OriginalInvestigation | PharmacyandClinicalPharmacology … · Current smoking 1942 (6) Estimated...

Original Investigation | Pharmacy and Clinical Pharmacology

Bisphosphonate Treatment Beyond 5 Years and Hip Fracture Risk in Older WomenMonika A. Izano, PhD; Joan C. Lo, MD; Annette L. Adams, PhD; Bruce Ettinger, MD; Susan M. Ott, MD; Malini Chandra, MS, MBA; Rita L. Hui, PharmD, MS; Fang Niu, MS;Bonnie H. Li, MS; Romain S. Neugebauer, PhD

Abstract

IMPORTANCE Clinical trials have demonstrated the antifracture efficacy of bisphosphonate drugsfor the first 3 to 5 years of therapy. However, the efficacy of continuing bisphosphonate for as long as10 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 amongwomen who had completed 5 years of bisphosphonate treatment at study entry.

DESIGN, SETTING, AND PARTICIPANTS This cohort study included women who were members ofKaiser Permanente Northern and Southern California, 2 integrated health care delivery systems, andwho had initiated oral bisphosphonate and completed 5 years of treatment by January 1, 2002, toSeptember 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 hospitaldischarge diagnoses. Demographic, clinical, and pharmacological data were ascertained fromelectronic 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 withbisphosphonate discontinuation at study entry, there were no differences in the cumulativeincidence (ie, risk) of hip fracture if women remained on therapy for 2 additional years (5-year riskdifference [RD], −2.2 per 1000 individuals; 95% CI, −20.3 to 15.9 per 1000 individuals) or if womencontinued therapy for 5 additional years (5-year RD, 3.8 per 1000 individuals; 95% CI, −7.4 to 15.0 per1000 individuals). While 5-year differences in hip fracture risk comparing continuation for 5additional years with discontinuation at 2 additional years were not statistically significant (5-yearRD, 6.0 per 1000 individuals; 95% CI, −9.9 to 22.0 per 1000 individuals), interim hip fracture riskappeared 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 per1000 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 treatmentfor 5 additional years. If women continued for 2 additional years and then discontinued, their riskappeared lower than continuing for 5 additional years. Discontinuation at other times and fracturerates during intervening years should be further studied.

JAMA Network Open. 2020;3(12):e2025190. doi:10.1001/jamanetworkopen.2020.25190

Key PointsQuestion Is bisphosphonate therapybeyond 5 years associated with lower

risk of hip fracture?

Findings In this cohort study of 29 685older women who completed 5 years

of bisphosphonate treatment, if women

continued treatment for 5 additional

years, the risk of hip fracture was not

significantly different than if they

discontinued after the first 5 years. If

women continued for 2 additional years

and then discontinued, there was a

difference in hip fracture outcome

depending on the use of a grace period

for discontinuation.

Meaning In this study of women whocompleted 5 years of bisphosphonate

treatment, completing an additional 5

years of treatment was not associated

with a reduction in hip fracture risk; the

potential hip fracture benefit for

continuing 2 additional years but not for

5 additional years should be

further studied.

+ Supplemental contentAuthor affiliations and article information arelisted at the end of this article.

Open Access. This is an open access article distributed under the terms of the CC-BY License.

JAMA Network Open. 2020;3(12):e2025190. doi:10.1001/jamanetworkopen.2020.25190 (Reprinted) December 7, 2020 1/13

Downloaded From: https://jamanetwork.com/ by a Non-Human Traffic (NHT) User on 07/06/2021

https://jama.jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2020.25190&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamanetworkopen.2020.25190https://jama.jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2020.25190&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamanetworkopen.2020.25190

Introduction

For more than 2 decades, bisphosphonate drugs have been a first-line therapy for preventingosteoporotic fractures, based on strong clinical trial evidence showing significant fracture riskreduction within the first 3 to 5 years of treatment.1,2 However, data regarding the optimal durationof bisphosphonate treatment to minimize fracture risk beyond this initial period are limited.

In September 2015, a Task Force of the American Society Bone and Mineral Researchrecommended that a drug holiday be considered following 5 years of oral bisphosphonate treatmentin women who were not at high fracture risk, whereas ongoing treatment was felt to benefit womenat high fracture risk.3 Their recommendations were based on collective evidence from clinical trialsthat each included fewer than 1000 women who continued oral bisphosphonate treatment beyond5 years.3 The task force acknowledged the limited evidence as well as its primary focus onsymptomatic vertebral fractures and called for more studies of representative populations.3 The USFood and Drug Administration analyzed pooled data4 from the extension phase of majorbisphosphonate clinical trials5-7 and concluded that the benefits of continued treatment beyond 3 to5 years remained unclear. A retrospective Women’s Health Initiative (WHI) study of women whoself-reported at least 2 years of bisphosphonate use did not find significant associations of 3 to 5 or 6to 9 years of treatment with hip fracture, although a 5-year increase in bisphosphonate treatmentwas associated with increased risk of hip fracture.8 These reports emphasize the importance ofdistinguishing efficacy during the first 5 years of bisphosphonate treatment from efficacy beyondthis period.9

Difficulty in randomizing patients to treatment cessation or continuation beyond 5 years, theinclusion of sufficient numbers of women, and the long follow-up required are challenges faced bytrials seeking to examine the efficacy of bisphosphonate treatment beyond 5 years.9 On the otherhand, real-world clinical populations can provide as much as 2 decades of experience with oralbisphosphonate drugs, beginning with the market introduction of alendronate in 1995 andrisedronate in 1998.10 In this study, we used data from Kaiser Permanente Northern and SouthernCalifornia, the 2 largest integrated health care delivery systems within the western United States,whose centralized databases have tracked both oral bisphosphonate exposure and hip fractureevents for more than 2 decades.11-16 Our analytic approach uses observational data to emulate theresults of a 5-year trial to examine the association of bisphosphonate discontinuation at study entry(total exposure, 5 years), discontinuation 2 years later (total exposure, 7 years), and continuation for5 additional years (total exposure, 10 years) with the risk of hip fracture in older women whocompleted 5 years of treatment.

Methods

Study PopulationThis retrospective study used data from Kaiser Permanente Northern (KPNC) and Southern California(KPSC) to identify women who initiated oral bisphosphonate therapy with alendronate, risedronate,or ibandronate between January 1, 1997, and September 30, 2009; were aged 45 to 80 years atbisphosphonate initiation; had health plan membership during the 2 prior years; and received at least60% adherent bisphosphonate treatment in each of the 5 years after initiation. Drug adherence wasbased on the days’ supply of dispensed prescriptions. Study follow-up commenced between 2002to 2014, after the first 5 years of treatment, referred to as the index date. Women were also requiredto have received bisphosphonate treatment within 60 days prior to the index date. Women wereexcluded if they previously received intravenous bisphosphonate or etidronate; receiveddenosumab, teriparatide, raloxifene, or estrogen in the 2 years prior to the index date; had advanced(grade 4-5) or end-stage kidney disease; or were diagnosed with a metabolic bone condition (Pagetdisease, osteogenesis imperfecta, hypophosphatasia, or primary hyperparathyroidism), secondaryor metastatic cancer, or multiple myeloma, as previously described.17,18 Participants were followed up

JAMA Network Open | Pharmacy and Clinical Pharmacology Bisphosphonate Treatment Beyond 5 Years and Hip Fracture Risk in Older Women



from their index date until the earliest occurrence of a hip fracture (n = 507), death (n = 1164), anexclusionary event (n = 1676), end of membership (n = 1958), or study end 5 years after index date(n = 24 353).

The study was approved by the KPNC and KPSC institutional review boards, and waivers ofinformed consent were obtained due to the nature of the study. This report follows theStrengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guideline.

Bisphosphonate Exposure AssessmentFollowing the index date and for each successive 90-day interval (quarter) of follow-up, women werecategorized as receiving bisphosphonate if at least 60% of the time period was covered by days’supply of drug in health plan pharmacy records (proportion of days covered [PDC], �0.60).17,18

Women were considered not receiving bisphosphonate if they received drug for less than thespecified PDC. Stockpiling was allowed for bisphosphonate prescriptions that overlapped by 30 daysor less. When prescriptions overlapped for more than 30 days, the second prescription tookprecedence.19 Classification of the 3 bisphosphonate regimens examined is described in StatisticalAnalysis section.

Hip Fracture AssessmentThe primary end point was proximal femur (hip) fracture, defined by a principal hospital dischargediagnosis of closed fracture of the femur (transcervical, pertrochanter, or femoral neck, InternationalClassification of Diseases, Ninth Revision [ICD-9] codes 820.0x, 820.2x, or 820.8x), excluding openfractures codes and those associated with major trauma (ICD-9 codes E800-E848).

CovariatesWe considered an extensive set of baseline and time-dependent covariates that may be associatedwith treatment17 or the risk of hip fracture. Baseline measures included age (in 5-year increments)and self-reported race/ethnicity (classified as non-Hispanic White, Hispanic/Latina, Black, Asian orPacific Islander, and other or unknown). We used US Census data to estimate surrogate markers ofsocioeconomic status, including low educational attainment (residence in a census block where>25% of individuals aged >25 years had less than a 12th grade education) and low income (residencein a census block with a median annual household income

was imputed, and an indicator of whether the value was imputed was included in analyses.24-26 Thelast observed value was carried forward (LOVCF) to subsequent quarters, and the indicator of LOVCFwas included in the covariate adjustment set.27

BMD measurements up to 5 years before the index date and during follow-up included femoralneck, total hip, and lumbar spine BMD and T scores28 from Hologic (KPNC) and GE Lunar (KPSC)bone densitometers. The lowest BMD T score (from measured sites for each BMD test) was used inanalyses and categorized as greater than −2.0, −2.0 to −2.4, −2.5 to −2.9, and−3.0 or less. The meanBMD T score was imputed for participants with missing BMD at baseline (18 156 [61%]), and anindicator of whether T score was imputed was included in analyses.

Statistical AnalysisOur analytic approach used observational data to emulate the results29 of a 5-year trial in whichwomen in the study cohort would have been randomized at their index date to 1 of 3 exposureregimens of interest: regimen 1, discontinuation of bisphosphonate therapy and continuous absenceof adherent treatment thereafter (ie, total 5 years of bisphosphonate use); regimen 2,discontinuation of bisphosphonate therapy at the end of 2 additional years of treatment andcontinuous absence of adherent treatment thereafter (ie, total 7 consecutive years ofbisphosphonate use); and regimen 3, continuous bisphosphonate therapy for 5 additional years (ie,total 10 years of bisphosphonate use). For the first 2 exposure groups, the emulated trial protocoladditionally allowed a 6-month window (ie, grace period)30 for bisphosphonate discontinuation tooccur. That is, discontinuation could occur in the first 6 months after the index date for the firstregimen, and in the six months following 2 additional years of treatment after the index date for thesecond regimen.

To estimate the three 5-year survival curves and corresponding cumulative risk differences(RDs) between any 2 groups of the emulated trial, we used inverse probability weighting (IPW),31,32

a propensity score approach, instead of standard statistical methods to properly adjust for complextime-varying confounding. Standard analytic methods (eg, Cox regression or propensity scorematching) cannot properly handle time-varying confounding by a factor that is affected by pastexposure status and is associated with both future exposure status and subsequent outcomes.Separate multivariable logistic regression models were fit to estimate propensity scores, whichinclude the probability of bisphosphonate initiation and continuation as well as the probability ofeach of the 4 censoring events (ie, death, disenrollment, study end, and exclusionary events). Modelsincluded all baseline and last-observed time-dependent covariates as described earlier. In addition,we adjusted for cumulative bisphosphonate exposure, for length of follow-up, and for the time sincethe most recent BMD test, given that recent BMD results may be a more important determinant oftreatment continuation than historical measurements. IPWs were stabilized33,34 and truncated at 50;truncation of stabilized weights affected less than 2% of observations. Distributions of stabilizedweights are provided in eTables 1, 2, 3, 9, and 10 in the Supplement.

In addition to our main IPW analyses, we computed effect estimates using targeted minimumloss-based estimation (TMLE),35 an approach that can also properly adjust for time-varyingconfounding and additionally has desirable statistical properties (eg, more precise effect estimates)discussed in the eAppendix in the Supplement. Distributions of unstabilized weights used by TMLEare provided in eTables 5, 6, 7, 12, and 13 in the Supplement. Analytic data sets were created in SASversion 9.4 (SAS Institute) using the MSMStructure SAS Macro.36 Measurements on exposure,outcome (incident hip fracture), censoring, and time-dependent covariates were updated everyquarter between the index date until the end of follow-up. Analyses were performed using the stremrpackage37 in R version 3.4.4 (R Project for Statistical Computing). The level of significance was set atP < .05, and all tests were 2-tailed.

We note that our analytic approach did not make arbitrary assumptions such as theproportionality assumption, ie, hazards ratios were permitted to change over time. Thus, we report




https://jama.jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2020.25190&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamanetworkopen.2020.25190https://jama.jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2020.25190&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamanetworkopen.2020.25190https://jama.jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2020.25190&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamanetworkopen.2020.25190

adjusted survival curves and cumulative RDs as the primary effect measures as opposed tohazard ratios.38

Results

Demographic and clinical characteristics of our study population are presented in Table 1. Our studyincluded 29 685 women who had completed 5 initial years of bisphosphonate treatment at the startof follow-up (index date) with a median (interquartile range) age of 71 (64-77) years; 17 778 (60%)

Table 1. Baseline Characteristics of Women Who Received 5 Yearsof Bisphosphonate Therapy

CharacteristicNo. (%)(N = 29 685)

Location

Northern California 12 391 (42)

Southern California 17 294 (58)

Age, median (IQR), y 71 (64-77)

Race/ethnicity

Non-Hispanic White 17 778 (60)

African-American or Black 1281 (4)

Hispanic or Latina 3785 (13)

Asian or Pacific Islander 6045 (20)

Other, mixed race, or unknown 796 (3)

Index BMI category

Normal or underweight,

were non-Hispanic White individuals, 3785 (13%) were Hispanic/Latina individuals, 6045 (20%)were Asian or Pacific Islander individuals, and 1281 (4%) were Black individuals. Overall, 666participants (2%) had experienced a hip fracture; 3384 (11%), humerus, spine, or wrist fracture; and8224 (28%), any clinical fracture. Among those with available BMD measurements prior to the indexdate, 4291 (37%) had osteoporosis. Among all women who entered the cohort, 11 105 (37%)continued bisphosphonate treatment for 2 additional years, for a total of 7 years of treatment, and2725 (9.2%) remained on treatment for all 5 follow-up years, completing a total of 10 years oftreatment. The numbers of regimen followers in each quarter of follow-up are provided in eFigure 1and eFigure 5 in the Supplement.

We identified 507 incident hip fractures during the 5 years of follow-up after study entry,including 292 (58%) and 251 (50%) that occurred while women were following 1 of the regimens,with and without a 6-month grace period, respectively. Crude and adjusted survival curves showedno differences in hip fracture–free survival between continuing bisphosphonate therapy for 5additional years vs discontinuing bisphosphonate at study entry (Figure 1; eFigures 2, 3, 6, and 7 inthe Supplement). Adjusted survival curves suggested better hip fracture–free survival if womeninterrupted bisphosphonate at 2 additional years compared with either discontinuing at study entryor continuing for 5 additional years, but these differences were attenuated when the 6-month graceperiod for bisphosphonate discontinuation was not included (Figure 1; eFigures 2, 3, 6, and 7 in theSupplement). The TMLE survival curves followed a similar pattern (eFigure 4 and eFigure 8 in theSupplement).

The 5-year cumulative incidences (risks) of hip fracture were 23.0 and 20.8 per 1000 individualsif women stopped taking bisphosphonate at study entry or after 2 additional years of treatmentwhen allowing a 6-month grace period (Table 2). The 5-year risk of hip fracture was 26.8 per 1000individuals if women remained on bisphosphonate for all 5 years. There were no statisticallysignificant differences between continuing bisphosphonate for 5 additional years and discontinuingat study entry with a 6-month grace period (5-year RD, 3.8 per 1000 individuals; 95% CI, −7.4 to 15.0per 1000 individuals) (Figure 2; eTable 4 in the Supplement) or with no grace period (RD, 9.4 per1000 individuals; 95% CI, −1.3 to 20.1 per 1000 individuals) (eTable 11 in the Supplement).Additionally, there were no significant differences in the 5-year hip fracture risk if womendiscontinued treatment after 2 additional years compared with discontinuation of treatment at studyentry (with a 6-month grace period: 5-year RD, −2.2 per 1000 individuals; 95% CI, −20.3 to 15.9 per1000 individuals; with no grace period: 5-year RD, 18.4 per 1000 individuals; 95% CI, −27.7 to 64.5

Figure 1. Hip Fracture Survival

1

0.98

0.96

0.94

0.92

Surv

ival

pro

babi

lity

Time since index date, y

6-mo Grace periodA

0 1

29 01725 62825 628

2

351816 23716 237

3

250911 10510 194

4

192511996510

5

1388903

4024

No. at riskRegimen 1Regimen 2Regimen 3

No. at riskRegimen 1Regimen 2Regimen 3

1

0.98

0.96

0.94

0.92

Surv

ival

pro

babi

lity

Time since index date, y

No grace periodB

0 1

338925 62825 628

2

144216 23716 237

3

1028911

10 194

4

780434

6510

5

556332

4024

AdjustedRegimen 1Regimen 2Regimen 3

CrudeRegimen 1Regimen 2Regimen 3

Regimen 1 indicates discontinuation of bisphosphonate at study entry; regimen 2, discontinuation after 2 additional years of treatment; regimen 3, continuation of bisphosphonatetreatment for all 5 years of follow-up.




https://jama.jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2020.25190&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamanetworkopen.2020.25190https://jama.jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2020.25190&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamanetworkopen.2020.25190https://jama.jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2020.25190&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamanetworkopen.2020.25190https://jama.jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2020.25190&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamanetworkopen.2020.25190https://jama.jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2020.25190&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamanetworkopen.2020.25190https://jama.jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2020.25190&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamanetworkopen.2020.25190

per 1000 individuals), although a statistically significant decrease in the 4-year risk was seen ifwomen continued for 2 additional years compared with discontinuing at entry (4-year RD, −10.4 per1000 individuals; 95% CI, −19.7 to −1.1 per 1000 individuals), but only with the inclusion of a 6-monthgrace period. We did not observe significant differences in the 5-year risk of hip fracture if womencontinued bisphosphonate treatment for all 5 years compared with interrupting after 2 years (with agrace period: 5-year RD, 6.0 per 1000 individuals; 95% CI, −9.9 to 22.0 per 1000 individuals; withouta grace period: RD, −9.0 per 1000 individuals; 95% CI, −54.4 to 36.4 per 1000 individuals), althoughstatistically significant increases in the risk of hip fracture with continued treatment were seen inyears 3 (RD, 2.8 per 1000 individuals; 95% CI, 1.3 to 4.3 per 1000 individuals) and 4 (RD, 9.3 per1000 individuals; 95% CI, 6.3 to 12.3 per 1000 individuals) compared with discontinuing at 2 years,again only with inclusion of a 6-month grace period (Figure 2). The TMLE results followed a similarpattern (eTable 8 and eTable 14 in the Supplement).

Discussion

In a large cohort of older women who completed 5 initial years of bisphosphonate treatment, wefound a similar 5-year risk of hip fracture whether women discontinued bisphosphonate treatmentat study entry or continued adherent treatment for 5 additional years. These findings were evident inanalyses when defining discontinuation with or without a 6-month grace period. For comparisons ofhip fracture risk if women continued bisphosphonate treatment for 2 additional years, findings weremixed, depending on use of a 6-month grace period for discontinuation, which allowed the inclusionof a larger number of women. While our results suggest that interruption of bisphosphonatetreatment after approximately 2 additional treatment years may be associated with lower interim riskof hip fracture compared with women who continued bisphosphonate treatment for 5 additionalyears, the 5-year risk differences were not statistically significant and the numbers of women and hipfracture events in this exposure group were relatively small.

The Fracture Intervention Trials (FIT)39,40 and Vertebral Efficacy with Risedronate Therapy(VERT) trials41,42 demonstrated that bisphosphonate therapy reduced the risk of hip, vertebral, andnonvertebral clinical fractures in women with osteoporosis during the first 3 to 5 years. However, fewtrials to our knowledge have examined bisphosphonate efficacy beyond 5 years. A 5-year FIT trialextension (FLEX) conducted among 1099 women examined the efficacy of continuing or stoppingalendronate after 3 to 5 years and found that women who stopped experienced no greater overallfracture risk for most clinical fractures compared with those continuining alendronate to 10 years,except for clinical vertebral fracture risk reduction but not those measured radiographically.6 In posthoc subgroup analyses, nonvertebral fracture risk reduction occurred in those without existingvertebral fractures who had hip osteoporosis by BMD, but there was no significant benefit to longer-term alendronate in the highest risk group (ie, those with prior vertebral fractures and low BMD).6,43

Some felt that these findings and 4- to 7-year risedronate extension studies7 suggested thatbisphosphonate continuation beyond 3 to 5 years may afford fracture protection in higher risk

Table 2. Adjusted Cumulative Incidence of Hip Fracture at the End of Each Follow-up Year, With and Without a Grace Period

Year

Regimen 1, discontinuation at study entry Regimen 2, discontinuation at 2 y

Regimen 3, continuation for 5 y6-mo Grace period No grace period 6-mo Grace period No grace periodCumulativeincidence per1000 individuals

Events peryear, No.

Cumulativeincidence per1000 individuals

Events peryear, No.


Events peryear, No.


Events peryear, No.


Events peryear. No.

1 4.2 (1.7-6.6) 56 5.1 (0.0-10.2) 6 3.3 (2.6-4.1) 74 3.3 (2.6-4.1) 74 3.3 (2.6-4.1) 74

2 9.5 (4.3-14.7) 10 9.6 (2.5-16.6) 4 7.0 (5.8-8.3) 54 7.0 (5.8-8.3) 54 7.0 (5.8-8.3) 54

3 16.7 (7.9-25.5) 14 14.5 (5.8-23.3) 5 8.5 (7.0-10.0) 15 10.8 (3.4-18.2) 1 11.3 (9.3-13.3) 36

4 19.1 (9.8-28.3) 7 16.5 (7.4-25.6) 3 8.6 (7.1-10.2) 1 10.8 (3.4-18.2) 0 18.0 (14.7-21.2) 35

5 23.0 (13.1-32.9) 6 17.4 (8.0-26.7) 1 20.8 (5.6-36.0) 7 35.8 (0.0-80.9) 2 26.8 (21.6-32.1) 30




https://jama.jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2020.25190&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamanetworkopen.2020.25190

patients with osteoporosis, but existing trials examined fracture outcomes in relatively smallnumbers of women with more than 5 years of bisphosphonate therapy and were not able to examinehip fractures.

Our observational study was conducted in a large cohort of women previously exposed to long-term bisphosphonate treatment. Other observational studies evaluating long-term bisphosphonatetreatment on hip fracture risk reported mixed findings. A small study of 183 women who received 3to 5 years of bisphosphonate reported increased risk of new clinical fractures among patients whodiscontinued treatment.44 Another study examining 81 427 Medicare beneficiaries with at least 3years of bisphosphonate use (80% adherence; most

10 years and more than 10 years were both associated with 30% lower hip fracture risk comparedwith less than 5 years treatment.46 In contrast, the WHI study of 5120 women with at least 2 years ofbisphosphonate use found that each 5-year increase in use was associated with a statisticallysignificant increase in hip fracture risk (adjusted hazard ratio, 1.33).8 A recent retrospective study ofwomen with at least 3 years bisphosphonate therapy showed no increased hip fracture risk amongthose given a bisphosphonate holiday of at least 12 months.16 In our study, continuingbisphosphonate for 5 additional years did not appear to result in hip fracture benefit. However,whether there is hip fracture benefit from continuing bisphosphonate treatment for only 2 additionalyears should be further studied.

Strengths and LimitationsThis study has several strengths. A main strength is the inclusion of a large and diverse population ofolder women who already had long-term bisphosphonate use. Centralized electronic healthdatabases provided an accurate assessment of bisphosphonate exposure, hip fracture events, and acomprehensive set of time-dependent potential confounders. We used statistical methods thataccounted for numerous potential factors that could be simultaneously associated with bothtreatment continuation and hip fracture risk.

This study has limitations. First, we used observational data that required some imputation(including missing BMD), but indicators of missing data were used in our analyses.24,25 Second, thesefindings may not be applicable to older women at higher risk of osteoporotic fracture. Third, we usedan adherence threshold of 60% to reflect real-world treatment behaviors, although higher47 andlower16 thresholds have been used in studies examining fracture risk. We did not address the optimalduration of bisphosphonate treatment or effects of temporary interruption. Fourth, we cannotexclude the possibility that the outcome included atypical femur fracture, which has very lowincidence compared with hip fracture, but femoral shaft–coded fractures (a frequent site of atypicalfracture) were not included. Finally, our analytic approach used propensity scores to account fordifferences between treatment arms, but as in any observational study, residual unmeasuredconfounding is possible. Propensity scores were estimated using parametric regression modelsrather than more flexible machine learning approaches, which could result in residual confounding byobserved covariates.48

Conclusions

In this cohort study of older women who already received 5 years of bisphosphonate therapy, thereappeared to be neither hip fracture benefit nor harm associated with discontinuing treatment atstudy entry or continuing treatment for an additional 5 years. A potential benefit was suggested fromcontinuing an additional 2 years, but the association of discontinuation at 2 years and other pointswith fracture risk should be further studied in randomized clinical trials. Future investigation shouldalso examine whether such findings apply to women at higher or lower fracture risk and to whatdegree other fracture outcomes might be affected. Our findings of hip fracture risk are similar to theFLEX randomized clinical trial, in which overall clinical fracture risk was not significantly differentbetween those who took placebo or alendronate for an additional 5 years.6

ARTICLE INFORMATIONAccepted for Publication: September 10, 2020.

Published: December 7, 2020. doi:10.1001/jamanetworkopen.2020.25190

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2020 Izano MAet al. JAMA Network Open.




https://jama.jamanetwork.com/article.aspx?doi=10.1001/jamanetworkopen.2020.25190&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamanetworkopen.2020.25190https://jamanetwork.com/journals/jamanetworkopen/pages/instructions-for-authors#SecOpenAccess/?utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamanetworkopen.2020.25190

Corresponding Author: Monika A. Izano, PhD, Division of Research, Kaiser Permanente Northern California, 2000Broadway, Oakland, CA 94612 ([email protected]).

Author Affiliations: Division of Research, Kaiser Permanente Northern California, Oakland (Izano, Lo, Ettinger,Chandra, Neugebauer); Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena(Adams, Li); Department of Medicine, University of Washington School of Medicine, Seattle (Ott); PharmacyOutcomes Research Group, Kaiser Permanente California, Oakland (Hui, Niu).

Author Contributions: Drs Izano and Neugebauer had full access to all of the data in the study and takeresponsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Izano, Lo, Adams, Ettinger, Hui, Neugebauer.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Izano, Lo, Chandra, Neugebauer.

Critical revision of the manuscript for important intellectual content: Izano, Lo, Adams, Ettinger, Ott, Hui, Niu, Li,Neugebauer.

Statistical analysis: Izano, Chandra, Hui, Neugebauer.

Obtained funding: Lo, Neugebauer.

Administrative, technical, or material support: Izano, Lo, Adams, Hui.

Supervision: Lo, Neugebauer.

Conflict of Interest Disclosures: Dr Adams reported receiving grants from Radius Health, Merck, and Amgenoutside the submitted work. No other disclosures were reported.

Funding/Support: This study was supported a by grant 1R01AG047230, S1 from the National Institute on Agingand the National Institute of Arthritis, Musculoskeletal, and Skin Diseases of the National Institutes of Health.

Role of the Funder/Sponsor: The funder had no role in the design and conduct of the study; collection,management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; anddecision to submit the manuscript for publication.

Disclaimer: The opinions expressed in this publication are solely the responsibility of the authors and do notrepresent the official views of Kaiser Permanente or the National Institutes of Health.

REFERENCES1. Cosman F, de Beur SJ, LeBoff MS, et al; National Osteoporosis Foundation. Clinician’s guide to prevention andtreatment of osteoporosis. Osteoporos Int. 2014;25(10):2359-2381. doi:10.1007/s00198-014-2794-2

2. Bilezikian JP. Efficacy of bisphosphonates in reducing fracture risk in postmenopausal osteoporosis. Am J Med.2009;122(2)(suppl):S14-S21. doi:10.1016/j.amjmed.2008.12.003

3. Adler RA, El-Hajj Fuleihan G, Bauer DC, et al. Managing osteoporosis in patients on long-term bisphosphonatetreatment: report of a task force of the American Society for Bone and Mineral Research. J Bone Miner Res.2016;31(1):16-35. doi:10.1002/jbmr.2708

4. Whitaker M, Guo J, Kehoe T, Benson G. Bisphosphonates for osteoporosis—where do we go from here? N Engl JMed. 2012;366(22):2048-2051. doi:10.1056/NEJMp1202619

5. Black DM, Reid IR, Boonen S, et al. The effect of 3 versus 6 years of zoledronic acid treatment of osteoporosis:a randomized extension to the HORIZON-Pivotal Fracture Trial (PFT). J Bone Miner Res. 2012;27(2):243-254.doi:10.1002/jbmr.1494

6. Black DM, Schwartz AV, Ensrud KE, et al; FLEX Research Group. Effects of continuing or stopping alendronateafter 5 years of treatment: the Fracture Intervention Trial Long-term Extension (FLEX): a randomized trial.JAMA. 2006;296(24):2927-2938. doi:10.1001/jama.296.24.2927

7. Mellström DD, Sörensen OH, Goemaere S, Roux C, Johnson TD, Chines AA. Seven years of treatment withrisedronate in women with postmenopausal osteoporosis. Calcif Tissue Int. 2004;75(6):462-468. doi:10.1007/s00223-004-0286-7

8. Drieling RL, LaCroix AZ, Beresford SAA, et al. Long-term oral bisphosphonate therapy and fractures in olderwomen: the Women’s Health Initiative. J Am Geriatr Soc. 2017;65(9):1924-1931. doi:10.1111/jgs.14911

9. Ott SM. Long-term bisphosphonates: primum non nocere. Menopause. 2016;23(11):1159-1161. doi:10.1097/GME.0000000000000757

10. Wysowski DK, Greene P. Trends in osteoporosis treatment with oral and intravenous bisphosphonates in theUnited States, 2002-2012. Bone. 2013;57(2):423-428. doi:10.1016/j.bone.2013.09.008

11. Adams AL, Shi J, Takayanagi M, Dell RM, Funahashi TT, Jacobsen SJ. Ten-year hip fracture incidence rate trendsin a large California population, 1997-2006. Osteoporos Int. 2013;24(1):373-376. doi:10.1007/s00198-012-1938-5




mailto:[email protected]://dx.doi.org/10.1007/s00198-014-2794-2https://dx.doi.org/10.1016/j.amjmed.2008.12.003https://dx.doi.org/10.1002/jbmr.2708https://dx.doi.org/10.1056/NEJMp1202619https://dx.doi.org/10.1002/jbmr.1494https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.296.24.2927&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamanetworkopen.2020.25190https://dx.doi.org/10.1007/s00223-004-0286-7https://dx.doi.org/10.1007/s00223-004-0286-7https://dx.doi.org/10.1111/jgs.14911https://dx.doi.org/10.1097/GME.0000000000000757https://dx.doi.org/10.1097/GME.0000000000000757https://dx.doi.org/10.1016/j.bone.2013.09.008https://dx.doi.org/10.1007/s00198-012-1938-5

12. Lo JC, Pressman AR, Chandra M, Ettinger B. Fracture risk tool validation in an integrated healthcare deliverysystem. Am J Manag Care. 2011;17(3):188-194.

13. Lo JC, Srinivasan S, Chandra M, et al. Trends in mortality following hip fracture in older women. Am J ManagCare. 2015;21(3):e206-e214.

14. Lo JC, Zheng P, Grimsrud CD, et al. Racial/ethnic differences in hip and diaphyseal femur fractures. OsteoporosInt. 2014;25(9):2313-2318. doi:10.1007/s00198-014-2750-1

15. Lo JC, Pressman AR, Omar MA, Ettinger B. Persistence with weekly alendronate therapy amongpostmenopausal women. Osteoporos Int. 2006;17(6):922-928. doi:10.1007/s00198-006-0085-2

16. Adams AL, Adams JL, Raebel MA, et al. Bisphosphonate drug holiday and fracture risk: a population-basedcohort study. J Bone Miner Res. 2018;33(7):1252-1259. doi:10.1002/jbmr.3420

17. Izano MA, Lo JC, Ettinger B, et al. Determinants of oral bisphosphonate use beyond 5 years. J Manag Care SpecPharm. 2020;26(2):197-202. doi:10.18553/jmcp.2020.26.2.197

18. Izano MA, Neugebauer R, Ettinger B, et al. Using pharmacy data and adherence to define long-termbisphosphonate exposure in women. J Manag Care Spec Pharm. 2019;25(6):719-723. doi:10.18553/jmcp.2019.25.6.719

19. Hui RL, Adams AL, Niu F, et al. Predicting adherence and persistence with oral bisphosphonate therapy in anintegrated health care delivery system. J Manag Care Spec Pharm. 2017;23(4):503-512. doi:10.18553/jmcp.2017.23.4.503

20. Dawson-Hughes B; National Osteoporosis Foundation Guide Committee. A revised clinician’s guide to theprevention and treatment of osteoporosis. J Clin Endocrinol Metab. 2008;93(7):2463-2465. doi:10.1210/jc.2008-0926

21. Watts NB, Lewiecki EM, Miller PD, Baim S. National Osteoporosis Foundation 2008 clinician’s guide toprevention and treatment of osteoporosis and the World Health Organization Fracture Risk Assessment Tool(FRAX): what they mean to the bone densitometrist and bone technologist. J Clin Densitom. 2008;11(4):473-477.doi:10.1016/j.jocd.2008.04.003

22. FRAX Fracture Risk Assessment Tool. Welcome to FRAX. Accessed October 30, 2020. http://www.shef.ac.uk/FRAX/

23. Deyo RA, Cherkin DC, Ciol MA. Adapting a clinical comorbidity index for use with ICD-9-CM administrativedatabases. J Clin Epidemiol. 1992;45(6):613-619. doi:10.1016/0895-4356(92)90133-8

24. Blake HA, Leyrat C, Mansfield KE, et al. Propensity scores using missingness pattern information: a practicalguide. Stat Med. 2020;39(11):1641-1657. doi:10.1002/sim.8503

25. Stuart EA. Matching methods for causal inference: a review and a look forward. Stat Sci. 2010;25(1):1-21. doi:10.1214/09-STS313

26. Hernán MA, McAdams M, McGrath N, Lanoy E, Costagliola D. Observation plans in longitudinal studies withtime-varying treatments. Stat Methods Med Res. 2009;18(1):27-52. doi:10.1177/0962280208092345

27. Kreif N, Sofrygin O, Schmittdiel JA, et al. Exploiting nonsystematic covariate monitoring to broaden the scopeof evidence about the causal effects of adaptive treatment strategies. Biometrics. 2020. doi:10.1111/biom.13271

28. Schousboe JT, Shepherd JA, Bilezikian JP, Baim S. Executive summary of the 2013 International Society forClinical Densitometry Position Development Conference on bone densitometry. J Clin Densitom. 2013;16(4):455-466. doi:10.1016/j.jocd.2013.08.004

29. Hernán MA, Robins JM. Using big data to emulate a target trial when a randomized trial is not available. Am JEpidemiol. 2016;183(8):758-764. doi:10.1093/aje/kwv254

30. Cain LE, Robins JM, Lanoy E, Logan R, Costagliola D, Hernán MA. When to start treatment? a systematicapproach to the comparison of dynamic regimes using observational data. Int J Biostat. 2010;6(2):18. doi:10.2202/1557-4679.1212

31. Robins JM. Marginal structural models. In: 1997 Proceedings of the American Statistical Association, Section onBayesian Statistical Science. American Statistical Association; 1998:1-10. Accessed October 30, 2020. https://cdn1.sph.harvard.edu/wp-content/uploads/sites/343/2013/03/msm-web.pdf

32. Robins JM, Hernán MA, Brumback B. Marginal structural models and causal inference in epidemiology.Epidemiology. 2000;11(5):550-560. doi:10.1097/00001648-200009000-00011

33. Cole SR, Hernán MA. Constructing inverse probability weights for marginal structural models. Am J Epidemiol.2008;168(6):656-664. doi:10.1093/aje/kwn164

34. Petersen ML, Porter KE, Gruber S, Wang Y, van der Laan MJ. Diagnosing and responding to violations in thepositivity assumption. Stat Methods Med Res. 2012;21(1):31-54. doi:10.1177/0962280210386207




https://www.ncbi.nlm.nih.gov/pubmed/21504255https://www.ncbi.nlm.nih.gov/pubmed/26014308https://www.ncbi.nlm.nih.gov/pubmed/26014308https://dx.doi.org/10.1007/s00198-014-2750-1https://dx.doi.org/10.1007/s00198-006-0085-2https://dx.doi.org/10.1002/jbmr.3420https://dx.doi.org/10.18553/jmcp.2020.26.2.197https://dx.doi.org/10.18553/jmcp.2019.25.6.719https://dx.doi.org/10.18553/jmcp.2019.25.6.719https://dx.doi.org/10.18553/jmcp.2017.23.4.503https://dx.doi.org/10.18553/jmcp.2017.23.4.503https://dx.doi.org/10.1210/jc.2008-0926https://dx.doi.org/10.1210/jc.2008-0926https://dx.doi.org/10.1016/j.jocd.2008.04.003http://www.shef.ac.uk/FRAX/http://www.shef.ac.uk/FRAX/https://dx.doi.org/10.1016/0895-4356(92)90133-8https://dx.doi.org/10.1002/sim.8503https://dx.doi.org/10.1214/09-STS313https://dx.doi.org/10.1177/0962280208092345https://dx.doi.org/10.1111/biom.13271https://dx.doi.org/10.1016/j.jocd.2013.08.004https://dx.doi.org/10.1093/aje/kwv254https://dx.doi.org/10.2202/1557-4679.1212https://dx.doi.org/10.2202/1557-4679.1212https://cdn1.sph.harvard.edu/wp-content/uploads/sites/343/2013/03/msm-web.pdfhttps://cdn1.sph.harvard.edu/wp-content/uploads/sites/343/2013/03/msm-web.pdfhttps://dx.doi.org/10.1097/00001648-200009000-00011https://dx.doi.org/10.1093/aje/kwn164https://dx.doi.org/10.1177/0962280210386207

35. van der Laan MJ, Gruber S. Targeted minimum loss based estimation of causal effects of multiple time pointinterventions. Int J Biostat. 2012;8(1). doi:10.1515/1557-4679.1370

36. Leong TK, Tabada GH, Yang J, Zhu Z, Neugebauer R; Kaiser Permanente Northern California Division ofResearch. MSMstructure. Updated March 2017. Accessed November 4, 2020. https://divisionofresearch.kaiserpermanente.org/projects/biostatistics/causalinferencesoftware

37. Sofrygin O, Zhu Z, Schmittdiel JA, et al. Targeted learning with daily EHR data. Stat Med. 2019;38(16):3073-3090. doi:10.1002/sim.8164

38. Hernán MA. The hazards of hazard ratios. Epidemiology. 2010;21(1):13-15. doi:10.1097/EDE.0b013e3181c1ea43

39. Black DM, Cummings SR, Karpf DB, et al; Fracture Intervention Trial Research Group. Randomised trial ofeffect of alendronate on risk of fracture in women with existing vertebral fractures. Lancet. 1996;348(9041):1535-1541. doi:10.1016/S0140-6736(96)07088-2

40. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with lowbone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. 1998;280(24):2077-2082. doi:10.1001/jama.280.24.2077

41. Reginster J, Minne HW, Sorensen OH, et al; Vertebral Efficacy with Risedronate Therapy (VERT) Study Group.Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausalosteoporosis. Osteoporos Int. 2000;11(1):83-91. doi:10.1007/s001980050010

42. Sorensen OH, Crawford GM, Mulder H, et al. Long-term efficacy of risedronate: a 5-year placebo-controlledclinical experience. Bone. 2003;32(2):120-126. doi:10.1016/S8756-3282(02)00946-8

43. Schwartz AV, Bauer DC, Cummings SR, et al; FLEX Research Group. Efficacy of continued alendronate forfractures in women with and without prevalent vertebral fracture: the FLEX trial. J Bone Miner Res. 2010;25(5):976-982. doi:10.1002/jbmr.11

44. Mignot MA, Taisne N, Legroux I, Cortet B, Paccou J. Bisphosphonate drug holidays in postmenopausalosteoporosis: effect on clinical fracture risk. Osteoporos Int. 2017;28(12):3431-3438. doi:10.1007/s00198-017-4215-9

45. Curtis JR, Saag KG, Arora T, et al. Duration of bisphosphonate drug holidays and associated fracture risk. MedCare. 2020;58(5):419-426. doi:10.1097/MLR.0000000000001294

46. Abrahamsen B, Eiken P, Prieto-Alhambra D, Eastell R. Risk of hip, subtrochanteric, and femoral shaft fracturesamong mid and long term users of alendronate: nationwide cohort and nested case-control study. BMJ. 2016;353:i3365. doi:10.1136/bmj.i3365

47. Siris ES, Harris ST, Rosen CJ, et al. Adherence to bisphosphonate therapy and fracture rates in osteoporoticwomen: relationship to vertebral and nonvertebral fractures from 2 US claims databases. Mayo Clin Proc. 2006;81(8):1013-1022. doi:10.4065/81.8.1013

48. Neugebauer R, Schmittdiel JA, van der Laan MJ. A case study of the impact of data-adaptive versus model-based estimation of the propensity scores on causal inferences from three inverse probability weightingestimators. Int J Biostat. 2016;12(1):131-155. doi:10.1515/ijb-2015-0028

SUPPLEMENT.eAppendix. Brief Notes on the TMLEeFigure 1. Number of Women Who Continue to Follow, Are No Longer Following, or Were Censored from Regimens1, 2, and 3 (With Grace Period)eFigure 2. Crude Survival Probabilities for the 3 Regimens of Interest (With Grace Period)eTable 1. Distribution of Stabilized Weights Among Regimen 1 Followers, IPW (With Grace Period)eTable 2. Distribution of Stabilized Weights Among Regimen 2 Followers, IPW (With Grace Period)eTable 3. Distribution of Stabilized Weights Among Regimen 3 Followers, IPW (With Grace Period)eFigure 3. IPW Survival Probabilities for the 3 Regimens of Interest (With Grace Period)eTable 4. IPW Estimated Risk Differences per 1000 Women Comparing Regimens of Interest (With Grace Period)eTable 5. Distribution of Unstabilized Weights Among Regimen 1 Followers, TMLE (With Grace Period)eTable 6. Distribution of Unstabilized Weights Among Regimen 2 Followers, TMLE (With Grace Period)eTable 7. Distribution of Unstabilized Weights Among Regimen 3 Followers, TMLE (With Grace Period)eFigure 4. TMLE Survival Probabilities for the 3 Regimens of Interest (With Grace Period)eTable 8. TMLE Risk Differences per 1000 Women Comparing Regimens of Interest (With Grace Period)eFigure 5. Number of Women Who Continue to Follow, Are No Longer Following, or Were Censored fromRegimens 1, 2, and 3 (Without Grace Period)eFigure 6. Crude Survival Probabilities for the 3 Regimens of Interest (Without Grace Period)




https://dx.doi.org/10.1515/1557-4679.1370https://divisionofresearch.kaiserpermanente.org/projects/biostatistics/causalinferencesoftwarehttps://divisionofresearch.kaiserpermanente.org/projects/biostatistics/causalinferencesoftwarehttps://dx.doi.org/10.1002/sim.8164https://dx.doi.org/10.1097/EDE.0b013e3181c1ea43https://dx.doi.org/10.1097/EDE.0b013e3181c1ea43https://dx.doi.org/10.1016/S0140-6736(96)07088-2https://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.280.24.2077&utm_campaign=articlePDF%26utm_medium=articlePDFlink%26utm_source=articlePDF%26utm_content=jamanetworkopen.2020.25190https://dx.doi.org/10.1007/s001980050010https://dx.doi.org/10.1016/S8756-3282(02)00946-8https://dx.doi.org/10.1002/jbmr.11https://dx.doi.org/10.1007/s00198-017-4215-9https://dx.doi.org/10.1007/s00198-017-4215-9https://dx.doi.org/10.1097/MLR.0000000000001294https://dx.doi.org/10.1136/bmj.i3365https://dx.doi.org/10.4065/81.8.1013https://dx.doi.org/10.1515/ijb-2015-0028

eTable 9. Distribution of Stabilized Weights Among Regimen 1 Followers, IPW (Without Grace Period)eTable 10. Distribution of Stabilized Weights Among Regimen 2 Followers, IPW (Without Grace Period)eFigure 7. IPW Survival Probabilities for the 3 Regimens of Interest (Without Grace Period)eTable 11. IPW Estimated Risk Differences per 1000 Women Comparing Regimens of Interest (Without GracePeriod)eTable 12. Distribution of Unstabilized Weights Among Regimen 1 Followers, TMLE (Without Grace Period)eTable 13. Distribution of Unstabilized Weights Among Regimen 2 Followers, TMLE (Without Grace Period)eFigure 8. TMLE Survival Probabilities for the 3 Regimens of Interest (Without Grace Period)eTable 14. TMLE Risk Differences per 1000 Women Comparing Regimens of Interest (Without Grace Period)




OriginalInvestigation | PharmacyandClinicalPharmacology … · Current smoking 1942 (6) Estimated...

Documents

Transcript of OriginalInvestigation | PharmacyandClinicalPharmacology … · Current smoking 1942 (6) Estimated...