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Yakugaku Zasshi : Journal of the... 2020Since the first report in 2003, bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been increasing, without effective clinical strategies. Osteoporosis is... (Review)
Review
Since the first report in 2003, bisphosphonate-related osteonecrosis of the jaw (BRONJ) has been increasing, without effective clinical strategies. Osteoporosis is common in elderly women, and bisphosphonates (BPs) are typical and widely used anti-osteoporotic or anti-bone-resorptive drugs. BRONJ is now a serious concern in dentistry. As BPs are pyrophosphate analogues and bind strongly to bone hydroxyapatite, and the P-C-P structure of BPs is non-hydrolysable, they accumulate in bones upon repeated administration. During bone-resorption, BPs are taken into osteoclasts and exhibit cytotoxicity, producing a long-lasting anti-bone-resorptive effect. BPs are divided into nitrogen-containing BPs (N-BPs) and non-nitrogen-containing BPs (non-N-BPs). N-BPs have far stronger anti-bone-resorptive effects than non-N-BPs, and BRONJ is caused by N-BPs. Our murine experiments have revealed the following. N-BPs, but not non-N-BPs, exhibit direct and potent inflammatory/necrotic effects on soft-tissues. These effects are augmented by lipopolysaccharide (the inflammatory component of bacterial cell-walls) and the accumulation of N-BPs in jawbones is augmented by inflammation. N-BPs are taken into soft-tissue cells via phosphate-transporters, while the non-N-BPs etidronate and clodronate inhibit this transportation. Etidronate, but not clodronate, has the effect of expelling N-BPs that have accumulated in bones. Moreover, etidronate and clodronate each have an analgesic effect, while clodronate has an anti-inflammatory effect via inhibition of phosphate-transporters. These findings suggest that BRONJ may be induced by phosphate-transporter-mediated and infection-promoted mechanisms, and that etidronate and clodronate may be useful for preventing and treating BRONJ. Our clinical trials support etidronate being useful for treating BRONJ, although additional clinical trials of etidronate and clodronate are needed.
Topics: Animals; Bisphosphonate-Associated Osteonecrosis of the Jaw; Bone Density Conservation Agents; Clinical Trials as Topic; Clodronic Acid; Diphosphonates; Etidronic Acid; Humans; Inflammation; Jaw; Mice; Nitrogen; Phosphate Transport Proteins; Rats
PubMed: 31902887
DOI: 10.1248/yakushi.19-00125 -
British Journal of Clinical Pharmacology Jun 2019The biological effects of the bisphosphonates (BPs) as inhibitors of calcification and bone resorption were first described in the late 1960s. In the 50 years that have... (Review)
Review
The biological effects of the bisphosphonates (BPs) as inhibitors of calcification and bone resorption were first described in the late 1960s. In the 50 years that have elapsed since then, the BPs have become the leading drugs for the treatment of skeletal disorders characterized by increased bone resorption, including Paget's disease of bone, bone metastases, multiple myeloma, osteoporosis and several childhood inherited disorders. The discovery and development of the BPs as a major class of drugs for the treatment of bone diseases is a paradigm for the successful journey from "bench to bedside and back again". Several of the leading BPs achieved "blockbuster" status as branded drugs. However, these BPs have now come to the end of their patent life, making them highly affordable. The opportunity for new clinical applications for BPs also exists in other areas of medicine such as ageing, cardiovascular disease and radiation protection. Their use as inexpensive generic medicines is therefore likely to continue for many years to come. Fifty years of research into the pharmacology of bisphosphonates have led to a fairly good understanding about how these drugs work and how they can be used safely in patients with metabolic bone diseases. However, while we seemingly know much about these drugs, a number of key aspects related to BP distribution and action remain incompletely understood. This review summarizes the existing knowledge of the (pre)clinical and translational pharmacology of BPs, and highlights areas in which understanding is lacking.
Topics: Animals; Bone Density Conservation Agents; Bone Diseases, Metabolic; Bone Remodeling; Diphosphonates; Humans; Risk Factors; Treatment Outcome
PubMed: 30650219
DOI: 10.1111/bcp.13867 -
Journal of Bone and Mineral Research :... Jan 2022
Topics: Bone Density Conservation Agents; Diphosphonates
PubMed: 34841571
DOI: 10.1002/jbmr.4479 -
Kidney International Dec 2008Bisphosphonates are valuable agents for the treatment of post-menopausal osteoporosis (PMO), hypercalcemia of malignancy, and osteolytic bone metastases. Oral... (Review)
Review
Bisphosphonates are valuable agents for the treatment of post-menopausal osteoporosis (PMO), hypercalcemia of malignancy, and osteolytic bone metastases. Oral bisphosphonates are used mainly to treat PMO and are not associated with significant nephrotoxicity. In contrast, nephrotoxicity is a significant potential limiting factor to the use of intravenous (IV) bisphosphonates, and the nephrotoxicity is both dose-dependent and infusion time-dependent. The two main IV bisphosphonates available to treat hypercalcemia of malignancy and osteolytic bone disease in the United States are zoledronate and pamidronate. Patterns of nephrotoxicity described with these agents include toxic acute tubular necrosis and collapsing focal segmental glomerulosclerosis, respectively. With both of these agents, severe nephrotoxicity can be largely avoided by stringent adherence to guidelines for monitoring serum creatinine prior to each treatment, temporarily withholding therapy in the setting of renal insufficiency, and adjusting doses in patients with pre-existing chronic kidney disease. In patients with PMO, zoledronate and pamidronate are associated with significantly less nephrotoxicity, which undoubtedly relates to the lower doses and longer dosing intervals employed for this indication. Ibandronate is approved in the US for treatment of PMO and in Europe for treatment of PMO and malignancy-associated bone disease. Available data suggest that ibandronate has a safe renal profile without evidence of nephrotoxicity, even in patients with abnormal baseline kidney function.
Topics: Diphosphonates; Glomerulosclerosis, Focal Segmental; Humans; Imidazoles; Kidney Cortex Necrosis; Kidney Diseases; Pamidronate; Practice Guidelines as Topic; Zoledronic Acid
PubMed: 18685574
DOI: 10.1038/ki.2008.356 -
Archives of Disease in Childhood Jan 1997
Review
Topics: Adolescent; Adult; Bone Diseases; Calcinosis; Child; Child, Preschool; Diphosphonates; Female; Humans; Hypercalcemia; Osteoporosis
PubMed: 9059169
DOI: 10.1136/adc.76.1.73 -
Reumatismo Dec 2016Paget's disease of bone (PDB) is a focal disorder of osteoclasts, leading to chaotic bone remodelling, and it is characterized by the presence of focal areas of...
Paget's disease of bone (PDB) is a focal disorder of osteoclasts, leading to chaotic bone remodelling, and it is characterized by the presence of focal areas of excessive bone formation alongside with areas of focal bone resorption. The typical radiographic feature is the cotton wool appearance. To date, bisphosphonates are the mainstay of the treatment. We hereby report the case of a young woman presenting with mandible PDB, with a relevant diagnostic delay and mistakenly treated for five years with chronic oral corticosteroids. After our evaluation, the patient received treatment with intravenous neridronate (an amino-bisphosphonate licensed in Italy for the treatment of this disease), with achievement of clinical remission.
Topics: Administration, Intravenous; Adult; Bone Density Conservation Agents; Delayed Diagnosis; Diphosphonates; Female; Humans; Mandible; Osteitis Deformans; Treatment Outcome
PubMed: 27981818
DOI: 10.4081/reumatismo.2016.917 -
British Journal of Pharmacology May 2021The treatment of pain, in particular, chronic pain, remains a clinical challenge. This is particularly true for pain associated with severe or rare conditions, such as... (Review)
Review
The treatment of pain, in particular, chronic pain, remains a clinical challenge. This is particularly true for pain associated with severe or rare conditions, such as bone cancer pain, vulvodynia, or complex regional pain syndrome. Over the recent years, there is an increasing interest in the potential of bisphosphonates in the treatment of pain, although there are few papers describing antinociceptive and anti-hypersensitizing effects of bisphosphonates in various animal models of pain. There is also increasing evidence for clinical efficacy of bisphosphonates in chronic pain states, although the number of well-controlled studies is still limited. However, the mechanisms underlying the analgesic effects of bisphosphonates are still largely elusive. This review provides an overview of preclinical and clinical studies of bisphosphonates in pain and discusses various pharmacological mechanisms that have been postulated to explain their analgesic effects. LINKED ARTICLES: This article is part of a themed issue on The molecular pharmacology of bone and cancer-related bone diseases. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v178.9/issuetoc.
Topics: Animals; Chronic Pain; Diphosphonates
PubMed: 31347149
DOI: 10.1111/bph.14799 -
Journal of Musculoskeletal & Neuronal... Dec 2022Bisphosphonates represent an established treatment against bone resorption and osseous loss. Local application could help increase bone mineral density while minimizing... (Review)
Review
Bisphosphonates represent an established treatment against bone resorption and osseous loss. Local application could help increase bone mineral density while minimizing their systemic use side-effects. Bone cement, used on a large scale in orthopedic surgery and a historically successful drug carrier, could represent an effective scaffold. The aim of this review was to investigate the alterations produced on the cement's structure and properties by this mixture, as well as its antiosteoporotic and antitumor effect. After a thorough research of articles, title screening and duplicate removal we retained 51 papers. Two independent authors performed abstract and full-text reading, finally leaving 35 articles included in this review. In the current literature, acrylic and calcium phosphate bone cement have been used as carriers. A combination with nitrogen-containing bisphosphonates, e.g., zoledronic acid, provokes modifications in terms of setting time prolongation and mechanical strength decline within acceptable levels, on the condition that the drug's quantity stays beneath a certain plateau. Bisphosphonates in bone cement seem to have a powerful anti-osteoclastic and osteogenic local impact as well as a direct cytotoxic effect against several neoplastic lesions. Further investigation on the subject is required, with specifically designed studies focusing on this method's advantages and potential clinical applications.
Topics: Humans; Bone Cements; Diphosphonates; Zoledronic Acid; Bone Resorption; Orthopedic Procedures
PubMed: 36458394
DOI: No ID Found -
Breast Cancer Research : BCR 2002Bisphosphonates are synthetic compounds characterized by a P[bond]C[bond]P group, and are thus analogs of inorganic pyrophosphate. They are used in medicine mainly to... (Review)
Review
Bisphosphonates are synthetic compounds characterized by a P[bond]C[bond]P group, and are thus analogs of inorganic pyrophosphate. They are used in medicine mainly to inhibit bone resorption in diseases like osteoporosis, Paget's disease and tumor bone disease. They have been used for over a century in industry, and only in 1968 was it shown that bisphosphonates have biological effects. These effects consist mainly of an inhibition of bone resorption and, when given in large amounts, an inhibition of ectopic and normal calcification. While the latter effect is the consequence of a physical-chemical inhibition of calcium phosphate crystal formation, the former is due to a cellular effect involving both apoptosis of the osteoclasts and a destruction of the osteoclastic cytoskeleton, inducing a decrease in osteoclast activity. The biochemical basis of these effects for the nitrogen-containing compounds is an inhibition of the mevalonate pathway caused by the inhibition of farnesylpyrophosphate synthase, which leads to a decrease of the formation of isoprenoid lipids such as farnesylpyrophosphate and geranylgeranylpyrophosphate. The other bisphosphonates are incorporated into the phosphate chain of ATP-containing compounds so that they become non-hydrolyzable. The new P[bond]C[bond]P-containing ATP analogs inhibit cell function and may lead to apoptosis and death of osteoclasts.
Topics: Antineoplastic Agents; Bone Resorption; Breast Neoplasms; Diphosphonates; Female; Humans; Osteitis Deformans; Structure-Activity Relationship
PubMed: 11879557
DOI: 10.1186/bcr414 -
CMAJ : Canadian Medical Association... Apr 2017
Topics: Bone Density Conservation Agents; Diphosphonates; Femoral Fractures; Humans; Osteoporosis; Radiography
PubMed: 28396331
DOI: 10.1503/cmaj.160450