Bisphosphonates' Growing Role in Breast Cancer
Intravenous bisphosphonates, often used to treat metastases and bone pain in breast cancer patients, are now being used by clinicians for osteoporosis in these patients—pharmacists need to recommend appropriate screening and treatment.
Dr. LaFleur is a research assistant professor in the department of pharmacotherapy, University of Utah College of Pharmacy Pharmacotherapy Outcomes Research Center.
Nearly one third of women whodevelop cancer in the UnitedStates have breast cancer.1Should this cancer metastasize, mostwill eventually have bone involvement.2Thus, intravenous (IV) bisphosphonateslike pamidronate and zoledronate havehad a large role in breast cancer, as theytreat bone metastases and bone pain.2,3Now, clinicians also are using bisphosphonatesin these patients for a diseasethat is more familiar to most pharmacists—osteoporosis. Pharmacists needto understand breast cancer patients'risks for osteoporosis and recommendappropriate screening and treatment.
The Connection Between Osteoporosis and Breast Cancer
Breast cancer treatment increasesosteoporosis risk in 2 ways. One causeis development of chemotherapyinducedamenorrhea in premenopausalwomen.4 Most patients treated with acommon regimen (cyclophosphamide,methotrexate, and fluorouracil) for estrogen-receptor?positive (ER+) or negativebreast cancer developed amenorrhea.4These women have rapid and sustainedbone loss.5 A second cause exists onlyin women with ER+ cancers. In thesewomen, tamoxifen, which has been thegold standard for adjuvant endocrinetherapy for more than 2 decades, is nowbeing replaced by aromatase inhibitors(anastrazole, letrozole, examestane),which do not protect patients againstosteoporosis as well as tamoxifen. Infact, their estrogen-suppressing effectsactually increase the risk.6-8 Aromataseinhibitors reduce cancer recurrence byas much as an additional 30% overtamoxifen.9,10 Their risk of serious adverseevents like ischemic stroke, endometrialcancer, and venous thromboembolismis lower.6
Screening and Treating Osteoporosis in Breast Cancer
The American Society of ClinicalOncology (ASCO) recently issued a newguideline for osteoporosis screening andtreatment in breast cancer.3 It stresses theneed for oncology clinicians to expandtheir roles to evaluating bone healthroutinely and regularly.3 The breastcancer?specific guideline was based ona more general osteoporosis guidelineproduced by the US Preventive ServicesTask Force (USPSTF).11 The USPSTF recommendsroutine bone mineral density(BMD) screening in women at high riskfor osteoporosis. The USPSTF considerscertain women at high risk—those olderthan age 65, or between 60 and 64 andhaving other risk factors like a family historyof osteoporosis, or those with a lowbody weight (<154 lb) or a prior fragilityfracture. For breast cancer patients,ASCO adds 2 more high-risk categories:(1) postmenopausal women (of anyage) receiving aromatase inhibitors, and(2) younger women with chemotherapy-associatedpremature menopause.
The Figure shows the ASCO algorithmfor recommending BMD screening,lifestyle changes, and treatmentinterventions in women with and withoutthese high-risk designations. Likethe USPSTF, ASCO states that cliniciansshould encourage all patients to undertakepreventive measures. First, eating ahealthy diet supplemented with calcium and vitamin D maintainsadequate calcium to continually rebuild bone. Second, regularexercise strengthens bone and maintains high bone density, and,third, smoking avoidance helps prevent premature bone loss.These measures are recommended to all patients. High-riskpatients should also receive BMD scans every year, and patientswith BMD T-scores at or below the threshold for osteoporosis (-2.5)should receive treatment.
ASCO = American Society of Clinical Oncology; BMD = bone mineral density.
Adapted from reference 3.
Osteoporosis Treatments in Breast Cancer
A few of the agents approved by the FDA for osteoporosis preventionand treatment require special consideration in womenwith breast cancer. Raloxifene should be avoided in womenwho have had 5 years of treatment with tamoxifen becauseof concerns about higher cancer recurrence and mortalityrates.3,12 Teriparatide also is not recommended, because itcaused osteosarcoma in animals.3,13 Estrogen plus progestin isno longer recommended for osteoporosis prevention becauseof the increased risk for serious life-threatening adverseevents, including breast cancer.3,14 Generally, due to strongsafety profiles and a larger pool of evidence supporting theirbenefits, bisphosphonates are the treatment of choice inpatients with and without breast cancer.3
As in many symptomless chronic diseases, patient adherenceand persistence with osteoporosis treatment are poor. Arecent meta-analysis showed that only about half of patientspersist with bisphosphonates more than 6 months, and mostdiscontinue after the first month.15 Poor adherence is alarming;increasing evidence shows that patients need at least 6months exposure to reap treatment benefits.16 The newer oralbisphosphonates' longer dosing intervals may improve patientadherence.17 For patients who have difficulty persisting withoral bisphosphonates, even with longer dosing intervals, theonce-yearly bisphosphonate zoledronate may be an alternative.18 Zoledronate lacks the oral bisphosphonates' administrationrestrictions but must be infused intravenously; mostphysicians' offices are unable to infuse IV drugs. Additionally,a flu-like infusion reaction occurs after a first dose in about16% of patients.
Counseling Points for Pharmacists
Because the risk of osteoporosis increases in patients withbreast cancer, pharmacists need to be aware of the guidelinesfor preventing fractures, as well as counseling points for thesepatients.
- Talk with your patients with breast cancer about their riskfor osteoporosis, and encourage those with chemotherapy-induced amenorrhea or aromatase inhibitor treatmentto seek out yearly BMD screening
- Counsel all patients about the importance of exercising,eating right, avoiding tobacco smoke exposure, and takingcalcium and vitamin D supplements to strengthen bones
- Recommend a bisphosphonate as first-line treatment inpatients with breast cancer?induced osteoporosis
- Recommend agents with longer dosing intervals forpatients with poor adherence
FDA Approved Therapies for Osteoporosis: Their Role in Breast Cancer Patients
Dose Regimens for Prevention and Treatment
Considerations for Breast Cancer Patients
5 mg by mouth daily
35 mg by mouth weekly
70 mg by mouth weekly
Upper GI irritation, myalgias, arthralgias, rarely osteonecrosis of the jaw
2.5 mg by mouth daily
150 mg by mouth monthly
5 mg by mouth daily
35 mg by mouth weekly
5 mg by intravenous infusion given over 15 minutes yearly
Selective estrogen receptor modulators
60 mg by mouth daily
Do not use after tamoxifen due to occurrence of cross resistance
Hot flushes, leg cramps, deep vein thrombosis
20 U subcutaneously daily
Do not use in breast cancer patients due to osteosarcoma in animal models
Dizziness, leg cramps, hypercalcemia
Estrogen +/- progestin
Do not use in breast cancer or non?breast cancer patients due to adverse effects
Breast tenderness, vaginal bleeding, coronary heart disease, stroke, pulmonary embolism, breast cancer
200 U in one nostril daily
GI = gastrointestinal.
Adapted from reference 3.
- Landis SH, Murray T, Bolden S, Wingo PA. Cancer statistics, 1998. CA Cancer J Clin. 1998;48:6-29.
- Hillner BE, Ingle JN, Berenson JR, et al. American Society of Clinical Oncology guideline on the role of bisphosphonates in breast cancer. American Society of Clinical Oncology Bisphosphonates Expert Panel. J Clin Oncol. 2000;18:1378-91.
- Hillner BE, Ingle JN, Chlebowski RT, et al. American Society of Clinical Oncology 2003 update on the role of bisphosphonates and bone health issues in women with breast cancer. J Clin Oncol. 2003;21:4042-57.
- Bines J, Oleske DM, Cobleigh MA. Ovarian function in premenopausal women treated with adjuvant chemotherapy for breast cancer. J Clin Oncol. 1996;14:1718-29.
- 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. 2001;19:3306-11.
- Howell A, Cuzick J, Baum M, et al. Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years' adjuvant treatment for breast cancer. Lancet. 2005;365:60-2.
- Winer EP, Hudis C, Burstein HJ, et al. American Society of Clinical Oncology technology assessment on the use of aromatase inhibitors as adjuvant therapy for postmenopausal women with hormone receptor-positive breast cancer: status report 2004. J Clin Oncol. 2005;23:619-29.
- Coleman RE. Effect of anastrozole on bone mineral density: 5-year results from the 'Arimidex', Tamoxifen, Alone or in Combination (ATAC) trial. In: Journal of Clinical Oncology, 2006 American Society of Clinical Oncology Annual Meeting Proceedings Part I. 2006;24(18S):511. wwwascoorg/ASCO/Abstracts+%26+Virtual+Meeting/~ Accessed 8 March 2008.
- Goss PE, Ingle JN, Martino S, et al. A randomized trial of letrozole in postmenopausal women after five years of tamoxifen therapy for early-stage breast cancer. N Engl J Med. 2003;349:1793-802.
- Coombes RC, Hall E, Gibson LJ, et al. A randomized trial of exemestane after two to three years of tamoxifen therapy in postmenopausal women with primary breast cancer. N Engl J Med. 2004;350:1081-92.
- Screening for osteoporosis in postmenopausal women: recommendations and rationale. Am Fam Physician. 2002;66:1430-2.
- Fisher B, Dignam J, Bryant J, Wolmark N. Five versus more than five years of tamoxifen for lymph node-negative breast cancer: updated findings from the National Surgical Adjuvant Breast and Bowel Project B-14 randomized trial. J Natl Cancer Inst. 2001;93:684-90.
- Cranney A, Guyatt G, Griffith L, Wells G, Tugwell P, Rosen C. Meta-analyses of therapies for postmenopausal osteoporosis. IX: Summary of meta-analyses of therapies for postmenopausal osteoporosis. Endocr Rev. 2002;23:570-8.
- Rossouw JE, Anderson GL, Prentice RL, et al. Risks and benefits of estrogen plus progestin in healthy postmenopausal women: principal results From the Women's Health Initiative randomized controlled trial. JAMA. 2002;288:321-33.
- Kothawala P, Badamgarav E, Ryu S, Miller RM, Halbert RJ. Systematic review and meta-analysis of real-world adherence to drug therapy for osteoporosis. Mayo Clin Proc. 2007;82:1493-501.
- Weycker D, Macarios D, Edelsberg J, Oster G. Compliance with osteoporosis drug therapy and risk of fracture. Osteoporos Int. 2007;18:271-7.
- Lewiecki EM. Long dosing intervals in the treatment of postmenopausal osteoporosis. Curr Med Res Opin. 2007;23:2617-25.
- Black DM, Delmas PD, Eastell R, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809-22.