Bisphosphonates in the Prevention and Treatment of Bone Metastases
By Bhuvaneswari Ramaswamy, MD1, Charles L. Shapiro, MD2 |
September 1, 2003
1Instructor of Medicine, Breast Cancer Fellow
2Associate Professor of Medicine, Director of Breast Medical Oncology, Ohio State University Medical Center and Comprehensive Cancer Center, Columbus, Ohio
Bruce E. Hillner,MD
Bisphosphonates in the Prevention of Skeletal Metastases
Results of in vivo studies suggest a potential role for bisphosphonates in preventing skeletal metastases through apoptotic and antitumor effects.[ 21-25] Most of the randomized trials have focused on breast cancer, testing whether bisphosphonates will delay or prevent skeletal metastases. Two types of breast cancer patients have been enrolled in these trials: those at high risk for bone metastases, such as patients with evidence of extraskeletal metastases or presumed breast cancer cells in the bone marrow detected by immunohistochemistry but no radiographic evidence of skeletal metastases; and unselected patients with early-stage breast cancer. The results of these trials are described in Table 6.[56-61]
In a small trial in stage IV breast cancer patients without skeletal metastases, clodronate at 1,600 mg or placebo was administered for 3 years. The investigators reported a significant reduction in the total number of bone metastases (32 vs 63; P < .005). A similar trial of oral pamidronate(Drug information on pamidronate) failed to confirm these results, probably reflecting the poor oral bioavailability of pamidronate.
A larger trial of clodronate at 1,600 mg for 2 years was conducted in breast cancer patients with tumor cells in the bone marrow. At 3 years of follow-up, clodronate-treated patients had significantly fewer skeletal and visceral metastases and an improved overall survival. At 4.5 years of follow-up, the reductions in visceral metastases were no longer significant, but the reductions in skeletal metastases and improvements in survival were maintained. Potential weaknesses of this trial include a highly selected patient population (with tumor cells in the bone marrow identified by immunohistochemistry) and a non-placebo-controlled design.
The results of two randomized trials of adjuvant clodronate in localized, nonmetastatic breast cancer patients are conflicting. Saarto et al reported the results for 299 nodepositive breast cancer patients treated with adjuvant hormonal or chemotherapy with or without clodronate at 1,600 mg/d for 3 years. At the end of 5 years, the incidence of skeletal metastases was equivalent in the clodronate and control groups (21% vs 17%, P = .27). However, clodronate- treated patients had a significantly higher incidence of extraskeletal metastases (43% vs 25%, P = .0007) and a poorer disease-free (56% vs 71%, P = .007) and overall survival (70% vs 83%, P = .009).
Powles et al randomized 1,069 localized breast cancer patients receiving adjuvant tamoxifen(Drug information on tamoxifen), chemotherapy, or both, to either clodronate at 1,600 mg per day for 2 years or placebo.[ 61] At 5.5 years of follow-up, the overall incidence of skeletal metastases (12% vs 15%, P = .127) and extraskeletal metastases (21% vs 24%, P = .257) did not differ. However, in a predetermined subset analysis, skeletal metastases were less frequent (2% vs 5%, P = .016) in the clodronate arm during the 2-year treatment period. Surprisingly, the overall survival benefit just reached statistical significance among clodronate-treated patients (83% vs 79%, P = .047).
The problem of relatively low sample size and the inherent statistical uncertainty in the Saarto trial notwithstanding, it is hard to reconcile the opposite results in these trials. A confirmatory placebo-controlled trial of clodronate (National Surgical Adjuvant Breast and Bowel Project B-34 trial) in localized breast cancer patients is ongoing. At this time, bisphosphonates for the prevention of skeletal metastases should only be offered in the context of a clinical trial.
No published trials have addressed the prevention of skeletal metastases in multiple myeloma patients with osteopenia but without radiographic lytic lesions. However, the ASCO clinical practice guidelines concluded that it is reasonable to recommend bisphosphonates in this patient population.
Osteoporosis and osteopenia can occur in cancer patients secondary to treatment effects. This is particularly relevant in breast and prostate cancers due to the prevalence of these diseases.
Chemotherapy-induced ovarian failure is common among premenopausal breast cancer patients, with prospective studies documenting rapid and accelerated loss of bone mineral density. Three randomized controlled trials have shown that oral clodronate and risedronate (Actonel) decrease bone loss in premenopausal women receiving adjuvant chemotherapy.[ 65-67]
The Cancer and Leukemia Group B is currently performing a randomized trial of zoledronate in premenopausal women receiving adjuvant chemotherapy. In addition to adequate intake of vitamin D and calcium, weight-bearing exercise, and counseling about the relationship between bone loss and alcohol(Drug information on alcohol) and cigarette smoking, breast cancer patients who develop ovarian failure should have their bone density measured and, if appropriate, should be treated with bisphosphonates approved for the prevention and treatment of osteoporosis.
In postmenopusal breast cancer patients, the aromatase inhibitors act by inhibiting the aromatase enzyme responsible for estrogen production. Two such drugs, anastrozole(Drug information on anastrozole) (Arimidex) and letrozole(Drug information on letrozole) (Femara), are superior to tamoxifen in the treatment of postmenopausal metastatic breast cancer patients with estrogen-receptor- positive tumors and are approved for this indication. A recent large study demonstrated the superiority of anastrozole over tamoxifen in postmenopausal breast cancer patients with localized disease and led to its approval for this indication. One troubling side effect of anastrozole is skeletal fractures, which develop more frequently with longer follow-up in patients taking the drug. As in premenopausal breast cancer patients with ovarian failure, it is reasonable for patients taking this drug to get their bone density checked and, if appropriate, initiate bisphosphonate therapy. Ongoing randomized trials are evaluating aromatase inhibitors in combination with bisphosphonates in postmenopausal women with early-stage, estrogen-receptor- positive breast cancer.
Indications for Bisphosphonates in Cancer Patients
Men with prostate cancer who are castrated or receive gonadotropinreleasing hormone agonists lose bone and are at risk of osteoporosis. In a small-randomized study, prostate cancer patients were treated with these agonists, with or without pamidronate.[ 71] The pamidronate-treated patients did not lose bone mineral density, whereas patients treated with the gonadotropin-releasing hormone agonist alone experienced significant bone loss. Awareness of bone loss is particularly important for prostate cancer patients who are receiving these agonists in the adjuvant setting. It is reasonable to measure bone density in these patients as well.
The current indications for bisphosphonate use in cancer patients are described in Table 7. For skeletal metastases in patients with breast cancer, multiple myeloma, or other solid tumors, bisphosphonates are important adjuncts to systemic therapy. Pamidronate at 90 mg infused over 90 to 120 minutes is comparable in efficacy and side effects to zoledronate at 4 mg infused over 15 minutes.
Mentioned in This Article
(zoledronic acid, Zometa)
Brand names are listed in parentheses only if a drug is not available generically and is marketed as no more than two trademarked or registered products. More familiar alternative generic designations may also be included parenthetically.
For prostate cancer patients with skeletal metastases, the results with zoledronate are promising, but additional trials are needed before bisphosphonates become part of standard treatment for metastatic prostate cancer. The available trials on the use of bisphosphonates for the prevention of skeletal metastases in breast cancer patients have demonstrated mixed results. However, all the trials used clodronate, a less potent oral bisphosphonate. Ongoing trials are evaluating the preventive role of the third-generation bisphosphonates in breast cancer patients. Until the results of these trials are presented, bisphosphonates should only become a component of adjuvant treatment in the context of a clinical trial. Finally, bone loss is a common consequence of cancer treatment, and awareness of this complication is essential. Bone loss can be treated with the usual measures indicated for the management of osteoporosis, including bisphosphonates.
What does the future hold? Bisphosphonates have direct antitumor and antiangiogenic effects, and several trials in breast and multiple my myeloma patients have shown improved survival among bisphosphonatetreated patients. Dedicated randomized trials to evaluate the antitumor effects of bisphosphonates in combination with chemotherapy are warranted. Preclinical and recent studies in postmenopausal, osteoporitic patients and patients with breast cancer and multiple myeloma show promising results for recombinant osteoprotegerin as an inhibitor of bone resorption.[72,73] Parathyroid hormone- releasing protein is a potential target for cancer therapy in preclinical studies. Future studies of these novel agents in combination with bisphosphonates may prove them to be useful in the treatment and prevention of skeletal metastases.
Financial Disclosure: The authors have no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.
James R. Berenson,MD
Michelle A. Fanale,MD and Gabriel N. Hortobagyi,MD
1. Shapiro CL: Bisphosphonates in breast
cancer patients with skeletal metastases. Hematol
Oncol Clin North Am 8:153-163, 1994.
2. Lories RJ, Luyten FP: Osteoprotegerin
and osteoprotegerin-ligand balance: A new
paradigm in bone metabolism providing new
therapeutic targets. Clin Rheumatol 20:3-9,
3. Hofbauer LC, Neubader A, Heufelder
AE: Receptor activator of nuclear factor-kb
ligand and osteoprotegerin. Cancer 92:460-
4. Powell GJ, Southby J, Danks JA, et al:
Localization of parathyroid hormone-related
protein in breast cancer metastases-increased
incidence in bone compared with other sites.
Cancer Res 51:3059, 1991.
5. Guise TA: Molecular mechanisms of osteolytic
bone metastases. Cancer 88(suppl
6. Mundy GR, Toshiyuki Y: Bisphosphonates
as anticancer drugs. N Engl J Med
7. Yasuda H, Shima N, Nakagawa N, et al:
Identity of osteoclastogenesis inhibitory factor
(OCIF) and osteoprotegerin (OPG): A
mechanism by which OPG/OCIF inhibits osteoclastogenesis
in vitro. Endocrinology
8. Clohisy DR, Ramnaraine ML, Scully S,
et al: Osteoprotegerin inhibits tumor-induced
osteoclastogenesis and bone tumor growth in
osteopetrotic mice. J Orthop Res 18:967-976,
9. Goltzman D, Karaplis AC, Kremer R, et
al: Molecular basis of the spectrum of skeletal
complications of neoplasia. Cancer 88:2903-
10. Koutsilieris M, Frenette G, Lazure C,
et al: Urokinase-type plasminogen activator:
A paracrine factor regulating the bioavailability
of IGFs in PA-III cell-induced osteoblastic
metastases. Anticancer Res 13:481-486,
11. Cohen P, Graves HC, Peehl DM, et al:
Prostate-specific antigen (PSA) is an insulinlike
growth factor binding protein-3 (IGFBP-
3) protease found in seminal plasma. J Clin
Endocrinol Metab 75:1046-1053, 1992.
12. Van der Pluijm G, Vloedgraven H, van
Beek E, et al: Bisphosphonates inhibit the
adhesion of breast cancer cells to bone matrices
in vitro. J Clin Invest 98:698-705, 1996.
13. Boissier S, Magneto S, Frappart L, et al:
Bisphosphonates inhibit prostate and breast
carcinoma cell adhesion to unmineralized and
mineralized bone extracellular matrices. Cancer
Res 57:3890-3894, 1997.
14. David P, Hguyen H, Barbier A, et al:
The bisphosphonate tiludronate is a potent inhibitor
of the osteoclast vacuolar H(+)-ATPase.
J Bone Miner Res 11:1498-1507, 1996.
15. Rogers MJ, Gordon S, Benford HL, et
al: Cellular and molecular mechanisms of action
of bisphosphonates. Cancer 88:2961-2978,
16. Senaratne SG, Pirianov G, Mansi JL, et
al: Bisphosphonates induce apoptosis in human
breast cancer cells. Br J Cancer 82:1459-
17. Shipman CM, Rogers MJ, Apperley JF,
et al: Bisphosphonates induce apoptosis in human
myeloma cell lines: A novel anti-tumour
activity. Br J Haematol 98:665-672, 1997.
18. Hughes DE, MacDonald BR, Russell
RG, et al: Inhibition of osteoclast-like cell
formation by bisphosphonates in long-term
cultures of human bone marrow. J Clin Invest
19. Teronen O, Heikkila P, Konttinen YJ, et
al: MMP downregulation and inhibition by
bisphosphonates. Ann N Y Acad Sci 878:453-
20. Boissier S, Ferreras M, Peyruchaud O,
et al: Bisphosphonates inhibit breast and prostate
carcinoma cell invasion, an early event in
the formation of bone metastases. Cancer Res
21. Lee MV, Fong EM, Singer FR, et al:
Bisphosphonate treatment inhibits growth of
prostate cancer cells. Cancer Res 61:2602-
22. Fromigue O, Lagneaux L, Body JJ: Bisphosphonates
induce breast cancer cell death
in vitro. J Bone Miner Res 15:2211-2221, 2000.
23. Green J, Gschaidmeier H, Yoneda T, et
al: Zoledronic acid potently inhibits tumorinduced
osteolysis in two animal models of
breast cancer metastatic to bone. Ann Oncol
11(suppl 4):14, 2000.
24. Nobuyuki H, Hiraga T, Williams PJ, et
al: The bisphosphonate zoledronic acid inhibits
metastases to the bone and liver with suppression
of osteopontin production in mouse
mammary tumor. J Bone Miner Res 16(suppl
25. Green JR: Antitumor effects of bisphosphonates.
Cancer 97(3 suppl):840-847, 2003.
26. Hortobagyi GN, Theriault RL, Porter L,
et al: Efficacy of pamidronate in reducing skeletal
complications of breast cancer and lytic
bone metastases. N Engl J Med 335:1785-
27. 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 7:377-387, 2001.
28. Bajorunas DR: Clinical manifestations
of cancer-related hypercalcemia. Semin Oncol
29. Body JJ, Dumon JC: Treatment of tumor-
induced hypercalcemia with the bisphosphonate
relationship and influence of tumor type. Ann
Oncol 5:359-363, 1994.
30. Nussbaum SR, Younger J, Vandepol
CJ, et al: Single-dose intravenous therapy with
pamidronate for the treatment of hypercalcemia
of malignancy: Comparision of 30-, 60-,
90-mg doses. Am J Med 95:297-304, 1993.
31. 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 19:558-567,
32. Coleman RE: Skeletal complications of
malignancy. Cancer 80(8 suppl):1588-1594,
33. Theriault RL, Lipton A, Hortobagyi GN,
et al: Pamidronate reduces skeletal morbidity
in women with advanced breast cancer and
lytic bone lesions: A randomized, placebocontrolled
trial. J Clin Oncol 17:846-854, 1999.
34. Elomaa I, Blomqvist C, Porkka L, et al:
Treatment of skeletal disease in breast cancer:
A controlled clodronate trial. Bone 8(suppl
35. Paterson AH, Powles TJ, Kanis JA, et
al: Double-blind controlled trial of oral clodronate
in patients with bone metastases from
breast cancer. J Clin Oncol 11:59-65, 1993.
36. Van Holten-Verzantvoort AT, Kroon
HM, Bijvoet OL, et al: Palliative pamidronate
treatment in patients with bone metastases from
breast cancer. J Clin Oncol 11:491-498, 1993.
37. Conte PF, Latreille J, Mauriac L, et al:
Delay in progression of bone metastases in
breast cancer patients treated with intravenous
pamidronate: Results from a multinational randomized
controlled trial. J Clin Oncol 14:2552-
38. Hortobagyi GN, Theriault RL, Lipton
A, et al: Long-term prevention of skeletal complications
of metastatic breast cancer with pamidronate.
Protocol 19 Aredia Breast Cancer
Study Group. J Clin Oncol 16:2038-2044,
39. Cohen MH, Dagher R, Griebel DJ, et al:
US Food and Drug Administration Drug approval
summaries: Imatinib mesylate, mesna
tablets, and zoledronic acid. Oncologist 7:393-
40. Ali SM, Esteva FJ, Hortobagyi GN, et
al: Safety and efficacy of bisphosphonates beyond
24 months in cancer patients. J Clin
Oncol 19:3434-3437, 2001.
41. Hillner BE, Ingle JN, Berenson JR, et
al: American Society of Clinical Oncology
guideline on the role of bisphosphonates in
breast cancer. J Clin Oncol 18:1378-1391,
42. Hillner BE, Weeks JC, Desch CE, et al:
Pamidronate in prevention of bone complications
in metastatic breast cancer: A cost-effectiveness
analysis. J Clin Oncol 18:72-79, 2000.
43. Carlin BI, Andriole GL: The natural
history, skeletal complications, and management
of bone metastases in patients with prostate
carcinoma cancer. Cancer 88:2989-2994,
44. Elomaa I, Kylmala T, Tammela T, et al:
Effect of oral clodronate on bone pain. Int
Urol Nephrol 24:159-166, 1992.
45. Kylmala T, Taube T, Tammela TL, et
al: Concomittant IV and oral clodronate in the
relief of bone pain—A double-blind placebocontrolled
study in patients with prostate cancer.
Br J Cancer 76:939-942, 1997.
46. Ernst DS, Tannock IF, Venner PM, et
al: Randomized, placebo-controlled trial of
mitoxantrone/prednisone and clodronate versus
mitoxantrone/prednisone alone in patients
with hormone-refractory prostate cancer
(HRPC) and pain: National Cancer Institute of
Canada clinical trials group study (abstract
705). Proc Am Soc Clin Oncol 21:177a, 2002.
47. Lipton A, Small E, Saad F, et al: The
new bisphosphonate, zometa decreases skeletal
complications in both lytic and blastic lesions:
A comparision to pamidronate (abstract).
Cancer Invest 20:45-47, 2001.
48. Saad F, Gleason DM, Murray R, et al: A
randomized, placebo-controlled trial of
zoledronic acid in patients with hormone-refractory
metastatic prostate carcinoma. J Natl
Cancer Inst 94:1458-1468, 2002.
49. Canil CM, Tannock IF: Should bisphosphonates
be used routinely in patients with
prostate cancer metastatic to bone? J Natl Cancer
Inst 94:1422-1423, 2002.
50. Rosen L, Gordon D, Tchekmedyian S,
et al: Zoledronic acid significantly reduces
skeletal related events in patients with bone
metastases from solid tumors (abstract 1179).
Proc Am Soc Clin Oncol 21:295a, 2002.
51. McCloskey EV, MacLennan IC, Drayson
MT, et al: A randomized trial of the effects
of clodronate on skeletal morbidity in
multiple myeloma. MRC Working Party on
Leukemia in Adults. Br J Haematol 100:317-
52. Lahtinen R, Laakso M, Palva I, et al:
Randomized, placebo-controlled multicenter
trial of clodronate in multiple myeloma. Finnish
Leukemia Group. Lancet 340:1049-1052,
53. Brincker H, Westin J, Abildgaard N, et
al: Failure of oral pamidronate to reduce skeletal
morbidity in multiple myeloma: A doubleblind
placebo-controlled trial. Danish-Swedish
co-operative group. Br J Haematol 101:280-
54. 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 6:593-602, 1998.
55. Mennsen HD, Sakalova 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
56. Kanis JA, Powles T, Paterson AH, et al:
Clodronate decreases the frequency of skeletal
metastases in women with breast cancer.
Bone 19:663-667, 1996.
57. Ford JM, van Oosterom, Brincker H, et
al: Oral pamidronate: Negative results from
three double-blind, placebo controlled trials
in hypercalcemia, myeloma, and the prevention
of bone metastases (abstract). Bone 22(suppl
58. Diel IJ, Solomayer EF, Costa SD, et al:
Reduction in new metastases in breast cancer
with adjuvant clodronate treatment. N Engl J
Med 339:357-363, 1998.
59. Deil IJ, Solomayer EF, Gollan C, et al:
Bisphosphonates in the reduction of metastases
in breast cancer-results of the extended follow-
up of the study population (abstract 314).
Proc Am Soc Clin Oncol 19:82a, 2000.
60. Saarto T, Blomqvist C, Virkkunen P et
al: 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, 1996.
61. Powles T, Paterson S, Kanis JA, et al:
Randomized, placebo-controlled trial of clodronate
in patients with primary operable breast
cancer. J Clin Oncol 20:3219-3224, 2002.
62. Berenson J, Hillner BE, Kyle RA, et al:
American Society of Clinical Oncology practice
guidelines: The role of bisphosphonates
in multiple myeloma. J Clin Oncol 20:3719-
63. Pfeilschifter J, Diel IJ: Osteoporosis
due to cancer treatment: Pathogenesis and
management. J Clin Oncol 18:1570-1593,
64. Shapiro CL, Manola J, Leboff M: Ovarian
failure after adjuvant chemotherapy is associated
with rapid bone loss in women with
early-stage breast cancer. J Clin Oncol
65. Delmas PD, Balena R, Confravreux E,
et al: Bisphosphonate risendronate prevents
bone loss in women with artificial menopause
due to chemotherapy of breast cancer: A double-
blind, placebo-controlled study. J Clin
Oncol 15:955-962, 1997.
66. Vehmanen L, Saarto T, Elomaa I, et al:
Long-term impact of chemotherapy-induced
ovarian failure on bone mineral density (BMD)
in premenopausal breast cancer patients. The
effect of adjuvant clodronate treatment. Eur J
Cancer 37:2373-2378, 2001.
67. Saarto T, Blomqvist C, Valimaki M, et
al: Chemical castration induced by adjuvant
cyclophosphamide, methotrexate, and fluorouracil
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.
68. Watts NB: Treatment of osteoporosis
with bisphosphonates. Endocrinol Metab Clin
North Am 27:419-439,1998.
69. The ATAC Trialists’ group: Anastrozole
alone or in combination with tamoxifen
versus tamoxifen alone for adjuvant treatment
of postmenopausal women with early breast
cancer: First results of the ATAC randomized
trial. Lancet 359:2131-2139, 2002.
70. Mittan D, Lee S, Miller E, et al: Bone
loss following hypogonadism in men with
prostate cancer treated with GnRH analogs.
J Clin Endocrinol Metab 87:3656-3661,
71. Smith MR, McGovern FJ, Zietman AL,
et al: Pamidronate to prevent bone loss during
androgen deprivation therapy for prostate cancer.
N Engl J Med 345:948-955, 2001.
72. Body JJ, Greipp P, Coleman RE, et al:
A phase I study of AMGN-0007, a recombinant
osteoprotegerin construct, in patients with
multiple myeloma or breast carcinoma related
bone metastases. Cancer 97(3 suppl):887-892,
73. Croucher PI, Shipman CM, Van Camp
BV, et al: Bisphosphonates and osteoprotegerin
as inhibitors of myeloma bone disease. Cancer
97(3 suppl):818-824, 2003.
74. Ogata E: Parathyroid hormone-related
protein as a potential target of therapy for
cancer-associated morbidity. Cancer 88(12