This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sverrisdóttir, A. Articles by Rutqvist, L.E. Search for Related Content PubMed PubMed Citation Articles by Sverrisdóttir, A. Articles by Rutqvist, L.E.

Bone Mineral Density Among Premenopausal Women With Early Breast Cancer in a Randomized Trial of Adjuvant Endocrine Therapy

From the Departments of Oncology and Radiology, Karolinska Institute and University Hospital, Stockholm, Sweden

Address reprint requests to Á. Sverrisdóttir, MD, Department of Oncology, Karolinska University Hospital, Huddinge S-E 118 83, Stockholm, Sweden; e-mail: asgerdur.sverrisdottir{at}kus.se

	ABSTRACT

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
PURPOSE: To examine the effects on bone mineral density of 2 years of treatment with a luteinizing hormone-releasing hormone (LHRH) agonist alone or in combination with tamoxifen or tamoxifen alone in premenopausal breast cancer.

PATIENTS AND METHODS: We recruited 89 women from two centers in Stockholm participating in a randomized multicenter trial of three different endocrine approaches in the adjuvant setting (Zoladex in Premenopausal Patients Trial). The women were assigned to receive the LHRH agonist goserelin with or without tamoxifen, tamoxifen alone, or no endocrine therapy. The treatment was given for 2 years. We measured total-body bone density before start of treatment and at 12, 24, and 36 months.

RESULTS: After 2 years of treatment, there was a significant loss of bone mineral density (mean change, –5%; P < .001) in the women receiving goserelin alone. The combined goserelin and tamoxifen treatment, as well as tamoxifen alone, resulted in a lesser but statistically significant decline in bone mineral density (mean change, –1.4%; P = .02; and –1.5%; P < .001). One year after cessation of treatment, the goserelin group alone showed a partial recovery from bone loss (mean change, 1.5%; P = .02).

CONCLUSION: Two years of ovarian ablation from goserelin treatment caused a significant reduction in bone mineral density but there was a partial recovery from the bone loss 1 year after cessation of treatment. The addition of tamoxifen seems to partially counteract the demineralizing effects of goserelin.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Ovarian ablation improves survival in premenopausal women with early breast cancer.¹ Similarly, early results from trials using luteinizing hormone-releasing hormone (LHRH) analogs in the adjuvant setting have indicated significant benefits in terms of prolonged disease-free survival and improved survival with only 2 years of treatment, regardless of other systemic treatments.^2,3 Recent results from trials comparing LHRH analog treatment alone or in addition to tamoxifen versus chemotherapy with cyclophosphamide, methotrexate, and fluorouracil show similar or even better results among those allocated to endocrine treatment compared with those treated with chemotherapy alone.^4-6 However, there is concern that a premature menopause may be associated with long-term side effects, such as decreased bone mineral density (BMD).

Bone metabolism is highly affected by changes in ovarian function. After the onset of menopause, decrease in estrogen levels are associated with loss of bone, and early menopause is one of the strongest predictors of osteoporosis.^7-9 Estrogen-sensitive changes in BMD are most rapidly seen in the lumbar spine and the hip, where osteoporotic fractures also are frequent.¹⁰ LHRH analogs are efficient suppressors of ovarian function and induce a so-called chemical castration.⁵ In adjuvant chemotherapy trials, women who become amenorrheic develop decreased bone mass compared with those who maintain their ovarian function.^11,12The effect of LHRH agonists on the ovaries is reversible, but reports on bone mass changes after cessation of treatment are scanty.

Tamoxifen for 5 years is widely considered to be a standard treatment for estrogen receptor–positive breast cancer patients, irrespective of menopausal status.^13,14 Tamoxifen is a selective estrogen receptor modulator, acting estrogenic in some tissues and antiestrogenic in others.^15-20 In postmenopausal women, tamoxifen has well-studied agonistic estrogenic effects in bone.^10,21,22 In contrast, there is some evidence that tamoxifen may decrease BMD in premenopausal women, although the exact mechanism remains unclear.²³

These above data^4-6 suggest that suppression of ovarian function with LHRH agonists is an alternative to chemotherapy in premenopausal patients with estrogen receptor–positive tumors. The additional effect of concurrent tamoxifen treatment remains unclear, but the estrogenic properties of the drug may be of value in moderating the putative negative effects of estrogen depletion. A multicenter randomized trial (Zoladex in Premenopausal Patients [ZIPP]) was initiated in the late 1980s, which compared the effects of the LHRH agonist goserelin alone or in combination with tamoxifen versus no endocrine treatment in premenopausal women with breast cancer.^2,3 At two Stockholm centers, a subprotocol including regular measurements of BMD was initiated in 1990 to detect changes in bone mass of clinical significance for long-term survivors. This article presents the results of a 3-year follow-up of total-body bone density (TBBD).

	PATIENTS AND METHODS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The ZIPP trial was designed as a randomized, controlled, multicenter trial of three different endocrine approaches in the adjuvant setting for premenopausal women with node-positive or node-negative early breast cancer. A total of 2,648 women were recruited to the trial in Stockholm, Southeast Sweden, United Kingdom (Cancer Research Campaign), and Italy (Gruppo Interdisciplinare Valutazione Interventi in Oncologica). The study design was pragmatic, allowing local centers to predefine local treatment, the use of adjuvant chemotherapy, and whether tamoxifen was given by random assignment or electively. The first results from the ZIPP trial showed a significant benefit in recurrence-free survival for women randomly assigned to goserelin treatment compared with women allocated to no goserelin (P = .001).²

The study had a 2 x 2 factorial design, randomly assigning women to receive goserelin alone, tamoxifen plus goserelin, tamoxifen alone, or no endocrine therapy. In the Stockholm part of the trial, all node-positive women received adjuvant polychemotherapy (six cycles of cyclophosphamide, methotrexate, and fluorouracil intravenously on days 1 and 8 every 28 days), in addition to the endocrine therapy. Patients who underwent breast-conserving surgery received postoperative radiotherapy to the breast at a dose of 50 Gy over 5 weeks. In addition, patients with four or more positive lymph nodes received locoregional irradiation that included the chest wall, axillary, and supraclavicular lymph nodes at a dose of 46 Gy over 4.5 weeks. The dose of tamoxifen was 40 mg/d orally and the dose of goserelin was 3.6 mg subcutaneously every 28 days. For goserelin, every injection was documented in the patient records. The treatment duration for both tamoxifen and goserelin was 2 years.

The inclusion criteria were as follows: invasive breast cancer, premenopausal menstrual status (defined as last menstruation < 6 months earlier), primary surgery consisting of a mastectomy or lumpectomy plus axillary node dissection, histopathologic tumor size greater than 10 mm, and no clinical evidence of distant metastases. The exclusion criteria were inoperable breast cancer, prior radiotherapy or neoadjuvant chemotherapy, and prior or concurrent endocrine therapy.

The randomization was stratified in three groups: node-negative patients receiving no chemotherapy, patients with one to three positive lymph nodes receiving chemotherapy, and patients with four or more positive lymph nodes receiving both chemotherapy and locoregional radiotherapy. Randomization was carried out by telephone to a central office where the patient identifiers were recorded before the allocated treatment was revealed to the responsible physician. Treatment allocation was based on balanced lists using the permuted block technique. Informed consent was obtained from the patients before randomization. The study was approved by the Karolinska Institute Regional Ethics Committee.

Bone Mineral Examination
Within the ZIPP trial, the Stockholm Breast Cancer Study Group initiated a study of bone mineral effects. Between October 1990 and June 1994, patients at two of four Stockholm hospitals participating in the trial were recruited to the study. Only patients from the strata not receiving chemotherapy were eligible for the bone mineral study. A total of 89 (81% of eligible patients at the two participating hospitals during the period of entry) node-negative patients from the four randomized groups were recruited to the bone mineral study. Of the eligible women, 27 patients had been assigned to groups either receiving tamoxifen or tamoxifen plus goserelin, 26 patients had been assigned to receive goserelin alone, and 30 patients had been assigned to the control group. Women with recurrent or metastatic disease were withdrawn from further bone mineral examinations.

Bone Densitometry
Bone densitometry was carried out before initiation of treatment and at 12 months, 24 months, and 36 months later (ie, the last examination was made 1 year after treatment finished). TBBD was measured by dual-energy x-ray absorptiometry using a Lunar DPX-L device (Lunar Corporation, Madison, WI). The precision of the technique is 1% and the accuracy is 10%.²⁴ BMD of the lumbar spine (L2 to L4) was as well measured at baseline for the patients for validation of the equipment used. An experienced investigator blinded to the individual patients analyzed the scans. All measurements were made with the same equipment and evaluation procedures.

Statistical Analyses
All analyses were performed according to the intention-to-treat principle. The analyses included all women for whom at least three measurements were available. Eighty-nine patients agreed to participate in the bone density study. For 23 patients, data were unavailable after 12 months, and these patients were excluded from further analysis (three patients died, six patients had no data because of patient preference, and 14 patients had no data because of administrative errors). Of the remaining 66 patients, a total of 53 patients underwent all four measurements as defined in the protocol. In addition, BMD of the lumbar spine was measured at baseline in 85 of the 89 study patients.

Mean difference in TBBD between examination at 24 months and baseline and between 36 and 24 months within the treatment groups were tested using the paired t test. Differences in TBBD change between the treatment groups were estimated using multiple linear regression, controlling for baseline TBBD values. Results are presented as mean differences with 95% CIs together with two-sided P values.

	RESULTS

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
Of the 66 patients included in the analyses, 18 were randomly allocated to receive tamoxifen treatment (T group), 14 patients were assigned to treatment with tamoxifen plus goserelin (TG group), 13 patients were assigned to treatment with goserelin (G group), and 21 patients were allocated to receive no endocrine therapy (controls). The groups were similar in regard to clinical and histopathologic characteristics (Table 1). Three patients in the T group never initiated treatment. In the TG group, one patient did not receive tamoxifen and one patient received neither tamoxifen nor goserelin. One patient in the TG group stopped goserelin treatment after 15 months because of side effects. All patients in the G group and one patient in the control group received treatment with goserelin for 2 years. Therefore, overall compliance to goserelin was 100%, compliance to tamoxifen was 83%, compliance to tamoxifen plus goserelin was 86%, and compliance to no endocrine therapy was 95%.

View larger version (15K): [in this window] [in a new window]   Fig 1. Mean change in total-body bone density (TBBD, in grams per centimeter squared) in the treatment groups. (A) Two years of measurements for 66 patients; (B) 3 years of measurements for 53 patients. T, tamoxifen; TG, tamoxifen plus goserelin; G, goserelin; C, control.

Baseline measurements of BMD of the lumbar spine showed a correlation with TBBD (r = 0.8).

	DISCUSSION

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The present study shows that goserelin causes a 5% reduction in BMD after 2 years of treatment. This represents rapid bone loss in women not yet in menopause and may be an important determinant of fracture risk, as several other studies have shown.^25-27 In our study, treatment with tamoxifen reduced the BMD slightly. These results differ from the well-known estrogen agonistic effects on bone among postmenopausal women but confirm similar results that Powles et al²³ have reported for premenopausal women in a tamoxifen chemoprevention trial. This apparent menstrual status–dependent effect can be explained by the difference in endocrine milieu in which tamoxifen is acting. In premenopausal women, the demineralizing effect on bone may be caused by tamoxifen antagonizing the more potent activity of endogenous estrogen.²⁸ Before menopause, the levels of endogenous estrogens are much higher than levels in postmenopausal women. The net effect of tamoxifen may therefore be opposite, depending on the basic estrogenic stimulation.

Among patients treated with goserelin in addition to tamoxifen, the effect on bone mass was similar to that in the group treated with tamoxifen alone. In this group, it seems that tamoxifen at least partially counteracts the demineralizing effects of goserelin. The mechanism of this action is not clear. In premature menopause from LHRH analog treatment, it seems that tamoxifen when added to goserelin has similar agonistic estrogenic effects on bone as in postmenopausal women. The adverse effect of LHRH analog treatment on bone may be substantial, but unlike the frequently irreversible amenorrheic effect of cytotoxic chemotherapy, the reversible effect on the ovarian function seems to be partially reversible on bone density as well.

Compliance was good in all study groups. Data on possible confounders such as smoking, calcium intake, and physical exercise were unavailable, but randomization minimized the risk of an uneven distribution of such factors in the different treatment groups.

At the time of this study, standard duration of endocrine treatment was 2 years. Today, the standard recommendation of tamoxifen therapy is 5 years, and studies on the possible benefit of 10 years of treatment are ongoing. Thus our 3 years of follow-up are short in terms of endocrine therapy. Considering this, in addition to the limited sample size of our study, the results should be interpreted cautiously. However, the optimal length of ovarian ablative treatment has not yet been established, and data on treatment past 2 years are limited.

At present, BMD measurements of the spine and hip are generally regarded as the method of choice for assessing fracture risk because of the frequency of fractures and their morbidity at these sites. This study was initiated before this was widely accepted. Therefore, it may be a limitation of our study that we did not measure prospectively BMD at the spine or hip. At the time, we considered whole-body measurement to be the method of choice because it detects small changes with a higher sensitivity than regional measurements.²⁹ Several investigators have later shown a strong correlation on group level between BMD at different regions and the whole body, which supports the clinical relevance of our data.^30-32 Furthermore, the Epidemiologie de l’Osteoporose study showed that a decrease in whole-body BMD was associated with an increased risk of hip fracture.³³ In our study, BMD of the lumbar spine was correlated with TBBD at baseline. Whole-body measurements of BMD can therefore be used to detect bone loss as a systemic disease that is not limited to the axial skeleton.^34-36

As shown by Klijn et al³⁷ in the meta-analysis of randomized trials comparing LHRH agonist with LHRH agonist plus tamoxifen in advanced disease and by the European Breast Cancer Trialists' Collaborative Group overview of randomized trials in the adjuvant setting,¹ concomitant treatment with tamoxifen and goserelin is favorable in terms of survival or recurrence-free survival compared with goserelin treatment alone.

In this randomized trial of premenopausal women with breast cancer, 2 years of treatment with an LHRH analog resulted in a demineralizing effect on bone, which partially recovers after the completion of treatment. Our results are consistent with previous reports that show decrease in BMD from loss of ovarian function in premenopausal women.^11,12,38 Despite the adverse effects from ovarian ablation on BMD, our results showing the partially reversible demineralization after completed treatment and the compensating effect of concomitant tamoxifen treatment seem to favor combined treatment as well.

	Authors' Disclosures of Potential Conflicts of Interest

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
The following authors or their immediate family members have 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. Consultant/advisory role: LarsErik Rutqvist, AstraZeneca. Honoraria: LarsErik Rutqvist, AstraZeneca. Research funding: LarsErik Rutqvist, AstraZeneca. For a detailed description of these categories, or for more information about American Society of Clinical Oncology's conflict of interest policy, please refer to the Author Disclosure Declaration form and the Disclosures of Potential Conflicts of Interest section of Information for Contributors found in the front of every issue.

	Acknowledgment

 
We thank Marianne Nystedt, Berit Kummetz, Cecilia Arewald, and Madelen Palm, Department of Oncology, Karolinska University Hospital, Solna and Huddinge, Sweden, for their excellent work coordinating patient visits, tests, and questionnaires. We also thank Shirley Kalén and Ingegärd Abbors-Svenzon, Department of Radiology, Karolinska University Hospital, for their work with the bone mineral measurements. The statistical expertise of Hemming Johansson is also highly appreciated.

	NOTES

 
Supported by a grant from the Swedish Cancer Society, Stockholm, Sweden.

Presented at the 37th Annual Meeting of the American Society of Clinical Oncology, San Francisco, CA, May 12-15, 2001.

Authors' disclosures of potential conflicts of interest are found at the end of this article.

	REFERENCES

TOP ABSTRACT INTRODUCTION PATIENTS AND METHODS RESULTS DISCUSSION Authors' Disclosures of... REFERENCES

 
1. Early Breast Cancer Trialists' Collaborative Group: Ovarian ablation in early breast cancer: Overview of the randomized trials. Lancet 348:1189-1196, 1996[CrossRef][Medline]

2. Rutqvist LE: The ZIPP trial of adjuvant zoladex in premenopausal patients with early breast cancer: An update at five years. Proc Am Soc Clin Oncol 18, 1999 (abstr 251)

3. The ZIPP International Collaborators' Group: Adjuvant goserelin in premenopausal patients with early breast cancer: Results from the "zoladex" in premenopausal patients (ZIPP) trial. (in press)

4. Boccardo F, Rubagotti A, Amoroso D, et al: Cyclophosphamide, methotrexate, and fluorouracil versus tamoxifen plus ovarian suppression as adjuvant treatment of estrogen receptor-positive pre-/perimenopausal breast cancer patients: Results of the Italian Breast Cancer Adjuvant Study Group 02 randomized trial. J Clin Oncol 18:2718-2727, 2000[Abstract/Free Full Text]

5. Jonat W: Role of LHRH agonists in premenopausal women with oestrogen receptor-positive breast cancer: The ZEBRA experience. Eur J Cancer 38:S39-S40, 2002 (suppl 6)

6. Jakesz R, Hausmaninger H, Samonigg H: Chemotherapy versus hormonal adjuvant treatment in premenopausal patients with breast cancer. Eur J Cancer 38:327-332, 2002

7. Lindsay R, Hart DM, Aitken JM, et al: Long-term prevention of postmenopausal osteoporosis by oestrogen: Evidence for an increased bone mass after delayed onset of oestrogen treatment. Lancet 1:1038-1041, 1976[CrossRef][Medline]

8. Richelson LS, Wahner HW, Melton LJ III, et al: Relative contributions of aging and estrogen deficiency to postmenopausal bone loss. N Engl J Med 311:1273-1275, 1984[Abstract]

9. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy: Osteoporosis prevention, diagnosis, and therapy. JAMA 285:785-795, 2001[Abstract/Free Full Text]

10. Love RR, Mazess RB, Barden HS, et al: Effects of tamoxifen on bone mineral density in postmenopausal women with breast cancer. N Engl J Med 326:852-856, 1992[Abstract]

11. Bruning PF, Pit MJ, de Jong-Bakker M, et al: Bone mineral density after adjuvant chemotherapy for premenopausal breast cancer. Br J Cancer 61:308-310, 1990[Medline]

12. Headley JA, Theriault RL, LeBlanc AD, et al: Pilot study of bone mineral density in breast cancer patients treated with adjuvant chemotherapy. Cancer Invest 16:6-11, 1998[Medline]

13. Swedish Breast Cancer Cooperative Group: Randomized trial of two versus five years of adjuvant tamoxifen for postmenopausal early stage breast cancer. J Natl Cancer Inst 88:1543-1549, 1996[Abstract/Free Full Text]

14. Early Breast Cancer Trialists' Collaborative Group: Tamoxifen for early breast cancer: An overview of the randomized trials. Lancet 351:1451-1467, 1998[CrossRef][Medline]

15. Furr BJ, Jordan VC: The pharmacology and clinical uses of tamoxifen. Pharmacol Ther 25:127-205, 1984[CrossRef][Medline]

16. Fornander T, Rutqvist LE, Cedermark B, et al: Adjuvant tamoxifen in early breast cancer: Occurrence of new primary cancers. Lancet 1:117-120, 1989[Medline]

17. Love RR, Newcomb PA, Wiebe DA, et al: Effects of tamoxifen therapy on lipid and lipoprotein levels in postmenopausal patients with node-negative breast cancer. J Natl Cancer Inst 82:1327-1332, 1990[Abstract/Free Full Text]

18. Fornander T, Rutqvist LE, Wilking N: Effects of tamoxifen on the female genital tract. Ann N Y Acad Sci 622:469-476, 1991[CrossRef][Medline]

19. McDonald CC, Stewart HJ: Fatal myocardial infarction in the Scottish adjuvant tamoxifen trial: The Scottish Breast Cancer Committee. BMJ 303:435-437, 1991

20. Fisher B, Costantino JP, Wickerham DL, et al: Tamoxifen for prevention of breast cancer: Report of the National Surgical Adjuvant Breast and Bowel Project P-1 Study. J Natl Cancer Inst 90:1371-1388, 1998[Abstract/Free Full Text]

21. Fornander T, Rutqvist LE, Sjoberg HE, et al: Long-term adjuvant tamoxifen in early breast cancer: Effect on bone mineral density in postmenopausal women. J Clin Oncol 8:1019-1024, 1990[Abstract]

22. Powles TJ, Jones AL, Ashley SE, et al: The Royal Marsden Hospital pilot tamoxifen chemoprevention trial. Breast Cancer Res Treat 31:73-82, 1994[CrossRef][Medline]

23. Powles TJ, Hickish T, Kanis JA, et al: Effect of tamoxifen on bone mineral density measured by dual-energy x-ray absorptiometry in healthy premenopausal and postmenopausal women. J Clin Oncol 14:78-84, 1996[Abstract]

24. Lunar Corporation: Lunar DPX-L Operator's Manual. Madison, WI, Lunar Corporation,

25. Christiansen C, Riis BJ, Rodbro P: Prediction of rapid bone loss in postmenopausal women. Lancet 1:1105-1108, 1987[Medline]

26. Hansen MA, Overgaard K, Riis BJ, et al: Role of peak bone mass and bone loss in postmenopausal osteoporosis: 12 year study. BMJ 303:961-964, 1991

27. Riis BJ, Hansen MA, Jensen AM, et al: Low bone mass and fast rate of bone loss at menopause: Equal risk factors for future fracture—A 15-year follow-up study. Bone 19:9-12, 1996[Medline]

28. Osborne CK: Tamoxifen in the treatment of breast cancer. N Engl J Med 339:1609-1618, 1998[Free Full Text]

29. LeBlanc AD, Schneider VS, Engelbretson DA, et al: Precision of regional bone mineral measurements obtained from total-body scans. J Nucl Med 31:43-45, 1990[Abstract/Free Full Text]

30. Ambrahamsen B, Hansen TB, Jensen LB, et al: Site of osteodensitometry in perimenopausal women: Correlation and limits of agreement between anatomic regions. J Bone Miner Res 12:1471-1479, 1997[CrossRef][Medline]

31. Ljunggren-Ribom E: Muscles, Estrogen and Bone (thesis). Uppsala, Sweden, Uppsala University, 2003

32. Nuti R, Martini G, Righi G, et al: Comparison of total-body measurements by dual-energy x-ray absorptiometry and dual-photon absorptiometry. J Bone Miner Res 6:681-687, 1991[Medline]

33. Schott AM, Cormier C, Hans D, et al: How hip and whole-body bone mineral density predict hip fracture in elderly women: The EPIDOS prospective study. Osteoporos Int 8:247-254, 1998[CrossRef][Medline]

34. Blake GM, Fogelman I: Bone densitometry and the diagnosis of osteoporosis. Semin Nucl Med 31:69-81, 2001[CrossRef][Medline]

35. Kanis JA: Diagnosis of osteoporosis and assessment of fracture risk. Lancet 359:1929-1936, 2002[CrossRef][Medline]

36. Marshall D, Johnell O, Wedel H: Meta-analysis of how well measures of bone mineral density predict occurrence of osteoporotic fractures. BMJ 312:1254-1259, 1996[Abstract/Free Full Text]

37. Klijn JG, Blamey RW, Boccardo F, et al: Combined tamoxifen and luteinizing hormone-releasing hormone (LHRH) agonist versus LHRH agonist alone in premenopausal advanced breast cancer: A meta-analysis of four randomized trials. J Clin Oncol 19:343-353, 2001[Abstract/Free Full Text]

38. Saarto T, Blomqvist C, Valimaki M, et al: Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes rapid bone loss that is reduced by clodronate: A randomized study in premenopausal breast cancer patients. J Clin Oncol 15:1341-1347, 1997[Abstract/Free Full Text]

Submitted August 22, 2003; accepted June 19, 2004.

This article has been cited by other articles:

				F. Saad, J. D. Adachi, J. P. Brown, L. A. Canning, K. A. Gelmon, R. G. Josse, and K. I. Pritchard Cancer Treatment-Induced Bone Loss in Breast and Prostate Cancer J. Clin. Oncol., November 20, 2008; 26(33): 5465 - 5476. [Abstract] [Full Text] [PDF]

				M. Parton and I. E. Smith Controversies in the Management of Patients With Breast Cancer: Adjuvant Endocrine Therapy in Premenopausal Women J. Clin. Oncol., February 10, 2008; 26(5): 745 - 752. [Full Text] [PDF]

				J. R. Gralow Bone Density in Breast Cancer: When to Intervene? J. Clin. Oncol., August 1, 2007; 25(22): 3194 - 3197. [Full Text] [PDF]

				K. W. Reeves, K. Faulkner, F. Modugno, T. A. Hillier, D. C. Bauer, K. E. Ensrud, J. A. Cauley, and for the Study of Osteoporotic Fractures Research G Body Mass Index and Mortality among Older Breast Cancer Survivors in the Study of Osteoporotic Fractures Cancer Epidemiol. Biomarkers Prev., July 1, 2007; 16(7): 1468 - 1473. [Abstract] [Full Text] [PDF]

				M. F.X. Gnant, B. Mlineritsch, G. Luschin-Ebengreuth, S. Grampp, H. Kaessmann, M. Schmid, C. Menzel, J. C. Piswanger-Soelkner, A. Galid, M. Mittlboeck, et al. Zoledronic Acid Prevents Cancer Treatment-Induced Bone Loss in Premenopausal Women Receiving Adjuvant Endocrine Therapy for Hormone-Responsive Breast Cancer: A Report From the Austrian Breast and Colorectal Cancer Study Group J. Clin. Oncol., March 1, 2007; 25(7): 820 - 828. [Abstract] [Full Text] [PDF]

				L. B. Michaud and S. Goodin Cancer-treatment-induced bone loss, part 1 Am. J. Health Syst. Pharm., March 1, 2006; 63(5): 419 - 430. [Abstract] [Full Text] [PDF]

				L. Vehmanen, I. Elomaa, C. Blomqvist, and T. Saarto Tamoxifen Treatment After Adjuvant Chemotherapy Has Opposite Effects on Bone Mineral Density in Premenopausal Patients Depending on Menstrual Status J. Clin. Oncol., February 1, 2006; 24(4): 675 - 680. [Abstract] [Full Text] [PDF]

				M. Vanhuyse, C. Fournier, and J. Bonneterre Chemotherapy-induced amenorrhea: influence on disease-free survival and overall survival in receptor-positive premenopausal early breast cancer patients Ann. Onc., August 1, 2005; 16(8): 1283 - 1288. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a colleague Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Save to my personal folders Download to citation manager Rights & Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Sverrisdóttir, A. Articles by Rutqvist, L.E. Search for Related Content PubMed PubMed Citation Articles by Sverrisdóttir, A. Articles by Rutqvist, L.E.