Changes on Bone Mineral Density after Adjuvant Treatment in Women with Non-metastatic Breast Cancer

Summary Purpose. Adjuvant therapies have prolonged survival of non-metastatic breast cancer (NMBC) patients, but they also decrease bone mineral density (BMD). We have analyzed the effects of chemotherapy, hormone therapy with tamoxifen or both, on BMD of women with NMBC. Patients and methods. We prospectively included 168 women with NMBC (stage I–III) referred to the Medical Oncology Service of University Hospital of Canary Islands between 1997 and 2001 (55 ± 12 years; 37% premenopausal; 43 ± 13 months of follow-up). We measured lumbar and hip BMD (g/cm²) at diagnosis, after chemotherapy and after 12 months of tamoxifen. If a low BMD was detected, women were treated with bisphosphonates. Results. BMD after chemotherapy (n = 83) significantly decreased at lumbar (1.014 ± 0; 0.995 ± 0, p = 0.0001), trochanter (0.701 ± 0; 0.690 ± 0, p = 0.001), intertrochanter (1.095 ± 0; 1.078 ± 0, p = 0.0001) and total hip (0.924 ± 0; 0.915 ± 0, p = 0.046) areas. Although 60% of the premenopausal women suffered amenorrhea after chemotherapy, there were not significant differences in BMD between them and women who retained menses. BMD of women who received 12 months of tamoxifen after chemotherapy increased – total hip (0.907 ± 0; 0.922 ± 0, p = 0.005) and intertrochanter (1.071 ± 0; 1.091 ± 0, p = 0.003) – or remained stable – lumbar, femoral neck, trochanter, and Ward's triangle (n = 39). When tamoxifen was the only adjuvant treatment, BMD after 12 months (n = 22) increased in trochanter area (0.644 ± 0; 0.663 ± 0, p = 0.011), and remained stable in all other sites. 50 (30%) patients were treated with bisphosphonates because of osteopenia. Conclusion. Women with NMBC are affected by early bone loss after adjuvant chemotherapy. This bone loss is attenuated by one year of tamoxifen treatment. This article presented in part at the 2000 (December) 23rd Annual San Antonio Breast Cancer Symposium, and at the 2004 (September-October) 27th World Congress of Internal Medicine at Granada, Spain.     

Efficacy of anastrozole after tamoxifen in early breast cancer patients with chemotherapy-induced ovarian function failure

The DATA study (NCT00301457) compared 6 and 3 years of anastrozole in postmenopausal women with hormone receptor-positive early breast cancer after 2–3 years of tamoxifen. Patients with chemotherapy-induced ovarian function failure (CIOFF) were also eligible, but could be at risk of ovarian function recovery (OFR). The current analysis compared the survival of women with CIOFF with definitely postmenopausal women and examined the influence of OFR on survival. Therefore, we selected patients from the DATA study aged 45–57 years at randomization who had received (neo)adjuvant chemotherapy. They were classified by reversibility of postmenopausal status: possibly reversible in case of CIOFF (n = 395) versus definitely postmenopausal (n = 261). The former were monitored by E2 measurements for OFR. The occurrence of OFR was incorporated as a time-dependent covariate in a Cox-regression model for calculating the hazard ratio (HR). We used the landmark method to calculate residual 5-year survival rates. When comparing CIOFF women with definitely postmenopausal women, the survival was not different. Among CIOFF women with available E2 follow-up values (n = 329), experiencing OFR (n = 39) had an unfavorable impact on distant recurrence-free survival (HR 2.27 [95% confidence interval [CI] 0.98–5.25; p = 0.05] and overall survival (HR 2.61 [95% CI 1.11–6.13; p = 0.03]). After adjusting for tumor features, the HRs became 2.11 (95% CI 0.89–5.02; p = 0.09) and 2.24 (95% CI 0.92–5.45; p = 0.07), respectively. The residual 5-year rate for distant recurrence-free survival was 76.9% for women with OFR and 92.1% for women without OFR, and for 5-year overall survival 80.8% and 94.4%, respectively. Women with CIOFF receiving anastrozole may be at increased risk of disease recurrence if experiencing OFR.     

Fracture incidence after 3 years of aromatase inhibitor therapy

BackgroundThe purpose of this study was to describe the fracture incidence and bone mineral density (BMD) evolution in a large cohort of post-menopausal women with breast cancer after 3 years of aromatase inhibitor (AI) therapy.Patients and methodsA prospective, longitudinal study in real-life setting. Each woman had an extensive medical assessment, a biological evaluation, a BMD measurement, and systematic spinal X-rays at baseline and after 3 years of AI therapy. Women with osteoporosis at baseline (T-score < -2.5 and/or non-traumatic fracture history) were treated by oral weekly bisphosphonates.ResultsAmong 497 women (mean age 63.8 ± 9.6 years) included in this study, 389 had a bone evaluation both at baseline and after 3 years of AI therapy: 267 women (mean age 61.2 ± 8.6) with no osteoporosis at baseline and 122 women (mean age 67.2 ± 9.1) with osteoporosis at baseline justifying a weekly oral bisphosphonate treatment. Women without bisphosphonates had a significant decrease in spine BMD (-3.5%, P < 0.01), neck BMD (-2.0%, P < 0.01), and total hip BMD (-2.1%, P < 0.01) over the 3 years but only 15 of them (5.6%) presented an incident vertebral or non-vertebral fracture. In osteoporotic women treated with bisphosphonates, spine and hip BMD were maintained at 3 years but 12 of them (9.8%) had an incident fracture. These fractured women were significantly older (74.1 ± 9.8 versus 66.5 ± 8.8) but also presented BMD loss during treatment suggesting poor adherence to bisphosphonate treatment.ConclusionThis real-life study confirmed that AIs induced moderate bone loss and low fracture incidence in post-menopausal women without initial osteoporosis. In women with baseline osteoporosis and AI therapy, oral bisphosphonates maintain BMD but were associated with a persistent fracture risk, particularly in older women.     

Management of anastrozole-induced bone loss in breast cancer patients with oral risedronate: results from the ARBI prospective clinical trial

Introduction

The aim of this multicenter, phase III, prospective open label clinical trial was to investigate the effect of risedronate (R) on bone mineral density (BMD) in postmenopausal, early breast cancer (BC) patients scheduled to receive anastrozole (A).

Methods

Pre-treatment BMD of 213 patients with hormone receptor-positive BC was evaluated at lumbar spine (LS) and hip (HP). Patients were categorized according to their baseline BMD T-score as being at low, moderate and high risk of osteoporosis. Low risk patients received anastrozole only (A), moderate risk were randomized to anastrozole +/- risedronate (A+/-R) administration and high risk patients received anastrozole + risedronate (A+R). Anastrozole was given at a dosage of 1 mg/day while oral risedronate was given at 35 mg/week. BMD was then assessed at 12 and 24 months. All patients received daily supplements of calcium (1000 mg/day) and vitamin D (400 IU/day).

Results

At 24 months, in the moderate risk group, treatment with A+R resulted in a significant increase in BMD at LS and HP compared to treatment with A only (5.7% v -1.5%, Wilcoxon test P = 0.006, and 1.6% v -3.9% Wilcoxon test P = 0.037, respectively), while no significant difference was found at 12 months; 24.3% of the patients moved to normal BMD region. In the high risk group, a significant increase for LS was detected both at 12 and 24 months (6.3% and 6.6%, P < 0.001) but not for HP; BMD in 14% of patients improved to the osteopenic region. In the low risk group, a significant decrease of BMD was detected at 12 months for LS and HP (-5.3% P < 0.001 and -2.4% P < 0.001, respectively,); at 24 months, a significant decrease of BMD was detected only for LS (-2.5%, P < 0.001). However, 22% of patients became osteopenic and only 4% became osteoporotic.

Conclusions

The addition of oral risedronate in post-menopausal breast cancer patients receiving anastrozole has a favorable effect on BMD. Patients with pre-treatment osteopenic to osteoporotic status should be treated with a combination of both therapies in order to avoid bone loss induced by aromatase inhibition. Patients with normal BMD before starting treatment with anastrozole have a very low risk to develop osteoporosis.

Trial registration

ClinicalTrials.gov Identifier NCT00809484.     

Off-treatment bone mineral density changes in postmenopausal women receiving anastrozole for 5 years: 7-year results from the IBIS-II prevention trial

Background Anastrozole has been associated with substantial accelerated bone mineral density (BMD) loss during active treatment.Methods One thousand four hundred and ten women were included in a BMD substudy and stratified into three strata according to their baseline T-score at spine or femoral neck. The primary objective of this analysis was to investigate whether DXA BMD at the spine and hip changed two years after treatment cessation (between years 5 and 7) in those who did not receive risedronate.Results Five- and seven-year BMD data were available for a total of 528 women who did not receive risedronate. In women with normal BMD at baseline, an increase in BMD at the lumbar spine after anastrozole withdrawal was observed 1.25% (95% CI 0.73 to 1.77) (P = 0.0004), which was larger than in those on placebo (0.14% (−0.29 to 0.56))). At the hip, BMD remained unchanged between years 5 and 7 for those previously on anastrozole but continued to a decrease in those who had been randomised to placebo (−1.35% (−1.70 to −0.98)).Conclusions These are the first results reporting BMD changes after stopping anastrozole in a breast cancer prevention setting. Our results show that the negative effects of anastrozole on BMD in the preventive setting are partially reversible.Subject terms: Breast cancer, Randomized controlled trials     

Low bone mineral density linked to colorectal adenomas: a cross-sectional study of a racially diverse population

Background

Epidemiologic studies suggest that lower bone mineral density (BMD) is associated with an increased risk for colorectal adenoma/cancer, especially in postmenopausal women. The aim of this study is to investigate the association between osteopenia and/or osteoporosis and colorectal adenomas in patients from a New York community hospital.

Methods

We performed a cross-sectional observational study on 200 patients who underwent screening colonoscopies and bone density scan (dual-energy X-ray absorptiometry) at Nassau University Medical Center from November 2009 to March 2011. Among these, 83 patients were identified as osteoporosis (T score of −2.5 or below) and 67 were osteopenia (T score between −1.0 and −2.5). Logistic regression model was performed to assess the association between osteopenia and/or osteoporosis and colorectal adenomas.

Results

Among the patients with osteopenia and osteoporosis, the mean ages were 59.1 years [standard deviation (SD) =8.9] and 61.5 (SD =8.9), respectively. There were 94.0%, 85.1% and 74.7% women, respectively, in normal BMD, osteopenia and osteoporosis groups. The prevalence of colorectal adenomas was 17.9% and 25.3% in the osteopenia and osteoporosis groups, respectively, and 18.0% in the normal BMD group. After adjustment for potential confounders including age, sex, race, body mass index (BMI), tobacco use, alcohol use, history of diabetes, hypertension, or dyslipidemia, osteoporosis was found to be associated with presence of colorectal adenomas more than 2, compared to the normal BMD group. No significant associations were found for the prevalence, size, and location of adenomas.

Conclusions

Our study suggests that osteoporosis is significantly associated with the presence of multiple colorectal adenomas. Prospective studies with a larger sample size are warranted in the future.     

Loss of bone mineral density and secondary hyperparathyroidism are complications of autologous stem cell transplantation

Patients who underwent autologous stem cell transplantation (ASCT) are prone to decreased bone mineral density (BMD). We measured BMD in 180 patients who underwent ASCT for hematologic malignancies. Patients were evaluated with a median of 6.2 years after ASCT. Twenty patients who received only chemotherapy were evaluated as controls. The loss of bone mass was greater during the first year after ASCT, since majority of patients recover BMD and normalize bone turnover markers during the following years. After ASCT, over half of the patients show osteopenia or osteoporosis independent of the sex. According to the results of other groups, our results emphasize the potential usefulness of antiresorptive agents to prevent or treat post-ASCT osteopenia or osteoporosis, and the importance of the measurement of BMD as an integral component to the follow-up of ASCT.     

Baseline bone mineral density of the total lumbar spine may predict for chemotherapy-induced ovarian failure

Summary Age at treatment and the total cumulative dose of cyclophosphamide are established predictors of chemotherapy-induced ovarian failure in premenopausal women with breast cancer. In a prospective trial of 49 women receiving adjuvant chemotherapy, we sought to identify whether other factors including family history of osteoporosis, lifestyle factors, reproductive hormones, bone turnover markers, or bone mineral density (BMD) of the hip or total spine measured before (baseline) and 6 months after chemotherapy increased the risk of ovarian failure. Univariate logistic regression analyses were used to identify the variables related to the risk of ovarian failure, and a multivariate logistic regression model was used to find the best of predictors of ovarian failure among the variables. In the multivariate model a higher total spine BMD at baseline (OR=6.0, p=0.02, 95% CI 1.4–27.3), and a 10% change in estradiol (E₂) from baseline to six months (OR=0.80, p=0.02, 95% CI 0.67–0.97) were predictive of ovarian failure adjusted for age. In particular, as total spine BMD at baseline increases by 0.1 g/cm² the odds of developing chemotherapy-induced ovarian failure increases by 6-fold. The multivariate model provides a good fit to the data (GOF p-value=0.8852), and provides excellent discrimination between those women who will and will not develop ovarian failure (Area under ROC=0.9487). If confirmed in larger data sets, using baseline spinal BMD to identify women who are at higher risk of developing ovarian failure independent of their age would be of value.     

Aromatase inhibitors and bone loss

The aromatase inhibitors (AIs) anastrozole (Arimidex), letrozole (Femara), and exemestane (Aromasin) are significantly more effective than the selective estrogen-receptor modulator (SERM) tamoxifen in preventing recurrence in estrogen receptor-positive early breast cancer. Aromatase inhibitors are likely to replace SERMs as first-line adjuvant therapy for many patients. However, AIs are associated with significantly more osteoporotic fractures and greater bone mineral loss. As antiresorptive agents, oral and intravenous bisphosphonates such as alendronate (Fosamax), risedronate (Actonel), ibandronate (Boniva), pamidronate (Aredia), and zoledronic acid (Zometa) have efficacy in preventing postmenopausal osteoporosis, cancer treatment-related bone loss, or skeletal complications of metastatic disease. Clinical practice guidelines recommend baseline and annual follow-up bone density monitoring for all patients initiating AI therapy. Bisphosphonate therapy should be prescribed for patients with osteoporosis (T score < -2.5) and considered on an individual basis for those with osteopenia (T score < -1). Modifiable lifestyle behaviors including adequate calcium and vitamin D intake, weight-bearing exercise, and smoking cessation should be addressed. Adverse events associated with bisphosphonates include gastrointestinal toxicity, renal toxicity, and osteonecrosis of the jaw. These safety concerns should be balanced with the potential of bisphosphonates to minimize or prevent the debilitating effects of AI-associated bone loss in patients with early, hormone receptor-positive breast cancer.     

Impact of osteopenia on surgical and oncological outcomes in patients with pancreatic cancer

Introduction

Osteopenia, which is defined as a decrease in bone mineral density, has been recently recognized as a metabolic and an oncological biomarker for surgery in patients with malignancy. We aimed to study the prognostic impact of osteopenia in patients with pancreatic cancer (PC) after resection.

Methods

A total of 56 patients who underwent curative resection of PC were retrospectively investigated. The skeletal muscle index at the third lumbar spine and bone mineral density at the 11th thoracic vertebra were measured using computed tomography.

Results

Sarcopenia and osteopenia were identified in 24 (43%) and 27 (48%) patients, respectively. The overall and disease-free survival rates were significantly lower in the sarcopenia group than in the non-sarcopenia group (p?<?0.01 and p?<?0.01, respectively) and in the osteopenia group than in the non-osteopenia group (p?<?0.01 and p?<?0.01, respectively). In multivariate analysis, sarcopenia (odds ratio [OR] 4.05; 95% confidence interval [CI] 1.23–13.38; p?=?0.02) was a significant independent predictor of 1-year disease-free survival. Further, sarcopenia (OR 6.00; 95% CI 1.46–24.6; p?=?0.01) and osteopenia (OR 4.66; 95% CI 1.15–18.82; p?=?0.03) were significant independent predictors of 2-year overall survival.

Conclusion

Osteopenia is a significant negative factor for 2-year overall survival after curative resection of PC.

     

唑来膦酸预防芳香化酶抑制剂引起骨丢失的临床研究*

目的：探讨唑来膦酸预防绝经后乳腺癌患者芳香化酶抑制剂内分泌治疗引起骨丢失的效果。方法：选取2005年6 月至2007年6 月天津医科大学附属肿瘤医院63例绝经后激素受体阳性乳腺癌患者,随机分为治疗组（唑来膦酸与芳香化酶抑制剂连用）和对照组（单用芳香化酶抑制剂）。 随访24个月,观察不同时期两组患者腰椎（L2～L4）前后位骨密度,骨量减少和骨质疏松发生率的变化。结果：治疗6 个月,唑来膦酸组腰椎的骨密度与单用芳香化酶抑制剂组相比有增高趋势,但差异无统计学意义（P=0.099）。 两组骨丢失事件的发生没有统计学差异（骨量减少：P=0.124,骨质疏松：P=0.573）。 12个月时,治疗组腰椎骨密度较对照组明显升高（P=0.008）,治疗组骨量减少和骨质疏松的发生率低于对照组（骨量减少：P=0.048,骨质疏松：P=0.042）。 24个月时,治疗组的腰椎骨密度明显高于对照组（P=0.000）。 治疗组骨量减少和骨质疏松的发生率明显低于对照组（骨量减少：P=0.027,骨质疏松：P=0.011）。 治疗期间,除治疗组骨痛发生率与对照组相比较高外（P=0.039）,两组的不良事件的发生率相似（P>0.05）。结论：唑来膦酸对芳香化酶抑制剂内分泌治疗引起的骨丢失有明显的预防作用,且不良反应轻微,安全有效,耐受性好。     

Loss of bone mass and vitamin D deficiency after hematopoietic stem cell transplantation: standard prophylactic measures fail to prevent osteoporosis.

Bone mineral density (BMD) and biochemical markers of bone metabolism were analyzed in 67 adults with ALL (n = 27), AML (n = 14), MDS (n = 6) and CML (n = 20) before and after allogeneic stem cell transplantation (SCT). Median age was 36 years (17-56). Twenty-six out of 53 patients (49%) had osteopenia and osteoporosis before SCT, 21/26 had acute leukemias and 5/26 had chronic myeloid leukemia (CML). T-score before SCTwas -1.23 in patients with acute leukemias and 0.62 in CML patients (P = 0.001). After SCT, a significant loss of BMD was observed in all patients. After 6 months, 24 of 36 evaluable patients (67%) had pathologic BMD, 11 of them (30%) had developed osteoporosis. After 12 months, 20 of 32 evaluable patients (62%) had BMD values below normal and nine of them (28%) had osteoporosis. Increased pyridinium excretion was observed in 12/20 patients (60%) with acute leukemias, but only in 3/13 (23%) with CML (P = 0.014). A prolonged vitamin D deficiency for more than 6 months developed early after SCT in all patients. Patients with acute leukemias frequently have osteopenia and osteoporosis before SCT. After SCT, a further loss of BMD occurs independent from the underlying disease. Standard prophylactic measures are not sufficient to prevent loss of bone mass. Studies on prophylactic interventions are needed to prevent severe osteoporosis in long-term survivors of SCT.     

Bisphosphonates and pathologic complete response to taxane- and anthracycline-based neoadjuvant chemotherapy in patients with breast cancer

BACKGROUND:

Several studies have suggested that bisphosphonates have an antitumor effect. In the current study, the authors sought to evaluate whether the use of bisphosphonates increased the rate of pathological complete response (pCR) in patients with breast cancer.

METHODS:

The authors identified 1449 patients with breast cancer who were receiving taxane‐ and anthracycline‐based neoadjuvant chemotherapy between 1995 and 2007 at The University of Texas MD Anderson Cancer Center. Patients who received bisphosphonates for osteopenia or osteoporosis while receiving chemotherapy were also identified. The primary outcome was the percentage of patients achieving a pCR. Groups were compared using the chi‐square test. A multivariable logistic regression model was fit to examine the relation between the use of bisphosphonates and pCR. An exploratory survival analysis using the Kaplan‐Meier method was performed; groups were compared using the log‐rank test.

RESULTS:

Of the 1449 patients included, 39 (2.7%) received bisphosphonates. Those receiving bisphosphonates were older (P < .001) and less likely to be obese (P = .04). The pCR rate was 25.4% in the bisphosphonate group and 16% in the nonbisphosphonate group (P = .11). In the multivariable model, patients treated with bisphosphonates tended to have higher rates of pCR (odds ratio, 2.18; 95% confidence interval, 0.90‐5.24); however, the difference was not found to be statistically significant. With a median follow‐up of 55 months (range, 3 months‐145 months), no differences in disease recurrence or survival were observed.

CONCLUSIONS:

The use of bisphosphonates at the time of neoadjuvant chemotherapy was not found to be associated with a statistically significant increase in the rates of pCR. The observed estimates suggest a positive effect; however, the small percentage of patients receiving bisphosphonates likely affected the power to detect a statistically significant difference. Cancer 2011;. © 2011 American Cancer Society.     

A multicenter prospective study to evaluate bone fracture related to adjuvant anastrozole in Japanese postmenopausal women with breast cancer: two-year interim analysis of Saitama Breast Cancer Clinical Study Group (SBCCSG-06)

Background

Because of its superior efficacy to tamoxifen, anastrozole has been widely used in Japan as an adjuvant treatment for postmenopausal, hormone-responsive breast cancer patients. However, anastrozole may affect bone in Japanese patients similar to its effects in Western patients. The aim of this study is to evaluate the rate of bone fracture and bone mineral density (BMD) during anastrozole treatment in Japanese patients.

Patients and methods

In this study, 350 postmenopausal women with hormone-responsive, stage I to IIIA breast cancer were enrolled and scheduled to receive adjuvant anastrozole treatment for up to 5 years. Patients underwent clinical examination for bone fractures and annual measurement of BMD during treatment.

Results

After a median follow-up of 33.0 months, bone fractures occurred in 1.8 %. Annual fracture rates were 0.3 and 1.2 % during the first and second year, respectively. The overall median BMD significantly decreased, measuring 87.5, 84.3, and 83.5 % at baseline and after 1 and 2 years, respectively. Musculoskeletal disorders were the most common (26.1 %), and hot flashes were the second most common adverse event (7.9 %). Severe adverse events occurred in 5.5 % of all the cases.

Conclusions

In this interim analysis, the bone fracture rate was lower than that in the Western population despite a significant reduction of BMD after 2 years of treatment with anastrozole. Adjuvant anastrozole treatment was well tolerated in Japanese postmenopausal women with breast cancer. Long-term follow-up data is necessary to elucidate the racial disparities of the safety profile of anastrozole.     

Serum 25-hydroxy Vitamin D Status is Not Related to Osteopenia/Osteoporosis Risk in Colorectal Cancer Survivors

Background: The incidence of colorectal cancer increases with vitamin D deficiency as shown in recentlypublished studies. In addition, prospective investigations have indicated that low vitamin D levels may beassociated with increased mortality of colorectal cancer, especially in stage III and IV cases. However, the exactincidence of vitamin D deficiency and the relation between vitamin D deficiency and osteopenia/osteporosis isstill not known. The aim of this study is to identify severity of vitamin D deficiency and absolute risk factors ofosteopenia/osteoporosis in colorectal cancer survivors. Materials and Methods: A total of 113 colorectal cancersurvivors treated with surgery and/or chemotherapy ± radiotherapy were recruited from medical oncologyoutpatient clinics during routine follow-up visits in 2012-2013. Bone mineral densitometry (BMD) was performed,and serum 25-OH vitamin D levels were also checked on the same day of the questionnaire. The patients wasdivided into 2 groups, group A with normal BMD and group B with osteopenia/osteoporosis. Results: Themedian age of the study population was 58 (40-76). Thirty (30.0%) were female, whereas 79 (70.0%) were male.The median follow-up was 48 months (14-120 months). Vitamin D deficiency was found in 109 (96.5%); milddeficiency (20-30 ng/ml) in 19 (16.8%), moderate deficiency (10-20 ng/ml) in 54 (47.8%) and severe deficiency(<10 ng/ml) in 36 (31.9%). Osteopenia was evident in 58 (51.4%) patients whereas osteoporosis was noted in 17(15.0%) . Normal BMD was observed in 38 (33.6%). No apparent effects of type of surgery, presence of stoma,chemotherapy, radiotherapy and TNM stage were found regarding the risk of osteopenia and osteoporosis.Also, the severity of the vitamin D deficiency had no effect in the risk of osteopenia and osteporosis (p=0.93). Infemale patients, osteopenia/osteoporosis were observed in 79.5% patients as compared to 60.7% of male patients(p=0.04). Conclusions: In our study, vitamin D deficiency and osteopenia/osteoporosis was observed in 96.5%and 66.4% of colorectal cancer survivors, respectively. There is no defined absolute risk factor of osteopeniaand osteoporosis in colorectal cancer survivors. To our knowledge, in the literature, our study is the first toevaluateall the risk factors of osteopenia and osteoporosis in colorectal cancer survivors.     

Bone Loss in Lymphoma Patients Prior to Receiving Front-line Therapy

IntroductionPatients diagnosed with lymphoma are at high risk of developing osteoporosis. When treated with alkylating agents or corticosteroids, especially if the patient develops hypogonadism, the risk is further increased. Osteoporotic bone cannot easily be restored to normal levels of strength; thus, prevention of bony loss is crucial. The percentage of healthy patients with osteoporosis dramatically increases with advanced age, suggesting that progressive bone loss is common, even without the above-mentioned cancer-related factors. Pamidronate can reduce the risk of bone loss and vertebral fractures in patients with lymphoma receiving chemotherapy. Zoledronic acid, a bisphosphonate approximately 100-fold more potent than pamidronate, has not been evaluated in patients with lymphoma. Urinary N-telopeptide cross-linked collagen type I (NTx), a marker of bone resorption, has early predictive value for long-term bony outcomes in patients treated with bisphosphonates. Bone-specific alkaline phosphatase (AP), a marker of bone formation, also correlates with response to bisphosphonate therapy. We have conducted a phase III trial to evaluate the effect of zoledronic acid on the change in bone mineral density (BMD) in patients with untreated lymphoma undergoing chemotherapy. We report the striking number of untreated lymphoma patients who present with osteopenia and thus would be at significant risk for future bone-related sequelae.Patients and MethodsAll patients with newly diagnosed lymphoma seen at our institution from 2005 to 2009 were evaluated for protocol eligibility. Exclusion criteria included bone fractures, BMD T-scores worse than ?2.0, creatinine clearance < 60 mL/min, dental problems, and recent steroid or bisphosphonate use. Patients on study were stratified as male, premenopausal female, or postmenopausal female. Accrued patients were randomized to receive either: (1) oral calcium and vitamin D (Ca + D), or (2) Ca + D and 4 mg zoledronic acid intravenously (I.V.) at baseline and at 6 months. Urine NTx and bone-specific AP levels were measured at baseline, 3, 6, 9, and 12 months.ResultsTo date, 46 patients have completed the study and have evaluable data. Patient characteristics include 27 male, 4 premenopausal female, 15 postmenopausal female, median age of 62 years (range, 33-80 years). Twenty-one patients had indolent lymphoma (18 follicular, 1 follicular center, 2 small lymphocytic), 19 had large B-cell lymphoma (17 diffuse large B-cell, 2 primary mediastinal B-cell lymphoma), 3 patients had Hodgkin lymphoma, 2 patients had mantle cell lymphoma, and 1 patient had Waldenström macroglobulinemia. Twenty-two patients (48% of all patients) had osteopenia at baseline enrollment in the trial, including 15 men (56% of men) and 7 women (37% of women). We have previously reported our significant findings of stable T scores in the zoledronic treatment group at all locations during the 12-month observation, and the T-scores of the control group decreased at every location evaluated (location: L1-4, P = .004; L neck, P = .001; L hip, P = .118; R neck, P = .009; R hip, P = .04). We have also reported our significant findings of the bone markers urine NTx and BSAP decreasing in the zoledronic acid treatment group and increasing in the control group. The bone makers were similar at baseline in both groups, and demonstrated early response at 3 months for BSAP and 6 months for urine NTx.ConclusionsTreatment with zoledronic acid in newly-diagnosed lymphoma patients prevents the bone mineral density loss commonly seen in this population. Bone mass lost is difficult to restore, thus necessitating effective prevention strategies. Urine NTx and bone-specific AP levels demonstrate early response to bisphosphonate therapy, which may allow for early intervention and potentially prevention of further bone loss. With improving long-term survival for lymphoma patients, the need to address survivorship issues will prove more relevant to avoid preventable morbidity. We found a much-larger-than-expected portion of men with osteopenia at baseline. The etiology of the baseline low bone mass is unknown, but further evaluation of this finding in future trials is warranted to determine the significance. The portion of all lymphoma patients with baseline osteopenia in our trial, prior to any therapy, is striking and argues for baseline screening of all patients.     

Association between serum uric acid and bone health in general population: a large and multicentre study

Previous studies proposed that serum uric acid (UA), an endogenous antioxidant, could be a protective factor against bone loss. However, recently, a study with a population of US adults did not note the protective effects of serum UA. Therefore, the exact association between serum UA and bone health remains unclear. We performed a retrospective consecutive cohort study in a Chinese population to examine the association between serum UA and bone health. This cross-sectional study included 17,735 individuals who underwent lumbar spine bone mineral density (BMD) measurements as part of a health examination. In covariance analyses (multivariable-adjusted), a high serum UA level was associated with a high BMD, T-score, and Z-score. In binary logistic regression analyses (multivariable-adjusted), a high serum UA level was associated with low odds ratios (ORs) for at least osteopenia and osteoporosis in male (age ≥50 years) (OR = 0.72–0.60 and OR = 0.49–0.39, respectively) and postmenopausal female participants (OR = 0.61–0.51 and OR = 0.66–0.49, respectively). In conclusion, serum UA is associated with BMD, the T-score, and the Z-score, and has a strong protective effect against at least osteopenia and osteoporosis.     

The effects of neoadjuvant anastrozole and tamoxifen on circulating vascular endothelial growth factor and soluble vascular endothelial growth factor receptor 1 in breast cancer.

PURPOSE: Vascular endothelial growth factor (VEGF) is a key angiogenic factor mediating neovascularization. Soluble VEGF receptor 1 (sVEGFR-1) is an intrinsic negative counterpart of VEGF signaling and the ratio of sVEGFR-1 to VEGF has been shown to be a prognostic factor. Estrogen-bound estrogen receptor enhances VEGF expression, providing a common link between these signaling pathways that may be targeted by endocrine therapy. We investigated the effects of anastrozole and tamoxifen over time on serum VEGF and sVEGFR-1. EXPERIMENTAL DESIGN: The Immediate Preoperative Anastrozole, Tamoxifen, or Combined with Tamoxifen (IMPACT) trial compared the preoperative use of anastrozole with tamoxifen in postmenopausal women with estrogen receptor-positive primary operable breast cancer over 12 weeks. Circulating VEGF and sVEGFR-1 were measured by ELISA in 106 patients treated with anastrozole or tamoxifen alone at baseline and after 2 and 12 weeks of treatment. RESULTS: The increase in serum VEGF from baseline to 12 weeks was significantly different between anastrozole and tamoxifen (anastrozole versus tamoxifen, 6% versus 38%; P = 0.047). There was a significant increase in sVEGFR-1 levels after 12 weeks of anastrozole (P = 0.037). The sVEGFR-1/VEGF ratio significantly decreased in the tamoxifen arm (P = 0.013) and the change in sVEGFR-1/VEGF ratio from baseline to 12 weeks was significantly different between anastrozole and tamoxifen (anastrozole versus tamoxifen, 24% increase versus 34% decrease; P = 0.013). CONCLUSIONS: Treatment with anastrozole and tamoxifen resulted in differential effects on serum angiogenic markers. This may be related to the relative effectiveness of the treatments. These data provide further support for cross talk between estrogen receptor and VEGF.     

Reversal of skeletal effects of endocrine treatments in the Intergroup Exemestane Study

The adjuvant use of aromatase inhibitors in breast cancer is associated with adverse effects on bone health. We previously reported a decline in bone mineral density (BMD) following the switch from tamoxifen to exemestane in the Intergroup Exemestane Study (IES). Here we report effects of endocrine treatment withdrawal on BMD, bone turnover markers (BTM) and fracture rates. 4,724 patients took part in IES, and 206 patients were included in a bone sub-study. BMD and BTM were assessed pre-randomization, during and after the end of treatment (EOT). To evaluate treatment withdrawal effects, 12- and 24-month post EOT BMD results are available for 122 and 126 patients, respectively. Similar patient numbers had BTM measured post EOT. Following treatment withdrawal, the differences in BMD observed between the two endocrine strategies were partially reversed. At 24 months from EOT, spine BMD increased by 1.53% (95%CI 0.63–2.43; p = 0.001) after stopping exemestane and fell by 1.93% (95%CI −2.91 to 0.95; p = 0.0002) following tamoxifen withdrawal. A similar pattern of changes was observed at the hip. At 2 years post EOT, BMD changes from baseline were similar with both treatment strategies. Corresponding inverse changes in BTM were seen, with an increase following tamoxifen withdrawal and a reduction after exemestane. A higher number of fractures occured during exemestane treatment, but fracture rates were similar after treatment withdrawal. With the switch strategy used in IES, the on treatment adverse bone effects of exemestane are reversed. Ongoing monitoring of BMD is therefore not routinely required.     

Long-term effects of anastrozole on bone mineral density: 7-year results from the ATAC trial

BackgroundThis ‘Arimidex’, Tamoxifen, Alone or in Combination (ATAC) trial sub-study examined the effects of anastrozole and tamoxifen on bone mineral density (BMD) following 5 years of treatment.Patients and methodsLumbar spine and total hip BMD were assessed at years 6 and 7 in a total of 71 eligible patients. In total, 50 patients had evaluable data.ResultsFollowing anastrozole treatment, the lumbar spine median BMD increased by 2.35% (P = 0.04) and 4.02% (P = 0.0004) at years 6 and 7, while total hip median BMD increased by 0.71% (P = 0.3) and 0.5% (P = 0.8). After tamoxifen treatment, lumbar spine median BMD decreased by 0.79% (P = 0.2) and 0.30% (P = 0.9) at years 6 and 7, while total hip median BMD decreased by 2.09% (P = 0.0003) and 2.52% (P = 0.0002). Patients with a normal BMD or who were osteopenic at 5 years did not become osteoporotic.ConclusionsAnastrozole treatment-related bone loss did not continue into the off-treatment follow-up period. The recovery in lumbar spine BMD and absence of further loss at the hip is consistent with the reduction in the annual rate of fracture observed after treatment cessation in the main ATAC trial.