Managing bone mineral density with oral bisphosphonate therapy in women with breast cancer receiving adjuvant aromatase inhibition

The use of adjuvant aromatase inhibitors is associated with an increased risk of osteoporosis and fractures. The oral bisphosphonate, risedronate - dosed as the US Food and Drug Administration approved for the treatment or prevention of postmenopausal osteoporosis - appears to mitigate bone loss associated with 2 years of adjuvant anastrozole in women with early-stage breast cancer.

Th e estrogen deprivation associated with the adjuvant aromatase inhibitors (AIs) has been shown to increase the risk of bone loss and fragility fractures. Minimizing treat ment toxicities and preserving bone health are important aspects of adjuvant breast cancer care.
Markopoulos and colleagues performed a phase III multicenter clinical trial investigating the aff ect of the oral bisphosphonate, risedronate, on bone mineral density (BMD) changes in postmenopausal women with hormone receptor (HR)-positive early-stage breast cancer receiving adjuvant anastrozole [1]. Th is study -given the moniker ARBI -enrolled women with HR-positive early-stage breast cancer scheduled to receive adjuvant anastrozole 1 mg daily, and the study participants were stratifi ed into three categories based on their baseline BMD. Th ose with BMD of at least -1.0 (low risk for fracture) were treated with anastrozole without bisphos phonate therapy. Th ose with BMD of at least -2.0 were treated with anastrozole plus risedronate 35 mg weekly (higher risk for fracture). Th e women to receive anastro zole with BMD less than -1.0 but greater than -2.0 were considered at inter mediate risk for fracture and were randomized to either risedronate 35 mg weekly or control. All patients received calcium and vitamin D supple men tation.
Th e study design of the ARBI study, like those of the ARIBON [2] and SABRE [3] trials, is extremely practical. Th e study participants are postmenopausal women and the drug, dose and schedule of the study intervention are couched in the literature for managing bone mass in postmenopausal women. Each of these three studies categorizes the patients' risk of fragility fracture by BMD into a low, intermediate or higher risk group and assigns the study bisphosphonate accordingly. Th e threshold for the intermediate group in the ARIBON trial (T score = -1.0 to -2.5) diff ers slightly from that of the other two studies (T score = -1.0 to -2.0), and each of the three studies randomized the intermediate group to bisphosphonate or not. Th e studies each use an oral bisphosphonate, risedronate or ibandronate, in doses and schedules that are US Food and Drug Administration (FDA) approved for the prevention and treatment of postmenopausal osteoporosis. Th ese three studies directly test whether an existing regimen for managing bone health is suffi cient to manage BMD in postmenopausal women with breast cancer receiving adjuvant AI therapy. All three studies are of short duration (2 years) and are powered for changes in BMD, a surrogate for fracture risk. Th ese studies were not designed to assess changes in fracture rates or in the risk of breast cancer recurrence. Th e changes in BMD in these three studies are outlined in Table 1 and are generally positive, demonstrating that the oral bisphosphonates are able to preserve bone mass in the setting of adjuvant anastrozole.
Th e use of oral bisphosphonate therapy has been well established as an effi cacious means of managing BMD in postmenopausal osteoporosis [4]. Both the ARIBON and SABRE trials demonstrated that the patients receiving oral bisphosphonate therapy experienced either stabilization of or an increase in BMD at 2 years. In the ARBI study, however, there were was evidence of slight bone loss in the hip of those in the higher risk category receiving risedronate, and the diff erence between the two arms in the intermediate group was modest. Th e diff erence between hip BMD in the inter mediate group therapies may relate to the ARBI sample size, which was based on the expected diff erences between the randomized groups. Th irty-six patients per arm were planned for the hip BMD analysis; at the 2-year analysis, however, the intermediate risk arm had 26 patients in the anastrozole plus risedronate arm and 21 patients in the anastrozole only arm. Factors that may have also aff ected the results include poor compliance with bis phosphonate therapy, although the ARBI trial included compliance assessment at each follow-up visit and missed tablets were reported by <10% of the study patients. Compliance is a concern with oral bisphosphonate therapy, as was shown in a cohort study of 8,822 women prescribed risedronate (daily or weekly) in which 31% of the patients were noncompliant after 1 year of treatment [5]. Compliance and persistence rates may vary inter nationally; the compliance with oral bisphosphonate at 1 year appears to vary between 58 and 74% in the United States, the United Kingdom and France [6].
Zoledronic acid and the intravenously administered form of ibandronate are FDA approved for the management of low bone mass. Intravenous administration within the medical offi ce assures the clinician confi rmation of drug delivery. Th e data supporting the use of intravenous bisphosphonate therapy in the manage ment of AI-induced bone loss in women receiving an AI for early-stage HR-positive breast cancer includes zoledronic acid 4 mg administered every 6 months for 3 to 5 years [7][8][9]. Th is bisphosphonate regimen has demon strated the ability to maintain bone mass in this setting. It is notable that the FDA-approved dosing of zoledronic acid in the management of low bone mass is 5 mg annually when treating osteoporosis and is 5 mg every 2 years when treating postmenopausal osteopenia, and that Brown and colleagues demonstrated a 4 to 5% increase in BMD at 3 years with a single zoledronic acid dose of 4 mg in patients with osteopenia after cancer therapy given with curative intent [10]. Th e optimal dose and interval of zoledronic acid to manage BMD in the setting of AI therapy have not been defi ned.
Th e clinical trials investigating women at risk for chemotherapy-induced amenorrhea have studied both oral and intravenous bisphosphonates. Th e results of these studies have for the most part demonstrated that the bisphosphonates preserve BMD [11]. One phase III study of risedronate 35 mg weekly versus placebo in this younger patient population, however, demonstrated that BMD loss in the lumbar spine and hip at 1 year was similar in both arms [12]. Although the ARBI, ARIBON, and SABRE trials have demonstrated that bisphos phonates dosed as the FDA has approved for the treatment or prevention of postmenopausal osteoporosis can control loss of BMD in the setting of adjuvant AI use, the study by Hines and colleagues raises the question of whether the bone loss associated with chemotherapyinduced amenorrhea may respond less well to risedronate 35 mg weekly. Longer follow-up and additional studies will shed light on the management of BMD in this younger patient population.
In conclusion, when managing patients with breast cancer receiving adjuvant AI therapy, the bisphosphonates may be viewed as a supportive therapy to treat or prevent osteoporosis. Th e data support treating individuals with osteo porosis, but the threshold for initiating pharmacologic interventions for osteopenia is less well defi ned. Th e ARBI study presents clinically useful data on the manage ment of bone mass in women with breast cancer receiv ing adjuvant AI therapy. In addition to managing BMD, adjuvant bisphosphonate therapy may provide antitumor aff ects. Studies