cholecalciferol and Bone-Neoplasms

A rapidly growing understanding of the biochemical and physiological processes that underlie the metabolism of vitamin D has provided new insights into the pathogenesis of oestomalacia. Many of the vitamin D--resistant osteomalacia syndromes can now be explained on the basis of defects in the metabolic conversion of vitamin D to the biologically active dihydroxylated metabolite 1,25(OH)2D and perhaps, in some instances, to impairement of the actions of 1,25(OH)2D on target tissues. The availability of this new information has made possible the synthesis of 1-hydroxylated forms of the vitamin for therapeutic use in states of vitamin D resistance. Although many questions regarding the pathogenesis and most effective approaches in the management of osteomalacia remain unanswered, considerable progress has been made in this direction as a result of continued research on the subject.

Topics: Bone Neoplasms; Chemical Phenomena; Chemistry; Cholecalciferol; Dihydroxycholecalciferols; Ergocalciferols; Giant Cell Tumors; Humans; Hydroxycholecalciferols; Hypoparathyroidism; Hypophosphatemia, Familial; Kidney Failure, Chronic; Metabolism, Inborn Errors; Nephrectomy; Osteomalacia; Phosphates; Pseudohypoparathyroidism; Vitamin D; Vitamin D Deficiency

Vitamin D deficiency has potential roles in breast cancer etiology and progression. Vitamin D deficiency has also been associated with increased toxicity from bisphosphonate therapy. The optimal dose of vitamin D supplementation is unknown, but daily sunlight exposure can generate the equivalent of a 10,000-IU oral dose of vitamin D(3). This study therefore aimed to assess the effect of this dose of vitamin D(3) in patients with bone metastases from breast cancer.. Patients with bone metastases treated with bisphosphonates were enrolled into this single-arm phase 2 study. Patients received 10,000 IU of vitamin D(3) and 1000 mg of calcium supplementation each day for 4 months. The effect of this treatment on palliation, bone resorption markers, calcium metabolism, and toxicity were evaluated at baseline and monthly thereafter.. Forty patients were enrolled. No significant changes in bone resorption markers were seen. Despite no change in global pain scales, there was a significant reduction in the number of sites of pain. A small but statistically significant increase in serum calcium was seen, as was a significant decrease in serum parathyroid hormone. Treatment unmasked 2 cases of primary hyperparathyroidism, but was not associated with direct toxicity.. Daily doses of 10,000 IU vitamin D(3) for 4 months appear safe in patients without comorbid conditions causing hypersensitivity to vitamin D. Treatment reduced inappropriately elevated parathyroid hormone levels, presumably caused by long-term bisphosphonate use. There did not appear to be a significant palliative benefit nor any significant change in bone resorption.

Topics: Adult; Aged; Aged, 80 and over; Biomarkers; Bone Neoplasms; Bone Resorption; Breast Neoplasms; Cholecalciferol; Dietary Supplements; Diphosphonates; Female; Humans; Hypoparathyroidism; Middle Aged; Pain

Denosumab-induced hypocalcemia is sometimes severe, and although a natural vitamin D/calcium combination is used to prevent hypocalcemia, some patients rapidly develop severe hypocalcemia even under supplementation. It is clinically important to predict this risk. This study aimed to develop a risk prediction model for grade ≥2 hypocalcemia within 28 days after the first denosumab dose under natural vitamin D/calcium supplementation. Using a large database containing multicenter practice data, 2399 patients with bone metastasis who were treated with denosumab between June 2013 and May 2020 were retrospectively analyzed. Background factors in patients who developed grade ≥2 hypocalcemia within 28 days after the first denosumab dose and those who did not were compared by univariate analysis. Multivariate analysis was conducted to develop a risk prediction model. The model was evaluated for discriminant performance (receiver operating characteristic-area under the curve, sensitivity, specificity) and predictive performance (calibration slope). A total of 124 patients in the hypocalcemia group and 1191 patients in the nonhypocalcemia group were extracted. A risk prediction model consisting of sex, calcium, albumin, alkaline phosphatase, osteoporosis, breast cancer, gastric cancer, proton pump inhibitor combination, and pretreatment with zoledronic acid was developed. The receiver operating characteristic-area under the curve was 0.87. Sensitivity and specificity were 83% and 81%, respectively, and the calibration slope indicated acceptable agreement between observed and predicted risk. This model appears to be useful to predict the risk of denosumab-induced hypocalcemia and thus should be helpful for risk management of denosumab treatment in patients with bone metastases.

Topics: Bone Density Conservation Agents; Bone Neoplasms; Calcium; Cholecalciferol; Denosumab; Humans; Hypocalcemia; Retrospective Studies; Vitamin D

Long-term severe hyperparathyroidism leads to thinning of cortical bone and cystic bone defects referred to as osteitis fibrosa cystica. Cysts filled with hemosiderin deposits may appear colored as "brown tumors." Osteitis fibrosa cystica and brown tumors are occasionally visualized as multiple, potentially corticalis-disrupting bone lesions mimicking metastases by bone scintigraphy or. We report a case of a 72-year-old white woman who presented with malaise, weight loss, and hypercalcemia. She had a history of breast cancer 7 years before. The practitioner, suspecting bone metastases, initiated bone scintigraphy, which showed multiple bone lesions, and referred her to our hospital for further investigations. Laboratory investigations confirmed hypercalcemia but revealed a constellation of primary hyperparathyroidism and not hypercalcemia of malignancy; in the latter condition, a suppressed rather than an increased value of parathyroid hormone would have been expected. A parathyroid adenoma was found and surgically removed. The patient's postoperative course showed a hungry bone syndrome, and brown tumors were suspected. With the background of a previous breast cancer and lytic, partly corticalis-disrupting bone lesions, there was a great concern not to miss a concomitant malignant disease. Biopsies were not diagnostic for either malignancy or brown tumor. Six months after the patient's neck surgery, imaging showed healing of the bone lesions, and bone metastases could be excluded.. This case shows essential differential diagnosis in a patient with hypercalcemia and multiple bone lesions. Whenever multiple, fluorodeoxyglucose-avid bone lesions are found, malignancy and metabolic bone disease should both be included in the differential diagnosis. Fluorodeoxyglucose-avid and corticalis-disrupting lytic lesions also occur in benign bone disease. There may be very few similar cases with heterogeneous and widespread bone lesions reported in the literature, but we think our patient's case is particularly remarkable for its detailed imaging and the well-documented course.

Topics: Aged; Bone Neoplasms; Breast Neoplasms; Calcium; Cholecalciferol; Diagnosis, Differential; Female; Humans; Hypercalcemia; Hyperparathyroidism, Primary; Osteitis Fibrosa Cystica; Parathyroid Neoplasms; Parathyroidectomy; Positron Emission Tomography Computed Tomography; Treatment Outcome; Vitamins

Brown tumours caused by vitamin D deficiency are rare. Most cases are caused by primary hyperparathyroidism, and are rarely caused by secondary hyperparathyroidism in cases of renal failure. We present a case of Brown tumours of the tibia and second metacarpal bone in a 50-year-old woman who had a low dietary intake of vitamin D and had worn a veil for most of her adult life. The Brown tumours were caused by vitamin D deficiency and secondary hyperparathyroidism. The patient improved on treatment with vitamin D3 and calcium supplements. This is a rare case and the first, to our knowledge, with a Brown tumour of the tibia caused by vitamin D deficiency due to decreased dietary intake and decreased exposure to sunlight. The course of treatment and investigations of the patient are described.

Topics: Bone Neoplasms; Calcium, Dietary; Cholecalciferol; Clothing; Diet; Female; Hand; Humans; Hyperparathyroidism, Secondary; Leg; Metacarpal Bones; Middle Aged; Osteitis Fibrosa Cystica; Sunlight; Tibia; Vitamin D Deficiency

The N-myc downstream regulated gene 1 (NDRG1)/Cap43 is closely associated with cell differentiation, and its expression is induced by hypoxia and increasing intracellular calcium levels. Whether the NDRG1/Cap43 expression in cancer cells is a predictive marker of good or poor prognosis in patients, depends upon tumor types and differentiation status. In this study, we examined whether the NDRG1/Cap43 expression was involved in the differentiation of osteosarcoma cells, using three osteosarcoma cell lines, MG63, U2OS and SaOS2. The NDRG1/Cap43 expression in MG63 and U2OS was significantly enhanced by vitamin D3, which also induced the production of osteocalcin, a differentiation marker of osteoblasts. The knockdown of NDRG1/Cap43 using small interfering RNA also suppressed the production of osteocalcin and enhanced cell proliferation, accompanied by the suppression of p21 expression. Furthermore, the acquired invasiveness of osteosarcoma cells during the invasion in Matrigel resulted in the decreased expression of NDRG1/Cap43. On the basis of these results, our proposed role for NDRG1/Cap43 would be in the capacity of differentiation and invasion in osteosarcoma cells.

Topics: Bone Neoplasms; Cell Cycle Proteins; Cell Differentiation; Cell Line, Tumor; Cell Movement; Cholecalciferol; Cyclin-Dependent Kinase Inhibitor p21; Gene Expression Regulation, Neoplastic; Humans; Intracellular Signaling Peptides and Proteins; Neoplasm Invasiveness; Osteocalcin; Osteosarcoma; RNA Interference; Time Factors

A proteomic analysis of proteins bound to the osteocalcin OSE2 sequence of the mouse osteocalcin promoter identified TRPS1 as a regulator of osteocalcin transcription. Mutations in the TRPS1 gene are responsible for human tricho-rhino-phalangeal syndrome, which is characterized by skeletal and craniofacial abnormalities. TRPS1 has been shown to bind regulatory promoter sequences containing GATA consensus binding sites and to repress transcription of genes involved in chondrocyte differentiation. Here we show that TRPS1 can directly bind the osteocalcin promoter in the presence or absence of Runx2. TRPS1 binds through a GATA binding sequence in the proximal promoter of the osteocalcin gene. The GATA binding site is conserved in mice, humans, and rats, although its location and orientation are not. Mutation of the mouse or human GATA binding sequence abrogates binding of TRPS1 to the osteocalcin promoter. We show that TRPS1 is expressed in osteosarcoma cells and upon induction of osteoblast differentiation in primary mouse bone marrow stromal cells and that TRPS1 regulates the expression of osteocalcin in both cell types. The expression of TRPS1 modulates mineralized bone matrix formation in differentiating osteoblast cells. These data suggest a role for TRPS1 in osteoblast differentiation, in addition to its previously described role in chondrogenesis.

Topics: Androgens; Animals; Binding Sites; Blotting, Western; Bone Density Conservation Agents; Bone Marrow; Bone Neoplasms; Calcification, Physiologic; Cell Differentiation; Cells, Cultured; Cholecalciferol; Chromatin Immunoprecipitation; Chromatography, Liquid; Core Binding Factor Alpha 1 Subunit; DNA Primers; DNA-Binding Proteins; DNA, Neoplasm; Enzyme-Linked Immunosorbent Assay; GATA Transcription Factors; Gene Expression Regulation; Humans; Immunoprecipitation; Luciferases; Mice; Osteoblasts; Osteocalcin; Osteosarcoma; Promoter Regions, Genetic; Rats; Regulatory Sequences, Nucleic Acid; Repressor Proteins; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; RNA, Small Interfering; Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; Stromal Cells; Transcription Factors; Transfection

The remodeling of chromatin is required for tissue-specific gene activation to permit interactions of transcription factors and coregulators with their cognate elements. Here, we investigate the chromatin-mediated mechanisms by which the bone-specific osteocalcin (OC) gene is transcriptionally activated during cessation of cell growth in ROS 17/2.8 osteosarcoma cells and during normal osteoblast differentiation. Acetylation of histones H3 and H4 at the OC gene promoter was assayed during the proliferative and postproliferative stages of cell growth by using chromatin immunoprecipitation assays with antibodies that recognize different acetylated forms of histones H3 or H4. The results show that the promoter and coding regions of the OC gene contain very low levels of acetylated histones H3 and H4 during the proliferative period of osteoblast differentiation when the OC gene is inactive. Active expression of the OC gene in mature osteoblasts and confluent ROS 17/2.8 cells is functionally linked to preferential acetylation of histone H4 and, to a lesser extent, to acetylation of histone H3. Histone acetylation at the loci for RUNX2 (CBFA1), alkaline phosphatase, bone sialoprotein, osteopontin, and the cell growth regulator p21, which are expressed throughout osteoblast differentiation, is not altered postproliferatively. We conclude that acetylation of histones H3 and H4 is functionally coupled to the chromatin remodeling events that mediate the developmental induction of OC gene transcription in bone cells.

Topics: Acetylation; Alkaline Phosphatase; Amino Acid Sequence; Animals; Bone Neoplasms; Cell Differentiation; Cells, Cultured; Cholecalciferol; Chromatin; Core Binding Factor Alpha 1 Subunit; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Gene Expression Regulation; Histones; Integrin-Binding Sialoprotein; Molecular Sequence Data; Neoplasm Proteins; Osteoblasts; Osteocalcin; Osteopontin; Osteosarcoma; Promoter Regions, Genetic; Rats; Sialoglycoproteins; Transcription Factors; Transcription, Genetic; Transcriptional Activation

The level of osteocalcin in serum is lower in lead-intoxicated children than in their normal counterparts. To explain this clinical observation, we investigated the mechanism of action of lead on vitamin D3-dependent osteocalcin production. Lead (5-20 microM) blocked the stimulating effects of vitamin D3 on osteocalcin production in cultured rat osteosarcoma cells (ROS 17/2.8). It is often suggested that activation of protein kinase C (PKC) is a critical mediator of the toxic actions of lead. Treatment of ROS cells with Gö6976, an inhibitor of PKC alpha and beta isozymes, produced similar effects as lead on vitamin D3-dependent osteocalcin production, while activation of PKC by phorbol-12-myristate-13-acetate (TPA) did not reverse or mimic this effect of lead. Thus activation of PKC is not consistent with the actions of lead on vitamin D3-dependent osteocalcin production. Measurement of PKC enzyme activity showed that 10 microM lead treatment does not activate or inhibit the activity of PKC in ROS cells. Western blot analysis indicated that lead treatment does not translocate PKC alpha, beta, or zeta from cytosol to membrane. Therefore, we concluded that PKC does not mediate the cellular toxicity of lead on vitamin D3-dependent osteocalcin production.

Topics: Alkaline Phosphatase; Animals; Blotting, Western; Bone and Bones; Bone Development; Bone Neoplasms; Cell Fractionation; Cholecalciferol; Electrophoresis, Polyacrylamide Gel; Lead; Osteoblasts; Osteocalcin; Osteosarcoma; Parathyroid Hormone; Protein Kinase C; Rats; Receptors, Glucocorticoid; Tumor Cells, Cultured

Topics: Adenocarcinoma; Aged; Bone Neoplasms; Cholecalciferol; Disease Progression; Fatal Outcome; Flutamide; Humans; Male; Osteomalacia; Phosphates; Potassium Compounds; Prostate-Specific Antigen; Prostatic Neoplasms; Tomography, X-Ray Computed

Vitamin D3: 1-alpha, 25(OH)2D3 (calcitriol), 22-oxa-1,25(OH)2D3 (OCT), cholecalciferol (vitamin D3), and retinoids: all-trans retinoic acid (ATRA) and 9-cis retinoic acid, induced morphological changes in POS canine osteosarcoma cells into elongated, spindle or fibroblast like-shaped cells, and apoptotic like cell death characterized by cell shrinkage, condensation and margination of the nucleus for all drugs at 10(-6)M-10(-9)M after 72 to 120 hr culture. Apoptosis as shown by DNA laddering was induced at 48 hr by all drugs at 10(-6)M, 10(-7)M at 96 hr, 10(-8)M and 10(-9)M at 120 hr respectively. These vitamins are suggested to adjunct antineoplastic agents in canine osteosarcoma therapy by induction of apoptosis.

Topics: Animals; Apoptosis; Bone Neoplasms; Calcitriol; Cholecalciferol; Dog Diseases; Dogs; Electrophoresis, Agar Gel; Osteosarcoma; Retinoids; Tumor Cells, Cultured

Osteoclastic cells from giant cell tumour of bone (GCT) of bone provide a rich source for investigation of cellular mechanisms leading to formation of multinucleated cells, the resorption process and involvement of hormones and cytokines in these events. In the present study we investigated the effect of 1,25-dihydroxyvitamin D3 (VD3) and leukaemia inhibitory factor (LIF) on the resorbing potential of osteoclast of GCT origin using quantitative image-analysis of resorption lacunae in an in vitro dentine model. While VD3 unsignificantly increased the number of resorption pits and implicated surface after 7 days of GCT cell culturing, the stimulative effect of LIF was statistically significant. In cultures supplemented with LIF (5000 U/ml) the number of lacunae and resorption surface increased by 38% and 55%, respectively, when compared with control cultures. We suggest that both osteotropic agents increased osteoclastic activity, as the number of multinucleated cells was similar in control and experimental cultures. Seeding of GCT cells on biphasic calcium phosphate substratum revealed the relative inability of osteoclastic cells to resorb this synthetic material.

Topics: Adult; Bone Neoplasms; Bone Resorption; Cholecalciferol; Culture Techniques; Giant Cell Tumor of Bone; Growth Inhibitors; Humans; Image Processing, Computer-Assisted; Interleukin-6; Leukemia Inhibitory Factor; Lymphokines; Male; Microscopy, Electron, Scanning; Osteoclasts; Tumor Cells, Cultured

It has been previously reported that several human cancer cell lines possess specific receptors for 1,25-dihydroxyvitamin D3. In the present study, the concentration of the 1 alpha,25 dihydroxyvitamin D3 receptors has been determined in four human osteosarcoma cell lines--MG63, OST, MNNG-HOS, and KHOS-NP, and we report the effect of 1 alpha, 25 dihydroxyvitamin D3 on these cells. The concentration of 1 alpha, 25 dihydroxyvitamin D3 receptors in MG63, OST, MNNG-HOS and KHOS-NP was 31.1, 12.1, 5.9 and 3.0 fmol/mg of cytosol protein, respectively. These cell lines were classified into two groups according to the concentration of the receptors. The two receptor-rich cell lines were MG63 and OST, and the receptor-poor cell lines were MNNG-HOS and KHOS-NP. In a colony-forming assay, 1 alpha, 25 dihydroxyvitamin D3 (10(-8)M, 10(-9)M) was found to significantly suppress the growth of the receptor-rich cell lines (p < 0.01), but did not suppress that of the receptor-poor cell lines. In an antitumor assay, athymic mice received a transplantation of tumor cells and were treated with 2.5 nmol/kg of 1 alpha hydroxyvitamin D3. Then the relative mean weight of the tumor was measured (MG63 was, however, not transplantable into athymic mice.) As a result, 1 alpha hydroxyvitamin D3 was found to have significantly suppressed the relative mean tumor weight of OST and MNNG-HOS compared with a control group (p < 0.05), but did not suppress that of KHOS-NP. Histologically, 1 alpha hydroxyvitamin D3 induced marked chondrogenetic differentiation in OST alone.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Animals; Bone Neoplasms; Cell Differentiation; Cell Division; Cholecalciferol; Female; Humans; Mice; Mice, Inbred BALB C; Osteosarcoma; Receptors, Calcitriol; Tumor Cells, Cultured

T3 is required for normal skeletal development, but its cellular targets in bone are unknown. T3 regulates target gene transcription via a specific nuclear receptor (T3R), which can heterodimerize with 9-cis-retinoic acid, 1 alpha, 25-dihydroxyvitamin D3, or retinoic acid receptors to modify T3 responsiveness. Serum-free cultures were developed to investigate hormone interactions in three osteosarcoma cell lines, ROS25/1, UMR106, and ROS17/2.8, that express fibroblast-like, preosteoblast, and mature osteoblast phenotypes. ROS25/1 expressed T3R alpha 1, but only low levels of T3R beta 1, whereas UMR106 and ROS17/2.8 cells expressed both receptor proteins. All cells expressed c-erb-A alpha 2 protein and equal levels of 1 alpha,25-dihydroxyvitamin D3 receptor, 9-cis-retinoic acid receptor, and retinoic acid receptor messenger RNAs. Endogenous T3R activity and the effects of D3 and 9-cis-RA on T3 responsiveness were determined in transfections using reporter genes containing T3 response elements from rat malic enzyme or alpha-myosin heavy chain genes. Cell-specific T3 responses were associated with differing patterns of T3R gene expression and stages of osteoblast phenotype expression. A change in T3R beta 1 gene expression during osteoblast phenotype differentiation may modify T3 action in developing bone.

Topics: Animals; Base Sequence; Bone Neoplasms; Cholecalciferol; Molecular Probes; Molecular Sequence Data; Osteoblasts; Osteosarcoma; Phenotype; Rats; Receptors, Thyroid Hormone; Retinoids; Signal Transduction; Triiodothyronine; Tumor Cells, Cultured

Topics: Animals; Bone Neoplasms; Cholecalciferol; Cyclic AMP; Diagnosis, Differential; Humans; Hypercalcemia; Hyperparathyroidism; Mice; Neoplasms; Paraneoplastic Syndromes; Parathyroid Hormone; Peptides

A female pet wooly monkey with metabolic bone disease initially presented with a proliferating bony mass in the left humerus which had many features of osteosarcoma. At necropsy, parathyroid hyperplasia, osteoclastic resorption, proliferative osteoid deposition in the calvarium and cortex of long bones, and fibrous proliferation of the marrow indicated the presence of generalized osteodystrophia fibrosa. The dietary history of deficient vitamin D3 and protein and minimal exposure to sunlight supported this diagnosis, as did depressed levels of serum calcium and elevated levels of serum parathyroid hormone, alkaline phosphatase, and acid phosphatase.

Topics: Animals; Bone Neoplasms; Calcium; Cholecalciferol; Diagnosis, Differential; Female; Fibrous Dysplasia of Bone; Haplorhini; Humerus; Monkey Diseases; Osteosarcoma; Vitamin D Deficiency

Topics: Biopsy; Bone Neoplasms; Calcitonin; Calcium; Cholecalciferol; Humans; Hypocalcemia; Intestinal Absorption; Male; Middle Aged; Neoplasm Metastasis; Osteomalacia; Phosphorus; Prostatic Neoplasms

Topics: Aged; Antineoplastic Agents; Bone Neoplasms; Calcinosis; Calcitonin; Cholecalciferol; Cyclophosphamide; Ergocalciferols; Fractures, Spontaneous; Humans; Hypercalcemia; Kidney Calculi; Lung Neoplasms; Male; Neoplasm Metastasis; Osteitis Deformans; Plicamycin; Podophyllin; Quinones; Sarcoma; Vitamin D

Topics: Animals; Bone Neoplasms; Carcinogens; Cholecalciferol; Injections, Subcutaneous; Methylcholanthrene; Neoplasm Metastasis; Neoplasms; Parathyroid Glands; Pathology; Pharmacology; Rats; Research; Sarcoma; Sarcoma, Experimental; Sodium Chloride; Tissue Extracts