Bisphosphonates and Bone Turnover in Premenopausal Women Receiving Adjuvant Chemotherapy

Awareness of cancer-induced bone loss (CIBL) and treatmentinduced bone loss has increased among clinicians. Premenopausal women who undertake chemotherapy for breast cancer may lose up to 7% or more of their bone mass in the first year postchemotherapy. Chemotherapy induces ovarian atrophy and estrogen decline at a rate depending on the regimen used, but is much faster than occurs with natural menopause. The bone loss after chemotherapy (and the luteinizing hormone-releasing hormone agonists) in the first year implies a rapid and profound switching to a net resorption pattern of bone turnover. That all this results in real morbidity was shown by Kanis et al, who reported a fourto five-fold increase in the first-year incidence of vertebral fractures in women with newly diagnosed breast cancer compared with an age-matched cohort of healthy women in the metropolitan London area. Attempts to ameliorate the unwanted side effect of CIBL have concentrated on the use of bisphosphonates, and it has sometimes been assumed that standard postmenopausal doses of bisphosphonates will be useful in this patient group. This may not be the case. Hines et al report in this issue of Journal of Clinical Oncology a phase III, placebo-controlled, randomized trial of the bisphosphonate risedronate for the prevention of bone loss in premenopausal women receiving adjuvant chemotherapy for primary breast cancer. This article has unexpected, but explainable, results. Two hundred and sixteen premenopausal women receiving chemotherapy were allocated to weekly oral risedronate or a placebo, and their bone mineral density (BMD) was measured at baseline and 1 year. The change in average BMD at 1 year in the lumbar spine was similar in both active and placebo groups; there was also little difference in the total hip and femoral neck bone mineral densities at 1 year. There was a nonsignificant numerical trend for patients receiving risedronate to have less bone loss at the lumbar spine, femoral neck, and total hip, as well as a numerical but nonsignificant trend for less osteopenia and osteoporosis in the risedronate group. Compliance was good, running at more than 86% in the risedronate arm, and tamoxifen and taxane usage was evenly spread in the two arms. All except two patients had systemic adjuvant chemotherapy, and most would be expected to undergo premature menopause. The results support the clinical impression that it is harder to suppress bone turnover and subsequent bone loss with standard postmenopausal osteoporosis dosing of bisphosphonates in premenopausal women undergoing chemotherapy-induced premature menopause than in older, postmenopausal women. Is this merely a question of inadequate drug dosing in the presence of a powerful wave of estrogen deprivation–induced bone resorption? Or does a preor perimenopausal state confer some kind of protection from the effects of bisphosphonates? Successful inhibition of bone turnover has been achieved in premenopausal women in several studies. Delmas et al have previously reported in JCO that risedronate was effective in the treatment of chemotherapy-induced bone loss in premenopausal women. In this smaller study, the patients (all of whom were premenopausal before adjuvant chemotherapy) were postmenopausal on entry to the trial with endocrine levels in the postmenopause range. Furthermore, patients were administered 30 mg risedronate orally daily for 2 weeks with a 10-week rest period for a total of eight cycles. This regime differs from the 35 mg weekly dose in this study (a standard dose for osteoporosis), and although the total amount of drug during 1 year is similar (1,680 mg in the Delmas et al study v 1,820 mg in the Hines et al study), the initial loading of 420 mg risedronate over 2 weeks may have been sufficient to inhibit bone turnover. However, using a 35 mg weekly dosing of residronate, van Londen et al have demonstrated improvement in hip structural geometry and BMD compared with a placebo group at 1 year. Powles et al reported BMD measurements at 1 and 2 years in women with breast cancer receiving oral clodronate versus placebo demonstrating inhibition of bone turnover in premenopausal women at 1 year ( 1.57% compared with 4.4%), although the effect was lost at 2 years ( 3.99% compared with 3.94%), possibly related to compliance. Postmenopausal women experienced a significant gain in BMD during the first and second years compared with the placebo group. Gnant et al showed the effectiveness of parenteral bisphosphonates in patients who were premenopausal on study entry. All received continuous goserelin for 3 years, thereby converting them to a biologic state similar to postmenopause. In that setting, intravenous zoledronic acid was effective in preventing the reduction in BMD seen in the untreated postmenopausal woman. Likewise, Hershman et al have shown a reduction of BMD loss with zoledronic acid in premenopausal women with CIBL. Estrogens have a beneficial effect on bone health by suppressing bone resorption and enhancing formation. Mechanisms for this effect JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 27 NUMBER 7 MARCH 1 2009

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