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

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Abstract

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.

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Notes

  1. Under the trade name Forteo in the USA and some other countries and Forsteo in the UK and Europe. Teriparatide is the generic term for hPTH(1–34). The Lilly product is produced by recombinant DNA technology.

  2. Lilly's familiarity with this clinical problem was likely influenced by the fact that the company is located in central Indiana, not far from the nationally prominent clinics that pioneered thyroid surgery.

  3. This change was made because a patent had been awarded to another scientist, Adolph Hanson, whose extraction methods had been published in 1923 prior to those of Collip.

  4. Aurbach's paper made an additional point which is of sufficient interest to quote here: “Early crude extracts which had marked effects on calcium metabolism also enhanced the excretion of phosphate in the urine. Other investigators had proposed that a distinct hormone may account for the latter effect. The isolation of a single substance, a potent mediator of both biological effects, seems to end this controversy [10].”

  5. The moratorium on human trials was voluntary and not required by FDA. In fact, a number of non-Lilly studies remained active throughout this period of uncertainty.

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Acknowledgments

This article is dedicated to the memory of Gerald Aurbach. I thank Drs. John Potts, Robert Jilka, and David Dempster for their input and assistance.

Conflicts of interest

The author is a retiree of Eli Lilly and Company. Advisory and speaking activities: Lilly, GlaxoSmithKline, Amgen.

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  1. Stanford University, Stanford, CA, USA

    R. Marcus

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Marcus, R. Present at the beginning: a personal reminiscence on the history of teriparatide. Osteoporos Int 22, 2241–2248 (2011). https://doi.org/10.1007/s00198-011-1598-x

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