Gonadotrophins or clomiphene citrate in women with normogonadotropic anovulation and CC failure: does the endometrium matter?

STUDY QUESTION: Is endometrial thickness (EMT) a biomarker to select between women who should switch to gonadotropins and those who could continue clomiphene citrate (CC) after six failed ovulatory cycles? SUMMARY ANSWER: Using a cut-off of 7 mm for EMT, we can distinguish between women who are better off switching to gonadotropins and those who could continue CC after six earlier failed ovulatory CC cycles. WHAT IS ALREADY KNOWN: For women with normogonadotropic anovulation, CC has been a long-standing first-line treatment in conjunction with intercourse or intrauterine insemination (IUI). We recently showed that a switch to gonadotropins increases the chance of live birth by 11% in these women over continued treatment with CC after six failed ovulatory cycles, at a cost of €15 258 per additional live birth. It is unclear whether EMT can be used to identify women who can continue on CC with similar live birth rates without the extra costs of gonadotropins. STUDY DESIGN, SIZE, DURATION: Between 8 December 2008 and 16 December 2015, 666 women with CC failure were randomly assigned to receive an additional six cycles with a change to gonadotropins (n = 331) or an additional six cycles continuing with CC (n = 335), both in conjunction with intercourse or IUI. The primary outcome was conception leading to live birth within 8 months after randomisation. EMT was measured mid-cycle before randomisation during their sixth ovulatory CC cycle. The EMT was available in 380 women, of whom 190 were allocated to gonadotropins and 190 were allocated to CC. PARTICIPANTS/MATERIALS, SETTING, METHODS: EMT was determined in the sixth CC cycle prior to randomisation. We tested for interaction of EMT with the treatment effect using logistic regression. We performed a spline analysis to evaluate the association of EMT with chance to pregnancy leading to a live birth in the next cycles and to determine the best cut-off point. On the basis of the resulting cut-off point, we calculated the relative risk and 95% CI of live birth for gonadotropins versus CC at EMT values below and above this cut-off point. Finally, we calculated incremental cost-effectiveness ratios (ICER). MAIN RESULTS AND THE ROLE OF CHANCE: Mid-cycle EMT in the sixth cycle interacted with treatment effect (P < 0.01). Spline analyses showed a cut-off point of 7 mm. There were 162 women (45%) who had an EMT ≤ 7 mm in the sixth ovulatory cycle and 218 women (55%) who had an EMT > 7 mm. Among the women with EMT ≤ 7 mm, gonadotropins resulted in a live birth in 44 of 79 women (56%), while CC resulted in a live birth in 28 of 83 women (34%) (RR 1.57, 95% CI 1.13-2.19). Per additional live birth with gonadotropins, the ICER was €9709 (95% CI: €5117 to €25 302). Among the women with EMT > 7 mm, gonadotropins resulted in a live birth in 53 of 111 women (48%) while CC resulted in a live birth in 52 of 107 women (49%) (RR 0.98, 95% CI 0.75-1.29). LIMITATIONS, REASONS FOR CAUTION: This was a post hoc analysis of a randomised controlled trial (RCT) and therefore mid-cycle EMT measurements before randomisation during their sixth ovulatory CC cycle were not available for all included women. WIDER IMPLICATIONS OF THE FINDINGS: In women with six failed ovulatory cycles on CC and an EMT ≤ 7 mm in the sixth cycle, we advise switching to gonadotropins, since it improves live birth rate over continuing treatment with CC at an extra cost of €9709 to achieve one additional live birth. If the EMT > 7 mm, we advise to continue treatment with CC, since live birth rates are similar to those with gonadotropins, without the extra costs. STUDY FUNDING/COMPETING INTEREST(S): The original MOVIN trial received funding from the Dutch Organization for Health Research and Development (ZonMw number: 80-82310-97-12067). C.B.L.A. reports unrestricted grant support from Merck and Ferring. B.W.M. is supported by a NHMRC Practitioner Fellowship (GNT1082548) and reports consultancy for Merck, ObsEva, IGENOMIX and Guerbet. All other authors have nothing to declare. TRIAL REGISTRATION NUMBER: Netherlands Trial Register, number NTR1449.

Neonatal abstinence syndrome and early childhood morbidity and mortality in Washington state: a retrospective cohort study.

OBJECTIVE: The objective of the study was to evaluate the association between neonatal abstinence syndrome (NAS) and long-term childhood morbidity and infant mortality. STUDY DESIGN: We conducted a cohort study of infants born in Washington State during 1990 to 2008 who were diagnosed with NAS (n=1900) or were unexposed (n=12,283, frequency matched by birth year). 5-year hospital readmissions and infant mortality were ascertained. RESULTS: Children with history of NAS had increased risk of readmission during the first 5 years of life relative to unexposed children; this remained statistically significant after adjustment for maternal age, maternal education, gestational age and intrapartum smoking status (readmission rates: NAS=21.3%, unexposed=12.7%, adjusted relative risk (aRR) 1.54, 95% confidence interval (CI) 1.37 to 1.73). NAS was associated with increased unadjusted infant mortality risk, but this did not persist after adjustment (aRR 1.94, 95% CI 0.99 to 3.80). CONCLUSION: The observed increased risk for childhood hospital readmission following NAS diagnosis argues for development of early childhood interventions to prevent morbidity.Journal of Perinatology advance online publication,.

Endometrial thickness in women undergoing IUI with ovarian stimulation. How thick is too thin? A systematic review and meta-analysis.

STUDY QUESTION: Is pre-ovulatory endometrial thickness (EMT) in women with unexplained subfertility undergoing IUI with ovarian stimulation (OS) associated with pregnancy chances? SUMMARY ANSWER: We found no evidence for an association between EMT and pregnancy chances. WHAT IS KNOWN ALREADY: It has been suggested that OS with clomiphene citrate (CC) results in a lower EMT than with gonadotrophins or aromatase inhibitors, but the clinical consequences in terms of pregnancy are unclear. STUDY DESIGN, SIZE, DURATION: We performed a systematic review and meta-analysis of studies comparing CC, gonadotrophins or aromatase inhibitors in an IUI program reporting on EMT and pregnancy rates in women with unexplained subfertility. PARTICIPANTS/MATERIALS, SETTING, METHODS: We searched MEDLINE, EMBASE and the non-MEDLINE subset of PubMed from inception to 28th June 2016 and cross-checked references of relevant articles. Outcome measures were clinical pregnancy rate and mean pre-ovulatory EMT. We calculated mean differences (MD) with 95% CIs with a fixed effect model, and in case of heterogeneity with an I2 > 50% a random effect model. We performed a meta-regression analysis to determine if stimulating drugs interacted with the estimated effect of EMT. MAIN RESULTS AND THE ROLE OF CHANCE: Our search retrieved 1563 articles of which 23 were included, totaling 3846 women. There were 17 RCTs and 6 cohort studies. The average study quality was low and there was considerable to substantial statistical heterogeneity. Seven studies provided data on EMT in relation to pregnancy. There was no evidence of a difference in EMT between women who conceived and women that did not conceive (1525 women, MDrandom: 0.51 mm, 95% CI: -0.05 to 1.07). Women treated with CC had a significantly thinner EMT than women treated with gonadotrophins (two studies, MD: -0.33, 95% CI: -0.64 to -0.01). There was no evidence of a difference in EMT when comparing CC with letrozole (five studies, MDrandom: -0.84, 95% CI: -1.97 to 0.28). The combination of CC plus gonadotrophins resulted in a slightly thinner endometrium than letrozole (nine studies, MDrandom: -0.79, 95% CI: -1.37 to -0.20). Letrozole resulted in a thinner EMT than gonadotrophins (two studies, MDrandom: -1.31, 95% CI: -2.08 to -0.53). LIMITATIONS, REASONS FOR CAUTION: The overall quality of the included studies was low to moderate. We found considerable to substantial heterogeneity in the comparisons, hampering firm conclusions. WIDER IMPLICATIONS OF THE FINDINGS: We found no evidence for an association between EMT and pregnancy rates during IUI -OS. As a consequence, canceling IUI cycles because of a thin endometrial lining may negatively affect clinical care. Although we found some evidence for very small differences in EMT when comparing various drugs, we cannot make inferences on their effect on pregnancy chances since these differences may be coincidental. STUDY FUNDING/COMPETING INTEREST(S): None. REGISTRATION NUMBER: N/A.

Pneumonia and the incidence of cancer: a Danish nationwide cohort study.

OBJECTIVES: To examine the risk of a subsequent pulmonary or extra-pulmonary cancer diagnosis following a first-time hospital-based diagnosis of pneumonia. DESIGN: Population-based cohort study using Danish medical registries. SETTING: All hospitals in Denmark. SUBJECTS: A total of 342,609 patients with a first-time hospital-based (inpatient, emergency room or outpatient clinic) diagnosis of pneumonia between 1995 and 2011. MAIN OUTCOME MEASURES: We quantified the excess risk of various cancers amongst pneumonia patients compared to the expected risk in the general population, using relative [standardised incidence ratios (SIRs)] and absolute risk calculations. Follow-up started 1 month after a hospital-based diagnosis of pneumonia and ended on 31 December 2011. RESULTS: A total of 28,496 cancers were observed, compared with 21,625 expected, amongst 342,609 pneumonia patients followed for a median of 4.2 years. The absolute risk of a cancer diagnosis 1 to <6 months following a pneumonia diagnosis was 1.4%, with a corresponding SIR of 2.48 [95% confidence interval (CI) 2.41-2.55]. This was mainly due to an increased risk of lung cancer (eightfold) and haematological cancers (fourfold). The SIR for any cancer remained increased at 1.35 (95% CI 1.30-1.40) during 6-12 months of follow-up, and 1.20 (95% CI 1.18-1.22) during 1-5 years of follow-up. Beyond 5 years, an increased risk was maintained for lung, oesophageal, liver and bladder cancers, squamous cell carcinoma of the skin, lymphoma and multiple myeloma. CONCLUSIONS: A hospital-based pneumonia diagnosis was associated with an increased risk of a cancer diagnosis, especially in the ensuing months, but the absolute risk was small.

A screening study of drug-drug interactions in cerivastatin users: an adverse effect of clopidogrel.

An analysis of a case-control study of rhabdomyolysis was conducted to screen for previously unrecognized cytochrome P450 enzyme (CYP) 2C8 inhibitors that may cause other clinically important drug-drug interactions. Medication use in cases of rhabdomyolysis using cerivastatin (n = 72) was compared with that in controls using atorvastatin (n = 287) for the period 1998-2001. The use of clopidogrel was strongly associated with rhabdomyolysis (odds ratio (OR) 29.6; 95% confidence interval (CI), 6.1-143). In a replication effort that used the US Food and Drug Administration (FDA) Adverse Event Reporting System (AERS), it was found that clopidogrel was used more commonly in patients with rhabdomyolysis receiving cerivastatin (17%) than in those receiving atorvastatin (0%, OR infinity; 95% CI = 5.2-infinity). Several medications were tested in vitro for their potential to cause drug-drug interactions. Clopidogrel, rosiglitazone, and montelukast were the most potent inhibitors of cerivastatin metabolism. Clopidogrel and its metabolites also inhibited cerivastatin metabolism in human hepatocytes. These epidemiological and in vitro findings suggest that clopidogrel may cause clinically important, dose-dependent drug-drug interactions with other medications metabolized by CYP2C8.

Lifetime risk of surgical management for pelvic organ prolapse or urinary incontinence.

The objective of our study was to estimate the age-specific incidence and lifetime risk of surgically managed pelvic organ prolapse (POP) and urinary incontinence (UI). Women aged 20 and older who underwent primary surgical management of POP or UI in 1993 were identified from the database of a health maintenance organization using ICD-9 codes and confirmed through chart abstraction. From a population of 147,719 women, 135 were identified who underwent prolapse surgery only, 82 incontinence only, and 34 surgery for both conditions. From the age-specific incidence, we estimated the lifetime risk of undergoing an operation by age 80 to be 11.8%. Our findings agree with a previous estimate that approximately 11% of women will undergo surgery for POP or UI by age 80. POP and UI appear to be common problems, undoubtedly affecting an even larger proportion of the women than suggested by this high cumulative incidence of surgery.

Chronic kidney disease in long-term survivors of hematopoietic cell transplant.

We conducted a cohort study to identify risk factors of chronic kidney disease (CKD) among long-term survivors of hematopoietic cell transplant (HCT). We studied 1635 patients transplanted at the Fred Hutchinson Cancer Research Center (FHCRC) between 1991 and 2002, who survived to day +131 after transplant and had serum creatinine measured on at least two occasions after day +131. CKD was defined as a glomerular filtration rate < 60 ml/min/m(2) on two occasions separated by at least 30 days between days 100 and 540 post transplant. Cox regression models estimated hazard ratios (HRs) describing associations between demographic data, clinical variables and the risk of developing CKD. A total of 376 patients (23%) developed CKD at a median of 191 days post transplant (range 131-516 days). An increased risk of CKD was associated with acute renal failure (ARF) (HR=1.7, 95% confidence interval (CI) 1.3-2.1), acute graft-vs-host disease (aGVHD) grade II (HR=2.0, 95% CI 1.4-2.9) and grades III/IV (HR=3.1, 95% CI 2.1-4.6) and chronic GVHD (HR=1.8, 95% CI 1.4-2.2). Total body irradiation (TBI) (HR=1.0, 95% CI 0.8-1.3) was not associated with an increased risk of CKD. CKD is relatively common among survivors of HCT. The presence of ARF and GVHD, but not receipt of TBI, appears to be associated with the occurrence of CKD.

Serum bilirubin and colorectal cancer risk: a population-based cohort study.

BACKGROUND: Bilirubin has antioxidant properties and has been postulated to protect against the development of malignancies. AIM: To investigate whether baseline serum bilirubin concentration predicts the incidence of colorectal cancer in a nationally representative sample of the US population. METHODS: Participants of the first National Health and Nutrition Examination Survey were divided into four groups based on quartiles of baseline serum bilirubin concentration in mg/dL: <0.38 (n = 1410), 0.38 to <0.5 (n = 1287), 0.5 to <0.6 (n = 1048) and > or = 0.6 (n = 1742). The incidence of colorectal cancer during the following 20 years was determined from hospitalization records and death certificates. RESULTS: 110 cases of colorectal cancer-related death or hospitalization were identified among 5487 participants during 88,339 person-years of follow-up (12 per 10,000 person-years). There was no association between baseline serum bilirubin concentration and the incidence of colorectal cancer either in unadjusted analyses or after adjusting for age, gender, ethnicity, smoking, body mass index, alcohol consumption and educational attainment. CONCLUSIONS: Baseline serum bilirubin concentration did not predict the subsequent incidence of colorectal cancer in this population-based cohort study.

Use of antidepressant medications in relation to the incidence of breast cancer.

Although associations have been reported between antidepressant use and risk of breast cancer, the findings have been inconsistent. We conducted a population-based case-control study among women enrolled in Group Health Cooperative (GHC), a health maintenance organization in Washington State. Women with a first primary breast cancer diagnosed between 1990 and 2001 were identified (N = 2904) and five controls were selected for each case (N = 14396). Information on antidepressant use was ascertained through the GHC pharmacy database and on breast cancer risk factors and screening mammograms from GHC records. Prior to one year before diagnosis of breast cancer, about 20% of cases and controls had used tricyclic antidepressants (adjusted odds ratio = 1.06, 95% CI 0.94-1.19) and 6% of each group had used selective serotonin reuptake inhibitors (OR = 0.98, 95% CI 0.80-1.18). There also were no differences between cases and controls with regard to the number of prescriptions filled or the timing of use. Taken as a whole, the results from this and other studies to date do not indicate an altered risk of breast cancer associated with the use of antidepressants overall, by class, or for individual antidepressants.

A case-control study of endogenous hormones and cervical cancer.

Both parity and oral contraceptive use are associated with elevated circulating levels of sex hormones, at least transiently, and with increased risk of cervical cancer in human papillomavirus (HPV)-infected women. We directly evaluated whether elevations in the physiologic levels of these hormones predispose to the development of cervical neoplasia. We identified 67 premenopausal and 43 postmenopausal women with cervical intraepithelial neoplasia 2, 3, or cervical cancer (>/=CIN2) diagnosed during enrollment of a population-based cohort of 10 077 women. Four controls, two chosen randomly and two chosen from women testing positive for cancer-associated HPV, were matched to each case on menopausal status, age, days since last menses (pre), or years since menopause (post). Sex hormone-binding globulin, oestradiol, oestrone, oestrone-sulphate, dehydroepiandrosterone sulphate, and progesterone were measured in enrollment plasma. There was no consistent association between the sex hormones and risk of >/=CIN2. Excluding cases with invasive disease had a minimal impact on results. Though this case-control study was based on a well-defined population, it was limited by reliance on a single measure of hormone levels taken at the time of diagnosis. Nonetheless, our results do not support the hypothesis that plasma levels of sex hormones have an important bearing on the risk of cervical neoplasia in HPV-infected women.

Recreational physical activity and endometrial cancer risk.

To investigate the association between recreational physical activity and endometrial cancer risk, a population-based case-control study was conducted in Washington State. The study included 822 incident cases of endometrial cancer diagnosed between 1985 and 1991 and 1,111 randomly selected population-based controls. Detailed information on recreational physical activities as well as other endometrial cancer risk factors was obtained in structured, in-person interviews. Unconditional logistic regression, adjusted for age, county, energy intake, unopposed estrogen use, income, and, in separate models, body mass index (kg/m(2)), was used to estimate the odds ratios and their 95% confidence intervals, relating endometrial cancer to each level of physical activity. A greater proportion of controls (49.3%) than cases (40.5%) reported doing regular exercise (compared with no exercise: adjusted odds ratio = 0.62, 95% confidence interval: 0.51, 0.76) in the 2-year period prior to diagnosis date. There was little evidence of a trend of decreasing risk with increasing duration or intensity of recreational physical activities. These results provide support for an association between the lack of recent recreational physical activity and endometrial cancer risk. However, the absence of a difference by duration or intensity levels and the inconsistent results from other studies suggest caution before interpreting this association as causal.

Risk factors for synchronous primary endometrial and ovarian cancers.

PURPOSE: The incidence of synchronous primary endometrial and ovarian cancer is 2- to 10-fold higher than that expected based on the incidence of each cancer alone. We sought to evaluate reasons for this in a case-control study. METHODS: We combined data on a maternal history of cancer and reproductive and menstrual factors from 56 women with synchronous multiple primary disease who had participated in three population-based studies of gynecologic cancer. For comparison, we analyzed the same information from 280 women with endometrial cancer alone, 280 with ovarian cancer alone, and 280 without a history of either cancer. RESULTS: The reduced risk of multiple primary disease associated with high parity (2 or more births vs 0: OR = 0.37, 95% Cl, 0.19-76) and long-term use of oral contraceptives (12 or more months vs none: OR = 0.60, 95% Cl, 0.24-1.5) tended to be more pronounced than that associated with endometrial cancer alone or with ovarian cancer alone. CONCLUSIONS: Though limited by relatively small numbers, our results suggest that the presence of some common etiologies is a basis for the unusually high co-occurrence of endometrial and ovarian cancers.

Colorectal cancer following tamoxifen therapy for breast cancer (United States).

BACKGROUND: An analysis combining data from several clinical trials has raised concern that tamoxifen therapy may increase the risk of a subsequent colorectal malignancy. We conducted a nested case-control study to test this hypothesis. METHODS: A cohort of women diagnosed with breast cancer in 1978-1992 was identified from the western Washington population-based cancer registry. Cases included women who subsequently developed colorectal cancer prior to 1995. Controls were a random sample of the cohort who did not develop a second primary malignancy, matched to cases on age, stage, and year of initial cancer diagnosis. Tamoxifen use was ascertained by medical record abstraction and physician questionnaires. RESULTS: Thirty-six percent of the 122 cases for whom information could be obtained received tamoxifen versus 38% of 194 controls. Relative to non-users and adjusted for receipt of other therapies, there was no increased risk of colorectal cancer associated with tamoxifen use in general (matched odds ratio [mOR] = 0.9, 95% CI 0.6-1.6), longer durations of use (for > or =37 months, mOR = 0.8, 95% CI 0.4-1.9), higher cumulative doses of therapy (for > or =15 g, mOR = 0.8, 95% CI 0.4-1.6), or use that started at least 5 years prior to the end of study follow-up (mOR = 1.1, 95% CI 0.3-3.7). CONCLUSIONS: We found no overall increased risk for colorectal cancer among tamoxifen users.

Risk of recurrent coronary events in relation to use and recent initiation of postmenopausal hormone therapy.

BACKGROUND: The finding from the Heart and Estrogen/Progestin Replacement Study (HERS) of increased coronary risk restricted to the first year after starting postmenopausal hormone therapy raises new questions about the role of hormone therapy in women with coronary heart disease. We assessed the risk of recurrent myocardial infarction or coronary heart disease death associated with the use and recent initiation of hormone therapy in women who survived a first myocardial infarction. METHODS: The setting for this population-based inception cohort study was Group Health Cooperative, a health maintenance organization. We studied 981 postmenopausal women who survived to hospital discharge after their first myocardial infarction between July 1, 1986, and December 31, 1996. We obtained information on hormone use from the Group Health Cooperative computerized pharmacy database and identified recurrent coronary events by medical record review. RESULTS: During median follow-up of 3.5 years, there were 186 recurrent coronary events. There was no difference in the risk of recurrent coronary events between current users of hormone therapy and other women (adjusted relative hazard [RH], 0.96; 95% confidence interval [CI], 0.62-1.50). Relative to the risk in women not currently using hormones, there was a suggestion of increased risk during the first 60 days after starting hormone therapy (RH, 2.16; 95% CI, 0.94-4.95) and reduced risk with current hormone use for longer than 1 year (RH, 0.76; 95% CI, 0.42-1.36). CONCLUSION: These results are consistent with the findings from the HERS, suggesting a transitory increase in coronary risk after starting hormone therapy in women with established coronary heart disease and a decreased risk thereafter.

Tamoxifen therapy for primary breast cancer and risk of contralateral breast cancer.

BACKGROUND: Women diagnosed with breast cancer have a twofold to sixfold greater risk of developing contralateral breast cancer than women in the general population have of developing a first breast cancer. Tamoxifen therapy reduces this risk, but it is unclear if this benefit exists for both estrogen receptor (ER)-positive and ER-negative contralateral tumors. METHODS: Using data from a population-based tumor registry that collects information on the ER status of breast tumors, we followed 8981 women residing in western Washington State who were diagnosed with a primary unilateral invasive breast cancer during the period from 1990 through 1998 to identify cases of contralateral breast cancer. We restricted our analyses to women who were at least 50 years old and whose first breast cancer had a localized or regional stage; women who received adjuvant hormonal therapy but not chemotherapy (n = 4654) were classified as tamoxifen users, while those who received neither adjuvant hormonal therapy nor chemotherapy (n = 4327) were classified as nonusers of tamoxifen. By reviewing selected patient abstracts, we estimated that 94% of the subjects were classified correctly with respect to tamoxifen use. The risk of contralateral breast cancer associated with tamoxifen use was estimated with the use of Cox regression. All statistical tests were two-sided. RESULTS: Of the 89 tamoxifen users and 100 nonusers of tamoxifen diagnosed with contralateral breast cancer, 112 had ER-positive tumors, 20 had ER-negative tumors, and 57 had tumors with an ER status that was unknown or had not been determined by an immunohistochemical assay. The risk of developing an ER-positive and an ER-negative contralateral tumor among tamoxifen users was 0.8 (95% confidence interval [CI] = 0.5 to 1.1) and 4.9 (95% CI = 1.4 to 17.4), respectively, times that of nonusers of tamoxifen. This difference in risk by ER status was statistically significant (P<.0001). CONCLUSIONS: Tamoxifen use appears to decrease the risk of ER-positive contralateral breast tumors, but it appears to increase the risk of ER-negative contralateral tumors.

Bone mineral density and endogenous hormones and risk of breast cancer in postmenopausal women (United States).

OBJECTIVE: This case-cohort study was designed to examine whether total hip bone mineral density (BMD) is independently associated with breast cancer over and above its association with other determinants, including levels of total and bioavailable estradiol and testosterone and sex-hormone binding globulin. METHODS: Our study population was selected from a cohort of 8,203 postmenopausal women who were screened for the Fracture Intervention Trial in 1992, at which time BMD was assessed, and blood samples were obtained. A total of 109 women developed breast cancer during four years of follow-up; 173 other randomly selected women from the larger cohort were also selected. Cox proportional hazards with robust variance adjustment was used for these analyses. RESULTS: Relative to women in the lower fourth of the BMD distribution, the risk associated with being in the upper fourth was 2.6 (95% confidence interval (CI) 1.1-5.8). After adjusting for serum hormone levels, the corresponding relative risk was 2.5 (95% CI 0.9-5.2). With body mass index and number of years since menopause added to the multivariate analysis, the relative risk decreased to 1.4 (95% CI 0.5-4.0). CONCLUSIONS: BMD may not influence breast cancer risk independent of its relationship with endogenous hormones and measured covariates.