The Effect Of Calcium And Vitamin D On Bone Mineral Density In Women With Early Breast Cancer

BackgroundThe incidence of breast cancer has increased steadily in china over the past few decades, breast cancer is the most common malignancy in woman in Beijing, Shanghai, and other large city, this tendency will continue in each big city, and gradually extended to the countryside. The comprehensive treatment of Breast cancer is mainly by operation therapy, supplemented by chemotherapy, hormonal therapy and molecular targeted therapy. Many Studies found that allocation to about6months of anthracycline-based polychemotherapy (e.g. with FAC or FEC) reduces the annual breast cancer death rate. Such regimens are significantly more effective than CMF chemotherapy. An adjuvant treatment strategy incorporating an aromatase inhibitor (AI) as primary (initial endocrine therapy), sequential (using both tamoxifen and an AI in either order), or extended (AI after5years of tamoxifen) therapy reduces the risk of breast cancer recurrence compared with5years of tamoxifen alone. In women who did not take tamoxifen, there was a large benefit of goserelin treatment on survival and recurrence, and in women who did take tamoxifen, there was a marginal potential benefit on these outcomes when goserelin was added. Survival has improved largely because of these advances in adjuvant hormone therapy and chemotherapy, as well as early detection strategies.As people with breast cancer survive longer, and the propensity of older adults in general toward the development of osteoporosis, skeletal effects of cancer treatment are becoming more pronounced. Bone health is one of the important factors that ensure patients have a higher quality of life. Results of a long-term follow-up study show that postmenopausal survivors of breast cancer were more likely to have low BMD in comparison to other women of the same age, and15%increased rate of fractures in breast cancer survivors. Women diagnosed before age55had an increased relative risk of1.78for vertebral compression fractures.Risk factors for osteoporosis are increased in breast cancer survivors. Many breast cancer patients received4-8cycles of chemotherapy, chemotherapy have a direct effect on bone cells, resulted in decreased bone mass. Chemotherapy-induced ovarian failure, also resulted in bone loss accelerated. Endocrine therapy generally lasts five years, goserelin and AIs will cause loss of bone mass in pre-and post-menopausal women during this period, the incidence of fractures was significantly higher in postmenopausal patients who treated with AIs than in patients taking tamoxifen which has a protective effect on bone mass. Consequently, the survivors of breast cancer are at increased risk for clinical fractures. Because the symptoms caused by osteoporosis will seriously affect the quality of life and Low-Trauma Osteoporotic Fracture were associated with increased mortality risk for5to10years. ASCO has drawn up guidelines for the prevention of breast cancer treatment-induced bone loss.Adequate calcium and vitamin D intake is required for normal bone mineralization and plays an important role in maintain normal bone density. A meta-analysis of29large clinical randomized clinical trials showed that supplementation with calcium and vitamin D is contribute to prevent bone loss and reduce the fracture rate, Author also found a greater treatment effect with older patients, a lower bodyweight, and a higher baseline risk.The study including two randomized clinical trials, aimed to determine the efficacy of Calcium-vitamin D in preventing bone loss in both pre-and post-menopausal women during the period of endocrine therapy for early-stage breast cancer and provide the experimental basis for clinical practice.Objective1. To examine the effect of calcium and vitamin D on preventing bone loss in premenopausal women during the first1year of endocrine therapy for early-stage breast cancer.2. To examine the effect of calcium and vitamin D on preventing anastrozole treatment-induced bone loss in postmenopausal patients with early breast cancerMethod1. The selection of the patients1.1premenopausal patientsThe study included54premenopausal women with hormone receptor-positive early-stage breast cancer between August2008and August2010.1.1.1Inclusion criteria:(1) With normal menstruation, FSH and estradiol in the premenopausal range before Chemotherapy.(2) Pathological diagnosis as invasive breast cancer, had undergone Auchincloss modified radical mastectomy.(3) Pathologic stage Ⅰ-Ⅲ A.(4) Received adjuvant chemotherapy, according to the latest version of NCCN clinical practice guidelines in breast cancer. (5) Hormone receptor-positive, follow-up of endocrine therapy with tamoxifen (20mg per day given orally) or toreimifene (60mg per day given orally).(6) No evidence of osteoporosis (T score>-2.5SD) before endocrine therapy according to the WHO diagnostic criteria.1.1.2Exclusion criteria:(1) With history of hypertension, diabetes, coronary heart disease and other chronic diseases.(2) With history of bone and joint diseases or fracture history.(3) Had taken drugs that affect bone metabolism in the past three months.(4) The presence of bone metastasis during treatment.(5) With liver and kidney dysfunction, including kidney stones.(6) Physical activity is restricted.(7) Tobacco and alcohol addiction.(8) Special occupation such as athletes, dancers etc.(9) Medication possession ratio less than80%of eligible days.(10) Withdrawal from the study due to personal reasons, or loss to follow up.1.2postmenopausal patientsThe study included72postmenopausal women with hormone receptor-positive early-stage breast cancer between January2008and January2010.1.2.1Inclusion criteria:(1) Amenorrheic for12or more months in the absence of Chemotherapy, tamoxifen, toremifene, or ovarian suppression and FSH and estradiol in the postmenopausal range.(2) Reference to the inclusion criteria of premenopausal patients.(3) Reference to the inclusion criteria of premenopausal patients.(4) Reference to the inclusion criteria of premenopausal patients. (5) Hormone receptor-positive, follow-up of endocrine therapy with anastrozole (1mg per day given orally).(6) Reference to the inclusion criteria of premenopausal patients.1.2.2Exclusion criteria:reference to the exclusion criteria of premenopausal patients2. MethodAccording to completely random design, eligible premenopausal and postmenopausal patients were randomly assigned (in equal proportions with the use of the random number table) to treatment group or control group respectively. Age, height, weight, age of menarche, pathological stage, chemotherapy and other basic information were collected. The age of menopause of postmenopausal patients were collected and calculate the menopausal period.The treatment group was treated with Caltrate D tablet (Wyeth, LiDa Pharmaceutical Co., Ltd., Suzhou, each tablet contains Ca600mg, vitamin D3125IU,1tablets/day orally); the control group without interventions. All patients were to encourage to participate in outdoor activity (such as walking, Tai Chi exercise), a balanced diet, eat more foods high in calcium.All patients were followed-up when they return to the hospital to review every three months. Record the following:functions of liver and kidney and serum phosphorus, serum calcium; the appearance of distant metastases, especially bone metastasis; average weekly outdoor activity time (unit:hour/Week); the number of days that adhere to medication; the patients of control group who take calcium supplementation or other drugs for treating osteoporosis.3. AssessmentsBMD was measured by dual-energy X-ray absorptiometry on a Lunar DPX-L (General Electric lunar, USA). Analysis software (en CORETM V10.5version2006).To avoid bias, the original scan analysis was not altered. To make sure the equipment was working within specifications and no major fluctuations were occurring that might affect the accuracy of the final DEXA result:DEXA scanning procedures were standardized and the equipment was operated by a specific technician. Before the study, instrument quality-control procedures included quality-assurance scans defined in the manufacturer’s operating manual and daily scans of the manufacturer’s spine phantom. The coefficients of variation of measuring at lumbar spine and hip are0.41%and0.53%respectively. Bone density is reported in g/cm2, T scores (the difference [in SD units] between the patient’s bone density and the mean bone density of young normal women),According to the WHO diagnostic criteria, osteoporosis is defined as a bone density that is2.5SD (expressed as a t-score) below peak bone mass or the mean bone density for young white adult women. Osteopenia, or low bone mass, is defined as a t-score of-1to-2.5below the normal score for young adult women.BMD was determined for the lumbar spine (L1-L4) and the total hip, which includes the femoral neck, trochanter, intertrochanter, and Ward’s triangle. Measurements at these sites follow the recommendations of the International Society of Clinical Densitometry (ISCD) for osteoporosis surveillance before initiating endocrine therapy and at12months, postmenopausal patients repeat underwent measurements at24months.4. Statistical analysis:All datas were analysed by SPSS13.0statistic software.Unless otherwise stated, data were expressed as mean±S.D. The basic situation between two groups are analysised by Independent-Samples T Test for Measurement datas and chi-square test for Count datas, Using analysis of covariance to analysis the datas of pre-menopausal patients between the two groups; each position BMD of Post-menopausal patients between two groups and of each group are analysed by Repeated Measures. P values<0.05were considered significant. Result1. Pre-menopausal patients1.1Of54premenopausal patients who were randomly assigned and completed baseline evaluation,27assigned to treatment group,27assigned to control group, in the control group,1case taken calcium tablet during study,1case did not finish the BMD measure; in the treatment group,1case changed the toremifene therapy to letrozole therapy after six months,1case was lose to follow up. Finally,50(92.6%) completed the12-month evaluation.1.2Baseline characteristics were comparable between the groups. There is no significant difference in age (P=0.275), height (P=0.200), weight (P=0.835), body mass index (0.741), chemotherapy period,(P=0.382), the pathological staging (P=0.220), age of menarche (P=0.298), menstrual recovery rate (P=0.387) and weekly outdoor activity time (P=0.423) between the two groups. After chemotherapy, all patients were amenorrhea for more than3months. At the12-month evaluation,11patients (44%) in the control group retained menstrual function higher than8patients (32%) in the treatment group, but the difference was not statistical significance (P=0.560).1.3After12months, the mean percentage changes of BMD (measured by g/cm2) from baseline in each group are compared as follows:lumbar (-4.86%VS.-2.74%, P=0.347), femoral neck (-1.95%VS.-0.006%, P=0.146), total hip (-4.55%VS.2.42%, P=0.177). The results show that although the average decline rate of each position BMD of the treatment groups was less than the control group, but the difference was not statistically significant (P>0.05).2. Postmenopausal patients2.1Of72postmenopausal patients who were randomly assigned and completed baseline evaluation,36assigned to treatment group,36assigned to control group. in the control group,2cases taken calcium tablet during study,1case did not finish the BMD measures; in the treatment group,1case was diagnosis as bone metastasis during treatment,2case was lose to follow up. Finally,66(91.7%) completed the12-month and24-month evaluation.2.2Baseline characteristics were comparable between the groups. There is no significant difference in age (P=0.983), height (P=0.396), weight (P=0.853), body mass index (P=0.801), chemotherapy period (P=0.463), the pathological staging (P=0.181), age of menarche (P=0.478), age of menopause (P=0.801), years since menopause (P=0.733), weekly outdoor activity time (P=0.909) between the two groups.2.3After12months, the mean percentage change of BMD (measured by g/cm2) from baseline in both groups are compared as follows:lumbar (-4.05%VS.-1.52%, P<0.001), femoral neck (-3.04%VS.-1.77%, P=0.031), total hip (-3.04%VS.2.60%, P=0.591), These observations reflected a higher decline rate of the bone mineral density of control group than that of treatment group, except at the total hip; After24months, the mean percentage changes of BMD from baseline in each group are compared as follows:lumbar (-6.57%VS.-2.71%, P<0.001), femoral neck (-5.21%VS.-2.55%, P<0.001), total hip (-5.58%VS.-2.55%, P<0.001), the results suggest that patients in the control group experienced a more rapid rate of BMD loss during the first12months of study. During the second year of study, the rate of BMD loss slowed in the control group, but still higher than that of treatment group.3. Safety and TolerabilityNone of patients in the study reported clinical fractures. Serum phosphorus and serum calcium in the normal range, Liver and kidney function showed no abnormal in all patients. Some patients in the treatment group reported gastrointestinal symptoms such as light-to-moderate constipation, bloating or gas, but the symptoms spontaneous remission after a period of time or through diet adjustment. No case withdrawal because of the adverse reactions of the drug.Conclusion1. In premenopausal women who are receiving endocrine therapy for breast cancer, dietary supplementation with calcium600mg and vitamin D125IU didn’t reduced treatment-related bone loss during the first1year of endocrine therapy.2. In Postmenopausal patients who receiving AIs therapy for breast cancer, dietary supplementation with calcium600mg and vitamin D125IU can reduce AIs induced bone loss.3. Administration of calcium-vitamin D during the period of endocrine therapy is an effective and well-tolerated strategy for preventing the aromatase inhibitors treatment induced bone loss. Clinical oncology physicians should pay more attention to the supplementation of calcium-vitamin D for the breast cancer patients without osteoporosis.