AB0840 INFLUENCE OF PSORIATIC ARTHRITIS (PsA) ON BONE LOSS AND ANALYSIS BETWEEN AXIAL AND PERIPHERAL PsA IN JAPANESE PATIENTS

Background:Osteoporosis is one of the major comorbidities in patients with psoriasis and psoriatic arthritis (PsA). It has been reported that PsA induces fragility bone structure1and high risk of osteoporosis2. However, there is no report about relationship between psoriatic arthritis and osteoporosis in Japanese patients and its mechanism has not been elucidated.Objectives:The objective of this study is to investigate influence of PsA on bone mineral density (BMD) and its mechanism including analysis between axial and peripheral PsA in Japanese patients.Methods:This study was retrospective study. We examined 58 cases of PsA and 29 cases of RA that underwent DXA tests at our facility from January 2017 to July 2019 (Table 1). The axial PsA was classified as axial SpA using the ASAS classification criteria. First, we investigated influence of PsA containing both axial (n=30,19 males, 11 females, mean age: 50.6 years) and peripheral (n=28, 19 males, 9 females, mean age: 58.0 years) subtypes on BMD measured by dual-energy X-ray absorptiometry. Second, we measured serum bone metabolism markers (P1NP: type I procollagen-N-propeptide, TRACP-5b: tartrate-resistant acid phosphatase 5b) and bone remodeling effector molecules (Dkk1: Dickkopf1, sclerostin, 25(OH)D: 25-hydroxyvitamin D) to elucidate differences in BMD between axial and peripheral PsA. Furthermore, rheumatoid arthritis (RA) (n=29, 2 males, 27 females, mean age: 66.2 years), as a reference disease, was also evaluated for comparison with axial and peripheral PsA.Osteoporosis and Osteopenia were defined as T-score ≤ -2.5 or %YAM ≤70%., -1.0< T-score >-2.5 or 80>%YAM >70% respectively.Results:58 patients with PsA indicated low T-score, Z-score and %YAM in both lumbar spine and proximal femur (Table 1). Axial PsA and peripheral PsA showed osteoporosis in 16.7% and 35.7%, and osteopenia in 20.0% and 32.1%, respectively, despite the fact that there were many middle-aged men. Comparison between axial and peripheral PsA, axial PsA showed higher BMDthan peripheral PsA. In bone remodeling makers, P1NP in both PsA were almost same, but TRACP-5b, bone resorption marker, in axial PsA was lower than that in peripheral PsA(Table 2). In bone remodeling influencer molecules, Dkk1, and sclerostin in axial PsA was slightly higher than those in peripheral PsA, whereas 25(OH)D is almost same as the both PsA. On the other hand, RA also indicated low T-score and %YAM in both lumbar spine. P1NP in RA showed slightly lower, but TRACP-5b and Homocysteine in RA higher than those in axial and peripheral PsA. Dkk1 and sclerostin in RA were slightly lower than those in both PsA.Conclusion:Peripheral PsA indicated more severe bone loss than axial PsA in our study. There were some differences in bone remodeling markers and bone remodeling effector molecules between axial and peripheral PsA, but the relationships between BMD and these parameters were not confirmed. Further studies are needed to elucidate bone loss mechanism in these PsA.References:[1]Zhu TY, et al. Osteoporosis Int. 2015; 26:261–272.[2]Kathuria R, et al. J Am Acad Dermatol. 2017;76:1045-53.Disclosure of Interests:Shigeyoshi Tsuji Grant/research support from: Eli Lilly, Speakers bureau: AbbVie, Asahi Kasei, Chugai, Daiichi Sankyo, Eli Lilly, Eisai, Mitsubishi Tanabe, Celgene, and Novartis Pharma K.K., Tetsuya Tomita Consultant of: Eli Lilly and Company, Mari Higashiyama: None declared, Takaaki Noguchi: None declared, Toshikazu Mouri: None declared, Jun Hashimoto Speakers bureau: AbbVie, Asahi Kasei, Chugai, Daiichi Sankyo, Eli Lilly, Eisai, Mitsubishi Tanabe, Celgene, and Novartis Pharma K.K.

Download Full-text

Bone remodeling in patients with type I and type II diabetes mellitus in pre- and postmenopausal periods

Obstetrics Gynecology and Reproduction ◽

10.17749/2313-7347/ob.gyn.rep.2020.149 ◽

2020 ◽

Vol 14 (5) ◽

pp. 611-618

Author(s):

S. S. Safarova ◽

S. S. Safarova

Keyword(s):

Diabetes Mellitus ◽

Lumbar Spine ◽

Bone Remodeling ◽

Type Ii Diabetes ◽

Type Ii Diabetes Mellitus ◽

Control Group ◽

Type I ◽

Type Ii ◽

Reparative Osteogenesis ◽

T Score

Aim: to perform structural and functional analysis of the activity of reparative osteogenesis processes at pre- and postmenopausal women with diabetes mellitus (DM).Materials and Methods. There were enrolled 142 pre- and postmenopausal patients with type I and type II diabetes mellitus type (DM-1 and DM-2) as well as 43 females in control group. Subjects taking medicines acting on bone metabolism comorbid with chronic diseases were excluded from the study. All patients underwent Dual-energy X-ray Absorptiometry (DXA) to assess bone mineral density (BMD, T-score). Serum markers of bone remodeling (alkaline phosphatase, ALP; procollagen type I N propeptide, PINP; beta-Cross laps, b-CTx), metabolic and hormone parameters (glycated hemoglobin, parathyroid hormone, calcitonin, vitamin D, electrolytes) were also measured.Results. A positive correlation was found between the duration of DM-1 and DM-2 and b-CTx level (DM-1: г = 0.349, р = 0.08; DM-2: г = 0.214, р = 0.04). A negative correlation was found between the lumbar spine T-score and the duration of diabetes (DM-1: r = -0.568, p = 0.001; DM-2: r = -0.267, p = 0.04). A statistically significant correlation was found between the lumbar spine T-score and b-CTx levels (DM-1: r = -0.452, p = 0.002; DM-2: r = -0.357, p = 0.09).Conclusion. The results of current study suggest that reparative osteogenesis in patients with post-menopausal DM-1 vs. DM-2 and the control group was moderately increased. In patients with DM-2, a less pronounced change in BMD was determined in parallel with inconsistent bone remodeling processes, which casts doubt on the ability of DXA to predict fractures in these patients. Such changes contribute to decreased bone quality, which distinguishes diabetic osteopathy from traditional menopausal osteoporosis manifested mainly by low BMD.

Download Full-text

Osteoporosis in Sickle Cell/β-Thalassemia Is Primarily Caused by an Imbalance at the RANKL/OPG Pathway.

Blood ◽

10.1182/blood.v106.11.3173.3173 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3173-3173

Author(s):

Ersi Voskaridou ◽

Ioannis Papassotiriou ◽

Evangelos Premetis ◽

John Meletis ◽

Dimitris Loukopoulos ◽

...

Keyword(s):

Bone Marrow ◽

Renal Function ◽

Bone Resorption ◽

Bone Loss ◽

Sickle Cell ◽

Type I ◽

Mineral Density ◽

T Score ◽

Tracp 5B ◽

Marrow Expansion

Abstract Bone involvement is the commonest clinical manifestation of sickle cell disease (SCD) including chronic disorders, such as osteopenia/osteoporosis. The aim of the present study is to evaluate the bone mineral density (BMD) of patients with SCD/β-thalassemia (S/β-th) in parallel with markers of bone turnover in an attempt to better understand the pathophysiology of bone loss in these patients. We studied 52 patients with S/β-th (23M/29F; median age 40 y). The BMD of the lumbar spine (L) and femoral neck (F) was evaluated by DEXA. Bone remodeling was assessed using the following serum indices: (a) bone resorption markers [C-telopeptide of type-I collagen (CTX), tartrate-resistant acid phosphatase isoform-5b (TRACP-5b)], (b) bone formation markers [bone-alkaline phosphatase (bALP), osteocalcin (OC), and C-terminal propeptide of collagen type-I (CICP)], and (c) osteoclast stimulating factors [soluble receptor activator of nuclear factor κB ligand (sRANKL), and osteoprotegerin (OPG)]. Moreover, all patients had a thorough evaluation of their renal function (creatinine clearance, and cystatin-C serum levels), bone marrow expansion (soluble transferin receptors, sTfR), serum erythropoietin (Epo) and parathyroid hormone (PTH) levels. The same biochemical parameters were also determined in 25 age- and gender-matched controls. According to WHO criteria, 17 patients (32.6%; 8M/9F, median age 45 y) had osteopenia or osteoporosis (median L/T-score: −2.26; L/BMD: 0.9 g/cm2; F/T-score: −1.86; F/BMD: 0.68 g/cm2). In contrast, 30 patients (57.6%; 12M/18F, median age 40 y) had osteosclerosis (median L/T-score: +3.15; L/BMD: 1550.5 g/m2; F/T-score: +0.52; F/BMD: 1113.5 g/cm2). Renal function, Epo, Hb and sTfR levels and the number of crises/year were similar between both groups. All patients displayed increased levels of OPG, bALP, and CICP compared with controls (p<0.02). CTX levels in the osteosclerotic patients were significantly lower than those of both controls (p<0.0001) and osteopenic/osteoporotic patients (p<0.003); this finding implies a diminished bone resorption. Moreover, bALP and PTH in the osteopenia/osteoposis group were higher than those of the osteosclerosis group (p<0.01, and <0.03, respectively). BMD of the osteopenic/osteoporotic patients showed a strong correlation with OPG and CTX levels (p=0.01, and 0.008, respectively). This result, in combination with the significant correlations observed between OPG and sRANKL, TRACP-5b, and bALP in these patients suggests that osteopenia/osteoporosis in S/β-th results mainly from an imbalance at the RANKL/OPG axis. Conversely, considering the absence of correlation between BMD and sTfR in the same patient group, the potential contribution of bone marrow expansion in the development of osteopenia appears much weaker. No correlation between BMD and bone indices observed in osteosclerotic group. In conclusion, this study suggests that the development of bone loss in S/β-th patients is mainly due to an imbalance in RANKL/OPG pathway. Novel agents that target this system, as well as bisphosphonates, maybe useful in the management of this common SCD complication.

Download Full-text

Zoledronic Acid Is an Effective Treatment for Osteoporosis in Patients with Thalassemia Major: Results of a Randomized, Placebo-Controlled, Trial.

Blood ◽

10.1182/blood.v106.11.3656.3656 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3656-3656

Author(s):

Ersi Voskaridou ◽

Dimitris Loukopoulos ◽

Eleni Stoupa ◽

Eugenia Spyropoulou ◽

John Meletis ◽

...

Keyword(s):

Lumbar Spine ◽

Zoledronic Acid ◽

Bone Remodeling ◽

Bone Pain ◽

Thalassemia Major ◽

Type I ◽

Tracp 5B ◽

Group A ◽

Group B ◽

To Receive

Abstract Osteoporosis in thalassemia major (TM) is due to several factors, including bone marrow expansion, iron overload, hormonal deficiency, and increased osteoclast activity. Potent inhibitors of osteoclast function, such as bisphosphonates, have been recently used in the management of TM-induced osteoporosis. The aim of this trial was to determine the efficacy and safety of a third-generation aminobisphosphonate, zoledronic acid, on osteoporosis and bone remodeling in patients with TM. Sixty-six patients with TM-induced osteoporosis (21M/45F; median age 35.5 years) have been enrolled in this study. The majority of patients had pathological fractures and/or bone pain due to osteoporosis at baseline. Patients were randomized to receive zoledronic acid at a dose of 4 mg, iv, in 15 min infusion, every 6 months (23 patients; group A) or every 3 months (21 patients; group B), or to receive placebo every 3 months (22 patients; group C), for a period of one year. All patients were under oral calcium (500 mg) administration during the treatment period. Effects were monitored by measuring bone mineral density (BMD) in comparison with a series of serum 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 [receptor activator of nuclear factor-κB ligand (RANKL), and osteoprotegerin (OPG)]. BMD of the lumbar spine, femoral neck and forearm was determined using DEXA, before and 12 months after treatment. The above biochemical parameters were measured at baseline and before the administration of zoledronic acid or placebo in each cycle. We also evaluated these markers in 30 healthy, age and gender-matched, controls. All patients had increased values of CTX, TRACP-5b, bALP, CICP, sRANKL, OPG, and sRANKL/OPG ratio, compared with controls (p<0.02). Patients of group A showed no differences in terms of BMD of all three evaluated sites after 12 months of treatment, while they showed a reduction in serum levels of CTX (p=0.02), bALP (p=0.02) and OC (p=0.01). Conversely patients of group B achieved a significant increase in their lumbar spine BMD after 12 months of therapy (p=0.007), which was accompanied by a dramatic decrease in serum CTX (p=0.004), bALP (p<0.0001), CICP (p<0.0001), and OC (p=0.005). Patients of group C showed an aggravation of BMD of the lumbar spine (p=0.041) at 12 months, while there was no alteration in BMD of other sites as well as in markers of bone remodeling. There was no effect of zoledronic acid on sRANKL and OPG in all patients. Zoledronic acid reduced bone pain in patients of groups A and B, while there was no bone pain relief in placebo group. No severe side-effects were observed in this study. We conclude that zoledronic acid, at a dose of 4 mg, iv, every 3 months is an effective treatment in increasing BMD and reducing osteoclast activity and bone resorption in TM-induced osteoporosis. Longer follow-up studies are required to clarify the exact role of zoledronic acid in the management of these patients.

Download Full-text

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

Blood ◽

10.1182/blood.v106.11.2498.2498 ◽

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.

Download Full-text

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

Blood ◽

10.1182/blood.v108.11.506.506 ◽

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.

Download Full-text

Increased Bone Resorption Is Implicated in the Pathogenesis of Bone Loss in Hemophilia Patients: Correlations with Severity of Hemophilic Arthropathy and HIV Infection.

Blood ◽

10.1182/blood.v110.11.493.493 ◽

2007 ◽

Vol 110 (11) ◽

pp. 493-493 ◽

Cited By ~ 1

Author(s):

O. Katsarou ◽

Evangelos Terpos ◽

P. Hatzismalis ◽

S. Provelengios ◽

T. Adraktas ◽

...

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Bone Turnover ◽

Hiv Infection ◽

Clinical Score ◽

Hiv Positive ◽

T Score ◽

Hemophilic Arthropathy ◽

Tracp 5B ◽

Radiological Score

Abstract Osteoporosis has been recently recognized as a comorbidity factor, which affects significantly the quality of life in hemophilia patients. Prolonged immobilization and severity of arthropaphy have been considered as the major factors contributing to the pathogenesis of osteoporosis in hemophilia. However, the exact mechanisms of bone loss have not been fully clarified in this disorder. The aim of this study was to evaluate the incidence of osteoporosis in hemophilia patients, and investigate the possible correlations with clinical and laboratory data in an attempt to better understand the pathogenetic mechanisms that are involved in its development. Ninety-three hemophilia patients were evaluated. Their median age was 36 years (range: 24–46 years). Eighty patients (86%) had severe and 13 patients (13%) moderate haemophilia. Fifty-seven patients (61%) were HIV negative and 36 (38%) HIV positive. The severity of hemophilic arthropahty was assessed using WFH clinical score and Petterson radiological score in all patients. Bone mineral density of the lumbar spine(LS) and the femoral neck(FN) was measured using DEXA technique in 78 out of 93 patients. Bone turnover was studied by the measurement of a series of serum indices: bone resorption markers [N- and C-telopeptide of type-I collagen (NTX and CTX, respectively), and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b)], bone formation markers [bone-alkaline phosphatase (bALP), and osteocalcin], and osteoclast stimulating factors [receptor activator of nuclear factor-kB ligand (RANKL), osteoprotegerin (OPG), and tumor necrosis factor-alpha]. Osteopenia(−2,5<T-score<−1.5) or osteoporosis (T-score<−2,5) was found in 83.9% and 60% of the patients in the FN and LS respectively. Osteoporosis was more common among HIV positive patients in both FN (65.3%vs.41.6%; p=0.007) and LS (17.86%vs.5.41%, p=0.004).The severity of osteoporosis in the FN correlated with patients’ total clinical and radiological score (p=0.001). Hemophilia patients showed increased serum levels of all markers of bone resorption and bALP compared with 15 controls of similar gender and age (median NTX: 19.4 vs. 17.4 nM BCE, p=0.018; CTX: 0.61 vs. 0.47 ng/mL, p=0.028; TRACP-5b: 2.7 vs. 1.3 U/L, p<0.01; and bALP: 20.0 vs. 16.9 U/L, p=0.048; for patients and controls, respectively). This increased osteoclastic activity was not found to be mediated by RANKL/RANK/OPG system as we observed no difference in terms of sRANKL/OPG ratio between patients and controls. Therefore it seems that other factors are involved in the increased bone resorption observed in hemophiliacs. In multivariate analysis, HIV infection (p=0.05) and total clinical score (p=0.001), were found to be independent prognostic factors for developing osteoporosis. Our study has shown that the incidence of osteoporosis is high among hemophilia patients and is related to the severity of hemophilic arthropathy. We report for the first time that hemophilia patients have high bone turnover, which seems not to be due to an imbalance of the RANKL/OPG system. HIV infection increases the negative effects of hemophilia on bone metabolism and may contribute to the pathogenetic mechanisms involved in osteoporosis development.

Download Full-text

First-Line Chemotherapy Leads to High Bone Turnover and Reduced Bone Mass in Patients with Non-Hodgkin's Lymphoma (NHL).

Blood ◽

10.1182/blood.v114.22.1951.1951 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1951-1951 ◽

Cited By ~ 1

Author(s):

Konstantinos Anargyrou ◽

Theodoros P. Vassilakopoulos ◽

Konstantinos Tsionos ◽

Panayiotis Kokkoris ◽

Georgios Boutsikas ◽

...

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Cell Lymphoma ◽

Lumbar Vertebra ◽

First Line ◽

High Bone Turnover ◽

T Score ◽

Tracp 5B ◽

High Bone ◽

Line Chemotherapy

Abstract Abstract 1951 Poster Board I-974 Chemotherapy associated osteoporosis is a severe problem in patients with malignant diseases as it increases the risk for fractures and deteriorates quality of life. There are very limited data in the literature for the effect of chemotherapy on bone metabolism of adult patients with NHL. To elucidate this issue we scheduled a prospective study in which patients with newly-diagnosed NHL had a thorough evaluation of bone remodeling pre- and post- first-line chemotherapy. As of June 2009, 33 (20M/13F, median age 61 years, range: 28-90 years) of 52 patients, who were entered into this study, had completed their chemotherapeutic scheme: 19 patients (57%) had diffuse large B-cell lymphoma, 5 (15%) follicular lymphoma (grade III), 4 (12%) mantle-cell lymphoma, 4 marginal-zone lymphoma and one T-cell NHL. Twelve (36%) of those had stage IV disease and 17 (51%) had B-symptoms before therapy. Twenty-six patients (78%) received R-CHOP (25 every 21 days and 5 every 14 days), 2 received R-COP and one CHOP as first-line therapy for their disease. Bone mineral density (BMD) of the lumbar spine (L1-L4, antero-posterior view), and femoral neck (FN) was measured by dual energy X-ray absorptiometry (DXA) using a Hologic QDR-1000 scanner on day 1 of cycle 1 (baseline) and on day 30 post the last cycle of chemotherapy. The following serum indices of bone metabolism were measured on the days of DXA: i) osteoclast stimulators [sRANKL and osteoprotegerin (OPG)], ii) osteoblast inhibitor dickkopf-1 (Dkk-1), iii) bone resorption markers [C-telopeptide of collagen type-I (CTX) and tartrate-resistant acid phosphatase-5b (TRACP-5b)], and iv) bone formation markers [bone alkaline phosphatase (bALP) and osteocalcin (OC)]. The above markers were also evaluated in 24 healthy controls of similar gender and age. Patients were assessed for skeletal-related events (SREs) throughout the period of the study. At baseline, NHL patients had a median T-score of L1-L4 BMD of -0.65 (range -4.27 to +3.68) and of FN BMD of -1.1 (-4.01 to +0.2). The median T-score of the lumbar vertebra with the major bone loss was -1.44 (-4.6 to +3.03). At baseline patients had increased levels of Dkk-1 (p=0.036) and reduced levels of OC (p<0.001) compared to controls. In terms of bone resorption, CTX, TRACP-5b and sRANKL/OPG ratio did not differ between patients and controls. There was a strong correlation between L1-L4 and FN BMD (r=0.64, p<0.0001) as well as between L1-L4 BMD and Dkk-1 (r=-0.617, p<0.0001) and between CTX with TRACP-5b (r=0.65, p<0.0001) and sRANKL (r=0.413, p=0.036). There was no correlation between BMD and NHL stage. The administration of chemotherapy resulted in a dramatic reduction of BMD in L1-L4 (median T-score: -1.32; range -4.6 to +3.04; p=0.001 and median T-score of the lumbar vertebra with the major loss: -1.95; range: -4.84 to +2.72; p=0.002) and in a less impressive reduction in FN BMD (median T-score: -1.2; range: -3.68 to +0.38; p=0.022) compared to baseline values. The reduction of L1-L4 BMD post-chemotherapy was more profound in males (p=0.01) than in females (p=0.05) and in patients of >55 years (p=0.007) compared to all others (p=0.059). This reduction was irrespective of the NHL stage (I/II vs. III/IV), while patients who received 8 cycles of chemotherapy had a greater reduction of L1-L4 (p<0.0001) and FN (p=0.044) BMD compared to all others. The administration of chemotherapy also resulted in a dramatic increase of CTX (p=0.019) which was mainly due to a similar increase of sRANKL/OPG ratio (p=0.005). Both markers of bone formation, bALP (p=0.001) and OC (p<0.0001) were increased, while Dkk-1 showed a borderline increase post-therapy (p=0.1). All studied markers of bone remodeling were increased in NHL patients post-chemotherapy compared to controls (p<0.01 for CTX, TRACP-5b, bALP, Dkk-1, sRANKL and OPG; p=0.04 for OC and sRANKL/OPG ratio). There was a greater increase of CTX (p=0.04), sRANKL/OPG (p=0.015), TRACP-5b (p=0-.03), bALP (p=0.003) and OC (p<0.0001) in patients who received 8 cycles of chemotherapy compared to all others. During study period, one patient had a pathological fracture in his right FN. Our on-going study suggests that first-line chemotherapy results in high bone turnover, which leads to increased bone loss and reduced BMD of L1-L4 and FN in NHL patients. The confirmation of these results in a larger cohort of patients may lead to the prophylactic use of anti-resorptive agents, such as bisphosphonates in these patients. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

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

Blood ◽

10.1182/blood.v110.11.4745.4745 ◽

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.

Download Full-text

Low Bone Mineral Density and High Bone Turnover In Patients with Non-Hodgkin's Lymphoma (NHL) Who Receive Frontline Therapy: Results of a Multicenter Prospective Study

Blood ◽

10.1182/blood.v116.21.5071.5071 ◽

2010 ◽

Vol 116 (21) ◽

pp. 5071-5071 ◽

Cited By ~ 1

Author(s):

Konstantinos Anargyrou ◽

Theodoros P. Vassilakopoulos ◽

Konstantinos Tsionos ◽

Panayiotis Kokkoris ◽

Georgios Boutsikas ◽

...

Keyword(s):

Bone Loss ◽

Cell Lymphoma ◽

Lumbar Vertebra ◽

Mineral Density ◽

First Line ◽

High Bone Turnover ◽

T Score ◽

Tracp 5B ◽

High Bone ◽

Baseline Values

Abstract Abstract 5071 Chemotherapy-associated bone loss is a severe problem in patients with malignancies as it increases the risk for fractures and deteriorates quality of life. However, there are very limited reports in the literature describing the effects of chemotherapy on bone metabolism of adult patients with NHL. To elucidate this issue we scheduled a prospective study in which patients with newly-diagnosed non-Hodgkin's lymphoma (NHL) had a thorough evaluation of bone remodeling, pre- and post- frontline chemotherapy. As of June 2009, 53 patients (33M/20F, median age 59 years, range: 18–90 years) had completed their first-line treatment: 36 patients (67.9%) had diffuse large B-cell lymphoma, 5 (9.4%) follicular lymphoma (grade III), 4 (7.5%) mantle-cell lymphoma, 6 (11.3%) marginal-zone lymphoma and 2 (3.8%) T-cell NHL. Nineteen patients (35.8%) had stage IV disease and B-symptoms before therapy initiation. Forty-seven patients (88.7%) received R-CHOP (40 every 21 days and 7 every 14 days), 4 received R-COP and 2 received CHOP as first-line therapy for their disease. Bone mineral density (BMD) of the lumbar spine (L1-L4, antero-posterior view), and femoral neck (FN) was measured by dual energy X-ray absorptiometry (DXA) on day 1 of cycle 1 (baseline) and on day 30 of the last cycle of chemotherapy. The following serum indices of bone metabolism were measured on the days of DXA: i) osteoclast stimulators [sRANKL and osteoprotegerin (OPG)], ii) osteoblast regulators [parathyroid hormone, vitamin-D, and dickkopf-1 (Dkk-1)], iii) bone resorption markers [C-telopeptide of collagen type-I (CTX) and tartrate-resistant acid phosphatase-5b (TRACP-5b)], and iv) bone formation markers [bone alkaline phosphatase (bALP) and osteocalcin (OC)]. The above markers were also evaluated in 30 healthy controls of similar gender and age. Patients were assessed for skeletal-related events (SREs) throughout the period of the study. At baseline, NHL patients had a median T-score of L1-L4 BMD of -0.63 (range -4.27 to +3.68) and of FN BMD of -0.875 (-4.01 to +2.07). The median T-score of the lumbar vertebra with the major bone loss was -1.425 (-4.6 to +3.03). At baseline patients had reduced levels of OC (p=0.01) compared to controls, while CTX, TRACP-5b and sRANKL/OPG ratio did not differ between patients and controls. There was a strong correlation between L1-L4 and FN BMD (r=0.64, p<0.0001) as well as between CTX with TRACP-5b (r=0.467, p=0.001), sRANKL (r=0.479, p=0.001) and Dkk-1 (r=0.442, p=0.003). Strong correlations were also observed between bALP and sRANKL/OPG ratio (r=0.406, p=0.006), Dkk-1 and TRACP-5b, (r=0.421, p=0.004), sRANKL and CTX (r=0.479, p=0.001). There was no correlation between BMD and NHL stage. The administration of chemotherapy resulted in a dramatic reduction of BMD in L1-L4 (median T-score: -1.12; range -4.49 to +3.04; p<0.001 and median T-score of the lumbar vertebra with the major loss: -1.45; range: -4.84 to +2.72; p=0.001) and in FN BMD (median T-score: -1.115; range: -3.68 to +1.12; p<0.001) compared to baseline values. The reduction of L1-L4 and FN BMD post-chemotherapy was more profound in males (p=0.003 and p=0.001 respectively) than in females (p=0.011 and p=0.01) and in patients of >55 years (p=0.001 and p<0.001 respectively) compared to all others (p=0.037 and p=0.014). This reduction was irrespective of the NHL stage (I/II vs. III/IV), while patients who received 8 cycles of chemotherapy had a greater reduction of L1-L4 (p<0.001) and FN (p=0.001) BMD compared to all others. The administration of chemotherapy also resulted in a dramatic increase of CTX (p=0.017), TRACP-5b (p<0.001), bALP (p<0.001), OC (p<0.001) and Dkk-1 (p=0.022) compared to baseline values. All studied markers of bone remodeling, with the exception of OPG and sRANKL, were significantly increased in NHL patients post-chemotherapy compared to controls (p=0.05 for CTX, p<0.001 for TRACP-5b and Dkk-1, p=0.01 for bALP, p=0.015 for OC). During study period, one male patient had a pathological fracture in his right FN. We conclude that frontline treatment with the combination of chemotherapy and/or rituximab results in high bone turnover, which leads to increased bone loss and reduced BMD of L1-L4 and FN in NHL patients. The prophylactic use of anti-resorptive agents, such as bisphosphonates, or the administration of agents with anti-Dkk-1 activity may be useful for preventing bone loss in these patients. Disclosures: No relevant conflicts of interest to declare.

Download Full-text

A multicenter prospective study on the efficacy and safety of denosumab in gastrointestinal cancer patients receiving short-term periodic steroid premedication for prevention of chemotherapy-induced nausea and vomiting (ESPRESSO-02/HGCSG1602).

10.21203/rs.3.rs-400213/v1 ◽

2021 ◽

Author(s):

Michio Nakamura ◽

Tetsuhito Muranaka ◽

Masataka Yagisawa ◽

Yasuyuki Kawamoto ◽

Satoshi Yuki ◽

...

Keyword(s):

Lumbar Spine ◽

Adverse Events ◽

Gastrointestinal Cancer ◽

Type I Collagen ◽

Bone Fractures ◽

Japanese Patients ◽

Type I ◽

Life Questionnaire ◽

Efficacy And Safety ◽

Significant Difference

Abstract Purpose We previously reported that the periodic premedication of glucocorticoids during chemotherapy for gastrointestinal cancer (GIC) caused the reduction of bone mineral densities (BMD) (ESPRESSO-01). We conducted this study to evaluate the efficacy and safety of denosumab in the prevention of chemotherapy-induced decreased BMD. Methods Forty-two Japanese patients were studied. Denosumab was administered as a single 60 mg subcutaneous injection before the start of chemotherapy. The primary endpoint was BMD change in the lumbar spine from baseline to 16 weeks. Secondary endpoints were changes in serum cross-linked N-telopeptides of type I collagen (sNTX) and bone alkaline phosphatase (sBAP), complications including hypocalcemia and osteonecrosis of the jaw, new bone fractures, changes in the Japanese Osteoporosis Quality of Life Questionnaire. Results Lumbar spine BMD significantly increased in 71.4% of cases: 2.772% (95% CI, 1.350–4.195%: P < 0.0001). There were also significant decreases in sNTX (P = 0.034) and sBAP levels (P < 0.001). Although one case (2.4%) of jaw osteonecrosis was diagnosed, no fractures occurred. In a cross-trial comparison with ESPRESSO-01, there was no significant difference in the incidence of National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) grade 3 or higher adverse events. However, inclusion of grade ≤ 2 showed significantly higher incidence of hypocalcemia with any CTCAE grade in ESPRESSO-02 (28.4% in ESPRESSO-01, 54.8% in ESPRESSO-02, P = 0.006) Conclusion Denosumab administration prevented secondary BMD reduction in GIC patients undergoing chemotherapy, and was associated with decreased serum levels of the bone turnover markers BAP and NTX.

Download Full-text