Bone Loss In Premenopausal Women Research Articles

Cartilage and bone loss in premenopausal women with rheumatoid arthritis: Radiological and laboratory assessments.

To investigate the radiological and laboratory features of bone and cartilage losses in premenopausal women with rheumatoid arthritis (RA). This case-control study is the continuation of a study that was conducted on 48 women with RA and 48 matched healthy volunteers. All RA patients were previously subjected to clinical examination, disease activity assessment using the 28-joint Disease Activity Score (DAS28) and Clinical Disease Activity Index (CDAI), serological tests, dual-energy X-ray absorptiometry measuring bone mineral density (BMD), and plain X-ray of both hands. Added to these, matrix metalloproteinase 3 (MMP-3) and cartilage oligomeric matrix protein (COMP) were measured by enzyme-linked immunosorbent assay. There were statistically significant differences between patients and controls regarding COMP and MMP-3, being higher in patients (p < .001). COMP and MMP-3 have significant positive correlation with serum levels of anti-cyclic citrullinated peptide (anti-CCP) and anti-carbamylated protein (anti-CarP). The original Sharp erosion score was positively correlated with the serum level of the studied antibodies and disease duration, but no significant correlation was found with either COMP, MMP-3, or DAS-28. Spine BMD and Z score were negatively correlated with disease activity and anti-CarP. There were significant positive relationhsips between indices of local cartilage and bone loss and the indices of systemic bone loss. MMP-3 had no correlation with indices of local cartilage and bone loss and disease activity scores. The pathogenic mechanism of hand joint damage involved the three studied autoantibodies namely, rheumatoid factor, anti-CCP and anti-CarP antibodies. Anti-CarP antibody was involved in the reduction of BMD of the spine. The association between systemic osteoporosis and hand joint damage pointed to a common pathogenic mechanism.

The volume of brisk walking is the key determinant of BMD improvement in premenopausal women.

SummaryOsteoporosis is an increasing health problem in postmenopausal women. Our findings indicated that long-term brisk walking with a volume greater than 16 per week is effective for improving BMD in premenopausal women.PurposeTo examine the effects of brisk walking on bone mineral density (BMD) in premenopausal women, and further determine the effective frequency, intensity, time and volume (frequency x duration) of brisk walking for training strategy prescription.Methods222 healthy premenopausal women were recruited for BMD measurement. According to the survey of their physical activity level, 84 subjects (age: 46±1.8) whose physical activity index ≥40 were categorized into the brisk walking group, and 138 subjects (age: 47±2.2) whose physical activity index <40 were assigned to the sedentary group. The BMD of these two groups were statistically compared with an independent t test. Next, 35 subjects from the original sedentary group were recruited for BMD measurement after 2-year moderate brisk walking. According to the volume of physical activity per week, they were divided into the control group (n = 10, aged 49±0.9), volume 8 group (n = 4, aged 48±1.2), volume 12 group (n = 7, aged 49±1.4), volume 16 group (n = 8, aged 49±1.3), and volume 20 group (n = 6, aged 49±1.5). ANOVA was used to analyze BMD before and after brisk walking among the five groups.ResultsThe BMD in the brisk walking group (1.00±0.008 g/cm2) was significantly higher than that in the sedentary group (0.89±0.008 g/cm2) (P<0.001). Stepwise regression analysis revealed that the volume of brisk walking was significantly correlated with BMD (P<0.001). In particular, brisk walking with a volume greater than 16 (a score of duration up to 4 and a score of frequency up to 4 or 5) per week is effective for improving BMD in premenopausal women (P = 0.03, P = 0.002, respectively).ConclusionsLong-term brisk walking is an efficient way to improve BMD. Taking brisk walks for 30 minutes per day 3 or more times per week (volume>16) is recommended to prevent bone loss in premenopausal women.

Premenopausal osteoporosis in a patient with autoimmune polyglandular syndrome: A case report

Osteoporosis is a skeletal disease characterized by low bone mass associated with decreased bone strength and increased risk of fractures. Low bone mass in premenopausal women is less common than in postmenopausal women, and bone loss in premenopausal women is usually due to secondary causes such as estrogen deficiency, glucocorticoid exposure, malabsorption, thyroid disorders, and hyperparathyroidism. In women with premenopausal osteoporosis, treatment should be planned according to the underlying secondary causes. In this case report, the importance of investigating the secondary causes leading to premenopausal osteoporosis and its treatment are discussed.

Five-year follow-up results of aerobic and impact training on bone mineral density in early breast cancer patients

SummaryA 12-month exercise program reversibly prevented hip bone loss in premenopausal women with early breast cancer. The bone-protective effect was maintained for 2 years after the end of the program but was lost thereafter.PurposeBreast cancer survivors are at an increased risk for osteoporosis and fracture. This 5-year follow-up of a randomized impact exercise intervention trial evaluated the maintenance of training effects on bone among breast cancer patients.MethodsFive hundred seventy-three early breast cancer patients aged 35–68 years and treated with adjuvant therapy were allocated into a 12-month exercise program or a control group. Four hundred forty-four patients (77%) were included in the 5-year analysis. The exercise intervention comprised weekly supervised step aerobics, circuit exercises, and home training. Areal bone mineral density (aBMD) was measured by dual-energy X-ray absorptiometry. Physical activity was estimated in metabolic equivalent (MET) hours per week and physical performance assessed by 2-km walking and figure-8 running tests.ResultsIn premenopausal patients, the 12-month exercise program maintained femoral neck (FN) and total hip (TH) aBMD for 3 years, but the protective effect was lost thereafter. The mean FN aBMD change in the exercise and control groups was − 0.2% and − 1.5% 1 year, − 1.1% and − 2.1% 3 years and − 3.3% versus − 2.4% 5 years after the beginning of the intervention, respectively. Lumbar spine (LS) bone loss was not prevented in premenopausal women and no training effects on aBMD were seen in postmenopausal women. The main confounding element of the study was the unexpected rise in physical activity among patients in the control group. The physical performance improved among premenopausal women in the exercise group compared with the controls.ConclusionThe 12-month exercise program prevented FN and TH bone loss in premenopausal breast cancer patients for 3 years. The bone-protective effect was reversible and lost thereafter.

Interleukin 33 in premenopausal women with rheumatoid arthritis: Is it related to generalized bone loss?

AimThe aim was to study the role of interleukin (IL)-33 in rheumatoid arthritis (RA)-induced generalized bone loss in premenopausal women and its relation to general disease activity and various laboratory markers.Patients and methodsA total of 60 premenopausal women with RA were enrolled in this work as a study group and 30 age-matched healthy women as a control group. The participants were subjected to full clinical, radiological, and laboratory assessments. The following were assessed in patients and controls by enzyme-linked immunosorbent assay technique: serum level of IL-33, 25-hydroxyvitamin D3 [25(OH) D3], and bone turnover markers, osteocalcin and C-terminal telopeptide of type I collagen. Bone mineral density was assessed using dual-energy X-ray absorptiometry.ResultsIL-33 was higher in patients with RA than controls (33.445 ± 10.07 vs 13.713 ± 0.70 pg/ml, P < 0.001). In patients with RA, serum level of IL-33 was found to be positively correlated with clinical and laboratory makers of disease activity (disease activity score 28 and C-reactive protein), anticyclic citrullinated peptide antibodies titer (P < 0.001), and bone erosions using Larsen's score (P = 0.026), in addition to serum level of C-terminal telopeptide of type I collagen (P = 0.023). No correlations were detected between serum level of IL-33 and osteocalcin, 25(OH) D3, or bone mineral density.ConclusionHigh serum level of IL-33 in patients with RA was found to be positively correlated with disease activity, bone erosions, and marker of bone resorption, suggesting its possible role in local and generalized bone loss in this disease, but larger studies are needed to ensure this effect.

Prospective Study Evaluating Changes in Bone Quality in Premenopausal Women With Breast Cancer Undergoing Adjuvant Chemotherapy

BackgroundOvarian suppression from chemotherapy results in bone loss in premenopausal women with breast cancer (BC). Less is known about bone microarchitecture changes. We used high-resolution peripheral quantitative computed tomography (HR-pQCT) to measure volumetric bone density and trabecular and cortical microarchitecture in this population. Materials and MethodsThe primary endpoint was to assess changes in cortical thickness and trabecular bone density by HR-pQCT. Premenopausal women with stage I to III BC undergoing adjuvant chemotherapy underwent a bone mineral density (BMD) dual energy x-ray absorptiometry scan and HR-pQCT (voxel size, 82 microns) at baseline and 12 months. Paired t tests were used to observe the change over time in bone microarchitecture and areal and volumetric density. ResultsEighteen patients were evaluated, of which 12 patients had baseline and matched 12-month imaging. The mean age was 45.2 years (range, 35-51 years), 17 (94%) patients had hormone receptor-positive BC, and 16 (89%) initiated tamoxifen. At 12 months, there was a significant decrease in femoral neck (P < .05) and lumbar spine and total hip (P < .01) BMD. Changes detected by HR-pQCT at 12 months included significant decreases in cortical thickness and area at the tibia (P < .05), and total and cortical volumetric BMD at the radius and tibia (P < .01), as well as an increase in tibial trabecular area (P < .05). ConclusionPremenopausal women undergoing chemotherapy experience BMD decline and trabecular and cortical bone microarchitecture deterioration. In this population, future efforts should focus on therapy-induced bone loss and optimizing bone density-related management.

A Randomized Controlled Trial of Exercise to Prevent Bone Loss in Premenopausal Women with Breast Cancer.

Premenopausal women (n = 206) age ≤ 55 years at cancer diagnosis who were within two years of receiving adjuvant chemotherapy were randomized to a 12-month exercise program or a control group. BMD was measured by dual-energy X-ray absorptiometry at baseline and after 1 year; blood was drawn for skeletal markers. Change from baseline to end of study was compared within and between treatment groups using paired and unpaired t-tests. Lumbar spine BMD declined in both treatment groups with no significant difference between treatment groups (-0.008 ± 0.003 g/cm2 exercise vs. -0.014 ± 0.003 g/cm2 control, p = 0.24). However, among the women who did not lose lean mass during the study (n = 100, 54 control, 46 exercise), the exercise intervention prevented lumbar spine bone loss (0.001 ± 0.005 g/cm2 treatment group vs. -0.014 ± 0.005 g/cm2 control group, p = 0.03). Bone turnover markers decreased significantly in both groups with no differences between groups. Among women who maintained lean mass, our exercise intervention prevented bone loss; however, our intervention did not prevent bone loss among women who lost muscle mass. Additional investigation into exercise regimens that can prevent both bone and muscle loss may help prevent long-term consequences of premenopausal breast cancer treatment.

Atrophic Gastritis as a Risk Factor for Bone Loss in Premenopausal Women in Their 40s: A Retrospective Cohort Study

This study assessed the effects of atrophic gastritis on bone mineral density (BMD) in premenopausal women in their 40s. We performed a retrospective analysis of medical records of premenopausal women in their 40s who underwent a health checkup, esophagogastroduodenoscopy, and bone densitometry at least thrice, 24months apart, between January 2006 and December 2016. Based on first-visit esophagogastroduodenoscopy results, patients were divided into atrophic and non-atrophic gastritis groups; BMD changes over time were analyzed. Patients were further divided into subgroups depending on atrophic gastritis persistence; differences and absolute changes in BMD were assessed. BMD in both groups exhibited group-by-time interaction (p < 0.001). After adjusting for confounding factors, the mean BMD was significantly different at the 24-month and the 48-month follow-up (p = 0.049, p < 0.001, respectively). Subgroup analysis after adjusting for confounding factors showed a mean BMD of 1.128 and 1.104 at baseline, 1.110 and 1.100 at the 24-month follow-up, and 1.106 and 1.065 at the 48-month follow-up for persistent atrophic and non-atrophic gastritis groups, respectively. The difference between mean BMD was not significant at baseline (p = 0.171), but was significant at the 24-month and 48-month follow-ups (p = 0.044 and p < 0.001, respectively). Absolute changes in BMD over 48months were - 0.010 and - 0.051 for the two subgroups, which was significantly different (p < 0.001). Atrophic gastritis reduces BMD in premenopausal women in their 40s. Patients with atrophic gastritis exhibited lower BMD than patients without, and patients with persistent atrophic gastritis exhibited a greater decrease in BMD.

Prevention of breast cancer treatment-induced bone loss in premenopausal women treated with zoledronic acid: Final 5-year results from the randomized, double-blind, placebo-controlled ProBONE II trial.

Premenopausal women receiving chemotherapy or endocrine treatment for early breast cancer are at increased risk for cancer treatment induced bone loss (CTIBL). The aim of the randomized, double-blind ProBONE II trial was to investigate whether a 2-year adjuvant treatment with 4 mg intravenous zoledronic acid (ZOL) every 3 months versus placebo would prevent CTIBL after a five-year period. Thirty-one of the 34 participants in the ZOL arm and thirty-four of the 36 participants in the placebo arm were followed-up to the 5-year visit and completed the study as planned. The changes in Bone Mass Density (BMD) were assessed at baseline and each visit after treatment initiation. After 24 months, BMD at the lumbar spine showed a 2.9% increase in patients treated with ZOL vs. a 7.1% decrease in placebo-treated participants compared to baseline (p < 0.001). Over the 60-month study period, we found a decrease of 2.2% vs. 7.3% in the BMD at the lumbar spine in patients receiving ZOL and placebo respectively (p < 0.001). Over the 60-month study period, BMD in the placebo arm showed a continuous decrease at all sites (p < 0001), whereas patients treated with ZOL reached baseline BMD-values at the femoral neck and total hip. In ProBone II, a 2-year treatment with ZOL 4 mg intravenous every 3 months prevented cancer treatment induced bone loss in premenopausal women with breast cancer and maintained the BMD up to 3 years post-treatment.

Is drug-induced bone loss acceptable in premenopausal women? A practical fracture risk modeling exercise.

It is logical that drug-induced loss of bone mass and microarchitecture in young adults increase fracture risk later in life. However, no existing data quantify how drug-induced bone loss in younger adults impacts fracture risk later in life. As such, no guidance exists to address the question "How much, if any, drug-induced bone loss in premenopausal women is acceptable?" Thus, we performed a systematic fracture risk modeling exercise examining various degrees of bone loss, and estimated the impact on 10-year major osteoporosis-related fracture risk later in life. The FRAX® tool was used in conjunction with BMD and trabecular bone score (TBS) adjustment to estimate major osteoporotic fracture probability later in life resulting from varying degrees of hypothetical premenopausal drug-induced BMD and TBS loss. The resulting 10-year fracture probabilities were assessed against the US and the UK treatment guidance to determine the amount of premenopausal BMD and TBS loss that would result in a recommendation to initiate medical treatment to reduce fracture risk later in life that would not otherwise have been recommended in the absence of premenopausal bone loss. For women whose peak bone mass is between the 5th and 50th percentiles, varying degrees of BMD and TBS loss could be tolerated without reaching treatment thresholds. The degree of tolerable bone loss was primarily dependent on baseline bone status. Those whose peak BMD and TBS are in the 50th percentile or above could tolerate a 10% reduction in BMD and TBS without reaching treatment thresholds by age 75, whereas those in the 5th percentile would reach treatment thresholds by age 75 with no drug-induced reduction in BMD or TBS. Women in the 25th percentile could tolerate a 4% BMD loss and 2% TBS decline without reaching treatment thresholds by age 75. For clinicians and regulatory bodies to assess the consequence of drug-induced premenopausal bone loss, we propose an individualized approach considering both loss of BMD and TBS in concert with baseline bone status and the resultant effect on fracture risk in later life using the assumption that such losses are irreversible.

Skeletal and Uterotrophic Effects of Endoxifen in Female Rats.

Endoxifen, the primary active metabolite of tamoxifen, is currently being investigated as a novel endocrine therapy for the treatment of breast cancer. Tamoxifen is a selective estrogen receptor modulator that elicits potent anti-breast cancer effects. However, long-term use of tamoxifen also induces bone loss in premenopausal women and is associated with an increased risk of endometrial cancer in postmenopausal women. For these reasons, we have used a rat model system to comprehensively characterize the impact of endoxifen on the skeleton and uterus. Our results demonstrate that endoxifen elicits beneficial effects on bone in ovary-intact rats and protects against bone loss following ovariectomy. Endoxifen is also shown to reduce bone turnover in both ovary-intact and ovariectomized rats at the cellular and biochemical levels. With regard to the uterus, endoxifen decreased uterine weight but maintained luminal epithelial cell height in ovariectomized animals. Within luminal epithelial cells, endoxifen resulted in differential effects on the expression levels of estrogen receptors α and β as well as multiple other genes previously implicated in regulating epithelial cell proliferation and hypertrophy. These studies analyze the impact of extended endoxifen exposure on both bone and uterus using a Food and Drug Administration-recommended animal model. Although endoxifen is a more potent breast cancer agent than tamoxifen, the results of the present study demonstrate that endoxifen does not induce bone loss in ovary-intact rats and that it elicits partial agonistic effects on the uterus and skeleton in ovariectomized animals.

Exercise for improving bone health in women treated for stages I-III breast cancer: a systematic review and meta-analyses.

The purpose of this study was to evaluate the efficacy of exercise, either alone or in combination with other interventions, compared to a control, for the preservation of bone mineral density (BMD) in early breast cancer (BC) patients. A systematic search was conducted to identify randomized or quasi-randomized trials which met inclusion criteria including prescribed exercise for ≥12months. Ten publications from seven randomized controlled trials (RCTs), involving 1199 participants, were identified. Data on primary and secondary outcome measures related to BMD at the lumbar spine, total hip, femoral neck and greater trochanter were analysed. Meta-analyses were limited to subgroups by menopausal status as other data could not be pooled. Based on mean differences or mean percentage differences between groups at 1year, exercise did not preserve BMD or bone mineral content at any site in post-menopausal women. In contrast, evidence from one RCT (n=498) found that exercise reduced bone loss in pre-menopausal women at the femoral neck [% MD=1.20 (95% CI 0.22-2.18); P=0.02] but not at the lumbar spine. Although this review indicated that exercise may result in a clinically important preservation of bone health among pre-menopausal but not post-menopausal women, further studies are needed to confirm whether or not exercise is important in preservation of bone health in women diagnosed with early BC. Exercise alone may not be sufficient to prevent bone loss in post-menopausal women at high risk of osteoporosis. Further evidence is required to determine if it provides any benefit to pharmacological therapy.

Bone remodeling markers predict bone loss in premenopausal women

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Abstract P5-11-05: Examining bone degeneration as a side effect of treatment in premenopausal breast cancer patients

Abstract Background: Although it is widely known that adjuvant treatments cause osteoporosis in postmenopausal women, the effect of treatment and the exact degree of bone loss in premenopausal women is not well understood. For this reason, this study examined the relationship between the changes of bone mineral density(BMD) and the types of treatment in premenopausal breast cancer patients. Method: This retrospective study looks at preoperative and annual spine bone densitometry tests conducted on breast cancer patients during their observational period following initial treatment for their diagnosis. 461 premenopausal patients who received treatment from January 2006 to April 2007 were the study cohort because of the availability of bone mineral density (BMD) data (L-spine and femur T scores) for a two-year period. The data from the patients were separated into groups according to their treatment plans: observation, adjuvant chemotherapy, adjuvant chemotherapy followed by use of Tamoxifen, and GnRHa(Gonadotropin Releasing Hormone agonist) followed by Tamoxifen. Results: Of the 461 patients, 21 received no treatment aside from surgery, 75 received only Tamoxifen, 34 only chemotherapy, 166 chemotherapy and Tamoxifen, and 165 Zoladex and Tamoxifen. The no treatment group demonstrates the standard annual change in BMD. At first year, the chemotherapy only group and tamoxifen after chemotherapy group showed significant bone loss in the first year (p&amp;lt;0.005, both). The patients who received tamoxifen alone or tamoxifen with goserelin showed decrease BMD but not significant. After 2 years, tamoxifen with goserelin group showed significant decreased BMD in both spine and femur (p&amp;lt;0.001, p=0.001, both). Chemotherapy group showed partial recovery from the first year bone loss. Conclusion: The patients who received chemotherapy or GnRHa as treatment showed the greatest degree of bone degeneration but at different periods. However, Tamoxifen used along with these treatments seemed to lessen the extent of bone degeneration. Significant bone loss from hormone treatment occurred two years after surgery as compared to one year for chemotherapy. Citation Format: Kim M, Kim HJ. Examining bone degeneration as a side effect of treatment in premenopausal breast cancer patients [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-11-05.

FSH Levels Predict Bone Loss in Premenopausal Women Treated for Breast Cancer More Than One Year After Treatment

Biomarkers to predict bone loss in premenopausal women after breast cancer treatment have not been examined. To determine whether baseline FSH predicts subsequent bone loss. Secondary data analysis of the Exercise for Bone Health: Young Breast Cancer Survivors study, in which women were randomized to a 12-month exercise program or monthly health newsletter. Community dwelling women. A total of 206 women age less than or equal to 55 years at breast cancer diagnosis who had received adjuvant chemotherapy and were at least 1 year after diagnosis. Serum collected at baseline (an average of 302 ± 148 d after completing chemotherapy) was analyzed for FSH. Change in bone mineral density. In linear regression models, baseline FSH levels predicted bone loss over the ensuing 12 months at the lumbar spine and femoral neck including after adjustment for age, ethnicity, treatment group (exercise vs control), baseline bone density, and high-sensitivity C-reactive protein (P < .001). In multiply adjusted models, the 12-month rate of change in bone density was +0.007% in the lowest tertile of FSH (FSH = 9 ± 7 IU/L, mean ± SD), -0.96% in the middle tertile (mean FSH = 41 ± 11 IU/L), and -2.2% in the highest tertile (mean FSH = 86 ± 19 IU/L), P for trend <.001. Among premenopausal women with breast cancer treated with chemotherapy, baseline FSH levels are strongly associated with subsequent bone loss. Further studies are needed to establish the optimal timing of FSH measurement in relation to breast cancer treatment and to investigate potential strategies to prevent bone loss.

Premenopausal osteoporosis

Osteoporosis has traditionally been considered a disorder of postmenopausal women, but low bone mass and accelerated bone loss can also occur early in life causing premenopausal osteoporosis. There are a few risk factors that increase a woman's risk of premenopausal osteoporosis, including drugs, hormonal and nutritional factors, and physical in-activity, which need to be identified and managed accordingly. Lifestyle modification is of importance in preventing progressive bone loss in premenopausal women and should be actively encouraged.

Metformin- A Promising Agent for Chemoprevention in BRCA1 Carriers

Women who carry germline mutations in the BRCA1 gene (BRCA1 carriers) have the highest individual lifetime risk for breast cancer (BCa) known [1-3], with 50% of carriers developing breast cancer by age 50. BRCA2 carriers also have a higher risk but relatively lower than BRCA1 carriers. Currently available options for both BRCA1 and BRCA2 carriers include high-risk surveillance, risk reducing mastectomy or chemoprevention with the ant-estrogens Tamoxifen (TAM) and Raloxifene. Chemoprevention has been controversial in that BRCA1 carriers tend to make estrogen receptor negative tumors. Selective estrogen receptor modulators (SERMs) such as tamoxifen and raloxifene reduce the risk of estrogen receptor positive breast cancers. For example, results from the National Surgical Adjuvant Breast and Bowel Project (NSABP1) Tamoxifen chemoprevention study suggested that TAM is not effective in carriers of a BRCA1 mutation [4]. Regardless, there is conflicting evidence on this point and both TAM and Raloxifene are offered to BRCA1 carriers as well as BRCA2 carriers [5]. As a chemoprotective agent in the general population, Raloxifene shows a similar reduction in risk for invasive breast cancer to TAM, but not for in situ cancers, which comprise >20% of newly diagnosed cases; the incidence of noninvasive breast cancer is approximately 40% lower for women on TAM compared with Raloxifene [6,7]. Both TAM and Raloxifene are effective only against estrogen receptor-positive tumors [8], and Raloxifene is typically only prescribed in women who are postmenopausal and have decreased bone density [9]. Both drugs increase risk for serious side effects, including venous thrombosis and pulmonary embolism [10,11]. TAM is also associated with an increased risk for endometrial cancer and stroke [12-14]. Other side effects of both drugs include dyspareunia, cataracts, musculoskeletal complaints including leg cramps, weight gain, hot flashes, vaginal discharge, bone loss in premenopausal women and bladder control problems [15]. More recently, long-term administration of TAM was observed to cause hepatic tumors in rats, induced via a genotoxic mechanism [16]. Compounding the unfavorable side affect profile studies have determined that approximately 5 – 10% of the population carries a homozygous variant of the CYP2D6 gene that imparts low activity to convert TAM from its less active form to its active metabolite [17]. This research led the FDA to require a change in the labeling of Tamoxifen to include this information [18]. Concerns about the risk: benefit ratio have thus limited the use of TAM for prevention. Recent evidence suggests that only approximately 8.4% of BRCA carriers who have not undergone prophylactic mastectomy and are eligible to take Tamoxifen or Raloxifene [19], for risk reduction do so [20]. Certainly, there is an urgent need to identify other agents for breast cancer prevention in this high-risk group. In fact, data from our own Inherited Cancer Registry (ICARE) at Moffitt indicated that of 253 female BRCA1 and BRCA2 mutation carriers, 127 had remaining at risk breast tissue (including 40 with a prior breast cancer diagnosis). Of these women, 18.1% indicated that they had taken either TAM or Raloxifene (including 7/60 (11.7%) of BRCA1 carriers and 16/67 (23.9%) of BRCA2 carriers. Consequently, the poor uptake of existing breast cancer prevention options, which appears to be more marked in those with BRCA1 compared to BRCA2, serves to illustrate the urgent need to identify other agents for breast cancer prevention in this high-risk group.

Normal vitamin D and low free estradiol levels in women on enzyme-inducing antiepileptic drugs

Relationships between reproductive hormone levels, bone turnover marker levels, bone mineral density, and rates of bone loss were evaluated in premenopausal women with epilepsy taking enzyme-inducing antiepileptic drugs (EIAEDs: phenytoin or carbamazepine) or lamotrigine. Calciotropic and reproductive hormone levels, bone turnover marker levels, and bone mineral density were measured at baseline and 1year. Bone mineral density did not differ between groups. Serum calcium (P<0.001) and estrone (P<0.001) levels were lower in the EIAED group. Sex hormone-binding globulin levels were higher (P<0.001) and percentage free estradiol levels were lower (P<0.001) in the EIAED group. We detected no relationship between bone mineral density change and calciotropic hormone or bone turnover marker levels. Women with higher sex hormone-binding globulin and lower free estradiol levels sustained more bone loss at the total hip (P=0.04 and P=0.02) and a trend toward more bone loss at the lumbar spine (P=0.07 and P=0.08). These findings suggest that lower estrogen levels may contribute to bone loss in premenopausal women with epilepsy.

Zoledronic acid preserves bone mineral density in premenopausal women who develop ovarian failure due to adjuvant chemotherapy: Final results from CALGB trial 79809

Background Chemotherapy-induced ovarian failure (CIOF) is a frequent side-effect of adjuvant chemotherapy that results in rapid bone loss. We hypothesised that zoledronic acid (ZA), a third-generation amino bisphosphonate, would prevent bone loss in premenopausal women who developed CIOF. Methods Women (439) were randomised to intravenous (i.v.) ZA 4 mg every 3 months for 2 years starting within 1–3 months after randomization (arm A) or 1 year after randomization (arm B, controls). CIOF was prospectively defined as ⩾3 months of amenorrhoea, follicle-stimulating hormone (FSH) ⩾30 MIU/ml and non-pregnant at 1 year. The primary end-point was the percentage change in bone mineral density (BMD) in the lumbar spine (LS) from baseline to 12 months in the ZA and in control groups in women who developed CIOF; the secondary end-point was BMD in LS at 3 years in all randomised women. Findings One hundred and fifty (56%) met the definition of CIOF at 1 year. Overall, grade 3 toxicities of ZA were fatigue (1%) arthralgias (21%) and pain (84%). The median percent change (interquartile range, IQR) at 1 year was +1.2% (−0.5% to +2.8%) and −6.7% (−9.7% to −2.9%) p < 0.001 and at 3 years was +1.0% (−1.6% to +5.2%) and −0.5% (−3.7% to +3.2%) p = 0.019 in arms A and B, respectively. Interpretation ZA every 3 months is well tolerated and prevents rapid bone loss in premenopausal women that develop CIOF. Giving ZA with rather than 1 year after the start of adjuvant chemotherapy is the preferred sequence to prevent bone loss.

Zoledronic acid prevents bone loss in premenopausal women with early breast cancer undergoing adjuvant chemotherapy: a phase III trial of the Korean Cancer Study Group (KCSG-BR06-01)

To determine whether zoledronic acid (ZA) can prevent bone loss in premenopausal women undergoing adjuvant chemotherapy for breast cancer. In this randomized, open-label, phase III multicenter trial, premenopausal women >40 years were randomly assigned to ZA treatment (4 mg IV, every 6 months) or observation after surgery. All patients were treated with four cycles of AC followed by four cycles of taxane. Between March 2007 and May 2008, we assessed a total of 112 premenopausal women, all of whom developed amenorrhea at 1 year after chemotherapy. The mean percent change of BMD in the lumbar spine (LS) was -1.1% in the ZA group versus -7.5% in observation group at 12 months. Differences in percent change of BMD from baseline between the two groups were 6.4% for the LS, and 3.6% for the femoral neck. The mean levels of bone turnover at 12 months were significantly lower in the ZA group. ZA was generally well tolerated. Infusion of ZA 4 mg every 6 months effectively prevented bone loss within the first year in premenopausal women receiving adjuvant chemotherapy for early breast cancer. Regular BMD measurements and early bisphosphonate therapy should be considered in these patients.