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Bone Loss With Exemestane: Is the Jury Still Out?

Osteoporosis Program and Women’s Health Program, Department of Medicine, University Health Network and Mount Sinai Hospital, University of Toronto, Toronto, Ontario, Canada

George Tomlinson

Department of Medicine, University Health Network, University of Toronto, Toronto, Ontario, Canada

Paul E. Goss

Massachusetts General Hospital Cancer Center, Harvard University, Boston, MA

To the Editor:

The article by Lønning et al¹ in the August 1, 2005 issue of the Journal of Clinical Oncology is the first to investigate the effects of exemestane on bone mineral density (BMD) and bone biomarkers in a double-blind placebo-controlled randomized trial. They evaluated change in BMD in 128 postmenopausal women with early breast cancer (62 receiving exemestane and 66 receiving placebo) and found mean annual rates of BMD loss of 2.17% versus 1.84% (P = .568) in the lumbar spine and 2.72% versus 1.48% (P = .024) in the femoral neck in the exemestane and placebo groups, respectively. Based on these results, they concluded that exemestane modestly enhanced bone loss from the femoral neck.

We feel that this conclusion may be premature. Of the four commonly reported sites for BMD measurements (lumbar spine, total hip, trochanter, and femoral neck), femoral neck is the least precise (that is, it has the highest coefficient of variation) and the most dependent on positioning.² Slight differences in the rotation of the hip will result in apparent changes in femoral neck BMD. The International Society of Clinical Densitometry in its 2002 position statement has recommended that changes in bone density be considered significant only if they equal or exceed the least significant change, which is calculated for 95% confidence based on the precision of measurement at each site.³ Based on published studies on precision in bone densitometry, a clinically significant change would have to be equal to or greater than 5% to 10% at the femoral neck and 3% at the lumbar spine; an observed difference smaller than these can be secondary to random variation.^2,4-6 Thus, none of the differences in BMD changes observed in the Lønning study¹ were clinically meaningful changes (0.66% for lumbar spine and 2.48% for femoral neck over 2 years).

Previous studies have also shown that BMD measurements are highly variable across test locations and densitometers.^2-7 Most osteoporosis studies that use BMD as an end point have measures in place both to ensure that the scans are done correctly as well as to reduce variation across centers. These measures include specific protocols for scanning, central analysis of all scans, scanning of a standardized phantom across centers, and the review of quality control data at the various centers.⁸ Without such measures, measurement variation across centers will create more noise in the data, decrease the power to detect a clinically and statistically significant difference, and increase the potential to have spurious findings.

Exemestane is a third generation steroidal aromatase inhibitor (AI), structurally related to the natural substrate androstenedione. Both the parent compound and its principal metabolite, 17-hydroexemestane, are androgenic. The effect of exemestane on bone may be different from the nonsteroidal AIs because of this androgenicity. Our group has performed preclinical studies that showed exemestane to have positive effects on bone metabolism.^8-10 Administration of exemestane or 17-hydroexemestane to ovariectomized (OVX) rats results in a significant reduction of both bone resorption and formation markers, to levels seen in nonOVX control rats.^9,11 In contrast, letrozole-treated OVX rats had bone turnover markers similar to those seen in OVX rats.^10,11 In addition, administration of exemestane or 17-hydroexemestane to OVX rats demonstrated a significant dose-dependent protection against BMD reduction at both the lumbar spine and the total hip. Lumbar spine BMD in rats given exemestane was 99.7% of BMD in intact controls and 11% higher than in OVX rats (P < .0001). Total hip BMD in rats receiving exemestane was 99.9% of the BMD in intact controls and 7.1% higher than in OVX rats (P < .001). In contrast, letrozole did not protect against the loss of BMD associated with the loss of estrogen.¹¹

We have also performed a study in postmenopausal women to evaluate the short-term effects of exemestane on bone.^12-13 Our study was a placebo-controlled trial examining the effects of 6 months of 25 mg of exemestane versus 2.5 mg of letrozole daily on bone formation and resorptive markers in 79 postmenopausal women without osteoporosis. Our results indicated that all AIs have similar effects on bone resorption while exemestane is the only AI with a statistically significant increase in bone formation marker. These results are consistent with the data from the Lønning study, which showed increases in both bone resorption and bone formation markers for women on exemestane.¹ The increases in bone formation markers observed with exemestane likely reflect the androgenicity of the parent compound and its principal metabolite.

Whether these increases in bone formation markers counterbalance the increases in bone resorption markers and result in a neutral effect on fracture risk remains to be determined. The Intergroup Exemestane Study bone sub-protocol studied 206 postmenopausal women with primary breast cancer who were disease free after 2 to 3 years of tamoxifen.¹⁴ They showed that women who switched from tamoxifen to exemestane had significant bone loss at 1 year: 2.9% and 2.1% reduction in lumbar spine and total hip BMD, respectively. However, it is unclear whether this drop in BMD is due to the withdrawal of tamoxifen or to the effect of exemestane or both. The Lønning study showed a mean annual difference of 1.24% (90% CI, 0.34% to 2.14%) for femoral neck BMD between the exemestane group and the placebo group.¹ To us, this suggests that we can be 95% confident that the rate of bone loss at the femoral neck is not greater than 2.14% per year (5% confidence on values above 2.14, 90% on values between 0.34 and 2.14, and 5% on values below 0.34) or 4.28% over two years (changes that are not considered clinically meaningful). Thus, our conclusion, based on the Lønning data, is that the jury is still out on whether exemestane causes bone loss. This important issue may be clarified by ongoing trials, such as the National Cancer Institute of Canada Clinical Trials Group MA 27 clinical trial, which has a specific bone substudy to compare the bone effects of exemestane to those of anastrozole in women with early stage breast cancer.

Authors’ Disclosures of Potential Conflicts of Interest

Although all authors completed the disclosure declaration, the following author or 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 discription 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.

Authors Employment Leadership Consultant Stock Honoraria Research Funds Testimony Other Paul E. Goss Novartis (A); Pfizer (A); Astra Zeneca (A) Novartis (N/R)

Dollar Amount Codes (A) < $10,000 (B) $10,000–99,000 (C) $100,000 (N/R) Not Required

REFERENCES

1. Lønning PE, Geisler J, Krag LE, et al: Effects of exemestane administered for 2 years versus placebo on bone mineral density, bone biomarkers, and plasma lipids in patients with surgically resected early breast cancer. J Clin Oncol 23:1-12, 2005[Free Full Text]

2. Baim S, Wilson CR, Lewiecki EM, et al: Precision assessment and radiation safety for dual-energy X-ray absorptiometry. J Clin Densitom 8:371-378, 2005[CrossRef][Medline]

3. Lenchik L, Kiebzak GM, Blunt BA: What is the role of serial bone mineral density measurements in patient management? J Clin Densitom 5:S29–S38, 2002[Medline]

4. Bonnick SL: Monitoring Changes in Bone Density. in Bone Densitometry in Clinical Practice: Application and Interpretation. 2nd ed. Humana Press Inc, New Jersey, 2004, pp 281-283

5. Henzell S, Dhaliwal S, Pontifex R, et al: Precision error of fan-beam dual X-ray absorptiometry scans at the spine, hip, and forearm. Journal of Clinical Densitometry 3:359-364, 2000[CrossRef][Medline]

6. Patel R, Blake GM, Rymer J, et al: Long-term precision of DXA scanning assessed over seven years in forty postmenopausal women. Osteoporosis International 11:68-75, 2000[Medline]

7. Bonnick SL: Bone Density Data. in Bone Densitometry in Clinical Practice: Application and Interpretation. 2nd ed. Humana Press Inc, New Jersey, 2004, pp 120-121

8. Cawte SA, Pearson D, Green DJ, et al: Cross-calibration, precision and patient dose measurements in preparation for clinical trials using dual energy X-ray absorptiometry of the lumbar spine. British Journal of Radiology 72:354-362, 1999[Abstract]

9. Goss P, Gryripas M, Qi S, et al: The effects of exemestane on bone and lipids in the ovariectomized rat. Breast Cancer Res Treat 69:224, 2001

10. Goss PE, Cheung AM, Lowery C, et al: Comparison of the effects of exemestane, 17-hydroxyexemestane and letrozole on bone and lipid metabolism in the ovariectomized rat. Breast Cancer Res Treat 76:A107, 2002 (suppl 1; abstr 415)

11. Goss PE, Qi S, Cheung AM, et al: Effects of the steroidal aromatase inhibitor exemestane and the nonsteroidal aromatase inhibitor letrozole on bone and lipid metabolism in ovariectomized rats. Clinical Cancer Res 10:5717-5723, 2004[Abstract/Free Full Text]

12. Goss PE, Thomsen T, Banke-Bochita J, et al: Effects of steroidal and nonsteroidal aromatase inhibitors on markers of bone turnover and lipid metabolism in healthy volunteers. Breast Cancer Res Treat 82:S101, A427, 2003 (suppl 1; abstr 427)

13. Subar M, Goss PE, Thomsen T, et al: Effects of steroidal and nonsteroidal aromatase inhibitors (AIs) on markers of bone turnover and lipid metabolism in healthy volunteers. Proc Ann Meet Am Soc Clin Oncol 23:734, A8038, 2004

14. Coleman RE, Banks LM, Hall E, et al: Intergroup Exemestane Study: 1 year results of the bone sub-protocol. Breast Cancer Res Treat 88:S35, 2005

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• In Reply:
  Per Eystein Lønning and Jurgen Geisler
  JCO 2005 23: 9434-9435 [Full Text]

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