considered first-line therapy for the prevention and treatment of postmenopausal osteoporosis in 1984. Evidence from a large, randomized clinical trial in 2002 proved the efficacy of estrogen in the prevention of all types of osteoporosis-related fractures. Ironically, estrogen was relegated to second-line therapy, based on perceived safety concerns. The historical background to these decisions is presented. It is argued that this decision is not a reasonable reflection of the available evidence, especially in comparison to other available drugs.

[A history of the research on bone metabolism for the past 50 years in Japan and a memory of Dr. Hirotoshi Morii].

It has been 20 years since the monthly Journal "CLINICAL CALCIUM" was published in November, 1991. This review Journal edited by Drs. Hirotoshi Morii and Yoshio Yazaki has contributed a lot to the understanding of the importance of calcium in bone and cardiovascular systems. This article describes a history of the research on bone metabolism for the past 50 years in Japan. Also, a memory of my dear friend, Hirotoshi Morii, is retraced.

Present at the beginning: a personal reminiscence on the history of teriparatide.

The ability of parathyroid glandular extracts to stimulate bone acquisition in rodents was established in the 1920s, but interest in this action lay dormant for almost 50 years until application of contemporary laboratory methods permitted the large-scale production of an amino-terminal fragment of PTH, (1-34) hPTH (teriparatide), which was capable of carrying out all known actions of the full-length (1-84) PTH molecule. In the 1970s, largely stimulated by the efforts of a British pharmacologist, Dr. John Parsons, the scientific community began to revisit these anabolic actions and showed that single daily injections of teriparatide dramatically increased bone mass in several mammalian species and restored bone in oöphorectomized rats. Shortly thereafter, human studies confirmed a striking increase in trabecular bone mass and showed also that an important part of teriparatide's action is to increase cortical bone. Eli Lilly and Company conducted a formal registration trial in postmenopausal women with osteoporosis. The unexpected occurrence of osteosarcomas in Fisher 344 rats treated long-term with teriparatide provoked an abrupt cessation of that trial, but ambiguity concerning the relevance of this rat finding to human disease, combined with significant anti-fracture efficacy, led to FDA approval of teriparatide for men and postmenopausal women with osteoporosis "at high risk for fracture" in 2002. Subsequently, teriparatide has been approved also for treatment of patients with glucocorticoid-associated osteoporosis, and papers indicating utility of this agent for dental and orthopedic applications have begun to appear.

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.

SOLAR ultraviolet radiation and vitamin D: a historical perspective.

Rickets, the state of vitamin D deficiency, has reemerged as a potential problem in the United States. At the dawn of the 20th century, rickets was pervasive among infants residing in the polluted cities of Europe and the northeastern United States. Important milestones in the history of rickets were the understanding that photosynthesized vitamin D and dietary vitamin D were similar, the discernment of the antirachitic potency of artificial and natural ultraviolet rays, and the discovery that ultraviolet irradiation could render various foods antirachitic. Clinical guidelines were instituted to promote sensible exposure to sunlight and artificial ultraviolet radiation. In addition, irradiated ergosterol from yeast became the major vitamin D source for food fortification and the treatment of rickets, leading to a public health campaign to eradicate rickets by the 1930s. We review the sequence and turn of events pertaining to the discovery of vitamin D and the strategies for the eradication of the reemerging rickets problem.

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.