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Changes in Bone Mineral Density After Adjuvant Aromatase Inhibitors and Fracture Risk in Breast Cancer Patients

Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Oncologia Medica Azienda Ospedaliera San Luigi, Orbassano, Italy

Mara Ardine

Oncologia Medica, Azienda Sanitaria Locale 8, Chiezi, Italy

Luigi Dogliotti

Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Oncologia Medica Azienda Ospedaliera San Luigi, Orbassano, Italy

Alberto Angeli

Dipartimento di Scienze Cliniche e Biologiche, Università di Torino, Medicina Interna Azienda Ospedaliera San Luigi, Orbassano, Italy

Francesco Bertoldo

Dipartimento di Scienze Biomediche e Chirurgiche, Università di Verona, Sezione Medicina D, Policlinico GB Rossi, Verona, Italy

To the Editor:

The widespread use of aromatase inhibitors (AIs) in the adjuvant treatment of breast cancer patients has increased the attention of medical oncologists on the long-term effects of these drugs on bone health. AI treatment is notoriously associated with an increased risk of fractures as opposed to tamoxifen therapy (11.0% v 7.7% after 5 years in the Arimidex, Tamoxifen Alone, or in Combination [ATAC] trial), and it is actually not clear which patients should receive preventive measures (ie, bisphosphonates). The results of prospective studies evaluating the long-term effects of AI treatment on bone mineral density have been recently presented. An article published in the Journal of Clinical Oncology by Perez et al¹ reported the results of the effect of letrozole administered after 5 years of tamoxifen therapy in 226 patients enrolled on the MA-17 trial. The study showed a relatively modest decrease in bone mineral density (–3.5% in total hip and –5.35% in lumbar spine) after 2 years of treatment. These data are consistent with bone mineral density changes data after 5 years of anastrozole therapy in 167 patients enrolled on the ATAC trial presented at the 2006 annual meeting of the American Society of Clinical Oncology (ASCO; 7.2% and 6.1%, respectively).² It should be noted that in the latter study bone mineral density decrease slowed down from the third to the fifth year and no patients with normal bone mineral density at baseline became osteoporotic at the end of observation. It seems from these data that bone loss induced by AIs is lower than expected. What is the impact of these data? Should preventive measures be confined mainly to osteopenic/osteoporotic patients? It should be noted that the target of preventive measures is not bone loss but fracture risk. The latest ASCO guidelines identified bone mineral density as a valid tool in treatment decision making. Some recent studies have shown that up to one half of patients with incident fractures have baseline bone mineral density higher than the WHO diagnostic threshold of osteoporosis (T score –2.5). The relatively poor sensitivity of bone mineral density means that many women who will experience fractures in their lifetime will not be identified as high risk on the basis of bone mineral density assessment alone.³ This is because several clinical risk factors contribute to fracture risk independently of bone mineral density. These include age, prior fragility fracture, a family history of hip fracture, the use of corticosteroids, and high bone turnover.⁴ Recently, the International Osteoporosis Foundation, the National Osteoporosis Foundation, and some updated national guidelines recommended that treatment should be offered to women with a bone mineral density T-score above the –2.5 diagnostic threshold in the presence of independent risk factors.^5,6

It is somewhat surprising that many of these risk factors were not included in the aforementioned bone mineral density studies. In addition, no information on the interaction between risk factors and bone mineral density changes has been provided in both studies. Several important questions arise from these studies: how many fractures are attributable to bone loss after AIs? Are changes in bone microenvironment induced by AIs comparable with those induced by postmenopausal osteoporosis? Mincey et al⁷ conducted an interesting survey on 12.368 unselected breast cancer patients recruited among 5 million employees from 31 American companies. They found a significant increased risk of osteoporosis (relative risk [RR], 1.29) and bone fracture (RR, 1.35) in patients treated with AIs compared with untreated patients. These data are expected but the similar RR of undergoing osteoporosis and developing fractures is surprising. If the increased risk of fractures is mainly attributable to bone mineral density decrease then the RR for osteoporosis should have been much greater than the RR of fracture. These data suggest that other factors (eg, bone geometry, bone microstructure, and other elements of bone quality) may contribute to the fracture risk.

Pathophysiology underlying AI induced bone loss may be different from that of postmenopausal osteoporosis. The total suppression of estrogen levels induced by AIs could inhibit insulin-like growth factor 1⁸ and vitamin D bioavailability (by interfering with the protein carrier),⁹ thus resulting in a multiple hormone ablation. As the value of a bone mineral density T-score below –2.5 for fracture threshold is applicable only for postmenopasual osteoporosis, the AIs users, as well as patients with other iatrogenic osteoporosis (ie, glucorticoid osteoporosis), could have a higher bone mineral density fracture threshold than the nonusers.

In conclusion, it is presently unknown which patients undergoing AIs should be addressed to bisphosphonate therapy. The coexistence of independent predictive factors of fracture risk and the the possible increased bone mineral density fracture threshold in patients undergoing AIs compared to postmenopausal osteoporosis should be carefully taken into account in the clinical decision making process.

AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST

Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.

Employment: N/A Leadership: N/A Consultant: Alfredo Berruti, Novartis; Alberto Angeli, Novartis Stock: N/A Honoraria: Alfredo Berruti, Novartis; Luigi Dogliotti, Novartis; Alberto Angeli, Novartis Research Funds: N/A Testimony: N/A Other: N/A

REFERENCES

1. Perez E, Josse RG, Pritchard KI, et al: Effect of letrozole versus placebo on bone mineral density in women with primary breast cancer completing 5 or more years of adjuvant tamoxifen: A companion study to NCIC CTG MA.17. J Clin Oncol 24:3629-3635, 2006[Abstract/Free Full Text]

2. Coleman RE: Effect of anastrozole on bone mineral density: 5-year results from the Arimidex Tamoxifen Alone or in Combination (ATAC) trial. J Clin Oncol 24:5s, 2006 (abstr 511)

3. Johnell O, Kanis J, Oden A: Predictive value of BMD for hip and other fractures. J Bone Min Res 7:1185-1194, 2005

4. Kanis J. Borgstrom F, De Laet C, et al: Assessment of fracture risk. Osteoporos Int 16:581-589, 2005[CrossRef][Medline]

5. Kanis J, Black Cooper C, et al: A new approach in the development of assessment guidelines for osteoporosis. Osteoporos Int 13:527-536, 2002[CrossRef][Medline]

6. Brown JP, Josse RG, for the Scientific Advisory Council of the Osteoporosis Society of Canada: Clinical practice guidelines for the diagnosis and management of osteoporosis in Canada. CMAJ 167:s1–s34, 2002 (suppl 10)[Abstract/Free Full Text]

7. Mincey BA, Duh MS, Thomas SK, et al: Risk of cancer treatment-associated bone loss and fractures among women with breast cancer receiving aromatase inhibitors. J Clin Oncol 24:17s, 2006 (abstr 557)

8. Leung KC, Johannsson G, Leong GM, et al: Estrogen regulation of growth hormone action. Endocrin Rev 25:693-721, 2004[Abstract/Free Full Text]

9. Lips P: Vitamin D physiology. Prog Biophys Mol Biol 92:4-8, 2006[CrossRef][Medline]

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