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Short-Term Intermittent Intravenous Clodronate in the Prevention of Bone Loss Related to Chemotherapy-Induced Ovarian Failure

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Abstract

Chemotherapy-induced ovarian failure causes rapid bone loss in premenopausal women with early breast cancer. The aim of the present study was to investigate the effect of intravenous intermittent clodronate during adjuvant chemotherapy in prevention of this rapid bone loss. 45 premenopausal women with early stage breast cancer were treated with adjuvant chemotherapy. In addition, all women were randomly allocated to receive either seven cycles of intravenous clodronate infusions (1500 mg each) parallel to the chemotherapy or no further therapy. The mean bone loss in the lumbar spine at 6 months was −0.5% in the clodronate group and −1.4% in the control group (p= 0.22) and, at 12 months, −3.9% and −3.6%, respectively (p= 0.62). Type I collagen metabolite PINP levels at six months were significantly lower in the clodronate group than in the control group: 22.6 μg/l (range 15.7–55.8 μg/l) and 44.0 μg/l (range 12.5–91.9 μg/l), respectively (p= 0.0001). At 12 months, no difference between the PINP levels in clodronate and control groups were seen. In conclusion, in this small study a short-term intermittent intravenous clodronate treatment did not seem to prevent clinically significantly the bone loss related to chemotherapy-induced ovarian failure in premenopausal women with early stage breast cancer, even though a significant reduction of a biochemical marker of bone turnover (PINP) was seen during the therapy.

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References

  1. Genant HK, Cann CE, Ettinger B, Gordan GS: Quantitative computed tomography of vertebral spongiosa: a sensitive method for detecting early bone loss after oophorectomy. Ann Intern Med 97: 699–705, 1982

    Google Scholar 

  2. Richelson LS, Wahner HW, Melton LJ III, Riggs BL: Relative contributions of aging and estrogen de ciency to postmenopausal bone loss. N Engl J Med 311: 1273–1275, 1984

    Google Scholar 

  3. Pouilles JM, Tremollieres F, Bonneu M, Ribot C: Influence of early age at menopause on vertebral bone mass. J Miner Res 9: 311–315, 1994

    Google Scholar 

  4. Bines J, Oleske DM, Cobleigh MA: Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol 14: 1718–1729, 1996

    Google Scholar 

  5. Saarto T, Blomqvist C, Välimäki M, Mäkelä P, Sarna S, Elomaa I: Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and. uorouracil chemotherapy causes rapid bone loss that is reduced by clodronate: a randomized study in premenopausal breast cancer patients. J Clin Oncol 15: 1341–1347, 1997

    Google Scholar 

  6. Storm T, Thamsborg G, Steiniche T, Genant HK, Sorensen OH: Effect of intermittent cyclical etidronate therapy on bone mass and fracture rate in women with postmenopausal osteoporosis. N Engl J Med 322: 1265–1271, 1990

    Google Scholar 

  7. Watts NB, Harris ST, Genant HK, Wasnich RD, Miller PD, Jackson RD, Licata AA, Ross P, Woodson GC III, Yanover MJ: Intermittent cyclical etidronate treatment of postmenopausal osteoporosis. N Engl J Med 323: 73–79, 1990

    Google Scholar 

  8. Giannini S, D'Angelo A, Malvasi L, Castrignano R, Pati T, Tronca R, Liberto L, Nobile M, Crepaldi G: Effects of oneyear cyclical treatment with clodronate on postmenopausal bone loss. Bone 14: 137–141, 1993

    Google Scholar 

  9. Harris ST, Watts NB, Jackson RD, Genant HK, Wasnich RD, Ross P, Miller PD, Licata AA, Chesnut CH III: Four-year study of intermittent cyclic etidronate treatment of postmenopausal osteoporosis: three years of blinded ther-apy followed by one year of open therapy. Am J Med 95: 557–567, 1993

    Google Scholar 

  10. Filipponi P, Pedetti M, Fedeli L, Cini L, Palumbo R, Boldrini S, Massoni C, Cristallini S: Cyclic clodronate is Effective in preventing postmenopausal bone loss: a com-parative study with transcutaneous hormone replacement therapy. J Bone Miner Res 10: 697–703, 1995

    Google Scholar 

  11. Filipponi P, Cristallini S, Rizzello E, Policani G, Fedeli L, Gregorio F, Boldrini S, Troiani S, Massoni C: Cyclical intravenous clodronate in postmenopausal osteoporosis: results of a long-term clinical trial. Bone 18: 179–184, 1996

    Google Scholar 

  12. Liberman UA, Weiss SR, Broll J, Minne HW, Quan H, Bell NH, Rodriguez-Portales J, Downs RW Jr, Dequeker J, Favus M: Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. N Engl J Med 333: 1437–1443, 1995

    Google Scholar 

  13. Black DM, Cummings SR, Karpf DB, Cauley JA, Thomp-son DE, Nevitt MC, Bauer DC, Genent HK, Haskell WL, Marcus R, Ott SM, Torner JC, Quandt SA, Reiss TF, Ensrud KE: Randomized trial of Effect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet 348: 1535–1541, 1996

    Google Scholar 

  14. Cummings SR, Black DM, Thompson DE, Applegate WB, Barrett-Connor E, Musliner TA, Palermo L, Prineas R, Rubin SM, Scott JC, Vogt T, Wallace R, Yates AJ, LaCroix AZ: Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results of the fracture intervention trial. JAMA 280: 2077–2082, 1998

    Google Scholar 

  15. Harris ST, Watts NB, Genant HK, McKeever CD, Han-gartner T, Keller M, Chesnut CH III, Brown J, Eriksen EF, Hoseyni MS, Axelrod DW, Miller PD: Effects of risedro-nate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. JAMA 282: 1344–1352, 1999

    Google Scholar 

  16. McClung MR, Geusens P, Miller PD, Zippel H, Bensen WG, Roux C, Adami S, Fogelman I, Diamond T, Eastell R, Meunier PJ, Reginster JY: Hip intervention Progran Study Group. Effect of risedronate on the risk of hip fracture in elderly women. New Engl J Med 344: 333–340, 2001

    Google Scholar 

  17. Vehmanen L, Saarto T, Elomaa I, Mäkelä P, Välimäki M, Blomqvist C: Long-term impact of chemotherapy-induced ovarian failure on bone mineral density (BMD)in pre-menopausal breast cancer patients. The Effect of adjuvant clodronate treatment. Eur J Cancer 37: 2373–2378, 2001

    Google Scholar 

  18. Saarto T, Vehmanen L, Elomaa I, Välimäki M, Mäkelä P, Blomqvist C: The Effect of clodronate and antioestrogens on bone loss associated with oestrogen withdrawal in postmenopausal women with breast cancer. Br J Cancer 84: 1047–1051, 2001

    Google Scholar 

  19. Elomaa I, Blomqvist C, Gröhn P, Porkka L, Kairento AL, Selander K, Lamberg-Allardt C, Holmstrom T: Long-term controlled trial with diphosphonate in patients with oste-olytic bone metastases. Lancet 1: 146–149, 1983

    Google Scholar 

  20. Martoni A, Guaraldi M, Camera P, Biagi R, Marri S, Beghe F, Pannuti F: Controlled clinical study on the use of dichloromethylene diphosphonate in patients with breast cancer metastasizing to skeleton. Oncology 48: 97–101, 1991

    Google Scholar 

  21. Paterson AH, Powles TJ, Kanis JA, McCloskey E, Hanson J, Ashley S: Double-blind controlled trial of oral clodronate in patients with bone metastases from breast cancer. J Clin Oncol 11: 59–65, 1993

    Google Scholar 

  22. van Holten-Verzantvoort ATM, Kroon HM, Bijvoet OL, Cleton FJ, Beex LV, Blijham G, Hermans J, Neijt JP, Papapoulos SE, Sleeboom HP: Palliative pamidronate treatment in patients with bone metastases from breast cancer. J Clin Oncol 11: 491–498, 1993

    Google Scholar 

  23. Conte PF, Latreille J, Mauriac L, Calabresi F, Santos R, Campos D, Bonneterre J, Francini G, Ford JM: Delay in progression of bone metastases in beast cancer patients treated with intravenous pamidronate: results from a multinational randomized controlled trial. J Clin Oncol 14: 2552–2559, 1996

    Google Scholar 

  24. Hortobagyi GN, Theriault RL, Lipton A, Porter L, Blayney D, Sinoff C, Wheeler H, Simeone JF, Seaman JJ, Knight RD, Heffernan M, Mellars K, Reitsma DJ.: Long-term prevention of skeletal complications of metastatic breast cancer with pamidronate. J Clin Oncol 16: 2038–2044, 1998

    Google Scholar 

  25. Theriault RL, Lipton A, Hortobagyi GN, Leff R, Gluck S, Stewart JF, Costello S, Kennedy I, Simeone J, Seaman JJ, Knight RD, Mellars K, Heffernan M, Reitsma DJ: Pamidronate reduces skeletal morbidity in women with advanced breast cancer and lytic bone lesions: a random-ized, placebo-controlled trial. J Clin Oncol 17: 846–854, 1999

    Google Scholar 

  26. Diel IJ, Solomayer EF, Costa SD, Gollan C, Goerner R, Wallwiener D, Kaufmann M, Bastert G: Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 339: 357–363, 1998

    Google Scholar 

  27. Saarto T, Blomqvist C, Virkkunen P, Elomaa I: Adjuvant clodronate treatment does not reduce the frequency of skeletal metastases in node-positive breast cancer patients: 5-year results of a randomized controlled trial. J Clin Oncol 19, 10–17, 2001

    Google Scholar 

  28. Powles TJ, Paterson S, Kanis JA, McCloskey E, Ashley S, Tidy A, Rosenqvist K, Smith I, Ottestad L, Legault S, Pajunen M, Nevantaus A, Mannisto E, Suovuori A, Atula S, Nevalainen J, Pylkkanen L: Randomized, placebo-controlled trial of clodronate in patients with primary operable breast cancer. J Clin Oncol 20: 3219–3224, 2002

    Google Scholar 

  29. Riis BJ, Johansen J, Christiansen C: Continuous oestrogen–progestogen treatment and bone metabolism in post-men-opausal women. Maturitas 10: 51–58, 1988

    Google Scholar 

  30. Uebelhart D, Schlemmer A, Johansen JS, Gineyts E, Christiansen C, Delmas PD: Effect of menopause and hormone replacement therapy on the urinary excretion of pyridinium cross-links. J Clin Endocrinol Metab 72: 367–373, 1991

    Google Scholar 

  31. Bonde M, Qvist P, Fledelius C, Riis BJ, Cristiansen C: Applications of an enzyme immunoassay for a new marker of bone resorption (cross laps): Follow-up on hormone replacement therapy and osteoporosis risk assessment. J Clin Endocrinol Metab 80: 864–868, 1995

    Google Scholar 

  32. Bjarnason NH, Christiansen C: Early response in biochemical markers predicts long-term response in bone mass during hormone replacement therapy in early postmenopausal women. Bone 26: 551–552, 2000

    Google Scholar 

  33. Watts NB, Nolan JC, Brennan JJ, Yang HM: Esterified estrogen therapy in postmenopausal women. Relationships of bone marker changes and plasma estradiol to BMD changes: a two-year study. Menopause 7: 375–382, 2000

    Google Scholar 

  34. Garnero P, Shih WJ, Gineyts E, Karpf DB, Delmas PD: Comparison of new biochemical markers of bone turnover in late postmenopausal osteoporotic women in response to alendronate treatment. J Clin Endocrinol Metab 79: 1693–1700, 1994

    Google Scholar 

  35. Pedrazzoni M, Alfano F, Gatti C, Fantuzzi M, Girasole G, Campanini C, Basini G, Passeri M: Acute Effects of biphosphonates on new and traditional markers of bone resorption. Calcif Tissue Int 57: 25–29, 1995

    Google Scholar 

  36. Fink E, Cormier C, Steinmetz P, Kindermans C, Le Bouc Y, Souberbielle JC: Differences in the capacity of several biochemical bone markers to assess high bone turnover in early menopause and response to alendronate therapy. Osteoporosis International 11: 295–303, 2000

    Google Scholar 

  37. Watts NB, Jenkins DK, Visor JM, Casal DC, Geusens P: Comparison of bone and total alkaline phosphatase and bone mineral density in postmenopausal osteoporotic women treated with alendronate. Osteoporosis Interna-tional 12: 279–288, 2001

    Google Scholar 

  38. Saarto T, Blomqvist C, Risteli J, Risteli L, Sarna S, Elomaa I: Aminoterminal propeptide of type I procollagen (PINP) correlates to bone loss and predicts the efficacy of antire-sorptive therapy in pre-and postmenopausal non metastatic breast cancer patients. Br J Cancer 78: 240–245, 1998

    Google Scholar 

  39. Melkko J, Kauppila S, Niemi S, Risteli L, Haukipuro K, Jukkola A, Risteli J: Immunoassay for the intact amino-terminal propeptide of human type I procollagen (PINP). Clin Chem 42: 947–954, 1996

    Google Scholar 

  40. Risteli J, Elomaa I, Niemi S, Novamo A, Risteli L: Radioimmunoassay for the pyridoline cross-linked carboxy-terminal telopeptide of type I collagen: a new serum marker of bone collagen degradation. Clin Chem 39: 635–640, 1993

    Google Scholar 

  41. Purohit OP, Radstone CR, Anthony C, Kanis JA, Coleman RE: A randomised double-blind comparison of intravenous pamidronate and clodronate in the hypercalcaemia of malignancy. BJC 72: 1289–1293, 1995

    Google Scholar 

  42. Atula ST, Tahtela RK, Nevalainen JI, Pylkkanen LH: Clodronate as a single-dose intravenous infusion Effectively provides short-term correction of malignant hypercalcemia. Acta Oncol 42: 735–740, 2003

    Google Scholar 

  43. Major P, Lortholary A, Hon J, Abdi E, Mills G, Menssen HD, Yunus F, Bell R, Body J, Quebe-Fehling E, Seaman J: Zoledronic acid is superior to pamidronate in the treatment of hypercalcemia of malignancy: a pooled analysis of two randomized, controlled clinical trials. J Clin Oncol 19: 558–567, 2001

    Google Scholar 

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Vehmanen, L., Saarto, T., Risteli, J. et al. Short-Term Intermittent Intravenous Clodronate in the Prevention of Bone Loss Related to Chemotherapy-Induced Ovarian Failure. Breast Cancer Res Treat 87, 181–188 (2004). https://doi.org/10.1023/B:BREA.0000041624.00665.4e

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