Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0005940 (bone disease)
 7,459 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

In a double blind randomized study, the bisphosphonate drug Pamidronate (Aredia) significantly protected Durie-Salmon stage III multiple myeloma patients from osteolytic bone disease. In the patient sub-group on salvage chemotherapy. Pamidronate treatment was also significantly associated with prolonged survival. To test if this drug could induce direct antitumor effects, we exposed myeloma cells to increasing concentrations of Pamidronate or a more potent bisphosphonate, Zoledronate. A concentration- and time-dependent cytotoxic effect was detected on four of five myeloma cell lines as well as three specimens obtained directly from myeloma patients. Zoledronate-induced cytotoxicity was significantly greater than that of Pamidronate. Cytotoxicity could not be explained by bisphosphonate-induced chelation of extracellular calcium or secondary decrease in production of the myeloma growth factor interleukin-6. Morphological examination, DNA electrophoresis and cell cycle analysis indicated that the bisphosphonate-induced cytotoxic effect consisted of a combination of cytostasis and apoptotic myeloma cell death. Enforced expression of BCL-2 protected against the apoptotic death but not against cytostasis. Most cytotoxic effects were seen between 10 and 100 microM of drug. The results suggest a possible direct anti-tumor effect in myeloma patients treated with bisphosphonates which may participate in their significantly increased survival. This hypothesis should now be further tested in clinical trials.
Leukemia 1998 Feb
PMID:In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates. 951 85

The osteoprotegerin (OPG)/receptor activator of NF-kappa B ligand (RANKL) system has a major role in the pathogenesis of bone disease in myeloma (MM). The effect of autologous stem cell transplantation (ASCT) on bone turnover in MM was evaluated in 51 patients (35M/16F). Markers of bone resorption (NTX, TRACP-5b), bone formation (bone-alkaline phosphatase (bALP), osteocalcin), OPG and sRANKL were measured pre- and every month post-ASCT. The median follow-up period was 12 months. Four patients were transplanted in CR, 44 were transplanted in PR and three patients had progressive/resistant disease. All patients received bisphosphonates both pre- and post-ASCT. At baseline the majority of patients had increased NTX, TRACP-5b levels, and sRANKL/OPG ratio, while markers of bone formation were strongly suppressed. ASCT produced a significant reduction of sRANKL/OPG ratio, with a concomitant decrease of NTX, and TRACP-5b levels, starting the second month post-ASCT. Bone formation markers, osteocalcin and bALP, started to increase after the 9th and 11th month post-ASCT, respectively, while the increase of OPG preceded this. These results provide biochemical evidence that ASCT normalizes the abnormal bone resorption in MM patients possibly through the decrease of RANKL/OPG ratio, while bone formation requires a longer period to return to normal.
Leukemia 2004 Aug
PMID:Autologous stem cell transplantation normalizes abnormal bone remodeling and sRANKL/osteoprotegerin ratio in patients with multiple myeloma. 1521 75

The aim of this study was the evaluation of the effect of intermediate doses of thalidomide with dexamethasone (Thal/Dex) on disease course and bone disease in patients with refractory/relapsed myeloma who were under zoledronic acid therapy. We studied 35 patients, who received thalidomide at a dose of 200 mg/daily. We measured, pre-, 3 and 6 months post-treatment soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), osteoprotegerin (OPG), osteopontin (OPN), markers of bone resorption and formation. Before treatment, patients had increased levels of sRANKL/OPG ratio, bone resorption markers and OPN, while they had suppressed bone formation. The pretreatment sRANKL/OPG ratio correlated with the extent of bone disease. Thal/Dex administration resulted in a significant reduction of sRANKL/OPG ratio, and bone resorption. Bone formation, OPG and OPN did not show any alteration. Changes of sRANKL/OPG ratio correlated with changes of bone resorption markers. Thal/Dex was given for a median time of 10 months and the median follow-up period was 22 months. The response rate was 65.7%. The median survival was 19.5 months. beta2-microglobulin, type of response and International Staging System predicted for survival. These results suggest that the combination of intermediate dose of Thal/Dex is effective in patients with refractory/relapsed myeloma and improves abnormal bone remodeling through the reduction of sRANKL/OPG ratio.
Leukemia 2005 Nov
PMID:The combination of intermediate doses of thalidomide with dexamethasone is an effective treatment for patients with refractory/relapsed multiple myeloma and normalizes abnormal bone remodeling, through the reduction of sRANKL/osteoprotegerin ratio. 1607 95

Chromosomal hyperdiploidy is the defining genetic signature in 40-50% of myeloma (MM) patients. We characterize hyperdiploid-MM (H-MM) in terms of its clinical and prognostic features in a cohort of 220 H-MM patients entered into clinical trials. Hyperdiploid-myeloma is associated with male sex, kappa immunoglobulin subtype, symptomatic bone disease and better survival compared to nonhyperdiploid-MM (median overall survival 48 vs 35 months, log-rank P = 0.023), despite similar response to treatment. Among 108 H-MM cases with FISH studies for common genetic abnormalities, survival is negatively affected by the existence of immunoglobulin heavy chain (IgH) translocations, especially those involving unknown partners, while the presence of chromosome 13 deletion by FISH did not significantly affect survival (median overall survival 50 vs 47 months, log-rank P = 0.47). Hyperdiploid-myeloma is therefore a unique genetic subtype of MM associated with improved outcome with distinct clinical features. The existence of IgH translocations but not chromosome 13 deletion by FISH negatively impacts survival and may allow further risk stratification of this population of MM patients.
Leukemia 2006 May
PMID:Prognostic factors for hyperdiploid-myeloma: effects of chromosome 13 deletions and IgH translocations. 1651 10

In multiple myeloma, the overexpression of receptor activator of nuclear factor kappa B (NF-kappaB) ligand (RANKL) leads to the induction of NF-kappaB and activator protein-1 (AP-1)-related osteoclast activation and enhanced bone resorption. The purpose of this study was to examine the molecular and functional effects of proteasome inhibition in RANKL-induced osteoclastogenesis. Furthermore, we aimed to compare the outcome of proteasome versus selective NF-kappaB inhibition using bortezomib (PS-341) and I-kappaB kinase inhibitor PS-1145. Primary human osteoclasts were derived from CD14+ precursors in presence of RANKL and macrophage colony-stimulating factor (M-CSF). Both bortezomib and PS-1145 inhibited osteoclast differentiation in a dose- and time-dependent manner and furthermore, the bone resorption activity of osteoclasts. The mechanisms of action involved in early osteoclast differentiation were found to be related to the inhibition of p38 mitogen-activated protein kinase pathways, whereas the later phase of differentiation and activation occurred due to inhibition of p38, AP-1 and NF-kappaB activation. The AP-1 blockade contributed to significant reduction of osteoclastic vascular endothelial growth factor production. In conclusion, our data demonstrate that proteasomal inhibition should be considered as a novel therapeutic option of cancer-induced lytic bone disease.
Leukemia 2007 Sep
PMID:Bortezomib inhibits human osteoclastogenesis. 1758 12

Immunomodulatory drugs (IMiDs) and bortezomib have been recently used in the management of patients with both newly diagnosed and relapsed/refractory multiple myeloma. Except of their direct anti-myeloma effect, these agents also alter the interactions between myeloma cells and marrow microenvironment. Several recent studies have investigated their potential effect on myeloma bone disease. Preclinical studies have demonstrated that IMiDs reduce osteoclast formation and function in vitro. Clinical studies have confirmed that thalidomide reduces markers of bone resorption, while lenalidomide induces osteoclast arrest in myeloma patients. However, IMiDs seem to have no effect on osteoblast exhaustion present in myeloma. The proteasome inhibitor bortezomib restores abnormal bone remodeling through the inhibition of osteoclast function and the increase in osteoblast differentiation and activity in vitro. In myeloma patients, bortezomib reduces biochemical markers of bone resorption and normalizes the RANKL/osteoprotegerin ratio, while at the same time increases bone formation markers reducing levels of dickkopf-1 protein. Whether these effects are direct and not only a consequence of the agents' antimyeloma activity is not totally clear. This review summarizes all available data for these attractive agents that combine potent anti-myeloma activity with beneficial effects on bone and may alter the way of management of myeloma-related bone disease.
Leukemia 2007 Sep
PMID:The effect of novel anti-myeloma agents on bone metabolism of patients with multiple myeloma. 1797 55

We describe a new model of myeloma bone disease in which beta2m NOD/SCID mice injected with KMS-12-BM cells develop medullary disease after tail vein administration. Micro-computed tomography analysis demonstrated significant bone loss in the tibiae and vertebrae of diseased animals compared to controls, with loss of cortical bone (P<0.01), as well as trabecular bone volume, thickness and number (P<0.05 for all). Bone marrow of diseased animals demonstrated an increase in osteoclasts (P<0.01) and reduction in osteoblasts (P<0.01) compared to control animals. Both bone loss and osteoclast increase correlated with the degree of disease involvement. Mesenchymal stem cells (MSCs) were lentivirally transduced to express human osteoprotegerin (hOPG). Systemic administration of OPG expressing MSC reduced osteoclast activation (P<0.01) and trabecular bone loss in the vertebrae (P<0.05) and tibiae of diseased animals, to levels comparable to non-diseased controls. Because of its predominantly medullary involvement and quantifiable parameters of bone disease, the KMS-12-BM xenogeneic model provides unique opportunities to test therapies targeted at the bone marrow microenvironment.
Leukemia 2007 Oct
PMID:A new xenograft model of myeloma bone disease demonstrating the efficacy of human mesenchymal stem cells expressing osteoprotegerin by lentiviral gene transfer. 1787 22

Several prognostic markers, including parameters of tumor burden and cytogenetics, were adopted to identify high-risk patients in multiple myeloma (MM). Recently, the International Staging System (ISS), including beta2-microglobulin (beta2M) and albumin, was introduced for patients with symptomatic MM. As bone disease is a hallmark of MM, we investigated the prognostic impact of the bone resorption marker carboxy-terminal telopeptide of type-1 collagen (ICTP) in combination with ISS, beta2M, albumin, deletion of chromosome 13 and high-dose therapy (HDT) in 100 patients with newly diagnosed symptomatic MM. beta2M alone, albumin alone, ISS, HDT, del(13q14) and ICTP were significant prognostic factors for overall survival (OS). In a multivariate analysis, ICTP was the most powerful prognostic factor (log-rank P<0.001, hazard ratio: ninefold increase). ICTP clearly separated two subgroups with a good and a worse prognosis within each of the three ISS stages (ISS I: P=0.027, ISS II: P=0.022, ISS III: P=0.013). Incorporation of ICTP in a combined ICTP-ISS score significantly (P<0.001) separated four risk groups with a 5-year OS rate of 95, 64, 46 and 22%, [corrected] respectively. These data demonstrate for the first time that the inclusion of the collagen-I degradation product ICTP, as a biomarker of bone resorption, adds to the prognostic value of ISS.
Leukemia 2008 Sep
PMID:Incorporation of the bone marker carboxy-terminal telopeptide of type-1 collagen improves prognostic information of the International Staging System in newly diagnosed symptomatic multiple myeloma. 1858 Sep 57

Osteolytic bone disease in multiple myeloma (MM) is caused by enhanced osteoclast (OCL) activation and inhibition of osteoblast function. Lenalidomide and bortezomib have shown promising response rates in relapsed and newly diagnosed MM, and bortezomib has recently been reported to inhibit OCLs. We here investigated the effect of lenalidomide on OCL formation and osteoclastogenesis in comparison with bortezomib. Both drugs decreased alpha V beta 3-integrin, tartrate-resistant acid phosphatase-positive cells and bone resorption on dentin disks. In addition, both agents decreased receptor activator of nuclear factor-kappaB ligand (RANKL) secretion of bone marrow stromal cells (BMSCs) derived from MM patients. We identified PU.1 and pERK as major targets of lenalidomide, and nuclear factor of activated T cells of bortezomib, resulting in inhibition of osteoclastogenesis. Furthermore, downregulation of cathepsin K, essential for resorption of the bone collagen matrix, was observed. We demonstrated a significant decrease of growth and survival factors including macrophage inflammatory protein-alpha, B-cell activating factor and a proliferation-inducing ligand. Importantly, in serum from MM patients treated with lenalidomide, the essential bone-remodeling factor RANKL, as well as the RANKL/OPG ratio, were significantly reduced, whereas osteoprotegerin (OPG) was increased. We conclude that both agents specifically target key factors in osteoclastogenesis, and could directly affect the MM-OCL-BMSCs activation loop in osteolytic bone disease.
Leukemia 2008 Oct
PMID:Lenalidomide inhibits osteoclastogenesis, survival factors and bone-remodeling markers in multiple myeloma. 1859 40

Bone disease in multiple myeloma (MM) is characterized by lytic bone lesions, which can cause severe bone pain, pathologic fractures and hypercalcemia. However, the lytic bone disease in MM differs from that in other cancer patients who have lytic bone metastases. Although increased osteoclastic bone destruction is involved in MM and other tumors involving bone, in contrast to other tumors, once the MM tumor burden exceeds 50% in a local area, osteoblast activity is either suppressed or absent. The basis for this severe imbalance between increased osteoclastic bone resorption and decreased bone formation has been a topic of intensive investigation over the last several years and will be reviewed in this article.
Leukemia 2009 Mar
PMID:Pathogenesis of myeloma bone disease. 1903 21


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