Chemical castration induced by adjuvant cyclophosphamide, methotrexate, and fluorouracil chemotherapy causes rapid bone loss that is reduced by clodronate: a randomized study in premenopausal breast cancer patients.

1997 ◽  
Vol 15 (4) ◽  
pp. 1341-1347 ◽  
Author(s):  
T Saarto ◽  
C Blomqvist ◽  
M Välimäki ◽  
P Mäkelä ◽  
S Sarna ◽  
...  

PURPOSE In the majority of premenopausal breast cancer patients, an adjuvant chemotherapy-induced early menopause occurs, which is known to be a strong predictor of osteoporosis. We present data on the effect of adjuvant cyclophosphamide, methotrexate, and fluorouracil (CMF) therapy on bone mineral density (BMD) and the efficacy of clodronate on the prevention of bone loss in 148 premenopausal breast cancer patients without skeletal metastases. MATERIALS AND METHODS Patients were randomized to receive oral clodronate 1,600 mg/d or to a control group. In addition, patients were treated with six cycles of CMF therapy. BMD of the lumbar spine and femoral neck was measured by dual-energy x-ray absorptiometry (DEXA) before therapy and at 1 and 2 years. RESULTS Changes in the BMD of lumbar spine and femoral neck were -5.9% and -2.0% without clodronate and -2.2% and +0.9% with clodronate at 2 years (P = .0005 and .017, respectively). Patients who developed amenorrhea after chemotherapy had a rapid bone loss, which was significantly reduced by clodronate. In controls, bone loss was 9.5% in the lumbar spine and 4.6% in the femoral neck, while in the clodronate group, bone loss was 5.9% and 0.4%, respectively, at 2 years. Patients with preserved menstruation had only marginal changes in BMD. CONCLUSION Chemotherapy-induced ovarian failure causes rapid bone loss in premenopausal breast cancer patients. Women older than 40 years are at particularly high risk. Clodronate significantly reduces this bone loss.

2020 ◽  
Vol 26 (46) ◽  
pp. 6007-6012
Author(s):  
Karin Baatjes ◽  
Armand Peeters ◽  
Micheal McCaul ◽  
Maria M. Conradie ◽  
Justus Apffelstaedt ◽  
...  

Background: Significant individual variation in bone loss associated with aromatase inhibitors (AIs) emphasizes the importance of identifying postmenopausal breast cancer patients at high risk for this adverse effect. The study explores the clinical relevance of genetic variation in the Cytochrome P450 19A1 (CYP19A1) gene in a subset of South African patients during the first year of taking AIs for estrogen receptor (ER)-positive breast cancer. Methods: The study population consisted of ER-positive breast cancer patients on AIs, followed in real-life clinical practice. Body mass index was measured and bone mineral density (BMD) was determined at baseline and at month 12. CYP19A1 genotyping was performed using real-time polymerase chain reaction analysis of rs10046, extended to Sanger sequencing and whole exome sequencing in 10 patients with more than 5% bone loss at month 12 at the lumbar spine. Results: After 12 months of AI treatment, 72 patients had completed BMD and were successfully genotyped. Ten patients (14%) experienced more than 5% bone loss at the lumbar spine over the study period. Genotyping for CYP19A1 rs10046 revealed that patients with two copies of the A-allele were 10.79 times more likely to have an ordinal category change of having an increased percentage of bone loss or no increase at the lumbar spine, compared to patients with the GA or GG genotypes (CI of 1.771- 65.830, p=0.01). None of the 34 patients without lumbar spine bone loss at month 12 were homozygous for the functional CYP19A1 polymorphism. At the total hip region, patients with the AA genotype were 7. 37 times more likely to have an ordinal category change of having an increased percentage of bone loss or no increase (CI of 1.101- 49.336, p=0.04). Conclusions: Homozygosity for the CYP19A1 rs10046 A-allele may provide information, in addition to clinical and biochemical factors that may be considered in risk stratification to optimize bone health in postmenopausal breast cancer women on AIs. Further investigation is required to place the clinical effect observed for a single CYP19A1 gene variant in a genomic context.


1997 ◽  
Vol 15 (3) ◽  
pp. 955-962 ◽  
Author(s):  
P D Delmas ◽  
R Balena ◽  
E Confravreux ◽  
C Hardouin ◽  
P Hardy ◽  
...  

PURPOSE To determine the effectiveness and safety of the bisphosphonate risedronate in preventing bone loss in young women with breast cancer and early menopause induced by chemotherapy who are at major risk for the development of postmenopausal osteoporosis. PATIENTS AND METHODS Fifty-three white women, aged 36 to 55 years, with breast cancer and artificially induced menopause were stratified according to prior tamoxifen use. Thirty-six patients received tamoxifen (20 mg/d). Within each stratum, patients were randomly assigned to receive risedronate (n = 27) or placebo (n = 26). Treatment consisted of eight cycles oral risedronate 30 mg/d or placebo daily for 2 weeks followed by 10 weeks of no drug (12 weeks per cycle). Patients were monitored for a third year without treatment. RESULTS Main outcomes of the study were changes in lumbar spine and proximal femur (femoral neck, trochanter, and Ward's triangle) bone mineral density (BMD), and biochemical markers of bone turnover. In contrast to a significant decrease of BMD at the lumbar spine and hip in the placebo group, there was an increase in BMD in the risedronate group. On treatment withdrawal, bone loss ensued, which suggests that treatment needs to be continuous to maintain a protective effect on bone mass. At 2 years, the mean difference (+/- SEM) between groups was 2.5% +/- 1.2%, (95% confidence interval [CI], 0.2 to 4.9) at the lumbar spine (P = .041) and 2.6% +/- 1.1%, (95% CI, 0.3 to 4.8) at the femoral neck (P = .029). Similar results were observed at the hip trochanter. Results by stratum indicate a beneficial, although partial, effect of tamoxifen in reducing bone loss. Risedronate was well tolerated and showed a good safety profile, with no evidence of laboratory abnormalities. CONCLUSION Risedronate appears to be a safe treatment that prevents both trabecular and cortical bone loss in women with menopause induced by chemotherapy for breast cancer.


2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 676-676 ◽  
Author(s):  
T. Saarto ◽  
L. Vehmanen ◽  
C. Blomqvist ◽  
I. Elomaa

676 Background: We have previously reported that clodronate prevents bone loss in breast cancer patients (JCO 1997;15:1341, BJC 1997;75(4):602 and EJC 2001;37:2373). Here we report the 10-year follow-up data. Methods: 268 pre- (PRE) and postmenopausal (POST) node positive breast cancer patients were randomized to clodronate (CL), orally 1.6 g daily, or control groups for 3 years. PRE were treated with adjuvant chemotherapy and POST with antiestrogens (AE), tamoxifen 20 mg or toremifene 60 mg, for 3 years. The BMD of the lumbar vertebrae L1–4 (BMDLS) and femoral neck (BMDFN) was measured before the treatment and at 1, 2, 3, 5 and 10 years. 93 patients were eligible for 10-year analyses: 53 PRE and 40 POST. 132 patients had metastatic disease or died and 39 were either lost to follow-up or had to be excluded because having diseases or medications that influences bone metabolism. Results: PRE: BMDLS decreased -12.4% in the control and −8.7% in the CL group in 10 years: from 0 to 3 years −6.9 % vs. −4.2% and from 3 to 10 years −5.5% and −4.5%, respectively. BMDFN decreased −8.8% and −7.2%: from 0 to 3 years −2.9% vs. −2.6% and from 3 to 10 years −5.9% vs. −4.6%, respectively. POST: BMDLS decreased −3.0% in the AE and −1.7% in the AE+CL group in 10 years: from 0 to 3 years −1.5% vs. + 1.2% and from 3 to 10 years −1.5% vs. −2.9%, respectively. BMDFN decreased −7.7% and −6.0%: from 0 to 3 years −0.1% vs. +1.9% and from 3 to 10 years −7.6% vs. −7.9%, respectively. These differences do not reach statistical significance. At 10-years 18 patients had osteoporosis in LS and 15 in FN. Only 4 patients who had osteoporosis at 10 years had normal BMD before the therapy. Conclusions: As reported previously, clodronate prevents the bone loss during treatment in pre- and postmenopausal women. This beneficial effect seems to be maintained at least for 7 years after treatment termination in premenopausal. In postmenopausal women the effect seems to diminish within time. Due to small numbers of patients these differences are no longer statistically significant. Patients at risk of developing osteoporosis are among those who has pretreatment osteopenia i.e. baseline BMD measurement has predictive value. No significant financial relationships to disclose.


2013 ◽  
Vol 31 (15_suppl) ◽  
pp. e11604-e11604
Author(s):  
Hiroaki Inoue ◽  
Akira Hirano ◽  
Kaoru Ogura ◽  
Akinori Hattori ◽  
Mari Kamimura ◽  
...  

e11604 Background: Adjuvant therapy with aromatase inhibitors (AI) is associated with increased bone loss in postmenopausal women. We assessed changes in bone mineral density (BMD) from baseline to 60 months of treatment in patients receiving anastrozole (ANA) as initial adjuvant therapy with/without oral bisphosphonates (Bis). Methods: Postmenopausal women with endocrine responsive breast cancer receiving ANA as adjuvant therapy at our hospital since 2004 were enrolled in this study. BMD was assessed by dual-energy X-ray absorptiometry at baseline and after 6, 12, 24, 36, 48 and 60 months. Oral Bis (risedronate or alendronate) treatment was initiated when patients were diagnosed as having osteoporosis with a T-score of -2.5 or lower. Results: Fifty-seven patients were enrolled in the study between 2004 and 2011. Patients’ median age was 65 years (range 50~85) and the median follow-up period was 46.3 months (9.6~83.8). Thirty-five patients were administered Bis (risedronate in 27 patients, alendronate in 8 patients). Within 6 months of hormone therapy, BMD decreased by 0.3% from baseline at the lumbar spine and BMD decreased by 1.2% at the femoral neck. However, BMD increased by 2.8% at the lumbar spine and BMD decreased 0.5% at the femoral neck for 60 months of treatment. In patients treated with upfront Bis (n=24), 4.9% BMD increase from baseline was noted at the lumbar spine whereas in those without Bis (n=20) BMD decreased by 4.6% from baseline within 24 months (p=0.0002). Fractures were observed in 4 patients (7.0%), and 1 patient (1.8%) had fragility fracture. Conclusions: Oral Bis prevented ANA-induced bone loss, and upfront treatment of Bis significantly increased BMD at the lumber spine.


2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 552-552
Author(s):  
Katsuhiko Nakatsukasa ◽  
Takayuki Matsuda ◽  
Tetsuya Taguchi

552 Background: Adjuvant aromatase inhibitor (AI) therapy is well established in postmenopausal women with hormone receptor-positive breast cancer, but such therapy is associated with bone loss and increased fracture risk. Denosumab, a fully human monoclonal antibody against receptor of nuclear-κB ligand, was previously proven to protect against AI-induced bone loss. In Japan, however, the efficacy of denosumab in the treatment of AI-associated bone loss has not been proven in a prospective study. Methods: This non-randomized prospective study was conducted at four institutions in Japan. we prospectively evaluated the bone mineral density (BMD) of the lumbar spine and bilateral femoral neck in hormone-receptor positive clinical stageⅠ–ⅢA, postoperative postmenopausal breast cancer patients who were scheduled for treatment with AI as adjuvant endocrine therapy or during AI adjuvant therapy. They received supplemental calcium, vitamin D and subcutaneous denosumab 60mg (n=103) every six months. At enrollment, all patients were required to have evidence of low bone mass, excluding osteoporosis. The primary endpoint was percentage change in lumbar spine BMD from baseline to month 12. The secondary endpoint was percentage change in bilateral femoral neck BMD from baseline to month 12. This is the first trial where the right and left femoral neck BMD are measured separately. Results: We enrolled 103 patients between November, 2014 to October, 2016. At 12 months, lumber spine BMD increased by 4.7 %. The patients who were administered prior AI therapy (n=60) had a 4.8 % increase, and the patients without prior AI therapy (n=40) had a 4.6 % increase. At 12 months, the right and left femoral neck BMD increased by 2.9 % and 2.0 %, respectively. Hypocalcemia ≥ grade2, osteonecrosis of the jaw (ONJ) and non-traumatic clinical fracture were absent in this study. Conclusions: Twice-yearly treatment with denosumab was associated with consistently greater gains in BMD among Japanese women receiving adjuvant AI therapy, regardless of whether prior AI therapy was administered. Clinical trial information: UMIN000013863.


2019 ◽  
Vol 21 (1) ◽  
pp. 21-25
Author(s):  
Munshi Md Arif Hosen ◽  
Nasrin Begum ◽  
Pervez Ahmed ◽  
Mosharrof Hossain ◽  
Shefaly Khatun ◽  
...  

Breast cancer is the most common malignant tumor of females, the incidence increases with age. Bone is the most common site to which breast cancer metastasizes. Between 30% to 85% of patients with metastatic breast cancer develop bone metastases during the course of the disease. Bone scan is the most commonly used means of detecting bone metastasis; it visualizes increases in osteoblastic activity and skeletal vascularity. Many radio-pharmaceuticals (radionuclides) have been used in bone scan including technetium-99m bound to methylene diphosphonate (MDP). Published sensitivity and specificity rates of bone scan for diagnosis varies, with sensitivity ranging from 62% to 100% and specificity from 78% to 100%. However, bone scan is generally considered sensitive for detecting bone metastases on whole-body images.The aim of this study was to evaluate the pattern of distribution of skeletal metastases in patients with breast carcinoma by using Tc-99m MDP bone scan. A retrospective study was conducted on 245 consecutive female breast carcinoma patients irrespective of clinical staging, menopausal status and pre-operative / post- mastectomy status, referred for bone scan to Institute of Nuclear Medicine and Allied Sciences, Rajshahi from July 2015 to June 2017.  The mean age of the patients was 43.4 ± 13.8 years (mean ± SD) with range from 29 to 66 years. Bone scan was performed by an intravenous bolus injection of 20 mCi Tc99m-MDP. Bone phase images were taken at three hours after injection of the radiotracer. Out of 245 studied patients, 163 patients (66.53%) were negative for skeletal metastasis and 82 patients (33.47%) were positive for skeletal metastasis. Out of 82 patients with positive skeletal metastasis, 68 (82.93%) patients had multiple sites (two or more) and 14 (17.07%) patients had solitary site of bony involvement. Out of 68 patients with multiple sites of skeletal metastasis, highest number was noted in thoraco-lumbar spine (80.89%), followed by ribs including sternum and clavicle (57.35%), pelvic bones (47.06%), upper extremities including scapula (41.18%), lower extremities (33.82%), cervical spine (23.53%) and skull bone (8.82%). Among 14 patients with solitary skeletal metastasis, maximum number was noted in thoraco-lumbar spine (64.29%), followed by cervical spine (14.29%), pelvic bone (07.14%), ribs (07.14%) and sternum (07.14%). Skeletal metastases were  much more common in multiple sites than solitary lesion in breast cancer patients. Thoraco-lumbar spine was the most common site of involvement in both solitary and multiple lesions in our study. Axial skeleton was more commonly involved than the appendicular skeleton. Bone scan may pick up bone metastases up to 18 months earlier than conventional radiology, with an average lead of four months. 99m Tc- MDP bone scan is very cost effective in comparison to other imaging modalities (CT, MRI, and PET) and play a major role in early detection of skeletal metastasis in breast cancer patients. Bangladesh J. Nuclear Med. 21(1): 21-25, January 2018


2018 ◽  
Vol 1 (1) ◽  
Author(s):  
Reid Wilson ◽  
Gabriel M. Pagnotti, PhD ◽  
Khalid S. Mohammad, MD, PhD ◽  
Theresa A. Guise, MD

Background and Hypothesis:  Post-menopausal, estrogen-receptor positive breast cancer patients are treated with aromatase inhibitors (AIs) to limit tumor progression; however, this causes adverse musculoskeletal effects. Zoledronic acid (ZA) is prescribed to inhibit bone resorption. Mechanical signals, delivered via low intensity vibration (LIV), stimulate bone formation. We hypothesize that combining LIV with ZA will mitigate bone loss in a murine model of complete estrogen-deprivation more effectively than either treatment alone.  Project Methods:  21-week-old C57BL/6 mice (n=20/group) were ovariectomized, receiving daily letrozole injections (OVX/AI) with LIV (OVX/AI+LIV), ZA (OVX/AI+ZA), LIV and ZA (OVX/AI+LIV/ZA) or underwent sham surgery with daily PBS (vehicle) injections (SH-OVX) for 22 weeks. Longitudinal dual energy X-ray absorptiometry (DEXA) and micro-computed tomography scans were analyzed for changes in body composition and bone microarchitecture, respectively.  Results:  OVX/AI reduced whole body (p< 0.0001) and lumbar spine (p<0.0001) bone mineral density (BMD) as compared to SH-OVX by 11% and 28%, respectively, as measured via DEXA. At 22w, OVX/AI+LIV/ZA had greater BMD across both regions-of-interest relative to OVX/AI (p<0.0001). Cortical bone area fraction (p<0.0001) and cortical thickness (p[Symbol]0.001) in distal femora decreased by 8% and 9%, respectively, in OVX/AI relative to SH-OVX. In OVX/AI+LIV/ZA, these parameters were greater relative to OVX/AI (p[Symbol]0.0001). OVX/AI+ZA and OVX/AI+LIV groups were not significantly different from OVX/AI in either cortical bone area fraction or cortical thickness.  Conclusion and Potential Impact:  Complete estrogen-deprivation reduced bone mineral density and altered microarchitecture. Mechanical signals provided via LIV combined with ZA prevent bone loss in aged estrogen-deprived mice. Combining these treatment strategies may reduce skeletal morbidity in breast cancer patients.


2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 553-553 ◽  
Author(s):  
J. E. Lester ◽  
S. A. Gutcher ◽  
S. P. Ellis ◽  
R. Thorpe ◽  
J. M. Horsman ◽  
...  

553 Background: The aromatase inhibitor anastrozole is a highly effective treatment for breast cancer with superior efficacy and tolerability advantages over tamoxifen. However its use is associated with significant declines in bone mineral density (BMD) with an increase in fracture risk. The ARIBON trial is a double blind, randomised, placebo-controlled study designed to evaluate the impact of bisphosphonate treatment on BMD in women taking anastrozole. The study also aims to explore the relationship between levels of biochemical markers of bone metabolism with longer term changes in BMD as measured by Dual energy Xray Absorptiometry (DXA). Methods: 131 postmenopausal, surgically treated breast cancer patients were recruited from oncology clinics in Leeds and Sheffield, UK. Following consent, baseline bone densitometry showed that 68, 50 and 13 patients were found to be normal (T >-1.0), osteopenic (T -1.0 to -2.5) and osteoporotic (T < -2.5) respectively. All patients were treated with anastrozole 1mg once a day and offered calcium and vitamin D supplementation. In addition, osteopenic patients were randomised on a 1:1 basis to receive either treatment with ibandronate 150 mg orally every month or placebo. Osteoporotic patients were treated with open label ibandronate orally 150mg every month. Results: After I year, osteopenic patients treated with ibandronate gained +2.78% (range -3.8, +15.1) and +1.35% (range -4.1, +5.6) at the lumbar spine and hip respectively. Patients treated with placebo however lost -2.61% (range -11.0, +2.2) at the lumbar spine and -2.34% (range -10.4, +5.2) at the hip. The differences between the two treatment arms were statistically significant at both sites (p<0.001, independent samples t-test). Patients with osteoporosis gained +5.05% (range -8.7, +15.2) at the lumbar spine and +2.62% (range -1.0, +8.6) at the hip after 1 year. Conclusions: Ibandronate 150 mg by mouth once a month prevents anastrozole induced bone loss and results in significant increases in BMD at the hip and lumbar spine in osteopenic and osteoporotic patients. Analysis of the biochemical markers of bone metabolism is underway and relationships between biochemical and BMD changes will be presented. No significant financial relationships to disclose.


2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e22187-e22187
Author(s):  
H. J. Kim ◽  
E. Park ◽  
W. Lim ◽  
J. Sei ◽  
B. Koh ◽  
...  

e22187 Background: Bone mass has been proposed as a marker of cumulative exposure to estrogen in women. We have studied the association between bone mass and breast cancer in postmenopausal women. Methods: We investigated the association between bone mineral density(BMD), as measured at the lumbar spine and femoral neck and the breast cancer in women age 50 or older, who were received an initial diagnosis of stage 0-III breast cancer, confirmed by pathologic assessment of breast tissue. We recruited 718 women with newly diagnosed breast cancer in a Asan Medical Center from 1, Jun. 2006 to 31, Dec. 2007. BMD was measured by lunar EXPERT-XL for breast cancer patients Results: Median age at diagnosis was 58 (range 47–82). Patients with higher BMD at lumbar spine were found to have low grade disease (p<0.005). The patients with hormone receptor positive breast tumor showed higher BMD at lumbar spine and lower serum 25(OH)D than hormone receptor negative tumor. Serum estradiol level did not show a relation to BMD. There were no significant differences between breast cancer stage and serum 25(OH)D and BMD. Conclusions: The patients who have hormone receptor positive breast cancer had higher Lumbar spine BMD and lower 25(OH)D than hormone receptor negative patients. No significant financial relationships to disclose.


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