Κυριακή, 30 Απριλίου 2017

PREVENTING FRACTURES IN PATIENTS RECEIVING AROMATASE INHIBITORS

A new position statement, jointly issued by seven international and European organizations, provides new guidance for the management of aromatase inhibitor (AI)–related bone loss (AIBL) in postmenopausal women receiving treatment for hormone-sensitive breast cancer.
The position paper was published April 25 in the Journal of Bone Oncology.
"AIBL leads to a marked increase of bone resorption, with a 2–4 fold increased bone loss compared to physiologic postmenopausal BMD [bone mineral density] loss," lead author, Peyman Hadji, MD, PhD, Krankenhaus Nordwest, Frankfurt, Germany, and colleagues write.
"As a result, women receiving adjuvant AI therapy for breast cancer are at increased risk for fractures…, which leads to increased morbidity and mortality," they add.
In an effort to prevent fractures and the morbidity and mortality that accompany them, multicenter colleagues reviewed well-designed, randomized controlled trials and developed recommendations based on the best available evidence on the management of AI-treated postmenopausal women to reduce fracture risk.
"All patients beginning AI therapy should be advised to exercise moderately (resistance and weight-bearing exercise)," the investigators state.
Physicians are also advised to recommend that women supplement their diet with calcium 1200 mg daily and vitamin D 800 to 1000 IU daily.  The paper adds that elderly women, as well as women with minimal levels of physical activity or exposure to sunlight, may need higher levels of both calcium and vitamin D a day in order to prevent fracture.
For women at high risk for fracture, which may include the elderly, clinicians should measure 25-OH vitamin D levels and recommended high-dose vitamin D supplements if patients are vitamin D deficient, the authors write.
"For other postmenopausal women receiving AI therapy, a dose of at least 800 (and up to 2000) IU of vitamin D every day is recommended to maintain replete levels," they add.
That said, statement authors were careful to point out that recent evidence indicates vitamin D supplementation with or without calcium is not effective on its own to prevent fractures in women with breast cancer.
"For patients initiating an AI treatment not receiving bisphosphonate for recurrence prevention, a BMD measurement is advised," they continue.
If results indicate that patients have a T-score in excess of –2.0 — and they have no other risk factors for fracture — their BMD should be reassessed in 12 months and their fracture risk recalculated.
Important BMD decrements of 5% to 10% a year should serve as a red flag for physicians to investigate patients for a possible secondary cause of BMD loss, such as vitamin D deficiency. In such patients, physicians need to start treatment with an antiresorptive agent in order to prevent fractures.
Similarly, patients receiving treatment with an AI should also receive concomitant antiresorptive therapy if their T-score is less than –1.5, if they are older than age 65 years, and if their body mass index is under 20 kg/m2.
Other risk factors that warrant the same preventive approach include a family history of hip fracture, a patient's own history of sustaining a fragility fracture after age 50, taking an oral corticosteroid for longer than 6 months, and having a current or past history of smoking.
Among patients receiving treatment with an AI who have a T-score of less than –2.0, the presence of risk factors is irrelevant and physicians need to introduce an antiresorptive agent in this patient group as well.
"Based on current evidence, subcutaneous denosumab (60 mg twice yearly) and intravenous zoledronate (4 mg q6mo) are the preferred agents for prevention and treatment of AIBL," the investigators write.
Evidence suggests that twice-yearly injections of denosumab or once-yearly infusions of zoledronate are recommended for prevention of AIBL during the full AI treatment course. The authors also recommend that physicians favor zoledronate when prevention of disease recurrence is a priority and favor denosumab when fracture risk is the predominant concern.
Risedronate has the most robust support for the prevention of AIBL among the bisphosphonate drug class at a recommended dose of 35 mg a week. Regardless of the bisphosphonate used, BMD should be assessed every 1 to 2 years, along with adherence to the regimen, the latter possibly by measuring bone resorption markers.
"In case of poor compliance or unsatisfactory BMD changes after 1–2 years, a switch to denosumab or intravenous bisphosphonate is recommended," the researchers note — and BMD should be monitored at intervals recommended by local guidelines. 
The authors underscore the direct association between adherence to the treatment regimen and good clinical outcomes.
Thus, "strategies to improve patients' compliance and persistence with oral bisphosphonate therapy are necessary to ensure benefit from these agents in the AIBL setting," they suggest.

Prevention of Disease Recurrence

As the authors point out, experts now recommend routine use of adjuvant bisphosphonates in women who are at intermediate or high risk for disease because of adverse clinical or biological features, such a node-positive disease. For these women, bisphosphonates are recommended regardless of fracture risk, but BMD does not necessarily require monitoring.
To date, studies on the prevention of disease recurrence with the help of denosumab have been too short to determine whether it, too, reduces the risk for disease recurrence, but ongoing studies will help determine whether denosumab has a role in this setting as well.
"As fragility fractures often result in prolonged disability and loss of independent, it is important that women who are being treated for hormone-sensitive breast cancer are managed to prevent bone loss and related fractures," Dr Hadji said in a statement.
"And given that recent research has revealed the potential anticancer benefits of antiresorptive agents in early breast cancer, these agents can also play a role in preventing disease recurrence," he added.  
Once patients have finished their course of AI therapy, bone turnover returns to normal, partially reducing fracture risk.
Dr Hadji has received honoraria, grants, and research funding from Amgen, AstraZeneca, Eli Lilly, MSD, Novartis, Pfizer, and Roche. 
J Bone Oncol. Published online April 25, 2017. Full text

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