Bisphosphonates' Growing Role in Breast Cancer

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&#8212;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.

Figure

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

Patient Adherence

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

Table

FDA Approved Therapies for Osteoporosis: Their Role in Breast Cancer Patients

Approved Treatments

Dose Regimens for Prevention and Treatment

Considerations for Breast Cancer Patients

Adverse Effects

Bisphosphonates

Alendronate

5 mg by mouth daily

35 mg by mouth weekly

70 mg by mouth weekly

Recommended

Upper GI irritation, myalgias, arthralgias, rarely osteonecrosis of the jaw

Ibandronate

2.5 mg by mouth daily

150 mg by mouth monthly

Risedronate

5 mg by mouth daily

35 mg by mouth weekly

Zoledronate

5 mg by intravenous infusion given over 15 minutes yearly

Selective estrogen receptor modulators

Raloxifene

60 mg by mouth daily

Do not use after tamoxifen due to occurrence of cross resistance

Hot flushes, leg cramps, deep vein thrombosis

Parathyroid hormone

Teriparatide

20 U subcutaneously daily

Do not use in breast cancer patients due to osteosarcoma in animal models

Dizziness, leg cramps, hypercalcemia

Estrogen +/- progestin

Varies

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

Calcium regulators

Calcitonin

200 U in one nostril daily

None

Rhinitis

GI = gastrointestinal.

Adapted from reference 3.

References

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