Prevention and Treatment of Osteoporosis in Women With Breast Cancer

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Prevention and Treatment of Osteoporosis in Women With Breast Cancer BETTY

A. MINCEY,

MD; THOMAS

J. MORAGHAN, MD; AND EDITH A. PEREZ, MD

Women who have had breast cancer may be at higher risk for osteoporosis than other women. First, they are more likely to undergo early menopause, due to chemotherapyinduced ovarian failure or oopherectomy. In addition, chemotherapy may have a direct adverse effect on bone minerai density (BMD), and osteoclastic activity may increase from the breast cancer itself. While estrogen therapy is considered standard for the prevention and treatment of osteoporosis, use of estrogen in women with a history of breast cancer is usually contraindicated. The approach to osteoporosis in women with breast cancer is also affected by the use of tamoxifen in many, as this drug appears to have opposite effects on BMD in premenopausal and postmenopausal women. We have reviewed therapeutic alternatives for the prevention and treatment of osteoporosis, focusing on patients with a history of breast cancer. Alendronate and raloxifene are currently approved in the United States for the prevention of osteoporosis; alendronate, raloxifene, and calcitonin are approved for treatment. Alendronate has the greatest positive effect on BMD and reduces the incidence of vertebral and nonvertebral fractures. Raloxifene and calcitonin appear to reduce the incidence of vertebral fractures; their effects on the incidence of nonvertebral fractures are not yet proven. Although no published studies specifically address the use of

these approved agents for osteoporosis in women with breast cancer, understanding their relative effects on BMD in postmenopausal women in general will facilitate therapy selection in this population. Postmenopausal women with a history of breast cancer should undergo bone mineral analysis. Normal results and absence of other risk factors ensure that calcium and vitamin D intake are adequate. If osteopenia or other risk factors are present, preventive therapy with alendronate or raloxifene should be considered. For osteoporosis, treatment with alendronate should be strongly considered. Raloxifene and calcitonin are alternatives when alendronate is contraindicated. Further studies are needed to evaluate the optimal timing of initial bone mineral analysis in premenopausal women after breast cancer diagnosis and to determine the value of preventive treatment in women scheduled to undergo chemotherapy. Mayo Clin Proc. 2000;75:821-829 AACE = American Association of Clinical Endocrinologists; BMD = bone mineral density; CI = confidence interval; FDA = Food and Drug Administration; MORE =Multiple Outcomes of Raloxifene Evaluation; NSABP P-I = National Surgical Adjuvant Breast and Bowel Project P-I Study; WHO =World Health Organization

A

lthough the prevention and treatment of osteoporosis is a health concern for many, particular consideration is required for women who are breast cancer survivors. The risk for osteoporosis in these women may be increased due to the effects of cancer therapy and the cancer process itself. Because estrogen therapy, a standard treatment for osteoporosis, is generally contraindicated in women with a history of breast cancer, other treatmentoptions are necessary. Osteoporosis is a state of decreased bone mass leading to skeletal fragility, resulting in an increased risk for fracture with minimal or no trauma. It is most common in white and Asian women and affects approximately 30% of postmenopausal white women in the United States.' Osteopenia and osteoporosis are diagnosed by measuring bone mineral density (BMO). According to World Health

Organization (WHO) criteria,' osteopenia is defined as a BMO of 1 to 2.5 SOs less than the mean for young adults (denoted asa Tscore between-l and-2.5). Osteoporosis is defined as a T score of -2.5 or less, indicating a BMO that is at least 2.5 SDs less than the mean for young adults. Osteoporosis leads to increased risk of fracture, particularly of the spine, hip, and forearm, causing pain and debilitation. Between 12% and 20% of patients sustaining a hip fracture die within 1 year, and of those surviving, less than 50% are able to live independently.' Each year, approximately 250,000 women in the United States suffer hip fractures, which result in health care costs of approximately $10 billion.' Thus, prevention and treatment of osteoporosis are important health interventions. Risk factors for the development of osteoporosis include age, family history of fracture, early menopause, low calcium intake, and physical inactivity (Table 1). Decreased bone mass is the most important risk factor for fracture in patients with osteoporosis. Bone mass gradually declines with age in both men and women. However, women experience an accelerated rate of bone loss at the time of menopause. Up to 15% of total bone mass may be lost around the

From the Division of General Internal Medicine (BAM.), Division of Endocrinology and Internal Medicine (T.J.M.), and Division of Hematology/Oncology and Internal Medicine (E.A.P.), Mayo Clinic, Jacksonville, Fla. Address reprint requests and correspondence to Betty A. Mincey, MD, Division of General Internal Medicine, Mayo Clinic, 4500 San Pablo Rd, Jacksonville, FL 32224. Mayo Clin Proc. 2000;75:821-829

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© 2000 Mayo Foundationfor Medical Education and Research

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Table l. Risk Factors for Osteoporosis

Personal history of fracture Fracture in a first-degree relative Tobacco or alcohol abuse Thin body habitus White race Estrogen deficiency Lowcalcium intake Drugs (glucocorticoids, phenytoin, heparin, warfarin) Physical inactivity

time of natural menopause and up to 20% within 18 months after surgical menopause.' Breast cancer is the most commonly diagnosed cancer in women, with an estimated 182,800 new cases predicted to be diagnosed in 2000 in the United States." Progress in breast cancer detection and therapy has resulted in an increasing number of women who are long-term survivors of the disease. In a IO-year survey, the National Cancer Data Base reported lO-year survival rates of 95%, 88%, 66%, 36%, and 7% for patients diagnosed with stages 0 through IV breast cancer, respectively.' Compared with women in general, women with breast cancer may be at increased risk for osteoporosis (Table 2). Chemotherapy may induce age-related premature ovarian failure in the 22% of women who are premenopausal at the time of breast cancer diagnosis. Approximately 50% of women aged 35 to 40 years and 75% to 90% of women in their 40s may experience premature menopause after treatment with chemotherapy.v' Headley et al'? studied the effect of adjuvant chemotherapy on BMD of the lumbar spine in 27 women who had undergone breast cancer treatment with doxorubicin, cyclophosphamide, and fluorouracil within the previous 2 years. Women who also received tamoxifen for no more than 1 year were included. Sixteen of the women remained premenopausal after treatment' while 11 ceased menses during treatment. Those who remained premenopausal had an average age of 39 years, while those who became postmenopausal had an average age of 47.5 years. Those who became postmenopausal had a mean BMD 14% lower than those who remained premenopausal and 7% lower than that expected for a 55-yearold woman. Bruning et alii conducted a case-control study of BMD in 44 pairs of Dutch women with breast cancer. Cases (axillary node involvement without distant metasTable 2. Proposed Additional Risk Factors for Osteoporosis in Women With Breast Cancer

Premature ovarian failure Direct effectof chemotherapy drugs Directeffectof breastcancer Effectof antiestrogen hormonal agents

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tases) had received adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil; controls (node negative) received no chemotherapy. In cases, the mean age at menopause was 41 years (compared with the normal age at menopause of 51-52 years for Dutch women), and 71% were postmenopausal at the time of the study. In controls, the mean age at menopause was 47 years, and 16% were postmenopausal at the time of the study. Premenopausal women had significantly higher BMD than postmenopausal women, regardless of treatment group. The outcomes of these 2 studies indicate that women treated with adjuvant chemotherapy for breast cancer are likely to undergo a premature menopause accompanied by an acceleration of bone loss. As a result, they may have an increased risk for fracture at an earlier age than normal. In addition to the risk for early menopause induced by surgical or chemotherapeutic ovarian ablation, chemotherapeutic agents used in the treatment of breast cancer may have a direct adverse effect on BMD. Both doxorubicin and methotrexate lead to decreased trabecular bone volume and decreased bone formation in rats, and methotrexate increases bone resorption in rats." Breast cancer itself may predispose to osteoporosis by increasing osteoclast activity. Patients with cancer but without bone metastases have been shown to have increased bone resorption as indicated by biochemical markers of bone turnover." Kanis et alB compared vertebral fracture incidence in 2 groups of women with breast cancer with a cohort of women in the general population. Eighty-two women with recurrent breast cancer and 352 women with a first diagnosis of breast cancer (regardless of stage) were enrolled in separate studies of the effects of clodronate on incidence of skeletal metastases. None of the women had skeletal metastases at the time of enrollment. The age-adjusted prevalence of vertebral fracture was similar in the group at first diagnosis and the control population; in women with recurrent breast cancer it was 6-fold higher (P<.OOOI). However, compared with the general population, the annual incidence of vertebral fracture in women followed up from first breast cancer diagnosis was nearly 5 times greater (P<.OOOl), and in women with recurrent disease it was more than 20 times greater (P<.OOOI). When women who developed skeletal metastases during the study period were excluded from analysis, the odds ratios for the annual incidence of vertebral fracture in women followed up from first breast cancer diagnosis and those with recurrent disease compared with the control population were 2.8 (95% confidence interval [CI], 1.3-6.2) and 24.5 (95% CI, 10.755.9), respectively. The authors of this study proposed that the risk of vertebral fracture demonstrated was actually an underestimate, because half the women with breast cancer were receiving clodronate, which has positive effects on

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Table 3. Effect of US Food and Drug Administration-Approved Antiresorptive Agents on Bone Mineral Density*

Drug and dose Agents approved for prevention Alendronate, 5 mg/d Raloxifene, 60 mg/d Agents approved for treatment Alendronate, 10 mg/d

Calcitonin, 200 IU/d

Raloxifene, 60 mg/d Estrogen, 0.625 mg/d

Study

Hosking et aI'9 McClung et a1'° Delmas et aI"

Chesnut et aI" Devogelaer et al'3 Adami et al 24 Liberman et al" Pols et al'6 Kapetanos et al" Thamsborg et aP8 Overgaard et al 29 Ettinger et apo PEPI Trial"

No. of patients

Mean age (y)

906 178 302

54 52 55

61 307 139 530 1908 46 62 81 7705 875

63 63 59 64 63 58 65 70 67 56

Mean time since menopause (y)

6

2 5

16 16 12 16 16 3.5 15 22 19 1-10

Difference between drug and placebo groups in mean % change and bone mineral density (Pvalue) Total hip

Follow-up (mo)

Lumbar spine

Femoral neck

24 36 24

+5.3 «.001) +6.4 «.001) +2.4 «.001)

+2.4 «.001) +5.1 «.001) +2.5 (NR)

+3.3 «.001) NR +2.4 «.001)

NR +5.5 «.001) +3.77 «.05) +5.9 «.001) +2.4 «.001) +15.2 «.05) -0.6 (NS) NR +2.7 «.001) NR

+6.47 «.001) NR NR NR +3 (.001) NR NR NR NR +3.4

24 36 24 36 12 12 24 24 36 36

+8.56 «.001) +7.4 «.001) +5.21 «.001) +8.8 «.001) +4.9 «.001) +6.9 (NR) +0.8 (NS) +2 (.008) +2.6 «.001) +5.3-+6.8 (NR)t

*NR = not reported; NS = not significant. t Alone or with various progestin-dosing schedules.

BMD and has been shown to decrease the incidence of vertebral fracture in women with breast cancer and women with osteoporosis. PREVENTION AND TREATMENT The American Association of Clinical Endocrinologists (AACE) recommends basic osteoporosis preventive measures for women with T scores between -1.5 and -2.5 and consideration of antiresorptive therapy if the T score is -2.5 or lower or if basic preventive measures are ineffective at preserving bone density.' The National Osteoporosis Foundation advises treatment of women without risk factors who have T scores of -2.0 or lower or women with risk factors who have T scores of -1.5 or lower. 14 Although estrogen therapy is usually considered a standard option for prevention and treatment, most experts agree that the use of estrogen following a diagnosis of breast cancer should be approached with caution, and most believe that it should be avoided, except within the setting of a clinical trial. 15·18 Concerns include the stimulatory potential of estrogen on breast cancer cell growth in patients with estrogen receptor-positive breast cancer and the potential increased risk for breast cancer recurrence. We agree that estrogen replacement therapy is not a good choice for prevention and management of osteoporosis in women with a history of breast cancer and provide the following review of treatment options currently available in the United States.

Currently 2 agents, excluding estrogen, have US Food and Drug Administration (FDA) approval for prevention of postmenopausal osteoporosis (alendronate and raloxifene), and 3 agents have approval for treatment (alendronate, raloxifene, and calcitonin). Table 3 summarizes the findings of the major published studies evaluating the effects of each of these agents on BMD. Data on estrogen are included for comparison. Studies chosen for inclusion in Table 3 met the following criteria: (1) they involved only agents that currently have FDA approval for prevention or treatment of osteoporosis; (2) they included only women who were postmenopausal (natural or surgical), with or without osteoporosis, who were living in the community (outpatients); (3) they were designed to assess the efficacy of prevention and treatment measures for osteoporosis; (4) primary outcomes measured included BMD of the lumbar spine and/or femoral neck (data on the total hip were included when available); and (5) all were randomized placebo-controlled trials. Each agent is discussed in detail below, along with other standard components of prevention and treatment programs (calcium, vitamin D, and exercise). Drugs that have been specifically evaluated for osteoporosis in women with breast cancer (clodronate, risedronate, and zoledronate), although not currently available for clinical use in the United States, and the effects of tamoxifen are also discussed.

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Calcium and Vitamin D Calcium and vitamin D supplementation is recommended for all women with or at risk for osteoporosis. Daily supplementation with calcium (1200 mg) and vitamin D (800 ill) has been shown to result in a substantial reduction in hip and other peripheral fractures.? Calcium alone has also been shown to have a beneficial effect on the rate of bone loss in postmenopausal women." Variable effects of calcium and vitamin D on fracture incidence across studies may be due to differences in the populations studied, as supplementation is most likely to decrease fracture rates in patients with low dietary intake. Calcium and vitamin D therapy is an essential component of osteoporosis prevention and treatment for all women with a history of breast cancer. National Institutes of Health guidelines" suggest a daily calcium intake of 1500 mg in postmenopausal women aged 65 years or younger who are not receiving hormone replacement therapy and in all women older than 65 years. Bisphosphonates Alendronate.-Alendronate is approved for both prevention (5 mg/d) and treatment (10 mg/d) of osteoporosis in the United States. It compares favorably to estrogen in its positive effect on BMD.19,20,31 Alendronate reduces fracture incidence and, of the options discussed herein, appears to be the most effective agent for prevention and treatment of osteoporosis (Table 3). A significant positive effect on BMD in postmenopausal women treated with alendronate was reported in a large trial by Hosking et al.'? The study enrolled women aged 45 to 59 years, 1174 of whom were randomly assigned to receive 2.5 mg or 5 mg of alendronate or placebo. An additional 435 women were randomly assigned to one of these treatment groups or to open-label estrogen-progestin therapy (0.625/5 mg). The mean baseline lumbar spine BMD was 0.94 g/cm 2, and although no T scores were given, less than 10% of women enrolled had a baseline lumbar spine BMD of less than 0.8 g/cm 2. Followup was for 2 years. Women taking 5 mg of alendronate (n=445) daily had a mean increase in BMD of the lumbar spine of 3.5% at 2 years (P<.OOl), while women taking placebo (n=461) had a mean loss of 1.8%. Similarly, women in the 5-mg alendronate group had a mean increase in femoral neck BMD of 1.3% at 2 years (P<.OOl) compared with a decrease of 1.6% (P<.OOl) in the placebo group. The differences between groups were statistically significant at both sites (P<.OOI). Only 5% to 6% of women treated with alendronate lost more than 2% BMD compared with 40% to 46% of those receiving placebo. The women assigned to the estrogen group had an increase in BMD that was 1 or 2 percentage points greater than that seen for the group receiving 5 mg of alendronate. The authors concluded that alendronate is an effective altema-

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tive to estrogen for postmenopausal women in whom the primary goal is maintenance of bone mass. McClung et aFo also found alendronate, 5 mg/d, to be an effective option for osteoporosis prevention in early postmenopausal women, with a slightly greater difference in BMD between treatment and placebo groups than that observed by Hosking et al.'? Alendronate is also effective in patients with preexisting osteoporosis. In a large study of 994 postmenopausal women with osteoporosis (T scores ~-2.5), randomized to 1 of 3 different alendronate dosing schedules or placebo, Liberman et aF5 found significant differences in mean change in BMD between the placebo group and the group assigned to alendronate, 10 mg/d, of 8.8 percentage points at the lumbar spine, 7.8 percentage points at the trochanter, and 5.9 percentage points at the femoral neck (all P<.OOI). Other smaller studies have shown similar effects. 22-24 Three large studies have evaluated the effect of alendronate on fracture incidence in postmenopausal women with osteopenia or osteoporosis. In the study by Liberman et al," 6.2% of women assigned to placebo had at least 1 new vertebral fracture compared with 3.2% in the alendronate groups (relative risk, 0.52; P=.03). There was no significant difference in the incidence of nonvertebral fracture. In the Fracture Intervention Trial Research Group study.v-" postmenopausal women with low femoral neck BMD (~0.68 g/cm2, corresponding to a T score of -1.6) were randomized to receive either alendronate or placebo. The initial dosage of alendronate was 5 mg/d, but this was changed to 10 mg/d at 24 months. The women were divided into 2 groups, based on presence or absence of 1 or more vertebral fractures at baseline. In the group with preexisting vertebral fractures, 2027 women were enrolled, and follow-up was for 36 months. New vertebral fractures, identified radiographically, were observed in 8% of women assigned to alendronate and in 15% assigned to placebo (relative risk, 0.53; P<.OOI). The incidence of clinically apparent vertebral fractures was 2.3% in the alendronate group and 5% in the placebo group (relative risk, 0.45; P<.OOl), and the risk of any clinical fracture was 13.6% in the alendronate group and 18.2% in the placebo group (relative risk, 0.72; P=.004). In the group without preexisting vertebral fractures, 4432 women were enrolled and followed up for 4 years. Although there was an overall reduction in clinical fractures of 14% in the alendronate vs the placebo group, this difference was not statistically significant. A significant reduction of 36% was found, however, in a subset analysis of women with T scores at the femoral neck of -2.5 or less. There was an overall reduction in radiographically detected vertebral fractures of 44% in the alendronate group. Pols et aF6 demonstrated a significant reduction in nonvertebral fractures in postmenopausal women with T

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scores of -2 or less who were randomized to alendronate vs placebo for 12 months (P=.021). A meta-analysis of alendronate therapy, compiling data from 5 studies and 1347 patient-years, was performed by Karpf et al." The estimated relative risk of nonvertebral fractures after 3 years in patients treated with alendronate was 0.71 compared with placebo. The estimated cumulative fracture incidence was 9% in alendronate-treated patients and 12.6% in patients receiving placebo. The main adverse effects of alendronate are gastrointestinal.and include dyspepsia, nausea, vomiting, abdominal pain, and esophageal irritation. Although there is concern over reports of esophageal ulcers and esophageal strictures associated with alendronate, serious or severe esophageal reactions have been reported in only 1.3% to 1.5% of patients. 38,39 These adverse effects can largely be avoided if the patient drinks 8 oz of water with each dose and maintains an upright posture for at least 30 minutes. Inability to do so is a contraindication to the use of alendronate, as are preexisting esophageal stricture and achalasia. Gastroesophageal reflux is a relative contraindication. Hypocalcemia and hypersensitivity to bisphosphonates are the only other contraindications to the use of alendronate. The portion of the drug that is not absorbed by bone (approximately 50%) is excreted renally. No dosage adjustment is necessary for patients with creatinine clearance of at least 35 mL/min, but if creatinine clearance is less than this, the drug should be used with caution, if at all. The approximate cost of a 30-day supply of alendronate (5-mg or 10-mg dosage) is $69 (written communication, J. S. Novak, RPh, Mayo Clinic Outpatient Pharmacy, Jacksonville, Fla, March 1999). Other Bisphosphonates.-Although an extensive search revealed no similar studies involving alendronate, several studies have evaluated the effectiveness of other bisphosphonates (available in Europe) in the prevention of osteoporosis in breast cancer patients. Delmas et a140 randomized 53 women who had been postmenopausal for at least 6 months secondary to adjuvant chemotherapy to receive oral risedronate or placebo for 2 years. After 3 years of follow-up (1 year after discontinuation of study drug), both groups had lost bone mass. However, there was significantly less decrease in BMD of the lumbar spine and the femoral neck in patients who received risedronate. Saarto et a14 1 evaluated the effect of clodronate on BMD in premenopausal women treated with adjuvant chemotherapy for breast cancer. The study randomized 148 women with newly diagnosed,nonmetastatic primary breast tumors with axillary node involvement to receive oral clodronate (1600 mg/d) or placebo for 3 years. All patients were treated with mastectomy or breast-conserving surgery with axillary node dissection, postoperative

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radiation therapy, and 6 cycles of adjuvant chemotherapy with cyclophosphamide, methotrexate, and fluorouracil. Oral clodronate was started with the first cycle of chemotherapy. Of the 113 women included in the first-year analysis, 38% were amenorrheic at the end of the first year, 36% had irregular menses, and 22% continued to have regular menses; data on 4% of the patients were not provided. The mean ages in each of these groups were 48, 43, and 37 years, respectively. All patients who received placebo lost bone mass at the lumbar spine and femoral neck (mean decreases in BMD, -5.9% and -2.0%, respectively) with the greatest loss in women who became amenorrheic (-9.5% at the lumbar spine and -4.6% at the femoral neck). There was significantly less bone loss in women treated with clodronate (-2.2% at the lumbar spine and +0.9% at the femoral neck), and treated women who continued to have regular menses actually gained bone mass at both sites. The P values for the differences between the changes in BMD of placebo and control groups at the lumbar spine and femoral neck were .0005 and .017, respectively. Powles et a1 42 evaluated the effectiveness of clodronate on BMD as part of a larger study of its effect on the incidence of bone metastases in women with primary breast cancer. In this study, 311 women with operable primary breast cancer were randomly assigned to receive clodronate or placebo for 2 years. Clodronate had a significant positive effect on the mean change in BMD at both the hip and the lumbar spine (differences between placebo and control groups of 1.72% at the lumbar spine and 1.85% at the total hip; P=.04 and .008, respectively). The results of these 2 studies indicate that preventive treatment for osteoporosis in premenopausal women undergoing therapy for breast cancer may be beneficial. Further study is required to identify which groups of women would benefit most from such an approach and to better define other effects of bisphosphonates in this population. Calcitonin

Although intranasal calcitonin has been shown to have a positive effect on BMD, it is not as effective in this regard as alendronate (Table 3). It is approved for treatment of osteoporosis but not for prevention. In a dose-finding trial conducted by Overgaard et al," 81 women with osteopenia (no T scores reported) were randomized to receive either placebo or intranasal calcitonin, 200 IV/d, and followed up for 2 years. There was an increase in mean bone mineral content of the lumbar spine of 3% in the calcitonin group, compared with an increase of 1% in the placebo group (P=.008). There was also a significant reduction of the vertebral fracture rate in the treated group (3% vs 15% in the placebo group), but the total number of fractures was small (10 new fractures).

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Thamsborg et aP evaluated calcitonin therapy in 62 postmenopausal women with previous Colles fractures and mean lumbar spine BMD at baseline of 0.83 g/cm 2 (no T scores reported). No significant differences were found between treatment and placebo groups in percentage change in BMD of the lumbar spine or femoral neck after 2 years of follow-up. However, Kapetanos et al27 found a dramatic difference in percentage change of lumbar spine, femoral neck, and trochanter BMD (6.9, 15.2, and 26.8 g/cm", respectively) between treatment and placebo groups in 46 women followed up for I year. Study participants in this trial were carefully selected (postmenopausal women with at least 1 previous vertebral fracture, lumbar spine BMD less than 0.85 g/cm2 , and biochemical indicators of rapid bone turnover), possibly accounting, at least in part, for the discrepancy between the results of this study and that conducted by Thamsborg et aI.28 In a study designed to evaluate the effectivene ss of calcitonin in preventing bone loss in healthy postmenopausal women, Reginster et al43 reported a difference in percentage change from baseline of lumbar spine BMD between placebo and calcitonin groups of 6.1 percentage points for a dose of 50 IU/d and of 8.31 percentage points for a dose of 200 IU/d. The study involved 251 women, and follow-up was for 2 years. The authors concluded that calcitonin, given intranasally in a dose of 50 IU/d, was effective in preventing bone loss in the lumbar spine of postmenopausal women. Another study of calcitonin (100 IU/d), conducted by Overgaard et al" in 52 early postmenopausal women, showed that although there was a significant reduction of bone loss at the lumbar spine, there was no effect on peripheral bone loss (determined by bone mineral content of the total skeleton and forearm). .In summary, calcitonin appears to be effective in treating postmenopausal osteoporosi s, although less so than alendronate. The effect may be greater in women with high rates of bone turnover. The interim results of a large randomized controlled trial of calcitonin for the prevention of recurrent osteoporotic fractures indicate that treatment with calcitonin may lead to a significant reduction in the number of new vertebral fractures in women with osteoporosis." A significant reduction in hip fractures has not yet been shown with the use of calcitonin . Our literature search produced no studies that assessed the use of calcitonin in women with breast cancer. The approximate cost of a 30day supply of intranasal calcitonin is $65 (written communication, J. S. Novak, March 1999). Selective Estrogen Receptor Modulators

Raloxifene.-Raloxifene is a selective estrogen receptor modulator with a positive effect on BMD and lipid

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profile and no effect on endometrial thickness compared with placebo. It is approved in the United States for prevention and treatment of osteoporosis. Its positive effect on BMD is less than that of a1endronateor estrogen but greater than that ofcalcitonin (Table 3). Delmas et al" randomized 601 postmenopausal women aged 45 to 60 years to receive either raloxifene or placebo for 24 months. Three doses of raloxifene were used (30 mg, 60 mg, 150 mg): 150 women received placebo and 152 received raloxifene, 60 mg/d. Only these groups are considered here, as the FDA-approved dose of raloxifene is 60 mg. At baseline, the mean lumbar spine BMD was 0.94 g/ ern? (T scores between -2.5 and +2). At the end of 2 years, significant differences were noted between these 2 groups in the mean percentage change in BMD of the lumbar spine, femoral neck, and total hip (differences of 2.4,2.5, and 2.4 percentage points, respectively). In the 60-mg raloxifene group, there was an increase of 2.4% in BMD of the lumbar spine and total hip (P< .OOl). The effect at the hip was comparable to that of alendronate or estrogen, but the effect at the spine was less than that of either of these other drugs. Of importance, raloxifene appeared to increase BMD without stimulating endometrial proliferation. Raloxifene also had a positive effect on serum cholesterol levels, demonstrating a significantly greater reduction of total cholesterol and low-density lipoprotein levels than placebo. There was no significant effect on high-density lipoprotein cholesterol or triglyceride levels. In the Multiple Outcomes of Raloxifene Evaluation (MORE) study," 7705 women aged 31 to 80 years who met WHO standards for osteoporosi s and were at least 2 years postmenopausal were randomized to receive raloxifene (60 or 120 mg/d) or placebo . There was a statistically significant reduction in the incidence of new vertebral fractures in both raloxifene groups compared with placebo (relative risk, 0.7 [95% CI, 0.5-0.8] for the 60-mg group vs placebo). The difference was found in women with and without preexisting vertebral fractures. There was no difference between treatment and placebo groups in the incidence of nonvertebral fractures. Significant increases in BMD of the lumbar spine and femoral neck were noted for both the 60mg and the 120-mg groups compared with placebo (2.6% and 2.7%, respectively; P<.OOI). Our literature search identified no studies evaluating raloxifene' s effect .on osteoporosis in women with breast cancer. In the MORE trial, there was a significant reduction of breast cancer incidence in women treated with raloxifene, and a multicenter study is under way to compare the relative efficacies of raloxifene and tamoxifen for prevention of breast cancer in high-risk women. Important adverse effects of raloxifene include hot flashes, leg cramps, and a slight increase in the incidence of

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venous thrombosis (similar to that seen with estrogen). Data compiled from several trials that included 10,400 women indicate that the relative risk of deep venous thrombosis for women taking raloxifene compared with placebo is 3.46 The approximate cost of a 30-day supply of raloxifene is $70 (written communication, J. S. Novak, March 1999). Tamoxifen.-Tamoxifen is a standard part of therapy for women with estrogen receptor-positive breast cancer in both adjuvant and metastatic settings. It has also been approved recently to decrease the incidence of breast cancer for certain women at high risk. Tamoxifen is an estrogen antagonist in breast tissue and has variable effects on bone. Although it is not approved for prevention or treatment of osteoporosis, consideration of its effect on BMD is important. In premenopausal women, tamoxifen has been shown to decrease BMD compared with placebo, while in postmenopausal women, it has the opposite effect." These factors must be taken into consideration in decisions about preventing and treating bone loss in women for whom tamoxifen is prescribed. In a study conducted by Love et al," 140 postmenopausal women with node-negative breast cancer were randomized to receive tamoxifen or placebo for 2 years. In the tamoxifen group, lumbar spine BMD increased by 0.61 % per year (P=.04), while it decreased by 1% per year (P<.OOl) in the placebo group. Radial BMD decreased significantly in both groups. In a large retrospective study of 1716 postmenopausal Danish women with primary breast cancer randomized to receive radiation therapy with or without tamoxifen, Kristensen et al49 found no statistically significant difference in femoral fractures between groups. In the National Surgical Adjuvant Breast and Bowel Project P-l Study (NSABP P-l), Fisher et al" observed a nonstatistically significant reduction in hip, radius (Colles), and spine fractures in women treated with tamoxifen. Fracture was not a primary end point of this trial, however, and separate results for premenopausal and postmenopausal women were not reported. Phytoestrogens.-Phytoestrogens are plant compounds with mixed estrogen agonist and antagonist properties. They are found in many different foods, including soy, and are contained in numerous over-the-counter supplements. Beneficial effects on bone have been proposed for these substances but remain unproven at this time. Ipriflavone,":" a synthetic derivative of naturally occurring soy isoflavones, is under investigation for a possible preventive or treatment role in osteoporosis, but conclusive data are not yet available. Thus, there is insufficient evidence on which to base recommendations for or against the use of these agents in prevention or treatment of osteoporosis. Additionally, the effect of these agents on the

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risk of breast cancer has not been adequately assessed, making it even more premature to recommend this in women who have already been diagnosed with this disease. Other Agents

Sodium fluoride has been shown to have a large positive effect on cancellous (lumbar spine) BMD but to lead to a decrease in cortical BMD,54 perhaps by causing a redistribution of bone. It has an inconsistent effect on fracture incidence, with some studies actually showing an increase in fracture incidence. 54 It has been proposed that the formulation of sodium fluoride used in previous studies caused excessive exposure to fluoride, and more recent studies with different formulations of sodium fluoride at lower doses have been carried OUt. 55-57 These studies have confirmed the positive effect of sodium fluoride on vertebral BMD and have shown positive or negligible effects on hip BMD and mixed effects on vertebral fracture rates. Sodium fluoride is not FDA approved for prevention or treatment of osteoporosis at this time, but studies are ongoing. Parathyroid hormone is being studied for its effect on bone mass and fracture incidence, with some encouraging results in small studies.58 It does not have FDA approval for either the prevention or treatment of osteoporosis at this time. Studies of recombinant human growth hormone are also in the early stages. 59.60 RECOMMENDATIONS

Women with breast cancer who are postmenopausal or otherwise considered to be at risk for osteoporosis should undergo a screening bone mineral analysis. The decision to use antiresorptive therapy for prevention should be individualized on the basis of age, overall health and functional status, assessment of risk factors, and T scores. For those on a basic prevention program, the AACE recommends bone mineral analysis every 1 to 2 years until bone mass is stable, after which follow-up measurements can be done every 2 to 3 years. For those on a therapeutic program with antiresorptive agents, their recommendation is for 3 consecutive annual measurements, followed by biannual testing if bone mass is stable.' Calcium and vitamin D are fundamental components of osteoporosis prevention and treatment but cannot be considered a substitute for antiresorptive therapy in women with significant osteoporosis or in osteopenic women at high risk for further bone loss or fracture. The recommended daily intake of calcium is 1000 mg for young to middle-aged adults and 1500 mg for postmenopausal women older than 50 years who are not taking estrogen." Dietary supplementation with 400 IU/d of vitamin D (the amount contained in most multivitamins) is generally recommended.

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Regular physical activity is also beneficial and should be encouraged. In a prospective cohort study of 9704 nonblack women aged 65 years or older, higher levels of physical activity were positively correlated with fewer hip fractures, even after adjustments for falls, functional and overall health status, age, and diet. There was a relative risk reduction of 33% to 42% in hip and vertebral fractures in moderately to highly active women compared with inactive women." The FDA-approved antiresorptive agents for prevention of osteoporosis, other than estrogen, include alendronate and raloxifene. The efficacy of alendronate appears to be greater than that of raloxifene. However, raloxifene has a beneficial effect on total and low-density lipoprotein cholesterol levels and may therefore be a good choice for women with hyperlipidemia. Whether raloxifene should be favored as the preventive agent of choice for osteoporosis in women with a history of or at high risk for breast cancer remains to be determined. The use of raloxifene in women previously treated for breast cancer with tamoxifen has not yet been evaluated in controlled clinical trials. The ongoing Study of Tamoxifen and Raloxifene is designed to compare the effectiveness of these 2 drugs in the prevention of breast cancer. The study seeks to enroll 22,000 postmenopausal women at high risk for breast cancer development. Since women who previously participated in NSABP P-I will be included, the study will provide important information on the sequential use of tamoxifen and raloxifene. Studies to evaluate the effect of raloxifene on breast cancer recurrence in women with a history of the disease (with and without previous tamoxifen treatment) who are treated with this agent for osteoporosis need to be conducted. For treatment of established osteoporosis, FDA-approved choices in this population include alendronate, raloxifene, and calcitonin. Based on the data reviewed, alendronate appears to be the best choice, unless it is contraindicated or not tolerated. The efficacy of combination treatments remains to be established. The results of a phase 2 study by Johnell et al62 indicate that the combination of alendronate and raloxifene may increase BMD in postmenopausal women with osteoporosis more than either drug alone. Since limited data are available to date, however, combination therapy should be reserved for women with osteoporosis who have failed therapy with a single agent. In conclusion, medications effective at preventing and treating osteoporosis without increasing the risk of breast cancer recurrence are available, and women with breast cancer should be made aware of these options. Further studies are needed to evaluate the optimal timing of initial bone mineral analysis in premenopausal women after breast cancer diagnosis and to determine the value of pre-

ventive treatment in women scheduled to undergo chemotherapy.

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