ONCOLOGY. Vol. 17 No. 9

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REVIEW ARTICLE

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

Prevention of Bone Metastases

TABLE 6

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.[56] 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.[57]

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.[58] 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.[59] 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.[60] 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.[62]

Bisphosphonates in the Treatment of Osteoporosis in Cancer Patients

Osteoporosis and osteopenia can occur in cancer patients secondary to treatment effects.[63] This is particularly relevant in breast and prostate cancers due to the prevalence of these diseases.

Premenopausal Women

Chemotherapy-induced ovarian failure is common among premenopausal breast cancer patients, with prospective studies documenting rapid and accelerated loss of bone mineral density.[64] 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.[68]

Postmenopausal Women

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.[69] 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.

Men

TABLE 7

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.[70] 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.

Summary

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.

REFERENCE GUIDE

Therapeutic Agents
Mentioned in This Article

Anastrozole (Arimidex)
Clodronate
Letrozole (Femara)
Pamidronate
Risedronate (Actonel)
Tamoxifen
Zoledronate
(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.[74] 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.

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This article reviewed

Commentary (Fanale/Hortobagyi): Bisphosphonates in the Prevention and Treatment of Bone Metastases

Commentary (Hillner): Bisphosphonates in the Prevention and Treatment of Bone Metastases

Commentary (Berenson): Bisphosphonates in the Prevention and Treatment of Bone Metastases

Bruce E. Hillner,MD
James R. Berenson,MD
Michelle A. Fanale,MD and Gabriel N. Hortobagyi,MD

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