Risk of complete atypical femur fracture with Oral bisphosphonate exposure beyond three years.

BACKGROUND: Bisphosphonate (BP) therapy has been associated with atypical femur fracture (AFF). However, the threshold of treatment duration leading to increased AFF risk is unclear. In a retrospective cohort of older women initiating BP, we compared the AFF risk associated with treatment for at least three years to the risk associated with treatment less than three years. METHODS: We used observational data from a large population of female members of an integrated healthcare system who initiated oral BP during 2002-2014. Women were retrospectively followed for incident AFF confirmed by radiologic adjudication. Demographic data, pharmacologic exposures, comorbidity, bone density, and fracture history were ascertained from electronic health records. Inverse probability weighting was used to estimate risk differences comparing the cumulative incidence (risk) of AFF if women discontinued BP within three years to the cumulative incidence of AFF if women continued BP for three or more years, adjusting for potential time-dependent confounding by the aforementioned factors. RESULTS: Among 87,820 women age 45-84 years who initiated BP (mean age 68.6, median T-score - 2.6, 14% with prior major osteoporotic fracture), 16,180 continued BP for three or more years. Forty-six confirmed AFFs occurred during follow-up in the two groups. AFF-free survival was greater for BP treatment < 3 years compared to treatment ≥3 years (p = 0.004 comparing areas under survival curves). At five years, the risk of AFF was 27 per 100,000 (95% confidence interval, CI: 8-46) if women received BP treatment < 3 years and 120 per 100,000 (95% CI: 56-183) if women received BP treatment ≥3 years (risk difference 93 per 100,000, 95% CI: 30-160). By ten years, the risks were 27 (95% CI: 8-46) and 363 (95% CI: 132-593) per 100,000 for BP treatment < 3 and ≥ 3 years, respectively (risk difference 336 per 100,000, 95% CI: 110-570). CONCLUSIONS: Bisphosphonate treatment for 3 or more years was associated with greater risk of AFF than treatment for less than 3 years. Although AFFs are uncommon among BP-treated women, this increased risk should be considered when counseling women about long-term BP use. Future studies should further characterize the dose-response relationship between BP duration and incident AFF and identify patients at highest risk.

Validation of FRC, a fracture risk assessment tool, in a cohort of older men: the Osteoporotic Fractures in Men (MrOS) Study.

We evaluated the performance of the Fracture Risk Calculator (FRC) in 5893 men who participated in the baseline visit (March 2000-April 2002) of the Osteoporotic Fractures in Men Study. FRC estimates for 10-yr hip and major osteoporotic (hip, clinical spine, forearm, and shoulder) fractures were calculated and compared with observed 10-yr fracture probabilities. Possible enhancement of the tool's performance when bone mineral density (BMD) was included was evaluated by comparing areas under receiver operating characteristic curves and by Net Reclassification Improvement (NRI). A total of 5893 men were followed-up for an average of 8.4 yr. For most quintiles of predicted fracture risk, the ratios of observed to predicted probabilities were close to unity. Area under the curves improved when BMD was included (p<0.001; 0.79 vs 0.71 for hip fracture and 0.70 vs 0.66 for major osteoporotic fracture, respectively). Using National Osteoporosis Foundation clinical treatment thresholds, BMD inclusion increased NRI significantly, 8.5% (p<0.01) for hip and 4.0% (p=0.01) for major osteoporotic fracture. We conclude that the FRC calibrates well with hip and major osteoporotic fractures observed among older men. Further, addition of BMD to the fracture risk calculation improves the tool's performance.

The effects of tibolone in older postmenopausal women.

BACKGROUND: Tibolone has estrogenic, progestogenic, and androgenic effects. Although tibolone prevents bone loss, its effects on fractures, breast cancer, and cardiovascular disease are uncertain. METHODS: In this randomized study, we assigned 4538 women, who were between the ages of 60 and 85 years and had a bone mineral density T score of -2.5 or less at the hip or spine or a T score of -2.0 or less and radiologic evidence of a vertebral fracture, to receive once-daily tibolone (at a dose of 1.25 mg) or placebo. Annual spine radiographs were used to assess for vertebral fracture. Rates of cardiovascular events and breast cancer were adjudicated by expert panels. RESULTS: During a median of 34 months of treatment, the tibolone group, as compared with the placebo group, had a decreased risk of vertebral fracture, with 70 cases versus 126 cases per 1000 person-years (relative hazard, 0.55; 95% confidence interval [CI], 0.41 to 0.74; P<0.001), and a decreased risk of nonvertebral fracture, with 122 cases versus 166 cases per 1000 person-years (relative hazard, 0.74; 95% CI, 0.58 to 0.93; P=0.01). The tibolone group also had a decreased risk of invasive breast cancer (relative hazard, 0.32; 95% CI, 0.13 to 0.80; P=0.02) and colon cancer (relative hazard, 0.31; 95% CI, 0.10 to 0.96; P=0.04). However, the tibolone group had an increased risk of stroke (relative hazard, 2.19; 95% CI, 1.14 to 4.23; P=0.02), for which the study was stopped in February 2006 at the recommendation of the data and safety monitoring board. There were no significant differences in the risk of either coronary heart disease or venous thromboembolism between the two groups. CONCLUSIONS: Tibolone reduced the risk of fracture and breast cancer and possibly colon cancer but increased the risk of stroke in older women with osteoporosis. (ClinicalTrials.gov number, NCT00519857.)

Methods for assessing fracture risk prediction models: experience with FRAX in a large integrated health care delivery system.

Area under the receiver operating characteristics (AUROC) curve is often used to evaluate risk models. However, reclassification tests provide an alternative assessment of model performance. We performed both evaluations on results from FRAX (World Health Organization Collaborating Centre for Metabolic Bone Diseases, University of Sheffield, UK), a fracture risk tool, using Kaiser Permanente Northern California women older than 50yr with bone mineral density (BMD) measured during 1997-2003. We compared FRAX performance with and without BMD in the model. Among 94,489 women with mean follow-up of 6.6yr, 1579 (1.7%) sustained a hip fracture. Overall, AUROCs were 0.83 and 0.84 for FRAX without and with BMD, suggesting that BMD did not contribute to model performance. AUROC decreased with increasing age, and BMD contributed significantly to higher AUROC among those aged 70yr and older. Using an 81% sensitivity threshold (optimum level from receiver operating characteristic curve, corresponding to 1.2% cutoff), 35% of those categorized above were reassigned below when BMD was added. In contrast, only 10% of those categorized below were reassigned to the higher risk category when BMD was added. The net reclassification improvement was 5.5% (p<0.01). Two versions of this risk tool have similar AUROCs, but alternative assessments indicate that addition of BMD improves performance. Multiple methods should be used to evaluate risk tool performance with less reliance on AUROC alone.

Variation in fracture risk estimation among East Asian women.

OBJECTIVES: Bone mineral density (BMD) testing and fracture risk calculation help clinicians assess fracture risk and counsel patients. However, predicted fracture risks and outcomes for US East Asian individuals remain understudied. STUDY DESIGN: Retrospective cohort study. METHODS: Using standardized clinical profiles for East Asian women aged 70 years, fracture probabilities were estimated using the US Fracture Risk Assessment Tool (FRAX) version 4.1 and corresponding FRAX tools for East Asian countries. Next, clinical and BMD data from 3785 US Asian women aged 65 to 74 years were used to estimate 10-year hip fracture risk (US-Asian FRAX-v3.1) in comparison with actual observed 10-year hip fracture risk (Kaplan-Meier product limit estimate). RESULTS: For the same patient profile entered in the US-Asian FRAX and country-specific FRAX, the calculated 10-year hip fracture probability varied. Compared with the US-Asian FRAX calculator, the estimate was 2-fold higher using the Taiwan FRAX and Hong Kong FRAX, somewhat higher using the South Korea FRAX and Japan FRAX, and similar using the China FRAX. Among 3785 US Asian women (mean [SD] age, 69 [3] years), 23 experienced a hip fracture during a median follow-up of 6.8 years. Their observed 10-year hip fracture risk was 1.5% (95% CI, 0.8%-2.7%), and their median (interquartile range) predicted fracture probability (US-Asian FRAX-v3.1) was 1.1% (0.6%-2.0%). CONCLUSIONS: Country-specific FRAX estimates varied between the United States and East Asian countries. For US Asian women, the US FRAX-predicted hip fracture probabilities were in the lower range of observed risk. Although these findings support the use of the US-Asian FRAX for hip fracture risk assessment in US East Asian women, further studies are needed, including the examination of Asian subgroups.

Bone Mineral Density in Older U.S. Filipino, Chinese, Japanese, and White Women.

BACKGROUND/OBJECTIVES: Bone mineral density (BMD) reference data exist for U.S. White, Black, and Hispanic (Mexican American) populations but not for U.S. Asians. Few studies have compared BMD findings among different U.S. Asian ethnicities. DESIGN: Retrospective observational study. SETTING: Large northern California healthcare system. PARTICIPANTS: Asian and White women aged 50 to 79 years with BMD testing from 1998 to 2017 excluding those with estrogen or osteoporosis treatment, recent fracture, or select disorders affecting skeletal health. MEASUREMENTS: Femoral neck (FN)-BMD and height data. METHODS: Differences in FN-BMD were examined by ethnicity and age, comparing Filipino, Chinese, and Japanese women and non-Hispanic White women. Differences in BMD were also examined after adjustment for height. RESULTS: There were 37,224 Asian women (including 11,147 Filipino, 10,648 Chinese, and 2,519 Japanese) and 115,318 non-Hispanic White women. Mean height was similar among the Asian subgroups and about 6 to 8 cm lower than Whites. Mean FN-BMDs differed by less than 3% for Filipino, Chinese, and Japanese and all were lower than Whites, with smaller Asian-White differences among younger women (<3%; ages 50-59) and larger differences among older women (6-8%; ages 65-79). Adjusting FN-BMD for height reduced White-Asian differences by about 30% to 40%. CONCLUSION: Mean FN-BMD and height for Filipino, Chinese, and Japanese women were similar but consistently lower than White women, especially among older women. Although Asian-White BMD differences were substantially attenuated after height adjustment; some differences persisted for older women. Future studies should investigate potential age-cohort effects and the extent to which these BMD differences influence fracture risk and clinical care.

Bisphosphonate Treatment Beyond 5 Years and Hip Fracture Risk in Older Women.

Importance: Clinical trials have demonstrated the antifracture efficacy of bisphosphonate drugs for the first 3 to 5 years of therapy. However, the efficacy of continuing bisphosphonate for as long as 10 years is uncertain. Objective: To examine the association of discontinuing bisphosphonate at study entry, discontinuing at 2 years, and continuing for 5 additional years with the risk of hip fracture among women who had completed 5 years of bisphosphonate treatment at study entry. Design, Setting, and Participants: This cohort study included women who were members of Kaiser Permanente Northern and Southern California, 2 integrated health care delivery systems, and who had initiated oral bisphosphonate and completed 5 years of treatment by January 1, 2002, to September 30, 2014. Data analysis was conducted from January 2018 to August 2020. Exposure: Discontinuation of bisphosphonate at study entry (within a 6-month grace period), discontinuation at 2 years (within a 6-month grace period), and continuation for 5 additional years. Main Outcomes and Measures: The outcome was hip fracture determined by principal hospital discharge diagnoses. Demographic, clinical, and pharmacological data were ascertained from electronic health records. Results: Among 29 685 women (median [interquartile range] age, 71 [64-77] years; 17 778 [60%] non-Hispanic White individuals), 507 incident hip fractures were identified. Compared with bisphosphonate discontinuation at study entry, there were no differences in the cumulative incidence (ie, risk) of hip fracture if women remained on therapy for 2 additional years (5-year risk difference [RD], -2.2 per 1000 individuals; 95% CI, -20.3 to 15.9 per 1000 individuals) or if women continued therapy for 5 additional years (5-year RD, 3.8 per 1000 individuals; 95% CI, -7.4 to 15.0 per 1000 individuals). While 5-year differences in hip fracture risk comparing continuation for 5 additional years with discontinuation at 2 additional years were not statistically significant (5-year RD, 6.0 per 1000 individuals; 95% CI, -9.9 to 22.0 per 1000 individuals), interim hip fracture risk appeared lower if women discontinued after 2 additional years (3-year RD, 2.8 per 1000 individuals; 95% CI, 1.3 to 4.3 per 1000 individuals; 4-year RD, 9.3 per 1000 individuals; 95% CI, 6.3 to 12.3 per 1000 individuals) but not without a 6-month grace period to define discontinuation. Conclusions and Relevance: In this study of women treated with bisphosphonate for 5 years, hip fracture risk did not differ if they discontinued treatment compared with continuing treatment for 5 additional years. If women continued for 2 additional years and then discontinued, their risk appeared lower than continuing for 5 additional years. Discontinuation at other times and fracture rates during intervening years should be further studied.

Determinants of Oral Bisphosphonate Use Beyond 5 Years.

BACKGROUND: Few studies have examined factors that determine bisphosphonate (BP) continuation beyond 5 years in clinical practice. OBJECTIVE: To investigate factors associated with BP continuation among women who completed 5 years of BP therapy. METHODS: Women who received 5 consecutive years of oral BP treatment entered the cohort during 2002-2014 and were followed up to 5 additional years. Multivariable logistic regression was used to evaluate the association of demographic and clinical factors with adherent treatment continuation. RESULTS: The cohort included 19,091 women with a median age of 72 years. Baseline and time-varying factors associated with increased odds of BP continuation after 5 years were (a) most recent bone mineral density (BMD) T-score -2 to -2.4 (OR = 1.31, 95% CI = 1.25-1.38), T-score -2.5 to -2.9 (OR = 1.48, 95% CI = 1.39-1.57), and T-score ≤ -3.0 (OR = 1.57, 95% CI = 1.47-1.68) versus T-scores above -2.0; (b) index date before 2008 (OR =1.35, 95% CI = 1.29-1.41); and (c) diabetes mellitus (OR = 1.08, 95% CI = 1.01-1.16). In contrast, factors associated with decreased odds of BP continuation were (a) recent hip (OR = 0.61, 95% CI = 0.52-0.71) or humerus (OR = 0.79, 95% CI = 0.66-0.94) fracture or fracture other than hip, wrist, spine, or humerus (OR = 0.90, 95% CI = 0.84-0.97); (b) Charlson Comorbidity Index score > 2 (OR = 0.91, 95% CI = 0.84-0.98); (c) history of rheumatoid arthritis (OR = 0.89, 95% CI = 0.80-0.99); (d) Hispanic (OR = 0.89, 95% CI=0.85-0.94) or Asian (OR = 0.90, 95% CI = 0.85-0.94) race/ethnicity; and (e) use of proton pump inhibitors (OR = 0.65, 95% CI = 0.59-0.71). Patient age and fracture before BP initiation were not associated with treatment continuation. CONCLUSIONS: Clinical factors predicting continued BP treatment beyond 5 years include low BMD T-score, absence of recent fracture, and earlier era of treatment. Use of proton pump inhibitors was associated with lower likelihood of BP continuation. Other clinical and demographic factors were also noted to have variable effects on BP treatment continuation. DISCLOSURES: This study was supported by a grant from the National Institute on Aging and National Institute of Arthritis, Musculoskeletal and Skin Diseases at the National Institutes of Health (NIH; R01AG047230, S1). The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH or Kaiser Permanente. Lo has received previous research funding from Amgen and Sanofi, unrelated to the current study. Adams has received previous research funding from Merck, Amgen, Otsuka, and Radius Health, unrelated to the current study. Ettinger has served as an expert witness for Teva Pharmaceuticals, unrelated to the current study. Ott previously attended a scientific advisory meeting for Amgen but declined the honorarium. The other authors have nothing to disclose. These data were presented at the 2018 Annual Meeting of the American Society of Bone and Mineral Research (ASBMR), September 28-October 1, 2018, Montreal, Quebec, Canada.

Using Pharmacy Data and Adherence to Define Long-Term Bisphosphonate Exposure in Women.

BACKGROUND: Assigning drug exposure is a necessary first step in examining bisphosphonate (BP) treatment in observational studies using pharmacy data. OBJECTIVE: To determine whether the choice of adherence level using the proportion of days covered (PDC) affected BP exposure assignment. METHODS: 10,381 female health plan members who initiated oral BP therapy between 2002 and 2010 and had received 5 consecutive years of treatment were identified and subsequently followed up to 5 additional years. In each 90-day interval of follow-up, a woman was considered "on treatment" if she received the drug for more than a predetermined PDC based on pharmacy days supply and "off treatment" if she received the drug for less than that PDC. Women who continued on therapy above the PDC threshold during follow-up were considered continuously on therapy. Women who were off treatment during the first 90-days of follow-up were classified as off therapy and were followed to determine if they remained continuously off treatment. This study evaluated the extent to which varying the PDC threshold (≥ 0.5, ≥ 0.6, and ≥ 0.7) affected the proportion of women classified as "continuously on" or "continuously off" BP during follow-up. RESULTS: Under PDC thresholds of 0.5, 0.6, and 0.7, 48%, 43%, and 36% of women who remained on follow-up were categorized as continuously on treatment at year 2 of follow-up, and 18%, 14%, and 12% were categorized as continuously on treatment by the end of follow-up. Using these same PDC thresholds, 9%, 12%, and 15% of women were categorized as off therapy during the first quarter of follow-up and were highly likely to remain off therapy: 4%, 5%, and 5% were classified as continuously off therapy at year 2, and 4% of women were classified as such by the end of follow-up for all 3 thresholds. CONCLUSIONS: A PDC of 0.6 was chosen as a practical threshold for drug adherence. Varying the PDC to 0.5 or 0.7 resulted in modest changes in the proportions of women considered continuously on BP therapy. DISCLOSURES: This study was supported by a grant from the National Institute of Aging and National Institute of Arthritis, Musculoskeletal and Skin Diseases at the National Institutes of Health (R01AG047230, S1). Lo has received previous research funding from Amgen and Sanofi, outside of the current study. Chandra has received previous research funding from Amgen outside of the current study. Adams has received previous research funding from Merck, Amgen, Otsuka, and Radius Health, outside of the current study. Ott previously attended a scientific advisory meeting for Amgen but declined the honorarium. Ettinger previously served as an expert witness for Teva Pharmaceuticals.

Bone mineral density changes during the menopause transition in a multiethnic cohort of women.

CONTEXT: Rates of bone loss across the menopause transition and factors associated with variation in menopausal bone loss are poorly understood. OBJECTIVE: Our objective was to assess rates of bone loss at each stage of the transition and examine major factors that modify those rates. DESIGN, SETTING, AND PARTICIPANTS: We conducted a longitudinal cohort study of 1902 African-American, Caucasian, Chinese, or Japanese women participating in The Study of Women's Health Across the Nation. Women were pre- or early perimenopausal at baseline. OUTCOME MEASURE: We assessed bone mineral density (BMD) of the lumbar spine and total hip across a maximum of six annual visits. RESULTS: There was little change in BMD during the pre- or early perimenopause. BMD declined substantially in the late perimenopause, with an average loss of 0.018 and 0.010 g/cm2.yr from the spine and hip, respectively (P<0.001 for both). In the postmenopause, rates of loss from the spine and hip were 0.022 and 0.013 g/cm2.yr, respectively (P<0.001 for both). During the late peri- and postmenopause, bone loss was approximately 35-55% slower in women in the top vs. the bottom tertile of body weight. Apparent ethnic differences in rates of spine bone loss were largely explained by differences in body weight. CONCLUSIONS: Bone loss accelerates substantially in the late perimenopause and continues at a similar pace in the first postmenopausal years. Body weight is a major determinant of the rate of menopausal BMD loss, whereas ethnicity, per se, is not. Healthcare providers should consider this information when deciding when to screen women for osteoporosis.

Endometrial effects of tibolone in elderly, osteoporotic women.

OBJECTIVE: To investigate endometrial effects of tibolone administered to postmenopausal women for 3 years. METHODS: Postmenopausal women (N=3,519) aged 60-85 years (mean 68 years) with a uterus and with osteoporosis were randomly assigned to receive tibolone orally, 1.25 mg per day, or identical placebo. We evaluated effects on endometrial thickness in all women, and examined endometrial histology in 635 participants considered to be at increased risk for abnormalities (with unexpected vaginal bleeding or endometrial thickness more than 4 mm). RESULTS: During the first year of study, mean endometrial thickness increased 1 mm in women receiving tibolone (P<.001), but no further increases were noted during the next 2 years. Diagnostic biopsies among 499 women receiving tibolone and 136 who were receiving placebo showed cumulative incidences of endometrial hyperplasia less than 1%. Among the 15% of women whose biopsy showed an endometrial polyp (similar rate in tibolone and placebo), those receiving tibolone were more than twice as likely to show hyperplasia within the polyp. A marginal increase in grade 1 endometrioid adenocarcinoma (P=.06 compared with placebo) was found among women receiving tibolone. Prevalences of vaginal bleeding during the study were 10.8% in the tibolone group and 2.8% in the placebo group (P<.001). CONCLUSION: Tibolone treatment during 3 years minimally increased endometrial thickness, hyperplastic polyps, endometrial carcinoma, and vaginal bleeding.

Continuation of postmenopausal hormone replacement therapy: comparison of cyclic versus continuous combined schedules.

Discontinuation of hormone replacement therapy (HRT) is much more common than what is reported in randomized, double-blind clinical trials. Our purpose in this retrospective study, using a prescription database, was to compare the continuation rate among women who took cyclic combination therapy adding progesterone to estrogen (CYC-PERT) or continuous combined estrogen progestin therapy (CC-PERT). The study subjects were 1,532 women, ≥45 years old, who initially filled index prescriptions for 0.625 mg conjugated estrogens. They were divided into two groups (CYC-PERT = 644, CC-PERT = 888) on the basis of coprescribed medroxyprogesterone. We found that for all women initiating therapy, 35-40% did not return for a refill and 76-81% stopped therapy within 3 years. Those prescribed CC-PERT initially were more likely to stop than those prescribed CYC-PERT (rate ratio [RR] = 1.20; 95% confidence interval [CI] = 1.06-1.35). Adjustments for age, year of starting medication, cost of medication, and prescriber specialty did not affect the difference in discontinuation between the two regimens (RR 1.18, 95% CI = 1.04-1.34). We conclude that the likelihood of women continuing HRT beyond 3 years of initiation is low. Furthermore, compared with CYC-PERT users, those receiving CC-PERT have a slightly higher probability of discontinuation. Efforts should be made to understand why three quarters of women beginning HRT will stop it long before it can provide major long-term benefit.

Long-term postmenopausal estrogen therapy may be associated with increased risk of breast cancer: a cohort study.

Reports of a role of postmenopausal estrogen replacement therapy in the development of breast cancer have been inconsistent. Although many epidemiologic studies have failed to show an association between short-term use of estrogen and breast cancer, there are indications that long-term use may present an increased risk. We undertook a long-term, retrospective cohort study of the incidence of breast cancer in women who had taken long-term estrogen (average 17.2 years), compared to women who had not taken estrogen. Subjects were 454 women born between 1900 and 1915, who were members of a large health maintenance organization in northern California. By the end of 1995, 26 (11.2%) of estrogen users developed breast cancer, as did 9 (4.1%) of the nonusers; the relative risk (RR) for estrogen use was 2.8 [95% confidence interval (95% CI) 1.3-5.9]. Adjustment for age and multiple breast cancer risk factors, including breast cancer surveillance, reduced the RR for estrogen to 2.0 (95% CI 0.9-4.5). We conclude that long-term estrogen use is associated with a substantially increased risk of breast cancer.

Evolution of postmenopausal hormone therapy between 2002 and 2009.

OBJECTIVE: The results of the Women's Health Initiative led to a sharp decline in postmenopausal hormone therapy use. Subsequently, treatment guidelines were revised to recommend hormone therapy at the lowest effective dose for the shortest possible duration. The objective of this analysis was to assess trends in nationwide hormone therapy prescription claims from 2002 to 2009. METHODS: This study was a retrospective database analyses of pharmacy claims from MedImpact Healthcare Systems Inc. Data from women with claims for oral or transdermal hormone therapy were analyzed to assess trends in hormone therapy claims, including route of administration, dose, and physician specialty. RESULTS: By the end of 2002, the total number of hormone therapy claims dropped approximately 30% from 2002 second quarter claims. This trend continued during the next 7 years, and by 2009, hormone therapy claims were reduced by more than 70%. The proportion of low-dose oral claims rose fourfold, whereas the proportion of standard/high-dose claims decreased 30%. The proportion of claims for transdermal formulations more than doubled, and the proportion of claims for low-dose transdermal hormone therapy increased 10-fold. Although reductions in overall claims, routes of administration, and dose categories were similar between physician specialties, obstetrician/ gynecologists prescribed transdermal hormone therapy nearly twice as often as all other types of providers. CONCLUSIONS: Since the publication of the Women's Health Initiative results, there has been a sustained decrease in hormone therapy claims. The proportional use of low-dose oral and transdermal formulations has increased, but as of 2009, claims for these formulations accounted for approximately one in four total hormone therapy claims.

Endogenous estrogen levels and the effects of ultra-low-dose transdermal estradiol therapy on bone turnover and BMD in postmenopausal women.

UNLABELLED: In a randomized controlled trial of a 0.014 mg/d transdermal estradiol patch, serum bone turnover markers decreased to a greater degree in postmenopausal women with lower versus higher endogenous estradiol levels. This suggests that the protective effects of ultra-low-dose estrogen therapy on the postmenopausal skeletal health may depend critically on women's endogenous estrogen levels before treatment. INTRODUCTION: Postmenopausal women with very low or undetectable estradiol levels have lower BMD, increased bone turnover, and increased risk of hip and vertebral fracture. We assessed whether the effects of ultra-low-dose 0.014 mg/d transdermal estradiol (Menostar; Berlex, Montvale, NJ, USA) on bone turnover and BMD are influenced by endogenous estradiol levels. MATERIALS AND METHODS: We analyzed data from postmenopausal women (mean age, 66 yr) randomized to an 0.014-mg/d transdermal estradiol patch or placebo in the ultra-low-dose transdermal estrogen (ULTRA) trial. The free estradiol index (FEI), calculated as the ratio of total estradiol (by mass spectometry) to sex hormone-binding globulin (SHBG; by immunoradiometric assay) x 100, was used to estimate bioavailable estradiol at baseline. Among the 382 women who adhered to >or=80% of study medication, we examined change in serum osteocalcin and bone-specific alkaline phosphatase levels at 12 mo and total hip and lumbar spine BMD at 24 mo in each quintile of FEI. RESULTS: Compared with women in the highest quintile of FEI, those in the lowest quintile of FEI had a 26% greater reduction in bone-specific alkaline phosphatase and 15% greater reduction in osteocalcin in response to ultra-low estradiol treatment (p for trend across quintiles < 0.05). There was a trend toward greater improvement in total hip BMD (p = 0.06) but not spine BMD (p = 0.90) in those with lower versus higher FEI levels. CONCLUSIONS: The beneficial effects of ultra-low-dose 0.014-mg/d transdermal estrogen therapy on skeletal health may depend critically on women's endogenous estrogen levels before treatment.

Tibolone for prevention and treatment of postmenopausal osteoporosis.

Tibolone has been widely accepted as remedy for vasomotor symptoms and for prevention of bone loss. Studies over the past 25 years have documented its effects on bone mineral density in younger and older women. Tibolone reduces bone turnover substantially (about the same amount as hormone therapy). Increases in bone mineral density (BMD) accompany this reduction in bone turnover, but like all other antiresorptive therapies, reduction in fracture risk (i.e. 50%) is always greater than would be predicted from BMD change. Finally, as with hormone therapies, dosage reductions have been prompted by new evidence of low dosage efficacy and concern over dose-related side effects. Solid evidence has now emerged from large, dose-ranging studies that the 1.25mg tibolone dosage is adequate for preservation of BMD and for reduction of fracture risk. Now that fracture efficacy has been added to the list of tibolone's documented bone benefits, physicians must consider this in the overall risks and benefits of its use.

Rationale for use of lower estrogen doses for postmenopausal hormone therapy.

In placebo-controlled clinical trials low dose estrogens have been shown to reduce hot flashes an average of 65%. Low dosage is effective in preventing bone loss in early menopause and both low and ultralow estrogen dosages can prevent bone loss among women many years beyond menopause. Epidemiological studies indicate less risk of cardiovascular disease and venous thromboembolism in women who use low dose estrogens compared to standard dose. Low dosages of estrogens are less likely to produce unacceptable side effects, such as vaginal bleeding or breast tenderness. When prescribing low dosage estrogen, one can safely use less progestogen, either less daily dosage or less frequent cycles. Older women on ultralow estrogen may not require regular progestogen because the endometrium is not stimulated. In conclusion, there is a strong rationale for use of lower estrogen dosage in HT. Low dosage estrogen can relieve vasomotor symptoms and can prevent postmenopausal bone loss. Women taking low dosages of estrogens are less likely to have unacceptable side effects, such as vaginal bleeding or breast tenderness. Moreover, the potential harm caused by standard dosages of estrogen with progestin, including coronary heart disease, venous thromboembolism, stroke, and breast cancer may be mitigated by use of lower estrogen doses that do not require daily or monthly progestin opposition.

Predicting Adherence and Persistence with Oral Bisphosphonate Therapy in an Integrated Health Care Delivery System.

BACKGROUND: Examining drug exposure is essential to pharmacovigilance, especially for bisphosphonate (BP) therapy. OBJECTIVE: To examine differences in 4 measures of oral BP exposure: treatment discontinuation, adherence, persistence, and nonpersistence. METHODS: Among women aged ≥ 50 years who initiated oral BP therapy during 2002-2007 with at least 3 years of health plan membership follow-up, discontinuation was defined by evidence of no further treatment during the study observation period. Among those with at least 2 filled BP prescriptions during the study period, adherence was calculated for each year of follow-up using the (modified) proportion of days covered (mPDC) metric that allows for stockpiling of prescription/refills overlap ≤ 30 days supply. Persistence was quantified by treatment duration, allowing a gap of up to 60 days between prescription/refill days covered. Nonpersistence was quantified by the periods without drugs outside this allowable gap. Multivariable logistic regression was used to compare age and race groups and the relationships of early adherence (adherence during the first year) with subsequent adherence. RESULTS: Among 48,390 women initiating oral BP therapy and followed for 3 years, 26.7% discontinued in year 1, and 14.7% of the remaining 35,456 women discontinued in year 2. Discontinuation rates were slightly higher (29.4%, P < 0.001) for women aged ≥ 75 years and somewhat lower (21.1%, P < 0.001) for Asian women. During the first year, 60.4% of the women achieved an mPDC of ≥ 75%, with demographic differences in adherence similar to that seen for treatment discontinuation. Over the 3 years, the median mPDC levels for BP therapy were 86%, 84%, and 85% in years 1, 2, and 3, respectively, for those receiving treatment. Cumulative persistence was 2.3 years (median, IQR = 1.0-3.0) overall and slightly greater for Asian versus white women and lower for older women. There were 18,174 (42.9%) women with at least 1 period of nonpersistence during 3 years follow-up in excess of the 60-day allowable gap between prescription/refills (median cumulative nonpersistence = 0.65, IQR = 0.30-1.25 years). Women with mPDC ≥ 75% during the first year had a 12-fold and 6-fold increased odds of mPDC ≥ 75% during year 2 and year 3, respectively. CONCLUSIONS: BP discontinuation rates are highest for women during the first year. Among those continuing treatment in subsequent years, adherence rates were relatively stable. Persistence and adherence varied slightly by age and was somewhat higher in Asians, contributing to differences in cumulative BP exposure. We also found evidence that optimal adherence in the first year was highly predictive of optimal adherence in the subsequent 1-2 years. Hence, subgroups of patients receiving oral BP drugs may require different levels of support and monitoring to maximize treatment benefit, especially based on early patterns of use. DISCLOSURES: This study was supported by grants from the Kaiser Permanente Northern California Community Benefit Program and the National Institutes of Health, 1R01AG047230-01A1. The opinions expressed in this publication are solely the responsibility of the authors and do not represent the official views of Kaiser Permanente or the National Institutes of Health. Hui, Yi, and Chandra have received past research funding from Amgen not related to the current study. Adams has received research funding from Amgen, Merck, and Otsuka not related to the current study. Niu has received research funding from Bristol-Myers Squibb not related to the current study. Ettinger has received past legal fees in litigation involving Fosamax. Lo has received past research funding from Amgen and current research funding from Sanofi not related to the current study. The data from this study were presented at the Academy of Managed Care Pharmacy Annual Meeting; April 19-22, 2016; San Francisco, California. Study concept and design were contributed primarily by Hui and Lo, along with Adams, Niu, Yi, and Ettinger. Hui took the lead in data collection, along with Chandra, and data interpretation was performed by Niu, Yi, and Lo, along with the other authors. The manuscript was written by Hui, Adams, and Lo, along with Niu, Yi, and Ettinger, and revised by Ettinger, Hui, Lo, and Niu, along with the other authors.

Trends in bisphosphonate initiation within an integrated healthcare delivery system.

In the setting of changing temporal trends in the management of osteoporosis, we examined how select characteristics of new oral bisphosphonate (BP) initiators changed over time among 94,073 women within a large, integrated healthcare organization during the period 2004 to 2012. In the earlier era (2004-2007), approximately half of women younger than 65 years initiating BP therapy (47%-54%) had osteoporosis by bone mineral density (BMD) criteria, but this proportion increased sharply in the later era (2008-2012), with 55% to 81% having osteoporosis. This trend was not evident in older women (≥65 years). The proportion of younger women with prior fracture increased from 15% in 2008 to 32% in 2012, after remaining relatively stable (10%-15%) during the earlier era. Again, this trend was not observed among older women. Thus, among women younger than 65 years, we observed a marked temporal shift in initiation of BP treatment toward women at high risk (including those with prior fracture and those with osteoporosis by BMD testing) and away from those at lower risk (such as those with osteopenia and/or no prior fracture).