Endocrine Therapy and Bone Loss in Breast Cancer: Time to Close in the RANK(L)?
Authors: Per E. Lønning
Journal: Journal of Clinical Oncology (2008)

Osteoporosis is a major health problem for the aging female population worldwide. Defined as a T-score below 2.5, it has been estimated that 75 million females world-wide may fall into this category. The problem is illustrated by the fact that, of the female population, approximately 15% are expected to have vertebral fracture and 20% will suffer from hip joint fracture during their life time. In some places, like Scandinavia, the life-time risk for a hip-joint fracture may exceed 25%, probably due to a combination of factors, including low UV exposure. With osteoporotic fractures being most prominent in the very aged population, studies have suggested an elevated mortality ratio of more than 6 with respect to hip fractures and more than 8 for clinical osteoporotic vertebral fractures at least during the first year after the incident. In addition, many patients will experience reduced quality of life, with osteoporotic fractures inflicting significant demands on the health care system apart from suffering by the individual. Tamoxifen, the endocrine agent which up to recently was first choice of therapy for patients with preas well as postmenopausal early (and advanced) breast cancer, imposes little problems to bone health. While causing a moderate loss in bone mineral density (BMD) among premenopausal women, in postmenopausal women it expresses beneficial effects on bone tissue, improving the density of the lumbar spine (spongious) but also the hip (compact) bone. The issue is different for aromatase inhibitors, or for estrogen deprivation in general. Following a peak level around age of 30, females express a continuous reduced bone density for the rest of their life, but with an enhanced rate of loss during the years of menopause. Considering that estrogens prevent bone loss, a major concern for implementing potent third-generation aromatase inhibitors for early breast cancer has been the potential of a detrimental effect on bone metabolism. While the novel potent third-generation aromatase inhibitors (anastrozole, letrozole, and exemestane) each increase bone fracture rate moderately compared to tamoxifen, such a comparison is influenced by the bone-sparing effect of tamoxifen in postmenopausal women. Compared with placebo, exemestane and letrozole each enhanced bone loss in the hip area over a 24-month period by a mean of 2.5% and 2.9%, respectively (both significant); similar figures for the lumbar area were 0.7% (nonsignificant) and 4.7% (significant), respectively. For the total population in the National Cancer Institute of Canada MA.17 trial, a nonsignificant increase in total fracture rate of 137 events versus 119 events were recorded after a median follow-up time of 30 months. Notably, the effects of exemestane on BMD were partially reversed one year after terminating treatment. Similar, in the Arimidex, Tamoxifen, Alone or in Combination (ATAC) adjuvant breast cancer trial the increased fracture risk on anastrozole therapy disappeared shortly after terminating treatment. While these data may be reassuring with respect to today’s standard of therapy, this may change in the future. The first reason for that relates to the optimal duration of aromatase inhibitor therapy; clearly, to extend treatment beyond 5 into perhaps a 10-year time frame— or even life-long therapy—amplifies the problem. The second reason is the potential for aggravated estrogen suppression—using combinations of luteinizing hormone-releasing hormone (LHRH) analogs and aromatase inhibitors in premenopausal women. Although the Austrian Breast and Colorectal Cancer Study Group trial 12 has reported similar efficacy of anastrozole and tamoxifen in premenopausal women when combined with an LHRH analog, more follow-up is needed for definitive conclusions. The same trial has previously shown significantly more bone loss in the LHRH plus anastrozole arm when compared to the LHRH plus tamoxifen arm. The effects of calcium plus vitamin D supplementation on osteoporotic fracture rate is modest. The effect of bisphosphonates, in particular when administered by the parenteral route, is well documented by the finding of the Austrian Breast Group that zoledronic acid may fully prevent bone loss due to combined use of goserelin plus anastrozole in premenopausal women. While multiple adverse effects from bisphosphonates have been recorded, in general they are mild, except for the rare, but feared, complications of osteonecrosis of the jaw and tubular necrosis. We now face a new therapeutic option for osteoporosis; inhibition of the receptor activator of NFB ligand (RANKL) system. The RANK receptor (receptor activator of nuclear factor kappa B) is expressed on the surface of osteoclasts as well as several other cell types in the body. Stimulated by its natural ligand, RANKL, the RANKL/ RANK system is vital to osteoclast formation function and survival. The system is under feedback control through osteoprotegerin, a natural decoy receptor for the RANKL ligand. Denosumab is a fully human antibody against RANKL. An advantage for this compound compared with osteoprotegerin is its long half-life (33 to 46 days) after subcutaneous administration, allowing 3 (or 6) monthly intervals for administration. Denosumab has been evaluated as a therapeutic agent for postmenopausal women with a low bone density in a phase II study. A total of 412 women JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 30 OCTOBER 2