History of etidronate

doi:10.1016/j.bone.2020.115222

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Volume 134, May 2020, 115222

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Highlights

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Etidronate, a non-nitrogen-containing bisphosphonate, was the first in this class to be used clinically
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In the 1970s, 80s and early 90s, etidronate was widely use for treatment of Paget’s disease and osteoporosis
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Clinical use has markedly diminished, but etidronate is still used for treatment of heterotopic ossification

Abstract

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.

Introduction

Etidronate (disodium ethane-1-hytdroxy-1,1-bisphosphonate) is a non-nitrogen-containing bisphosphonate – two phosphonate groups bound to a carbon [Fig. 1] – was first synthesized in 1897. Because it binds with calcium and inhibits crystal formation and dissolution, Procter & Gamble considered it as an additive to toothpaste (to prevent build-up of tartar) [1] and detergent (to bind calcium and increase sudsing in “hard” water) [2]. Subsequent references need to be renumbered.

Preclinical studies showed potential therapeutic effects. In addition to inhibiting crystal formation and dissolution [3], reduced osteoclast activity and increased bone volume were observed [4].

Given the common use of nitrogen containing bisphosphonates today, some of the unique properties of etidronate may have been forgotten or not appreciated [Table 1].

The first ad hoc clinical use of etidronate was in 1968, for treatment of a child with fibrodysplasia ossificans progressiva [7]. After extensive off-label use, the first approved clinical use (oral, 1977) was for treatment of Paget's disease of bone. Other approved indications were heterotopic ossification (oral, 1980) and hypercalcemia of malignancy (intravenous, 1987), with a host of off-label uses (Table 2). Because of its unique properties, it remains the bisphosphonate of choice for treatment of heterotopic ossification but has largely been supplanted by newer (nitrogen-containing) bisphosphonates or other agents for other uses.

Section snippets

Paget's disease

Injectable salmon calcitonin was approved by the FDA for treatment of Paget's disease in 1975 but had limited effectiveness and side effects that were sometimes severe. A number of reports of the benefits of etidronate for Paget's disease emerged in the early 1970s [8,9] and etidronate was approved by the FDA for this indication in 1977. Etidronate for Paget's disease was given orally, 5 mg/kg/d, for no longer than 6 months (to reduce the chance of impaired mineralization). Either alone or

Osteoporosis studies

In the 1980s, estrogen preparations were commonly used for prevention and treatment of osteoporosis (though never officially approved for “treatment”). Identification of patients was largely limited to those with fractures, as bone densitometry as we know it today was not available. Injectable salmon calcitonin was approved by the FDA for treatment of osteoporosis in 1986 but use was limited by the need for injection as well as side effects, sometimes severe. The data for efficacy of injectable

Osteoporosis approval process

The US FDA held an Advisory Committee hearing on etidronate in 1995. The day before, the committee recommended approving nasal spray salmon calcitonin for treatment of osteoporosis based on study results that were less than compelling [11]. In the etidronate study, vertebral fracture rates were significantly reduced with treatment from baseline through Month 24 but the difference was no longer significant by Month 36 [21] (in Year 3, there were 18 new fractures in the non-etidronate group and

Reflections

The US study of cyclical etidronate was the first of its kind and laid the foundation for all modern-day Phase 3 trials for osteoporosis – a multicenter trial, protocol developed and refined with input from the investigators with standardized bone density measurements, vertebral fractures assessed by an expert radiologist who developed the semiquantitative grading scale [25], careful outside monitoring of study centers, a priori definitions of statistical power (but naively assuming that a n of

Acknowledgements

We fondly recall the people at Norwich Eaton and Proctor & Gamble who were involved with the pivotal etidronate study for postmenopausal osteoporosis. Names below are from memory (we apologize if we have forgotten some) and are in alphabetical order: Barb Anderson, Bill Au, Doug Axelrod, Raffaella Balena, Pascale Baudry-Thevenot, John Bevan, Enoch Bortey, Lisa Bosch, Charlotte Brokaw, Kent Buckingham, Shirley Bunn, Mike Burns, Brian Chamberlain, Karen Cooman, Beth Crimmins, Ray D'Alonzo, Reg

References (25)

G.A. Nixon et al.
Preliminary safety assessment of disodium etidronate as an additive to experimental oral hygiene products
Toxicol. Appl. Pharmacol.
(1972)
C.A.L. Bassett et al.
Diphosphonates in the treatment of myositis ossificans
Lancet
(1969)
C.H. Chesnut et al.
A randomized trial of nasal spray salmon calcitonin in postmenopausal women with established osteoporosis: the Prevent Recurrence of Osteoporotic Fractures study
Am. J. Med.
(2000)
A.B. Hodsman
Effects of cyclical therapy for osteoporosis using an oral regimen of inorganic phosphate and sodium etidronate: a clinical and bone histomorphometric study
Bone Miner.
(1989)
S.T. Harris et al.
Effects of four years of intermittent cyclical etidronate treatment for postmenopausal osteoporosis
Am. J. Med.
(1993)
P.D. Miller et al.
Cyclical etidronate in the treatment of postmenopausal osteoporosis: efficacy and safety after 7 years of treatment
Am. J. Med.
(1997)
M.D. Francis et al.
Historical perspectives on the clinical development of bisphosphonates in the treatment of bone diseases
J Musculoskel Neuronal Interact
(2007)
H. Fleisch et al.
The influence of pyrophosphate analogues (diphosphonates) on the precipitation and dissolution of calcium phosphate in vitro and in vivo
Calcif. Tissue Res.
(1968)
R. Schenk et al.
Effect of ethane-1-hydroxy-1,1-diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl 2 MDP) on the calcification and resorption of cartilage and bone in the tibial epiphysis and metaphysis of rats
Calcif. Tissue Res.
(1973)
T. Thomas et al.
Atypical osteomalacia after 2 year etidronate intermittent cyclic administration in osteoporosis
J. Rheumatol.
(1995)

C. Mautalen et al.

Spontaneous fractures of uninvolved bones in patients with Paget’s disease during unduly prolonged treatment with disodium etidronate (EHDP)

Clin. Orthop. Relat. Res.

(1986)

R.D. Altman et al.

Influence of disodium etidronate on clinical and laboratory manifestations of Paget’s disease of bone (osteitis deformans)

N. Engl. J. Med.

(1973)

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Characterization of the structure of amorphous disodium etidronate
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Disodium ethane-1-hydroxy-1,1-bisphosphonate (disodium etidronate) is a first-generation bisphosphonate that is widely used in treating osteoporosis and Paget’s disease. Pharmaceuticals prepared using disodium etidronate as the drug substance have a crystalline form. Compared with crystalline formulations, amorphous formulations exhibit higher water solubility. However, stable amorphization has not yet been achieved, and clarification of its structural origin is still needed. In this study, high-energy X-ray diffraction and reverse Monte Carlo structural modeling were performed to determine the static structures of amorphous compounds. Na ions have to be placed both within and outside the molecules, such as between phosphate and hydroxyl groups and outside the phosphate groups, respectively, to reproduce the structural factors contributing to amorphization.
Comparison of the physical properties of disodium etidronate amorphous forms prepared by different manufacturing methods
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Amorphous forms of disodium etidronate were prepared by three manufacturing methods, heat drying, freeze drying, and anti-solvent precipitation, and the effects of these methods on the physical properties of disodium etidronate amorphous forms were evaluated for the first time. Variable temperature X-ray powder diffraction and thermal analyses revealed that these amorphous forms had different physical properties such as glass transition point, water desorption, and crystallization temperatures. These differences can be explained by the molecular mobility and water content in amorphous forms. The differences in the structural characteristics related to the differences in these physical properties could not be detected clearly by the spectroscopic methods like Raman spectroscopy and X-ray absorption near-edge spectroscopy. Dynamic vapor sorption analyses demonstrated that all amorphous forms were hydrated to form I, a tetrahydrated form, at above 50% relative humidity, and the transition to form I was irreversible. These amorphous forms require strict humidity control to avoid crystallization. Among the three amorphous forms of disodium etidronate, the amorphous form prepared by heat drying was the most suitable for manufacturing the solid formulation, considering the low water content and low molecular mobility.
A drug-loaded bio-functional anticorrosion coating on Mg alloy for orthopedic applications
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Citation Excerpt :
Inspired by our previous works [5,8], a comprehensive screening has been performed to select effective corrosion inhibitors from commercial drugs and tried to combine them with coating technologies aiming to simultaneously give Mg alloys the anti-corrosion property and bio-functions. Etidronate (ETN), one type of bisphosphonates, effectively inhibits the osteoclast bone resorption and have been used in the treatment of bone loss and osteoporotic fractures [9]. In this study, ETN was used as a corrosion inhibitor to construct a bio-functional anti-corrosion coating on Mg alloy.
Etidronate (ETN), a bisphosphonate (BPs) drug for treating bone diseases, was found to show inhibition effect on Mg corrosion. The ETN-loaded composite coating was fabricated through micro-arc oxidation and silanization treatment. The tests suggested the ETN-loaded coated sample showed enhanced corrosion resistance and the desired biocompatibility as orthopedic implants. In this work, a strategy was proposed to prepare the bio-functionalized anticorrosion coating by loading commercial drugs that have an inhibition effect on Mg corrosion. This provides a new idea for the design of multifunctional coatings on Mg alloy for biomedical applications.
Bisphosphonates: The role of chemistry in understanding their biological actions and structure-activity relationships, and new directions for their therapeutic use
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Citation Excerpt :
Several reviews have described the chemistry of the current leading BPs used globally in clinical therapy (clodronate (CLO), alendronate (ALE), pamidronate (PAM), risedronate (RIS), and zoledronate (ZOL)) (Fig. 1) [2]. More recently, additional reviews of the specific clinically important BPs have appeared, providing even more details of their discovery and commercialization history (CLO: [7]; ALE: [8]; PAM: [9]; RIS: [10]; ZOL: [11]; Etidronate (ETI): [12]; Minodronate (MIN): [13]). In addition, multiple reviews regarding other general chemistry advances have also been published in the last decade, covering the topic from various perspectives.
The bisphosphonates ((HO)₂P(O)CR¹R²P(O)(OH)₂, BPs) were first shown to inhibit bone resorption in the 1960s, but it was not until 30 years later that a detailed molecular understanding of the relationship between their varied chemical structures and biological activity was elucidated. In the 1990s and 2000s, several potent bisphosphonates containing nitrogen in their R² side chains (N-BPs) were approved for clinical use including alendronate, risedronate, ibandronate, and zoledronate. These are now mostly generic drugs and remain the leading therapies for several major bone-related diseases, including osteoporosis and skeletal-related events associated with bone metastases. The early development of chemistry in this area was largely empirical and only a few common structural features related to strong binding to calcium phosphate were clear. Attempts to further develop structure-activity relationships to explain more dramatic pharmacological differences in vivo at first appeared inconclusive, and evidence for mechanisms underlying cellular effects on osteoclasts and macrophages only emerged after many years of research. The breakthrough came when the intracellular actions on the osteoclast were first shown for the simpler bisphosphonates, via the in vivo formation of P-C-P derivatives of ATP. The synthesis and biological evaluation of a large number of nitrogen-containing bisphosphonates in the 1980s and 1990s led to the key discovery that the antiresorptive effects of these more complex analogs on osteoclasts result mostly from their potency as inhibitors of the enzyme farnesyl diphosphate synthase (FDPS/FPPS). This key branch-point enzyme in the mevalonate pathway of cholesterol biosynthesis is important for the generation of isoprenoid lipids that are utilized for the post-translational modification of small GTP-binding proteins essential for osteoclast function. Since then, it has become even more clear that the overall pharmacological effects of individual bisphosphonates on bone depend upon two key properties: the affinity for bone mineral and inhibitory effects on biochemical targets within bone cells, in particular FDPS. Detailed enzyme–ligand crystal structure analysis began in the early 2000s and advances in our understanding of the structure-activity relationships, based on interactions with this target within the mevalonate pathway and related enzymes in osteoclasts and other cells have continued to be the focus of research efforts to this day. In addition, while many members of the bisphosphonate drug class share common properties, now it is more clear that chemical modifications to create variations in these properties may allow customization of BPs for different uses.
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Full Length ArticleHistory of etidronate

Highlights

Abstract

Introduction

Section snippets

Paget's disease

Osteoporosis studies

Osteoporosis approval process

Reflections

Acknowledgements

Toxicol. Appl. Pharmacol.

Lancet

Am. J. Med.

Bone Miner.

Am. J. Med.

Am. J. Med.

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

J Musculoskel Neuronal Interact

The influence of pyrophosphate analogues (diphosphonates) on the precipitation and dissolution of calcium phosphate in vitro and in vivo

Calcif. Tissue Res.

Effect of ethane-1-hydroxy-1,1-diphosphonate (EHDP) and dichloromethylene diphosphonate (Cl 2 MDP) on the calcification and resorption of cartilage and bone in the tibial epiphysis and metaphysis of rats

Calcif. Tissue Res.

Atypical osteomalacia after 2 year etidronate intermittent cyclic administration in osteoporosis

J. Rheumatol.

Spontaneous fractures of uninvolved bones in patients with Paget’s disease during unduly prolonged treatment with disodium etidronate (EHDP)

Clin. Orthop. Relat. Res.

Influence of disodium etidronate on clinical and laboratory manifestations of Paget’s disease of bone (osteitis deformans)

N. Engl. J. Med.

Full Length Article
History of etidronate