Bruce Ettinger, MD

 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.

 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).

 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%).

 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.

Few studies address fracture risk prediction for US East Asian individuals, many of whom are immigrants.

There is variation in the predicted risk of hip fracture for country-specific East Asia Fracture Risk Assessment Tool (FRAX) calculators and the US-Asian FRAX.

Hip fracture outcome data among 3785 US Asian women with baseline bone density measurement and US-Asian FRAX–calculated fracture risk indicate that the predicted 10-year risk of hip fracture is within the lower range of the observed risk.

These findings support use of the US-Asian FRAX for predicting hip fracture risk among US East Asian women, but further studies are needed, including the examination of Asian subgroups.

Over the past 2 decades, the US population has become increasingly diverse. By the year 2030, it is estimated that 53.8 million US residents will be foreign-born.

 Those of Asian race comprise a growing proportion of the aging immigrant population who remain understudied. For older women of Asian race, understanding and optimizing fracture risk assessment has become increasingly relevant, given their lower bone mineral density (BMD) and more likely diagnosis of osteoporosis

 but lower risk of fracture compared with their White counterparts.

 However, the evidence base for determining whether BMD treatment thresholds are the same for Asian individuals as they are for White individuals is lacking.

Within the United States, an important quality metric for fracture prevention care is osteoporosis screening through BMD assessment. Current guidelines from the US Preventive Services Task Force recommend BMD assessment for all women 65 years and older, as well as for younger postmenopausal women at increased risk for osteoporosis.

 Coupling clinical information with BMD, the Fracture Risk Assessment Tool (FRAX)

 estimates the 10-year probability of hip and major osteoporotic fractures to assist clinical decision-making, counseling, and management. To estimate fracture risk, US providers typically choose from 1 of 4 US FRAX calculators based on the patient’s race/ethnicity: US Caucasian, US Black, US Hispanic, and US Asian.

 A calibration factor is included in the US model for races/ethnicities other than non-Hispanic White; for US Asian women, this calibration factor is 0.5,

 based on the lower incidence of hip fracture for Asian women compared with White women from published epidemiologic observations among Asians residing in the United States.

 FRAX calculators developed for various East Asian countries are also available online,

 including for China, Hong Kong, Taiwan, Japan, and South Korea. However, for the same standardized patient profile, the results from these country-specific FRAX calculators can vary depending on the underlying fracture rate and mortality of the population, parameters that are incorporated in FRAX.

One consideration for estimating fracture risk in immigrants is the suggestion that their country of origin’s FRAX might yield a more accurate fracture risk assessment.

 To examine potential differences that might be evident when calculating hip fracture probability for US East Asian immigrants by their country of origin’s FRAX, we first compared the results for the US-Asian FRAX calculator and results from various FRAX calculators of countries in East Asia for (hypothetical) standardized profiles of Asian women aged 70 years with osteopenia, focusing on the 10-year estimated risk of hip fracture. After observing large differences in these hypothetical FRAX estimates, we examined actual hip fracture outcome data from a historical cohort of similarly aged Northern California women identified as Asian at the time of BMD testing

 to compare their observed hip fracture risk with the estimates predicted by the US-Asian FRAX.

We created a hypothetical profile of an East Asian woman, aged 70 years, who weighed 120 pounds, was 62 inches tall, and had a femoral neck (hip) BMD T-score of –2.0 and no other clinical risk factors. Using input data for this case scenario for the web-based FRAX calculator,

 we first estimated her 10-year probability of hip fracture using the US-Asian FRAX calculator and then the FRAX calculators for Japan, Korea, Taiwan, Hong Kong, and China. These countries and regions are likely places of origin for women of East Asian descent now residing in the United States. The standardized profile was also entered into the US-Caucasian FRAX and the Philippines FRAX. Additional calculations were performed to determine how the probabilities of hip fracture across countries would change for this hypothetical Asian woman when other clinical risk factors were added to the profile—specifically, having a prior fracture and 1 or 2 clinical risk factors. All FRAX calculations for these hypothetical cases were conducted online using FRAX version 4.1.

In the second phase of this study, we used a previously developed retrospective cohort of Northern California women with BMD assessed in 1997-2003,

 without bisphosphonate treatment in the prior year, among whom hip fracture events were ascertained up to 2010.

 The subset of 3785 women with race/ethnicity identified as Asian (based on BMD race/ethnicity code “O”) who were aged 65 to 74 years at the time of BMD testing were included in these analyses. In addition to age, race, body mass index (BMI), and femoral neck BMD, the following FRAX input variables were derived from health plan ambulatory, hospitalization, and pharmacy databases as previously described

: oral glucocorticoid therapy, based on a cumulative prednisone dose equivalent of at least 1825 mg in the prior year; diagnoses of rheumatoid arthritis and conditions associated with secondary bone loss in the prior year; current smoking; and fracture within the prior 10 years after age 45 years (excluding fractures of the fingers, toes, face, and skull, and fractures associated with severe trauma). The 10-year probability of hip fracture was calculated using the US-Asian FRAX (version 3.1), with missing input parameters (eg, parental history, alcohol use) set to null or imputed (eg, population mean BMI, if missing), as previously described.

 Femoral neck BMD was classified based on BMD T-score

 calculated using Hologic National Health and Nutrition Examination Survey III peak BMD for young adult White women (0.849 ± 0.111 g/cm

 with osteoporosis defined by a BMD T-score of –2.5 and below and osteopenia by a BMD T-score between –1.0 and –2.5.

 Women were retrospectively followed up to 10 years or through December 2010, censoring at the first hip fracture event, membership termination, death, or receipt of a fourth prescription for an oral bisphosphonate drug (a treatment that could reduce fracture risk). Kaplan-Meier product limit estimates were used to determine the 10-year probability of hip fracture.

 In sensitivity analyses, we also examined these findings without censoring at the fourth bisphosphonate prescription. The study was approved by the Kaiser Permanente Northern California Institutional Review Board and a waiver of informed consent was obtained due to the nature of the study. Analyses were performed using SAS version 9.4 (SAS Institute).

When calculating the 10-year probability of hip fracture using FRAX for the hypothetical East Asian woman, aged 70 years, with osteopenia (T-score, –2.0), we observed the following differences based on the country-specific FRAX calculator used (

). The East Asian woman with no clinical risk factors had an estimated probability of hip fracture that was lowest based on the US-Asian FRAX (1.3%) and similarly low for the China FRAX (1.4%). Hip fracture FRAX probability estimates were somewhat higher for Japan (1.8%) and South Korea (2.2%), considerably higher for Hong Kong (2.6%), and yet higher for Taiwan (3.2%). The US-Asian FRAX estimate was nearly half that of the US-Caucasian FRAX estimate (2.3%), and the FRAX estimate was even lower for a (Filipina) woman in the Philippines (0.8%). Although 10-year hip fracture probability estimates changed with the addition of each additional risk factor (clinical factors and prior fracture) (Figure), the incremental change within each country’s FRAX was virtually the same and indicated that the FRAX tools of different countries likely weighed risk factors similarly. For these hypothetical case scenarios, the much higher hip fracture probability estimates using the Hong Kong or Taiwan FRAX tools approached or exceeded the US 3% treatment threshold (recommended by the National Osteoporosis Foundation)

 in contrast to the US-Asian FRAX. Note that Taiwan uses a higher 7% treatment threshold for hip fracture

 that offsets the higher calculated hip fracture probability.

We next examined the subset of 3785 Northern California Asian women who were aged 65 to 74 years at the time of BMD testing; the mean (SD) age of the cohort was 69 (3) years. Based on femoral neck BMD T-score (median T-score, –1.9), 53% and 27% of women met BMD criteria for osteopenia and osteoporosis, respectively. During a median (interquartile range [IQR]) follow-up of 6.8 (1.6-8.2) years, 23 experienced a hip fracture, resulting in a 10-year observed hip fracture probability of 1.5% (95% CI, 0.8%-2.7%). For this same cohort of 3785 women, the median (IQR) predicted 10-year risk of hip fracture based on the US-Asian FRAX (version 3.1) was similar, albeit slightly lower, at 1.1% (0.6%-2.0%).

In a sensitivity analysis, without censoring for bisphosphonate use (which affected 40.3% at some point during follow-up), there were a total of 41 hip fracture events among 3785 women during a median (IQR) follow-up of 8.0 (7.2-9.2) years, and the observed 10-year hip fracture probability was 1.6% (95% CI, 1.1%-2.5%).

Based on our examination of FRAX calculators from various countries across East Asia, we found that the 10-year estimated risk of hip fracture varied depending on the FRAX calculator used, consistent with previous observations.

 This report highlights the clinical relevance of these differences for clinicians providing care to ethnically diverse populations in the United States. Findings from our cohort of US Asian women demonstrate that the predicted hip fracture probabilities using the US Asian FRAX were within the lower range of the observed hip fracture risk.

Among first-generation US Asian immigrants, use of the FRAX tool developed for their country of origin might be considered. Based on the evidence that foreign-born adults in Sweden have a lower risk of fracture than native populations,

 FRAX experts have suggested that using a patient’s country-of-origin FRAX may be more appropriate for fracture risk assessment in Sweden.

 Hong Kong, Taiwan, and China are the 3 primary regions of origin for US naturalized Chinese Americans in California. However, this approach may be not be appropriate for East Asian immigrants from Hong Kong and Taiwan, where region-specific FRAX calculators yield 2-fold or higher estimates compared with the US-Asian FRAX. Our study indicates that the US-Asian FRAX calculation would be preferable for such women residing in the United States.

Our study has some limitations, including the small size of our US Asian cohort, resulting in few observed hip fracture events, and the lack of Asian ethnic subgroup differentiation. However, the assignment of Asian race at BMD testing (1997-2003) favored identification of East and Southeast Asians, with Chinese as the largest Asian subgroup in our source cohort

; many were likely to be first-generation immigrants due to early US legislative limits on immigration from Asia prior to the 1950s.

 Our findings do not apply to US South Asians, minimally represented in our cohort,

 whom some feel have a fracture risk closer to US White women.

 Additionally, although bisphosphonate treatment might influence hip fracture risk, our sensitivity analysis indicates minimal difference with or without treatment censoring during follow-up. Further, we did not examine the probability of other osteoporotic fractures, such as vertebral fractures, which may be higher in East Asians.

 Finally, the clinical variables for FRAX input were derived from electronic health records, where missing values were imputed or set to null,

 resulting in potential underestimation of calculated fracture risk.

To avoid potential overtreatment of US East Asian women for hip fracture prevention, our initial observations suggest that providers caring for older US East Asian women can continue to rely on the US-Asian FRAX-Hip calculation (as provided in the BMD clinical report) rather than the country-of-origin FRAX, until more data are available. However, further research is needed, with a focus on US Asian subgroups where specific population fracture rates have not been well studied. Whether the US-Asian FRAX is more appropriate for predicting major osteoporotic fracture risk is less clear, because major osteoporotic fracture incidence data are largely lacking for both US Asians and Asian ethnicity subgroups. Consistent with the need for more ethnogeriatric research,

 future studies should examine fracture risk and outcomes for the different Asian ethnicities represented in the large and growing Asian diaspora within the United States.

The authors would like to thank Kate Michi Ettinger, JD, for her review and insightful comments on this paper.

 Division of Research, Kaiser Permanente Northern California (JCL, MC, BE), Oakland, CA; Department of Medicine (JCL, SN, BY) and Department of Graduate Medical Education (MRW), Kaiser Permanente Oakland Medical Center, Oakland, CA; Department of Medicine, Kaiser Permanente Roseville Medical Center (MP), Roseville, CA.

 The authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article.

 Concept and design (JCL, SN, MP, MC, BE); acquisition of data (JCL, SN, MP, MC); analysis and interpretation of data (JCL, SN, MP, MC, BY, MRW, BE); drafting of the manuscript (JCL, SN, MP, BE); critical revision of the manuscript for important intellectual content (JCL, SN, MP, MC, BY, MRW, BE); statistical analysis (MC); provision of patients or study materials (JCL, SN, MP, MC); administrative, technical, or logistic support (JCL, MC, BY, MRW); and supervision (JCL).

 Joan C. Lo, MD, Division of Research, Kaiser Permanente Northern California, 2000 Broadway, Oakland, CA 94612. Email: Joan.C.Lo@kp.org.

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Articles

Fracture prediction tools for East Asian individuals vary by country. In the United States, the US-Asian Fracture Risk Assessment Tool provides hip fracture probabilities that correspond to observed estimates.

Variation in Fracture Risk Estimation Among East Asian Women

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). 

Examination of osteoporosis treatment patterns within healthcare systems should consider the effect of temporal trends in disease management. In Kaiser Permanente Southern California (KPSC), a large-scale osteoporosis program was established in 2002 to reduce fracture rates by 1) increasing bone mineral density (BMD) screening in women 65 years or older and those older than 50 years with fracture and 2) increasing bisphosphonate (BP) treatment for those with osteoporosis by BMD criteria and those with fracture.

 In 2008, osteoporosis metrics, quality measures, and changes in disease management were promulgated nationally, focusing on women 65 years or older and those at higher fracture risk.

In this context, we examined characteristics of new oral BP initiators over time, including age, prior fracture status, and BMD findings. Of the 94,073 women 50 years or older who initiated oral BP within KPSC from 2004 to 2012, 65% were 65 years or older and 21% had a fracture diagnosis within the 5 years prior to BP initiation. There were 75% with accessible BMD data within 2 years of BP initiation, of whom 62% had osteoporosis based on the lowest T-score (≤—2.5) of the hip or spine. 

Examining time trends among women who initiated BP and had available BMD data, we found that during 2004 to 2007, approximately half of the women younger than 65 years had osteoporosis by BMD criteria (47%-54%); the remaining 43% to 50% had osteopenia and 2% to 3% had normal BMD. In contrast, during 2008 to 2012, the proportion of women younger than 65 years with osteoporosis by BMD increased from 55% to 81% (

). This temporal trend was not evident among women 65 years or older who initiated BP, of whom about two-thirds had osteoporosis by BMD in both the earlier (62%-66%) and later (59%-70%) time periods.

Initiation of BP among younger women (<65 years) was notable for a progressively increasing proportion with prior fracture, from 15% in 2008 to 32% in 2012 (

). This focus on treatment of higher-risk women was reflected in a declining proportion of women younger than 65 years (42% in 2007 to 21% in 2012) among those without prior fracture. 

Similar observations were seen in Kaiser Permanente Northern California,

 a healthcare delivery system equal in size to KPSC but providing care independently, where a regional osteoporosis program was not implemented until 2008. For both health plans, major shifts toward treatment of older, rather than younger, women were observed beginning in 2008.

In summary, beginning in 2008 there was a marked shift toward treating higher-risk subsets among younger postmenopausal women, including women with prior fracture and those with osteoporosis by BMD, and away from women at lower risk (younger age, osteopenia, and no prior fracture). Health plan attention toward assessment of integrated fracture risk and national quality metrics disseminated in 2008

 likely contributed to these observed patterns. These findings highlight the importance of considering changing initiatives and guidelines that may impact temporal trends and patterns of BP initiation within integrated healthcare systems.

The authors wish to thank Shireen Fatemi, Nora Strick, Shelley Cao, and Kathryn Williams of the KPSC Healthy Bones program for their input and review of this letter.

 Department of Medicine, Kaiser Permanente Oakland Medical Center (RJH, JCL), Oakland, CA; Division of Research, Kaiser Permanente Northern California (JCL, BE), Oakland, CA; Department of Research & Evaluation, Kaiser Permanente Southern California (BHL, ALA), Pasadena, CA; Pharmacy Outcomes Research Group, Kaiser Permanente California (FN), Downey, CA; Pharmacy Outcomes Research Group, Kaiser Permanente California (RLH), Oakland, CA.

 These analyses were supported by a grant from the National Institute of Aging at the National Institutes of Health, 1R01AG047230.

 Dr Lo has received past research funding from Amgen and current research funding from Sanofi, unrelated to the current study. Dr Ettinger has previously received payments for providing expert testimony on the relationship between bisphosphonate use and atypical femur fracture in litigation involving Merck and Fosamax. Dr Adams has received research funding from Amgen, Merck, and Otsuka, unrelated to the current study. The remaining authors report no relationship or financial interest with any entity that would pose a conflict of interest with the subject matter of this article. 

 Concept and design (RJH, JCL, RLH, ALA); acquisition of data (BHL, FN, ALA); analysis and interpretation of data (RJH, JCL, BE, BHL, FN, RLH, ALA); drafting of the manuscript (RJH, JCL, ALA); critical revision of the manuscript for important intellectual content (BE, BHL, FN, RLH); statistical analysis (BHL); provision of patients or study materials (BHL, FN, ALA); and obtaining funding (JCL).

 Annette L. Adams, PhD, MPH, Kaiser Permanente Southern California, 100 S Los Robles Ave, 2nd Fl, Pasadena, CA 91101. E-mail: Annette.L.Adams@kp.org.

1. Dell R, Greene D, Schelkun SR, Williams K. Osteoporosis disease management: the role of the orthopaedic surgeon. 

2008;90(suppl 4):188-194. doi: 10.2106/JBJS.H.00628.

Clinician’s Guide to Prevention and Treatment of Osteoporosis. 

Washington, DC: National Osteoporosis Foundation; 2008.

3. NQF-Endorsed national voluntary consensus standards for physician-focused ambulatory care: appendix A—NCQA measure technical specifications. National Committee for Quality Assurance website. ncqa.org/portals/0/hedisqm/NQF_Posting_Appendix.pdf. Published April 2008. Accessed March 21, 2017. 

4. Curtis JR, Adachi JD, Saag KG. Bridging the osteoporosis quality chasm. 

2009;24(1):3-7. doi: 10.1359/jbmr.081116.

5. Lee DR, Ettinger B, Chandra M, Hui RL, Lo JC. Changing patterns in oral bisphosphonate initiation in women between 2004 and 2012. 

2017;65(3):656-658. doi: 10.1111/jgs.14723.

The authors observed a marked shift toward treatment of higher-risk subsets of younger postmenopausal women (with prior fracture and/or with osteoporosis), and away from women at lower risk.

Trends in Bisphosphonate Initiation Within an Integrated Healthcare Delivery System

To evaluate the utility of the Fracture Risk Calculator (FRC, Foundation for Osteoporosis Research and Education) for predicting 10-year hip fracture risk within a “real world” population.

 We identified female members of Kaiser Permanente Northern California aged ≥50 years with bone mineral density (BMD) measured during 1997-2003. Hospitalization for hip fracture was ascertained up to 10 years following the BMD date, and 10-year observed hip fracture probabilities   were calculated. Baseline data for fracture risk calculation were extracted from health plan databases, including age, race/ethnicity, smoking, body mass index, prior fracture, rheumatoid arthritis, glucocorticoid use, disorders associated with bone loss, and femoral neck BMD. Predicted 10-year FRC hip fracture probabilities were compared with observed 10-year hip fracture probabilities.

Among 94,489 women (mean age 62.8 ± 8.6 years, average femoral neck Z-score 0.1), the median duration of follow-up was 6.6 years, during which 1579 (1.7%) hip fractures occurred. Using the FRC, 23% met or exceeded the National Osteoporosis Foundation’s 3% hip fracture threshold. The FRC somewhat underestimated observed hip fracture probabilities; across 10-year risk categories <1%, 1% to 2.9%, and 3% to 4.9%, ratios of observed to median predicted probabilities ranged from 1.3 to 1.4.

The FRC tool can be applied to assess fracture risk in large populations using data from administrative databases. Despite some underestimation, this relatively simple tool may assist targeting of at-risk populations for more complete fracture risk assessment.

	The utility of the Fracture Risk Calculator (FRC) for predicting 10-year hip fracture risk within a “real world” population was evaluated.

		The FRC provided rapid assessment of population fracture risk with some underestimation.

		Bone mineral density as an input parameter appeared to have little overall effect on the tool’s discrimination.

		While the FRC underestimated observed 10-year hip fracture probabilities by 30% to 40%, the ability to rapidly assess fracture risk using population data may be useful for osteoporosis programs in the initial identification of high-risk patients.

	To better comply with current osteoporosis Healthcare Effectiveness Data and Information Set (HEDIS) measures,

 many healthcare delivery systems have developed programs to identify and track women after fracture. Some health plans have also developed quality improvement programs that expand osteoporosis management beyond the HEDIS requirements to include all women and men at increased risk of fracture.

In large part, the stimulus for such targeting has been evidence that preventive osteoporosis treatment for those at increased risk of fracture is cost-effective

 and that comprehensive and widespread interventions can substantially reduce hip fracture rates and thereby produce savings for health plans.

 However, adequate information technology resources must be available to capture information on patients, and management systems must be in place to mount large osteoporosis evaluation and treatment initiatives. Many health plans lack the organization for major fracture prevention outreach efforts, and more importantly, lack a simple, convenient system to identify those at increased risk.

	Several Web-based fracture risk tools are available,

 but these are designed for entry of individual patient-level information and currently do not function in an easily accessible, large-scale, batch mode where data on thousands of individuals can be instantly uploaded for fracture risk estimation. The most widely used fracture risk tool is FRAX, developed by the World Health Organization Collaborating Centre for Metabolic Bone Disease, University of Sheffield, UK

This tool first solicits information on a number of key, independent clinical risk factors and then calculates 10-year probabilities of hip and of any 1 of 4 major osteoporotic fractures. While some of these risk variables are easily obtained from administrative data sets (eg, age, sex), others may be obtained with some effort (eg, race/ethnicity, height and weight, prior fracture, high-dose glucocorticoid exposure, history of rheumatoid arthritis, other conditions known to contribute to osteoporosis, current smoking). Certain variables (eg, family history of osteoporosis, heavy alcohol use) may not be obtained without direct patient questioning. In addition, although many patients have undergone bone mineral  density (BMD) testing, numeric results may not be easily accessible; fortunately, fracture risk tools can produce results with or without BMD. Indeed, fracture risk tools can provide accurate probability estimates with less than complete input data.

 Especially for the purpose of population categorization and targeting osteoporosis outreach programs, results based on a limited data input tool would be considered adequate.

	In this study, we modified an existing Web-based fracture risk tool (the Fracture Risk Calculator [FRC])

 to provide batch outputs using input values obtained from administrative data in a large population of women undergoing BMD testing. We evaluated the performance of the FRC batch tool against observed 10-year hip fracture rates. The FRC tool was chosen because it was highly accessible, efficient, and transparent. Furthermore, the FRC batch estimates were provided at no cost, and results were instantly available via a Web interface. We compared observed 10-year fracture rate estimates with average predicted rates in more than 90,000 female members over age 50 years who received a BMD test in Kaiser Permanente Northern California (KPNC) between 1997 and 2003. Our primary goals were to determine what proportion met or exceeded the National Osteoporosis Foundation (NOF) 3% 10-year hip fracture risk threshold

and to assess whether the tool overestimated or underestimated the true risk of hip fracture.

	Kaiser Permanente Northern California is a large integrated healthcare delivery system serving more than 3 million members in Northern California; approximately 0.5 million are women over the age of 50 years. Since 1991, bone densitometry has been available using Hologic dual-energy x-ray absorptiometry (DXA) scanners (Waltham, MA). By 1995, KPNC had a fully integrated, systemwide patient data collection system that included ambulatory visit diagnoses, radiologic records, and prescription drugs that complemented long-standing hospitalization databases. Therefore, we selected as our study cohort all women aged 50 to 85 years who underwent a hip bone density scan on a Hologic scanner (models QDR 2000, 4500, or Delphi), selecting the first scan during 1997-2003. We excluded those who did not have at least 1 year of continuous (<90-day gap) membership both prior to and following the DXA scan date, those for whom DXA data were not electronically accessible, and those with missing race/ethnicity. We also excluded women who had filled a prescription for a bisphosphonate in the year prior to the DXA test. The study was approved by the Institutional Review Board of KPNC.

	The fracture model estimate began with population-based 10-year fracture probability for age, sex, and race/ethnicity. Next, specific patient characteristics were compared with those of the base population, and relative risks were applied to factors that differed between the individual patient and the base population. In very simplistic terms, the product of base rate times the risk differences yielded the predicted absolute 10-year risk. The current base US 10-year fracture risks for men and for women used by the FRC are those calculated from the 2006 US National Inpatient Survey by Ettinger et al.

 The FRC model’s relative risks for various clinical risk factors are shown in 

. A detailed manual of operations for the Web-based FRC batch tool is available through the Foundation for Research and Education (www.fore.org).

	Age, race/ethnicity, and body mass index (BMI) were determined at the index BMD scan date. Those with missing BMI were assigned a null value of 25 kg/m2, which was the median value in our cohort. Using ambulatory care, hospitalization, and pharmacy databases, we obtained each patient’s data from the 1 year prior to the DXA measurement to secure the following exposures and diagnoses: glucocorticoid use ≥1825 mg of cumulative prednisone dose equivalent in the prior year (average 5 mg/day), rheumatoid arthritis diagnoses, and secondary causes of bone loss (diabetes mellitus with insulin use, malabsorption syndrome, chronic liver disease, and osteogenesis imperfecta). We determined prior history of fracture after age 45 years (up to 10 years prior to the DXA date) based on hospitalization and outpatient diagnoses of fracture (

International Classification of Diseases,Ninth Revision

] codes 800-829), excluding open fractures, fractures related to severe trauma (

 E-codes 800-845), and fractures of the fingers, toes, facial bones, and skull, since these are not generally considered to be osteoporotic. Information on alcohol consumption and parental history of hip fracture was not available, and smoking status was not uniformly available. We assumed that all missing input values were null.

	Under the auspices of institutional agreements for protection of proprietary interests, batch data without patient identifiers were securely uploaded to the Foundation for  Osteoporosis Research and Education FRC Web site. Ten-year fracture probabilities were returned, calculated both with and without BMD inputs.

Follow-up and Observed Hip Fracture Outcome

	Individual patient data were examined from the index BMD scan date until the earliest of the following: the fourth prescription for a bisphosphonate, likely indicating 1 year of exposure because typical prescriptions provide a 3-month supply (N = 19,440, 20.6%); a principal diagnosis of hip fracture (

 code 820.0X, 820.2X, and 820.8X, excluding open fractures and those associated with major trauma, 

 E-codes 800- 845); death; disenrollment (>90-day gap in membership); or when 10 years had elapsed from the index date.

	Differences between women with and without subsequent hip fracture were compared using the 

2 test for categorical variables and the Student t test for continuous variables. Incident hip fracture rates and 95% confidence intervals (CIs) were calculated per 1000 person-years up to 10 years followup, the censoring date, or December 2009 (whichever occurred first). We used Kaplan Meier product-limit estimates to calculate the 10-year hip fracture probabilities from observed events over time and compared these with the median predicted 10- year hip fracture risk for the subcategories <1%, 1% to 2.9%, and 3% to 4.9%, as well as 5% to 6.9%, 7% to 9.9%, and >10%. We also compared the proportions of women in each decade of age meeting or exceeding the NOF’s 3% cost-effectiveness hip fracture risk threshold

both with and without inclusion of BMD as an input parameter. We used the area under the receiver operating characteristic (ROC) curve (C statistic) to compare sensitivity and specificity of the FRC results, with and without BMD.

 The C statistic ranges from 0.5 (the predictions are no better than chance) to 1.0 (a perfect predictive model). Statistical analyses were performed using SAS version 9.1 (SAS Institute, Cary, NC) and Stata version 9.2 (Stata- Corp, College Station, TX).

	Hologic BMD data were available for 94,489 women between the ages of 50 and 85 years, after excluding those not meeting health plan membership criteria (n = 19,178), those with missing race/ethnicity (n = 318), those with missing BMD data (n = 257), and those who received bisphosphonate drugs in the year prior to the index BMD date(n  = 2730).

shows the characteristics of the cohort at baseline. The mean femoral neck Z-score was 0.14, suggesting that the study population overall was comparable to the Hologic reference range (National Health and Nutrition Examination Survey III).14 The median duration of follow-up was 6.6 years (interquartile range 3.6-8.3 years), during which 1579 hip fractures were observed. Those who subsequently suffered a hip fracture were older, more likely to be white, had lower BMI, had other risk factors for osteoporosis, and were less likely to be users of hormone therapy. The mean age at hip fracture was 78 years and hip fracture incidence rates increased markedly with age (

). The incidence of hip fracture in nonwhites (Asians, Blacks, and Hispanics) was approximately half the incidence in whites.

	When applying the NOF’s 3% 10-year hip fracture probability threshold, the FRC yielded an overall population proportion of 23% with a strong relationship to age (

). Thus, the proportion of women qualifying under this criterion for osteoporosis management increased from about 1 in 25 at age 50 to 59 years to about 4 in 5 women at 75 years and older. The overall proportion identified as high risk showed no change when BMD was removed from the calculator input; however, when BMD was excluded, the proportion was lower among women aged 60 to 69 years (7.2% vs 17.1%) and higher among women aged 70 to 79 years (81.1% vs 59.4%).

 shows the predicted 10-year hip fracture probabilities compared with the observed 10-year hip fracture probabilities. The FRC underestimated the true fracture probabilities by 30% to 40%, particularly in the higher predicted risk categories (

). Although 40% of our cohort used hormone therapy at baseline, a factor not included in the FRC model, this did not explain the model’s tendency to underestimate the observed fracture probability (data not shown). The area under the ROC performances of the FRC tool were similar regardless of whether BMD was included (C statistic = 0.85; 95% CI 0.84, 0.86) or not (C statistic = 0.83; 95% CI 0.82, 0.84).

	We found that the FRC, a relatively simple, transparent fracture risk tool, provided rapid assessment of population fracture risk with some underestimation. When applied to our large population of women 50 years and older, approximately 1 in 4 were found to potentially qualify for osteoporosis treatment based on the NOF threshold of 3% 10-year hip fracture risk. Although the FRC somewhat underestimated the observed fracture probabilities in our cohort, similar underestimates have been reported by Sornay-Rendu et al when using FRAX to assess the risk of major osteoporotic fracture in a cohort of French women.

 Both the FRC and FRAX use the same base rate for 10-year fracture risk in women as this rate is provided by the same source

; the same risk input variables are also used, although the relative risks differ

 The FRAX model is also more complex mathematically, because it uses Poisson regressions to accommodate interaction terms and to calculate fracture probability offset by expected mortality.

	The inclusion or exclusion of BMD as an input parameter for the FRC batch calculator appeared to have little effect overall on discrimination, as measured by the C statistic (C statistic 0.85 and 0.83 with and without BMD, respectively). Several studies have also shown that FRAX yields similar C statistic estimates in the range of 0.7 to 0.8,

 including comparison between different models or with different input variables.

 It should be recognized, however, that there may be limitations to the utility of ROC curves in assessing clinical risk prediction since very large relative risks of included (or removed) variables are necessary to change the statistical outcome.

	We believe that both the calibration and discrimination of the FRC tool would be improved with more complete data input, particularly with inclusion of family history datain  the model. Epidemiologic studies indicate that parental history of hip fracture increases from about 5% in women in their 50s to about 15% to 20% for women 70 years and older

; the model’s fracture prediction would nearly double for women with such a history. In addition, our ascertainment of prior fractures, limited to 10 years prior to baseline, yielded a prior fracture prevalence of about half that reported in epidemiologic studies

; here too, the model predictions would nearly double for women with such a history. Other missing data (eg, alcohol intake missing for all, BMI missing for 30% of the cohort) are less important in the model’s calibration since thinness and heavy alcohol intake are not common in aging women.

These factors, along with more complete ascertainment of smoking status and other conditions contributing to bone loss, could be important when calculating risk for an individual.

	Our analyses did not examine thresholds for clinical actions and further did not consider cost-effectiveness of such actions. The threshold for treatment depends on available resources; Kanis et al have suggested for the United Kingdom a changing threshold dependent on age,

 while in the United States, the NOF thresholds of 3% hip fracture and 20% major osteoporotic fracture probabilities are applied to women irrespective of age.

The FORE Fracture Risk Calculator provided rapid assessment of population hip fracture risk with some underestimation compared with observed hip fracture probabilities.

Bruce Ettinger, MD

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Fracture Risk Tool Validation in an Integrated Healthcare Delivery System

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Continuation of Postmenopausal Hormone Replacement Therapy in a Large Health Maintenance Organization: Transdermal Matrix Patch versus Oral Estrogen Therapy

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