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

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.

Bisphosphonate-associated atypical sub-trochanteric femur fractures: Paired bone biopsy quantitative histomorphometry before and after teriparatide administration

“…The data does suggest that teriparatide might increase bone turnover in this study group, even in those with absent bone turnover at baseline. Our data does not provide any evidence that would indicate that teriparatide would heal an early cortical fracture detected by an early radiological examination, though fracture healing has been described in clinical reports and case series with teriparatide use [43][44][45][46][47]. Our data does call for larger studies of teriparatide or future bone anabolics in this population, especially in those with non-displaced fractures.…”

Antiresorptives overlapping ongoing teriparatide treatment result in additional increases in bone mineral density

“…This is reflected in an elevation of biochemical and histomorphometric markers of bone formation, and therapy results in an increase of bone volume and bone mineral density (BMD). (2)(3)(4)(5)(6)(7) Increased bone formation with a modest elevation of resorption characterizes the initial phase of therapy with subcutaneous daily injections of TPTD. (2)(3)(4)(5) This initial phase is early treatment period, dominated by bone formation, lasts for 6 to 9 months and is also referred to as the anabolic window.…”

“…This is reflected in an elevation of biochemical and histomorphometric markers of bone formation, and therapy results in an increase of bone volume and bone mineral density (BMD). (2)(3)(4)(5)(6)(7) Increased bone formation with a modest elevation of resorption characterizes the initial phase of therapy with early treatment period, dominated by bone formation, lasts for 6 to 9 months and is also referred to as the anabolic window. (8,9) During this time, bone resorption activities, while on the increase, are still moderate, with bone formation processes constantly remaining at a high level.…”

The efficacy of teriparatide on lumbar spine bone mineral density, vertebral fracture incidence and pain in post-menopausal osteoporotic patients: A systematic review and meta-analysis

“…First line pharmacotherapy includes bisphosphonates, which prevent bone resorption ultimately preventing fractures. A second line treatment that is a recombinant form of parathyroid hormone (PTH), teriparatide, works to prevent new fractures by increasing and subsequently maintaining anabolic equilibrium between bone formation and resorption ( Akhter et al, 2018 ; Marcus, 2011 ; Ohtori et al, 2012 ). Teriparatide has been increasingly used in spine surgery to prevent osteoporotic related surgical complications ( Akhter et al, 2018 ; Lin and Lane, 2004 ; Marcus, 2011 ; Ohtori et al, 2012 ; Ohtori et al, 2013 ; Rizzoli et al, 2011 ; Parfitt, 1989 ; Ejersted et al, 1993 ; Oxlund et al, 1993 ).…”

“…Teriparatide has shown efficacy across multiple studies, notably in postmenopausal women, for faster bone healing, vertebral and non-vertebral fracture prevention and treatment, and fracture associated pain ( Akhter et al, 2018 ; Marcus, 2011 ; Ohtori et al, 2012 ; Ohtori et al, 2013 ; Rizzoli et al, 2011 ; Eriksen and Robins, 2004 ; Fukuda et al, 2014 ; Pietrogrande and Raimondo, 2013 ; Ebata et al, 2017 ). It also reduces hardware complications following spinal fusion, as well as improves bone mineral content (BMC), bone mineral density (BMD), fusion duration, and fusion rates ( Ohtori et al, 2012 ; Ohtori et al, 2012 ; Yagi et al, 2016 ; Chaudhary and Lee, 2017 ; Aslan et al, 2011 ).…”