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Originally published as JCO Early Release 10.1200/JCO.2008.17.7451 on October 27 2008 © 2008 American Society of Clinical Oncology. Prevalence of Secondary Causes of Bone Loss Among Breast Cancer Patients With Osteopenia and Osteoporosis
From the Divisions of Endocrinology and Metabolism, Hematology/Oncology Institute, and Department of Medicine, Loyola University Medical Center, Maywood, IL Corresponding author: Pauline M. Camacho, MD, FACE, Loyola University Medical Center, 2160 S First Ave, Bldg 54, Maywood, IL 60153; e-mail: pcamach{at}lumc.edu
Purpose To determine the prevalence of secondary causes of bone loss among patients with breast cancer with osteopenia and osteoporosis. Patients and Methods All women referred to a bone health clinic over a 6-year period for bone evaluation were included in this retrospective study and stratified based on presence or absence of a breast cancer history. The prevalence of secondary causes of bone loss in the two groups was compared. Results Of the 238 women identified, 64 women had breast cancer. The non–breast cancer group (n = 174) was significantly older (P = .015), had a lower mean weight (P = .019), lower 25 hydroxy-vitamin D level (P = .019), and greater degree of bone loss in both the spine and hip (P < .001 and 0.004, respectively). The presence of at least one secondary cause of bone loss, excluding cancer-related therapies, was seen in 78% of the breast cancer patient group and in 77% of the non–breast cancer group (P = not significant). Newly diagnosed metabolic bone disorders were seen in 58% of the breast cancer population. The most common was vitamin D deficiency, seen in 38% of patients in the breast cancer group and 51% of patients in the non–breast cancer group. Idiopathic hypercalciuria was diagnosed in 15.6%, primary hyperparathyroidism in 1.6%, and normocalcemic hyperparathyroidism in 3.1% of the breast cancer population. Conclusion A high prevalence of secondary causes of bone loss among patients with breast cancer supports a comprehensive evaluation in these patients, particularly those considering therapy with an aromatase inhibitor.
Osteoporosis results from an imbalance between bone formation and bone resorption. Subsequent micro-architectural changes in bone lead to an increased susceptibility to develop fractures. This disease affects one in three postmenopausal women world-wide,1 and it is estimated that white women aged 50 years or older have a 40% chance of developing an osteoporotic fracture throughout their lifetime.2 After peak bone mass is reached, there is a slow and steady decline in bone mineral density (BMD) until menopause, after which bone loss accelerates at an annual rate of approximately 3% over 5 years. This rapid decline is mostly due to the decrease in circulating estrogens and is followed by a slower rate of approximately 0.5% per year, mostly attributed to aging.3-5 Secondary causes of osteoporosis are disease states or conditions other than menopause and aging, which can cause or accelerate bone loss. Failure to diagnose and address these secondary causes may lead to failure of osteoporosis therapy or suboptimal response to antiresorptive and anabolic agents. The prevalence of secondary causes of bone loss ranges from 30% to 50% among women with osteoporosis.6,7 The more common causes of secondary osteoporosis include vitamin D deficiency, idiopathic hypercalciuria, glucocorticoid excess, primary and secondary hyperparathyroidism, hyperthyroidism, malabsorption, medications, solid-organ (lung, liver, heart, and kidney) failure, and transplantation. Standard chemotherapy agents for breast cancer have been shown to increase the progression of bone loss through both direct and indirect effects.8,9 However, endocrine-based adjuvant therapy has mixed actions on bone. Tamoxifen, a selective estrogen receptor modulator, acts as a stimulatory molecule, with action similar to the positive effects of estrogen on bone. Several studies of postmenopausal, low-risk patients with breast cancer treated with tamoxifen versus placebo demonstrated an increase in lumbar and appendicular skeleton BMD.10-12 Postmenopausal women with breast cancer treated adjuvantly with aromatase inhibitors have a prolonged disease-free survival and time-to-disease recurrence when compared with those treated with tamoxifen.12 These drugs may be divided into the reversibly inhibiting drugs (anastrazole and letrozole), or the irreversibly inhibiting steroidal-derived drugs (exemestane). In contrast to tamoxifen, aromatase inhibitors are associated with declines in bone mineral density and an increased fracture risk in postmenopausal women.12-14 Knowing that these frequently prescribed agents may have detrimental effects on bone, it is vital that patients with breast cancer who are given these drugs receive proper bone evaluation. Our study sought to examine the prevalence of secondary causes of bone loss among patients referred to our clinics for this specific reason.
Study Population A retrospective chart review of all consecutive postmenopausal patients with osteoporosis and osteopenia who were referred to the Loyola University Osteoporosis and Metabolic Bone Disease Center from 2000 to 2006 was conducted. The cohort was divided into two groups: patients with a biopsy-proven invasive breast cancer without distant metastases referred from the Cardinal Bernardin Cancer Center and patients without a known diagnosis of breast cancer referred from primary care physicians. Patients with natural, surgical menopause and chemically induced ovarian suppression were included. Patients with breast cancer were referred to the bone clinic as part of the routine evaluation before breast cancer adjuvant therapy with aromatase inhibitors, regardless of the severity of their bone loss. Patient characteristics including height, weight, sex, race, past medical and surgical history, osteoporosis risk factors, current medications, prior breast cancer therapy, social history, and family history were obtained during the initial visit. Assessment of chronic disease states, pertinent imaging studies (echocardiograms, computed tomography scans) were obtained through chart review. Physical examination findings of kyphosis, limbic calcifications, thyroid abnormalities, and clinical evidence of calcium and vitamin D deficiency were noted. The project was approved by the institutional review board of Loyola University Medical Center (LUMC).
Biochemical Assays
Definition of Secondary Causes
Imaging
Statistical Analysis All statistical tests were performed using SPSS 13.0 (2004, SPSS Inc, Chicago, IL), and significance was determined at the .05 level.
There were 238 patients identified, of whom 64 patients had early-stage breast cancer and 174 patients had no known breast malignancy. The two groups were different in mean age of 64.2 ± 14.2 years in the non–breast cancer group versus 59.5 ± 10.6 years in the breast cancer group (P = .015) and degree of bone loss. A lower BMD in the femoral neck of 0.762 g/cm2 in the non–breast cancer group versus 0.818 g/cm2 in the breast cancer group (P = .004) and T scores of –1.968 versus –1.665, respectively (P = .071), were found. There was a lower mean BMD in the spine of 0.948 g/cm2 in the non–breast cancer group versus 1.089 g/cm2 in the breast cancer group (P  .001) and T scores of –1.966 and 0.918, respectively (P .001; Table 1).
The non–breast cancer group also had a statistically significant lower mean weight of 63.53 kg versus 73.62 kg in the breast cancer group (P = .001). The mean 25 OHD level of 28.7 ng/mL ± 13.1 was lower in the non–breast cancer group versus 34 ng/mL ± 15.1 in the breast cancer group (P = .019). The overall prevalence of at least one secondary cause of bone loss, including cancer-related therapies, was 87.5% in the breast cancer group and 77.6% in the non–breast cancer population (P = .093; Tables 2 and 3). When the use of gonadotropin-releasing hormone analogs to induce ovarian suppression, chemotherapy, and aromatase inhibitors were excluded in the breast cancer group, the prevalence of at least one secondary cause in the breast cancer population was 78.1%, similar to the non–breast cancer population prevalence of 77% (P = .856; Table 3). The prevalence of newly diagnosed metabolic bone disorders in the breast cancer population was 57.8% (Table 4). The most common disorders were vitamin D deficiency (37.5%), idiopathic hypercalciuria (15.6%), normocalcemic hyperparathyroidism (3.1%) and primary hyperparathyroidism (1.6%). One patient developed thyroid carcinoma after the diagnosis of breast cancer and required suppression therapy with levothyroxine. Two patients developed Graves disease just before and during the course of treatment. There was a trend toward a higher prevalence of idiopathic hypercalciuria in the breast cancer population (15.6%) versus the non–breast cancer group (8%; P = .085).
Use of aromatase-inhibitor among breast cancer patients at the time of review was 42.2% (P < .007), previous chemotherapy was 35.9% (P .007), and use of gonadotropin-releasing hormone analogs was 6.3% (P < .007). Each variable, as expected, was significantly higher in the breast cancer population.
Osteoporosis and osteopenia are growing concerns among breast cancer survivors and their physicians and often are attributed to treatment. Our study demonstrated that a significant proportion of patients with breast cancer have treatable secondary causes of bone loss unrelated to their cancer therapy. New chemotherapeutic agents used for breast cancer have negative effects on bone density.12-14 Aromatase inhibitors, which lower plasma estradiol, estrone, and estrone sulfate concentrations by up to 98%, have a negative impact on bone remodeling.15,16 The effects of estrogen deficiency include increased activation of osteoclasts, augmentation of osteoclast survival and recruitment, increased osteoblastic apoptosis, and an increase in the depth and number of bone remodeling units.17-21 Breast cancer patients treated with aromatase inhibitors suffer from a decrease in bone density within a few years of use.12-14 Secondary causes of bone loss are factors other than menopause and aging that can lead to osteoporosis. If present, these conditions can potentially amplify the negative effects of breast cancer therapy on skeletal health. Vitamin D deficiency was the most common secondary cause found in both groups in this study. These findings are consistent with other investigators who have found that vitamin D deficiency could be the most important factor accelerating bone loss among patients treated with an aromatase inhibitor.22,23 Idiopathic hypercalciuria was slightly more common in the breast cancer group than in the non–breast cancer group. This is disease characterized by increased urinary calcium excretion in the absence of diuretic use and conditions that lead to hypercalcemia, such excessive calcium or vitamin D intake, primary hyperparathyroidism, sarcoidosis, and malignancies. Intact PTH levels are usually normal, as well as serum calcium, phosphorus, and 25 OHD levels. Complications of idiopathic hypercalciuria include osteoporosis and nephrolithiasis. There is usually a drastic reduction of urinary calcium excretion after a few weeks of treatment with hydrochlorothiazide, which further confirms the diagnosis. Other authors previously reported a prevalence of 9.8% in a general osteoporosis population seen in their bone center. To our knowledge, ours is the first report of the prevalence of idiopathic hypercalciuria in a group of women with breast cancer. Interestingly, our study demonstrated a higher 25 OHD level in the breast cancer group, all of whom had early-stage disease. Other studies have reported lower levels in patients with breast cancer as compared with patients without breast cancer, and patients with locally advanced breast cancer were found to have higher prevalence of vitamin D deficiency as compared with patients with early-stage breast cancer.22,23 Our findings, if prospectively verified, support closer attention to the evaluation and management of bone health in early-stage breast cancer. Considering that the vast majority of the breast cancer group was comprised of asymptomatic women with milder degrees of bone loss as evidenced by mean spine T score of –0.918 and hip T score of –1.665, well within one standard deviation of the age-matched controls, these findings are important in that addressing these secondary causes may limit future morbidity, regardless of whether aromatase inhibitors are used in the care plan. Although vitamin D deficiency was the most common secondary cause identified in this study (38%), measurement of serum TSH, calcium, PTH, and 24-hour urine calcium excretion revealed secondary causes of bone loss in more than 30% of the population. These conditions would not otherwise have been detected without the comprehensive work-up. Limitations of this study include its retrospective nature and a possible referral bias. However, only 3% of the patients with breast cancer were referred to the clinic because they had prediagnosed secondary causes of bone loss or because the degree of bone loss was perceived by the referring physician to be unusually severe. Ninety-seven percent of the population was referred as part of routine evaluation before breast cancer adjuvant therapy with aromatase inhibitors, regardless of the severity of their bone loss. The non–breast cancer population likely represents a larger referral bias, and the overall prevalence observed in this study may be higher than that of the general population. Another limitation of the study is the significant age difference between the patients with breast cancer and the patients without breast cancer and the corresponding differences in BMD. Despite these differences, however, the younger population of patients with breast cancer had a similar prevalence of secondary causes of bone loss as the older non–breast cancer group. Further studies should have age-matched controls to fully evaluate any differences. Future areas of research include a prevalence study in a much larger breast cancer population and a study to determine the effects of treating these secondary causes on BMD and fracture risk. The results of our study support the recommendation that postmenopausal patients with breast cancer should undergo metabolic bone evaluation, including a baseline dual energy x-ray absorptiometry scan, as well as a work-up for secondary causes of bone loss. This is especially important if they are to be given aromatase inhibitors.
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a "U" are those for which no compensation was received; those relationships marked with a "C" were compensated. 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 or Leadership Position: None Consultant or Advisory Role: None Stock Ownership: None Honoraria: None Research Funding: Pauline M. Camacho, Procter and Gamble Expert Testimony: None Other Remuneration: None
Conception and design: Pauline M. Camacho, Fadi A. Nabhan, Monica Agarwal, Kathy S. Albain Administrative support: Pauline M. Camacho Provision of study materials or patients: Pauline M. Camacho, Fadi A. Nabhan, Patricia A. Robinson, Kathy S. Albain Collection and assembly of data: Pauline M. Camacho, Amit S. Dayal, Josefina L. Diaz, Fadi A. Nabhan, Monica Agarwal, John G. Norton, Kathy S. Albain Data analysis and interpretation: Pauline M. Camacho, Amit S. Dayal, Josefina L. Diaz, Fadi A. Nabhan, John G. Norton, Kathy S. Albain Manuscript writing: Pauline M. Camacho, Amit S. Dayal, Fadi A. Nabhan, John G. Norton, Patricia A. Robinson, Kathy S. Albain Final approval of manuscript: Pauline M. Camacho, Josefina L. Diaz, Fadi A. Nabhan, Monica Agarwal, John G. Norton, Patricia A. Robinson, Kathy S. Albain
published online ahead of print at www.jco.org on October 27, 2008 Supported by an investigator-initiated grant from Procter and Gamble. Presented in part at the 2007 Annual Meeting of the American Society of Bone and Mineral Research in Honolulu, HI, September 16-19, 2007. Authors’ disclosures of potential conflicts of interest and author contributions are found at the end of this article.
1. France, International Osteoporosis Foundation: Osteoporosis in the European Community: A call to action-audit of policy developments since 1998. Lyon, France, International Osteoporosis Foundation, 2003 2. Cummings SR, Melton LJ: Epidemiology and outcomes of osteoporotic fractures. Lancet 359:1761-1767, 2002[CrossRef][Medline] 3. Camacho P, Miller PD: Osteoporosis: A Guide for Clinicians. Philadelphia, PA, Lippincott Williams & Wilkins, 2007 4. Riggs BL, Khosla S, Melton LJ 3rd: A unitary model for involutional osteoporosis: Estrogen deficiency causes both type I and type II osteoporosis in postmenopausal women and contributes to bone loss in aging men. J Bone Miner Res 13:763-773, 1998[CrossRef][Medline] 5. Riggs BL, Khosla S, Melton LJ 3rd: Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 23:279-302, 2002 6. Painter SE, Kleerekoper M, Camacho PM: Secondary osteoporosis: A review of the recent evidence. Endocr Pract 12:436-445, 2006[Medline] 7. Tannenbaum C, Clark J, Schwartzman K, et al: Yield of laboratory testing to identify secondary contributors to osteoporosis in otherwise healthy women. J Clin Endocrinol Metab 87:4431-4437, 2002 8. Greep NC, Giuliano AE, Hansen NM, et al: The effects of adjuvant chemotherapy on bone density in postmenopausal women with early breast cancer. Am J Med 114:653-659, 2003[CrossRef][Medline] 9. Shapiro CL, Manola J, Leboff M: Ovarian failure after adjuvant chemotherapy is associated with rapid bone loss in women with early-stage breast cancer. J Clin Oncol 19:3306-3311, 2001 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. Kristensen B, Ejlertsen B, Dalgaard P, et al: Tamoxifen and bone metabolism in postmenopausal low-risk breast cancer patients: A randomized study. J Clin Oncol 12:992-997, 1994 12. Howell A, Cuzick J, Baum M, et al: Results of the ATAC (Arimidex, Tamoxifen, Alone or in Combination) trial after completion of 5 years’ adjuvant treatment for breast cancer. Lancet 365:60-62, 2005[CrossRef][Medline] 13. Geisler J, Lonning PE, Krag LE, et al: Changes in bone and lipid metabolism in postmenopausal women with early breast cancer after terminating 2-year treatment with exemestane: A randomised, placebo-controlled study. Eur J Cancer 42:2968-2975, 2006[CrossRef][Medline] 14. Perez EA, 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 15. Dowsett M, Jones A, Johnston SR, et al: In vivo measurement of aromatase inhibition by letrozole (CGS 20267) in postmenopausal patients with breast cancer. Clin Cancer Res 1:1511-1515, 1995[Abstract] 16. Geisler J, Haynes B, Anker G, et al: Influence of letrozole and anastrozole on total body aromatization and plasma estrogen levels in postmenopausal breast cancer patients evaluated in a randomized, cross-over study. J Clin Oncol 20:751-757, 2002 17. Eriksen EF, Langdahl B, Vesterby A, et al: Hormone replacement therapy prevents osteoclastic hyperactivity: A histomorphometric study in early postmenopausal women. J Bone Miner Res 14:1217-1221, 1999[CrossRef][Medline] 18. Fuller K, Murphy C, Kirstein B, et al: TNFalpha potently activates osteoclasts, through a direct action independent of and strongly synergistic with RANKL. Endocrinology 143:1108-1118, 2002 19. Hughes DE, Dai A, Tiffee JC, et al: Estrogen promotes apoptosis of murine osteoclasts mediated by TGF-beta. Nat Med 2:1132-1136, 1996[CrossRef][Medline] 20. Kousteni S, Bellido T, Plotkin LI, et al: Nongenotropic, sex-nonspecific signaling through the estrogen or androgen receptors: Dissociation from transcriptional activity. Cell 104:719-730, 2001[Medline] 21. Weitzmann MN, Pacifici R: Estrogen deficiency and bone loss: An inflammatory tale. J Clin Invest 116:1186-1194, 2006[CrossRef][Medline] 22. Hershman DL, Irani D, Cucchiara K, et al: High prevalence of vitamin D deficiency in premenopausal women with early-stage breast cancer. J Clin Oncol 24:485s, 2006 (suppl; abstr 8568) 23. Palmieri C, MacGregor T, Girgis S, et al: Serum 25-hydroxyvitamin D levels in early and advanced breast cancer. J Clin Pathol 59:1334-1336, 2006 Submitted April 22, 2008; accepted July 9, 2008.
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
2 test of independence. Pairwise tests of the equality of column proportions was conducted using Z tests, adjusted for all pairwise comparisons within a row of each innermost subtable using the Bonferroni correction, and t tests were used to test for the equality between group means. 
