Bisphosphonates for Multiple Myeloma: A Systematic Review_Chinese Journal of Evidence-Based Medicine

Authors：

YAO Xiaojian ,  LIU Chunxia

The First Hospital of Lanzhou Universtiy, Lanzhou 730000, China;

Corresponding author：

LIU Chunxia, Email: lcx8942@sina.com.cn

Keywords：

Bisphosphonates; Multiple myeloma; Systematic review; Randomized controlled trial

DOI：

10.7507/1672-2531.20100568

Video：

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Objective 　To evaluate the efficacy of bisphosphonates in treating patients with Multiple Myeloma.
Methods 　The databases including The Cochrane Library, PubMed, EMBASE, CBM, and CNKI were searched. Quality assessment and data extraction were conducted by two reviewers independently, and disagreement, if any, was resolved by discussion. Meta-analyses were performed for homogeneous studies.
Results 　Eleven RCTs were included, all of which came from abroad. The methodological quality of the included studies was good. The baseline data of each trial were comparable. Meta-analyses showed that, the pooled analysis of the published evidence demonstrated the beneficial effect of bisphosphonates on prevention of pathological vertebral fractures (OR=0.59, 95%CI 0.45 to 0.78, P=0.000 1) and on relieving pain (OR=0.59, 95%CI 0.46 to 0.76, P=0.000 05). However, the analysis of the effect of bisphosphonates on pain was based on clinically heterogeneous data which must be interpreted with caution. Meanwhile, there was no significant effect of bisphosphonates on mortality (OR=0.99, 95%CI 0.88 to 1.12, P=0.9) and hypercalcemia (OR=0.76, 95%CI 0.56 to 1.03, P=0.07).
Conclusions 　Adding bisphosphonates to the treatment of myeloma can reduce pathological vertebral fractures and pain, but is not helpful to mortality and hypercalcemia.

Citation： YAO Xiaojian,LIU Chunxia. Bisphosphonates for Multiple Myeloma: A Systematic Review. Chinese Journal of Evidence-Based Medicine, 2010, 10(10): 1188-1193. doi: 10.7507/1672-2531.20100568 Copy

1.	Alexanian R, Dimopulos M. The treatment of multiple myeloma. N Eng J Med, 1994, 330: 484-489.
2.	Raje N, Anderson KC. Introduction: the evolving role of bisphosphonate therapy in multiple myeloma. Blood, 2000, 96(2): 381-383.
3.	Berenson JR, Lichtenstein A, Porter L, et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. J Clin Oncol, 1998, 16(2): 593-602.
4.	Aparicio A, Gardner A, Tu Y, et al. In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates. Leukemia, 1998, 12(2): 220-229.
5.	Shipman CM, Rogers MJ, Apperley JF. Bisphosphonates induce apoptosis in human myeloma cells: a novel anti-tumour activiy. Br J Haematol, 1997, 98(3): 665-672.
6.	Cohen J. A coemcient of agreement for nominal scales. Educ Psychol Meas, 1960, 20(42): 37-46.
7.	Belch AR, Bergsagel DE, Wilson K, et al. Effect of daily etidronate on the osteolysis of multiple myeloma. J Clin Oncol, 1991, 9(8): 1397-1402.
8.	Berenson JR, Lichtenstein A, Porter L, et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. J Clin Oncol, 1998, 16(2): 593-602.
9.	Brincker H, Westin J, Abildgaard N, et al. Failure of oral pamidronate to reduce skeletal morbidity in multiple myeloma: a double-blind placebo controlled trial. Br J Haematol, 1998, 101(2): 280-286.
10.	Daragon A, Humez C, Michot C, et al. Treatment of multiple myeloma with etidronate results of a multicentre double-blind study.Eur J Med, 1993, 2(8): 449-452.
11.	Delmas PD, Charhon S, Chapuy MC, et al. Long-term effects of dichloromethylene diphosphonate (CI2MDP) on skeletal lesions in multiple myeloma. Metab Bone Dis Relat Res, 1982, 4(3): 163-168.
12.	Heim ME, Clemens MR, Queiber W, et al. Prospective randomized trial of dichloromethilene bisphosphonate (clodronate) in patients with multiple myeloma. Onkologie, 1995, 18: 439-444.
13.	Lahtinen R, Laakso M, Palva I, et al. Randomized,placebo-controlled multicentre trial of clodronate in multiple myeloma. Lancet, 1992, 340(8827): 1049-1052.
14.	McCloskey EV, Dunn JA, Kanis JA, et al. Long-term follow-up of a prospective,double-blind,placebo-controlled randomized trial of clodronate in multiple myeloma. Br J Haematol, 2001, 113(4): 1035-1043.
15.	Fontana A, Herrmann Z, Menssen HD, et al. Effects of intravenous ibandronate therapy on skeletal related events (SRE)and survival in patients with advanced multiple myeloma. Blood, 1998, 92(Suppl1): 106a.
16.	Terpos E, Palermos J, Tsionos K, et al. Effect of pamidronate administration on markers of bone turnover and disease activity in multiple myeloma. Eur J Haematol, 2000, 65(5): 331-336.
17.	Kraj M, Poglod R, Pawlikowsky J, et al. The effect of pamidronate treatment on skeletal morbidity in advanced multiple myeloma. Acta Haematologica Polonica, 2000, 31: 379-389.
18.	Rosen LS, Gordon D, Kaminski M, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase Ⅲ, double - blind,comparative trial. Cancer J, 2001, 7(5): 377-387.
19.	Ali SM, Esteva FJ, Hortobagyi G, et al. Safety and efficacy of bisphosphonates beyond 24 months in cancer patients. J Clin Oncol, 2001, 19(14): 3434-3437.
20.	Croucher PI, Shipman CM, Lippitt J, et al. Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma.Blood, 2001, 98(13): 3534-3540.
21.	Mundy G, Garrett R, Harris S, et al. Stimulation of bone formation in vitro and in rodents by statins. Science, 1999, 286(5446): 1946-1949.

1. Alexanian R, Dimopulos M. The treatment of multiple myeloma. N Eng J Med, 1994, 330: 484-489.
2. Raje N, Anderson KC. Introduction: the evolving role of bisphosphonate therapy in multiple myeloma. Blood, 2000, 96(2): 381-383.
3. Berenson JR, Lichtenstein A, Porter L, et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. J Clin Oncol, 1998, 16(2): 593-602.
4. Aparicio A, Gardner A, Tu Y, et al. In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates. Leukemia, 1998, 12(2): 220-229.
5. Shipman CM, Rogers MJ, Apperley JF. Bisphosphonates induce apoptosis in human myeloma cells: a novel anti-tumour activiy. Br J Haematol, 1997, 98(3): 665-672.
6. Cohen J. A coemcient of agreement for nominal scales. Educ Psychol Meas, 1960, 20(42): 37-46.
7. Belch AR, Bergsagel DE, Wilson K, et al. Effect of daily etidronate on the osteolysis of multiple myeloma. J Clin Oncol, 1991, 9(8): 1397-1402.
8. Berenson JR, Lichtenstein A, Porter L, et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. J Clin Oncol, 1998, 16(2): 593-602.
9. Brincker H, Westin J, Abildgaard N, et al. Failure of oral pamidronate to reduce skeletal morbidity in multiple myeloma: a double-blind placebo controlled trial. Br J Haematol, 1998, 101(2): 280-286.
10. Daragon A, Humez C, Michot C, et al. Treatment of multiple myeloma with etidronate results of a multicentre double-blind study.Eur J Med, 1993, 2(8): 449-452.
11. Delmas PD, Charhon S, Chapuy MC, et al. Long-term effects of dichloromethylene diphosphonate (CI2MDP) on skeletal lesions in multiple myeloma. Metab Bone Dis Relat Res, 1982, 4(3): 163-168.
12. Heim ME, Clemens MR, Queiber W, et al. Prospective randomized trial of dichloromethilene bisphosphonate (clodronate) in patients with multiple myeloma. Onkologie, 1995, 18: 439-444.
13. Lahtinen R, Laakso M, Palva I, et al. Randomized,placebo-controlled multicentre trial of clodronate in multiple myeloma. Lancet, 1992, 340(8827): 1049-1052.
14. McCloskey EV, Dunn JA, Kanis JA, et al. Long-term follow-up of a prospective,double-blind,placebo-controlled randomized trial of clodronate in multiple myeloma. Br J Haematol, 2001, 113(4): 1035-1043.
15. Fontana A, Herrmann Z, Menssen HD, et al. Effects of intravenous ibandronate therapy on skeletal related events (SRE)and survival in patients with advanced multiple myeloma. Blood, 1998, 92(Suppl1): 106a.
16. Terpos E, Palermos J, Tsionos K, et al. Effect of pamidronate administration on markers of bone turnover and disease activity in multiple myeloma. Eur J Haematol, 2000, 65(5): 331-336.
17. Kraj M, Poglod R, Pawlikowsky J, et al. The effect of pamidronate treatment on skeletal morbidity in advanced multiple myeloma. Acta Haematologica Polonica, 2000, 31: 379-389.
18. Rosen LS, Gordon D, Kaminski M, et al. Zoledronic acid versus pamidronate in the treatment of skeletal metastases in patients with breast cancer or osteolytic lesions of multiple myeloma: a phase Ⅲ, double - blind,comparative trial. Cancer J, 2001, 7(5): 377-387.
19. Ali SM, Esteva FJ, Hortobagyi G, et al. Safety and efficacy of bisphosphonates beyond 24 months in cancer patients. J Clin Oncol, 2001, 19(14): 3434-3437.
20. Croucher PI, Shipman CM, Lippitt J, et al. Osteoprotegerin inhibits the development of osteolytic bone disease in multiple myeloma.Blood, 2001, 98(13): 3534-3540.
21. Mundy G, Garrett R, Harris S, et al. Stimulation of bone formation in vitro and in rodents by statins. Science, 1999, 286(5446): 1946-1949.

Chinese Journal of Evidence-Based Medicine

Bisphosphonates for Multiple Myeloma: A Systematic Review

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