Bisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy

Autor: Roger J. Phipps, Kathryn L. Kavanagh, Philippa A. Hulley, Roslin Russell, James T. Triffitt, Michael J. Rogers, James E. Dunford, Frank H. Ebetino, Zhidao Xia, Aaron Kwaasi, Udo Oppermann, Mark W. Lundy, Nelson B. Watts, Bobby Lee Barnett, F P Coxon
Jazyk: angličtina
Rok vydání: 2007
Předmět:
medicine.medical_specialty
Nitrogen
T-Lymphocytes
Osteoporosis
Farnesyl pyrophosphate
Osteoclasts
Bone Neoplasms
Pharmacology
chemistry
Models
Biological
Osteocytes
General Biochemistry
Genetics and Molecular Biology
Bone resorption
Bone and Bones
Bone remodeling
chemistry.chemical_compound
History and Philosophy of Science
Osteoclast
Internal medicine
medicine
Animals
Humans
Bone Resorption
Neoplasm Metastasis
Bone mineral
therapy
Diphosphonates
business.industry
General Neuroscience
medicine.disease
Endocrinology
medicine.anatomical_structure
Treatment Outcome
Models
Chemical
therapeutic use
Protein prenylation
Mevalonate pathway
Guanosine Triphosphate
pharmacology
business
Multiple Myeloma
secondary
Protein Processing
Post-Translational
metabolism
hormones
hormone substitutes
and hormone antagonists
Zdroj: Annals of the New York Academy of Sciences.
ISSN: 0077-8923
Popis: The bisphosphonates (BPs) are well established as the treatments of choice for disorders of excessive bone resorption, including Paget's disease of bone, myeloma and bone metastases, and osteoporosis. There is considerable new knowledge about how BPs work. Their classical pharmacological effects appear to result from two key properties: their affinity for bone mineral and their inhibitory effects on osteoclasts. Mineral binding affinities differ among the clinically used BPs and may influence their differential distribution within bone, their biological potency, and their duration of action. The inhibitory effects of the nitrogen-containing BPs (including alendronate, risedronate, ibandronate, and zoledronate) on osteoclasts appear to result from their inhibition of farnesyl pyrophosphate synthase (FPPS), a key branch-point enzyme in the mevalonate pathway. FPPS generates isoprenoid lipids used for the posttranslational modification of small GTP-binding proteins essential for osteoclast function. Effects on other cellular pathways, such as preventing apoptosis in osteocytes, are emerging as other potentially important mechanisms of action. As a class, BPs share several common properties. However, as with other classes of drugs, there are obvious chemical, biochemical, and pharmacological differences among the various individual BPs. Each BP has a unique profile that may help to explain potential important clinical differences among the BPs, in terms of speed of onset of fracture reduction, antifracture efficacy at different skeletal sites, and the degree and duration of suppression of bone turnover. As we approach the 40th anniversary of the discovery of their biological effects, there remain further opportunities for using their properties for medical purposes.
Databáze: OpenAIRE
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