Macrophage Inflammatory Protein-1 alpha (MIP-1α) Is Increased in Patients with Waldenstrom’s Macroglobulinemia and Correlates with the Severity of Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2498-2498
Author(s):  
Evangelos Terpos ◽  
Athanasios Anagnostopoulos ◽  
Efstathios Kastritis ◽  
Aristotelis Bamias ◽  
Konstantinos Tsionos ◽  
...  
Keyword(s):  
Platelet Count ◽  
Bone Remodeling ◽  
Active Phase ◽  
Serum Levels ◽  
Type I ◽  
Β2 Microglobulin ◽  
Severity Of Disease ◽  
Inflammatory Protein ◽  
Tracp 5B ◽  
Macrophage Inflammatory Protein

Abstract Macrophage inflammatory protein-1 alpha (MIP-1α) is a member of the CC chemokine family, which is implicated in the pathogenesis of myeloma (MM) bone disease. MIP-1α also correlates with survival in MM patients and markers of disease activity, such as β2-microglobulin. Despite the well-known effect of MIP-1α on MM pathophysiology, there is no information for its role in Waldenstrom’s macroglobulinemia (WM). The aim of this study was to evaluate MIP-1α serum levels in WM patients and correlate them with clinical data and markers of bone remodeling. We studied 53 serum samples of 38 patients with WM (26M/12F; median age: 74 years, range: 39–85 years) in different phases of their disease. Thirteen patients were evaluated prior any kind of treatment, while 24 patients were studied during an active phase of their disease and 12 patients during remission. Furthermore, 4 patients with IgM MGUS were also studied. MIP-1α serum levels were measured using an ELISA method (R&D Systems, Minneapolis, MN, USA) along with a series of bone remodeling indices: i) bone resorption markers [C-telopeptide of type-I collagen (CTX), tartrate-resistant acid phosphatase isoform-5b (TRACP-5b)], ii) bone formation markers [bone-alkaline phosphatase (bALP), osteocalcin (OC), and C-terminal propeptide of collagen type-I (CICP)], and iii) osteoclast stimulating factors [soluble receptor activator of nuclear factor-κB ligand (sRANKL), osteoprotegerin (OPG), and osteopontin (OPN)]. In all patients, we also evaluated hemoglobin, platelet count, β2-microglobulin, and albumin levels as well as the presence of splenomegaly, hepatomegaly and lymphadenopathy, at the time of sample collection. The above biochemical parameters were also studied in 20 age- and gender-matched controls. MIP-1α was elevated in WM patients compared with controls (mean ± SD: 72.5 ± 49.1 pg/ml vs. 22.7 ± 19.4 pg/ml; p=0.001), while there was no difference between IgM MGUS patients and controls. Furthermore, untreated WM patients had increased levels of MIP-1α compared with patients at remission (mean ± SD: 108.6 ± 68.5 pg/ml vs. 58.5 ± 25.8 pg/ml; p=0.026). Patients during an active phase of their disease had also increased levels of MIP-1α compared with controls (p=0.001); these levels were not different from those of untreated WM patients. RANKL serum levels were also elevated in WM patients compared with controls (mean ± SD: 0.73 ± 0.64 vs. 0.39 ± 0.48 pmol/l; p=0.04). Untreated WM patients had increased levels of OPG, and CICP compared with controls (p=0.002, and 0.003, respectively), while patients at remission had elevated values of OPG, TRACP-5b, bALP, and CICP (p=0.04, 0.001, <0.001, and <0.001, respectively); this observation suggests that active bone remodeling is present in untreated WM and is possibly aggravated after treatment even in responders. MIP-1α showed a positive correlation with β2-microglobulin (r=0.3; p=0.04), and presence of splenomegaly (mean values: 110.4 vs. 65.5 pg/ml, in patients with and without splenomegaly, respectively; p=0.04). Furthermore, there was a weak negative correlation between MIP-1α with hemoglobin and platelet count (p=0.06). In conclusion, MIP-1α is elevated in the serum of patients with active WM and correlates with the severity of disease. Our ongoing study indicates that MIP-1α may be a suitable target for the development of novel anti-WM treatment.

Bortezomib Reduces Serum Dickkopf-1 and RANKL Concentrations and Normalizes Indices of Bone Remodeling in Patients with Relapsed Multiple Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 506-506
Author(s):  
Evangelos Terpos ◽  
Deborah Heath ◽  
Amin Rahemtulla ◽  
Kostas Zervas ◽  
Andrew Chantry ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Remodeling ◽  
Serum Levels ◽  
Response To Therapy ◽  
Tartrate Resistant Acid Phosphatase ◽  
Type I ◽  
Lytic Lesions ◽  
Tracp 5B ◽  
Dickkopf 1

Abstract Bortezomib is a proteasome inhibitor, which is currently indicated for the treatment of relapsed/refractory myeloma (MM). Although the anti-myeloma effect of bortezomib has been clearly demonstrated, its effect on bone metabolism is still unclear. There are recent reports that bortezomib increases serum alkaline phosphatase (ALP) activity, which is consistent with enhanced osteoblast function. The aim of this study was to evaluate the effect of bortezomib on bone turnover in 34 patients with relapsed MM. Bortezomib was given alone at a dose of 1.3 mg/m2 on days 1, 4, 8, and 11 of a 3-week cycle for 4 cycles. Responders could continue for 4 more cycles, while non-responders could continue therapy with the addition of dexamethasone. The following serum indices were measured on day 1 of cycle 1, and then on day 21 of cycles 4 and 8: osteoblast inhibitor dickkopf-1 (DKK-1); osteoclast regulators: soluble RANKL (sRANKL) and osteoprotegerin (OPG); bone resorption markers: C-telopeptide of collagen type-I (CTX) and tartrate-resistant acid phosphatase type-5b (TRACP-5b); and bone formation markers: bone-specific ALP (bALP) and osteocalcin (OC). We also studied 33 healthy controls of similar gender and age. The objective response rate after 4 cycles of therapy was 66%: CR 8% and PR 58%. Sixteen responders and 3 non-responders continued on therapy for 4 more cycles. Myeloma patients at baseline had increased values of DKK-1 (p=0.007), sRANKL, sRANKL/OPG ratio, and both markers of bone resorption (p<0.0001) when compared to controls. In contrast, bone formation as assessed by serum bALP and OC was significantly reduced (p<0.001). There was a strong correlation between bone lytic disease and serum CTX (r=0.59, p<0.01), and sRANKL (r=0.4, p=0.03). Patients with severe bone disease (>9 lytic lesions, n=7) had elevated values of DKK-1 compared with all others (mean±SD: 223.4±264.4 ng/mL vs. 84±62.4 ng/mL; p=0.01). Moreover, serum levels of DKK-1 correlated with CTX levels (r=0.39, p=0.04), and weakly with bALP concentrations (r=−0.32, p=0.09). The administration of bortezomib produced a significant reduction of DKK-1 (p=0.035), sRANKL (p=0.01), CTX and TRACP-5b (p<0.001) after 4 cycles, which was still seen after 8 cycles of treatment (p<0.01). Bortezomib also produced a dramatic increase in both markers of bone formation, bALP and OC, after 4 and 8 cycles of therapy (p<0.01). Responders tended to have lower initial levels of DKK-1 compared with non-responders. Patients who achieved a CR or vgPR after 4 cycles of bortezomib had greater elevation of bALP than all others: mean±SD of increase: 306.3%±556.9% vs. 45.8%±56.5%; p=0.02. It is of interest that 3/4 non responders also had an increase in bALP (mean: 39.6%) after 4 cycles of bortezomib. There was no other correlation between response to therapy and alteration of bone markers. No healing of the lytic lesions was observed even in CR patients. This study suggests that bortezomib reduces serum levels of DKK-1 and RANKL, irrespective of response to therapy, in patients with relapsed myeloma and thus leads to normalization of abnormal bone remodeling through the increase of bone formation and reduction of bone resorption.

Serum levels of macrophage inflammatory protein-1 alpha (MIP-1α) correlate with the extent of bone disease and survival in patients with multiple myeloma

2003 ◽  
Vol 123 (1) ◽  
pp. 106-109 ◽  
Author(s):  
Evangelos Terpos ◽  
Marianna Politou ◽  
Richard Szydlo ◽  
John M. Goldman ◽  
Jane F. Apperley ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Serum Levels ◽  
Inflammatory Protein ◽  
Macrophage Inflammatory Protein

Serum Dickkopf-1 Is Increased and Correlates with Bone Mineral Density in Patients with Thalassemia-Induced Osteoporosis. Reduction Post Zoledronic Acid Administration

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3889-3889
Author(s):  
Ersi Voskaridou ◽  
Dimitrios Christoulas ◽  
Thodoris Pantelaros ◽  
Konstantinos Varvagiannis ◽  
Charoula Xirakia ◽  
...  
Keyword(s):  
Zoledronic Acid ◽  
Bone Markers ◽  
Collagen Type ◽  
Serum Levels ◽  
Collagen Type I ◽  
Type I ◽  
Tracp 5B ◽  
Group B ◽  
To Receive ◽  
Dickkopf 1

Abstract Osteoporosis represents an important cause of morbidity in adult patients with thalassemia. Its pathogenesis is multifactorial, and includes mainly bone marrow expansion, endocrine dysfunction and iron overload. Bone metabolism is altered in thalassemia. Osteoclast function is elevated, while osteoblast activity seems to be reduced and thus the balance of bone remodeling is in favor of bone loss. The exact mechanisms of osteoblast dysfunction have not been fully clarified to-date. Wingless-type (Wnt) signaling is an important pathway for osteoblast differentiation. Dickkopf-1 (Dkk-1) protein is an inhibitor of Wnt pathway and is implicated in the pathogenesis of several bone disorders. Collagen type-I is the main structural protein of the bone. The collagen type-I alpha (COLIA)-1 specific protein (Sp)-1 polymorphism has been related to osteoporosis in thalassemia. The aim of this study was to evaluate the serum levels of Dkk-1 in patients with thalassemia-induced osteoporosis who receive therapy with zoledronic acid (ZOL) and evaluate possible correlations with clinical and laboratory data, including the COLIA-1 Sp1 polymorphism. Sixty-six patients (21M/45F; median age 35.5 years) with thalassemia and osteoporosis were studied. Patients were blindly randomized to receive ZOL at a dose of 4 mg, iv, in 15 min infusion, every 6 months (group A, n=23) or every 3 months (group B, n=21), or to receive placebo every 3 months (group C, n=22) for a period of one year. All patients received oral calcium (500 mg) during the treatment period. Dkk-1 was measured at baseline and after 12 months of therapy using ELISA methodology (Biomedica Medizinprodukte, Wien, Austria) along with a series of serum bone remodeling indices: bone resorption markers [C-telopeptide of type-I collagen (CTX), tartrate-resistant acid phosphatase isoform-5b (TRACP-5b)], bone formation markers [bone-specific alkaline phosphatase (bALP), osteocalcin, and C-terminal propeptide of collagen type-I (CICP)], and osteoclast regulators [receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin (OPG), and osteopontin]. The above bone markers were also evaluated in 30, age- and gender-matched, healthy controls. The G-->T mutation at base 1 of intron 1 at the binding site of the Sp1 transcription factor of the COLIA-1 gene was detected by polymerase chain reaction using mutagenesis primers followed by restriction enzyme analysis in all patients. BMD of the lumbar spine (L1-L4), femoral neck (FN) and wrist (W) was determined using DEXA, before and 12 months after treatment. At baseline, all patients had increased serum levels of Dkk-1 (mean±SD: 39±17.1 pmol/L) compared to controls (27.4±9.7 pmol/L; p<0.0001). Furthermore, thalassemia patients had increased values of CTX (p<0.0001), bALP (p<0.001), CICP (p=0.003), sRANKL (p=0.02), and OPG (p=0.001) compared to controls. Results for the COLIA-1 Sp1 polymorphism were available for 53 patients. Seventeen patients (32%) were G/T heterozygotes at the polymorphic Sp1 site (Ss), while 3 (5.6%) were T/T homozygotes (ss). Dkk-1 serum levels correlated with L1-L4 BMD (r=−0.290, p=0.022) and W-BMD (r=−0.415. p=0.001), but also with TRACP-5b (r=0.310, p=0.011) and bALP levels (r=−0.289, p=0.018). Ss and ss patients tended to have lower L1-L4 BMD compared with SS patients (p=0.09). No significant correlations were observed between Ss and ss patients with the measured bone markers or the response to ZOL. As reported previously, patients of group B experienced an increase of L1-L4 BMD, while no other alterations in BMD were observed in the 3 studied groups after 12 months of ZOL administration. Interestingly, patients of groups A+B showed a strong reduction of Dkk-1 after 12 months of ZOL (from 39.6±16.6 to 28.9±16.3 pmol/L; p=0.004); indeed they almost normalized Dkk-1 levels (no difference from control values). In contrast, patients of group C showed a borderline increase of Dkk-1 (from 33.1±16.8 to 40.1±23.2 pmol/L, p=0.08). These results show for the first time in the literature that Dkk-1 is increased in the serum of patients with thalassemia and osteoporosis, correlates with their BMD and is reduced post-ZOL therapy. This Dkk-1 elevation may be at least partially responsible for osteoblast dysfunction in thalassemia and reveal a novel possible target for the development of new agents for the management of bone loss in thalassemia patients.

IL-1β Plays An Important Role On Thrombocytosis In An Immune Vasculitis Model Via Promoting Megakaryopoiesis

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2325-2325
Author(s):  
Mo Yang ◽  
Min Zhou ◽  
Su yi Li ◽  
Beng Chong ◽  
Xiao jing Li
Keyword(s):  
Bone Marrow ◽  
Platelet Count ◽  
Platelet Aggregation ◽  
Conflicts Of Interest ◽  
Serum Levels ◽  
Control Group ◽  
Type I ◽  
Anti Inflammation ◽  
Immune Vasculitis

Abstract Thrombocytosis and inflammation cytokines may be involved in the pathogenesis of vasculitis. Our previous study have showed that major inflammation cytokine IL-1β play an important role on in-vitro megakaryopoiesis (Yang M et al, Br J Haematol 2000). In this study, we investigated the changes of IL-1β and megakaryopoiesis and the effect of aspirin in an immune vasculitis model. Rabbit immune vasculitis model was established by intravenous injection of bovine serum albumin. In this model, platelet number and function of periphery blood, megakaryocyte number and the CFU-MK formation of the bone marrow, and serum levels of inflammatory cytokines were investigated. After treatment with BSA for 7 days, the platelet count, platelet aggregation and the expression of AnnexinⅤ were significantly increased in this vasculitis model group compared with normal control group (n=6). The serum levels of inflammatory cytokine IL-1β was also significantly higher in vasculitis model. There were positive correlations between platelet count and IL-1β levels (R=0.55), platelet aggregation and IL-1β levels (R=0.603). Treatment with aspirin (100 mg/kg/d) significantly decreased all these parameters, showing aspirin had anti-platelets and anti-inflammation effects. Our results also demonstrated that megakaryocyte number and the formation of CFU-MK were significantly increased in vasculitis group as compared to those in normal group. Treatment with aspirin significantly reduced the number of megakaryocytes and the formations of CFU-MK in bone marrow in this immune vasculitis model. Our study further demonstrated that IL-1β alone or in combination with TPO induced in-vitro CFU-MK formation. Using RT-PCR techniques, the mRNA of of IL-1 type I and type II receptors (IL-1 RI and RII) were detected in cultured CD61+ CD41+ cells and four megakaryocytic cell lines. The expression of IL-1 RI and RII was also confirmed by flow cytometry and immunofluorescence staining in bone marrow megakaryocytes. Moreover, the IL-1R bloker can reduced IL-1β induced megakaryopoiesis. This sudy showed that IL-1β may play an important role in the pathogenesis of immune vasculitis. Aspirin has anti-inflammation effects in this model which may be mediated via inhibiting megakaryopoiesis and platelet formation. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Inflammatory markers in a randomised soya intervention among men

2008 ◽  
Vol 101 (12) ◽  
pp. 1740-1744 ◽  
Author(s):  
Gertraud Maskarinec ◽  
Robert Oum ◽  
Ann K. Chaptman ◽  
Simona Ognjanovic
Keyword(s):  
Body Weight ◽  
Inflammatory Markers ◽  
Serum Levels ◽  
Repeated Measurements ◽  
Intervention Effect ◽  
Reactive Protein ◽  
Markers Of Inflammation ◽  
Inflammatory Protein ◽  
Macrophage Inflammatory Protein ◽  
Multiplex Bead

The present analysis investigated the effect of soya foods on serum levels of six inflammatory markers, leptin, adiponectin, monocyte attractant protein 1 (MCP-1), macrophage inflammatory protein-1b (MIP-1b), IL-6 and C-reactive protein (CRP), and their relationship with BMI and lifetime soya intake. We randomised twenty-four men to a high- (two daily servings with 30–35 mg isoflavones per serving) or a low-soya diet for 3 months. After a 1-month washout period, the men crossed over to the other treatment. We used a multiplex bead immunoassay to measure leptin, adiponectin, MCP-1 and MIP-1b and ELISA assays for IL-6 and CRP. The statistical analysis applied mixed models that incorporated the four repeated measurements. The men had a mean age of 58·7 (sd 7·2) years and a mean BMI of 28·4 (sd 4·9) kg/m2. We observed no significant intervention effect of the soya treatment on any of the six markers. After adjustment for age and ethnicity, highly significant associations of BMI and body weight with leptin and MCP-1 emerged. Men with high soya intake early in life also had higher levels of leptin and MCP-1, whereas no association was seen for soya intake during adulthood. MIP-1b, adiponectin, IL-6 and CRP were not related to BMI, body weight or soya intake at any time in life. No intervention effect of soya foods on markers of inflammation was observed in this small study, but adiposity and early-life soya intake were related to higher leptin and MCP-1 levels.

scholarly journals Effect of Intermittent Fasting on Glucose Homeostasis and Bone Remodeling in Glucocorticoid-Induced Osteoporosis Rat Model

2021 ◽  
Vol 28 (4) ◽  
pp. 307-316
Author(s):  
Majed G. Alrowaili ◽  
Abdelaziz M. Hussein ◽  
Elsayed A. Eid ◽  
Mohamed S. Serria ◽  
Hussein Abdellatif ◽  
...  
Keyword(s):  
Bone Remodeling ◽  
Bone Mineral ◽  
Serum Levels ◽  
Male Rats ◽  
Control Group ◽  
Intermittent Fasting ◽  
Tartrate Resistant Acid Phosphatase ◽  
Type I ◽  
Mineral Density ◽  
Trap 5B

Background: The present study examined the effect of intermittent fasting (IF) on bone mineral content (BMC) and bone mineral density (BMD) and the markers of bone remodeling in a glucocorticoid-induced osteoporosis (GIO) rat model.Methods: Forty male rats were allocated to 4 groups (N=10 per group): control group of normal rats; control+IF group (normal rats subjected to IF for 16-18 hr daily for 90 days); dexamethasone (DEX) group: (DEX [0.5 mg i.p.] for 90 days); and DEX+IF group (DEX and IF for 90 days). By the end of the experiment, BMD and BMC in the right tibia were measured. Serum levels of the following were measured: glucose; insulin; triglycerides (TGs); total cholesterol; parathyroid hormone (PTH); osteoprotegerin (OPG); receptor activator of nuclear factor-κB (RANK); bone-resorbing cytokines, including bone deoxypyridinoline (DPD), N-terminal telopeptide of collagen type I (NTX-1), and tartrate-resistant acid phosphatase 5b (TRAP-5b); and bone-forming cytokines, including alkaline phosphatase (ALP) and osteocalcin (OC).Results: DEX administration for 90 days resulted in significantly increased serum levels of glucose, insulin, TGs, cholesterol, PTH, OPG, DPD, NTX-1, and TRAP-5b and significantly decreased BMD, BMC, and serum levels of RANK, OC, and ALP (all P<0.05). IF for 90 days significantly improved all these parameters (all P<0.05).Conclusions: IF corrected GIO in rats by inhibiting osteoclastogenesis and PTH secretion and stimulating osteoblast activity.

The Combination of Bortezomib, Melphalan, Dexamethasone and Intermittent Thalidomide (VMDT) Is an Effective Regimen for Relapsed/Refractory Myeloma and Reduces Serum Levels of Dickkopf-1, RANKL, MIP-1α and Angiogenic Cytokines.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3541-3541 ◽  
Author(s):  
Evangelos Terpos ◽  
Athanasios Anagnostopoulos ◽  
Deborah Heath ◽  
Efstathios Kastritis ◽  
Dimitrios Christoulas ◽  
...  
Keyword(s):  
Bone Remodeling ◽  
Median Time ◽  
Objective Response ◽  
Serum Levels ◽  
Tartrate Resistant Acid Phosphatase ◽  
Type I ◽  
Significant Activity ◽  
Grade 3 ◽  
Dickkopf 1 ◽  
Angiogenic Cytokines

Abstract Bortezomib (V) and thalidomide (T) exert their anti-myeloma (MM) action partly through perturbation of the MM microenvironment. The aim of this phase II study was to determine the efficacy and safety of the combination of VT with melphalan (M) and dexamethasone (D) and its effect on angiogenesis and bone remodeling in relapsed/refractory MM. Bortezomib (1.0 mg/m2) was given iv, on days 1, 4, 8, and 11; oral melphalan (0.15 mg/kg) was administered on days 14, while thalidomide (100 mg/day) and dexamethasone (12 mg/m2) were given on days 1–4 and 17–20 of a 28-day cycle, for 4 cycles. Patients without progression continued for up to 8 cycles. Effect of VMDT on angiogenesis was evaluated by measuring serum levels of VEGF, angiogenin (ANG), angiopoietin-2 (ANGP-2), and basic fibroblast growth factor (bFGF) at baseline and after 4th and 8th cycle. Bone remodeling was studied by the measurement of serum indices:osteoclast stimulators [sRANKL, osteoprotegerin (OPG), osteopontin, MIP-1α],osteoblast inhibitor, dickkopf-1 (DKK-1),bone resorption markers [C-telopeptide of collagen type-I (CTX), tartrate resistant acid phosphatase-5b (TRACP-5b)], andbone formation markers [bone alkaline phosphatase (bALP), osteocalcin (OC), and CICP].Among 60 pts registered in this study, 53 have completed 4 courses of therapy as of June 2006 and form the basis for the current analysis. Median time from 1st treatment to VMDT was 36 months. The median number of previous treatments was 2 (range: 1–7). Prior agents included V (11%), M (43%), D (100%), T (56%), and ASCT (30%). The objective response rate was 60%(32/53 pts): CR 11%, vgPR 26% and PR 22%. Furthermore, 6 pts (11%) achieved a MR and 8 SD. Median time to response was 35 days. Median PFS was 9.5 months with a median follow-up period of 12 months. Adverse events included fatigue (58%), thrombocytopenia (20% grade 3/4), neutropenia (8% grade 3/4), anemia (5% grade 3), neuropathy (50% grade 1/2, and 7% grade 3), infections (45%, including 5 HZV cases), and hyponatremia (15%). No patient experienced DVT, while 2 pts died due to sepsis and one due to necrotizing fasciitis. At baseline, MM patients had increased serum levels of DKK-1, sRANKL, sRANKL/OPG ratio, MIP-1α, CTX, VEGF, ANG, ANGP-2, and bFGF (p<0.01) compared with controls (n=36), while serum levels of bALP, and OC were reduced (p<0.0001). DKK-1, sRANKL, sRANKL/OPG ratio, MIP-1α, CTX and all angiogenic cytokines were reduced significantly after 4 and 8 cycles of VMDT. Reduction (%) of RANKL correlated with reduction (%) of VEGF (p=0.003) and MIP-1α(p=0.04), while reduction (%) of VEGF also correlated with (%) changes of DKK-1 (p=0.01), ANG (p=0.005), and ANGP-2 (p=0.04). Only CTX reduction was greater in responders, while all other alterations of studied biochemical indices were observed irrespective of treatment response. In conclusion, VMDT has significant activity in relapsed/refractory MM, with manageable toxicities. Furthermore, this regimen reduces serum cytokines that are involved in the interaction between myeloma and stromal cells.

Bone Remodeling in Patients with Relapsed/Refractory Multiple Myeloma Who Receive Lenalidomide-Based Regimens.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4745-4745
Author(s):  
Evangelos Terpos ◽  
Dimitrios Christoulas ◽  
Efstathios Kastritis ◽  
Eirini Katodritou ◽  
Xenophon Papanikolaou ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Resorption ◽  
Bone Formation ◽  
Bone Metabolism ◽  
Bone Remodeling ◽  
Response To Therapy ◽  
Type I ◽  
Fracture Group ◽  
Lytic Lesions ◽  
Tracp 5B

Abstract Lenalidomide in combination with dexamethasone is very effective for the management of refractory/relapsed multiple myeloma (MM). However, there is very little information for the effect of lenalidomide on bone metabolism in MM. We evaluated bone remodeling in 36 patients (22M/14F; median age 64 years) with refractory/relapsed MM who received lenalidomide-based regimens: 27 received the combination of lenalidomide at the standard dose of 25mg/day x 21 days, every 28 days, with either high (n=18) or low (n=9) dose dexamethasone, while 9 patients received the combination of lenalidomide/low dose dexamethasone plus bortezomib (BDR) at a dose of 1 mg/m2, iv, on days 1, 4, 8, 11 every 28 days. The following serum indices of bone turnover were measured on day 1 of cycle 1, and then on day 28 of cycle 3: osteoblast inhibitor dickkopf-1 (Dkk-1); osteoclast regulators: soluble RANKL (sRANKL) and osteoprotegerin (OPG); bone resorption markers: C-telopeptide of collagen type-I (CTX) and tartrate-resistant acid phosphatase type-5b (TRACP-5b); and bone formation markers: bone-specific ALP (bALP) and osteocalcin (OC). We also studied 20 healthy controls of similar gender and age. The median number of previous therapies was 3 (range: 2–7). At baseline, 9 patients had no lytic lesions (group A), while 3 patients had 1–3 lytic lesions (group B) and 24 patients had more than 3 lytic lesions and/or a pathological fracture (group C) in plain radiography of the skeleton. After 3 cycles of therapy the objective response (CR+PR) rate was 77% (21/27) in lenalidomide/dexamethasone patients and 55% (5/9) in BDR patients. MM patients at baseline had increased levels of Dkk-1 (p=0.002), sRANKL (p=0.04), and both markers of bone resorption (p<0.01) compared to controls. In contrast, bone formation as assessed by serum bALP and OC was significantly reduced (p<0.01). Patients with advanced bone disease (group C) had increased levels of CTX (p<0.001), TRACP-5b (p<0.01), Dkk-1 (p=0.04) and reduced levels of OC (p=0.04) compared with all others. Moreover, serum levels of DKK-1 correlated with TRACP-5b (r=0.614, p<0.0001), CTX (r=0.29, p=0.03), sRANKL (r=0.423, p=0.001) and OPG (r=0.572, p<0.0001). The administration of lenalidomide-based regimens produced only a reduction of Dkk-1 (p=0.04) and TRACP-5b (p=0.03) after 3 cycles of therapy. Interestingly, patients who received BDR showed a dramatic reduction of sRANKL (p=0.02), sRANKL/OPG ratio (p=0.03) and Dkk-1 (p=0.02), which associated with an increase in both markers of bone formation (p=0.04). The % reduction of sRANKL and TRACP-5b and the % increase of bALP and OC was higher in BDR patients compared with others. There was no correlation between response to therapy and bone markers’ changes. In conclusion, the combination of lenalidomide plus dexamethasone seems not to have a clear effect on bone metabolism after 3 cycles of therapy, possibly due to administration of high dose dexamethasone in the majority of patients. BDR patients had a beneficial effect mainly on bone formation, reflecting the bone anabolic effect of bortezomib and/or the lower dose of dexamethasone given in these patients. Longer follow-up is needed to exact final conclusions for the effect of lenalidomide on bone metabolism in relapsed/refractory MM.

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