Clinical Science (2022) 136 1657–1659 https://doi.org/10.1042/CS20220040 Received: 03 August 2022 Revised: 27 October 2022 Accepted: 27 October 2022 Version of Record published: 21 November 2022 Commentary Fifty years of impact on treating bone disease: a commentary on Gasser et al. Elena L. Dent 1 and Michael J. Ryan 2,3 1 Department of Preventive Medicine, University of Mississippi Medical Center, Jackson, MS, U.S.A.; 2 Department of Pharmacology, Physiology & Neuroscience, University of South Carolina School of Medicine, Columbia, SC, U.S.A.; 3 Research Service, Columbia Veterans Affairs Health Care System, Columbia, SC, U.S.A. Correspondence: Michael J. Ryan (Michael.Ryan@uscmed.sc.edu) The precise control of whole-body calcium is essential for the maintenance of normal physi- ological function. Disruptions in calcium homeostasis can lead to pathology including osteo- porosis, kidney stone formation, and cardiac arrythmias. During the 1960s and early 1970s, a full understanding of calcium metabolism was still emerging. This commentary spotlights a seminal Clinical Science paper published in 1972 that signifcantly advanced the feld and contributed to the eventual approval of bisphosphonate drugs commonly used to treat post- menopausal osteoporosis, cancer metastases, and other calcium disorders. Calcium homeostasis is essential for normal physiological function and is tightly regulated by a vari- ety of mechanisms, the most important of which are parathyroid hormone and the vitamin D hormones. During the 1960s, the mechanisms controlling calcium metabolism were not fully understood, but were actively under investigation. In 1961, Drs. William Neumann and Herbert Fleisch made a critical observa- tion that significantly advanced the field. They noted that calcium phosphate was present in bodily fluids at supersaturated concentrations and that if collagen was added, the calcium phosphate would precipitate and form hydroxyapatite crystals. From this observation, given that collagen is a common protein in soft tissues, Neumann and Fleisch surmised that a mechanism must exist in the body that prevents the high concentrations of calcium from crystallizing in tissues [1]. Because polyphosphates were chemically used to ‘soften’ water and prevent calcium crystallization in industrial and home settings, Fleisch postulated that endogenously produced polyphosphates may exist to inhibit calcium phosphate precipitation in soft tissues of the body as well [2]. In 1962, Fleisch and Bisaz proved this hypothesis correct when they isolated urinary pyrophosphate and demonstrated it as an ef- fective inhibitor of calcium crystallization [3]. Another major advance in understanding bone physiology came in 1970 when it was demonstrated that both pyrophosphates and diphosphonates inhibited the dis- solution of hydroxyapatite crystals and bone resorption in response to parathyroid hormone [4,5]. These findings advanced the line of scientific inquiry related to how bisphosphonates might regulate whole-body calcium metabolism and the flux of calcium into and out of bone. The study also helped drive the field toward the eventual approval and clinical use of bisphosphonates that are now widely used in the treat- ment of primary osteoporosis (i.e. osteogenesis imperfecta) and secondary osteoporosis (postmenopausal, chronic glucocorticoid usage, and chronic inflammatory and immune disorders) in both children and adults. Bisphosphonates are also commonly used, and effective, to prevent cancer metastasis particularly in postmenopausal women [6], thus further illustrating the importance of these early preclinical studies to ultimately benefit patients. Clinical Science has been at the forefront of scientific discovery since its establishment in 1909 as the journal Heart: A study of the Circulation (renamed Clinical Science in 1933). Given the rich history of the journal, it is perhaps not surprising that influential papers on the control of calcium metabolism are contained within the volumes of Clinical Science. In 1972, the journal published ‘The Influence of Two Diphosphonates on Calcium Metabolism in the Rat’ [7]. The paper was authored by Drs. A.B. Gasser, © 2022 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society 1657 Downloaded from http://portlandpress.com/clinsci/article-pdf/136/22/1657/939728/cs-2022-0040c.pdf by guest on 23 November 2022