scholarly journals Menaquinone 4 Reduces Bone Loss in Ovariectomized Mice through Dual Regulation of Bone Remodeling

Nutrients ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 2570
Author(s):  
Huakai Wang ◽  
Nan Zhang ◽  
Longxian Li ◽  
Pan Yang ◽  
Yongxi Ma
Keyword(s):  
Body Weight ◽  
Bone Resorption ◽  
Bone Formation ◽  
Mrna Expression ◽  
Bone Remodeling ◽  
Corn Oil ◽  
The Body ◽  
Undercarboxylated Osteocalcin ◽  
Trabecular Thickness ◽  
Ovariectomized Mice

Epidemiologic studies showed that higher vitamin K (VK) consumption correlates with a reduced risk of osteoporosis, yet the dispute remains about whether VK is effective in improving bone mineral density (BMD). We sought to discover the anti-osteoporotic effect of menaquinone-4 (MK-4) and evaluate the expression of critical genes related to bone formation and bone resorption pathways in the body. Fifty female C57BL/6 mice (aged 13 weeks) were randomly arranged to a sham-operated group (SHAM, treated with corn oil) and four ovariectomized groups that were administered corn oil (OVX group), estradiol valerate (EV, 2 mg/kg body weight as the positive control), low or high doses of VK (LVK and HVK; 20 and 40 mg MK-4/kg body weight, respectively) by gavage every other day for 12 weeks. Body and uterine weight, serum biochemical indicators, bone microarchitecture, hematoxylin-eosin (HE) staining, and the mRNA expression of critical genes related to bone formation and bone resorption pathways were assessed. Either dose of MK-4 supplementation increased the alkaline phosphatase (ALP), decreased the undercarboxylated osteocalcin (ucOC) and tartrate-resistant acid phosphatase (TRACP, p < 0.05) levels, and presented higher BMD, percent bone volume (BV/TV), trabecular thickness (Tb.Th), and lower trabecular separation (Tb.Sp) and structure model index (SMI, p < 0.05) compared with the OVX group. Additionally, both doses of MK4 increased the mRNA expression of Runx2 and Bmp2 (p < 0.05), whereas the doses down-regulated Pu.1 and Nfatc1 (p < 0.05) mRNA expression, the high dose decreased Osx and Tgfb (p < 0.05) mRNA expression, and the low dose decreased Mitd and Akt1 (p < 0.05) mRNA expression. These data show the dual regulatory effects of MK-4 on bone remodeling in ovariectomized mice: the promotion of bone anabolic activity and inhibition of osteoclast differentiation, which provides a novel idea for treating osteoporosis.

scholarly journals The Development of Molecular Biology of Osteoporosis

2021 ◽  
Vol 22 (15) ◽  
pp. 8182
Author(s):  
Yongguang Gao ◽  
Suryaji Patil ◽  
Jingxian Jia
Keyword(s):  
Bone Resorption ◽  
Molecular Biology ◽  
Bone Formation ◽  
Bone Mass ◽  
Bone Remodeling ◽  
Bone Cells ◽  
Cell Activity ◽  
Bone Cell ◽  
Bone Disorders ◽  
Molecular Aspects

Osteoporosis is one of the major bone disorders that affects both women and men, and causes bone deterioration and bone strength. Bone remodeling maintains bone mass and mineral homeostasis through the balanced action of osteoblasts and osteoclasts, which are responsible for bone formation and bone resorption, respectively. The imbalance in bone remodeling is known to be the main cause of osteoporosis. The imbalance can be the result of the action of various molecules produced by one bone cell that acts on other bone cells and influence cell activity. The understanding of the effect of these molecules on bone can help identify new targets and therapeutics to prevent and treat bone disorders. In this article, we have focused on molecules that are produced by osteoblasts, osteocytes, and osteoclasts and their mechanism of action on these cells. We have also summarized the different pharmacological osteoporosis treatments that target different molecular aspects of these bone cells to minimize osteoporosis.

Catch-up Growth in Intrauterine Growth-restricted Piglets Associated with the Return of Pancreatic and Intestinal Functions via Porcine Glucagon-like peptide-2 Microspheres

2020 ◽  
Author(s):  
Ke-ke Qi ◽  
Jie Wu ◽  
Wen-Jun Zhou ◽  
Bo Deng ◽  
Xiao-ming Men ◽  
...  
Keyword(s):  
Body Weight ◽  
Birth Weight ◽  
Mrna Expression ◽  
Glucose Transporter ◽  
Serum Insulin ◽  
The Body ◽  
Peptide Transporter ◽  
Control Group ◽  
Intrauterine Growth ◽  
Glucagon Like Peptide

Abstract Background Intrauterine growth restriction (IUGR) results in abnormal morphology and gastrointestinal function. As a gastrointestinal growth factor, the manner by which the porcine glucagon-like peptide-2 (pGLP-2) microsphere administration catches up with the growth of IUGR piglets was investigated. Methods Fourteen newborn IUGR piglets were assigned into the IUGR and pGLP-2 microsphere groups. The piglets in the pGLP-2 microsphere group were intraperitoneally administered with 100 mg of pGLP-2 microspheres on day 1 of birth. Results From days 15 to 26 of trial, the body weight of the IUGR piglets treated with pGLP-2 microspheres was significantly higher than that in the control group. Importantly, the weaning weight in the pGLP-2 group catches up with the body weight of normal birth weight piglets. IUGR piglets treated with pGLP-2 microspheres significantly showed increased pancreas weight, serum insulin content, and activities of digestive enzymes (lipase, trypsin, chymotrypsin, and amylase). Injection of pGLP-2 microspheres returned the intestinal absorptive capacity by significantly increasing the mRNA expression of sodium-glucose cotransporter 1 in the jejunum, glucose transporter type 2 in the duodenum and jejunum, H + -coupled transporter, and peptide transporter 1 in the jejunum and ileum. It also returned the redox balance by increasing the catalase mRNA expression and decreasing the heat shock protein 70 mRNA expression. In addition, this improvement was associated with the significant increase in gut diameter, length, and weight induced by pGLP-2. Conclusions Injection of pGLP-2 microspheres was a suitable therapeutic strategy for compensatory growth in low birth weight IUGR piglet.

Mechanisms of bone destruction in multiple myeloma: the importance of an unbalanced process in determining the severity of lytic bone disease.

1989 ◽  
Vol 7 (12) ◽  
pp. 1909-1914 ◽  
Author(s):  
R Bataille ◽  
D Chappard ◽  
C Marcelli ◽  
P Dessauw ◽  
J Sany ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Resorption ◽  
Bone Formation ◽  
Bone Mass ◽  
Bone Remodeling ◽  
Cell Mass ◽  
Bone Destruction ◽  
Myeloma Cell ◽  
Bone Lesions ◽  
Mass Reduction

In order to clarify the mechanisms involved in the occurrence of lytic bone lesions (BL) in multiple myeloma (MM), we have compared the presenting myeloma-induced histological bone changes of 14 previously untreated MM patients with lytic BL with those of seven MM patients lacking lytic BL at presentation despite similar myeloma cell mass. A major unbalanced bone remodeling (increased bone resorption with normal to low bone formation) was the characteristic feature of patients presenting lytic BL. Furthermore, this unbalanced process was associated with a significant reduction of bone mass. Unexpectedly, a balanced bone remodeling (increase of both bone resorption and bone formation, without bone mass reduction) rather than a true lack of an excessive bone resorption was the usual feature of patients lacking lytic BL. Our current work clearly shows that a majority (72%) of patients with MM present an important unbalanced bone remodeling at diagnosis, leading to bone mass reduction and bone destruction (unbalanced MM). Some patients (20%) retain a balanced bone remodeling with initial absence of bone destruction (balanced MM). Few (8%) patients have pure osteoblastic MM without bone destruction.

scholarly journals Space Flight Is Associated with Rapid Decreases of Undercarboxylated Osteocalcin and Increases of Markers of Bone Resorption without Changes in Their Circadian Variation: Observations in Two Cosmonauts

2000 ◽  
Vol 46 (8) ◽  
pp. 1136-1143 ◽  
Author(s):  
Anne Caillot-Augusseau ◽  
Laurence Vico ◽  
Martina Heer ◽  
Dimitri Voroviev ◽  
Jean-Claude Souberbielle ◽  
...  
Keyword(s):  
Bone Resorption ◽  
Bone Remodeling ◽  
Vitamin K ◽  
Space Flight ◽  
Type I Collagen ◽  
Circadian Variation ◽  
Bone Alkaline Phosphatase ◽  
Type I ◽  
Undercarboxylated Osteocalcin ◽  
Type I Procollagen

Abstract Background: Microgravity induces bone loss by mechanism(s) that remain largely unknown. Methods: We measured biochemical markers related to bone remodeling in two cosmonauts before, during, and after 21- and 180-day space flights, respectively. Results: During both flights, type I procollagen propeptide and bone alkaline phosphatase decreased as early as 8 days after launch. Undercarboxylated osteocalcin percentage increased early and remained high during both flights. Vitamin K supplementation restored carboxylation of osteocalcin during the long-term flight. Urinary and serum C-telopeptide of type I collagen (CTX) increased as early as day 8 of the flights; the increase was greater in serum than in urine. Pyridinoline, free deoxypyridinoline, and N-telopeptide increased less than CTX during the short-term space flight. The circadian rhythm of bone resorption assessed by urine CTX and free deoxypyridinoline was not altered by microgravity. Conclusion: Vitamin K metabolism or action and bone remodeling may be altered in cosmonauts.

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&lt;0.0001) when compared to controls. In contrast, bone formation as assessed by serum bALP and OC was significantly reduced (p&lt;0.001). There was a strong correlation between bone lytic disease and serum CTX (r=0.59, p&lt;0.01), and sRANKL (r=0.4, p=0.03). Patients with severe bone disease (&gt;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&lt;0.001) after 4 cycles, which was still seen after 8 cycles of treatment (p&lt;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&lt;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.

The effect of tai chi chuan on bone remodeling and cytokines among breast cancer survivors: A feasibility trial

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9610-9610
Author(s):  
L. J. Peppone ◽  
K. Mustian ◽  
R. N. Rosier ◽  
K. M. Piazza ◽  
D. G. Hicks ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Bone Resorption ◽  
Bone Formation ◽  
Bone Remodeling ◽  
Bone Health ◽  
Tai Chi ◽  
Cell Function ◽  
Bone Cell ◽  
Post Intervention ◽  
Tai Chi Chuan

9610 Background: Weight-bearing exercise may slow the rate of bone loss associated with breast cancer treatment. The purpose of this study is to determine the effect of tai chi chuan (TCC) on bone health, as measured by the changes in the levels of bone resorption and bone formation. This study also aimed to investigate whether changes in bone health were correlated with growth and inflammation markers that serve as regulators of bone cell function. Methods: Female patients (N=16) who completed treatment for breast cancer within the past 30 months were randomly assigned to either the TCC group or the psycho-educational support group without exercise (ST) for 60 minutes, three times a week for a period of 12 weeks. Serum levels of bone resorption (N-telopeptides of type I collagen; NTx) and bone formation (bone specific alkaline phosphatase; BAP) were determined by ELISA at baseline and post-intervention. Using validated methods, a bone remodeling index (BRI) was calculated from levels of NTx and BAP. In addition, pre- and post-intervention levels of insulin-like growth factor binding protein 1 (IGFBP-1) and interleukin-2 (IL-2), markers associated with excessive bone resorption, were measured. Lastly, levels of interleukin-6 (IL-6), believed to enhance bone formation, were measured at both pre- and post-intervention. Results: ANCOVA analyses demonstrated that survivors in the TCC group experienced a greater increase in bone remodeling than those in the ST group (Δ BRITCC=1.6 vs Δ BRIST=0.2; p=0.04). All correlations were determined by Pearson's correlation coefficients. IGFBP-1 was negatively correlated with increasing bone remodeling levels (r=-0.43, p=0.14). IL-2 was also negatively correlated with increasing bone remodeling levels (r=-0.35, p=0.24). IL-6 was positively correlated with increasing bone remodeling levels (r=0.69, p=0.01). Conclusions: This pilot study suggests that TCC has positive effects on bone remodeling through changes in growth and inflammation factors that regulate bone cell function. A larger, more definitive trial examining the influence of TCC on bone remodeling is warranted. Funding: Sally Schindel Cone and R25 CA102618 No significant financial relationships to disclose.

scholarly journals Metabolic Consequences of Neuronal HIF1α-Deficiency in Mediobasal Hypothalamus in Mice

2021 ◽  
Vol 12 ◽  
Author(s):  
Azmat Rozjan ◽  
Weibi Shan ◽  
Qiaoling Yao
Keyword(s):  
Skeletal Muscle ◽  
Body Weight ◽  
Mrna Expression ◽  
Density Lipoprotein ◽  
The Body ◽  
Control Group ◽  
Mediobasal Hypothalamus ◽  
Akt Phosphorylation ◽  
Glucose And Lipid Metabolism ◽  
Mrna Expression Levels

ObjectiveThis study aims to investigate whether hypoxia-inducible factor 1α (HIF1α) in the neurons of the mediobasal hypothalamus is involved in the regulation of body weight, glucose, and lipid metabolism in mice and to explore the underlying molecular mechanisms.MethodsHIF1αflox/flox mice were used. The adeno-associated virus that contained either cre, GFP and syn, or GFP and syn (controls) was injected into the mediobasal hypothalamus to selectively knock out HIF1α in the neurons of the mediobasal hypothalamus. The body weight and food intake were weighed daily. The levels of blood glucose, insulin, total cholesterol (TC), triglyceride (TG), free fatty acid (FFA), high-density lipoprotein (HDL), and low-density lipoprotein (LDL)were tested. Intraperitoneal glucose tolerance test (IPGTT) was performed. The insulin-stimulated Akt phosphorylation in the liver, epididymal fat, and skeletal muscle were examined. Also, the mRNA expression levels of HIF1α, proopiomelanocortin (POMC), neuropeptide Y (NPY), and glucose transporter protein 4 (Glut4) in the hypothalamus were checked.ResultsAfter selectively knocking out HIF1α in the neurons of the mediobasal hypothalamus (HIF1αKOMBH), the body weights and food intake of mice increased significantly compared with the control mice (p &lt; 0.001 at 4 weeks). Compared with that of the control group, the insulin level of HIF1αKOMBH mice was 3.5 times higher (p &lt; 0.01). The results of the IPGTT showed that the blood glucose level of the HIF1αKOMBH group at 20–120 min was significantly higher than that of the control group (p &lt; 0.05). The serum TC, FFA, HDL, and LDL content of the HIF1αKOMBH group was significantly higher than those of the control group (p &lt; 0.05). Western blot results showed that compared with those in the control group, insulin-induced AKT phosphorylation levels in liver, epididymal fat, and skeletal muscle in the HIF1αKOMBH group were not as significantly elevated as in the control group. Reverse transcription-polymerase chain reaction (RT-PCR) results in the whole hypothalamus showed a significant decrease in Glut4 mRNA expression. And the mRNA expression levels of HIF1α, POMC, and NPY of the HIF1αKOMBH group decreased significantly in ventral hypothalamus.ConclusionsThe hypothalamic neuronal HIF1α plays an important role in the regulation of body weight balance in mice under normoxic condition. In the absence of hypothalamic neuronal HIF1α, the mice gained weight with increased appetite, accompanied with abnormal glucose and lipid metabolism. POMC and Glut4 may be responsible for this effect of HIF1α.

scholarly journals Biology of Bone Tissue: Structure, Function, and Factors That Influence Bone Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-17 ◽  
Author(s):  
Rinaldo Florencio-Silva ◽  
Gisela Rodrigues da Silva Sasso ◽  
Estela Sasso-Cerri ◽  
Manuel Jesus Simões ◽  
Paulo Sérgio Cerri
Keyword(s):  
Bone Resorption ◽  
Bone Formation ◽  
Bone Tissue ◽  
Bone Remodeling ◽  
Bone Cells ◽  
Current Data ◽  
Bone Diseases ◽  
Bone Homeostasis ◽  
Bone Biology ◽  
Structure And Functions

Bone tissue is continuously remodeled through the concerted actions of bone cells, which include bone resorption by osteoclasts and bone formation by osteoblasts, whereas osteocytes act as mechanosensors and orchestrators of the bone remodeling process. This process is under the control of local (e.g., growth factors and cytokines) and systemic (e.g., calcitonin and estrogens) factors that all together contribute for bone homeostasis. An imbalance between bone resorption and formation can result in bone diseases including osteoporosis. Recently, it has been recognized that, during bone remodeling, there are an intricate communication among bone cells. For instance, the coupling from bone resorption to bone formation is achieved by interaction between osteoclasts and osteoblasts. Moreover, osteocytes produce factors that influence osteoblast and osteoclast activities, whereas osteocyte apoptosis is followed by osteoclastic bone resorption. The increasing knowledge about the structure and functions of bone cells contributed to a better understanding of bone biology. It has been suggested that there is a complex communication between bone cells and other organs, indicating the dynamic nature of bone tissue. In this review, we discuss the current data about the structure and functions of bone cells and the factors that influence bone remodeling.

scholarly journals Chronic intermittent hypobaric hypoxia improves markers of iron metabolism in a model of dietary-induced obesity

2020 ◽  
Vol 17 (1) ◽  
Author(s):  
Fang Cui ◽  
Jing Guo ◽  
Hao-Fei Hu ◽  
Yi Zhang ◽  
Min Shi
Keyword(s):  
Body Weight ◽  
Risk Factor ◽  
Mrna Expression ◽  
Iron Metabolism ◽  
Hypobaric Hypoxia ◽  
The Body ◽  
High Fat ◽  
Intermittent Hypobaric Hypoxia ◽  
Obese Rats ◽  
Hepcidin Mrna

Abstract Background Obesity, a risk factor for many chronic diseases, is a potential independent risk factor for iron deficiency. Evidence has shown that chronic intermittent hypobaric hypoxia (CIHH) has protective or improved effects on cardiovascular, nervous, metabolic and immune systems. We hypothesized that CIHH may ameliorate the abnormal iron metabolism in obesity. This study was aimed to investigate the effect and the underlying mechanisms of CIHH on iron metabolism in high-fat-high-fructose-induced obese rats. Methods Six to seven weeks old male Sprague-Dawley rats were fed with different diet for 16 weeks, and according to body weight divided into four groups: control (CON), CIHH (28-day, 6-h daily hypobaric hypoxia treatment simulating an altitude of 5000 m), dietary-induced obesity (DIO; induced by high fat diet and 10% fructose water feeding), and DIO + CIHH groups. The body weight, systolic arterial pressure (SAP), Lee index, fat coefficient, blood lipids, blood routine, iron metabolism parameters, interleukin6 (IL-6) and erythropoietin (Epo) were measured. The morphological changes of the liver, kidney and spleen were examined. Additionally, hepcidin mRNA expression in liver was analyzed. Results The DIO rats displayed obesity, increased SAP, lipids metabolism disorders, damaged morphology of liver, kidney and spleen, disturbed iron metabolism, increased IL-6 level and hepcidin mRNA expression, and decreased Epo compared to CON rats. But all the aforementioned abnormalities in DIO rats were improved in DIO + CIHH rats. Conclusions CIHH improves iron metabolism disorder in obese rats possibly through the down-regulation of hepcidin by decreasing IL-6 and increasing Epo.

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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