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Prevention of bone loss by zoledronic acid in premenopausal women undergoing adjuvant chemotherapy persist up to one year following discontinuing treatment.

ABSTRACT: Adjuvant chemotherapy is associated with significant reductions in bone mineral density (BMD) in premenopausal women with breast cancer (BC) that is prevented with zoledronic acid (ZA) every 3 months for 1 yr.The aim of the study was to examine the effect on BMD of discontinuing ZA during the subsequent year.We conducted a randomized, double-blind trial.Premenopausal women (mean age, 42 yr) undergoing adjuvant chemotherapy for BC participated in the study.ZA (4 mg iv every 3 months) vs. placebo was administered for 12 months.We measured percentage change in BMD and bone turnover markers at 12 and 24 months (1 yr after last infusion).Of 101 women randomized, 85 completed 12-month and 62 completed 24-month evaluations. In the placebo group, serum C-telopeptide (CTX) increased progressively over the first 12 months, returned toward baseline but remained significantly above baseline by 24 months. Lumbar spine BMD decreased from baseline by 5.5% at 12 and 6.3% at 24 months. Similarly, by 24 months, total hip and femoral neck BMD declined by 2.6 and 2.4%, respectively. In ZA patients, BMD remained stable (P < 0.0001 compared to placebo). Serum CTX declined significantly by 6 months, but returned to baseline by 12 months, remaining there at 24 months.Premenopausal women receiving chemotherapy for BC sustained significant bone loss during the first year, without recovery during the second year. ZA effectively prevented bone loss during the first year of chemotherapy. BMD remained stable 1 yr after completion of ZA. Serum CTX increased significantly by 12 and 24 months. More frequent administration may be required to suppress bone resorption in this patient population.

SUBMITTER: Hershman DL

PROVIDER: S-EPMC2840866 | biostudies-other | 2010 Feb

REPOSITORIES: biostudies-other

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Prevention of bone loss by zoledronic acid in premenopausal women undergoing adjuvant chemotherapy persist up to one year following discontinuing treatment.

Hershman Dawn L DL McMahon Donald J DJ Crew Katherine D KD Shao Theresa T Cremers Serge S Brafman Lois L Awad Danielle D Shane Elizabeth E

The Journal of clinical endocrinology and metabolism 20091218 2

<h4>Context</h4>Adjuvant chemotherapy is associated with significant reductions in bone mineral density (BMD) in premenopausal women with breast cancer (BC) that is prevented with zoledronic acid (ZA) every 3 months for 1 yr.<h4>Objective</h4>The aim of the study was to examine the effect on BMD of discontinuing ZA during the subsequent year.<h4>Design</h4>We conducted a randomized, double-blind trial.<h4>Patients</h4>Premenopausal women (mean age, 42 yr) undergoing adjuvant chemotherapy for BC ...[more]

PMID: 20022990

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Project description:PurposeBariatric surgery is an effective treatment for severe obesity but causes substantial bone loss and increased risk of fractures. To date, there have been no studies examining whether pharmacologic treatments can prevent bone loss after bariatric surgery. We performed an exploratory study to examine the preliminary safety and efficacy of zoledronic acid (ZOL), a potent anti-resorptive bisphosphonate, to suppress bone turnover markers (BTM) and prevent declines in bone mineral density (BMD) after Roux-en-Y gastric bypass (RYGB) surgery.MethodsWe performed an open-label pilot study of pre-operative ZOL in postmenopausal women with obesity who were planning RYGB (n = 4). A single dose of zoledronic acid 5 mg was given intravenously prior to RYGB. Serum bone biochemistries including C-telopeptide (CTX) and procollagen type 1 N-terminal propeptide (P1NP) were measured at multiple timepoints throughout the 24-week study. BMD was also obtained at the spine and hip by dual-energy x-ray absorptiometry (DXA) and at the trabecular spine by quantitative computed tomography (QCT) at pre-operative baseline and 24 weeks. Results were compared against pre-operative baseline and against changes among RYGB historical controls (n = 10).ResultsAt 2 weeks after RYGB, there was a nonsignificant trend for CTX and P1NP levels to be lower than baseline levels in the ZOL group. By 24 weeks after RYGB, however, participants who received ZOL had a significant increase in CTX above pre-operative baseline (+0.228 ± 0.117 ng/dL, p = 0.030) but this CTX rise was less than that observed in the controls (+0.601 ± 0.307 ng/dL, p = 0.042 between groups). Despite ZOL use, participants had significant areal BMD loss at the total hip as compared to pre-operative baseline (-4.2 ± 1.5%, p = 0.012) that was similar in magnitude to total hip BMD loss in the controls (-5.5 ± 3.9%, p = 0.005). There was a suggestion that the ZOL group might be protected against trabecular spine volumetric bone loss as compared to the control group (+4.8 ± 8.0% vs. -5.9 ± 7.0%, p = 0.075 between groups). Serum calcium, 25-hydroxyvitamin D, and parathyroid hormone did not change in either group. No hypocalcemia or serious adverse events were reported after ZOL.ConclusionIn this proof of concept study, a single dose of ZOL prior to RYGB appeared to transiently mitigate but not fully prevent high bone turnover in the acute postoperative period. At 24 weeks after RYGB, our preliminary data suggest that ZOL was not sufficient to prevent bone loss at the hip, although it may preserve bone density at the trabecular spine. Further prospective, controlled studies are needed to confirm our findings and to identify the best strategies for preventing bone loss in bariatric patients receiving RYGB.

Project description:BackgroundIn the 2.8 years of the Diabetes Prevention Program (DPP) randomised clinical trial, diabetes incidence in high-risk adults was reduced by 58% with intensive lifestyle intervention and by 31% with metformin, compared with placebo. We investigated the persistence of these effects in the long term.MethodsAll active DPP participants were eligible for continued follow-up. 2766 of 3150 (88%) enrolled for a median additional follow-up of 5.7 years (IQR 5.5-5.8). 910 participants were from the lifestyle, 924 from the metformin, and 932 were from the original placebo groups. On the basis of the benefits from the intensive lifestyle intervention in the DPP, all three groups were offered group-implemented lifestyle intervention. Metformin treatment was continued in the original metformin group (850 mg twice daily as tolerated), with participants unmasked to assignment, and the original lifestyle intervention group was offered additional lifestyle support. The primary outcome was development of diabetes according to American Diabetes Association criteria. Analysis was by intention-to-treat. This study is registered with ClinicalTrials.gov, number NCT00038727.FindingsDuring the 10.0-year (IQR 9.0-10.5) follow-up since randomisation to DPP, the original lifestyle group lost, then partly regained weight. The modest weight loss with metformin was maintained. Diabetes incidence rates during the DPP were 4.8 cases per 100 person-years (95% CI 4.1-5.7) in the intensive lifestyle intervention group, 7.8 (6.8-8.8) in the metformin group, and 11.0 (9.8-12.3) in the placebo group. Diabetes incidence rates in this follow-up study were similar between treatment groups: 5.9 per 100 person-years (5.1-6.8) for lifestyle, 4.9 (4.2-5.7) for metformin, and 5.6 (4.8-6.5) for placebo. Diabetes incidence in the 10 years since DPP randomisation was reduced by 34% (24-42) in the lifestyle group and 18% (7-28) in the metformin group compared with placebo.InterpretationDuring follow-up after DPP, incidences in the former placebo and metformin groups fell to equal those in the former lifestyle group, but the cumulative incidence of diabetes remained lowest in the lifestyle group. Prevention or delay of diabetes with lifestyle intervention or metformin can persist for at least 10 years.FundingNational Institute of Diabetes and Digestive and Kidney Diseases (NIDDK).

Project description:BackgroundSuppression of ovarian estrogen production reduces the recurrence of hormone-receptor-positive early breast cancer in premenopausal women, but its value when added to tamoxifen is uncertain.MethodsWe randomly assigned 3066 premenopausal women, stratified according to prior receipt or nonreceipt of chemotherapy, to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression. The primary analysis tested the hypothesis that tamoxifen plus ovarian suppression would improve disease-free survival, as compared with tamoxifen alone. In the primary analysis, 46.7% of the patients had not received chemotherapy previously, and 53.3% had received chemotherapy and remained premenopausal.ResultsAfter a median follow-up of 67 months, the estimated disease-free survival rate at 5 years was 86.6% in the tamoxifen-ovarian suppression group and 84.7% in the tamoxifen group (hazard ratio for disease recurrence, second invasive cancer, or death, 0.83; 95% confidence interval [CI], 0.66 to 1.04; P=0.10). Multivariable allowance for prognostic factors suggested a greater treatment effect with tamoxifen plus ovarian suppression than with tamoxifen alone (hazard ratio, 0.78; 95% CI, 0.62 to 0.98). Most recurrences occurred in patients who had received prior chemotherapy, among whom the rate of freedom from breast cancer at 5 years was 82.5% in the tamoxifen-ovarian suppression group and 78.0% in the tamoxifen group (hazard ratio for recurrence, 0.78; 95% CI, 0.60 to 1.02). At 5 years, the rate of freedom from breast cancer was 85.7% in the exemestane-ovarian suppression group (hazard ratio for recurrence vs. tamoxifen, 0.65; 95% CI, 0.49 to 0.87).ConclusionsAdding ovarian suppression to tamoxifen did not provide a significant benefit in the overall study population. However, for women who were at sufficient risk for recurrence to warrant adjuvant chemotherapy and who remained premenopausal, the addition of ovarian suppression improved disease outcomes. Further improvement was seen with the use of exemestane plus ovarian suppression. (Funded by Pfizer and others; SOFT ClinicalTrials.gov number, NCT00066690.).

Project description:BACKGROUND:In the Suppression of Ovarian Function Trial (SOFT) and the Tamoxifen and Exemestane Trial (TEXT), the 5-year rates of recurrence of breast cancer were significantly lower among premenopausal women who received the aromatase inhibitor exemestane plus ovarian suppression than among those who received tamoxifen plus ovarian suppression. The addition of ovarian suppression to tamoxifen did not result in significantly lower recurrence rates than those with tamoxifen alone. Here, we report the updated results from the two trials. METHODS:Premenopausal women were randomly assigned to receive 5 years of tamoxifen, tamoxifen plus ovarian suppression, or exemestane plus ovarian suppression in SOFT and to receive tamoxifen plus ovarian suppression or exemestane plus ovarian suppression in TEXT. Randomization was stratified according to the receipt of chemotherapy. RESULTS:In SOFT, the 8-year disease-free survival rate was 78.9% with tamoxifen alone, 83.2% with tamoxifen plus ovarian suppression, and 85.9% with exemestane plus ovarian suppression (P=0.009 for tamoxifen alone vs. tamoxifen plus ovarian suppression). The 8-year rate of overall survival was 91.5% with tamoxifen alone, 93.3% with tamoxifen plus ovarian suppression, and 92.1% with exemestane plus ovarian suppression (P=0.01 for tamoxifen alone vs. tamoxifen plus ovarian suppression); among the women who remained premenopausal after chemotherapy, the rates were 85.1%, 89.4%, and 87.2%, respectively. Among the women with cancers that were negative for HER2 who received chemotherapy, the 8-year rate of distant recurrence with exemestane plus ovarian suppression was lower than the rate with tamoxifen plus ovarian suppression (by 7.0 percentage points in SOFT and by 5.0 percentage points in TEXT). Grade 3 or higher adverse events were reported in 24.6% of the tamoxifen-alone group, 31.0% of the tamoxifen-ovarian suppression group, and 32.3% of the exemestane-ovarian suppression group. CONCLUSIONS:Among premenopausal women with breast cancer, the addition of ovarian suppression to tamoxifen resulted in significantly higher 8-year rates of both disease-free and overall survival than tamoxifen alone. The use of exemestane plus ovarian suppression resulted in even higher rates of freedom from recurrence. The frequency of adverse events was higher in the two groups that received ovarian suppression than in the tamoxifen-alone group. (Funded by Pfizer and others; SOFT and TEXT ClinicalTrials.gov numbers, NCT00066690 and NCT00066703 , respectively.).

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Prevention of bone loss by zoledronic acid in premenopausal women undergoing adjuvant chemotherapy persist up to one year following discontinuing treatment.

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Prevention of bone loss by zoledronic acid in premenopausal women undergoing adjuvant chemotherapy persist up to one year following discontinuing treatment.

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