Using negative control outcomes to assess the comparability of treatment groups among women with osteoporosis in the United States.

PURPOSE: In contrast to randomized clinical trials, comparative safety and effectiveness assessments of osteoporosis medications in clinical practice may be subject to confounding by indication. We used negative control outcomes to detect residual confounding when comparing osteoporosis medications. METHODS: Using MarketScan Commercial and Supplemental claims, we identified women aged ≥55 years who initiated an oral bisphosphonate (BP) (risedronate, alendronate, or ibandronate), denosumab (an injected biologic), or intravenous zoledronic acid (ZA) from October 1, 2010 to September 30, 2015. Women with Paget's disease or cancer were excluded. We compared individual oral BPs to each other, denosumab to ZA, denosumab to oral BPs, and ZA to oral BPs, with respect to 11 negative control outcomes identified by subject matter experts. We estimated the 12-month cumulative risk difference (RD) using inverse probability of treatment and censoring weights. RESULTS: Among 148 587 women, most initiated alendronate (57%), followed by ibandronate (12%), ZA (11%), risedronate (10%), and denosumab (10%). Compared with denosumab, patients initiating ZA had similar risks of all negative control outcomes. Compared with oral BPs, patients initiating denosumab had a higher risk of a wellness visit (RD = 1.2%, 95% CI: 0.4, 1.9) and a lower risk of receiving herpes zoster vaccine (RD = -0.6%, 95% CI: -1.1, -0.2). Comparing ZA with oral BP initiators resulted in two outcomes with positive associations. CONCLUSIONS: Caution is warranted when comparing injectable vs oral osteoporosis medications, given the potential for unmeasured confounding. Evaluating negative control outcomes could be a standard validity check prior to conducting comparative studies.

Comparative effectiveness of Denosumab vs alendronate among postmenopausal women with osteoporosis.

Although clinical trials have shown that denosumab significantly increases bone mineral density at key skeletal sites more than oral bisphosphonates, evidence is lacking from head-to-head randomized trials evaluating fracture outcomes. This retrospective cohort study uses administrative claims data from Medicare fee-for service beneficiaries to evaluate the comparative effectiveness of denosumab versus alendronate in reducing fracture risk among women with postmenopausal osteoporosis (PMO) in the US. Women with PMO ≥ 66 years of age with no prior history of osteoporosis treatment, who initiated denosumab (n = 89 115) or alendronate (n = 389 536) from 2012 to 2018, were followed from treatment initiation until the first of a specific fracture outcome, treatment discontinuation or switch, end of study (December 31, 2019), or other censoring criteria. A doubly robust inverse-probability of treatment and censoring weighted function was used to estimate the risk ratio associated with the use of denosumab compared with alendronate for hip, nonvertebral (NV; includes hip, humerus, pelvis, radius/ulna, other femur), non-hip nonvertebral (NHNV), hospitalized vertebral (HV), and major osteoporotic (MOP; consisting of NV and HV) fractures. Overall, denosumab reduced the risk of MOP by 39%, hip by 36%, NV by 43%, NHNV by 50%, and HV fractures by 30% compared with alendronate. Denosumab reduced the risk of MOP fractures by 9% at year 1, 12% at year 2, 18% at year 3, and 31% at year 5. An increase in the magnitude of fracture risk reduction with increasing duration of exposure was also observed for other NV fracture outcomes. In this cohort of almost half-a-million treatment-naive women with PMO, we observed clinically significant reductions in the risk of MOP, hip, NV, NHNV, and HV fractures for patients on denosumab compared with alendronate. Patients who remained on denosumab for longer periods of time experienced greater reductions in fracture risk.

Osteoporosis-related fractures can have a significant impact on the health and quality of life of women with postmenopausal osteoporosis (PMO), as well as pose a significant burden to society. Although clinical trials have shown that denosumab is more effective at increasing bone mineral density compared to alendronate, there is a lack of evidence evaluating the fracture risk between these two commonly used osteoporosis therapies. In this study using Medicare claims data for almost 500 000 women with PMO with no prior history of osteoporosis medication use, we compared the risk of fracture, an important outcome to patients and health care providers, between denosumab and alendronate. Advanced analytic methods were implemented to ensure the study results were valid and were not unduly influenced by biases common in observational studies. We observed clinically meaningful reductions (from 30% up to 50%) in the risk of hip, nonvertebral, non-hip nonvertebral, hospitalized vertebral, and major osteoporotic fractures for patients treated with denosumab compared with alendronate. Patients who remained on denosumab for longer periods of time experienced greater reductions in fracture risk than those who remained on alendronate.

Cardiovascular Safety in Postmenopausal Women and Men With Osteoporosis Treated With Denosumab and Zoledronic Acid: A Post-Authorization Safety Study.

Osteoporosis and cardiovascular disease are common in older adults. Treatment of osteoporosis reduces the burden of debilitating fractures; however, it is important to understand the benefit versus risk of treatment. This study evaluates the risk of stroke (ischemic or hemorrhagic) and myocardial infarction (MI) among postmenopausal women and men initiating osteoporosis treatment with denosumab (receptor activator of nuclear factor κB ligand [RANKL] inhibitor) or zoledronic acid (bisphosphonate) between October 2010 and June 2019. A retrospective cohort study employing the new user/active comparator design was conducted. Analyses were conducted separately in two national US commercial databases, MarketScan® and Optum® for reproducibility. Inverse probability of treatment and censoring weighting was employed to control for confounding and informative censoring. Cumulative risks at 6-month, 12-month, and 36-month time points were calculated and adjusted risk ratios and differences (with 95% confidence intervals [CIs]) were estimated. In MarketScan® and Optum® databases, 96,611 and 73,127 patients met all study eligibility criteria, respectively. At 36 months, the risk ratio estimates (zoledronic acid referent group) were 1.22 (95% CI, 0.77-1.66) and 0.97 (95% CI, 0.63-1.32) for MI and 1.00 (95% CI, 0.61-1.40) and 0.87 (95% CI, 0.56-1.17) for stroke in MarketScan and Optum, respectively. Most of the treatment associations across the other time periods and outcomes also had 95% CIs including the null value. In these large samples of real-world US patients, no increased risk in MI and stroke were identified for up to 36 months of treatment in denosumab users compared with zoledronic acid users. © 2023 Amgen. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Comparability of Osteoporosis Treatment Groups Among Female Medicare Beneficiaries in the United States.

It is often difficult to obtain valid estimates of comparative treatment effectiveness and safety owing to differences across patient populations taking different medications in the real world. One approach for assessing comparability between treatment groups in effectiveness studies is to use negative control outcomes (NCOs). NCOs share similar sources of bias with the primary outcomes but have no plausible causal relationship to the treatment of interest. Observing differences in the risk of NCOs thus provides evidence for residual confounding between groups. This retrospective study assessed the comparability of postmenopausal women, treated with osteoporosis medications with various mechanisms of action such as denosumab (receptor activator of nuclear factor κB ligand [RANKL] inhibitor), zoledronic acid (bisphosphonate derivative), or oral bisphosphonates including alendronate. Administrative claims data were extracted from the US Centers for Medicare and Medicaid Services' Chronic Condition Warehouse database (May 2010-December 2016). Propensity scores were used to match denosumab patients 1:1 to comparators. Four nonfracture NCOs and three early fracture NCOs (before substantial biologic effects of treatment would be expected) were assessed over 1-year and 3-month follow-up periods, respectively. According to comparability decision rules established a priori, patients initiating denosumab were comparable to those initiating zoledronic acid or alendronate, irrespective of prior osteoporosis treatment experience. Among new users, new switchers, and in the historical fracture subgroup, no meaningful differences were observed in the cumulative incidence of the seven NCOs comparing denosumab to zoledronic acid. This empirical examination can assist in the selection of appropriate comparator groups for future comparability research using real-world data. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Vitamin D supplementation and depression in the women's health initiative calcium and vitamin D trial.

While observational studies have suggested that vitamin D deficiency increases risk of depression, few clinical trials have tested whether vitamin D supplementation affects the occurrence of depression symptoms. The authors evaluated the impact of daily supplementation with 400 IU of vitamin D(3) combined with 1,000 mg of elemental calcium on measures of depression in a randomized, double-blinded US trial comprising 36,282 postmenopausal women. The Burnam scale and current use of antidepressant medication were used to assess depressive symptoms at randomization (1995-2000). Two years later, women again reported on their antidepressant use, and 2,263 completed a second Burnam scale. After 2 years, women randomized to receive vitamin D and calcium had an odds ratio for experiencing depressive symptoms (Burnam score ≥0.06) of 1.16 (95% confidence interval: 0.86, 1.56) compared with women in the placebo group. Supplementation was not associated with antidepressant use (odds ratio = 1.01, 95% confidence interval: 0.92, 1.12) or continuous depressive symptom score. Results stratified by baseline vitamin D and calcium intake, solar irradiance, and other factors were similar. The findings do not support a relation between supplementation with 400 IU/day of vitamin D(3) along with calcium and depression in older women. Additional trials testing higher doses of vitamin D are needed to determine whether this nutrient may help prevent or treat depression.

Evaluating components of dental care utilization among adults with diabetes and matched controls via hurdle models.

BACKGROUND: About one-third of adults with diabetes have severe oral complications. However, limited previous research has investigated dental care utilization associated with diabetes. This project had two purposes: to develop a methodology to estimate dental care utilization using claims data and to use this methodology to compare utilization of dental care between adults with and without diabetes. METHODS: Data included secondary enrollment and demographic data from Washington Dental Service (WDS) and Group Health Cooperative (GH), clinical data from GH, and dental-utilization data from WDS claims during 2002-2006. Dental and medical records from WDS and GH were linked for enrollees continuously and dually insured during the study. We employed hurdle models in a quasi-experimental setting to assess differences between adults with and without diabetes in 5-year cumulative utilization of dental services. Propensity score matching adjusted for differences in baseline covariates between the two groups. RESULTS: We found that adults with diabetes had lower odds of visiting a dentist (OR = 0.74, p < 0.001). Among those with a dental visit, diabetes patients had lower odds of receiving prophylaxis (OR = 0.77), fillings (OR = 0.80) and crowns (OR = 0.84) (p < 0.005 for all) and higher odds of receiving periodontal maintenance (OR = 1.24), non-surgical periodontal procedures (OR = 1.30), extractions (OR = 1.38) and removable prosthetics (OR = 1.36) (p < 0.001 for all). CONCLUSIONS: Patients with diabetes are less likely to use dental services. Those who do are less likely to use preventive care and more likely to receive periodontal care and tooth-extractions. Future research should address the possible effectiveness of additional prevention in reducing subsequent severe oral disease in patients with diabetes.

Assessment of a Claims-Based ICD-9 and ICD-10 Medication-Related Osteonecrosis of the Jaw Algorithm in the United States.

PURPOSE: Medication-related osteonecrosis of jaw (MRONJ) is associated with certain drug therapies. Pharmacoepidemiologic studies often rely on electronic healthcare data to assess adverse events following drug exposure. Few studies have developed and validated claims-based MRONJ identification algorithms. This study assessed the performance of claims-based MRONJ algorithms by chart review of potential cases among postmenopausal (PM) women and women with postmenopausal osteoporosis (PMO). METHODS: Among PM and PMO women sourced from a large US commercial health insurance database affiliated with Optum, potential cases were identified by International Classification of Diseases, 9th and 10th Revisions (ICD-9, ICD-10) diagnosis codes; 200 were selected for chart retrieval, with the goal of obtaining 100 charts in each coding era. Procured charts were redacted and then reviewed by an oral surgeon who determined case status. Positive predictive values (PPV) and 95% confidence intervals (CI) were calculated overall, by cohorts, and coding eras. Baseline characteristics were assessed. Two potential algorithm refinements were explored: using a restricted set of ICD codes; requiring antibiotic use after MRONJ diagnosis. RESULTS: A total of 1273 potential cases were identified. Of the 200 potential cases selected, 104 (52%) were procured, and six cases were confirmed (PPV 5.8%, 95% CI 2.2, 12.1). Baseline characteristics were largely similar across all strata. Potential algorithm refinements yielded marginal PPV improvement. CONCLUSION: This study identified a small number of confirmed cases, and the resulting PPVs were low, but consistent with reported studies. Potential algorithm refinements yielded minimal improvements. To our knowledge, this study is the first to report on the identification of MRONJ using ICD-10 codes in the US.

Depressive symptoms, bone loss, and fractures in postmenopausal women.

BACKGROUND: Osteoporosis and depression may be associated through common physiologic systems or risk factors. OBJECTIVE: To assess the associations between depressive symptoms (Burnam's scale) or antidepressant use and bone outcomes. DESIGN: Prospective cohort study. PARTICIPANTS: A total of 93,676 postmenopausal women (50 to 79 years old) enrolled in the Women's Health Initiative Observational Study. MEASUREMENTS: Self-reported fractures (n = 14,982) (hip [adjudicated], spine, wrist, and "other"). Analyses included 82,410 women with complete information followed on average for 7.4 years. Bone mineral density (BMD) of the hip (n = 4539), spine (n = 4417), and whole body (n = 4502) was measured at baseline and 3 years in women enrolled at 3 densitometry study sites. RESULTS: Overall, there were no statistically significant associations between depressive symptoms or antidepressant therapy and 3-year change in BMD. In a subset of women not using antidepressants, there was a significant difference in whole-body BMD change between women with and without depressive symptoms (P = .05). Depressive symptoms (hazard ratio [HR] 1.08; 95% CI = 1.02 to 1.14) and antidepressant therapy (HR = 1.22; CI = 1.15 to 1.30) independently increased risk of any fracture, the majority of which occurred at "other" anatomic sites. Antidepressant therapy increased the risk of spine fracture (HR = 1.36; CI = 1.14 to 1.63). No associations were observed between depressive symptoms or antidepressant therapy and hip or wrist fracture. CONCLUSION: In this study of postmenopausal women, average age 64, we observed minimal association between depressive symptoms and 3-year changes in either BMD or fracture risk. Antidepressant use was not associated with changes in BMD, but was associated with increased risk of fractures at the spine and "other " anatomic sites.

Occurrence of Serious Infection in Patients with Rheumatoid Arthritis Treated with Biologics and Denosumab Observed in a Clinical Setting.

OBJECTIVE: Previous studies combining biologic disease-modifying antirheumatic drugs (bDMARD) to treat rheumatoid arthritis (RA) have shown an increased risk of infection. However, the risk of infection with concurrent use of denosumab, a biologic agent for the treatment of osteoporosis, and a bDMARD remains unclear. Here, we evaluated the incidence of serious and opportunistic infections in patients treated concurrently with denosumab and a bDMARD and patients treated with a bDMARD alone. METHODS: A chart review of patients with RA from 2 Canadian rheumatology practices between July 1, 2010, and July 31, 2014, identified 2 groups of patients: those taking denosumab and a bDMARD concurrently (concurrent group) and those taking only a bDMARD (biologic-alone group). Patients were followed from the time of initiation of denosumab, or a matched index date for the biologic-alone group, to the end of the study or loss to followup. Instances of serious or opportunistic infections were recorded. RESULTS: A total of 308 patients (n = 102 for the concurrent group and n = 206 for the biologic-alone group) were evaluated. Within the concurrent group, 3 serious infection events occurred. Within the biologic-alone group, 4 serious infection events and 1 opportunistic infection event occurred. In both groups, all patients with serious or opportunistic infection recovered, and there were no instances of death during the study period. CONCLUSION: This study demonstrated a low occurrence of serious and opportunistic infections in patients with RA taking bDMARD, including patients with concurrent denosumab use.

The effects of black cohosh therapies on lipids, fibrinogen, glucose and insulin.

OBJECTIVE: Black cohosh (Actaea racemosa) is an herb commonly used to treat menopausal symptoms. Little is known about its effect on other physiologic parameters that could result in untoward events. This study examines the effect of black cohosh on lipids, fibrinogen, glucose and insulin. METHODS: Three hundred and fifty-one, 45-55 years old, peri or post-menopausal women experiencing vasomotor symptoms participated in a 3-month, double blind trial with randomization to: (1) black cohosh (160 mg daily); (2) multibotanical including black cohosh (200 mg daily); (3) multibotanical plus soy diet counseling; (4) conjugated equine estrogen .625 mg, with or without medroxyprogesterone acetate 2.5mg daily, for women with or without a uterus, respectively; (5) placebo. Baseline and month 3 total cholesterol, high density lipoprotein (HDL) cholesterol, low density lipoprotein (LDL) cholesterol (calculated), triglyceride, insulin, glucose, and fibrinogen serum concentrations were measured in 310 women. Baseline information was also collected on medical history, demographic characteristics, and diet. RESULTS: There were no statistically significant differences in the adjusted mean change from baseline to 3 months between the herbal groups and placebo in total cholesterol, LDL, HDL, triglycerides, glucose, and insulin. Adjusted fibrinogen levels appear to increase in the multibotanical treatment group in comparison with the other herbal groups and placebo overall (P = .02), but there was no statistically significant difference in the pairwise test against placebo (P = .11). CONCLUSIONS: Black cohosh containing therapies had no demonstrable effects on lipids, glucose, insulin or fibrinogen.

The impact of persistence with bisphosphonates on health resource utilization and fracture risk in the UK: a study of patient records from the UK Clinical Practice Research Datalink.

RATIONALE, AIMS AND OBJECTIVES: Clinical trial data suggest that patients who have received bisphosphonates continue to benefit from them after discontinuation. However, data from real-world clinical practice are inconclusive. We assessed the impact of persistence and discontinuation on health resource utilization (HRU) and fracture rate in women who were prescribed oral bisphosphonates. METHOD: The study used data from the UK Clinical Practice Research Datalink. Women aged 50 years or older with a first prescription of oral bisphosphonate therapy between January 2000 and December 2007 were included. Multivariate modelling compared rate ratios for fracture and HRU between patients who had discontinued medication (shorter persistence group) and patients who took their medication for longer (longer persistence group). The interactions of elapsed time (measured as 6-month intervals) with HRU and with fracture rate for all patients within paired groups were also assessed. RESULTS: Overall, 36 320 patients were included. Pairwise comparisons showed that HRU and fracture rates were lower in longer persistence groups than in shorter persistence groups. Analysis by 6-month interval showed that, across all patients in persistence group pairs, HRU significantly increased for each additional 6 months elapsed; trends towards increased risk of fracture were also seen. CONCLUSION: In contrast to results from clinical trials, in this patient population the protective effect of oral bisphosphonates after discontinuation was not sufficient to reduce HRU and fracture rates to the levels that would be seen if patients had continued on therapy. Reducing the rate of treatment discontinuation may decrease the burden that osteoporosis places on both patients and health care systems.

Oral contraceptive use and fracture risk around the menopausal transition.

OBJECTIVE: The effect of oral contraceptive (OC) use on risk of fracture remains unclear, and use during later reproductive life may be increasing. To determine the association between OC use during later reproductive life and risk of fracture across the menopausal transition, we conducted a population-based case-control study in a Pacific Northwest HMO, Group Health Cooperative. METHODS: For the January 2008 to March 2013 interval, 1,204 case women aged 45 to 59 years with incident fractures, and 2,275 control women were enrolled. Potential cases with fracture codes in automated data were adjudicated by electronic health record review. Potential control women without fracture codes were selected concurrently, sampling based on age. Participants received a structured study interview. Using logistic regression, associations between OC use and fracture risk were calculated as odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Participation was 69% for cases and 64% for controls. The study sample was 82% white; mean age was 54 years. The most common fracture site for cases was the wrist/forearm (32%). Adjusted fracture risk did not differ between cases versus controls for OC use in the 10 years before menopause (OR 0.90, 95% CI 0.74, 1.11); for OC use after age 38 (OR 0.94, 95% CI 0.78, 1.14); for duration of use, or for other OC exposures. CONCLUSIONS: The current study does not show an association between fractures near the menopausal transition and OC use in the decade before menopause or after age 38. For women considering OC use at these times, fracture risk does not seem to be either reduced or-reassuringly-increased.

A comparison of self-reported oral contraceptive use and automated pharmacy data in perimenopausal and early postmenopausal women.

PURPOSE: Oral contraceptive (OC) use can occur throughout a woman's reproductive life span with the potential for long-term impacts on health. To assess potential measurement error in prior OC use, this study compared level of agreement between self-reported prior OC use and pharmacy dispensing data in perimenopausal and/or early postmenopausal women. METHODS: The study's 1399 women (ages, 45-59 years) were participants in a population-based case-control study of the association between OC use and fracture risk. Episodes of lifetime self-reported OC use (in months) were collected, by telephone interview, for January 1, 2008 through November 25, 2012. Pharmacy fills, back to 1980, were collected from automated data. Agreement was measured using the prevalence-adjusted and bias-adjusted kappa index. RESULTS: The number of women with OC pharmacy fills was 11% to 45% higher than those who reported OC use during each time period. Between-measures agreement was better for more recent use. Prevalence-adjusted and bias-adjusted kappa index values ranged from 0.88 (95% confidence interval, 0.85-0.90) within 5 years from the reference date to 0.65 (95% confidence interval, 0.59-0.71) within 15 to 20 years. CONCLUSIONS: For studies designed to assess the long-term effects of OC use, the current results are reassuring in noting moderate agreement between self-reported OC use and pharmacy data for up to 15 to 20 years before the interview.

Persistance and Compliance with Osteroporosis Therapies Among Women in a Commercially Insured Population in the United States.

BACKGROUND: Prior research has shown that rates of persistence and compliance with osteoporosis therapies are associated with significantly fewer vertebral, nonvertebral, and hip fractures. A number of studies have examined medication-taking behavior with oral bisphosphonates and teriparatide, and these 1-year persistence rates have ranged from 39.9% to 56.7%. Limited real-world data are available regarding persistence and compliance rates with newer therapies such as denosumab, a RANK ligand inhibitor administered every 6 months as a subcutaneous injection.  OBJECTIVE: To assess persistence and compliance rates over 1 year with newly initiated osteoporosis therapies, including denosumab, alendronate, ibandronate, risedronate, raloxifene, and teriparatide, within a cohort of commercially insured women.  METHODS: Health insurance claims data derived from Truven Health Analytics MarketScan Commercial Claims and Encounters and Medicare Supplemental and Coordination of Benefits databases (2010-2013) were used to conduct this retrospective cohort study. Adult females aged 18 years and older newly initiated on denosumab, raloxifene, teriparatide, or oral bisphosphonates (alendronate, ibandronate, or risedronate) between January 1, 2012, and March 31, 2012, were identified for inclusion. The date of the first qualifying osteoporosis prescription claim was defined as the index date. Patients were required to have at least 24 months of pre-index and at least 12 months of post-index continuous enrollment with medical and pharmacy benefits. Outcomes of patients initiating zoledronic acid (administered intravenously once yearly) were not assessed because a 12-month follow-up period would be insufficient for tracking persistence and compliance for this medication. Patients with Paget's disease of the bone, osteogenesis imperfecta, hypercalcemia, malignant cancer and metastasis, human immunodeficiency virus, and patients receiving preventive treatment for risk of breast cancer or denosumab in the pre-index period were excluded from the study. A subcohort of women aged 50 years and older at high risk for fracture (indicated by 1 or more of the following: aged ≥ 70 years, a pre-index fracture, or pre-index use of osteoporosis therapy that was discontinued at least 3 months prior to index) was analyzed separately. Propensity score weighting was used to adjust for differences in baseline demographic and clinical characteristics. Persistence, indicated by continuous use of the index therapy without a gap of 60 days or more; medication coverage ratio (MCR), the proportion of days covered by the index therapy; and compliance, defined as an MCR ≥ 0.80, were assessed during the 12-month follow-up. Logistic regression was used to estimate the odds of persistence and compliance for the treatment groups of interest. RESULTS: 10,863 female patients newly initiating osteoporosis medications (mean [SD] age: 66.2 [11.5] years) were identified. In the pre-index period, 35.8% of patients had a diagnosis of osteoporosis, while 11.5% had a diagnosis of osteopenia. Pre-index osteoporosis treatment was identified in 29.1% of patients, and 13.6% had an osteoporosis-related fracture in the pre-index period. Propensity score weight-adjusted 12-month persistence with the index medication varied from 28.9% to 35.1% for oral bisphosphonate users, 42.0% for raloxifene users, 59.1% for teriparatide users, and 68.3% for denosumab users (P less than 0.0001). The adjusted mean [SD] MCR was highest among patients treated with denosumab (0.83 [0.21]), followed by teriparatide (0.67 [0.31]), raloxifene, (0.57 [0.34]), ibandronate (0.54 [0.32]), alendronate (0.51 [0.33]), and risedronate (0.46 [0.33]; P less than 0.0001). The odds of being persistent and compliant across treatments favored denosumab (OR = 1.59 to 5.56, P less than 0.05 for persistence; OR = 2.44 to 7.69, P less than 0.0001 for compliance). Results were similar in the subcohort of women aged 50 years and older at high risk for fracture (n = 6,187; mean [SD] age: 71.9 [10.9] years). The odds of being persistent and compliant across treatments also favored denosumab (OR = 1.62 to 5.75, P less than 0.0001 for persistence; OR = 2.36 to 7.25, P less than 0.0001 for compliance). CONCLUSIONS: In a U.S. setting, rates of persistence and compliance over 12 months were higher among women initiating denosumab compared with those initiating other osteoporosis therapies.

Burden of illness for osteoporotic fractures compared with other serious diseases among postmenopausal women in the United States.

OBJECTIVES: To provide a national estimate of the incidence of hospitalizations due to osteoporotic fractures (OFs) in women; compare this with the incidence of myocardial infarction (MI), stroke, and breast cancer; and assess temporal trends in the incidence and length of hospitalizations. PATIENTS AND METHODS: The study included all women 55 years and older at the time of admission, admitted to a hospital participating in the US Nationwide Inpatient Sample for an outcome of interest. We performed a retrospective analysis of hospitalizations for OFs (hip, forearm, spine, pelvis, distal femur, wrist, and humerus), MI, stroke, or breast cancer, using the US Nationwide Inpatient Sample, 2000-2011. RESULTS: From 2000 to 2011, there were 4.9 million hospitalizations for OF, 2.9 million for MI, 3.0 million for stroke, and 0.7 million for breast cancer. Osteoporotic fractures accounted for more than 40% of the hospitalizations in these 4 outcomes, with an age-adjusted rate of 1124 admissions per 100,000 person-years. In comparison, MI, stroke, and breast cancer had age-adjusted incidence rates of 668, 687, and 151 admissions per 100,000 person-years, respectively. The annual total population facility-related hospital cost was highest for hospitalizations due to OFs ($5.1 billion), followed by MI ($4.3 billion), stroke ($3.0 billion), and breast cancer ($0.5 billion). CONCLUSION: These data provide evidence that in US women 55 years and older, the hospitalization burden of OFs and population facility-related hospital cost is greater than that of MI, stroke, or breast cancer. Prioritization of bone health and supporting programs such as fracture liaison services is needed to reduce this substantial burden.

Bone mineral density screening among women with a history of breast cancer treated with aromatase inhibitors.

BACKGROUND: Understanding adherence to bone mineral density (BMD) screening after breast cancer (BC) treatment with aromatase inhibitors (AI) is an important first step in preventing or treating BC-related osteoporosis. METHODS: This retrospective cohort study assessed receipt and adherence to BMD screening among 342 women diagnosed with BC who were at high risk for osteoporosis after BC treatment with AI between 2004 and 2007. Nonadherence to baseline and annual BMD screening (recommended by 2003 American Society of Clinical Oncology Guidelines) was assessed using descriptive statistics and Poisson regression models accounting for length of AI use and follow-up. RESULTS: In the year before AI initiation, 16% of women received BMD screening. Fifty-six percent had no BMD screening in the 14 months after a minimum of 9 months of continuous AI use, and 75% and 66% failed to have BMD screens during the second (14.1-26 month) and third (26.1-38 month) annual time periods after continuous AI use for at least 23 and 35 months, respectively. Overall, 24% had no BMD screening after 35 months of continuous AI use. Statistically significant predictors of nonadherence included predominant exemestane use, BMD screening before AI initiation, and diabetes mellitus history. Postcollege education, geographic region of primary care clinic, and never smoking were associated with a reduced risk of nonadherence. CONCLUSIONS: A significant proportion of breast cancer patients treated with AI did not receive guideline-recommended BMD screening. Findings should raise awareness of the importance of BMD screening and targeting women at increased risk of screening nonadherence.

Accuracy of ICD-9 codes to identify nonunion and malunion and developing algorithms to improve case-finding of nonunion and malunion.

OBJECTIVE: To evaluate the accuracy of using ICD-9 codes to identify nonunions (NU) and malunions (MU) among adults with a prior fracture code and to explore case-finding algorithms. STUDY DESIGN: Medical chart review of potential NU (N=300) and MU (N=288) cases. True NU cases had evidence of NU and no evidence of MU in the chart (and vice versa for MUs) or were confirmed by the study clinician. Positive predictive values (PPV) were calculated for ICD-9 codes. Case-finding algorithms were developed by a classification and regression tree analysis using additional automated data, and these algorithms were compared to true case status. SETTING: Group Health Cooperative. RESULTS: Compared to true cases as determined from chart review, the PPV of ICD-9 codes for NU and MU were 89% (95% CI, 85-92%) and 47% (95% CI, 41-53%), respectively. A higher proportion of true cases (NU: 95%; 95% CI, 90-98%; MU: 56%; 95% CI, 47-66%) were found among subjects with 1+ additional codes occurring in the 12months following the initial code. There was no case-finding algorithm for NU developed given the high PPV of ICD-9 codes. For MU, the best case-finding algorithm classified people as an MU case if they had a fracture in the forearm, hand, or skull and had no visit with an NU diagnosis code in the 12-month post MU diagnosis. PPV for this MU case-finding algorithm increased to 84%. CONCLUSIONS: Identifying NUs with its ICD-9 code is reasonable. Identifying MUs with automated data can be improved by using a case-finding algorithm that uses additional information. Further validation of the MU algorithms in different populations is needed, as well as exploration of its performance in a larger sample.

Validation of electronic medical record-based phenotyping algorithms: results and lessons learned from the eMERGE network.

BACKGROUND: Genetic studies require precise phenotype definitions, but electronic medical record (EMR) phenotype data are recorded inconsistently and in a variety of formats. OBJECTIVE: To present lessons learned about validation of EMR-based phenotypes from the Electronic Medical Records and Genomics (eMERGE) studies. MATERIALS AND METHODS: The eMERGE network created and validated 13 EMR-derived phenotype algorithms. Network sites are Group Health, Marshfield Clinic, Mayo Clinic, Northwestern University, and Vanderbilt University. RESULTS: By validating EMR-derived phenotypes we learned that: (1) multisite validation improves phenotype algorithm accuracy; (2) targets for validation should be carefully considered and defined; (3) specifying time frames for review of variables eases validation time and improves accuracy; (4) using repeated measures requires defining the relevant time period and specifying the most meaningful value to be studied; (5) patient movement in and out of the health plan (transience) can result in incomplete or fragmented data; (6) the review scope should be defined carefully; (7) particular care is required in combining EMR and research data; (8) medication data can be assessed using claims, medications dispensed, or medications prescribed; (9) algorithm development and validation work best as an iterative process; and (10) validation by content experts or structured chart review can provide accurate results. CONCLUSIONS: Despite the diverse structure of the five EMRs of the eMERGE sites, we developed, validated, and successfully deployed 13 electronic phenotype algorithms. Validation is a worthwhile process that not only measures phenotype performance but also strengthens phenotype algorithm definitions and enhances their inter-institutional sharing.

Oral contraceptive use and bone density change in adolescent and young adult women: a prospective study of age, hormone dose, and discontinuation.

CONTEXT: Oral contraceptive (OC) use is common, but bone changes associated with use of contemporary OC remain unclear. OBJECTIVE: The objective of the study was to compare bone mineral density (BMD) change in adolescent and young adult OC users and discontinuers of two estrogen doses, relative to nonusers. DESIGN AND SETTING: This was a prospective cohort study, Group Health Cooperative. PARTICIPANTS: Participants included 606 women aged 14-30 yr (50% adolescents aged 14-18 yr): 389 OC users [62% 30-35 µg ethinyl estradiol (EE)] and 217 age-similar nonusers; there were 172 OC discontinuers. The 24-month retention was 78%. MAIN OUTCOME MEASURE: The main outcome measure was BMD measured at 6-month intervals for 24-36 months. RESULTS: After 24 months, adolescents using 30-35 µg EE OCs, but not those using lower-dose OCs, had significantly smaller adjusted mean percentage BMD gains than nonusers at the spine [group means (95% confidence interval for between group differences) 1.32 vs. 2.26% (-1.89, -0.13%)] and whole body [1.45 vs. 2.03% (-1.29%, -0.13%)]. Adolescents who discontinued 30-35 µg EE OC showed significantly smaller gains than nonusers at the spine after 12 months [0.51 vs. 1.72% (-2.38%, -0.30%)]. Young adult OC users did not differ from nonusers. However, OC discontinuers of both doses differed significantly from nonusers at the spine 12 months after discontinuation [-1.32% < 30 µg EE, -0.92% 30-35 µg EE vs. +0.27% nonusers (-2.48, -0.54, and -1.94%, -0.55%, respectively)]. Results were similar for mean absolute BMD change (grams per square centimeter). CONCLUSIONS: Both OC use and discontinuation were associated with BMD losses/smaller gains relative to nonusers (differences < 2% after 12-24 months for all skeletal sites). The clinical significance of these results regarding future fracture risk is unknown. Study of longer-term trends after discontinuation is needed.