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134. Endocrinology. 1999 Oct;140(10):4779-88.
Vitamin D analogs, 20-Epi-22-oxa-24a,26a,27a,-trihomo-1alpha,25(OH)2-vitamin D3, 1,24(OH)2-22-ene-24-cyclopropyl-vitamin D3 and 1alpha,25(OH)2-lumisterol3 prime NB4 leukemia cells for monocytic differentiation via nongenomic signaling pathways, involving calcium and calpain.
Berry DM, Meckling-Gill KA.
Department of Human Biology and Nutritional Sciences, University of Guelph, Ontario, Canada.
Side-chain modified vitamin D analogs including 20-Epi-22-oxa-24a,26a,27a-trihomo-1alpha,2 5-dihydroxyvitamin D3 (KH1060), and 1,24-dihydroxy-22-ene-24-cyclopropyl-vitamin D3 (MC903) were originally designed to aid in the treatment of hyperproliferative disorders including psoriasis and cancer. Here we demonstrate that these analogs, as well as the 6-cis-locked conformer, 1alpha,25-dihydroxy-lumisterol3 (JN) prime NB4 cells for monocytic differentiation. Previously, the action of MC903 and KH1060 was presumed to be mediated by the nuclear vitamin D receptor (VDRnuc). Differentiation in response to all analogs was shown to be inhibited by 1beta,25-dihydroxyvitamin D3 (HL), the antagonist to the nongenomic activities of 1,25D3. These data suggest that although MC903 and KH1060 may bind the VDRnuc, that the differentiative activities of these agents requires nongenomic signaling pathways. Here we show that 1alpha,25(OH)2-d5-previtamin D3 (HF), JN, KH1060, and MC903 induce expression of PKC alpha and PKC delta and translocation of both isoforms to the particulate fraction, and PKC alpha to the nuclear fraction. The full differentiation response with combinations of analogs and TPA was inhibited 50% by the membrane permeable Ca2+ chelator, 1,2-bis(o-aminophenoxy)-ethane-N,N,N',N'-tetraacetic acid (BAPTA-AM) or calpain inhibitor I. These data demonstrate that intracellular free calcium and the calcium-dependent protease, calpain play critical roles in monocytic differentiation. Intracellular calcium appears to be most critical in the 1,25D3-priming stage of differentiation, while calpain is essential in the TPA maturation response.
135. Gen Pharmacol. 1999 Jan;32(1):143-54.
Leukemia cell differentiation: cellular and molecular interactions of retinoids and vitamin D.
James SY, Williams MA, Newland AC, Colston KW.
Division of Gastroenterology, Endocrinology, and Metabolism, St. George's Hospital Medical School, London.
1. The conventional approach to treatment of acute myeloid leukemia has been the use of chemotherapy, which although being cytotoxic to malignant clones, is also cytodestructive to normal cells. In addition, some leukemia cells develop resistance to chemotherapy and are therefore difficult to eradicate. 2. Differentiation therapy, whereby immature cells are induced to attain a mature phenotype by differentiation agents, has provided an alternative strategy in the treatment of hyperproliferative disorders. This has been highlighted by the use of all-trans retinoic acid (ATRA) in the treatment of acute promyelocytic leukemia (APL). 3. Another differentiation agent, 1,25-dihydroxyvitamin D3 (1,25(OH)2D3), directs monocytic maturation of normal and leukemic cells. Cellular studies have revealed that combinations of vitamin D derivatives and retinoids such as ATRA and 9-cis retinoic acid (9-cis RA) exhibit cooperative effects on differentiation in established leukemia cell lines such as HL-60, U937, and NB4. Furthermore, vitamin D compounds, although not able to induce apoptosis when used alone, potentiate apoptosis induced by 9-cis RA in HL-60 cells and differentially regulate the expression of the apoptosis-related gene products bcl-2 and bax. The molecular mechanisms involved in regulating differentiation and apoptosis by these agents are mediated through the interactions of the nuclear receptors for vitamin D (VDR), ATRA (RAR), and 9-cis RA (RXR), which are able to form homo- or heterodimeric complexes and transcriptionally activate or repress target gene expression. 4. There is evidence to suggest that nitric oxide may also play a role in leukemic cell differentiation and that 1,25(OH)2D3 may influence endogenous nitric oxide production either by directly increasing tumor necrosis factor-alpha (TNF-alpha) or through a secondary mediator such as the C-type lectin CD23.
136. Leuk Lymphoma. 1998 Oct;31(3-4):279-84.
Vitamin D analogs, leukemia and WAF1.
Munker R, Zhang W, Elstner E, Koeffler HP.
Medizinische Klinik III der LMU (Klinikum Grosshadern) Munich, Germany. munker@gsf.de
Vitamin D compounds induce differentiation of human leukemic cells and have potential for the treatment of leukemia. In this review we summarize some of the basic mechanisms underlying the action of vitamin D compounds. A variety of vitamin D analogues were synthesized until now, some of which have enhanced antileukemic activity and a decreased propensity to cause hypercalcemia. Most actions of vitamin D compounds are mediated by nuclear receptors. In vivo, vitamin D binding protein interacts with free vitamin D compounds. Both in normal and leukemic cells, vitamin D compounds cause a differentiation to monocytes and macrophages. A variety of genes are regulated by vitamin D compounds. Recently, the cell cycle inhibitory gene p21/WAF-1/CIP-1 was characterized. The expression de novo of WAF-1 in blasts of acute myelogenous leukemia is an independent factor of unfavorable prognosis. In HL-60 leukemic cells treated with vitamin D analogs, WAF-1 can be induced by nano- or picomolar concentrations of vitamin D analogs and correlates with the induction of a differentiated phenotype. When vitamin D analogs are combined in-vitro with retinoids, an irreversible differentiation is observed. Clinical trials of vitamin D analogs are indicated in the situation of minimal residual disease and in combination with standard chemotherapy.
137. Blood. 1998 Oct 1;92(7):2441-9.
19-nor vitamin-D analogs: a new class of potent inhibitors of proliferation and inducers of differentiation of human myeloid leukemia cell lines.
Asou H, Koike M, Elstner E, Cambell M, Le J, Uskokovic MR, Kamada N, Koeffler HP.
Division of Hematology/Oncology, Cedars-Sinai Medical Center, UCLA School of Medicine, Los Angeles, CA 90048, USA.
We have studied the in vitro biological activities and mechanisms of action of 1,25-dihydroxyvitamin D3 (1,25D3) and nine potent 1,25D3 analogs on proliferation and differentiation of myeloid leukemia cell lines (HL-60, retinoic acid-resistant HL-60 [RA-res HL-60], NB4 and Kasumi-1). The common novel structural motiff for almost all the analogs included removal of C-19 (19-nor); each also had unsaturation of the side chain. All the compounds were potent; for example, the concentration of analogs producing a 50% clonal inhibition (ED50) ranged between 1 x 10(-9) to 4 x 10(-11) mol/L when using the HL-60 cell line. The most active compound [1, 25(OH)2-16,23E-diene-26-trifluoro-19-nor-cholecalciferol (Ro 25-9716)] had an ED50 of 4 x 10(-11) mol/L; in contrast, the 1,25D3 produced an ED50 of 10(-9) mol/L with the HL-60 target cells. Ro 25-9716 (10(-9) mol/L, 3 days) was a strong inducer of myeloid differentiation because it caused 92% of the HL-60 cells to express CD11b and 75% of these cells to reduce nitroblue tetrazolium (NBT). This compound (10(-8) mol/L, 4 days) also caused HL-60 cells to arrest in the G1 phase of the cell cycle (88% cells in G1 v 48% of the untreated control cells). The p27(kip-1), a cyclin-dependent kinase inhibitor which is important in blocking the cell cycle, was induced more quickly and potently by Ro 25-9716 (10(-7) mol/L, 0 to 5 days) than by 1,25D3, suggesting a possible mechanism by which these analogs inhibit proliferation of leukemic growth. The NB4 promyelocytic leukemia cells cultured with the Ro 25-9716 were also inhibited in their clonal proliferation (ED50, 5 x 10(-11) mol/L) and their expression of CD11b was enhanced (80% positive [10(-9) mol/L, 4 days] v 27% untreated NB4 cells). Moreover, the combination of Ro 25-9716 (10(-9) mol/L) and all-trans retinoic acid (ATRA, 10(-7) mol/L) induced 92% of the NB4 cells to reduce NBT, whereas only 26% of the cells became NBT positive after a similar exposure to the combination of 1,25D3 and ATRA. Surprisingly, Ro 25-9716 also inhibited the clonal growth of poorly differentiated leukemia cell lines (RA-res HL-60 [ED50, 4 x 10(-9) mol/L] and Kasumi-1 [ED50, 5 x 10(-10) mol/L]). For HL-60 cells, Ro 25-9716 markedly decreased the percent of the cells in S phase of the cell cycle and increased the expression of the cyclin-dependent kinase inhibitor, p27(kip-1). In summary, 19-nor vitamin D3 compounds strongly induced differentiation and inhibited clonal proliferation of various myeloid leukemia cell lines, suggesting a therapeutic niche for their use in myeloid leukemia.
138. Leuk Res. 1997 Apr;21(4):321-6.
CB1093, a novel vitamin D analog; effects on differentiation and clonal growth on HL-60 and de novo leukemia cells.
Pakkala I, Savli H, Knuutila S, Binderup L, Pakkala S.
Transplantation Laboratory, University of Helsinki, and Helsinki University Central Hospital, Finland.
We studied the effects of a novel vitamin D analog CB1093, EB1089 (one of the most antileukemic analogs yet) and 1 alpha,25(OH)2D3 both on HL-60 cells and cells from 13 AML patients. Differentiation was measured both by induction of superoxide production and non-specific esterase. Cell proliferation was assessed by colony assay and 3H-thymidine incorporation. The effect on serum calcium was measured in rats. The CB1093 proved to be the most efficient of the analogs tested so far, both in inducing differentiation and in inhibiting proliferation. This, combined with its low hypercalcemic effect shown here, makes it a promising candidate for preclinical animal studies.
139. Blood. 1996 Sep 15;88(6):2201-9.
A new series of vitamin D analogs is highly active for clonal inhibition, differentiation, and induction of WAF1 in myeloid leukemia.
Munker R, Kobayashi T, Elstner E, Norman AW, Uskokovic M, Zhang W, Andreeff M, Koeffler HP.
Division of Hematology/Oncology, Cedars-Sinai Medical Center/UCLA School of Medicine 90048, USA.
The active form of vitamin D3 [1 alpha, 25-dihydroxyvitamin-D3 (1 alpha, 25(OH)2D3)] modulates the proliferation and differentiation of hematopoietic cells. Analogs of 1 alpha, 25(OH)2D3 that have greater potency may have the potential as adjuvant therapy for high-risk patients in remission for acute myelogenous leukemia (AML) and myelodysplastic syndromes. A new generation of 11 analogs of 1 alpha, 25(OH)2D3 has been synthesized, and we examined their effects on the human leukemic cell line HL-60. This cell line provides a sensitive monitor of activity of the 1 alpha, 25(OH)2D3 analogs. All the compounds were potent, producing a 50% clonal inhibition (ED50) in the range of 10(-8) to 10(-11) mol/L; nine of the 11 analogs had ED50s at concentrations that were at least 10-fold lower than those for the parental 1,25(OH)2D3. The most active compound [cmpd LA, (22R)-1 alpha, 25-(OH)2-16,22,23-triene-D3] had an ED50 of 2 x 10(-11) mol/L; it was also tested on clonogenic cells from patients with AML, and it achieved an ED50 of approximately 6 x 10(-11) mol/L, while 1 alpha, 25(OH)2D3 produced an ED50 of approximately 10(-8) mol/L on the same population of cells. Five different cell surface markers were examined on HL-60 cells exposed to the 1 alpha, 25(OH)2D3 analogs: HLA-DR and CD11b were induced by all of the compounds; CD13 was induced by six of the 12 compounds, including 1,25(OH)2D3; CD14 was strongly induced by all compounds; and CD38 was induced rather weakly by nine of 12 analogs. WAF1/CIP1/p21, a cyclin-dependent kinase inhibitor (CDKI), which is important in blocking the cell cycle, was examined by Western blot and was found to be induced by all of the compounds, suggesting a possible mechanism by which these analogs inhibit leukemic growth. The induction of WAF1 occurred at concentrations of vitamin D analogs as low as 10(-10) mol/L. This structure-function study showed that a new series of 1 alpha, 25(OH)2D3 analogs was active in clonal inhibition, as well as induction of differentiation and WAF1 expression of HL-60 cells. The key structural motifs included C-16 double bond, double and/or triple bonds in the side chain, lengthening of the side chain, 20-epi-conformation of the side chain, replacement of six hydrogens at the end of the side chain with fluorines, and the removal of C-19. Consideration should be given to further in vivo testing of toxicity and efficacy to move toward a clinical trial, especially in a setting of minimal residual disease.
140. Exp Cell Res. 1996 May 25;225(1):143-50.
Differential regulation of vitamin D receptors in clonal populations of a chronic myelogenous leukemia cell line.
Iwata K, Kouttab N, Ogata H, Morgan JW, Maizel AL, Lasky SR.
Roger Williams Medical Center, Experimental Pathology Section, Department of Pathology and Laboratory, Brown University School of Medicine, Providence, RI 02908, USA. stephen_lasky@brown.edu
RWLeu4 is a chronic myelogenous leukemia cell line that is sensitive to the antiproliferative and differentiation-inducing actions of 1alpha,25(OH)2-vitamin D3 (VD3). The JMRD3 cell line is a VD3-resistant variant of RWLeu4 that was selected by continuous passage of RWLeu4 in the presence of VD3. The isolation of a spontaneous VD3-resistant variant suggests that phenotypically different cells exist within the RWLeu4 cell population. Therefore, single-cell clones of RWLeu4 cells were isolated and characterized. Four clonal cell populations that fall into three groups differing in response to the antiproliferative and differentiation-inducing actions of VD3 were examined. Surprisingly, the extent of response of the clones to VD3 does not show a correlation with the basal level of the vitamin D receptor (VDR). RWLeu4-3 and RWLeu4-4 are the clones most sensitive to the antiproliferative actions of VD3 (ED50 approximately equal to 1 nM); however, RWLeu4-3 expresses basal levels of VDRs similar to those found in the parental cells and the RWLeu4-2 clone, while in RWLeu4-4, VD3 binding and VDR protein are below the limits of detection. Furthermore, RWLeu4-10 expresses the highest basal level of VDR protein but is relatively resistant to the antiproliferative actions of VD3 (ED50 > or = 30 nM). Like JMRD3, RWLeu4-10 is still capable of differentiating in response to VD3, as judged by the induction of biochemical processes and cell-surface antigen expression. Although VD3 treatment increases VDR protein levels and DNA-binding activity in all clones, altered DNA-protein complexes are detected in RWLeu4-4. Our results suggest that sensitivity to the antiproliferative and differentiation-inducing actions of VD3 is not dependent solely upon the level of VDR expressed, but may also require posttranslational modification of the VDR or complex interactions with other nuclear transcription factors.
141. Cancer Lett. 1995 Apr 14;90(2):225-30.
Induction of differentiation in murine erythroleukemia cells by 1 alpha,25-dihydroxy vitamin D3.
Radhika S, Choudhary SK, Garg LC, Dixit A.
Department of Zoology, University of Delhi, India.
The Friend murine erythroleukemia (MEL) cells can be stimulated to differentiate in response to a variety of chemical inducing agents. In the present study, the effect of 1 alpha,25-dihydroxyvitamin D3 on differentiation of MEL cells was investigated. Vitamin D3 induced differentiation of MEL cells in culture as determined by elevated hemoglobin content, a rise in the number of benzidine-positive cells and increase in acetylcholine esterase activity. The optimum concentration of the vitamin required to induce differentiation of MEL cells was found to be 750 nM. The pattern of induction of differentiation was similar to that observed with DMSO and the induction of differentiation by vitamin D3 was inhibited by dexamethasone.
142. Leuk Res. 1994 Jun;18(6):453-63.
1,25(OH)2-16ene-vitamin D3 is a potent antileukemic agent with low potential to cause hypercalcemia.
Jung SJ, Lee YY, Pakkala S, de Vos S, Elstner E, Norman AW, Green J, Uskokovic M, Koeffler HP.
Pusan Women's Junior College, Korea.
Compounds that induce cancer cells to differentiate are clinically effective for several types of malignancies. The 1,25-dihydroxyvitamin D3[1,25(OH)2D3(C)] induces leukemic cells, including HL-60, to differentiate and/or no longer proliferate, but it causes hypercalcemia. Development of vitamin D analogs that are more potent in their abilities to affect leukemic cells without causing greater hypercalcemia, may be useful therapeutically. A novel analog [1,25(OH)2-16ene-D3(HM)] has a double bond between C-16 and C-17; it appears to be an extremely effective antileukemic agent with the same or fewer effects on serum calciums. We define the potency of this compound and compare it with seven, previously reported, potent analogs of 1,25(OH)2D3. HM inhibited clonal growth of HL-60 cells by 50% at 1.5 x 10(-11) M. This was about equipotent to 1,25(OH)2-16ene-23yne-D3(V), about 100-fold more potent than many of the other analogs, and 1000-fold more potent than 1,25(OH)2D3. The rank order of leukemic inhibitory activity was: 1,25(OH)2-16ene-D3(HM) > or = 1,25(OH)2- 16ene-23yne-D3(V) > 1,25(OH)2-23ene-D3(EX) = 1,24(OH)2-22ene-24-cyclopropyl-D3(BT) = 22-oxa- 1,25(OH)2D3(EU) = 1,25(OH)2-24-homo-D3(ER) > 1,25(OH)2D3(C) > 1,25(OH)2-24- dihomo-D3(ES). The rank order of their effects on induction of differentiation of HL-60 cells, as measured by superoxide production and nonspecific esterase activity, was similar to their antiproliferative activities. In contrast, each analog slightly stimulated proliferation of normal human myeloid clonal growth. Serum calcium levels were the same or slightly less when either 1,25(OH)2-16ene-D3(HM) or 1,25(OH)2D3 (0.0625, 0.125, or 0.25 microgram) was given intraperitoneally to mice for 5 weeks. HM bound to 1,25(OH)2D3 receptors about 1.5-fold more avidly than 1,25(OH)2D3. In fact, this vitamin D3 appears to be the most avid binder to 1,25(OH)2D3 receptors that has been identified to date. In contrast, HM had a greater than 50-fold lower affinity for the D-binding proteins as compared with 1,25(OH)2D3, thus increasing the availability of the compound for target tissues. Further differentiation experiments showed that HM was more potent than 1,25(OH)2D3 in the presence of serum, but was equipotent in serum-free conditions. Taken together, our experiments suggest that 1,25(OH)2-16ene-D3(HM) may be more potent than 1,25(OH)2D3(C) because of its higher affinity to the 1,25(OH)2D3 receptors and its low affinity to the D-binding protein present in serum. HM is an ideal compound for clinical studies including patients with preleukemia and other neoplasia, as well as several skin disorders, such as psoriasis.
143. J Biol Chem. 1988 Nov 5;263(31):16039-44.
Ca2+ priming during vitamin D-induced monocytic differentiation of a human leukemia cell line.
Hruska KA, Bar-Shavit Z, Malone JD, Teitelbaum S.
Department of Medicine, Jewish Hospital, Washington University Medical Center, St. Louis, Missouri 63110.
1,25-Dihydroxyvitamin D3 (1,25-(OH)2D3) induces monocytic differentiation of the human promyelocytic leukemia line, HL-60, and enhances Ca2+ transport in target cells of the mineral metabolism system. Hence, we determined whether the steroid's maturational effect on HL-60 involves alterations of intracellular calcium [( Ca2+]i). We found that, as detected by indo-1 fluorescence, [Ca2+]i increases in a slow tonic manner from 99 +/- 11 nM in virgin HL-60 to 182 +/- 19 nM (p less than 0.001) in those treated with 1,25-(OH)2D3 for 24 h. The first apparent rise in [Ca2+]i occurs at between 6 and 12 h and parallels expression of alpha-thrombin and N-formyl-methionyl-leucyl-phenylalanine (fMLP) receptors. This increase in [Ca2+]i is derived from extracellular calcium as its reduction abolishes the effect. The increase in [Ca2+]i is associated with an increase in inositol trisphosphate-stimulated Ca2+ flux from intracellular stores. Interestingly, 1,25-(OH)2D3-mediated HL-60 differentiation as manifest by expression of the macrophage-specific antigen, 63D3, is not blocked by low extracellular calcium. In contrast, the fMLP-induced superoxide ion generation is diminished if the increase in [Ca2+]i is prevented. Furthermore, fMLP-stimulated signal transduction is also reduced by limiting the stimulation of [Ca2+]i during 1,25-(OH)2D3 treatment. Thus, although differentiation of HL-60 to the monocytic phenotype by 1,25-(OH)2D3 is Ca2+-independent, expression of response to regulatory stimuli requires priming of cellular Ca2+ stores. The latter appears to be induced by 1,25-(OH)2D3 via stimulated Ca2+ entry through the plasma membrane.
144. Arch Biochem Biophys. 1987 Nov 1;258(2):421-5.
Biological activity of fluorinated vitamin D analogs at C-26 and C-27 on human promyelocytic leukemia cells, HL-60.
Inaba M, Okuno S, Nishizawa Y, Yukioka K, Otani S, Matsui-Yuasa I, Morisawa S, DeLuca HF, Morii H.
Second Department of Internal Medicine, Osaka City University Medical School, Japan.
Vitamin D compounds added to the culture medium induce HL-60 cells to differentiate into macrophage/monocytes via a receptor mechanism. This system provides a biologically relevant assay for the study of biopotency of vitamin D analogs. Using this system, the biological activity of various fluorinated derivatives of vitamin D3 was compared with that of 1,25-dihydroxyvitamin D3 (1,25-(OH)2D3). As assessed by cell morphology, nitroblue tetrazolium reduction and nonspecific esterase activity, 26,26,26,27,27,27-hexafluoro-1,25-dihydroxyvitamin D3 (26,27-F6-1,25-(OH)2D3) and 26,26,26,27,27,27-hexafluoro-1,24-dihydroxyvitamin D3 (26,27-F6-1,24-(OH)2D3) were about 10 times as potent as 1,25-(OH)2D3 in suppressing HL-60 cell proliferation and inducing cell differentiation. The biological activity of 26,26,26,27,27,27-hexafluoro-1-hydroxyvitamin D3 (26,27-F6-1-OH-D3) was equal to that of 1,25-(OH)2D3 in this system. 1,25-(OH)2D3 and its fluorinated analogs exerted their effects on HL-60 cells in a dose-dependent manner. HL-60 cells have a specific receptor for 1,25-(OH)2D3 with an apparent Kd of 0.25 nM, identical with that of chick intestinal receptor. While the binding affinities of 26,27-F6-1,25-(OH)2D3 and 26,27-F6-1,24-(OH)2D3 for chick intestinal receptor were lower than that of 1,25-(OH)2D3 by factors of 3 and 1.5, respectively, they were as competent as 1,25-(OH)2D3 in binding to HL-60 cell receptor. The ability of 26,27-F6-1-OH-D3 to compete for receptor protein from HL-60 cells and chick intestine was about 1/70 that of 1,25-(OH)2D3. These results indicate that trifluorination of carbons 26 and 27 of vitamin D3 can markedly enhance the effect on HL-60 cells.
145. Endocrinology. 1986 Feb;118(2):679-86.
Reversibility of vitamin D-induced human leukemia cell-line maturation.
Bar-Shavit Z, Kahn AJ, Stone KR, Trial J, Hilliard T, Reitsma PH, Teitelbaum SL.
HL-60 cells are induced to differentiate along a monocytic pathway by the active metabolites of vitamin D3, e.g. 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. All such differentiated cells share a number of features in common but are heterogeneous in their ability to adhere to solid substrates and to resorb devitalized bone matrix. Here, we show that, in addition, as compared to the nonadherent, adherent cells are smaller, less likely to be in the S phase, more enriched in the human monocyte-specific cell surface antigen, 63D3, and contain less cmyc messenger RNA (mRNA). In addition, we document that removal of the hormone leads to dedifferentiation. For these susceptible mononuclear cells, removal of 1,25-(OH)2D3 results in a reversion to a more myeloblastic phenotype, renewed cell proliferation, and the rapid appearance of elevated levels of cmyc mRNA. Finally, we report that the cells that do not revert upon 1,25-(OH)2D3 removal are those that became multinucleated during treatment.
146. J Med Chem. 1985 Sep;28(9):1148-53.
Syntheses and differentiating action of vitamin D endoperoxides. Singlet oxygen adducts of vitamin D derivatives in human myeloid leukemia cells (HL-60).
Yamada S, Yamamoto K, Naito H, Suzuki T, Ohmori M, Takayama H, Shiina Y, Miyaura C, Tanaka H, Abe E, et al.
Singlet oxygen adducts of various vitamin D derivatives, 6,19-dihydro-6,19-epidioxyvitamin D (vitamin D endoperoxides, 2 and 2'), were chemically synthesized, and their biological activity in inducing differentiation of a human myeloid leukemia cell line (HL-60 cells) was examined. The potency of the endoperoxides derived from vitamin D derivatives possessing the 1 alpha-hydroxyl group such as 1 alpha, 25-dihydroxyvitamin D3 endoperoxides (2b and 2b') was markedly (10(-2)) diminished relative to the respective parent vitamin D compounds. In contrast, 25-hydroxyvitamin D3 endoperoxides [25-(OH)D3 endoperoxides, 2a and 2a'] and their analogues fluorinated at the 24- or 26- and 27-positions were 2.5-10 times more potent than 25-hydroxyvitamin D3 (1a) in spite of the absence of the conjugated triene structure typical of vitamin D compounds. The potency of these vitamin D endoperoxides (2 and 2'), especially those lacking the 1 alpha-hydroxyl group, in inducing differentiation of HL-60 cells was not correlated with their activity in binding to the cytosol receptor for 1 alpha, 25-dihydroxyvitamin D3 (1b). The binding efficiency to the receptor was relatively lower than the differentiating activity. To examine the action of vitamin D endoperoxides, carbon analogues of 25-(OH)D3 endoperoxides, two C-6 epimers of 25-hydroxy-6,19-dihydro-6,19-ethanovitamin D3 (6 and 6'), were synthesized. The carbon analogues (6 and 6') had no potential to induce differentiation of HL-60 cells. These results suggest that vitamin D endoperoxides (2 and 2') express their biological activity probably after being converted to some other compounds.
Neuroblastoma
147. Biochem Pharmacol. 2003 Jun 15;65(12):1943-55.
Effect of 20-epi-1alpha,25-dihydroxyvitamin D3 on the proliferation of human neuroblastoma: role of cell cycle regulators and the Myc-Id2 pathway.
Gumireddy K, Ikegaki N, Phillips PC, Sutton LN, Reddy CD.
Department of Pediatrics, Brown University School of Medicine, Providence, RI 02905, USA.
The antiproliferative effects of 1alpha,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)] and its epimer, 20-epi-1alpha,25-dihydroxyvitamin D(3) [20-epi-1,25(OH)(2)D(3)], in six human neuroblastoma (NB) cell lines (SH-SY5Y, NB69, SK-N-AS, IMR5, CHP134, and NGP) were investigated. We determined the ability of 1,25(OH)(2)D(3) and 20-epi-1,25(OH)(2)D(3) to influence cell viability by the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay, cell proliferation by bromodeoxyuridine (BrdU) incorporation, and their antineoplastic effect on colony formation in a soft agar assay. A concentration-dependent decrease in cell viability, inhibition of DNA synthesis, and suppression of clonal proliferation was observed with both compounds. 20-epi-1,25(OH)(2)D(3) was more potent in suppressing the proliferation of all six NB cell lines. To understand the mechanisms of action, we examined the effect of 20-epi-1,25(OH)(2)D(3) on the Myc-Id2 cell proliferative network and also on key regulators of the cell cycle. For the first time, we show that 20-epi-1,25(OH)(2)D(3) down-regulated Myc and Id2 expression by western blot analysis. Semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR) analysis revealed that 20-epi-1,25(OH)(2)D(3) induced the expression of retinoic acid receptor-beta and p21(Cip1), and down-regulated the expression of cyclin D1 resulting in decreased phosphorylation of retinoblastoma protein (pRB). In sum, we show that 20-epi-1,25(OH)(2)D(3) exerts strong antiproliferative effects by regulating key growth control networks (Myc-Id2-pRB) in NB cells.
148. Brain Res. 2002 Aug 2;945(2):181-90.
Calretinin and calbindin D-28k, but not parvalbumin protect against glutamate-induced delayed excitotoxicity in transfected N18-RE 105 neuroblastoma-retina hybrid cells.
D'Orlando C, Celio MR, Schwaller B.
Institute of Histology and General Embryology, University of Fribourg, CH-1705 Fribourg, Switzerland.
Excitotoxic effects leading to neuronal cell degeneration are often accompanied by a prolonged increase in the intracellular level of Ca(2+) ions and L-glutamate-induced toxicity is assumed to be mediated via a Ca(2+)-dependent mechanism. Due to their buffering properties, EF-hand Ca(2+)-binding proteins (CaBPs) can affect intracellular Ca(2+) homeostasis and a neuroprotective role has been attributed to some of the family members including calretinin, calbindin D-28k and parvalbumin. We have stably transfected N18-RE 105 neuroblastoma-retina hybrid cells with the cDNAs for the three CaBPs and investigated the effect of these proteins on the L-glutamate-induced, Ca(2+)-dependent cytotoxicity. Several clones for each CaBP were selected according to immunocytochemical staining and characterization of the overexpressed proteins by Western blot analysis. In calretinin- and parvalbumin-expressing clones, expression levels were quantitatively determined by ELISA techniques. Cytotoxicity of transfected clones was quantified by measurement of the activity of lactate dehydrogenase (LDH) that was released into the medium after L-glutamate (10 mM) exposure as a result of necrotic cell death. In untransfected and parvalbumin-transfected cells, LDH released into the medium progressively increased (starting from the 20th hour) reaching maximum levels after 28-30 h of glutamate application. In contrast, LDH release in both, calretinin and calbindin D-28k-transfected clones, was not significantly different from unstimulated transfected or untransfected cells over the same period of time. The results indicate that the 'fast' Ca(2+)-buffers calretinin and calbindin D-28k, but not the 'slow' buffer parvalbumin can protect N18-RE 105 cells from this type of Ca(2+)-dependent L-glutamate-induced delayed cytotoxicity.
149. J Steroid Biochem Mol Biol. 2001 Jun;77(4-5):213-22.
Synergistic anti-proliferative effects of vitamin D derivatives and 9-cis retinoic acid in SH-SY5Y human neuroblastoma cells.
Stio M, Celli A, Treves C.
Department of Biochemical Sciences, University of Florence, Viale Morgagni 50, 50134 Florence, Italy.
This study examines the effect of 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], 24,25-dihydroxyvitamin D(3) [24,25(OH)(2)D(3)], two vitamin D analogues (KH 1060 and EB 1089, which are 20-epi-22-oxa and 22,24-diene-analogues, respectively), 9-cis retinoic acid and all-trans retinoic acid on proliferation of SH-SY5Y human neuroblastoma cells, after treatment for 7 days. Cell number did not change when the cells were incubated with 1, 10 or 100 nM 1,25(OH)(2)D(3) or its derivatives, but significantly decreased in the presence of the two retinoids (0.001--10 microM final concentration). A synergistic inhibition was observed, when SH-SY5Y cells were treated combining 0.1 microM 9-cis retinoic acid and 10 nM 1,25(OH)(2)D(3) or 10 nM KH 1060, and 1 microM 9-cis retinoic acid and 10 nM 1,25(OH)(2)D(3) or 10 nM EB 1089. Acetylcholinesterase activity showed a significant increase, in comparison with controls, after treatment of the cells for 7 days with 0.1 or 1 microM 9-cis retinoic acid, alone or combined with 10 nM 1,25(OH)(2)D(3) or 10 nM KH 1060 or 10 nM EB 1089. This increase was synergistic, combining 1 microM 9-cis retinoic acid and 10 nM 1,25(OH)(2)D(3) or EB 1089. The levels of the c-myc encoded protein remarkably decreased after treatment of SH-SY5Y cells for 1, 3, 7 days with 0.1 and 1 microM 9-cis retinoic acid, alone or combined with 10 nM 1,25(OH)(2)D(3) or 10 nM KH 1060 or 10 nM EB 1089. In particular, the association of 1 microM 9-cis retinoic acid and 10 nM 1,25(OH)(2)D(3) or 10 nM EB 1089 resulted in a synergistic c-myc inhibition, in comparison with that obtained in the presence of the retinoid alone. These findings may have therapeutic implications in human neuroblastoma.
150. Biochem Biophys Res Commun. 1997 Jun 9;235(1):15-8.
1,25-dihydroxyvitamin D3 regulates the expression of N-myc, c-myc, protein kinase C, and transforming growth factor-beta2 in neuroblastoma cells.
Veenstra TD, Windebank AJ, Kumar R.
Nephrology Research Unit, Mayo Clinic Foundation, Rochester, Minnesota 55905, USA.
1alpha,25-Dihydroxyvitamin D3 (1,25(OH)2D3) alters the proliferation of neuroblastoma cells in culture in part via a nerve growth factor (NGF)-mediated pathway. This suggests that factors other than NGF also play a role in the growth arrest induced by 1,25(OH)2D3. To more fully characterize the effect of 1,25(OH)2D3 on neuroblastoma cells, we treated the cells with 10(-8) M 1,25(OH)2D3 and examined the cells for changes in the expression of N-myc, c-myc, transforming growth factor-beta2 (TGF-beta2), and protein kinase C (PKC) activity. Our results show that 1,25(OH)2D3 causes a decrease in the expression of N-myc and c-myc, as well as a two-fold increase in total PKC activity and a dose-dependent increase in TGF-beta2 expression. These results show that 1,25(OH)2D3 regulates the expression of growth-regulatory factors other than NGF in neuroblastoma cells and that 1,25(OH)2D3 influences the growth of neural cells via multiple growth regulatory pathways.
151. Brain Res Dev Brain Res. 1997 Mar 17;99(1):53-60. (Animal Study)
Effects of 1,25-dihydroxyvitamin D3 on growth of mouse neuroblastoma cells.
Veenstra TD, Londowski JM, Windebank AJ, Brimijoin S, Kumar R.
Nephrology Research Unit, Mayo Clinic Foundation, Rochester, MN 55905, USA.
Epitopes of the 1,25-dihydroxyvitamin D(1,25(OH)2D3) receptor have been shown in developing dorsal root ganglia in fetal mice, as well as in cells maintained in culture [Johnson, J.A., Grande, J.P., Windebank, A.J. and Kumar, R., 1,25-Dihydroxyvitamin D3 receptors in developing dorsal root ganglia of fetal rats, Dev. Brain Res., 92 (1996) 120-124]. To investigate a possible role for 1,25(OH)2D3 in neural cell growth and development, a murine neuroblastoma cell line that expresses 1,25(OH)2D3 receptors, was treated with 1,25(OH)2D3. Treatment with 1,25(OH)2D3 resulted in a decrease in cell proliferation, a change in cell morphology, and the expression of protein markers of mature neuronal cells. The decrease in cell proliferation was accompanied by an increase in the expression of nerve growth factor (NGF). Anti-NGF monoclonal antibody added to the growth medium blocked the decrease in cell proliferation caused by 1,25(OH)2D3 treatment. Our results show that the sterol hormone 1,25(OH)2D3, causes a decrease in the proliferation of mouse neuroblastoma cells through alterations in the expression of NGF.
152. Clin Exp Metastasis. 1996 May;14(3):239-45.
Vitamin D3 analogs inhibit growth and induce differentiation in LA-N-5 human neuroblastoma cells.
Moore TB, Koeffler HP, Yamashiro JM, Wada RK.
Department of Pediatrics, Division of Hematology/Oncology, UCLA School of Medicine, Los Angeles, CA 90024, USA.
The physiologically active metabolite of vitamin D3, 1,25-dihydroxycholecalciferol (D3), plays an important role in embryonic development and cell differentiation. Previously, we have demonstrated that D3 significantly induces differentiation and inhibits growth of LA-N-5 human neuroblastoma cells at concentrations of 24 nm and higher. In this study, we compared two D3 analogs, 20-epi-22oxa-25a,26a,27a-tri-homo-1,25-D3 (KH 1060) and 1,25-dihydroxy-22,24-diene, 24,26,27-trihomo (EB 1089), with D3 with respect to their effects on differentiation and growth inhibition. We report an inhibition of growth by 45-55% in cells treated with 0.24 nm EB 1089 and 0.24 nM KH 1060, similar to that seen in cells treated with 24 nM D3. At these concentrations, both EB 1089 and KH 1060 stimulate the differentiation of LA-N-5 neuroblastoma cells as shown by increased neurite outgrowth, decreased N-myc expression and decreased invasiveness in vitro. An increase in acetylcholinesterase activity, a functional measure of differentiation, was also exhibited. Previous reports have shown that treatment doses needed to achieve 24 nM serum concentrations of D3 in patients would result in hypercalcemia. EB 1089 and KH 1060 can cause the same in vitro effects on LA-N-5 human neuroblastoma cells at 1/100 of the concentration required of D3. These data suggest a potential clinical efficacy of EB 1089 and KH 1060 as biological response modifiers.
153. J Pediatr Hematol Oncol. 1995 Nov;17(4):311-7.
Differentiating effects of 1,25-dihydroxycholecalciferol (D3) on LA-N-5 human neuroblastoma cells and its synergy with retinoic acid.
Moore TB, Sidell N, Chow VJ, Medzoyan RH, Huang JI, Yamashiro JM, Wada RK.
Division of Pediatric Hematology/Oncology, UCLA School of Medicine 90095, USA.
PURPOSE: 1,25-Dihydroxycholecalciferol (D3) plays an important role in embryonic development and cell differentiation. It has previously been reported to decrease c-myc expression by HL-60 cells and downregulate c-myc expression by breast and ovarian cancer cells. We report the results of our investigations into the differentiating effects of D3 on LA-N-5 human neuroblastoma cells. METHODS: LA-N-5 human neuroblastoma cell line was treated with D3, retinoic acid (RA), D3 and RA, or solvent control. Growth inhibitory effects, neurite extension, acetylcholinesterase activity, invasiveness, motility, and N-myc protein expression were examined following treatment. RESULTS: Growth inhibition was observed at concentrations of > 24 nM. D3 stimulated the differentiation of LA-N-5 cells as demonstrated by increased neurite outgrowth, increased acetylcholinesterase activity, and decreased invasiveness. A decrease in N-myc expression was observed in immunostained cells treated with either agent alone, with a more profound effect appreciated with the combination. CONCLUSION: Vitamin D3 decreases N-myc expression in LA-N-5 human neuroblastoma cells, with extended treatment causing growth inhibition and differentiation. When used in combination with RA, these effects are more profound than with either agent alone. The therapeutic use of differentiating agent combinations such as D3 and RA may provide a relatively nontoxic means of treating susceptible tumor types.
154. Pediatr Hematol Oncol. 1994 Mar-Apr;11(2):173-9.
Effects of 1,25-dihydroxyvitamin D3 and retinoic acid on the proliferation and cell cycle phase distribution of neuroblastoma SK-N-SH cells.
Goplen DP, Brackman D, Aksnes L.
Institute of Pediatrics, University of Bergen, Norway.
The hormone 1,25-(OH)2D3 has been shown to modulate cell proliferation and induce differentiation in several normal and malignant cell lines. In this work, we examined the effect of the hormone on the neuroblastoma SK-N-SH cell line. The steroid did not influence cell growth and cell cycle distribution, while retinoic acid inhibited proliferation and induced an accumulation of the cells in the G0/G1 phase of the cell cycle. 1,25-(OH)2D3 did not alter cell morphology. The activities of the 1-alpha- and 24-hydroxylases were low and not regulated by the hormone. The level of the total 1,25-(OH)2D3 receptor was low. We conclude that the lack of effect of 1,25-(OH)2D3 on the SK-N-SH cell line is related to the low level of the 1,25-(OH)2D3 receptor.
Pancreatic Cancer
155. Endocrinology. 2003 May;144(5):1832-41.
Molecular pathways involved in the antineoplastic effects of calcitriol on insulinoma cells.
Galbiati F, Polastri L, Thorens B, Dupraz P, Fiorina P, Cavallaro U, Christofori G, Davalli AM.
Division of General Medicine, Unit of Endocrinology and Metabolic Disease, San Raffaele Scientific Institute, 20132 Milan, Italy.
We have previously reported that in tumorigenic pancreatic beta-cells, calcitriol exerts a potent antitumorigenic effect by inducing apoptosis, cell growth inhibition, and reduction of solid beta-cell tumors. Here we have studied the molecular pathways involved in the antineoplastic activity of calcitriol on mouse insulinoma beta TC(3) cells, mouse insulinoma beta TC expressing or not expressing the oncogene p53, and beta TC-tet cells overexpressing or not the antiapoptotic gene Bcl2. Our results indicate that calcitriol-induced apoptosis was dependent on the function of p53 and was associated with a biphasic increase in protein levels of transcription factor nuclear factor-kappa B. Calcitriol decreased cell viability by about 40% in p53-retaining beta TC and in beta TC(3) cells; in contrast, beta TC p53(-/-) cells were only minimally affected. Calcitriol-induced cell death was regulated by members of the Bcl-2 family of apoptosis regulatory proteins, as shown by calcitriol-induced up-regulation of proapoptotic Bax and Bak and the lack of calcitriol-induced cytotoxicity in Bcl-2-overexpressing insulinoma cells. Moreover, calcitriol-mediated arrest of beta TC(3) cells in the G(1) phase of the cell cycle was associated with the abnormal expression of p21 and G(2)/M-specific cyclin B2 genes and involved the DNA damage-inducible factor GADD45. Finally, in beta TC(3) cells, calcitriol modulated the expression of IGF-I and IGF-II genes. In conclusion, these findings contribute to the understanding of the antitumorigenic effects of calcitriol on tumorigenic pancreatic beta-cells and further support the rationale of its utilization in the treatment of patients with malignant insulinomas.
156. Pancreatology. 2003;3(1):41-6.
Vitamin d receptor is expressed in pancreatic cancer cells and a vitamin d(3) analogue decreases cell number.
Albrechtsson E, Jonsson T, Moller S, Hoglund M, Ohlsson B, Axelson J.
Department of Surgery, Lund University, Lund, Sweden.
BACKGROUND AND AIM: The vitamin D-receptor (VDR) has been detected in both normal and malignant cells of different tissues. Treatment with vitamin D(3) has been suggested as a possible therapy in malignant diseases such as pancreatic cancer. Synthetic analogues of vitamin D(3) have a less hypercalcemic effect than native vitamin D(3). The aim was to study the expression of the VDR in human pancreatic cancers and to study the in vitro effect of an analogue to vitamin D(3) on cell lines established from these cancers. METHODS: The pancreatic cancer cell lines were established from primary cultures with only cancer cells. A probe specific for the human VDR was used. After reverse-transcriptase PCR and Northern blotting, the expression of the VDR in normal pancreas and in pancreatic cancers was compared. The cell lines were incubated with EB 1089, a synthetic analogue vitamin of D(3), in dose-response studies. The cell number was measured by the XTT colorimetric method. RESULTS: The VDR was expressed in all cancers and in six of the cell lines the expression was increased more than 3-fold compared to normal pancreas. All cell lines developed from human pancreatic cancers responded with a decreased cell number to the vitamin D(3) analogue at concentrations of 10(-5) M or higher. CONCLUSION: The VDR was expressed in all pancreatic cancers studied. Cell lines derived from these cancers responded with a decrease in cell number to high concentrations of a vitamin D(3) analogue. These results, and the doses to use, have to be confirmed with in vivo studies. Copyright 2003 S. Karger AG, Basel and IAP
157. Endocrinology. 2002 Oct;143(10):4018-30.
Antitumorigenic and antiinsulinogenic effects of calcitriol on insulinoma cells and solid beta-cell tumors.
Galbiati F, Polastri L, Gregori S, Freschi M, Casorati M, Cavallaro U, Fiorina P, Bertuzzi F, Zerbi A, Pozza G, Adorini L, Folli F, Christofori G, Davalli AM.
Department of Medicine, San Raffaele Scientific Institute, Milan 20132, Italy.
Malignant insulinoma is a rare form of cancer with a poor prognosis because of metastatic dissemination and untreatable hypoglycemia. Effective chemotherapy of patients who are not cured by surgery is needed. Calcitriol has known anticancer properties on different neoplastic cell lines, but no data are available regarding its activity on tumorigenic pancreatic beta-cells. We analyzed the in vitro effects of calcitriol on the murine insulinoma cell line betaTC(3) and primary cultures of human isolated islets and benign insulinoma. The effect of in vivo calcitriol administration on insulinoma of recombinant insulin/Simian virus 40 oncogene-expressing transgenic mice was also investigated. In betaTC(3), calcitriol induced growth inhibition; apoptosis; down-regulation of insulin gene expression; and nongenomic activation of the MAPK pathway. MAPK kinase inhibitor (UO126) and staurosporine reduced calcitriol-mediated betaTC(3) death, and down-regulation of insulin gene transcription was prevented by staurosporine but not UO126. Calcitriol significantly decreased insulin release and mRNA levels of human islets and insulinoma cells. Finally, recombinant insulin/Simian virus 40 oncogene-expressing transgenic mice treated with calcitriol showed reduced insulinoma volumes because of increased apoptosis of adenomatous cells. Together, these findings provide the rationale for testing the efficacy of calcitriol in the treatment of patients with solid beta-cell tumors.
158. Br J Cancer. 2000 Jul;83(2):239-45.
Differential and antagonistic effects of 9-cis-retinoic acid and vitamin D analogues on pancreatic cancer cells in vitro.
Pettersson F, Colston KW, Dalgleish AG.
Department of Oncology, Gastroenterology, Endocrinology and Metabolism, St George's Hospital Medical School, London, UK.
Retinoids and vitamin D are known to exert important anti-tumour effects in a variety of cell types. In this study the effects of 9-cis-retinoic acid (9cRA) the vitamin D analogues EB1089 and CB1093 on three pancreatic adenocarcinoma cell lines were investigated. All compounds caused inhibition of in vitro growth but the vitamin D analogues were generally the more potent growth inhibitors. They were also more effective on their own than in combination with 9cRA. Growth arrest correlated with an increased proportion of cells in the G0/G1 phase. Apoptosis was induced in the three cell lines by 9cRA, whereas neither EB1089 nor CB1093 had this effect. Furthermore, addition of EB1089 or CB1093 together with 9cRA resulted in significantly reduced apoptosis. Our results show that retinoic acids as well as vitamin D analogues have inhibitory effects on pancreatic tumour cells but different and antagonistic mechanisms seem to be employed.
159. Br J Cancer. 1997;76(8):1017-20. (Animal Study)
Vitamin D receptors and anti-proliferative effects of vitamin D derivatives in human pancreatic carcinoma cells in vivo and in vitro.
Colston KW, James SY, Ofori-Kuragu EA, Binderup L, Grant AG.
Division of Gastroenterology, Endocrinology and Metabolism, St George's Hospital Medical School, London, UK.
The GER human pancreatic carcinoma cell line possesses receptors for 1,25-dihydroxyvitamin D3. We report that the vitamin D analogue EB 1089 inhibits the growth of these cells in vitro and when grown as tumour xenografts in immunodeficient mice. Tumour-bearing mice were given EB 1089 at a dose of 5 microg kg(-1) body weight i.p. thrice weekly for 4-6 weeks. Tumour growth was significantly inhibited in treated animals compared with controls in the absence of hypercalcaemia. These findings may have therapeutic implications in pancreatic cancer.
160. Br J Cancer. 1997;76(7):884-9.
Vitamin D analogues up-regulate p21 and p27 during growth inhibition of pancreatic cancer cell lines.
Kawa S, Nikaido T, Aoki Y, Zhai Y, Kumagai T, Furihata K, Fujii S, Kiyosawa K.
The Second Department of Internal Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
To obtain information regarding the growth-inhibitory effect of 1,25-dihydroxyvitamin D3 and its non-calcaemic analogue 22-oxa-1,25-dihydroxyvitamin D3 on pancreatic cancer cell lines, differences in the effects of G1-phase cell cycle-regulating factors were studied in vitamin D-responsive and non-responsive cell lines. Levels of expression of cyclins (D1, E and A), cyclin-dependent kinases (2 and 4) and cyclin-dependent kinase inhibitors (p21 and p27) were analysed by Western blotting after treatment with these compounds. In the responsive cells (BxPC-3, Hs 700T and SUP-1), our observations were: (1) marked up-regulation of p21 and p27 after 24 h treatment with 10(-7) mol l(-1) 1,25-dihydroxyvitamin D3 and 22-oxa-1,25-dihydroxyvitamin D3; and (2) marked down-regulation of cyclins, cyclin-dependent kinases and cyclin-dependent kinase inhibitors after 7 days' treatment. In non-responsive cells (Hs 766T and Capan-1), no such changes were observed. In conclusion, vitamin D analogues up-regulate p21 and p27 as an early event, which in turn could block the G1/S transition and induce growth inhibition in responsive cells.
161. Gastroenterology. 1996 May;110(5):1605-13.
Inhibitory effect of 220-oxa-1,25-dihydroxyvitamin D3 on the proliferation of pancreatic cancer cell lines.
Kawa S, Yoshizawa K, Tokoo M, Imai H, Oguchi H, Kiyosawa K, Homma T, Nikaido T, Furihata K.
Second Department of Internal Medicine, Shinshu University, School of Medicine, Matsumoto, Japan.
BACKGROUND & AIMS: Effective chemotherapy for pancreatic cancer is urgently needed. The aim of this study was to compare the anti-proliferative activity of a new vitamin D3 analogue, 22-oxa-1,25-dihydroxyvitamin D3 (22-oxa-calcitriol), on pancreatic cancer cells lines with that of 1,25-dihydroxyvitamin D3 (calcitriol) with analysis of vitamin D receptor status. METHODS: Antiproliferative effects of both agents were compared using the 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide method and by measuring the tumor size of xenograft inoculated into athymic mice. Vitamin D receptor contents by Scatchard analysis and mutational analysis of receptor complementary DNA were performed. RESULTS: In vitro, 22-oxa-calcitriol and calcitriol markedly inhibited the proliferation (3 of 9 cell lines) and caused a G1 phase cell cycle arrest by appearance of numerous domes. In vivo, 22-oxa-calcitriol inhibited the growth of BxPC-3 xenografts more significantly than calcitriol without including hypercalcemia. Hs 766T, showing no response to either agent, had the second highest receptor contents with no abnormalities in its primary structure deduced by receptor complementary DNA. CONCLUSIONS: 22-oxa-calcitriol may provide a more useful tool for the chemotherapy of pancreatic cancer than calcitriol. Also, the susceptibility of the cell lines to both agents is not well determined by evaluating either the contents or the mutation of vitamin D receptor.
162. Br J Cancer. 1996 Jun;73(11):1341-6.
Growth-inhibitory effects of vitamin D analogues and retinoids on human pancreatic cancer cells.
Zugmaier G, Jager R, Grage B, Gottardis MM, Havemann K, Knabbe C.
Department of Medical Oncology, Marburg University Medical Center, Germany.
Retinoids and vitamin D are important factors that regulate cellular growth and differentiation. An additive growth-inhibitory effect of retinoids and vitamin D analogues has been demonstrated for human myeloma, leukaemic and breast cancer cells. We set out to study the effects of the vitamin D analogue EB1089 and the retinoids all-trans- and 9-cis-retinoic acid on the human pancreatic adenocarcinoma cell lines Capan 1 and Capan 2 and the undifferentiated pancreatic carcinoma cell line Hs766T. The cell lines investigated expressed vitamin D receptor, retinoic acid receptor (RAR)-alpha and gamma as determined by polymerase chain reaction after reverse transcription. RAR-beta was expressed only in Hs766T cells. Addition of all-trans-retinoic acid increased the amount of RAR-alpha mRNA in the three cell lines and induced RAR-beta mRNA in Capan 1 and Capan 2 cells. All-trans-retinoic acid at a concentration of 10 nM inhibited the growth of Capan 1 and Capan 2 cells by 40% relative to controls. 9-cis-Retinoic acid was less effective. Neither all-trans-retinoic acid nor 9-cis-retinoic acid affected the growth of Hs766T cells. EB1089, if added alone to the cells, did not significantly inhibit growth. However, the combination of 1 nM EB1089 with 10 nM all-trans-retinoic acid exerted a growth-inhibitory effect of 90% in Capan 1 cells and of 70% in Capan 2 cells. Our data suggest that vitamin D analogues together with retinoids inhibit the growth of human pancreatic cancer cells. However, in vivo studies are necessary to examine the potential use of retinoids and vitamin D analogues on pancreatic cancer.
Multiple Sclerosis
163. Proc Soc Exp Biol Med. 1997 Oct;216(1):21-7.
Vitamin D and multiple sclerosis.
Hayes CE, Cantorna MT, DeLuca HF.
Department of Biochemistry, University of Wisconsin-Madison 53706, USA.
Recently, it has been clearly demonstrated that exogenous 1,25-dihydroxyvitamin D3, the hormonal form of vitamin D3, can completely prevent experimental autoimmune encephalomyelitis (EAE), a widely accepted mouse model of human multiple sclerosis (MS). This finding has focused attention on the possible relationship of this disease to vitamin D. Although genetic traits certainly contribute to MS susceptibility, an environmental factor is also clearly involved. It is our hypothesis that one crucial environmental factor is the degree of sunlight exposure catalyzing the production of vitamin D3 in skin, and, further, that the hormonal form of vitamin D3 is a selective immune system regulator inhibiting this autoimmune disease. Thus, under low-sunlight conditions, insufficient vitamin D3 is produced, limiting production of 1,25-dihydroxyvitamin D3, providing a risk for MS. Although the evidence that vitamin D3 is a protective environmental factor against MS is circumstantial, it is compelling. This theory can explain the striking geographic distribution of MS, which is nearly zero in equatorial regions and increases dramatically with latitude in both hemispheres. It can also explain two peculiar geographic anomalies, one in Switzerland with high MS rates at low altitudes and low MS rates at high altitudes, and one in Norway with a high MS prevalence inland and a lower MS prevalence along the coast. Ultraviolet (UV) light intensity is higher at high altitudes, resulting in a greater vitamin D3 synthetic rate, thereby accounting for low MS rates at higher altitudes. On the Norwegian coast, fish is consumed at high rates and fish oils are rich in vitamin D3. Further, experimental work on EAE provides strong support for the importance of vitamin D3 in reducing the risk and susceptibility for MS. If this hypothesis is correct, then 1,25-dihydroxyvitamin D3 or its analogs may have great therapeutic potential in patients with MS. More importantly, current research together with data from migration studies opens the possibility that MS may be preventable in genetically susceptible individuals with early intervention strategies that provide adequate levels of hormonally active 1,25-dihydroxyvitamin D3 or its analogs.
164. Proc Natl Acad Sci U S A. 1996 Jul 23;93(15):7861-4.
1,25-Dihydroxyvitamin D3 reversibly blocks the progression of relapsing encephalomyelitis, a model of multiple sclerosis.
Cantorna MT, Hayes CE, DeLuca HF.
Department of Biochemistry, University of Wisconsin, Madison 53706, USA.
Experimental autoimmune encephalomyelitis (EAE) is an autoimmune disease believed to be a model for the human disease multiple sclerosis (MS). Induced by immunizing B10.PL mice with myelin basic protein (MBP), EAE was completely prevented by the administration of 1,25-dihydroxyvitamin D3 [1,25-(OH)2D3]. 1,25-(OH)2D3 could also prevent the progression of EAE when administered at the appearance of the first disability symptoms. Withdrawal of 1,25-(OH)2D3 resulted in a resumption of the progression of EAE. Thus, the block by 1,25-(OH)2D3 is reversible. A deficiency of vitamin D resulted in an increased susceptibility to EAE. Thus, 1,25-(OH)2D3 or its analogs are potentially important for treatment of MS.
165. Med Hypotheses. 1986 Oct;21(2):193-200.
Multiple sclerosis: decreased relapse rate through dietary supplementation with calcium, magnesium and vitamin D.
Goldberg P, Fleming MC, Picard EH.
A group of young patients having multiple sclerosis was treated with dietary supplements containing calcium, magnesium and vitamin D for a period of one to two years. The experimental design employed self-pairing: the response of each patient was compared with his/her own case history as control. The number of exacerbations observed during the program was less than one half the number expected from case histories. No side effects were apparent. The dietary regimen may offer a new means of controlling the exacerbation rate in MS, at least for younger patients. The results tend to support a theory of MS which states that calcium and magnesium are important in the development, structure and stability of myelin.
Osteoporosis
166. J Cell Biochem. 2003 Feb 1;88(2):209-15.
Role of the vitamin D-endocrine system in the pathophysiology of postmenopausal osteoporosis.
Riggs BL.
Endocrine Research Unit, Mayo Clinic and Foundation, Rochester, Minnesota 55905, USA.
Impaired calcium absorption and impaired adaptation to a low calcium diet are common features of aging in women and these processes are even more severely impaired in patients with osteoporotic fractures. The calcium absorption defects are associated with several abnormalities of the vitamin D-endocrine system including secondary hyperparathyroidism, intestinal resistance to 1,25-dihydroxyvitamin D (1,25(OH)(2)D) action, decreased 1,25(OH)(2)D production due to impaired 25(OH)D 1alpha-hydroxylase activity, and, in some elderly persons, nutritional deficiency of vitamin D. However, in postmenopausal women, most of these abnormalities are normalized by administration of physiologic replacement dosages of estrogen and, thus, appear to be secondary consequences of estrogen deficiency. Nonetheless, a minority of them, especially nutritional vitamin D deficiency and impaired 25(OH)D 1alpha-hydroxylase activity late in life, appear to be primary and are independent of estrogen deficiency. Copyright 2002 Wiley-Liss, Inc.
167. J Cell Biochem. 2003 Feb 1;88(2):381-6. (Animal Study)
Rationale for active vitamin D and analogs in the treatment of osteoporosis.
Nishii Y.
Medical Culture, Inc., Tokyo, Japan. nishiiysh-mc@chugai-phram.co.jp
In 1981, Chugai Pharmaceutical succeeded in marketing alfacalcidol, a prodrug of calcitriol, as a therapeutic agent for renal osteodystrophy. In 1983, Chugai succeeded in extending the application of alfacalcidol to the treatment of osteoporosis as well. Clinicians in Japan have accepted alfacalcidol as a remedy for osteoporosis. However, the use of calcitriol and its analogs for the treatment of osteoporosis is still controversial. Some misunderstandings exist internationally about the efficacy of the active form of vitamin D for the treatment of osteoporosis. It is important to emphasize that patients with osteoporosis have intestinal calcium malabsorption and dysfunction in renal activation of vitamin D. When massive doses of parent vitamin D were administered to OVX rats, bone mass increased, but surprisingly, many porotic area were observed in the cortical bone. On the other hand, administration of alfacalcidol increased physiological bone without porotic observation. It is necessary to give the active form of vitamin D, D-hormone, with an RDA-equivalent supply of calcium. Alfacalcidol forms physiological strong bones that are hardly fractured by regulating calcium and bone metabolism. We proposed a new vitamin D analog, 2beta (3-hydroxypropoxy)calcitriol [ED-71] as a therapeutic drug for osteoporosis, which is more potent than calcitriol. ED-71 is now being investigated in phase 2 clinical studies in Japan. ED-71 will appear as more improved drugs for osteoporosis until 2010. Copyright 2002 Wiley-Liss, Inc.
168. Clin Exp Rheumatol. 2003 Jan-Feb;21(1):19-26.
Calcium, vitamin D and etidronate for the prevention and treatment of corticosteroid-induced osteoporosis in patients with rheumatic diseases.
Loddenkemper K, Grauer A, Burmester GR, Buttgereit F.
Department of Rheumatology and Clinical Immunology, Charite University Hospital, Humboldt University of Berlin, Berlin, Germany. konstanze.loddenkemper@charite.de
INTRODUCTION: Long-term glucocorticoid therapy, a major risk factor for the development of osteoporosis, is often necessary in chronically ill patients. At present there are no generally accepted guidelines for the prevention or treatment of steroid-induced osteoporosis. METHODS: In an open prospective study we investigated 99 patients with chronic rheumatic diseases receiving > or = 5 mg/day of prednisolone or the equivalent for at least one year. The objective was to identify osteoporosis risk factors in addition to glucocorticoid therapy and to evaluate the efficacy of prevention with calcium/vitamin D (group 1--patients with osteopenia) and treatment with cyclical etidronate (group 2--patients with osteoporosis). Biochemical markers of bone turnover, clinical parameters and bone mineral density (BMD) were measured. RESULTS: Increasing age and postmenopausal status were associated with more advanced manifestations of steroid-induced osteoporosis (p < 0.05). One year after the start of therapy parameters of bone metabolism increased significantly in group 1, while BMD did not change. In group 2, lumbar spine BMD increased significantly (p < 0.05) whereas femoral neck BMD and bone metabolism parameters remained constant. The intensity of back pain decreased in both groups (p < 0.05). There were fewer new fractures in group 2 than in group 1. CONCLUSION: Treatment with etidronate is effective in patients with glucocorticoid-induced osteoporosis.
169. Endocr Rev. 2002 Aug;23(4):560-9.
Meta-analyses of therapies for postmenopausal osteoporosis. VIII: Meta-analysis of the efficacy of vitamin D treatment in preventing osteoporosis in postmenopausal women.
Papadimitropoulos E, Wells G, Shea B, Gillespie W, Weaver B, Zytaruk N, Cranney A, Adachi J, Tugwell P, Josse R, Greenwood C, Guyatt G; Osteoporosis Methodology Group and The Osteoporosis Research Advisory Group.
OBJECTIVE: To review the effect of vitamin D on bone density and fractures in postmenopausal women. DATA SOURCE: We searched MEDLINE and EMBASE from 1966 to 1999 and examined citations of relevant articles and proceedings of international meetings. We contacted osteoporosis investigators and primary authors to identify additional studies and to obtain unpublished data. STUDY SELECTION: We included 25 trials that randomized women to standard or hydroxylated vitamin D with or without calcium supplementation or a control and measured bone density or fracture incidence for at least 1 yr. DATA EXTRACTION: For each trial, three independent reviewers assessed the methodological quality and abstracted data. DATA SYNTHESIS: Vitamin D reduced the incidence of vertebral fractures [relative risk (RR) 0.63, 95% confidence interval (CI) 0.45-0.88, P < 0.01) and showed a trend toward reduced incidence of nonvertebral fractures (RR 0.77, 95% CI 0.57-1.04, P = 0.09). Most patients in the trials that evaluated vertebral fractures received hydroxylated vitamin D, and most patients in the trials that evaluated nonvertebral fractures received standard vitamin D. Hydroxylated vitamin D had a consistently larger impact on bone density than did standard vitamin D. For instance, total body differences in percentage change between hydroxylated vitamin D and control were 2.06 (0.72, 3.40) and 0.40 (-0.25, 1.06) for standard vitamin D. At the lumbar spine and forearm sites, hydroxylated vitamin D doses above 50 microg yield larger effects than lower doses. Vitamin D resulted in an increased risk of discontinuing medication in comparison to control as a result of either symptomatic adverse effects or abnormal laboratory results (RR 1.37, 95% CI 1.01-1.88), an effect that was similar in trials of standard and hydroxylated vitamin D. CONCLUSIONS: Vitamin D decreases vertebral fractures and may decrease nonvertebral fractures. The available data are uninformative regarding the relative effects of standard and hydroxylated vitamin D.
170. Bone. 2002 Jul;31(1):114-8.
Amelioration of osteoporosis by menatetrenone in elderly female Parkinson's disease patients with vitamin D deficiency.
Sato Y, Honda Y, Kaji M, Asoh T, Hosokawa K, Kondo I, Satoh K.
Department of Rehabilitation Medicine, Hirosaki University School of Medicine, Hirosaki, Japan. noukenrs@cc.hirosaki-u.ac.jp
Significant reduction in bone mineral density (BMD) occurs in patients with Parkinson's disease (PD), correlating with immobilization and with vitamin D deficiency, and increasing the risk of hip fracture, especially in elderly women. As a biological indicator of compromised vitamin K status, an increased serum concentration of undercarboxylated osteocalcin (Oc) has been associated with reduced BMD in the hip and an increased risk of fracture in otherwise healthy elderly women. We evaluated treatment with vitamin K(2) (menatetrenone; MK-4) in maintaining BMD and reducing the incidence of nonvertebral fractures in elderly female patients with PD. In a random and prospective study of PD patients, 60 received 45 mg of MK-4 daily for 12 months, and the remaining 60 (untreated group) did not. At baseline, patients of both groups showed vitamin D and K(1) deficiencies, high serum levels of ionized calcium, and glutaminic residue (Glu) Oc, and low levels of parathyroid hormone (PTH) and 1,25-dihydroxyvitamin D [1,25-(OH)(2)D], indicating that immobilization-induced hypercalcemia inhibits renal synthesis of 1,25-(OH)(2)D and compensatory PTH secretion. BMD in the second metacarpals increased by 0.9% in the treated group and decreased by 4.3% in the untreated group (p < 0.0001). Vitamin K(2) level increased by 259.8% in the treated group. Correspondingly, significant decreases in Glu Oc and calcium were observed in the treated group, in association with an increase in both PTH and 1,25-(OH)(2)D. Ten patients sustained fractures (eight at the hip and two at other sites) in the untreated group, and one hip fracture occurred among treated patients (p = 0.0082; odds ratio = 11.5). The treatment with MK-4 can increase the BMD of vitamin D- and K-deficient bone by increasing vitamin K concentration, and it can also decrease calcium levels through inhibition of bone resorption, resulting in an increase in 1,25-(OH)(2)D concentration.
171. Med Clin (Barc). 2002 Jun 22;119(3):85-9.
[Prevalence of vitamin D deficiency in populations at risk for osteoporosis: impact on bone integrity]
[Article in Spanish]
Mezquita Raya P, Munoz Torres M, Lopez Rodriguez F, Martinez Martin N, Conde Valero A, Ortego Centeno N, Gonzalez Calvin J, Raya Alvarez E, Luna Jd Jde D, Escobar Jimenez F.
Area de Metabolismo Oseo, Servicio de Endocrinologia. Facultad de Medicina, Hospital Universitario San Cecilio, Granada, Spain.
BACKGROUND: Nowadays, severe deficiency of vitamin D is not a common finding in most developed countries. However, the prevalence of vitamin D insufficiency is relatively high and it can contribute to the descent of bone mass in osteoporosis risk populations. The objective of our study was to evaluate the prevalence of vitamin D insufficiency in postmenopausal women (PMW), patients with inflammatory bowel disease (IBD) and corticosteroid-dependent asthmatic patients (CAP) and to analyze its relationship with bone mineral density (BMD) and calciotropic hormones. PATIENTS AND METHOD: We studied 299 patients (PMW: 161; IBD: 61; CAP: 77). In all cases, serum levels of PTH and 25OHD were determined and the BMD (DXA, Hologic QDR1000) in lumbar spine (LS) and femoral neck (FN) was measured. RESULTS: Vitamin D insufficiency (25OHD < 15 ng/ml) was observed in 39.1% patients with PMW, 70.7% patients with IBD and 44.2% patients with CAP. 25OHD concentrations were lower in EII patients (p = 0.003) and PTH concentrations were higher in MPM (p < 0.001). We found a negative correlation between PTH and 25OHD in the overall group and this correlation persisted after considering each group separately. After adjusting for remaining variables, 25OHD was found to be significantly associated with BMD at lumbar spine and/or femoral neck in the three groups. CONCLUSIONS: In populations at risk of osteoporosis, there is a high prevalence of vitamin D insufficiency. This insufficiency has a significant effect on bone integrity.
172. Biogerontology. 2002;3(1-2):73-7.
Vitamin D deficiency and aging: implications for general health and osteoporosis.
Eriksen EF, Glerup H.
University Department of Endocrinology, Aarhus Amtssygehus, Denmark. eriksen_erik_f@lilly.com
Vitamin D deficiency is extremely prevalent in the elderly. Most often the first symptoms are caused by myopathy with muscle pain, fatigue, muscular weakness and gait disturbances. More severe deficiency causes osteomalacia with deep bone pain, reduced mineralization of bone matrix and low energy fractures. Recent data also suggest that hypovitaminosis D increases the risk of cancer of the prostate, colon and breast. Thus, hypovitaminosis D is associated with many diseases associated with aging. In order to diagnose hypovitaminosis D, the assessment of serum levels of 25-hydroxy vitamin D is mandatory. Screening based on other markers like alkaline phosphatase and parathyroid hormone (PTH) will be incomplete. The treatment of hypovitaminosis D is simple with administration of combined calcium (I g) and vitamin D supplements (calciferol, at least 800 IU). Severe cases may demand initial parenteral administration of vitamin D (repeated injections of 300,000 IU 2-3 times with monthly intervals). More potent analogues are rarely needed. One should aim at achieving S-25(OH)D values in the range 50-100 nmol/l.
173. Aliment Pharmacol Ther. 2002 May;16(5):919-27.
Osteoporosis in inflammatory bowel disease: effect of calcium and vitamin D with or without fluoride.
Abitbol V, Mary JY, Roux C, Soule JC, Belaiche J, Dupas JL, Gendre JP, Lerebours E, Chaussade S; Groupe D'etudes Therapeutiques des Affections Inflammatoires Digestives (GETAID).
Service de Gastroenterologie, Hopital Cochin, Paris, France, INSERM U444, Universite de Paris, Paris, France. vered@club-internet.fr
BACKGROUND: Previous data have indicated low bone formation as a mechanism of osteoporosis in inflammatory bowel disease. Fluoride can stimulate bone formation. AIM: To assess the effect of fluoride supplementation on lumbar spine bone mineral density in osteoporotic patients with inflammatory bowel disease treated in parallel with calcium and vitamin D. METHODS: In this prospective, randomized, double-blind, parallel and placebo-controlled study, 94 patients with inflammatory bowel disease (lumbar spine T score below - 2 standard deviations, normal serum 25OH vitamin D), with a median age of 35 years, were included. Bone mineral density was measured by dual-energy X-ray absorptiometry. Patients were randomized to receive daily either sodium monofluorophosphate (150 mg, n=45) or placebo (n=49) for 1 year, and all received calcium (1 g) and vitamin D (800 IU). The relative change in bone mineral density from 0 to 12 months was tested in each group (fluoride or placebo) and compared between the groups. RESULTS: Lumbar spine bone mineral density increased significantly in both groups after 1 year: 4.8 +/- 5.6% (n=29) and 3.2 +/- 3.8% (n=31) in the calcium-vitamin D-fluoride and calcium-vitamin D-placebo groups, respectively (P < 0.001 for each group). There was no difference between the groups (P=0.403). Similar results were observed according to corticosteroid intake or disease activity. CONCLUSIONS: Calcium and vitamin D seem to increase lumbar spine density in osteoporotic patients with inflammatory bowel disease; fluoride does not provide further benefit.
174. Bone. 2002 Apr;30(4):582-8. (Animal Study)
ED-71, a vitamin D analog, is a more potent inhibitor of bone resorption than alfacalcidol in an estrogen-deficient rat model of osteoporosis.
Uchiyama Y, HiguchI Y, Takeda S, Masaki T, Shira-Ishi A, Sato K, Kubodera N, Ikeda K, Ogata E.
Fuji Gotemba Research Laboratory, Chugai Pharmaceutical Co., Ltd., Shizuoka, Japan.
Although active vitamin D is used in certain countries for the treatment of osteoporosis, the risk of causing hypercalcemia/hypercalciuria means that there is only a narrow therapeutic window, and this has precluded worldwide approval. The results of our previous animal studies have suggested that the therapeutic effect of active vitamin D on bone loss after estrogen deficiency can be dissociated at least partly from its effect of enhancing intestinal calcium absorption and suppressing parathyroid hormone (PTH) secretion. To test this, we compared the effects of ED-71, a hydroxypropoxy derivative of 1alpha,25-dihydroxyvitamin D3, with orally administered alfacalcidol, on bone mineral density (BMD) and the bone remodeling process as a function of their effects on calcium metabolism and PTH, in a rat ovariectomy (ovx) model of osteoporosis. ED-71 increased bone mass at the lumbar vertebra to a greater extent than alfacalcidol, while enhancing calcium absorption (indicated by urinary calcium excretion) and decreasing serum PTH levels to the same degree as alfacalcidol. ED-71 lowered the biochemical and histological parameters of bone resorption more potently than alfacalcidol, while maintaining bone formation markers. These results suggest that active vitamin D exerts an antiosteoporotic effect by inhibiting osteoclastic bone resorption while maintaining osteoblastic function, and that these anticatabolic/anabolic effects of active vitamin D take place independently of its effects on calcium absorption and PTH. The demonstration that ED-71 is more potent in these properties than alfacalcidol makes it an attractive candidate as an antiosteoporotic drug.
175. Urol Nurs. 2002 Dec;22(6):405-9.
Osteoporosis--Part II: Dietary and/or supplemental calcium and vitamin D.
Moyad MA.
University of Michigan Medical Center, Department of Urology, Ann Arbor, MI, USA.
Osteoporosis is a significant problem in women and men. As osteoporosis has garnered more attention there seems to be more attention than ever placed on the potential benefits of calcium and vitamin D. Health professionals need to inform patients that there are numerous healthy dietary sources of calcium and vitamin D. Several forms of calcium supplements are commercially available today and health professionals need to understand the similarities and differences between them. Calcium and vitamin D in moderation also have an excellent safety profile and may actually have benefits far beyond osteoporosis therapy.
176. Pharmacol Ther. 2002 Jan;93(1):37-49.
Role of Ca(2+) and vitamin D in the prevention and treatment of osteoporosis.
Rodriguez-Martinez MA, Garcia-Cohen EC.
Unidad de Ensayos Clinicos y Area de Investigacion Farmacologica, Servicio de Farmacologia Clinica, Hospital Universitario Clinica Puerta de Hierro de Madrid, C/ San Martin de Porres 4, 28035 Madrid, Spain. mariangeles.rodriguez@uam.es
Osteoporosis is defined as a progressive systemic skeletal disease characterised by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture. The clinical relevance of osteoporosis derives from the fractures that it produces. More than one-third of the adult women will suffer one or more osteoporotic fractures in their lifetime. The lifetime risk in men is approximately one-half that in women. The decrease of the bone mineral density is the most important cause of risk fracture. Among other factors, Ca(2+) and vitamin D deficiencies are important risk factors for a decrease in bone mineral density, consequently inducing osteoporosis. The high prevalence of vitamin D deficiency in healthy elderly people living mainly in southern European countries increase the risk of osteoporotic fractures in these populations above those anticipated for the general elderly population of the European community. In addition, the ageing of the European population will double the number of osteoporotic fractures over the next 50 years, unless adequate preventative measures are undertaken. The efficacy and safety of Ca(2+) and vitamin D supplements at preventing bone loss and reducing the risk of hip and other fractures have been assessed in different clinical trials, which are extensively discussed in this review.
177. Med J Aust. 2001 Oct 15;175(8):401-5.
Vitamin D status of women in the Geelong Osteoporosis Study: association with diet and casual exposure to sunlight.
Pasco JA, Henry MJ, Nicholson GC, Sanders KM, Kotowicz MA.
The University of Melbourne, Department of Clinical and Biomedical Sciences--Barwon Health, The Geelong Hospital, VIC.
OBJECTIVE: To assess vitamin D intake and casual exposure to sunshine in relation to serum 25-hydroxyvitamin D (25OHD) levels. DESIGN: Cross-sectional study of a population-based, random sample of women aged 20-92 years, assessed between 1994 and 1997. SETTING AND PARTICIPANTS: 861 women from the Barwon Statistical Division (population, 218000), which includes the city of Geelong (latitude 38 degrees south) in Victoria. MAIN OUTCOME MEASURES: Vitamin D intake; serum 25OHD level; season of assessment; exposure to sunshine. RESULTS: Median intake of vitamin D was 1.2 microg/day (range, 0.0-11.4 microg/day). Vitamin D supplements, taken by 7.9% of participants, increased intake by 8.1% to 1.3 microg/day (range, 0.0-101.2 microg/day) (P< 0.001). A dose-response relationship in serum 25OHD levels was observed for sunbathing frequency before and after adjusting for age (P< 0.05). During winter (May-October), serum 25OHD levels were dependent on vitamin D intake (partial r2= 0.01; P<0.05) and were lower than during summer (November-April) (age-adjusted mean, 59nmol/L [95% Cl, 57-62] v 81 nmol/L [95% CI, 78-84]; P<0.05). No association was detected between serum 25OHD and vitamin D intake during summer. The prevalences of low concentrations of serum 25OHD were, for <28nmol/L, 7.2% and 11.3% overall and in winter, respectively; and, for <50 nmol/L, 30.0% and 43.2% overall and in winter, respectively. CONCLUSIONS: At latitude 38 degrees south, the contribution of vitamin D from dietary sources appears to be insignificant during summer. However, during winter vitamin D status is influenced by dietary intake. Australia has no recommended dietary intake (RDI) for vitamin D, in the belief that adequate vitamin D can be obtained from solar irradiation alone. Our results suggest that an RDI may be needed.
178. Leukemia. 2001 Nov;15(11):1701-5.
Loss of bone mass and vitamin D deficiency after hematopoietic stem cell transplantation: standard prophylactic measures fail to prevent osteoporosis.
Massenkeil G, Fiene C, Rosen O, Michael R, Reisinger W, Arnold R.
Department of Internal Medicine, Clinic for Nuclear Medicine and Institute of Radiology, University Hospital Charite, Berlin, Germany.
Bone mineral density (BMD) and biochemical markers of bone metabolism were analyzed in 67 adults with ALL (n = 27), AML (n = 14), MDS (n = 6) and CML (n = 20) before and after allogeneic stem cell transplantation (SCT). Median age was 36 years (17-56). Twenty-six out of 53 patients (49%) had osteopenia and osteoporosis before SCT, 21/26 had acute leukemias and 5/26 had chronic myeloid leukemia (CML). T-score before SCTwas -1.23 in patients with acute leukemias and 0.62 in CML patients (P = 0.001). After SCT, a significant loss of BMD was observed in all patients. After 6 months, 24 of 36 evaluable patients (67%) had pathologic BMD, 11 of them (30%) had developed osteoporosis. After 12 months, 20 of 32 evaluable patients (62%) had BMD values below normal and nine of them (28%) had osteoporosis. Increased pyridinium excretion was observed in 12/20 patients (60%) with acute leukemias, but only in 3/13 (23%) with CML (P = 0.014). A prolonged vitamin D deficiency for more than 6 months developed early after SCT in all patients. Patients with acute leukemias frequently have osteopenia and osteoporosis before SCT. After SCT, a further loss of BMD occurs independent from the underlying disease. Standard prophylactic measures are not sufficient to prevent loss of bone mass. Studies on prophylactic interventions are needed to prevent severe osteoporosis in long-term survivors of SCT.
179. Nurs Clin North Am. 2001 Sep;36(3):417-31, viii.
Role of calcium, vitamin D, and other essential nutrients in the prevention and treatment of osteoporosis.
Dowd R.
Department of Medicine, Creighton University Osteoporosis Research Center, Omaha, Nebraska 68131, USA. racheld@creighton.edu
Calcium is an essential nutrient for the prevention and treatment of osteoporosis. Despite universal recognition of its importance, most people still do not obtain recommended amounts. Recent additions to the treatment of osteoporosis with potent bone active drugs produce an even greater need for calcium and total nutrition for restoration of lost bone. Practitioners and patients need to emphasize and appreciate the role that calcium, vitamin D, and other nutrients play in the promotion of health and in the prevention and treatment of disease.
180. Exp Clin Endocrinol Diabetes. 2001;109(2):87-92.
Vitamin D status, trunk muscle strength, body sway, falls, and fractures among 237 postmenopausal women with osteoporosis.
Pfeifer M, Begerow B, Minne HW, Schlotthauer T, Pospeschill M, Scholz M, Lazarescu AD, Pollahne W.
Institute of Clinical Osteology Gustav Pommer and Clinic Der Furstenhof, Bad Pyrmont, Germany. iko_pyrmont@t.online.de
The aim of this study was to identify factors associated with fractures in patients with postmenopausal osteoporosis. The overall hypothesis was that trunk muscle strength, body sway and hypovitaminosis D would influence daily activities and the likelihood of falls and fractures. - In 237 women (mean age 62.9+/-7.4 years) osteoporosis was defined by a T-score at the femoral neck below -2.5 SD. Trunk muscle strength was determined using isokinetic dynamometry and body sway was measured according to Lord et al. Limitations in everyday life were assessed and the history of falls was documented. A fracture was defined as a vertebral height reduction of more than 20% or at least 4 mm. The assessment was carried out using the Spine Deformity Index (SDI) and was confirmed by an experienced radiologist. Pearson coefficients of correlation were calculated. - After correction for age, significant associations were found for body sway and 25-hydroxyvitamin D (p<0.001), body sway and falls (p<0.001), body sway and rib fractures (p<0.01), trunk muscle strength and limitations in everyday life (p<0.001), trunk muscle strength and SDI (p<0.001), trunk muscle strength and bone density (p<0.001), and bone density and 25-hydroxyvitamin D (p<0.001). No significant correlation was found for trunk muscle strength and 25-hydroxyvitamin D (p=0.712). - Findings suggest that hypovitaminosis D is associated with increased body sway and an elevated risk for falls and falls-related fractures. Musculoskeletal rehabilitation should include strengthening exercises for the trunk muscles and training of neuromuscular co-ordination and balance.
181. Cochrane Database Syst Rev. 2001;(1):CD000227.
Update of: Cochrane Database Syst Rev. 2000;(2):CD000227.
Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis.
Gillespie WJ, Avenell A, Henry DA, O'Connell DL, Robertson J.
Dunedin School of Medicine, University of Otago, PO Box 913, Dunedin, NEW ZEALAND. bill.gillespie@stonebow.otago.ac.nz
BACKGROUND: Due to their known effects on bone metabolism, vitamin D and related compounds have been proposed for the prevention of osteoporosis and fractures. OBJECTIVES: To determine the effects of supplementation with Vitamin D or a Vitamin D analogue in the prevention of fractures of the axial and appendicular skeleton in elderly men or women with involutional or post-menopausal osteoporosis. SEARCH STRATEGY: We searched MEDLINE, EMBASE, CINAHL, LILACS, CABNAR, BIOSIS, HEALTHSTAR, Current Contents, The Cochrane Database of Systematic Reviews, the Cochrane Musculoskeletal Injuries Group trials register, and bibliographies of identified trials and reviews. Date of the most recent search: September 2000. SELECTION CRITERIA: Any randomised or quasi-randomised trial which compared vitamin D or a vitamin D analogue, either alone or in combination with calcium supplementation, with a placebo, no intervention, or the administration of calcium supplements, with eligible fracture outcomes, in elderly men or women with involutional or post-menopausal osteoporosis. DATA COLLECTION AND ANALYSIS: Two reviewers independently assessed trial quality, by use of a nine item scale, and extracted data. Additional information was sought from trialists. Where possible the data were pooled. Pooling of data, where it was admissible, used pooled relative risk and fixed effects model. MAIN RESULTS: Almost all estimates of treatment effects are based on single studies. Administration of vitamin D3 alone without calcium co-supplementation was not associated with any reduction in incidence of hip fracture (relative risk (RR) 1.20, 95% confidence interval (CI) 0.83, 1.75) or other non-vertebral fracture. Administration of vitamin D3 with calcium co-supplementation to frail elderly people in sheltered accommodation was associated with a reduction in incidence of hip fracture (RR 0.74, 95% CI 0.60, 0.91). In healthy younger, ambulant participants the effect on hip fracture is unknown (RR 0.36, 95% CI 0.01, 8.78), although there appears to be a significant overall effect on non-vertebral fracture incidence in this group ( RR 0.46, 95% CI 0.23,0.90). Calcitriol (1,25 dihdyroxy vitamin D) was effective in reducing the incidence of vertebral deformity (RR 0.49, 95% CI 0.25, 0.95). Calcitriol was more effective than calcium in reducing the frequency of new vertebral deformities during the third year of treatment (RR 0.28, 95% CI 0.15, 0.52). 1-alpha-hydroxy vitamin D was effective in reducing the incidence of non-vertebral fractures in a single small study of elderly people whose mobility was impaired by neurological disease (RR 0.12, 95% CI 0.02, 0.95). No statistically significant effects were found for other comparisons of vitamin D or its analogues against each other, with and without calcium supplementation. REVIEWER'S CONCLUSIONS: Uncertainty remains about the efficacy of regimens which include vitamin D or its analogues in fracture prevention. Particularly if co-supplementation of calcium is required, significant cost differences are likely to exist between regimens. Further large randomised trials are currently being conducted to clarify the effectiveness of community fracture prevention programmes employing vitamin D supplementation.
182. Rheum Dis Clin North Am. 2001 Feb;27(1):101-30.
Calcium and vitamin D in osteoporosis.
Morgan SL.
Division of Clinical Nutrition and Dietetics, Departments of Nutrition Sciences and Medicine, Schools of Medicine, Health Related Professions, and Dentistry, University of Alabama at Birmingham, Birmingham, Alabama, USA. slmorgan@uab.edu
Calcium and vitamin D are useful adjunctive therapies in the prevention and treatment of osteoporosis. Peak BMD is optimally achieved with sustained optimal calcium and vitamin D intakes. Calcium and vitamin D intakes continue to be important after the third decade and into senescence. Although calcium and vitamin D are not therapies to be used alone to prevent early postmenopausal bone loss, they assume more prominent roles in late menopause and in the elderly to preserve bone health with advancing age. Calcium and vitamin D supplementation is an important adjunctive therapy to use together with antiresorptive therapies.
183. J Clin Endocrinol Metab. 2001 Mar;86(3):1212-21.
Erratum in: J Clin Endocrinol Metab 2001 Jul;86(7):3008.
A global study of vitamin D status and parathyroid function in postmenopausal women with osteoporosis: baseline data from the multiple outcomes of raloxifene evaluation clinical trial.
Lips P, Duong T, Oleksik A, Black D, Cummings S, Cox D, Nickelsen T.
Department of Endocrinology, Academic Hospital Vrije Universiteit, 1007 M.B. Amsterdam, The Netherlands. p.lips@azvu.nl
Vitamin D deficiency leads to secondary hyperparathyroidism, increased bone turnover, and bone loss and, when severe, to osteomalacia. Vitamin D deficiency is common in elderly people, especially the institutionalized. The definition of vitamin D deficiency is hampered by the fact that large interlaboratory differences exist in assays for serum 25-hydroxyvitamin D (25OHD), the main circulating metabolite. The international Multiple Outcomes of Raloxifene Evaluation study, a large prospective intervention trial in postmenopausal women with osteoporosis, offered the opportunity to compare vitamin D status and parathyroid function throughout many countries over the world. For this study, baseline data were available from 7564 postmenopausal women from 25 countries on 5 continents. All women had osteoporosis, i.e. bone mineral density (BMD) at femoral neck or lumbar spine was lower than t-score -2.5, or they had 2 vertebral fractures. Serum 25OHD was measured by RIA, and serum PTH was measured by immunoradiometric assay. BMD was measured by dual x-ray absorptiometry. The mean (+/-SD) serum 25OHD was 70.8 +/- 30.9 nmol/L. A low serum 25OHD (<25 nmol/L) was observed in 4.1% of all women in the Multiple Outcomes of Raloxifene Evaluation study, ranging from 0% in south east Asia (very few patients) to 8.3% in southern Europe. Serum 25OHD was between 25-50 nmol/L in 24.3% of the women. Serum 25OHD showed a significant seasonal relationship, with lower values in all regions in winter. Serum PTH correlated negatively with serum 25OHD (r = -0.25; P < 0.001). This significant negative correlation was observed in all regions. When serum 25OHD was less than 25, 25-50, or more than 50 nmol/L, respectively, mean serum PTH levels were 4.8, 4.1, and 3.5 pmol/L, respectively (by ANOVA, P < 0.001). Similarly, mean alkaline phosphatase levels were 83.7, 79.1, and 75.7 U/L (P < 0.001), respectively, with increasing serum 25OHD. The effect of serum 25OHD on BMD was only significant for the BMD of the trochanter where a serum 25OHD level less than 25 nmol/L was associated with a 4% lower BMD. After 6 months of treatment with vitamin D(3) (400-600 IU/day) and calcium (500 mg/day), serum 25OHD increased from 70.8 +/- 29.8 to 92.3 +/- 28.6 nmol/L. Serum PTH decreased significantly after 6 months of treatment, and this decrease depended on baseline serum 25OHD. When baseline serum 25OHD was less than 25, 25-50, or more than 50 nmol/L, respectively, serum PTH decreased by 0.8, 0.5, or 0.2 pmol/L, respectively (P < 0.001). In conclusion, serum 25OHD was less than 25 nmol/L in 4% of the women, and this was associated with a 30% higher serum PTH. In 24% of the women serum 25OHD was between 25-50 nmol/L, associated with a 15% higher level of serum PTH compared with women with a serum 25OHD greater than 50 nmol/L. A low serum 25OHD level was also associated with higher serum alkaline phosphatase and lower BMD of the trochanter. Treatment with vitamin D(3) and calcium increased serum 25OHD and decreased serum PTH significantly; the effect was greater for lower baseline serum 25OHD.
184. J Bone Miner Res. 2000 Nov;15(11):2276-83.
A randomized controlled trial of vitamin D supplementation on preventing postmenopausal bone loss and modifying bone metabolism using identical twin pairs.
Hunter D, Major P, Arden N, Swaminathan R, Andrew T, MacGregor AJ, Keen R, Snieder H, Spector TD.
Twin Research and Genetic Epidemiology Unit, St. Thomas' Hospital, London, United Kingdom.
Vitamin D supplementation, when given with calcium, has been shown to increase bone mineral density (BMD) and reduce the incidence of hip fracture in elderly subjects. Despite its widespread use, the benefits of vitamin D supplementation in younger women and as a single agent are less clear. We performed a randomized co-twin, placebo-controlled, double-blind trial over 2 years to measure the effect of vitamin D3 supplementation on bone density and bone metabolism in young postmenopausal women. Seventy-nine monozygotic (MZ) twin pairs (mean age, 58.7 years; range, 47-70 years) were recruited. For each twin pair, one was randomized to 800 IU cholecalciferol/day for 2 years and the other was randomized to placebo. BMD was measured at the spine and hip and heel ultrasound at baseline, 12, 18, and 24 months. Samples were collected at 0, 3, and 6 months to measure serum calcium, 25-hydroxyvitamin D [25(OH)D], parathyroid hormone (PTH), osteocalcin, and urinary deoxypyridinoline (DPD). In total, 64 pairs completed the study. No differences in baseline characteristics were seen between the groups. At 6 months, the treatment group had an increase in serum vitamin D [mean +/- SEM intrapair difference, 14.1+/-2.4 microg/liter (p < 0.001)]. There were no significant differences in other serum measurements or bone markers at 3 months or 6 months. At 24 months, no significant treatment effect was seen on BMD or calcaneal ultrasound change within pairs. Subanalysis of treatment response by vitamin D receptor (VDR) genotype revealed no significant difference in effect on BMD variables with treatment. On the basis of these results, vitamin D supplementation, on its own, cannot be recommended routinely as an osteoporosis prevention for healthy postmenopausal women with normal vitamin D levels under the age of 70 years.
185. Med Clin (Barc). 2000 Jun 10;115(2):46-51.
[Treatment of osteoporosis with calcium and vitamin D. Systematic review]
[Article in Spanish]
Vallecillo G, Diez A, Carbonell J, Gonzalez Macias J.
Servicio de Medicina Interna y Enfermedades Infecciosas, Hospital del Mar, Barcelona.
BACKGROUND: Systematic review of the efficacy of calcium and vitamin D for the treatment of osteoporosis. MATERIAL AND METHOD: Review of the database MEDLINE between 1996 and may 1998, by the key words: osteoporosis, calcium, vitamin D (and related terms) and randomized clinical trial. Review of the electronic versions of Best Evidence, The Cochrane Library, congress abstracts and references from two main textbooks. Ascending review of the literature. All the reviews were performed independently by two of the authors. Design parameters and main results of the primary publications of the identified trials were tabulated. Two independent observers carried out methodological scoring of the studies. Results were tabulated and a judgement made for the results. RESULTS: Eleven studies on calcium, 8 of vitamin D and 12 about calcitriol and other hormone derivatives were included. Studies with calcium were mainly performed on non-clinical populations and in three anti-fracture efficacy was analyzed. Results were positive in population with low baseline intake and substantial supplementation. Trials on vitamin D were done in non-clinical and on institutionalized populations. Trials with calcitriol were developed mainly in osteoporotic fracture populations and reached poorer methodological validity scores. Heterogeneity of the studies precluded a meta-analysis of the different treatments. Studies on calcium showed clinical efficacy in a more consistent way. Inter-observer score was good (kappa = 0.81) and there were no significant correlations between sample size and effect in the different studies. CONCLUSIONS: Calcium treatment is efficacious in populations with low intake receiving substantial supplementation. Vitamin D is efficacious associated with calcium mainly in deficient populations. Efficacy of calcitriol and other derivatives is more controversial.
186. Cochrane Database Syst Rev. 2000;(2):CD000952.
Calcium and vitamin D for corticosteroid-induced osteoporosis.
Homik J, Suarez-Almazor ME, Shea B, Cranney A, Wells G, Tugwell P.
Medicine, 562 Heritage Medical Research Centre, University Of Alberta, Edmonton, Alberta, Canada, T6G 2S2. jhomik@gpu.srv.ualberta.ca
OBJECTIVES: To assess the effects of calcium and vitamin D compared to calcium alone or placebo in the prevention of bone loss in patients taking systemic corticosteroids. SEARCH STRATEGY: We searched the Cochrane Musculoskeletal trials register, Cochrane Controlled Trials Register, EMBASE and Medline up to 1996. We also conducted a hand search of abstracts from various scientific meetings and reference lists of selected trials. SELECTION CRITERIA: All randomized trials comparing calcium and vitamin D to calcium alone or placebo in patients taking systemic corticosteroids. DATA COLLECTION AND ANALYSIS: Data was abstracted from trials by two investigators. Methodological quality was assessed in a similar manner. Analysis was performed using fixed effects models. MAIN RESULTS: Five trials were included, with 274 patients. The analysis was performed at two years after starting calcium and vitamin D. There was a significant weighted mean difference (WMD) between treatment and control groups in lumbar (WMD 2.6 (95% CI 0.7, 4.5), and radial bone mineral density (WMD 2.5 (95% CI 0.6, 4.4). The other outcome measures (femoral neck bone mass, fracture incidence, biochemical markers of bone resorption) were not significantly different. REVIEWER'S CONCLUSIONS: This meta-analysis demonstrated a clinically and statistically significant prevention of bone loss at the lumbar spine and forearm with vitamin D and calcium in corticosteroid treated patients. Because of low toxicity and cost all patients being started on corticosteroids should receive prophylactic therapy with calcium and vitamin D.
187. Arthritis Rheum. 1999 Aug;42(8):1740-51.
Comment in: Arthritis Rheum. 2000 May;43(5):1188-90.
The role of vitamin D in corticosteroid-induced osteoporosis: a meta-analytic approach.
Amin S, LaValley MP, Simms RW, Felson DT.
Boston University Arthritis Center, Massachusetts 02118, USA.
OBJECTIVE: To determine if vitamin D is more effective than no therapy or calcium alone in the management of corticosteroid-induced osteoporosis, and to determine how vitamin D compares with other osteoporosis therapies, e.g., bisphosphonates, calcitonin, or fluoride, for this condition. METHODS: We evaluated all formulations of vitamin D, including its active metabolites and analogs. A systematic search for published and unpublished studies was conducted using MEDLINE (1966-December 1997), bibliographic references, abstracts from proceedings of recent national meetings, and contact with pharmaceutical companies and content experts. We included all randomized controlled trials lasting at least 6 months (and reporting extractable results), of patients receiving oral corticosteroids, that compared vitamin D with either 1) no therapy or calcium alone, or 2) bisphosphonates, calcitonin, or fluoride. The primary outcome measure of interest was change in lumbar spine bone mineral density. RESULTS: We found a moderate beneficial effect of vitamin D plus calcium versus no therapy or calcium alone (9 trials) (effect size 0.60; 95% confidence interval [95% CI] 0.34, 0.85; P < 0.0001). In comparisons of vitamin D with other osteoporosis therapies, bisphosphonates were more effective than vitamin D (6 trials) (effect size 0.57; 95% CI 0.09, 1.05). Calcitonin was similar in efficacy to vitamin D (4 trials) (effect size 0.03; 95% CI -0.39, 0.45). Fluoride was more effective than vitamin D, but there were only 2 trials. CONCLUSION: Vitamin D plus calcium is superior to no therapy or calcium alone in the management of corticosteroid-induced osteoporosis. Vitamin D is less effective than some osteoporosis therapies. Therefore, treatment with vitamin D plus calcium, as a minimum, should be recommended to patients receiving long-term corticosteroids.
188. MMW Fortschr Med. 1999 Aug 12;141(31-32):32-6.
[Therapy of osteoporosis: native vitamin D or as hormone? Advantages of activated vitamin D in secondary osteoporosis]
[Article in German]
Scharla SH.
Abteilung Innere Medizin, Klinikum Berchtesgadener Land, Schonau am Konigssee.
Vitamin D and its active metabolite (D-Hormone) are major weapons in the therapeutic arsenal available for the treatment of osteoporosis. With regard to native vitamin D, controlled studies have confirmed the prophylactic effect of treatment with vitamin D (+ calcium) in the area of nonvertebral fractures, in particular in elderly women with vitamin D deficiency. The widespread prophylactic use of this form of treatment, which is both inexpensive and largely free of side effects, would presumably save costs by greatly reducing the incidence of fractures of the femur. Treatment with D-hormone (calcitriol) or the pro-hormone 1 alpha-hydroxy-vitamin D (alfacalcidol) is a specific form of treatment of osteoporosis that has been shown to prevent fractures, in particular of the vertebrae, in a number of controlled prospective studies. The D-hormone is of particular value in the treatment of secondary forms of osteoporosis (induced by glucocorticoids or chronic inflammatory disease). Although the incidence of severe side effects is low, monitoring of serum calcium ist nevertheless recommended.
189. Calcif Tissue Int. 1999 Oct;65(4):295-306.
Vitamin D therapy of osteoporosis: plain vitamin D therapy versus active vitamin D analog (D-hormone) therapy.
Lau KH, Baylink DJ.
Department of Medicine, Loma Linda University, and Musculoskeletal Disease Center (151), 11201 Benton Street, Loma Linda, California 92357 USA.
Normal intestinal calcium (Ca) absorption is an essential feature of bone homeostasis. As with many other organ systems, intestinal Ca absorption declines with aging, and this is one pathological factor that has been identified as a cause of senile osteoporosis in the elderly. This abnormality leads to secondary hyperparathyroidism, which is characterized by high serum parathyroid hormone (PTH) and an increase in bone resorption. Secondary hyperparathyroidism due to poor intestinal Ca absorption has been implicated not only in senile osteoporosis but also in age-related bone loss. Accordingly, in population-based studies, there is a gradual increase in serum PTH from about 20 years of age onward, which constitutes a maximum increase at 80 years of age of 50% of the basal value seen at 30 years of age. The cause of the increase in PTH is thought to be partly due to impaired intestinal Ca absorption that is associated with aging, a cause that is not entirely clear but at least in some instances is related to some form of vitamin D deficiency. There are three types of vitamin D deficiency: (1) primary vitamin D deficiency, which is due to a deficiency of vitamin D, the parent compound; (2) a deficiency of 1,25(OH)(2)D(3) resulting from decreased renal production of 1,25(OH)(2)D(3); and (3) resistance to 1,25(OH)(2)D(3) action owing to decreased responsiveness to 1, 25(OH)(2)D(3) of target tissues. The cause for the resistance to 1, 25(OH)(2)D(3) could be related to the finding that the vitamin D receptor level in the intestine tends to decrease with age. All three types of deficiencies can occur with aging, and each has been implicated as a potential cause of intestinal Ca malabsorption, secondary hyperparathyroidism, and senile osteoporosis. There are two forms of vitamin D replacement therapies: plain vitamin D therapy and active vitamin D analog (or D-hormone) therapy. Primary vitamin D deficiency can be corrected by vitamin supplements of 1000 U a day of plain vitamin D whereas 1,25(OH)(2)D(3) deficiency/resistance requires active vitamin D analog therapy [1, 25(OH)(2)D(3) or 1alpha(OH)D(3)] to correct the high serum PTH and the Ca malabsorption. In addition, in the elderly, there are patients with decreased intestinal Ca absorption but with apparently normal vitamin D metabolism. Although the cause of poor intestinal Ca absorption in these patients is unclear, these patients, as well as all other patients with secondary hyperparathyroidism (not due to decreased renal function), show a decrease in serum PTH and an increase in Ca absorption in response to therapy with 1, 25(OH)(2)D(3) or 1alpha(OH)D(3). In short, it is clear that some form of vitamin D therapy, either plain vitamin D or 1,25(OH)(2)D(3) or 1alpha(OH)D(3), can be used to correct all types of age-dependent impairments in intestinal Ca absorption and secondary hyperparathyroidism during aging. However, from a clinical standpoint, it is important to recognize the type of vitamin D deficiency in patients with senile osteoporosis so that primary vitamin D deficiency can be appropriately treated with plain vitamin D therapy, whereas 1,25(OH)(2)D(3) deficiency/resistance will be properly treated with 1,25(OH)(2)D(3) or 1alpha(OH)D(3) therapy. With respect to postmenopausal osteoporosis, there is strong evidence that active vitamin D analogs (but not plain vitamin D) may have bone-sparing actions. However, these effects appear to be results of their pharmacologic actions on bone formation and resorption rather than through replenishing a deficiency.
190. Clin Endocrinol (Oxf). 1999 Aug;51(2):217-21.
Vitamin D insufficiency increases bone turnover markers and enhances bone loss at the hip in patients with established vertebral osteoporosis.
Sahota O, Masud T, San P, Hosking DJ.
Ageing and Disability Research Unit, University Hospital, Nottingham, UK.
AIM: The aim of this study was to determine whether the presence of vitamin D insufficiency increases bone turnover and enhances bone loss by examining the relationship between bone turnover markers and Bone mineral density (BMD) in vitamin D insufficient and vitamin D sufficient patients, with established vertebral osteoporosis. SUBJECTS: 119 consecutive, active, community dwelling, elderly women were assessed over a 7-month period between the months of March to October. RESULTS: There was a significant correlation between parathyroid hormone (PTH) and 25 hydroxyvitamin D (25(OH)D), r = - 0. 42 (P < 0.01). The prevalence of vitamin D insufficiency was 26.9% (defined by a 25(OH)D >/= 6.1 microg/l and </= 12 microg/l). This resulted in a statistically significant increase in bone turnover markers compared to the vitamin D sufficient group: bone alkaline phosphatase (P < 0.05), osteocalcin (P < 0.01), hydroxyproline (P < 0.05), free deoxypyridinoline (P < 0.05) and lower bone mineral density at the total hip (P < 0.01). CONCLUSIONS: These results show that there is a high prevalence of vitamin D insufficiency in the active community dwelling elderly with established vertebral osteoporosis presenting to clinical attention, which leads to increased bone turnover, decreased BMD at the hip and thus enhanced risk of further osteoporotic fractures in comparison with vitamin D sufficient subjects.
191. Endocrinol Metab Clin North Am. 1998 Jun;27(2):389-98.
The roles of calcium and vitamin D in the prevention of osteoporosis.
Reid IR.
Department of Medicine, University of Auckland, New Zealand.
Calcium supplementation produces small beneficial effects on bone mass throughout postmenopausal life and may reduce fracture rates by more than this change would predict--possibly by as much as 50%. There is little reason to use vitamin D in young populations that are replete in this compound, but in the elderly at risk of vitamin D deficiency, there is now evidence of significant reductions in nonvertebral fracture rates from physiologic replacement regimens. Some of the most substantial reductions in fracture rates have been found with combined therapy with calcium and vitamin D, and in these protocols it is not clear which is the principal active agent or whether, in fact, the combination is necessary for optimal antifracture efficacy.
192. Nippon Rinsho. 1998 Jun;56(6):1505-10.
[Treatment of osteoporosis by active vitamin D]
[Article in Japanese]
Kawakami H, Morii H.
Osaka City University Medical School.
Supplementation of active vitamin D has been thought to be reasonable for those who convert insufficiently vitamin D to active form, especially for senile persons. Treatment of osteoporosis by vitamin D are accepted as not only supplementation of vitamin D but also direct activation of bone turnover. Several previous clinical trials suggest active vitamin D prevents fractures more effectively rather than the increase of the bone mass. The calcium intake of Japanese people is less than that of Western countries, and many of Japanese have the vitamin D receptor genotype which is more responsive to vitamin D. Therefore, it is probable that active vitamin D is more effective for Japanese than Western people.
193. J Bone Miner Res. 1998 Apr;13(4):544-8.
Seasonal deficiency of vitamin D in children: a potential target for osteoporosis-preventing strategies?
Docio S, Riancho JA, Perez A, Olmos JM, Amado JA, Gonzalez-Macias J.
Service of Pediatrics, Hospital Laredo, Santander, Spain.
Peak bone mass attained after skeletal growth is a major determinant of the risk of developing osteoporosis later in life, hence the importance of nutritional factors that contribute to bone mass gain during infancy and adolescence. An adequate supply of vitamin D is essential for normal bone homeostasis. This study was undertaken to determine what the levels are of 25-hydroxyvitamin D (25(OH)D) that may be considered desirable in children and to assess if normal children maintain these levels throughout the year. Vitamin D metabolites and parathyroid hormone (PTH) serum levels were measured in 21 children in March and October, prior to and after the administration of a daily supplement of 25(OH)D (40 microg for 7 consecutive days). There were inverse correlations between basal 25(OH)D levels and supplementation-induced changes in serum 1,25(OH)2D (r = 0.57, p < 0.05) and PTH (r = 0.41, p < 0.05). When basal levels of 25(OH)D were below 20 ng/ml, the supplement induced an increase in serum 1,25(OH)2D; with basal 25(OH)D under 10-12 ng/ml, the supplement also decreased serum PTH. The lowest serum level of 25(OH)D in 43 normal children studied in summer was 13 ng/ml. Those results suggested that the lowest limit for desirable levels of 25(OH)D in children was somewhere between 12 and 20 ng/ml. However, 31% of 51 normal children studied in winter had levels below 12 ng/ml, and 80% had levels lower than 20 ng/ml. Those children are likely to have suboptimal bioavailability of vitamin D, which might hamper their achievement of an adequate peak bone mass. Since cutaneous synthesis of vitamin D is rather limited in winter, oral vitamin D supplementation should be considered.
194. Am J Med Sci. 1996 Dec;312(6):278-86.
Therapy of osteoporosis: calcium, vitamin D, and exercise.
Reid IR.
Department of Medicine, University of Auckland, New Zealand.
Calcium supplementation has long been regarded as a fundamental part of the prevention and treatment of postmenopausal osteoporosis, but it is only in recent years that clear evidence has emerged demonstrating its impact on bone mass. Calcium supplementation does not completely arrest postmenopausal bone loss but slows the rate of decline by 30 to 50%. The effect of calcium supplementation on fracture incidence in postmenopausal women has not been established. Vitamin D deficiency is common in the frail elderly, particularly in countries where fortification or food with this vitamin is not practiced. Treatment of vitamin D deficiency has been associated with significant reductions in the number of hip fractures. The role of the potent vitamin D metabolites, calcitriol and alphacalcidol, in the management of postmenopausal osteoporosis is not clear. Although some studies show substantial benefits in bone density or |