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)

Bisphosphonates have been used to treat lytic lesions of multiple myeloma because of their inhibitory effects on osteoclasts. However, their effects on myeloma cells, per se, are not known to be correlated with specific markers. The goal of this study was to assess molecular concomitants of myeloma that might serve as markers for predicting the pharmacologic impact of bisphosphonates on malignant plasma cells. We tested the correlation of serum monoclonal immunoglobulin (Ig) level (IgG and IgA classes) with therapies utilizing two aminobisphosphonates, pamidronate (Aredia) and/or zoledronate (Zometa), in 19 patients with multiple myeloma. Myeloma cells from bone marrow biopsies were immunohistochemically stained for H-ras (p21 ras), N-ras, and the alpha subunit common to farnesyl and geranylgeranyl transferase (FTalpha/GGT alpha). Elevated expression level of H-ras in myeloma cells, rather than N-ras or FTalpha/GGTalpha, was significantly associated with a decrease of serum monoclonal Ig level following pamidronate treatment. The data suggest that pamidronate may have a direct inhibitory effect on the proliferation of myeloma cells, thus causing reduction in serum monoclonal Ig level. H-ras expression in myeloma cells may prove to be valuable in predicting the therapeutic effects of pamidronate.
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PMID:Morphoproteomic expression of H-ras (p21ras) correlates with serum monoclonal immunoglobulin reduction in multiple myeloma patients following pamidronate treatment. 1731 67

Zoledronic acid has been marketed for the past 5 years for the treatment of hypercalcemia of malignancy and malignant bone disease in patients with multiple myeloma or a broad range of solid tumors. The safety profile of zoledronic acid in this patient population is well established from the databases of several large, randomized, Phase III trials and postmarketing clinical experience. Zoledronic acid is well tolerated, with predictable side effects, primarily transient flu-like symptoms, which are manageable with standard treatment. Renal monitoring is recommended, with dose reductions for patients with renal dysfunction. Monitoring for electrolyte imbalance is also important as is calcium and vitamin D supplementation. Ocular complications are rare, and osteonecrosis of the jaw is uncommon and might be avoidable with appropriate dental care.
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PMID:The safety of zoledronic acid. 1748 Jan 79

Patients with metastatic bone disease are at risk for developing skeletal-related events that can negatively influence quality of life, contributing to loss of autonomy and functional capabilities. Bisphosphonates have become an important component in the treatment of patients with bone metastases as they delay the onset and reduce the risk of skeletal-related events and also palliate or control bone pain in multiple cancer types, thus preserving quality of life. Zoledronic acid has proven efficacy and safety in patients with bone lesions from breast cancer, prostate cancer, lung cancer, and other solid tumors, as well as in patients with multiple myeloma. Current data suggest that early treatment with zoledronic acid (before the onset of bone pain) may provide additional clinical benefits and also positive effects on survival in subsets of patients who have elevated levels of N-telopeptide of type I collagen (NTX), a biochemical marker of bone resorption. Studies have shown that in patients with breast cancer, prostate cancer, lung cancer, or other solid tumors, normalization of elevated levels of NTX was observed in the majority of patients who received zoledronic acid. Furthermore, normalization of NTX values correlated with extended survival.
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PMID:Clinical benefits and considerations of bisphosphonate treatment in metastatic bone disease. 1806 86

Nitrogen-containing biphosphonates are a group of medications that are increasingly used in the management of Paget's disease, fibrous dysplasia, osteoporosis, multiple myeloma and metastatic prostate or breast cancer bone disease. On 2004 it was established that nitrogen-containing biphosphonates may induce jaw osteonecrosis and since then, a substantial number of publications has supported this finding. Jaw osteonecrosis may be asymptomatic, lasting for about a year or symptomatic, accompanied with mild or severe pain. Jaw osteonecrosis usually results in patients with poor dental hygiene, or subjected to invasive dental procedures. Its incidence increases with the length of nitrogen-containing biphosphonates treatment and appears to be higher for the Zometa(TM) users. It is important to early recognize this entity, since early intervention can make a significant difference to the outcome of this debilitating side effect. We here report three patients who had a positive technetium-99m methylene diphosphonate ((99m)Tc-MDP) bone scan. One of these patients also had osteomyelitis and was treated aggressively. The other two were treated in a more conservative manner. Detailed dental examination supported the scintigraphic findings. Biopsy was performed only in one patient and also offered specimens for antibiotic cultures. In discussion, jaw biopsy is a debatable procedure in the setting of jaw osteonecrosis and many consider that it should be avoided in most cases, except if it is necessary to establish the diagnosis and suggest antibiotic treatment by obtaining samples for bacterial cultures. Although axial tomography and magnetic resonance imaging are useful in defining the extent of the disease, 3-phase (99m)Tc-MDP bone scan is the most sensitive imaging modality pinpointing the disease at its early stages. In conclusion, a 3-phase (99m)Tc-MDP scan with anterior and lateral views of the skull is indicated in all symptomatic or asymptomatic patients, with a history of long-term nitrogen-containing biphosphonate treatment, since this may lead to an early detection of the disease.
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PMID:Jaw uptake of technetium-99 methylene diphosphonate in patients on biphosphonates: a word of caution. 1808 61

Therapeutic doses of zoledronic acid markedly inhibit in vitro proliferation, chemotaxis, and capillarogenesis of bone marrow endothelial cells of patients with multiple myeloma. Zoledronic acid also induces a sizeable reduction of angiogenesis in the in vivo chorioallantoic membrane assay. These effects are partly sustained by gene and protein inhibition of vascular endothelial growth factor and vascular endothelial growth factor receptor 2 in an autocrine loop. Mevastatin, a specific inhibitor of the mevalonate pathway, reverts the zoledronic acid antiangiogenic effect, indicating that the drug halts this pathway. Our results provide evidence of a direct antiangiogenic activity of zoledronic acid on multiple myeloma patient-derived endothelial cells due to at least four different mechanisms identified either in vitro or in vivo. Tentatively, we suggest that the zoledronic acid antitumoral activity in multiple myeloma is also sustained by antiangiogenesis, which would partly account for its therapeutic efficacy in multiple myeloma.
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PMID:Zoledronic acid affects over-angiogenic phenotype of endothelial cells in patients with multiple myeloma. 1808 19

Zoledronic acid (Zometa is a third-generation nitrogen-containing parenteral bisphosphonate indicated for the treatment of bone metastases due to solid tumours or multiple myeloma and for hypercalcaemia of malignancy (HCM). In patients with advanced breast or prostate cancer, zoledronic acid 4 mg every 3-4 weeks for up to 15 months significantly reduced the proportion of patients with > or =1 skeletal-related event (SRE), excluding HCM, compared with placebo. In patients with advanced breast cancer or multiple myeloma, the incidence of SREs was similar in patients treated with zoledronic acid 4 mg or pamidronic acid 90 mg every 3-4 weeks for up to 25 months but, in breast cancer patients, zoledronic acid reduced the risk of SREs, including HCM, by an additional 20% compared with pamidronic acid. In modelled cost-utility studies comparing direct costs based on efficacy and resource-use data from these and/or other trials, results have varied. In the most recent study performed from the perspective of the UK NHS and modelled over a 10-year treatment period in women with advanced breast cancer, intravenous zoledronic acid and oral ibandronic acid were dominant over no treatment. Intravenous zoledronic acid was the most cost effective, in terms of incremental costs per QALY gained, followed by oral ibandronic acid, intravenous pamidronic acid and intravenous ibandronic acid. Two other modelled analyses in patients with advanced breast cancer, also conducted from the perspective of the NHS, evaluated the cost utility of three bisphosphonate therapies in patients receiving hormonal therapy or intravenous chemotherapy. Analyses were modelled over 14.3 months (i.e. expected survival) and assumptions varied markedly from results in clinical breast cancer trials. Also, efficacy assumptions for zoledronic acid were not based on clinical trials with the drug. The results of these analyses suggest that oral ibandronic acid is more cost effective than intravenous zoledronic acid and intravenous pamidronic acid in terms of incremental cost per QALY gained. In a global, 15-month modelled cost-effectiveness analysis of patients with advanced prostate cancer, conducted from a third-party perspective, the incremental cost per QALY gained for zoledronic acid versus no treatment was $US159 200 (year 2000 value), which is about 3-fold greater than commonly accepted thresholds for cost effectiveness. In conclusion, a recent modelled economic analysis suggests that intravenous zoledronic acid 4 mg is dominant relative to no treatment in the management of bone metastases in patients with advanced breast cancer. In contrast, in patients with advanced prostate cancer, the incremental cost per QALY gained for zoledronic acid 4 mg versus no treatment was predicted to be higher than commonly accepted thresholds. Compared with other bisphosphonates in the setting of advanced breast cancer, intravenous zoledronic acid was more cost effective than oral or intravenous ibandronic acid and intravenous pamidronic acid in one study, but less cost effective than oral ibandronic acid in another. Further efficacy and economic data comparing intravenous zoledronic acid with oral ibandronic acid are needed. Meanwhile, zoledronic acid appears to be the most cost effective intravenous bisphosphonate for the management of bone metastases in patients with advanced breast cancer and possibly in patients with different types of advanced solid tumours.
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PMID:Zoledronic acid: a pharmacoeconomic review of its use in the management of bone metastases. 1828 18

Zoledronic acid (Zometa), a third-generation amino-bisphosphonate, has been approved in the US, the EU and many other countries worldwide for the prevention of skeletal-related events in patients with bone metastases of malignancy. In several well designed trials, zoledronic acid 4 mg administered as a 15-minute infusion every 3-4 weeks was effective in reducing the occurrence of skeletal complications in patients with bone metastases secondary to multiple myeloma, breast cancer or prostate cancer. Zoledronic acid was as effective as pamidronic acid in reducing the occurrence of skeletal complications in patients with multiple myeloma or breast cancer. In patients with solid tumours other than breast or prostate cancer, zoledronic acid did not show significant clinical benefit over placebo in terms of the primary endpoint; however, some benefit of therapy in terms of secondary endpoints was observed with zoledronic acid relative to placebo. Its efficacy in a broad range of tumours and short infusion time (15 minutes) are an advantage over other available bisphosphonates. Modelled pharmacoeconomic analyses in patients with breast cancer suggested that zoledronic acid therapy is cost effective relative to no therapy with regard to the cost per quality-adjusted life-year (QALY) gained; however, results were mixed when zoledronic acid was compared with other commonly used bisphosphonates. Zoledronic acid is generally well tolerated; the risk of osteonecrosis of the jaw may be minimized by adhering to recommendations regarding dental therapy. Additional efficacy and economic data are required to definitively position zoledronic acid with respect to other bisphosphonates. Nevertheless, available clinical data indicate that zoledronic acid is an effective treatment option for the management of bone metastases of malignancy.
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PMID:Zoledronic acid : a review of its use in the management of bone metastases of malignancy. 1831 68

Nitrogen-containing bisphosphonates (N-BPs) inhibit osteoclast-mediated bone resorption and are widely used for tumor-associated osteolysis. The mechanism of action of these drugs has not been completely clarified, but it has been observed that N-BPs may inhibit squalene synthase or farnesyl pyrophosphate synthase. Zoledronic acid (ZA) represents a novel N-BP which also has antitumor activity. To explore the effects of ZA on serum lipids, we studied 26 patients with smoldering myeloma at diagnosis. Sixteen patients were treated with ZA (4 mg) at baseline and at months 1, 2, 4, and 6. The remaining 10 served as controls. In all subjects, total cholesterol (TC), triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), and C-terminal telopeptide of type I collagen (CTX) were measured at baseline and after 1, 3, and 6 months. In treated patients, we observed a progressive and significant reduction of TC, with a maximum decrease of 13% at 6 months. Moreover LDL-C decreased by 21% at 6 months, while no significant difference was appreciated in HDL-C and TGs. Also, the indexes of cardiovascular risk improved after ZA administration: TC/HDL-C ratio progressively decreased by 17% and HDL-C/LDL-C ratio increased by 36%, showing an effect that appears to be cumulative. In conclusion, ZA given intravenously at high doses in patients with smoldering myeloma seems to be able to modify the lipid profile with an improvement of atherosclerotic risk index.
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PMID:The effects of zoledronic acid on serum lipids in multiple myeloma patients. 1841 38

Bisphosphonates (BPs), as inhibitors of osteoclasts, are widely used in the management of metastatic bone disease and in the prevention of osteomalacia and osteoporosis. Recent cases of bone necrosis of the jaws have been associated with the use of bisphosphonate therapy. A case is presented of a patient with osteonecrosis of the maxilla with a history of long-term bisphosphonate therapy for metastatic breast cancer. The authors treated the patient and suggest appropriate patient management guidelines with reference to current knowledge. Although a definitive treatment for bisphosphonate-associated osteonecrosis has not yet been established, clinicians must be aware of the pharmacologic properties of several bisphosphonates currently available and their indications, susceptible risk factors in the development of osteonecrosis of the jaws, the clinical signs and symptoms, and recommendations for patient management, including prevention and early recognition. BPs, potent inhibitors of osteoclast-mediated bone resorption, were first introduced more than 20 years ago. Since then, they have been used widely in the management of bone diseases, including hypercalcemia related to malignancy, myeloma-related bone disease, Paget's disease and osteoporosis. They have also been shown to inhibit tumor cell proliferation and inhibit angiogenesis. These additional features have made BPs useful in the treatment of metastatic disease, including breast and prostate cancer, resulting in a rise in the medical use of these drugs. However, recent reports suggest that BPs, particularly the nitrogen-containing BPs pamidronate (Aredia) and zoledronic acid (Zometa), both manufactured by Novartis of East Hanover, NJ, are capable of causing bisphosphonate-associated osteonecrosis of the jaw (BON). With 2.5 million patients treated with pamidronate and/or zoledronate worldwide, BON occurs in about one per 10,000 treated patients (Novartis, unpublished data, 2004). Currently, the total number of reported cases associated with alendronate (Fosamax, Merck and Co. Inc., White-house Station, NJ) the most commonly prescribed oral bisphosphonate, is approximately 170 worldwide (C. Arsver, oral communication, March 2006). This corresponds to a spontaneous BON incidence of approximately 0.7 cases per 100,000-years exposure. However, there is insufficient data to determine why the osteonecrosis reported seems to particularly affect the jaw, with a slightly higher rate in the mandible than the maxilla. This report concerns the management of a patient with BON. Information provided includes: the pharmacologic properties of the several bisphosphonates currently available; the pathobiological mechanism; the clinical presentation of the oral lesions; and recommendations for the oral management of patients who have received BP therapy, with consideration of a preventative approach based on current knowledge.
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PMID:Bisphosphonate-associated osteonecrosis: a clinician's reference to patient management. 1876 52

Intravenous bisphosphonates-the potent inhibitors of osteoclast-mediated bone resorption are among the most commonly prescribed drugs in the management of multiple myeloma (MM). Zoledronic acid (ZA) is a new generation potent intravenous bisphosphonate that has been approved for the treatment and prevention of bone lesions, and/or hypercalcemia associated with MM. Osteonecrosis of the jaw (ONJ) is an emerging serious side effect of the new generation bisphosphonates with a growing number of reports related to this pathological entity. ONJ usually appears following oral surgical and dental procedures but sometimes occur spontaneously. These cases are mostly seen and treated by dentists and oral surgeons. The aim of this study was to discuss the frequency, characteristics, risk factors, management and histopathological features of ZA induced ONJ based on the literature and illustrated with five own cases. Thirty-two patients with MM who received ZA for a median period of 26.5 +/- 18.7 months (min: 5 months, max: 76 months) were evaluated. ONJ was detected in five patients and mean drug duration time was 34 months. The frequency was 15% and the patients were usually symptomatic. There was no significant difference in terms of the duration of ZA in patients with and without ONJ. Management of these established cases were performed with medical treatment, minor debridement, sequestrectomy, and combining bone resection with autologous platelet rich plasma. Our data indicate that ZA therapy has a major role in the development of ONJ a fact that should be considered by physicians treating MM patients.
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PMID:Osteonecrosis of the jaw in patients with multiple myeloma treated with zoledronic acid. 1924 Sep 69


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