Time to Benefit of Bisphosphonate Therapy for the Prevention of Fractures Among Postmenopausal Women With Osteoporosis: A Meta-analysis of Randomized Clinical Trials

William James Deardorff; Irena Cenzer; Brian Nguyen; Sei J Lee

doi:10.1001/jamainternmed.2021.6745

. 2021 Nov 22;182(1):1–9. doi: 10.1001/jamainternmed.2021.6745

Time to Benefit of Bisphosphonate Therapy for the Prevention of Fractures Among Postmenopausal Women With Osteoporosis

A Meta-analysis of Randomized Clinical Trials

William James Deardorff ^1,^2,^✉, Irena Cenzer ^1,², Brian Nguyen ^1,², Sei J Lee ^1,²

PMCID: PMC8609461 PMID: 34807231

Key Points

Question

What is the time to benefit of bisphosphonate therapy to prevent a nonvertebral fracture among postmenopausal women with osteoporosis?

Findings

In this meta-analysis of 10 randomized clinical trials involving 23 384 postmenopausal women with osteoporosis, 12.4 months was needed to avoid 1 nonvertebral fracture per 100 women who received bisphosphonate therapy.

Meaning

This study’s results suggest that bisphosphonate therapy is most likely to benefit postmenopausal women with osteoporosis who have a life expectancy greater than 12.4 months.

Abstract

Importance

The clinical decision to initiate bisphosphonate therapy for the treatment of osteoporosis requires balancing shorter-term harms and burdens (eg, gastroesophageal irritation or severe musculoskeletal pain) with longer-term benefits in reducing potential fractures.

Objective

To assess the time to benefit (TTB) of bisphosphonate therapy for the prevention of nonvertebral and other fractures among postmenopausal women with osteoporosis.

Data Sources

Randomized clinical trials (RCTs) were identified from systematic reviews commissioned by the US Preventive Services Task Force (1 review), the Agency for Healthcare Research and Quality (1 review), the Cochrane Library (2 reviews), and the Endocrine Society (1 review).

Study Selection

Studies selected were RCTs involving postmenopausal women with a diagnosis of osteoporosis based on existing vertebral fractures or bone mineral density T scores of −2.5 or lower. The selection process was focused on studies of alendronate, risedronate, and zoledronic acid because they are guideline-recommended first-line agents for reducing nonvertebral fractures. Studies were excluded if they did not focus on women with a primary diagnosis of osteoporosis, had no placebo arm, or had a lack of data on time to fracture.

Data Extraction and Synthesis

Random-effects Weibull survival curves were fitted and Markov chain Monte Carlo methods were used to estimate the absolute risk reduction (ARR) and TTB for each study. These estimates were pooled using a random-effects meta-analysis model.

Main Outcomes and Measures

The primary outcome was the time to 3 different ARR thresholds (0.002, 0.005, and 0.010) for the first nonvertebral fracture. Secondary outcomes included the time to 4 ARR thresholds (0.001, 0.002, 0.005, and 0.010) for hip fracture, any clinical fracture, and clinical vertebral fracture.

Results

Of 67 full-text articles identified, 10 RCTs comprising 23 384 postmenopausal women with osteoporosis were included either as the original RCT or part of subsequently published pooled analyses. Among the studies, the number of participants ranged from 994 to 7765, with mean (SD) age ranging from 63 (7) years to 74 (3) years and follow-up duration ranging from 12 to 48 months. The pooled meta-analysis found that 12.4 months (95% CI, 6.3-18.4 months) were needed to avoid 1 nonvertebral fracture per 100 postmenopausal women receiving bisphosphonate therapy at an ARR of 0.010. To prevent 1 hip fracture, 200 postmenopausal women with osteoporosis would need to receive bisphosphonate therapy for 20.3 months (95% CI, 11.0-29.7 months) at an ARR of 0.005. In addition, 200 postmenopausal women with osteoporosis would need to receive bisphosphonate therapy for 12.1 months (95% CI, 6.4-17.8 months) to avoid 1 clinical vertebral fracture at an ARR of 0.005.

Conclusions and Relevance

This meta-analysis found that the TTB of bisphosphonate therapy was 12.4 months to prevent 1 nonvertebral fracture per 100 postmenopausal women with osteoporosis. These results suggest that bisphosphonate therapy is most likely to benefit postmenopausal women with osteoporosis who have a life expectancy greater than 12.4 months.

This meta-analysis uses data from randomized clinical trials to assess the time to benefit of bisphosphonate therapy for the prevention of nonvertebral fractures among postmenopausal women with osteoporosis.

Introduction

Osteoporosis is common among older women and is associated with approximately 1.9 million fractures every year in the US, at an estimated annual cost of $57 billion.¹ Fractures among those with osteoporosis have been associated with increased functional impairment,² reduced quality of life,³ and increased risk of mortality.⁴ Despite its clinical importance, osteoporosis is often underdiagnosed and undertreated, even among patients who have already experienced a hip fracture.^5,6 Patterns in hip fracture rates over time suggest that this treatment gap is worsening, in part because of concerns about rare but serious adverse effects.^7,8,9

Several bisphosphonates (eg, alendronate, risedronate, and zoledronic acid) have been reported in randomized clinical trials (RCTs) to reduce fracture risk among older women with osteoporosis.¹⁰ However, bisphosphonate treatment can produce adverse effects and patient burdens.¹¹ Many patients have reported gastrointestinal (GI) adverse effects, such as acid reflux and esophageal irritation, while receiving oral bisphosphonates. Patients receiving alendronate and risedronate are advised to remain upright for at least 30 minutes after ingestion to reduce the risk of esophagitis and esophageal ulcers. Intravenous zoledronic acid has been associated with an infusion reaction that is characterized by fever, headache, myalgias, and malaise in up to 40% of patients after receipt of the first dose.^12,13 Thus, while bisphosphonates are a proven intervention to reduce or prevent fractures in many older women,¹⁰ these agents are associated with immediate burdens and harms; therefore, bisphosphonate therapy is most successful when targeted to older women who are most likely to benefit.

One framework that can help to identify older women who are most likely to benefit from bisphosphonate therapy is a comparison of life expectancy with time to benefit (TTB). Time to benefit is usually defined as the time between initiation of preventive intervention, when harms are most likely to occur, to the time when health outcomes improve.¹⁴ For cases in which life expectancy is shorter than TTB, preventive interventions may expose older adults to immediate risks and complications associated with those interventions, with little likelihood of surviving long enough to experience benefit. Given that increasing age and multimorbidity are important risk factors associated with fractures, estimating the TTB of bisphosphonate therapy is important to inform treatment discussions.^15,16

Time-to-benefit analyses have been conducted for several interventions, including colorectal cancer screening and statin therapy.^17,18 To our knowledge, only 1 study¹⁹ has formally estimated the TTB for bisphosphonate therapy; that study performed a post hoc analysis of a single osteoporosis clinical trial involving treatment with alendronate. To aid in clinical decision-making regarding the initiation of bisphosphonate therapy, we conducted a meta-analysis of RCTs involving bisphosphonates to assess the TTB for the prevention of nonvertebral and other fractures among postmenopausal women with osteoporosis.

Methods

Literature Search

We identified RCTs involving bisphosphonate therapy from 5 published reviews: a 2018 systematic review commissioned by the US Preventive Services Task Force,²⁰ a 2012 comparative effectiveness review prepared for the Agency for Healthcare Research and Quality,²¹ 2 systematic reviews from the Cochrane Library that were published in 2008,^22,23 and a 2019 systematic review and network meta-analysis partially funded by the Endocrine Society²⁴ (Figure 1). From December 2020 to April 2021, we performed forward citation tracing using a Google Scholar search of RCTs to identify additional studies that conducted post hoc or pooled analyses. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline for meta-analyses (eTable 1 in the Supplement).²⁵

Figure 1. — AHRQ indicates Agency for Healthcare Research and Quality; USPSTF, US Preventive Services Task Force.

Eligibility Criteria

We included studies involving postmenopausal women with a diagnosis of osteoporosis based on either an existing vertebral fracture or a bone mineral density (BMD) T score of −2.5 or lower. We chose this definition because it reflected a high-risk population that was frequently enrolled in clinical trials. We selected studies involving only alendronate, risedronate, and zoledronic acid because these bisphosphonates are recommended in clinical guidelines^10,26,27 as first-line therapies for the reduction of nonvertebral fractures in postmenopausal women with osteoporosis. We excluded clinical trials that focused on secondary prevention among postmenopausal women with initial hip fractures because these women had a substantially higher absolute risk of future fractures. We also excluded studies in which more than 50% of enrolled participants had osteopenia, studies that included both men and women, and studies that focused on secondary origins of osteoporosis (eg, glucocorticoid-induced osteoporosis). Given that our analysis focused on time to fracture, we excluded studies that either did not include a survival curve in the original article or were not part of a post hoc or pooled analysis that presented a survival curve. One author (W.J.D.) screened each record and obtained relevant data from the full-text articles.

Outcomes of Interest

The primary outcome was the time to 3 specific absolute risk reduction (ARR) thresholds (0.002, 0.005, and 0.010) for the first nonvertebral fracture. We chose this primary outcome because nonvertebral fractures represent a clinically relevant outcome for patients and are commonly assessed in clinical trials. Although the definition of nonvertebral fracture slightly varied across studies, the similarities outweighed the differences across all studies, including differences in the definitions of hip, clavicle, humerus, wrist, pelvis, and leg fractures²⁸ (eTable 2 in the Supplement). As secondary outcomes, we assessed the time to 4 specific ARR thresholds (0.001, 0.002, 0.005, and 0.010) for the first hip fracture, first clinical vertebral fracture, and first clinical fracture of any type.

Statistical Analysis

The probability and times of fractures were extracted from the survival curves using DigitizeIt software, version 2.5 (I. Bormann).^29,30 We then used the idpfc module in Stata software, version 17 (StataCorp LLC),³¹ to reconstruct time-to-event data for individual patients using cumulative event data and the number of participants at risk presented in each study.³² The main outcome of interest for this meta-analysis was TTB. Because studies did not report TTB, we first fit random-effects Weibull survival curves for the control and intervention groups to the extracted data for each study (eFigures 1-5 in the Supplement). Using 100 000 Markov chain Monte Carlo simulations, we obtained point estimates, SEs, and 95% CIs for the rate of fractures in the control and intervention arms of each study. We then obtained estimates of the time to specific ARR thresholds (0.002, 0.005, and 0.010 for the primary outcome, with the addition of 0.001 for specific secondary outcomes) for each study. The statistical significance threshold was 2-sided P < .05.

The ARR and TTB estimates from individual studies were pooled using a random-effects meta-analysis model. We combined the results across individual bisphosphonates (alendronate, risedronate, and zoledronic acid) because clinical guidelines and network meta-analyses have generally reported that the benefits of these agents are similar.²⁴ Heterogeneity was assessed using the I² statistic. We extracted risk of bias (ROB) assessments from the individual systematic reviews. To assess for publication bias in our primary outcome, we performed 2 sensitivity analyses; the first analysis used the trim-and-fill method, and the second was a cumulative meta-analysis, in which studies rated as having low ROB were added to the model first, allowing us to examine changes in TTB estimates as studies with higher or unclear ROB were added. These methods have been successfully used in previous TTB analyses focused on cancer screening¹⁷ and statin use.¹⁸ Additional details are provided in the eMethods in the Supplement.

Results

Included and Excluded Studies

We identified 110 records from the 5 published systematic reviews of bisphosphonate therapy^{20,21,22,23,24} (Figure 1). After removing 43 duplicate records, we excluded clinical trials that did not have a placebo arm (n = 4), did not focus on postmenopausal women with osteoporosis (n = 33), and did not report time-to-fracture data (n = 20), resulting in 10 RCTs^{33,34,35,36,37,38,39,40,41,42} selected for inclusion in the meta-analysis (Table 1). Because several RCTs did not present a survival curve in their originally published articles,^{35,36,37,38,39,40} we included them as part of subsequently published pooled analyses^43,44,45 that reported time-to-fracture data in the form of a survival curve (Table 1). Additional details of the excluded studies and the reasons for exclusion are shown in eTable 3 in the Supplement.

Table 1. Characteristics of Studies, Including Original Randomized Clinical Trials and Pooled Analyses.

Source	Study	Participants, No.	Mean age, y	Study population and inclusion criteria	Bisphosphonate type and dose	Follow-up duration, mo
Individual RCTs
Liberman et al,³³ 1995	Phase 3 osteoporosis treatment	994	64	Lumbar spine BMD T score ≤ −2.5 (~20% of women had baseline vertebral fractures)	Alendronate, 5.0 mg/d, 10.0 mg/d, or 20.0 mg/d	36
Pols et al,³⁴ 1999	FOSIT	1908	63	Lumbar spine BMD T score ≤ −2.0	Alendronate, 10.0 mg/d	12
Black et al,³⁵ 1996	FIT vertebral fracture arm	2027	71	Vertebral fracture at baseline and femoral neck BMD T score ≤ −1.6	Alendronate, 5.0 mg/d, for first 2 y, then 10.0 mg/d	36
Cummings et al,³⁶ 1998	FIT clinical fracture arm	4432	68	Femoral neck BMD T score ≤ −1.6 without baseline vertebral fracture	Alendronate, 5.0 mg/d, for first 2 y, then 10.0 mg/d	48
Harris et al,³⁷ 1999	VERT–North America	2458	69	≥2 vertebral fractures at baseline or 1 vertebral fracture and lumbar spine BMD T score ≤ −2.0	Risedronate, 2.5 or 5.0 mg/d	36
Reginster et al,³⁸ 2000	VERT–multinational	1226	71	≥2 vertebral fractures at baseline	Risedronate, 2.5 or 5.0 mg/d	36
McClung et al,³⁹ 1998	BMD–North America	648	62	Lumbar spine BMD T score ≤ −2.0	Risedronate, 2.5 or 5.0 mg/d	18
Fogelman et al,⁴⁰ 2000	BMD–multinational	543	65	Lumbar spine BMD T score ≤ −2.0 (~ 30% of women had baseline vertebral fractures)	Risedronate, 2.5 or 5.0 mg/d	24
McClung et al,⁴¹ 2001	Hip intervention program (osteoporosis group)	5445	74	Femoral neck BMD T score < −4.0 or < −3.0 plus 1 risk factor for hip fracture (~ 38% of women had baseline vertebral fractures)	Risedronate, 2.5 or 5.0 mg/d	36
Black et al,⁴² 2007	HORIZON–PFT	7765	73	Femoral neck BMD T score ≤ −2.5 or T score ≤ −1.5 with ≥2 mild vertebral fractures or 1 moderate vertebral fracture	Zoledronic acid, 5.0 mg, once per y	36
Pooled analyses
Black et al, 2000⁴³	FIT clinical fracture and vertebral fracture arms	3658	70	Femoral neck BMD T score < −2.5 without vertebral fracture or presence of baseline vertebral fracture	Alendronate, 5.0 mg/d, for first 2 y, then 10.0 mg/d	36
Harrington et al,⁴⁴ 2004	VERT–North America; VERT–multinational; BMD–North America; BMD–multinational	1172	66	Lumbar spine BMD T score < −2.5 with or without baseline vertebral fracture	Risedronate, 5.0 mg/d	36
Roux et al,⁴⁵ 2004	VERT–North America; VERT–multinational	2442	NR	Same inclusion criteria as VERT–North America and VERT–multinational	Risedronate, 5.0 mg/d	12

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Abbreviations: BMD, bone mineral density; FIT, Fracture Intervention Trial; FOSIT, Fosamax International Trial Study; HORIZON–PFT, Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly–Pivotal Fracture Trial; NR, not reported; RCT, randomized clinical trial; VERT, Vertebral Efficacy With Risedronate Therapy.

Data from a total of 23 384 women (994 from Liberman et al,³³ 1908 from Pols et al,³⁴ 5445 from McClung et al,⁴¹ 7765 from Black et al,⁴² 3658 from Black et al,⁴³ 1172 from Harrington et al,⁴⁴ and 2442 from Roux et al⁴⁵) were included in the pooled analysis. The number of participants in the included studies ranged from 994³³ to 7765⁴² (Table 1). The mean (SD) age of participants ranged from 63 (7) years³⁴ to 74 (3) years.⁴¹ When race and/or ethnicity were reported, most participants in the RCTs were White (typically >90%). Follow-up durations ranged from 12 months^34,45 to 48 months.³⁶ Dosages varied from 5.0 to 20.0 mg per day for alendronate,^33,34,35,36 2.5 to 5.0 mg per day for risedronate,^{37,38,39,40,41} and 5.0 mg per year for zoledronic acid.⁴²

Time to Fracture Prevention

The meta-analysis suggested that the benefit of bisphosphonate therapy increased in a nearly linear manner with increasing follow-up durations (Figure 2). For example, the number of nonvertebral fractures prevented per 100 postmenopausal women with osteoporosis receiving bisphosphonate therapy increased from 1.0 (95% CI, 0.4-1.6) at 12 months to 1.5 (95% CI, 0.8-2.3) at 18 months.

Figure 2. — Shaded areas represent 95% CIs.

We found that 100 postmenopausal women with osteoporosis would need to be treated with a bisphosphonate medication for 12.4 months (95% CI, 6.3-18.4 months) to prevent 1 nonvertebral fracture (ARR = 0.010) (Table 2). In addition, 200 postmenopausal women with osteoporosis would need to be treated with a bisphosphonate for 6.5 months (95% CI, 2.2-10.9 months) to prevent 1 nonvertebral fracture (ARR = 0.005), and 500 postmenopausal women with osteoporosis would need to be treated for 3.3 months (95% CI, 0.2-6.5 months) to prevent 1 nonvertebral fracture (ARR = 0.002).

Table 2. Time to Benefit of Bisphosphonate Therapy for the Prevention of Nonvertebral Fractures Among Postmenopausal Women With Osteoporosis.

Source	Bisphosphonate type	Time to benefit (95% CI), mo
Source	Bisphosphonate type	ARR = 0.002^a	ARR = 0.005^b	ARR = 0.010^c
Liberman et al,³³ 1995	Alendronate	12.5 (0.4-77.6)	16.6 (1.1-88.3)	22.7 (3.0-91.4)
Pols et al,³⁴ 1999	Alendronate	3.4 (0.6-10.6)	5.9 (1.3-16.0)	10.0 (2.6-25.3)
Black et al,⁴³ 2000	Alendronate	6.9 (1.1-24.0)	10.3 (2.9-26.9)	15.4 (6.0-32.8)
Harrington et al,⁴⁴ 2004	Risedronate	1.9 (0.5-4.5)	3.5 (1.0-9.0)	6.7 (2.1-15.7)
Black et al,⁴² 2007	Zoledronic acid	7.6 (2.0-20.6)	12.5 (5.0-26.3)	19.9 (10.1-35.3)
Summary time to benefit	NA	3.3 (0.2-6.5)	6.5 (2.2-10.9)	12.4 (6.3-18.4)
Test of heterogeneity
I², %	NA	0	0	0
P value	NA	.70	.56	.49

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Abbreviations: ARR, absolute risk reduction; NA, not applicable.

^{^a}

Time to prevent 1 nonvertebral fracture per 500 postmenopausal women with osteoporosis receiving bisphosphonate therapy.

^{^b}

Time to prevent 1 nonvertebral fracture per 200 postmenopausal women with osteoporosis receiving bisphosphonate therapy.

^{^c}

Time to prevent 1 nonvertebral fracture per 100 postmenopausal women with osteoporosis receiving bisphosphonate therapy.

The test of heterogeneity across studies was not statistically significant (for primary outcome: I² = 0% for ARR of 0.002 [P = .70], 0% for ARR of 0.005 [P = .56], and 0% for ARR of 0.010 [P = .49]). However, the time to an ARR of 0.010 varied from 6.7 months (95% CI, 2.1-15.7 months) in the Harrington et al⁴⁴ pooled analysis of 4 clinical trials involving risedronate to 22.7 months (95% CI, 3.0-91.4 months) in the Liberman et al³³ study involving alendronate (Table 2). In the 2 largest studies, the TTB was 15.4 months (95% CI, 6.0-32.8 months) for the pooled analysis of the Fraction Intervention Trial (FIT) study⁴³ involving alendronate (ARR = 0.010) and 19.9 months (95% CI, 10.1-35.3 months) for the HORIZON-PFT (Health Outcomes and Reduced Incidence With Zoledronic Acid Once Yearly–Pivotal Fracture Trial) study⁴² involving zoledronic acid (ARR = 0.010).

The TTB for the secondary outcomes of hip fracture, any clinical fracture, and clinical vertebral fracture are shown in Table 3. For hip fracture, the TTBs across studies were relatively similar, ranging from 17.0 months⁴³ to 23.6 months⁴² at an ARR of 0.005; a total of 200 postmenopausal women with osteoporosis would need to be treated with a bisphosphonate for 20.3 months (95% CI, 11.0-29.7 months) to prevent 1 hip fracture (ARR = 0.005) (Table 3). In addition, 200 postmenopausal women with osteoporosis would need to be treated for 7.7 months (95% CI, 3.3-12.1 months) to prevent any clinical fracture (ARR = 0.005). For clinical vertebral fracture, 200 women would need to be treated for 12.1 months (95% CI, 6.4-17.8 months) to prevent 1 fracture (ARR = 0.005). Forest plots of specific ARR thresholds for all outcomes are shown in eFigures 6 to 17 in the Supplement.

Table 3. Time to Benefit of Bisphosphonate Therapy for the Prevention of Hip Fracture, Any Clinical Fracture, and Clinical Vertebral Fracture Among Postmenopausal Women With Osteoporosis.

Outcome and source	Bisphosphonate type	Time to benefit (95% CI), mo
Outcome and source	Bisphosphonate type	ARR = 0.001^a	ARR = 0.002^b	ARR = 0.005^c	ARR = 0.010^d
Hip fracture
Black et al,⁴³ 2000	Alendronate	4.9 (0.9-15.5)	7.9 (2.1-21.4)	17.0 (6.6-36.3)	NR
McClung et al,⁴¹ 2001	Risedronate	9.4 (1.6-31.8)	12.5 (3.2-34.3)	20.8 (8.5-43.0)	NR
Black et al,⁴² 2007	Zoledronic acid	8.1 (1.8-23.7)	12.2 (4.0-29.1)	23.6 (11.4-43.6)	NR
Summary time to benefit	NA	6.7 (0.8-12.6)	10.3 (3.3-17.3)	20.3 (11.0-29.7)	NR
Test of heterogeneity
I², %	NA	0	0	0	NR
P value	NA	.83	.83	.85	NR
Any clinical fracture
Black et al,⁴³ 2000	Alendronate	NR	5.0 (1.0-15.9)	7.5 (2.4-18.3)	11.3 (4.9-22.6)
Black et al,⁴² 2007	Zoledronic acid	NR	4.4 (1.6-9.8)	7.8 (3.8-14.4)	12.9 (7.5-20.6)
Summary time to benefit	NA	NR	4.6 (0.9-8.3)	7.7 (3.3-12.1)	12.3 (7.0-17.5)
Test of heterogeneity
I², %	NA	NR	0	0	0
P value	NA	NR	.88	.95	.78
Clinical vertebral fracture
Black et al,⁴³ 2000	Alendronate	2.9 (0.6-8.5)	4.8 (1.2-12.7)	10.5 (3.8-23.1)	NR
Roux et al,⁴⁵ 2004	Risedronate	1.5 (0.5-3.2)	2.4 (0.6-6.0)	6.1 (1.5-16.3)	NR
Black et al,⁴² 2007	Zoledronic acid	6.2 (3.0-11.3)	8.9 (5.2-14.4)	15.5 (10.9-21.5)	NR
Summary time to benefit	NA	3.3 (0.4-6.2)	5.4 (1.2-9.6)	12.1 (6.4-17.8)	NR
Test of heterogeneity
I², %	NA	37	51	33	NR
P value	NA	.20	.13	.23	NR

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Abbreviations: ARR, absolute risk reduction; NA, not applicable; NR, not reported.

^{^a}

Time to prevent 1 fracture event per 1000 postmenopausal women with osteoporosis receiving bisphosphonate therapy.

^{^b}

Time to prevent 1 fracture event per 500 postmenopausal women with osteoporosis receiving bisphosphonate therapy.

^{^c}

Time to prevent 1 fracture event per 200 postmenopausal women with osteoporosis receiving bisphosphonate therapy.

^{^d}

Time to prevent 1 fracture event per 100 postmenopausal women with osteoporosis receiving bisphosphonate therapy.

Sensitivity Analyses

Risk of bias assessments are provided in eTable 4 in the Supplement. Results from the trim-and-fill analysis suggested that publication bias did not substantially change the results (hazard ratio, 0.73 [95% CI, 0.64-0.83] among the 5 observed studies^{33,34,42,43,44} vs 0.74 [95% CI, 0.63-0.88] among the 5 observed studies^{33,34,42,43,44} plus 1 imputed [hypothetical] study) (eTable 5 and eFigures 18-21 in the Supplement). In the cumulative meta-analysis (eFigures 22-24 in the Supplement), when only the 2 studies consistently rated as having low ROB (both arms of the FIT study^35,36,43 and the HORIZON-PFT⁴²) were included, the estimated TTB for nonvertebral fractures was 17.7 months (95% CI, 8.5-27.0 months) at an ARR of 0.010. The addition of studies with higher or unclear ROB^33,34,44 decreased the TTB to 12.4 months (95% CI, 6.3-18.4 months).

Discussion

In this meta-analysis of pooled results from 10 RCTs^{33,34,35,36,37,38,39,40,41,42} of bisphosphonate therapy, the TTB to prevent 1 nonvertebral fracture among 100 postmenopausal women with osteoporosis receiving a bisphosphonate medication was 12.4 months. These results suggest that bisphosphonate therapy is most likely to benefit postmenopausal women with osteoporosis who have a life expectancy greater than 12.4 months. Given the negative consequences that nonvertebral fractures can have for function, quality of life, and independence, our results suggest that the short-term benefits of bisphosphonate therapy likely outweigh the short-term harms for most postmenopausal older women.

Results vs Previous Studies

To our knowledge, only 1 other study¹⁹ has used quantitative methods to estimate the TTB of bisphosphonate therapy. Van de Glind et al¹⁹ conducted a post hoc analysis of the FIT study using a prespecified pooled cohort of women with osteoporosis receiving alendronate or placebo. Using statistical process control methods, the authors found that an ARR of 0.011 for any clinical fracture was achieved at 11 months. Our study adds to this previous work by performing a meta-analysis that included the FIT and other studies, finding an estimated pooled TTB of 12.3 months (95% CI, 7.0-17.5 months) at an ARR of 0.010 for any clinical fracture. In addition, we quantified the TTB for nonvertebral fractures (12.4 months at an ARR of 0.010), hip fractures (20.3 months at an ARR of 0.005), and clinical vertebral fractures (12.1 months at an ARR of 0.005).

Time to Benefit for Different Fracture Outcomes

Although the TTBs for the prevention of nonvertebral fractures and any clinical fracture were similar, the TTB for hip fractures was the longest of all fracture outcomes and achieved prevention at a lower ARR (20.3 months at an ARR of 0.005). Because of the decreased incidence of hip fractures compared with more common fractures, it takes longer for any intervention to achieve a given ARR threshold. Thus, the longer TTB for hip fractures is partially a consequence of lower hip fracture rates. In addition, the longer TTB for hip fractures may be associated with the mechanism of action of bisphosphonates because the hip contains more cortical bone, which turns over (ie, is reabsorbed and replaced with new bone) more slowly than trabecular bone.^46,47

Heterogeneity

Heterogeneity was generally low across the fracture outcomes, and the results of tests for heterogeneity were not statistically significant. For nonvertebral fractures at an ARR of 0.010, the shortest TTB was 6.7 months in the Harrington et al⁴⁴ pooled analysis of 4 clinical trials involving risedronate therapy compared with a TTB of 15.4 months in the Black et al⁴³ FIT study involving alendronate therapy. One possible reason for this finding is that the initial dose of alendronate was 5.0 mg per day for the first 2 years before the dose was increased to 10.0 mg per day after subsequent data suggested a greater benefit for BMD at this higher dose. The clinical trial involving zoledronic acid⁴² also reported a longer TTB of 19.9 months at an ARR of 0.010. This finding may be associated with differences in patient populations or a higher background incidence of previous receipt of medications for osteoporosis, including bisphosphonates (approximately 14.5% of patients in the Black et al⁴² study). For the secondary outcome of hip fracture, the TTBs across studies were relatively similar, ranging from 17.0 months⁴³ to 23.6 months⁴² at an ARR of 0.005.

Harms and Burdens of Bisphosphonate Therapy

Substantial uncertainty exists regarding which individual patients will experience some of the short- and long-term harms and burdens of bisphosphonate therapy. Oral bisphosphonates can be associated with upper GI adverse effects that are commonly reported as the primary reason for treatment discontinuation.^48,49 Notably, pooled analyses of RCTs^21,50 suggested either no increase or a slight increase in mild GI adverse effects (eg, acid reflux and esophageal irritation)²¹ and no increase in severe GI adverse effects (eg, esophageal ulcers or esophagitis).⁵⁰ Differences between RCTs and clinical experience may reflect selection bias (eg, participants in clinical trials may be healthier) or a high background incidence of GI problems in the general population.^51,52,53 For example, approximately 30% of participants reported GI problems in both the alendronate and placebo groups in the FIT study.⁵⁴ Patient counseling and education is needed to minimize the risk of erosive esophagitis associated with improper administration of treatment.⁵⁵ One immediate harm of intravenous zoledronic acid is an infusion reaction characterized by fever, myalgias, and fatigue.^12,13 Symptoms generally resolve within 1 to 3 days; however, in rare cases, patients can have musculoskeletal pain that lasts longer than 1 week.^13,56 Although more serious adverse events, such as atypical femur fractures and osteonecrosis of the jaw, can occur, the absolute risks are small compared with the reduction in fractures.⁵⁷

Individualization of Bisphosphonate Treatment Discussions

Our study has implications for individualizing treatment discussions and identifying older women with osteoporosis who may be most likely to benefit from bisphosphonate therapy. For some older women, the delayed benefits of bisphosphonates (decreased fracture risk) may be more important than the immediate risks (most commonly upper GI symptoms). For other older women, the prospect of experiencing immediate adverse effects in exchange for a 1 in 100 chance of benefit in 12.4 months may lead to a decision to forego bisphosphonate therapy. Given the uncertainty regarding harms and the substantial heterogeneity in life expectancy among older women, it is important to consider the values and preferences of individual older women when making decisions about bisphosphonate therapy.

Strengths and Limitations

This study has strengths. A major strength is that this meta-analysis is the first, to our knowledge, to use quantitative methods to estimate pooled TTBs for various fracture outcomes.

The study also has limitations. First, some included clinical trials used dosing regimens that were different than those commonly prescribed. For example, the FIT study used an initial dose of alendronate at 5.0 mg per day for 2 years, which was subsequently increased to 10.0 mg per day. In response to data suggesting that equivalent dosing (eg, 70.0 mg once weekly vs 10.0 mg once daily) is associated with increases in tolerability and adherence, alendronate is now typically prescribed at 70.0 mg once per week.⁵⁸

Second, our results may not be generalizable to populations that were not represented in the original RCTs (ie, postmenopausal women with diagnoses of osteoporosis that were based on low BMD or baseline vertebral fracture). We did not include RCTs involving men with osteoporosis or postmenopausal women with initial hip fracture. In addition, postmenopausal women with older age and multimorbidity were often excluded from the initial RCTs, despite having a high fracture risk even after accounting for competing mortality risk.^59,60 Treatment decisions in this population are challenging because guidelines generally do not provide recommendations, and the evidence supporting treatment benefits primarily comes from post hoc analyses, small RCTs, and observational studies.^{61,62,63,64,65} Many clinical practice guidelines^10,26,66 now recommend treatment initiation based on specific fracture risk thresholds using risk assessment tools, such as the Fracture Risk Assessment Tool, for patients who do not have a BMD T score of −2.5 or lower or a previous low-trauma fracture. Thus, for patients starting bisphosphonate therapy who were not well represented in the original RCTs included in our meta-analysis, the results of the present study may serve as a starting point for conversations that incorporate patient values and preferences rather than a definitive TTB value.⁶⁰

Third, our analyses assess the potential benefits of bisphosphonate therapy for the reduction and prevention of fractures, and we do not directly estimate the short- or long-term harms. For example, the risk of atypical femur fracture varies substantially based on duration of bisphosphonate treatment (eg, longer duration is associated with increases in risk) and race (eg, Asian women are at higher risk compared with White women).⁵⁷ This variation suggests that individualization of risk-benefit decisions based on specific patient characteristics and expected duration of bisphosphonate therapy (eg, when deciding to treat younger postmenopausal women with longer life expectancies) is needed.

Fourth, our sensitivity analysis comprising only studies with low ROB^42,43 revealed a longer TTB for nonvertebral fractures of 17.7 months (95% CI, 8.5-27.0 months) at an ARR of 0.010 compared with 12.4 months (95% CI, 6.3-18.4 months) at the same ARR threshold when all studies^{33,34,42,43,44} were included. The broad overlap between CIs suggests that our summary TTB estimates were not substantially biased by lower-quality studies. However, there does appear to be a pattern of lower-quality studies having shorter TTBs, with the inclusion of lower-quality studies decreasing the summary TTB estimates.

Conclusions

This meta-analysis found that 100 postmenopausal women with osteoporosis would need to be treated with a bisphosphonate medication for 12.4 months to avoid 1 nonvertebral fracture. This finding suggests that bisphosphonate treatment is most appropriate for postmenopausal women with a life expectancy greater than 12.4 months. These results can be used to inform discussions between clinicians and older postmenopausal women who seek to balance the potential immediate harms and burdens of bisphosphonate therapy with the delayed benefit of decreased fracture risk. Because most postmenopausal women have a life expectancy that is substantially greater than 12.4 months, the results suggest that bisphosphonate therapy is likely to be beneficial for most older women with osteoporosis.

Supplement.

eMethods. Additional Details Regarding Statistical Methods

eTable 1. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 Checklist

eTable 2. Definitions of Nonvertebral and Other Fractures Used Across Clinical Trials

eTable 3. Clinical Trials Excluded and Reasons for Exclusion

eTable 4. Risk of Bias Assessments From Systematic Reviews and Meta-analyses Included in Literature Search

eTable 5. Hazard Ratios and 95% CIs for Observed Studies and Observed Plus Imputed Studies in Trim-and-Fill Analysis for Primary Outcome of Nonvertebral Fracture

eFigure 1. Comparison Between Weibull Survival Curves and Kaplan-Meier Curves in Control and Intervention Groups From Black et al (2000) Study for Outcome of Nonvertebral Fracture

eFigure 2. Comparison Between Weibull Survival Curves and Kaplan-Meier Curves in Control and Intervention Groups for Black et al (2007) Study for Outcome of Nonvertebral Fracture

eFigure 3. Comparison Between Weibull Survival Curves and Kaplan-Meier Curves in Control and Intervention Groups for Harrington et al (2004) Study for Outcome of Nonvertebral Fracture

eFigure 4. Comparison Between Weibull Survival Curves and Kaplan-Meier Curves in Control and Intervention Groups for Liberman et al (1995) Study for Outcome of Nonvertebral Fracture

eFigure 5. Comparison Between Weibull Survival Curves and Kaplan-Meier Curves in Control and Intervention Groups for Pols et al (1999) Study for Outcome of Nonvertebral Fracture

eFigure 6. Time to Benefit for Nonvertebral Fracture Across Individual Studies for Absolute Risk Reduction of 0.010

eFigure 7. Time to Benefit for Nonvertebral Fracture Across Individual Studies for Absolute Risk Reduction of 0.005

eFigure 8. Time to Benefit for Nonvertebral Fracture Across Individual Studies for Absolute Risk Reduction of 0.002

eFigure 9. Time to Benefit for Hip Fracture Across Individual Studies for Absolute Risk Reduction of 0.005

eFigure 10. Time to Benefit for Hip Fracture Across Individual Studies for Absolute Risk Reduction of 0.002

eFigure 11. Time to Benefit for Hip Fracture Across Individual Studies for Absolute Risk Reduction of 0.001

eFigure 12. Time to Benefit for Any Clinical Fracture Across Individual Studies for Absolute Risk Reduction of 0.010

eFigure 13. Time to Benefit for Any Clinical Fracture Across Individual Studies for Absolute Risk Reduction of 0.005

eFigure 14. Time to Benefit for Any Clinical Fracture Across Individual Studies for Absolute Risk Reduction of 0.002

eFigure 15. Time to Benefit for Clinical Vertebral Fracture Across Individual Studies for Absolute Risk Reduction of 0.005

eFigure 16. Time to Benefit for Clinical Vertebral Fracture Across Individual Studies for Absolute Risk Reduction of 0.002

eFigure 17. Time to Benefit for Clinical Vertebral Fracture Across Individual Studies for Absolute Risk Reduction of 0.001

eFigure 18. Funnel Plot of Included Studies for Outcome of Time to Benefit in Preventing Nonvertebral Fracture at Absolute Risk Reduction of 0.010

eFigure 19. Funnel Plot of Trim-and-Fill Analysis With Imputed Studies

eFigure 20. Funnel Plot of Included Studies for Outcome of Nonvertebral Fracture Expressed as Hazard Ratio

eFigure 21. Funnel Plot of Trim-and-Fill Analysis for Outcome of Nonvertebral Fracture Expressed as Hazard Ratio

eFigure 22. Cumulative Meta-analysis Summary of Time to Benefit for Primary Outcome of Nonvertebral Fracture at Absolute Risk Reduction of 0.010

eFigure 23. Cumulative Meta-analysis Summary of Time to Benefit for Primary Outcome of Nonvertebral Fracture at Absolute Risk Reduction of 0.005

eFigure 24. Cumulative Meta-analysis Summary of Time to Benefit for Primary Outcome of Nonvertebral Fracture at Absolute Risk Reduction of 0.002

eReferences

Click here for additional data file.^{(1MB, pdf)}

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