The use of osteoclast inhibitors in patients with multiple myeloma
- James R Berenson, MD
James R Berenson, MD
- Medical and Scientific Director
- Institute for Myeloma and Bone Cancer Research
- Section Editors
- Robert A Kyle, MD
Robert A Kyle, MD
- Section Editor — Plasma Cell Disorders
- Professor of Medicine
- Mayo Medical School
- Reed E Drews, MD
Reed E Drews, MD
- Section Editor — Complications of Cancer
- Associate Professor of Medicine
- Harvard Medical School
Bisphosphonates are synthetic analogues to inorganic pyrophosphates found within the bone matrix that, unlike natural pyrophosphates, are resistant to hydrolysis by phosphatases found in the blood. Bisphosphonates inhibit bone resorption by suppressing osteoclast activity. They are widely used in the management of lytic bone lesions in patients with multiple myeloma (MM), in the treatment and prevention of osteoporosis, in the treatment of moderate to severe hypercalcemia, and in the therapy of certain other bone diseases.
Lytic skeletal lesions are present at the time of diagnosis in approximately 60 percent of patients with MM and almost all patients with MM will have lytic bone lesions at some point in their disease course. In addition, up to 20 percent of patients with MM will have osteopenia and 10 to 15 percent will have hypercalcemia. (See "Clinical features, laboratory manifestations, and diagnosis of multiple myeloma", section on 'Clinical presentation'.)
The use of bisphosphonate therapy and other osteoclast inhibitors in patients with MM will be presented here. The role of bisphosphonate therapy in the management of other disorders is presented separately, as are the specific side effects associated with each agent. (See "The use of bisphosphonates in postmenopausal women with osteoporosis" and "Treatment of hypercalcemia" and "Risks of therapy with bone antiresorptive agents in patients with advanced malignancy".)
MECHANISM OF ACTION
While the exact mechanism is unknown, bisphosphonates appear to inhibit bone resorption by suppressing osteoclast activity. Clinically, this translates into fewer lytic bone lesions and fewer skeletal events (eg, pathologic fracture) in patients with MM. Bisphosphonates are attracted to calcium and calcium containing molecules, such as hydroxyapatite, which is the major calcium-containing mineral in bone . Bone resorption by osteoclasts results in the exposure of molecules of hydroxyapatite within the lytic lesions. Bisphosphonates are attracted to the hydroxyapatite and accumulate in this space, thereby creating a high local concentration of drug and inhibiting further osteoclast activity [1-3]. Although the exact half-life is unknown, bisphosphonates that are incorporated into bone are thought to remain for at least 10 years .
There are two main classes of bisphosphonates, each with a different proposed mechanism of action . Etidronate and clodronate are non-nitrogen containing bisphosphonates. Non-nitrogen containing bisphosphonates are metabolized to cytotoxic ATP analogues, incorporated into the osteoclast, and induce osteoclast apoptosis. In contrast, nitrogen containing bisphosphonates are proposed to suppress osteoclast activity by binding to and inhibiting the enzyme farnesyl diphosphate synthase in the HMG-CoA reductase pathway. Pamidronate, zoledronic acid, ibandronate, and risedronate are examples of nitrogen-containing bisphosphonates.To continue reading this article, you must log in with your personal, hospital, or group practice subscription. For more information on subscription options, click below on the option that best describes you:
- Terpos E, Sezer O, Croucher PI, et al. The use of bisphosphonates in multiple myeloma: recommendations of an expert panel on behalf of the European Myeloma Network. Ann Oncol 2009; 20:1303.
- Boonekamp PM, van der Wee-Pals LJ, van Wijk-van Lennep MM, et al. Two modes of action of bisphosphonates on osteoclastic resorption of mineralized matrix. Bone Miner 1986; 1:27.
- Rowe DJ, Etre LA, Lovdahl MJ, Pietrzyk DJ. Relationship between bisphosphonate concentration and osteoclast activity and viability. In Vitro Cell Dev Biol Anim 1999; 35:383.
- Kimmel DB. Mechanism of action, pharmacokinetic and pharmacodynamic profile, and clinical applications of nitrogen-containing bisphosphonates. J Dent Res 2007; 86:1022.
- Mundy GR, Yoneda T. Bisphosphonates as anticancer drugs. N Engl J Med 1998; 339:398.
- Yin JJ, Selander K, Chirgwin JM, et al. TGF-beta signaling blockade inhibits PTHrP secretion by breast cancer cells and bone metastases development. J Clin Invest 1999; 103:197.
- Diel IJ, Solomayer EF, Costa SD, et al. Reduction in new metastases in breast cancer with adjuvant clodronate treatment. N Engl J Med 1998; 339:357.
- Aparicio A, Gardner A, Tu Y, et al. In vitro cytoreductive effects on multiple myeloma cells induced by bisphosphonates. Leukemia 1998; 12:220.
- Shipman CM, Rogers MJ, Apperley JF, et al. Bisphosphonates induce apoptosis in human myeloma cell lines: a novel anti-tumour activity. Br J Haematol 1997; 98:665.
- Dhodapkar MV, Singh J, Mehta J, et al. Anti-myeloma activity of pamidronate in vivo. Br J Haematol 1998; 103:530.
- Berenson JR, Lichtenstein A, Porter L, et al. Efficacy of pamidronate in reducing skeletal events in patients with advanced multiple myeloma. Myeloma Aredia Study Group. N Engl J Med 1996; 334:488.
- Berenson JR, Lichtenstein A, Porter L, et al. Long-term pamidronate treatment of advanced multiple myeloma patients reduces skeletal events. Myeloma Aredia Study Group. J Clin Oncol 1998; 16:593.
- Berenson JR, Rosen LS, Howell A, et al. Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases. Cancer 2001; 91:1191.
- 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; 7:377.
- Rosen LS, Gordon D, Kaminski M, et al. Long-term efficacy and safety of zoledronic acid compared with pamidronate disodium in the treatment of skeletal complications in patients with advanced multiple myeloma or breast carcinoma: a randomized, double-blind, multicenter, comparative trial. Cancer 2003; 98:1735.
- McCloskey EV, MacLennan IC, Drayson MT, et al. A randomized trial of the effect of clodronate on skeletal morbidity in multiple myeloma. MRC Working Party on Leukaemia in Adults. Br J Haematol 1998; 100:317.
- 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; 113:1035.
- Lahtinen R, Laakso M, Palva I, et al. Randomised, placebo-controlled multicentre trial of clodronate in multiple myeloma. Finnish Leukaemia Group. Lancet 1992; 340:1049.
- 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. Danish-Swedish co-operative study group. Br J Haematol 1998; 101:280.
- Laakso M, Lahtinen R, Virkkunen P, Elomaa I. Subgroup and cost-benefit analysis of the Finnish multicentre trial of clodronate in multiple myeloma. Finnish Leukaemia Group. Br J Haematol 1994; 87:725.
- Ross JR, Saunders Y, Edmonds PM, et al. Systematic review of role of bisphosphonates on skeletal morbidity in metastatic cancer. BMJ 2003; 327:469.
- Mhaskar R, Redzepovic J, Wheatley K, et al. Bisphosphonates in multiple myeloma: a network meta-analysis. Cochrane Database Syst Rev 2012; :CD003188.
- Menssen HD, Sakalová A, Fontana A, et al. Effects of long-term intravenous ibandronate therapy on skeletal-related events, survival, and bone resorption markers in patients with advanced multiple myeloma. J Clin Oncol 2002; 20:2353.
- Belch AR, Bergsagel DE, Wilson K, et al. Effect of daily etidronate on the osteolysis of multiple myeloma. J Clin Oncol 1991; 9:1397.
- Daragon A, Humez C, Michot C, et al. Treatment of multiple myeloma with etidronate: results of a multicentre double-blind study. Groupe d'Etudes et de Recherches sur le Myélome (GERM). Eur J Med 1993; 2:449.
- Petcu EB, Schug SA, Smith H. Clinical evaluation of onset of analgesia using intravenous pamidronate in metastatic bone pain. J Pain Symptom Manage 2002; 24:281.
- Morgan GJ, Davies FE, Gregory WM, et al. First-line treatment with zoledronic acid as compared with clodronic acid in multiple myeloma (MRC Myeloma IX): a randomised controlled trial. Lancet 2010; 376:1989.
- Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphosphonates in multiple myeloma. J Clin Oncol 2007; 25:2464.
- Lacy MQ, Dispenzieri A, Gertz MA, et al. Mayo clinic consensus statement for the use of bisphosphonates in multiple myeloma. Mayo Clin Proc 2006; 81:1047.
- Terpos E, Morgan G, Dimopoulos MA, et al. International Myeloma Working Group recommendations for the treatment of multiple myeloma-related bone disease. J Clin Oncol 2013; 31:2347.
- Engelhardt M, Terpos E, Kleber M, et al. European Myeloma Network recommendations on the evaluation and treatment of newly diagnosed patients with multiple myeloma. Haematologica 2014; 99:232.
- Anderson KC, Alsina M, Bensinger W, et al. Multiple myeloma. Clinical practice guidelines in oncology. J Natl Compr Canc Netw 2007; 5:118.
- Harrouseau JL, Greil R, Kloke O, ESMO Guidelines Task Force. ESMO Minimum Clinical Recommendations for diagnosis, treatment and follow-up of multiple myeloma. Ann Oncol 2005; 16 Suppl 1:i45.
- Musto P, Petrucci MT, Bringhen S, et al. A multicenter, randomized clinical trial comparing zoledronic acid versus observation in patients with asymptomatic myeloma. Cancer 2008; 113:1588.
- D'Arena G, Gobbi PG, Broglia C, et al. Pamidronate versus observation in asymptomatic myeloma: final results with long-term follow-up of a randomized study. Leuk Lymphoma 2011; 52:771.
- Berenson JR, Yellin O, Boccia RV, et al. Zoledronic acid markedly improves bone mineral density for patients with monoclonal gammopathy of undetermined significance and bone loss. Clin Cancer Res 2008; 14:6289.
- Major P, Lortholary A, Hon J, et al. 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 2001; 19:558.
- Morgan GJ, Davies FE, Gregory WM, et al. Effects of induction and maintenance plus long-term bisphosphonates on bone disease in patients with multiple myeloma: the Medical Research Council Myeloma IX Trial. Blood 2012; 119:5374.
- Durie BG. Use of bisphosphonates in multiple myeloma: IMWG response to Mayo Clinic consensus statement. Mayo Clin Proc 2007; 82:516.
- Gimsing P, Carlson K, Turesson I, et al. Effect of pamidronate 30 mg versus 90 mg on physical function in patients with newly diagnosed multiple myeloma (Nordic Myeloma Study Group): a double-blind, randomised controlled trial. Lancet Oncol 2010; 11:973.
- Berenson JR, Boccia R, Lopez T, et al. Results of a multicenter open-label randomized trial evaluating infusion duration of zoledronic acid in multiple myeloma patients (the ZMAX trial). J Support Oncol 2011; 9:32.
- Morgan GJ, Davies FE, Gregory WM, et al. Long-term follow-up of MRC Myeloma IX trial: Survival outcomes with bisphosphonate and thalidomide treatment. Clin Cancer Res 2013; 19:6030.
- Jackson GH, Morgan GJ, Davies FE, et al. Osteonecrosis of the jaw and renal safety in patients with newly diagnosed multiple myeloma: Medical Research Council Myeloma IX Study results. Br J Haematol 2014; 166:109.
- Larocca A, Child JA, Cook G, et al. The impact of response on bone-directed therapy in patients with multiple myeloma. Blood 2013; 122:2974.
- Himelstein AL, Qin R, Novotny PJ, et al. CALGB 90604 (Alliance): A randomized phase III study of standard dosing vs. longer interval dising of zoledronic acid in metastatic cancer (abstr). J Clin Oncol 33, 2015 (suppl; abstr 9501). Abstract available at http://meetinglibrary.asco.org/content/147845-156 (Accessed on July 09, 2015).
- Body JJ, Lichinitser MR, Diehl I, et al. Double-blind placebo-controlled trial of intravenous ibandronate in breast cancer metastatic to bone (abstract). Proc Am Soc Clin Oncol 1999; 35:575a.
- Terpos E, Viniou N, de la Fuente J, et al. Pamidronate is superior to ibandronate in decreasing bone resorption, interleukin-6 and beta 2-microglobulin in multiple myeloma. Eur J Haematol 2003; 70:34.
- Henry DH, Costa L, Goldwasser F, et al. Randomized, double-blind study of denosumab versus zoledronic acid in the treatment of bone metastases in patients with advanced cancer (excluding breast and prostate cancer) or multiple myeloma. J Clin Oncol 2011; 29:1125.
- Raje NS, Roodman GD, Willenbacher W, et al. Impact of denosumab (DMB) compared with zoledronic acid (ZA) on renal function in the treatment of myeloma bone disease (abstract 8005). J Clin Oncol 2017; 35.
- Major PP, Lipton A, Berenson J, Hortobagyi G. Oral bisphosphonates: A review of clinical use in patients with bone metastases. Cancer 2000; 88:6.
- Daley-Yates PT, Dodwell DJ, Pongchaidecha M, et al. The clearance and bioavailability of pamidronate in patients with breast cancer and bone metastases. Calcif Tissue Int 1991; 49:433.
- Morgan GJ, Child JA, Gregory WM, et al. Effects of zoledronic acid versus clodronic acid on skeletal morbidity in patients with newly diagnosed multiple myeloma (MRC Myeloma IX): secondary outcomes from a randomised controlled trial. Lancet Oncol 2011; 12:743.
- Vinholes JJ, Purohit OP, Abbey ME, et al. Relationships between biochemical and symptomatic response in a double-blind randomised trial of pamidronate for metastatic bone disease. Ann Oncol 1997; 8:1243.
- Kyle RA. The role of bisphosphonates in multiple myeloma. Ann Intern Med 2000; 132:734.
- Coleman R, Body JJ, Aapro M, et al. Bone health in cancer patients: ESMO Clinical Practice Guidelines. Ann Oncol 2014; 25 Suppl 3:iii124.
- Bird JM, Owen RG, D'Sa S, et al. Guidelines for the diagnosis and management of multiple myeloma 2011. Br J Haematol 2011; 154:32.
- MECHANISM OF ACTION
- BENEFITS OF BISPHOSPHONATES IN MYELOMA
- Use in symptomatic MM
- Use in smoldering MM, MGUS, or solitary plasmacytoma
- RISKS OF BISPHOSPHONATE THERAPY
- PRETREATMENT EVALUATION
- Laboratory evaluation
- Imaging studies
- Dental exam
- CHOICE OF AGENT
- Intravenous pamidronate
- Intravenous zoledronic acid
- Intravenous ibandronate
- ORAL BISPHOSPHONATES
- MONITORING DURING THERAPY
- DURATION OF THERAPY
- SOCIETY GUIDELINES
- INFORMATION FOR PATIENTS
- SUMMARY AND RECOMMENDATIONS