Methotrexate concentrations in synovial membrane and trabecular and cortical bone in rheumatoid arthritis patients

Bologna, C; Edno, L.; Anaya, Juan Manuel; Canovas, François; Berghe, Marie Vanden; Jørgensen, Christian; Galtier, M.; Combe, Bernard; Bressolle, Françoise; Sany, J

doi:10.1002/art.1780371210

Cited by 38 publications

(21 citation statements)

References 11 publications

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“…Reduction in the bone mineral density (BMD) has been observed as well as qualitative features of osteopenia, seen in radiograms as shrinking of the cortical bone, lower Singh index, more distinct (due to thinning) trabeculae or -in contrast -lack of the trabecular structure in imaging. Similar reports have been published based on observations in patients treated with MTX for collagenoses [9][10][11][12][13][14][15][16][17]. Apart from clinical symptoms, there was also described in this group of patients inhibition of osteoblast activity [13], as well as a significant reduction in osteocalcin synthesis by osteoblasts [14] -seen in both of the above studies after a weekly administration of MTX at low doses.…”

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confidence: 78%

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Bone tissue as the site of action of oncological drugs

Leśniewski-Kmak¹,

Radecka²,

Litwiniuk³

2011

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Anticancer therapy has multiple, sometimes life-threatening side effects, and their influence on bone is not seen as important. Data have been published confirming the existence of side effects chemotherapy has on bone, which affect patients' quality of life. They influence a bone tissue not only in a direct way, but also when suppressing the activity of gonads. We have no information on the impact of drugs on bone belonging to the "targeted therapies". There are, however, some attempts to create antibodies that target proteins involved in bone physiology. Relatively well known is the impact of anti-cancer hormone therapy on bone metabolism. Bone tissue is of special importance in the pathophysiology and the clinical course of neoplastic diseases. Metastases to bones do not pose a direct threat to the patient's life, yet they markedly lower the quality of life and may be associated with complications leading to severe disability and, in consequence, to shortening of the patient's life. In the clinical picture of certain neoplasms, such as multiple myeloma, prostate cancer, thyroid cancer or sometimes breast cancer, the dominating symptoms are those related to bone infiltration. On the other hand, there are also effects of the oncological treatment on the bone -both those concerning the physiological bone cycle (of increasing importance with the observed prolongation of patient life) and the interactions between the neoplastic cells and bone cells. Below, we present a literature review on this subject. The issue of steroid therapy's effects on bones is not addressed here as the multitude of usages of this drug class resulted in the subject being already extensively discussed in other publications. ChemotherapyAdverse effects of chemotherapy concerning bones may in a longer-term perspective lead to health complaints markedly lowering the quality of life, particularly in patients with good prognosis, even more so because this approach is often combined with different hormone and radiation therapies. As early as in 1965, a report was published presenting the results of a study on the effects of methotrexate (MTX) treatment on calcium metabolism, demonstrating elevated levels of this element in urine and stool, its lowered levels in blood serum, and indirectly its increased bone resorption [1]. The above data have been reflected in a clinical setting, in patients treated with MTX for acute myeloid leukaemia, where there have been observed pain and difficult uniting of fractures during the course of treatment and remission upon its completion [2][3][4][5][6][7][8]. Although the high doses of steroids have been of significance, the cytostatic agents have been deemed to play an important role here. Reduction in the bone mineral density (BMD) has been observed as well as qualitative features of osteopenia, seen in radiograms as shrinking of the cortical bone, lower Singh index, more distinct (due to thinning) trabeculae or -in contrast -lack of the trabecular structure in imaging. Similar reports have been published base...

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confidence: 78%

“…On the other hand, no effects of the drug on osteoblast differentiation have been found [16]. The MTX potential for directly affecting bones is indicated by its high level in the cortical and trabecular bone one day after its intramuscular administration [17]. Katz and colleagues [18] have…”

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confidence: 99%

Bone tissue as the site of action of oncological drugs

Leśniewski-Kmak¹,

Radecka²,

Litwiniuk³

2011

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“…Histologic evaluation revealed no apparent changes in the lowest concentrations used (0.5 nM) were similar to those found in human synovium and bone (0.28 and 0.29 nM, respectively) following administration of intramuscular MTX (14), and the highest concentration (0.6 ClM) was comparable with that found in serum following standard dosing (11). It must be noted that the MTX concentrations used were present in the cell cultures on a continuous basis, which is unlike the brief, weekly peaks noted in routine human dosing.…”

Section: Resultsmentioning

confidence: 55%

The effect of methotrexate on mouse bone cells in culture

May¹,

Mercill

McDermott

et al. 1996

Arthritis & Rheumatism

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Objective. We have recently shown that administration of long-term, lowdose methotrexate (MTX) causes severe osteopenia in female rats. This osteopenia is characterized both by decreased osteoblast function without a decrease in osteoblast numbers, and by increased bone resorption that is believed to represent a physiologic remodeling response by osteoclasts. The present study investigates the effects of varying doses of MTX on mouse bone cells in culture.Methods. Cells were obtained by sequential digestion of neonatal mouse calvariae, and cultured with fetal calf serum (10% for osteoblast-like cells and 2% for osteoclast-like cells). After 1 week, MTX was added to each culture in concentrations of 0.6 pM, 0.4 pM, 0.2 jdf, 0.1 jdf, 1 IN, and 0.5 nM. All experiments were done on 24 wells for each MTX concentration and for the controls. The effect on osteoblastic cells was assessed, at 7 days, by cell counts and by measurement of lysate alkaline phosphatase and supernatant osteocalcin levels, and, at 21 days, by analysis of the calcified matrix production, which was cultured with ascorbic acid and Fglycerophosphate. For osteoclastic cells, cell count and lysate acid phosphatase levels were determined.Resuks. Levels of osteoblastic cells and lysate alkaline phosphatase were not changed by any of the concentrations of MTX. Matrix calcification and supernatant osteocalcin levels were diminished by MTX in a dose-responsive manner. Osteoclast-like cell numbers and acid phosphatase levels were not significantly affected by MTX. Conclusion.These results suggest that diminished mouse osteoblastic cell function Occurs with very low mean concentrations of MTX, in a dose-responsive manner. The mechanism seems to be inability of the cell to synthesize and calcify matrix, possibly through defective osteocalcin production. Thus, low-dose MTX may have an important impact on bone density by slowing osteoblastic matrix production.Methotrexate (MTX) is a folate antagonist that is commonly used in the treatment of rheumatoid arthritis (RA) and other inflammatory diseases. It is known that administration of MTX in high doses to treat childhood leukemias and breast cancer has been associated with the development of bone pain, severe osteopenia, and fractures (14). The inhibition of conversion of folic acid to tetrahydrofolic acid by competitive inhibition of the enzyme, dihydrofolate reductase, and the subsequent inhibition of DNA synthesis, accounts for the antiproliferative effects of MTX on cancer cells, and may account for the osteopenia observed in these patients (1). Limited human data on high-dose regimens ( 2 4 , however, point to stimulation of bone resorption, rather than decrease in bone formation, as the etiologic mechanism of osteopenia in these patients. Our previous studies investigated the skeletal effects of long-term, low-dose MTX in rats, using a regimen similar to that used for inflammatory disease states. In those studies, we demonstrated significant osteopenia, which was characterized by diminished osteoblast fu...

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“…These 2 million PBMC were then cultured for 24 hours with PHA or PHA plus MTX at the same concentrations, and culture supernatants were stored at -80°C until cytokine levels were measured using specific ELISAs. The MTX concentration used was within the range of therapeutic serum levels obtained after intramuscular administration of 7.5-10 mg of MTX (36,37). PBMC viability after incubation with PHA or PHA plus MTX was studied by flow cytometry with propidium iodide staining and was, respectively, 98.2% and 97.8% after 8 hours, and 97.0% and 96.7% after 24 hours, of cell culture.…”

Section: Methodsmentioning

confidence: 99%