Aldehyde dehydrogenase 1 expression is a predictor of poor prognosis in node-positive breast cancers: a long-term follow-up study.

AIMS: Aldehyde dehydrogenase 1 (ALDH1) has been identified as a reliable marker of breast cancer stem cells. The aim was to determine the prognostic significance of ALDH1 expression in a long-term follow-up study. METHODS AND RESULTS: Immunohistochemical analyses were performed on 257 invasive ductal carcinomas (IDCs), 109 matched lymph node metastases and 190 ductal carcinomas in situ (DCISs), using paraffin-embedded sections. ALDH1 expression was found in 26% of IDCs, and correlated with larger tumour size (P=0.007), high histological grade (P<0.001), HER2 overexpression (P<0.001) and negative hormone receptor status (P<0.001). ALDH1 expression was observed in 14% of DCISs but was not correlated with any clinicopathological parameter. The IDC patients were followed up for 7-190 months (median: 120 months), and groups with ALDH1 expression had shorter relapse-free survival (P=0.0013) and overall survival (OS) (P=0.0005) by log-rank test. By Cox's multivariate analysis, it had a weak effect on OS (P=0.047), and its most significant effect on OS was observed in node-positive groups (P=0.013). No significant differences in OS stratified by ALDH1 expression status in lymph node metastases were noted. CONCLUSIONS: ALDH1 expression in primary cancer is an independent prognostic factor in node-positive breast cancer patients.

Aldehyde dehydrogenase 1 expression predicts poor prognosis in triple-negative breast cancer.

AIMS: Aldehyde dehydrogenase 1 (ALDH1) has been identified as a reliable marker of breast cancer stem cells, and its clinical significance as a prognostic indicator of breast cancer has been reported by several investigators. However, the clinical significance of ALDH1 expression in triple-negative (TN) breast cancer, a high-risk breast cancer lacking the benefit of specific therapy, remains to be solved. METHODS AND RESULTS: We performed immunohistochemical analyses of 106 TN breast cancers, using paraffin-embedded sections. The basal-like phenotype was also investigated with the use of basal cytokeratin 5/6 and epidermal growth factor receptor. ALDH1 expression in carcinoma cells was found in 59% of cases and was correlated with high histological grade alone (P < 0.006), whereas ALDH1 expression in stromal cells was found in 49% of cases but was not correlated with any clinicopathological parameter. Patients with ALDH1 expression in carcinoma cells had a shorter relapse-free survival (RFS) according to the log-rank test (P = 0.015). According to Cox multivariate analysis, ALDH1 expression in carcinoma cells was an independent prognostic indicator of RFS (P = 0.025). The log-rank test revealed that stromal expression of ALDH1 had no effect on RFS. CONCLUSIONS: ALDH1 expression in carcinoma cells is an independent prognostic factor in TN breast cancer patients.

[A patient with of metastatic breast cancer with a well-controlled quality of life using S-1 therapy as first-line chemotherapy].

We experienced a case of endocrine therapy-resistant recurrent breast cancer with liver and bone metastases, treated with S-1 as first-line chemotherapy and maintaining a good quality of life. The patient was a 31-year-old premenopausal woman. She was diagnosed with cancer of the left breast(T1(18mm), N0, M(-))and underwent breast-conserving surgery, sentinel lymph node biopsy, and radiation therapy in August 2002. As there was hormone sensitivity, she was treated with LHRH analog for 3 years and tamoxifen for 5 years as adjuvant therapy. After her first childbirth, she had a recurrence of liver and bone metastases. After treatment with endocrine therapy failed, an oral administration of S-1 was initiated as first-line chemotherapy considering her QOL. She received 8 months of S-1 therapy with no severe adverse reactions and maintained a high quality of life. Treatment with S-1 is thought to be useful for first-line chemotherapy if the treatment demonstrates a therapeutic equivalence with taxane on patients' overall survival.

[Comparison of the pharmacokinetics and safety of a paclitaxel injection NK and Taxol injection in breast cancer patients].

A paclitaxel injection NK (NK) is a generic product containing the same amount of ingredient as a Taxol Injection. We examined the pharmacokinetics and safety of NK compared to the original product in breast cancer patients. As a result, the transition of plasma paclitaxel concentration and pharmacokinetic parameter in NK and the original drug were almost equal, which suggested that these products were bioequivalent. In adjuvant therapy, there was no significant difference in adverse events reported, and these products were approximately equally safe.

[Preoperative therapy using trastuzumab and weekly paclitaxel in a stage IIIB inoperable locally advanced HER2- positive breast cancer with complete pathologic response].

A 63-year-old woman had a 12 cm tumor on her right breast with broad skin redness, satellite lesions and 8 cm ipsilateral lymph nodes swelling(T4bN2aM0, Stage IIIB). Core needle biopsy and immunohistochemistry of breast tumor showed invasive ductal carcinoma with negative hormone receptor(ER-, PgR-)and overexpression of HER2 (HercepTest 3+). She was treated with weekly paclitaxel(80 mg/m(2), 4 administrations with a week rest)and a com- bination with weekly trastuzumab(initially 4 mg/kg followed by 2 mg/kg every week, totally 11 administrations). After 3courses of administration, the breast tumor, skin redness and axillary swelling were completely disappeared(clinical complete response), then mastectomy with axillary dissection was performed. Histopathology of the breast and lymph nodes showed complete disappear of invasive cancer cells with only 2x1 mm residue of ductal component(pCR, grade 3, DC+). We conclude that the combination of weekly paclitaxel and trastuzumab is a promising neoadjuvant therapy regimen for HER2 positive, ER-negative breast cancer.

Bone mineral density in breast cancer patients with positive estrogen receptor tumor status.

AIM: The aim was to investigate bone mineral density (BMD) in breast cancer patients with positive estrogen receptor (ER) tumor status. METHODS: The participants were 110 postmenopausal breast cancer patients with positive estrogen receptor (ER+) tumor status. Two hundred and sixty-one age-matched, healthy postmenopausal women, all of whom were selected from our pooled data, served as controls. Age, age at menopause, years since menopause (YSM), height, weight, and body mass index (BMI, wt/ht(2)) were recorded. Lumbar spine (L2-4) BMD and Z-score were assessed by dual-energy X-ray absorptiometry. RESULTS: Bone mineral density in breast cancer patients was significantly higher than that in controls (0.89+/-0.12 g/cm(2) versus 0.84+/-0.16 g/cm(2), P<0.01). The Z-score in breast cancer patients was also higher than that in controls (110+/-13.6% versus 100+/-9.8%, P<0.001). Higher BMD and Z-score in breast cancer patients remained significant after adjusting for age, YSM, and BMI (P<0.05). CONCLUSIONS: Postmenopausal breast cancer patients with positive ER tumor status have higher BMD. Positive ER tumor status may be associated with higher cumulative exposure to estrogen.

Expression of estrogen receptor alpha and progesterone receptor in normal human breast epithelium.

BACKGROUND: Recently, the immunohistochemical detection of estrogen receptor alpha (ERalpha) expression in breast cancer has become a prerequisite for therapeutic decision-making, however, it remains unknown whether ERalpha or progesterone receptor (PgR) expression in histologically normal breast epithelium (NBE) adjacent to carcinoma can be a reliable internal positive control. PATIENTS AND METHODS: Tissues from a total of 220 breast cancer patients were investigated by immunohistochemistry of ERalpha and PgR expression in NBE adjacent to carcinoma, as well as in carcinoma. The expression pattern was divided into three groups: singular, one or two positive cells; scattered, scattered positive cells surrounded by negative cells; contiguous, ten or more positive cells in contact with each other. RESULTS: In NBE adjacent to carcinoma, the positivity of ERalpha and PgR was 99% (217 out of 220) and 89% (195 out of 220), respectively. The expression pattern of ERalpha and PgR was as follows: singular - 13 and 42 patients, scattered - 116 and 100 patients, and contiguous - 88 and 53 patients, respectively. The contiguous expression pattern of PgR was more frequently noted in premenopausal patients in contrast with ERalpha (p=0.0004). PgR expression was more frequently seen in premenopausal than postmenopausal patients (p=0.0034). PgR expression in carcinoma was more frequently seen in premenopausal than postmenopausal patients (p= 0.009). There was statistically significant correlation between PgR expression in carcinoma and NBE adjacent to carcinoma (p=0.0019). CONCLUSION: These findings suggest that more frequent PgR expression in NBE adjacent to carcinoma might be correlated with carcinogenesis in premenopausal breast cancer patients and that ERalpha expression, not PgR, in NBE adjacent to carcinoma could be a reliable internal positive control.

[Preoperative therapy with trastuzumab and paclitaxel in a stage IV advanced breast cancer with complete pathologic response].

A 53-year-old woman had a 105x100 mm tumor on her right breast with a 55x36 mm-sized bleeding ulcer of the skin and ipsilateral axillary and cervical lymph nodes swelling (T4bN3cM1, Stage IV). Core needle biopsy and immunohistochemistry of breast tumor showed invasive ductal carcinoma with negative hormone receptor (ER-, PgR-) and overexpression of HER 2 (Hercep Test score 3+). She was treated with weekly trastuzumab (initially 4 mg/kg followed by 2 mg/kg every week), and a combination of tri-weekly paclitaxel (175 mg/m(2), 6 courses). After 3 courses of administration, the breast tumor subsided, the ulcer became flat, and axillary and cervical nodes completely disappeared. Clinical CR was obtained after 6 courses of treatment, and mastectomy with axillary clearance was then performed. Histopathology of the breast and lymph nodes showed complete disappearance of cancer cells (pCR, Grade 3+3 (d) +3 (n)). The combination of trastuzumab and paclitaxel is a promising regimen for HER 2 positive advanced breast cancer.

[A case of inflammatory breast cancer achieving pathological complete response by primary systemic therapy with CEF (cyclophosphamide, epirubicin, 5-fluorouracil) followed by docetaxel].

A 48-year-old woman noticed her right breast swelling since a few weeks earlier. Rigidity in the AC area, hotness, swelling and peau d'orange appearance of the right whole breast were recognized. She was diagnosed as inflammatory breast cancer clinically and invasive ductal carcinoma with lymphatic invasion pathologically. The patient underwent primary systemic therapy with 4 cycles of CEF (cyclophosphamide 500 mg/m(2), epirubicin 100 mg/m(2), 5-fluorouracil 500 mg/m(2)) followed by 4 cycles of docetaxel (70 mg/m(2)). The effect of chemotherapy showed a partial response evaluated by mammography and ultrasonography, and complete response by MRI before surgery. Right mastectomy with level II lymph node dissection was performed. Pathologically, complete response was confirmed (pCR). Although IBC has been known for its poor outcome, this case suggests IBC will show a better prognosis by chemotherapy such as CEF followed by docetaxel.

Rim enhancement of breast cancers on contrast-enhanced MR imaging: relationship with prognostic factors.

BACKGROUND: There is little evidence regarding associations between magnetic resonance imaging (MRI) features and other important histopathological prognostic factors of breast cancer. The purpose of our study was to investigate the relationship between rim enhancement on MRI and common histopathological prognostic factors of breast cancers. METHODS: We reviewed the contrast-enhanced MR images of 106 consecutive women with histopathologically verified invasive breast carcinomas. Three radiologists assessed the images of each lesion for the presence of rim enhancement on early and delayed images, which were classified into four patterns. Statistical analyses were performed to explore the associations of these patterns with common histopathological prognostic factors and patient age. RESULTS: Positive ratios of lymph node metastasis and blood vessel invasion and negative ratios of hormone receptors were higher in the invasive cancers with rim enhancement than those without rim enhancement. Rim enhancement was more frequent in invasive ductal cancers with a higher histological grade and larger invasive cancers. The pattern of rim enhancement with centripetal progression showed a significantly increased risk of lymph node metastasis and was associated with a larger size of invasive lesion when compared with the other patterns. Invasive cancers with rim enhancement and little change between the early and delayed images and with centrifugal progression showed significantly less hormone receptor positivity than those without rim enhancement. CONCLUSIONS: Rim enhancement patterns of breast cancers on contrast-enhanced MRI are related to common histopathological prognostic factors and these patterns may be valuable in the preoperative evaluation of breast cancers.

Adjuvant therapy for breast cancer in Kyushu.

BACKGROUND: There is lack of information on the present status of adjuvant therapy for breast cancer in Kyushu. Therefore, the Kyushu Breast Cancer Study Group (KBC-SG) started registering newly diagnosed breast cancer patients who were to receive adjuvant therapy. METHODS: During a period from 2001 to 2003, institutions participating in KBC-SG registered new patients who underwent curative surgical treatment for breast cancer to the registration office. One year later, the office sent them inquiries to gather any missing information. RESULTS: A total of 2284 patients were registered from 49 institutions. The mean age was 55, ranging from 30 to 93 years, and 46% had stage I disease. Estrogen and/or progesterone receptor was positive in 71% by immunoperoxidase staining, and HER2 was expressed in 297 (33%) of 906 patients. Twenty percent of the patients underwent adjuvant radiation therapy with or without antineoplastic agents. Overall, 98% received hormonal and/or cytotoxic agents. Anthracycline-containing regimens were given to 628 of 1285 (49%) patients with chemotherapy, while 360 (28%) received oral 5-fluorouracil derivatives with or without oral cyclophosphamide. CONCLUSIONS: Anthracycline combination chemotherapy was commonly used as adjuvant therapy, but there were over a quarter of patients only given oral 5-FU derivatives, which might not be recommended by worldwide consensus. Adjuvant radiation therapy was also given to only 20% of the patients in Kyushu, which might be fewer than the report by the Japanese Breast Cancer Society. Based on these data, the KBC-SG will continue cooperative studies to improve the quality of adjuvant treatment for early breast cancer.

[Markedly effective regimen using bi-weekly trastuzumab and paclitaxel in an advanced breast cancer with multiple liver metastases].

A 69-year-old woman had a 7 x 6 cm tumor on her left breast with ipsilateral axillary lymph node swelling and multiple liver metastases as detected on CT scan (T 3 N 2 M 1 b, Stage IV). Core needle biopsy and immunohistochemistry of breast tumor showed invasive ductal carcinoma with negative hormone receptor and overexpression of HER 2. After a treatment failure of 3 months weekly trastuzumab monotherapy, a combination of bi-weekly trastuzumab and paclitaxel (weekly 6, bi-weekly 9 courses), was given. Tumor markers became negative 4 months later, and multiple liver nodules, breast tumor and axillary nodes completely disappeared 9 months later. Breast surgery was avoided, and CR was maintained more than 8 months only with bi-weekly trastuzumab. From the standpoint of the patient's convenience,a bi-weekly schedule of trastuzumab and paclitaxel could be a promising treatment choice for metastatic breast cancer.

[Neoadjuvant endocrine therapy with anastrozole significantly downstaged an elderly breast cancer woman with locally-advanced breast cancer which became operable].

A 73-year-old postmenopausal woman had a 13 cm-sized huge tumor in her left breast with an extensive purple skin color change. She had sternal destruction, axillary and supraclavicular lymph node metastases (T4bN3M1, Stage IV). Core needle biopsy showed invasive ductal carcinoma with positive hormone receptor (ER+++, PgR+++). She was treated with 1 mg per day of anastrozole. The tumor decreased in size gradually and became operable after 7.5 months of the anastrozole monotherapy. She underwent mastectomy and axillary node clearance. The resected specimen showed a 3.5 cm sized tumor with significant fibrosis and scanty viable tumor cells. We concluded that neoadjuvant therapy with anastrozole is a good choice for receptor-positive postmenopausal breast cancer, especially for elderly or poor risk women.

[Two cases of breast cancer markedly responded to neoadjuvant chemoendocrine therapy (2 cycles of CMF and tamoxifen, pCR and near pCR)].

Case 1 is a 38-year-old woman with a 6 cm tumor in her right breast. After incisional biopsy she received 2 cycles of CMF and tamoxifen in order to effect down staging. The tumor markedly decreased in size. She next underwent breast conserving surgery. Histopathologically, malignant cells completely disappeared (pCR). Case 2 is a 34-year-old woman with a 5.5 cm tumor in her left breast. After incisional biopsy she received the same regimen as in case 1. The tumor diminished significantly in size, and she underwent breast conserving surgery. Histopathologically, only a few fragments of degenerated tumor cells remained. Case 1 was hormone receptor positive, while case 2 was negative. The remarkable responsiveness (pCR and near pCR) to 2 cycles of CMF combined with tamoxifen was interesting. From these results we conclude that the CMF regimen is an useful neoadjuvant chemotherapy alternative to avoid alopecia and GI tract side effects.

[Effective weekly paclitaxel therapy for massive metastatic breast cancer].

A 36-year-old woman with a 12-year disease free interval after radical mastectomy for breast cancer presented with dyspnea and lumbago. Chest CT and bone scintigraphy revealed numerous bilateral pulmonary metastatic nodules, pleural effusion and multiple bone metastases. We treated her with weekly paclitaxel therapy at a dose of 80 mg/m2, which was continued for 3 weeks followed by 1 week rest, and bisphosphonate biweekly. Lung lesions markedly decreased in number and size after 6 infusions, and disappeared after 12. Bone scintigraphy showed partial response. Lung effect (CR) and bone effect (PR) have been maintained after 30 infusions on an outpatient basis. The patient tolerated the treatment well without adverse effect, except for moderate alopecia.

Clinical application of the one-step nucleic acid amplification method to detect sentinel lymph node metastasis in breast cancer.

BACKGROUND: The one-step nucleic acid amplification (OSNA) method can assess the expression level of cytokeratin 19 mRNA in sentinel lymph nodes in breast cancer. We compared the time required for diagnosis and concordance of results between the OSNA method and conventional intraoperative pathological examination. We then examined the relationship between the frequency of non-sentinel lymph node metastasis and (1) the expression level of CK19 mRNA in the sentinel lymph nodes and (2) clinico-pathological features of the primary tumor. METHODS: In the comparison study, pairs of sentinel lymph node sections from 53 consecutive patients were examined: one section by hematoxylin-eosin staining and the other by OSNA assay. The latter involved reverse-transcription loop-mediated isothermal amplification of cytokeratin 19 mRNA, assessed quantitatively. In the second phase, 306 sentinel lymph nodes were removed from 248 consecutive patients, and whole sentinel lymph nodes were examined by OSNA assay alone. RESULTS: OSNA assay was a little more time-consuming than conventional pathological diagnosis (34-45 vs. 22-25 min, p < 0.0001). Concordance between the two methods was 93%. The frequency of non-sentinel lymph node metastasis (p < 0.0001) and the total number of lymph node metastases (p < 0.0001) increased with the amount of cytokeratin 19 mRNA on OSNA assay. We found no significant relationship between the amount of cytokeratin 19 mRNA in sentinel lymph nodes and breast cancer immunohistochemical subtype. CONCLUSIONS: The OSNA method is suitable to detect sentinel lymph node metastasis and to predict the possibility of non-sentinel metastasis. This semi-automated quantitative analysis system reduces the burden on pathologists.

The relevance of intrinsic subtype to clinicopathological features and prognosis in 4,266 Japanese women with breast cancer.

BACKGROUND: Estrogen receptor (ER), progesterone receptor (PgR), and HER2 expression status in breast cancer function as prognostic and predictive factors that enable individualized treatment. Intrinsic subtype classification has also been performed based on these and other biological and prognostic characteristics. However, clinical analysis of such subtypes in a large number of Japanese breast cancer patients has not yet been reported. METHODS: Between January 2003 and December 2007, 4,266 patients with primary breast cancer were registered. Four subtypes based on immunohistochemically evaluated ER/PgR/HER2 status, clinicopathological features, and prognosis were analyzed retrospectively. RESULTS: The following subtype distribution was observed: luminal A type (ER+ and/or PgR+, HER2-), 3,046 cases (71%); luminal B type (ER+ and/or PgR+, HER2+), 321 cases (8%); HER2 type (ER-, PgR-, HER2+), 398 cases (9%); and triple negative (TN) type (ER-, PgR-, HER2-), 501 cases (12%). The HER2+ subtypes (luminal B and HER2 types) had a significantly higher incidence of lymph node metastasis and lymphatic permeation, while the hormone receptor negative subtypes (HER2 and TN types) showed a significantly higher nuclear grade. Overall, patients with HER2-type and TN-type disease had a significantly poorer prognosis than other subtypes. CONCLUSION: Intrinsic breast cancer subtypes are associated with clinicopathological features and prognosis in Japanese women. Long-term clinical observation of the relationship between each subtype and therapies used should provide useful information for selecting appropriately tailored treatments.

Mucocele-like lesions of the breast: a long-term follow-up study.

BACKGROUND: Mucocele-like lesions (MLL) of the breast were originally described as benign lesions composed of multiple cysts lined by uniform flat to cuboidal epithelium with extravasated mucin, but subsequent reports described the coexistence of columnar cell lesions (CCL), atypical ductal hyperplasia (ADH) and ductal carcinoma in situ (DCIS). Several reports have investigated whether core biopsy can diagnose MLL reliably; however, there is only one report with a long-term follow-up after excision of MLL. We report here 15 surgically excised MLL with a long-term follow-up. FINDINGS: Fifteen lesions diagnosed as MLL from 13 patients who had undergone excisional biopsy between January 2001 and December 2006 were retrieved and followed-up for 24-99 months (median 63.8). Two lesions were accompanied with CCL, 5 with ADH and 3 with low grade DCIS. Four lesions (2 ADH, 2 DCIS) were additionally resected and their histology revealed 2 ADH, one DCIS and one MLL with CCL. Of 4 lesions (3 ADH, one DCIS) without additional resection, one lesion (ADH) relapsed accompanied with DCIS at 37 months after excision. CONCLUSIONS: MLL were frequently accompanied with CCL, ADH or low grade DCIS. Complete resection may be recommended in case of MLL with ADH or DCIS because of intralesional heterogeneity and the probabilities of relapse.

Adverse events and bone health during anastrozole therapy in postmenopausal Japanese breast cancer patients.

BACKGROUND: Although anastrozole (ANA), an aromatase inhibitor (AI), has been widely used for breast cancer patients; adverse events during ANA therapy in Japanese patients have not been reported. METHODS: The study included 656 postmenopausal breast cancer patients receiving ANA as postoperative adjuvant therapy in our hospital. Adverse events during ANA therapy, such as musculoskeletal effects and cerebro- and cardiovascular accidents, were investigated over a 5-year period. The percentage changes in lumbar (L2-4) spine bone mineral density (BMD) were determined in 71 patients receiving ANA alone and 26 patients receiving bisphosphonate in combination with ANA for 7-24 months. RESULTS: The follow-up period ranged from 6 to 60 months (median 23 months). Joint pain, the most common adverse event, was observed in 3.6% (24/656) of the patients. Cerebral infarctions occurred in 0.3% (2/656) of the patients, and no cardiovascular accidents occurred. Bone fractures occurred in nine patients receiving ANA alone. The mean age and BMD of the nine patients were 67.6 years and 71.8% (compared to the young adult mean BMD), respectively. Accumulated and annual fracture rates were 1.3 and 0.8%, respectively. A decrease in BMD was observed in 62.0% (44/71) of the ANA group compared to 26.9% (7/26) of the combination bisphosphonate group (P < 0.01). CONCLUSION: Incidence of adverse events during AI therapy in this Japanese postmenopausal population appears to be lower than that of the ATAC trial. The incidence of bone fractures during AI therapy is lower in Japan, and the addition of bisphosphonates enhances bone health. We should perform a prospective trial in the future to investigate the precise risk of bone fractures in Japanese patients.

Aromatase inhibitor-induced bone mineral loss and its prevention by bisphosphonate administration in postmenopausal breast cancer patients.

AIM: To investigate aromatase inhibitor-induced bone mineral loss and its prevention by bisphosphonate administration in postmenopausal breast cancer patients. METHODS: Subjects were 17 postmenopausal breast cancer patients (mean age, 63.3 +/- 9.9 years) receiving non-steroidal aromatase inhibitor (AI; anastrozole, 1 mg daily) only and 10 such patients (mean age, 65.0 +/- 5.1 years) receiving AI + bisphosphonate (risedronate sodium, 2.5 mg daily) for 6 months. All of the subjects had undergone surgical resection and had positive estrogen receptor tumor status. Age, age at menopause, years since menopause, height, weight, and body mass index (Wt/Ht(2)) were recorded. Lumbar spine (L2-4) bone mineral density (BMD), T-, and Z-scores were assessed on dual-energy X-ray absorptiometry before and after therapy. RESULTS: In the AI-only group BMD, T-, and Z-scores significantly decreased from the baseline during the 6-month therapy period (P < 0.05). Mean decreases in L2-4 BMD and Z-score were 2.5% and 3.0%, respectively. In the AI + bisphosphonate group, however, BMD, T-, and Z-scores significantly increased from the baseline values (P < 0.01). Mean increases in L2-4 BMD and Z-score were 4.5% and 3.3%, respectively. CONCLUSION: AI carries a potential risk of bone mineral loss despite the short therapy duration. Bisphosphonate has a preventive effect on this loss.