Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0026764 (multiple myeloma)
 36,148 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Almost 70-80% of the patients with Multiple Myeloma (MM) in advancer phase, of the disease show osteolytic lesions and/or pathologic fractures, with or without secondary osteoporosis. An accelerated osteoclast-mediated bone absorption is believed to be the main cause of bone damage in MM. Osteoclast can be activated by a variety of microenvironmental factors. Bisphosphonates (BF) induce the apoptosis of osteoclasts and inhibit osteoclastogenesis, thus preventing bone absorption. As well as BFs, the so-called second-generation BF (N-BF) may impair the activity of osteoclast. Neridronic acid (NER) is a N-BF molecule officially registered for the treatment of osteogenesis imperfecta. Nevertheless, NER has shown a remarkable efficacy in Paget's disease, postmenopausal osteoporosis and, most recently, in androgen deprivation-treated prostatic carcinoma. The primary endpoint of this study was to evaluate hip and spine Bone Mineral Density (BMD) modifications over the 12-month treatment with NER in a group of patients affected by MM with evidence of initial skeletal damage. Secondary endpoints were (1) changes of calcium and total Alkaline Phosphatase (tAP) plasma levels during treatment with NER and (2) tolerability of 100 mg NER monthly administration for 12 months. These data suggest that NER, if administered at these doses and timing, might allow at least for one year sustained BMD increases in patients. NER has been highly tolerated in this study. The almost complete absence of adverse effects has prompted us to reduce the time of infusions at the end of the study. In conclusion, this study provides the first data on the efficacy and safety of NER in patients with MM-induced bone damage. These initial data encourage wider phase III trials to clearly assess its efficacy in preventing skeletal-related events and its possible anti-neoplastic properties.
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PMID:Intravenous neridronate for skeletal damage treatment in patients with multiple myeloma. 1717 86

Bone necrosis of the jaws is often related to head and neck radiotherapy, to surgical procedures at maxillary or mandibular level but also to various local and systemic factors such as haematological diseases, haemoglobinopathies and systemic lupus eritematosus; its pathogenesis maybe associated with defects of vascularization. Bisphosphonate are synthetic analogues of pyrophosphate used for the treatment of hypercalcemia in patients with malignancies and bone metastasis and for the treatment of many other disorders such as metabolic bone diseases, Paget's disease, and osteoporosis; their pharmacological activity is related to the inhibition of the osteoclastic function which leads to resorption and reduction of bone vascularization. Since the end of 2003 Bisphosphonate-associated Osteonecrosis (BON) has become an increasing problem and the test of that is the increase of the relative published case report and case series. Here we report 29 cases of bone necrosis of the jaws in patients treated with pamidronate (Aredia), zoledronate (Zometa) and alendronate: 15 underwent surgical procedures and 14 occurred spontaneously. Among these patients (21 females, 8 males; mean age between 45 and 83 years); 14 were treated for bone metastasis, 12 for multiple myeloma and 3 for osteoporosis. Bone necrosis involved only maxilla in 7 patients, only mandible in 20 patients and both in 2 patients. Six patients had multiple osteonecrotic lesions, 3 contemporary lesions and 3 non contemporary. In these patients we performed 3 kinds of therapy, associated or not: medical therapy (with antibiotic drugs, antimycotics and antiseptic mouthwashes), surgical therapy with curettage or sequestrectomy and Nd:YAG laser biostimulation.
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PMID:Bone necrosis of the jaws associated with bisphosphonate treatment: a report of twenty-nine cases. 1717 92

Bisphosphonates are a valuable class of drugs with potent anti-resorptive actions that make them ideal for skeletal protection in osteoporosis, cancer bone metastasis, multiple myeloma, and Paget's disease of bone. It has become apparent, however, that these drugs also have the potential to cause a number of adverse effects. While these do not limit bisphosphonate use, the incidence of these adverse events can be minimized if appropriate care is taken with their administration, and by maintaining appropriate surveillance and patient care. We review the range of adverse reactions to bisphosphonate therapy with a particular emphasis on the recently identified association between long-term bisphosphonate treatment and osteonecrosis of the jaw. This is a potentially serious side effect seen mostly in patients with multiple myeloma or breast cancer bone metastases who receive intravenous bisphosphonate treatment. While the etiology is uncertain, a strong association with dental pathology and interventions highlights the need for close attention to dental health in this patient group.
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PMID:Therapy insight: the risks and benefits of bisphosphonates for the treatment of tumor-induced bone disease. 1718 55

Bisphosphonates are pharmacological agents which are currently used both in osteoporosis than in other pathological conditions characterised by an increased bone resorption, such as Paget's disease of bone, malign hypocalcaemia during myeloma, osteolytic bone metastasis and fibrous dysplasia of bone. The most important biological effect of bisphosphonates is the reduction of bone remodelling through the inhibition of osteoclastic activity, but there are many clinical and experimental evidences of extra-skeletal biological effects of bisphosphonates. It has been shown that bisphosphonates exert their effects not only on bone tissue cells, but also on those of the immune system with an "immuno-modulating" effect, influencing the production of pro- and anti-inflammatory cytokines and changing the molecular expression involved in the immune processes and anti-inflammatory response. Although the available data are conflicting, there are several reports concerning the beneficial effects of bisphosphonates in controlling the progression of chronic joint inflammatory diseases, suggesting a wider use for these therapeutic agents in clinical practice.
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PMID:Extra-skeletal effects of bisphosphonates. 1790 Sep 60

Bisphosphonates as a group of drugs were introduced for the management of various conditions such as osteoporosis, Paget's disease, multiple myeloma, hypercalcemia of malignancy, breast cancer, prostate cancer, and other tumors. This group of drugs has improved the quality of life in many patients with proven efficacy in limiting pain and skeletal-related events. The controversy of osteonecrosis of the jaws and bisphosphonates is a recent and growing problem. Osteonecrosis of the jaws is recognized as a serious complication of bisphosphonate therapy, more commonly with the intravenous form of the drugs. However, there is limited scientific understanding about the association between osteonecrosis of the jaws and bisphosphonates. In the present article we discuss various mechanisms of action of bisphosphonates, the rationale for occurrence of osteonecrosis in the jaws, and treatment guidelines for the condition.
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PMID:Bisphosphonates and osteonecrosis of the jaws: science and rationale. 1744 9

Osteochemonecrosis of the jaws is a well described side effect of bisphosphonate therapy. Bisphosphonates are non metabolised analogues of pyrophosphate that are capable of localizing to bone, slowing both rate of growth and rate of dissolution therefore reducing the rate of bone turnover. Although the exact mechanism is not clear but it has been established that bisphosphonates target osteoclast, inhibiting their function in several ways: There are two types of bisphosphonates. The first are oral preparations of bisphosphonates, which include Alendronate and Risedronate. They are indicated for the treatment of osteoporosis. They are considered as lower risk of osteochemonecrosis. The second are administered intravenously. Pamindronate is a first generation bisphosphonate; 90 mg administered intravenouly over 2-24 hours every 3-4 weeks. The next generation of intravenous bisphosphonate is Zoldronic acid, which is more effective than Pamidronate in controlling hypercalcaemia of bone and reducing the skeletal related events in patients with metastatic breast cancer, multiple myeloma, hypercalcaemia of malignancy, paget's disease and bone metastasis from prostate and lung cancer.
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PMID:Osteochemonecrosis of jaws and bisphosphonates. 1749 45

Bisphosphonates are molecules derived from pyrophosphates,but, unlike pyrophosphates, they are resistant to enzymatic hydrolysis. Bisphosphonates are used in the treatment of Paget's disease, cancer-related osteolysis, myeloma, primary hyperparathyroidism, and osteoporosis. In dialysis patients bisphosphonates may be used to reduce bone pain due to renal osteodystrophy. We describe the case of a 60-year-old woman with a history of breast cancer who had been on dialysis for 8 years. She had been receiving clodronic acid at 100 mg per week intravenously for the last 2 years. A year ago, the patient underwent surgical extraction of the lower right second molar. Her jaw pain increased in the following days. An orthopanthograph and a CT scan of the head showed osteolysis, and a surgical osteotomy was performed. Histological examination led to a diagnosis of avascular osteonecrosis of the jaw. Avascular osteonecrosis is typically described in the jaw. In this case, prolonged bisphosphonate treatment may have worsened the osteonecrosis.
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PMID:[Avascular jaw osteonecrosis in a hemodialysis patient treated with bisphosphonates]. 1755 35

Increased osteoclastic activity is observed in many osteopathic disorders - including postmenopausal osteoporosis, Paget's disease, primary bone tumours, lytic bone metastases, multiple myeloma and rheumatoid arthritis - that involve increased bone resorption and a loss of bone mass. Bisphosphonates are highly effective inhibitors of bone resorption that selectively affect the osteoclasts. The aim of this study was to obtain more information about the mechanism of action of bisphosphonates such as neridronic acid using a dual-cell culture model. As a model of osteoclastogenesis we used a murine monocyte/macrophage cell line RAW 264.7 type CRL 2278 co-cultured with murine osteoblasts. The monocyte-osteoblast system allows physiological experimentation of bone anti-resorption drugs, simulating bone turnover in pathologies such as osteoporosis. The direct actions of neridronic acid on cell proliferation and functionality in the co-culture model were examined using tartrate-resistant acid phosphatase (TRAP) assay, immunohistochemical localization of actin, and transmission and scanning electron microscopy (SEM). Results showed that the percentage of TRAP-positive cells, an early marker of osteoclastic differentiation, was significantly higher in control cultures than in co-cultures treated with variable concentrations of neridronic acid. Neridronic acid induced dramatic morphological changes, characterized by the loss of the ruffled border. The actin ring associated with the plasma membrane of the cells treated with neridronic acid was shown to break down. The tissue-specific targeting of neridronic acid to bone mineral suggests that it may inhibit bone resorption by direct effects on osteoclasts or other bone cells in the immediate microenvironment of the osteoclasts. From our study, we conclude that structural alterations induced by neridronic acid in our co-culture system lead to decreased osteoclast function. This may encourage the use of neridronic acid to reduce bone resorption in the therapy of demineralizing metabolic bone disorders.
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PMID:Effects of neridronic acid on osteoclasts derived by physiological dual-cell cultures. 1757 55

Bisphosphonates are generally administered either orally or intravenously. Orally administered bisphosphonates are primarilly used in the treatment of postmenopausal osteoporosis, glucocorticoid-induced osteoporosis, and Paget's disease. When orally administered, only about 1% is absorbed from the tractus from the tractus digestivus. With intravenous administration, higher blood levels levels are reached. Intravenously administered bisphosphonates are used in the treatment of hypercalcaemia, Kahler's disease, and bone metastases of other malignancies. A few cases of osteonecrosis of the jaw(s) are seen especially when more powerful bisphosphonates are administered intravenously. This osteonecrosis is most often provoked by means of an invasive oral treatment. Bisphosphonate-associated osteonecrosis is very difficult to treat. Therefore, dental preventive measures and treatment of dental foci and other inflammations are recommended before starting bisphosphonate therapy.
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PMID:[Bisphosphonate-associated osteonecrosis of the jaws 1]. 1797 10

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.
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PMID:Bisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy. 1805 45


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