I. Introduction II. Chemistry III. Effects in Vivo A. Inhibition of calcification B. Inhibition of bone resorption C. Effects on bone formation D. Effects on noncalcified tissues IV. Mechanisms of Action A. Calcification B. Bone resorption C. Other effects V. Pharmacokinetics VI. Animal Toxicology and Human Adverse Events A. Animal toxicology B. Human adverse events VII. Conclusion

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Bisphosphonates: Mechanisms of Action

Because of its failure to act when given orally and its rapid hydrolysis when given parenterally, pyrophosphate was used therapeutically only in scintigraphy and against dental calculus. This prompted us to search for analogs that showed similar physicochemical activity but resisted enzymatic hydrolysis and, therefore, would not be degraded metabolically. The bisphosphonates fulfilled these conditions. This review will deal with the mechanisms of action of these compounds. In vitro results, as well as results both in animals and humans, will be integrated in an attempt to deduce the current state of the art. Various reviews have been published recently on bisphosphonates and may be consulted also for information on other aspects (8 ‐14). Since the literature in this field is plentiful, selective citation was necessary. Priority is given to papers dealing with the mechanisms of action. Since many papers often deal with the same finding, in most cases only the first ones are quoted. Subsequent papers are quoted only if they convey new knowledge.

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Bisphosphonates: mechanisms of action.

Publisher Summary Studies of receptor binding generally employ highly radioactive ligand derivatives; however, knowledge of the biological activity of the radioactive derivative is essential for a complete interpretation of the binding data. This chapter describes the relation between biological activity and binding, physicochemical detection and assay of receptors, solubilization of membrane receptors, provides examples of membrane-localized receptors, affinity techniques, polyvalent hormone derivatives, and receptor studies, and theoretical mechanisms of hormone–receptor binding and action. The biological response toward many neurotransmitters and hormones, such as insulin, acetylcholine, and epinephrine is rapid both in onset and in the termination of action on removal of these agents; therefore, it may be anticipated that the initial hormone–receptor interaction will also be reversible. The chapter shows that progress has been made toward understanding the way by which hormones, via interactions with cell–surface receptors, modulate overall cellular function. This interaction is only the first in a presumably complicated series of protein–protein interactions within the plane of the cell membrane; the mechanism, whereby the ultimate signal is transmitted to the internal cellular milieu is undoubtedly an equally intricate process. The chapter is considered to be useful in delineating the challenge that the elucidation of these processes presents and in providing a basis and incentive for more discoveries in this field.

Membrane receptors and hormone action.

AFTER the radioimmunoassay for parathyroid hormone (PTH) was introduced by Berson et al. in 1963,1 initial enthusiasm for its clinical application was tempered because widely differing results were...

The Peripheral Metabolism of Parathyroid Hormone

The bisphosphonates are a new class of drugs which have been developed in the past two decades for use in various diseases of bone, tooth, and calcium metabolism Three are on the market today, while others are under clinical or preclinical investigation This chapter will cover chemical and experimental aspects as well as clinical applications of these compounds Literature is essentially limited to one reference, usually the original report For two recent reviews, weighted somewhat differently and with more extensive references, see Fleisch (1983) and Francis and Martodam (1983)

Bisphosphonates: A New Class of Drugs in Diseases of Bone and Calcium Metabolism

1. Plasma membranes were purified from bovine kidney cortex, with a fourfold increase in specific activity of parathyroid hormone-sensitive adenylate cyclase over that in the crude homogenate. The membranes were characterized by enzyme studies. 2. Parathyroid hormone was labelled with 125I by an enzymic method and the labelled hormone shown to bind to the plasma membranes and to be specifically displaced by unlabelled hormone. Parathyroid hormone labelled by the chloramine-t procedure showed no specific binding. 75Se-labelled human parathyroid hormone, prepared in cell culture, also bound to the membranes. 3. Parathyroid hormone was shown to retain biological activity after iodination by the enzymic method, but no detectable activity remained after chloramine-t treatment. 4. High concentration of pig insulin inhibited binding of labelled parathyroid hormone to plasma membranes and partially inhibited the hormone-sensitive adenylate cyclase activity in a crude kidney-cortex preparation. 5. EDTA enhanced and Ca2+ inhibited binding of labelled parathyroid hormone to plasma membranes. 6. Whereas rat kidney homogenates were capable of degrading labelled parathyroid hormone to trichloroacetic acid-soluble fragments, neither crude homogenates nor purified membranes from bovine kidney showed this property. 7. Binding of parathyroid hormone is discussed in relation to metabolism and initial events in hormone action.

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Binding of parathyroid hormone to bovine kidney-cortex plasma membranes.

https://febs.onlinelibrary.wiley.com/doi/pdf/10.1016/0014-5793%2872%2980772-5

Effects of pyrophosphate and diphosphonates on parathyroid hormone- and fluoride-stimulated adenylate cyclase activity.

SUMMARY 1. Inorganic pyrophosphate (PPi) and diphosphonates inhibit glucagon-stimulated and fluoride-stimulated adenylate cyclase activity of rat liver.



2. Concentrations of diphosphonates required to produce inhibition are lower than those of PPi, and PPi inhibited fluoride-stimulated activity to a greater extent than glucagon-stimulated activity.



3. Diphosphonates have inhibitory activity in the presence and absence of an ATP regenerating system in the adenylate cyclase assay, and do not substantially affect the efficiency of the ATP regenerating system. No evidence was obtained that reversal of adenylate cyclase was responsible for PPi inhibition.



4. Fluoride virtually completely inhibits pyrophosphatase activity in crude membrane preparations from rat liver, whereas glucagon has no detectable effect.

H. S. Sutcliffe

Papers

Binding of parathyroid hormone to bovine kidney-cortex plasma membranes.

Effects of pyrophosphate and diphosphonates on parathyroid hormone- and fluoride-stimulated adenylate cyclase activity.

Influence of pyrophosphate and diphosphonates on rat liver adenylate cyclase.