Relative Effectiveness of Osteoporosis Treatments to Reduce Hip Fractures in Patients with Prostate Cancer on Continuous Androgen

Deprivation Therapy:

Systematic Review, Network Meta-Analysis and Cost-Effectiveness Analysis

by

Yeesha Poon

A thesis submitted in conformity with the requirements

for the degree of Doctor of Philosophy

Department of Pharmaceutical Sciences

University of Toronto © Copyright by Yeesha Poon, 2018

ii

Relative Effectiveness of Osteoporosis Treatments to Reduce Hip Fractures in Patients with

Prostate Cancer on Continuous Androgen Deprivation Therapy:

Systematic Review, Network Meta-Analysis and Cost-Effectiveness Analysis

Yeesha Poon

Doctor of Philosophy

Department of Pharmaceutical Sciences

University of Toronto

2018

Abstract

Background: Androgen deprivation therapy (ADT) is widely used in men with advanced prostate

cancer, and can lead to loss of bone mineral density (BMD) and fractures.

Osteoporosis treatments are effective in improving BMD, and reducing risk of hip fractures.

Given the potential benefits, risks, and widely varying costs of osteoporosis treatments in our

population, we assessed the effects and cost-effectiveness of treatments.

Methods: A systematic review and a network meta-analysis were conducted using randomized

controlled trials (RCT) that evaluated bisphosphonates, denosumab, toremifene, and raloxifene

in patients with non-metastatic prostate cancer on ADT. Outcomes included percentage change

in BMD from placebo at different bone sites and incidence rates of any fractures.

A cost-utility model was developed using a state transition model simulating the progression of

prostate cancer, the incidence of hip fractures and an adverse event from osteoporosis treatments.

The risk of fracture was conditional on BMD changes, which were modeled as the means of

determining the effect of treatment on health and cost outcomes. The outcomes were predicted

hip fracture incidence, quality-adjusted life years (QALYs), expected costs, and incremental

cost-effectiveness ratios.

iii

Results: Thirteen RCTs were included for analysis. The largest BMD improvement compared to

placebo at 12-month at femoral neck site was risedronate 6.77% (95% CrI:-6.87-20.27%). Two

studies reported fractures; toremifene and denosumab studies reported improved incidence of

new vertebral fracture outcome vs placebo (2.5% vs 4.9%;p

iv

Acknowledgments

Completing this thesis took tremendous amount of time, effort and perseverance. I would not

have been able to achieve such accomplishment without acknowledging the following people.

Dr. Murray Krahn was instrumental in guiding me through these years. His support, trust,

encouragement and patience during some turbulence time throughout this process were

characteristics of a true mentor.

I also would like to thank Dr. Shabbir Alibhai, who responded to my relentless questions on

clinical practice and Dr. Petros Pechlivanoglou on network meta-analysis. Knowing their times

were precious, I always felt their willingness to help. I also appreciated the support and advice

received from Dr. David Naimark, Dr. Jeffrey Hoch and Dr. Manny Papadimitropoulos. All of

them have pushed me to go that extra mile and get the most out of the learning process.

Last, but not least, I thank my husband, Paul, and our children, Caitlin, Brandon and Lucas, who

put up with my numerous nights and weekends on completing this thesis. Without their support

and understanding, none of this would have been possible.

v

Table of Contents

Acknowledgments ..................................................................................................................... iv

Table of Contents ........................................................................................................................v

List of Tables ............................................................................................................................ ix

List of Figures .............................................................................................................................x

List of Appendices .................................................................................................................... xi

1. Introduction .............................................................................................................................1

1.1 Background – Prostate Cancer.......................................................................................1

1.2 Treatments for Prostate Cancer .....................................................................................2

1.3 Hip Fractures ................................................................................................................3

1.3.1 Gender Differences in Risk of Hip Fractures ..........................................................3

1.3.2 ADT as a Risk Factor for Hip Fractures .................................................................3

1.3.3 BMD and Age as Risk Factors for Hip Fractures ....................................................4

1.3.4 Screening for Fracture Risks ..................................................................................5

1.4 Treatments for ADT-Induced Osteoporosis ...................................................................6

1.5 Rationale for Analyses ..................................................................................................7

2. Literature Review ....................................................................................................................9

2.1 Cost-effectiveness Analysis of Screening for Osteoporosis in Men with Prostate

Cancer .....................................................................................................................................9

2.2 Current Gaps ............................................................................................................... 10

vi

3. Methods ............................................................................................................................... 12

3.1 Systematic Review - Background .............................................................................. 12

3.2 Steps of the Systematic Review ................................................................................. 12

3.2.1 Research Question .............................................................................................. 12

3.2.2 Data Sources and Searches .................................................................................. 12

3.2.3 Study Selection ................................................................................................... 13

3.2.4 Quality of Study and Risk of Bias Appraisal ....................................................... 16

3.3 Network Meta-Analysis .............................................................................................. 17

3.3.1 Network Meta-Analysis - Background ................................................................. 17

3.3.2 Objective of the NMA .......................................................................................... 18

3.3.3 Analysis ............................................................................................................... 18

3.3.4 Evidence Presentation .......................................................................................... 20

3.4 Cost-Effectiveness Analysis ........................................................................................ 20

3.4.1 Cost-Utility Analysis – Background ..................................................................... 20

3.4.2 Economic Assumptions ........................................................................................ 21

3.4.3 Population ............................................................................................................ 21

3.4.4 Treatment Strategies ............................................................................................ 22

3.4.5 Model Structure ................................................................................................... 22

3.4.6 Model Parameters ................................................................................................ 23

3.4.7 Adverse Effects .................................................................................................... 25

vii

3.4.8 Mortality .............................................................................................................. 25

3.4.9 Quality of Life ..................................................................................................... 25

3.4.10 Costs .................................................................................................................... 26

3.5 Analysis and Outcomes ............................................................................................... 26

3.5.1 Expected Value of Perfect Information................................................................ 27

4. Results .................................................................................................................................. 30

4.1 Network Meta-Analysis ............................................................................................. 30

4.1.1 Data Synthesis and Analysis ................................................................................ 30

4.1.2 BMD Percentage Change Compared to Placebo .................................................. 31

4.1.3 BMD Percentage Change Between Active Treatments ........................................ 32

4.1.4 Fracture Risk ....................................................................................................... 32

4.2 Cost-Effectiveness Analysis ........................................................................................ 33

4.2.1 Model Validation ................................................................................................. 33

4.2.2 Base Case Analysis .............................................................................................. 34

4.2.3 Uncertainties ........................................................................................................ 36

4.3 Sensitivity Analyses ................................................................................................ 37

4.3.1 Deterministic Sensitivity Analyses ..................................................................... 37

4.4 Expected Value of Perfect Information ...................................................................... 38

5. Discussion and Conclusions .................................................................................................. 40

5.1 Network Meta-Analysis .......................................................................................... 40

viii

5.1.1 Strengths and Limitations..................................................................................... 42

5.2 Cost-Effectiveness Analysis ..................................................................................... 43

5.2.1 Strengths and Limitations..................................................................................... 45

5.2.2 Implications for Practice ...................................................................................... 46

5.2.3 Implications for Research ..................................................................................... 46

6. Tables.................................................................................................................................... 48

7. Figures .................................................................................................................................. 57

8. References............................................................................................................................. 69

9. Appendices ........................................................................................................................... 81

9.1 Appendix 1: Search Strategies ..................................................................................... 81

9.2 Appendix 2: Characteristics of Included Studies .......................................................... 83

9.3 Appendix 3: BMD Percentage Change from Baseline ................................................. 85

9.4 Appendix 4: Deterministic Sensitivity Analyses ......................................................... 87

9.5 Appendix 5: Maximum Net Benefit and Average Net Benefit per Strategy ................. 88

ix

List of Tables

Table 1: Cost-effectiveness Analysis - Model Input Parameters

Table 2: Utility Input Parameters

Table 3: Cost Input Parameters

Table 4: Result of Difference in Mean BMD Change between Active Treatments at Total Hip,

Lumbar Spine, and Femoral Neck Sites

Table 5: Probabilistic Analyses Base Case Results

Table 6: Probabilistic Analyses Base Case – Net Monetary Benefits Results

Table 7: Incidences of Hip Fracture

Table 8: Deterministic Sensitivity Analyses Results

x

List of Figures

Figure 1: Cost-effective Analysis Model Schematic

Figure 2: PRISMA Flow Diagram

Figure 3: Network Diagram of Treatments – Total Hip, Lumbar Spine and Femoral Neck Sites

Figure 4: Visual Inspection of Convergence for BMD Change Compared to Placebo at the

Femoral Neck Site

Figure 5: Results (BMD Percentage Change compared to Other Treatments) Total Hip

Figure 6: Results (BMD Percentage Change compared to Other Treatments) Lumbar Spine

Figure 7: Results (BMD Percentage Change compared to Other Treatments) Femoral Neck

Figure 8: Cost-Effectiveness Frontier

Figure 9: Cost-Effectiveness Acceptability Curve – PSA

Figure 10: Expected Value of Perfect Information Graph

Figure 11: Cumulative Distribution on Frequency of Incremental Net Health Benefit for

Probabilistic Analysis Results

xi

List of Appendices

Appendix 1: Search Strategies

Appendix 2: Characteristics of Included Studies

Appendix 3: BMD Percentage Change from Baseline

Appendix 4: Deterministic Sensitivity Analyses

Appendix 5: Maximum Net Benefit and Average Net Benefit per Strategy

1

1. Introduction

1.1 Background – Prostate Cancer

Prostate cancer is the most prevalent cancer in men in most developed countries.[1] Despite its

high prevalence, the prognosis for most diagnosed men is good, with 96% of treated patients

surviving for ≥5 years.[1] Prostate cancer is mainly a disease of older men. It is diagnosed most

frequently in men between 60 and 69 years of age.[1]

The etiology of prostate cancer starts in the early stages of cancerous transformation; in which

small clumps of cancer cells remain confined to the otherwise normal prostate gland. This is

known as localized disease. Over time, the cancer cells multiply and spread to the prostate and

beyond the prostate capsule to form a locally advanced tumour.[2] Localized tumours may

become metastasized, become more aggressive, and begin to invade nearby structures and spread

through the pelvic lymph nodes and, via the bloodstream, to distant parts of the body such as

lungs, bladder, liver, and adrenal glands. Metastatic prostate cancer most commonly affects the

bones.[2]

While localized prostate cancer is often asymptomatic, many patients with locally advanced

disease will suffer from urinary outflow obstruction, hematuria, urinary tract infections and

irritation during bladder voiding.[3] In metastatic disease, patients may suffer from bone pain,

weakness of the lower extremities or paralysis if the spinal cord is compressed by bony

metastases.[4] While these symptoms may be rare, they can have a significant impact on quality

of life.

2

However, if prostate cancer is detected early, treatment can be effective. The mortality rate for

prostate cancer has decreased by 3.3% per year since 2001. This is likely due to a combination of

earlier detection using prostate-specific antigen (PSA) tests to screen for prostate cancer and

improved treatment options.[1]

1.2 Treatments for Prostate Cancer

Androgen deprivation therapy (ADT) removes (or suppresses) testosterone from the body to

control prostate cancer. The suppression of testosterone by medication is known as medical

castration.[5] ADT is prescribed as primary, adjuvant, or neoadjuvant treatment [6] in men with

advanced prostate cancer or with biochemical recurrence.[7] It may prolong survival by

decreasing tumor size and activity by suppressing androgens.

ADT including long-acting synthetic luteinizing hormone releasing hormone (LHRH) agonists

were introduced in the 1980s and have improved the treatment of prostate cancer by allowing

effective reduction of testosterone levels without the psychological consequences of orchiectomy

or surgical castration.[8]

Due to the negative psychological effect of surgical castration,[9] LHRH agonists have become

the “gold standard” in many countries. In one study, 78% of patients chose medical castration

over orchiectomy.[10] LHRH agonists are the most commonly prescribed treatment for men with

advanced prostate cancer.[7]

3

1.3 Hip Fractures

1.3.1 Gender Differences in Risk of Hip Fractures

The prevalence of osteoporosis and the risk of fracture are both higher in women than in men.

This is partially due to differences in bone mineral density (BMD), bone size, and bone strength

between men and women. Even though women fracture more often, men tend to have worse

outcomes after fractures.[11]

Gender differences in the epidemiology of hip fracture were extensively reported. The following

results were found in meta-analyses:[12, 13]

• men had higher excess annual mortality after hip fracture than in women;

• men were at an average of 4 years younger than women at the time of fracture;

• men are sicker than age-matched controls and women with hip fractures;

• men had substantially higher mortality after hip fracture (i.e., the 1-year mortality for

men ranged from 9.4% to 37.1%, compared to 8.2% to 12.4% in women. At 2 years, mortality in

men was reported as high as 42%, compared to 23% for women.)

1.3.2 ADT as a Risk Factor for Hip Fractures

Androgen suppression can mediate increased rates of bone resorption and impair new bone

formation.[14] This can lead to the loss of BMD and subsequent fractures.[15]

A number of studies have shown that ADT is associated with significant bone loss and increased

osteoporotic fracture risk [16-20] and such risk increases over time with continued use. The

4

prevalence of osteoporosis was found to be higher at 49% after 4 years of ADT use and 81%

after 10 or more years compared to 35% for hormone-naive men with prostate cancer after 4

years.[21]

Two Canadian population-based studies in men with prostate cancer found that ADT use is

associated with increased fragility fracture risk compared to men without ADT (HR 1.65).[16,

22] Another study also found within 5 years of ADT initiation, 19.4% of subjects had a clinical

fracture compared to 12.6% of controls (p < 0.001). Moreover, statistically higher rates of

fracture were noted at every site examined, including spine, hip, radius, and skull.[18]

A systematic review that assessed long-term side effects of ADT in patients with non-metastatic

prostate cancer showed that its use was associated with substantial decline in BMD in the first

year, and slower decline in subsequent years, with increased fracture rates within 5 years.[23, 24]

1.3.3 BMD and Age as Risk Factors for Hip Fractures

Low BMD has been recognized as a major risk factor for fractures. Although BMD

measurements can be taken at different sites (i.e., total hip, lumbar spine and femoral neck),

BMD measurement at the femoral neck site is a well-accepted predictor of hip fractures.[25-27]

In fact, BMD measurements, as a measure of risk for hip fracture, have been considered to be

comparable with the measurements of blood pressure to determine risk for cardiovascular

disease.[26] The National Osteoporosis Foundation guidelines recommend initiation of drug

therapy based on the T-Score.[28], which is calculated from the BMD value. However,

prediction of hip fracture can be enhanced by employing other independent risk factors, in

particular, age, which is one of the most important risk factors.[26] As patients age, the risk of

hip fractures increases. This association has been shown to be reproducible in several

5

populations. Actual hip fracture rates were compared between Canada, US and Germany, all of

which showed a consistent steep increase in incidence of hip fracture with advancing age in both

men and women.[29]

1.3.4 Screening for Fracture Risks

Clinical practice guidelines on BMD testing in patients with prostate cancer on ADT are

lacking.[30] In Canada, the British Columbia Cancer Agency (BCCA) recommends baseline

BMD if ADT is used for >6 months [31] and Alberta Health Services [32] recommends using the

WHO Fracture Risk Assessment Tool (FRAX®) with BMD. The US Endocrine Society [33],

Ontario Prostate Cancer Guidelines [34] and the National Comprehensive Cancer Network [35]

suggest measuring BMD in men 50-69 with risk factors (e.g., ADT). Such testing identifies

persons with osteoporosis who could benefit from specific therapy.

The most established way of measuring BMD is the use of dual energy x-ray absorptiometry

(DXA) to diagnose for osteoporosis and for fracture risk assessment in men.[36]

The BMD value from white women is a standard reference used to calculate T-score, which is

the number of standard deviation (SD) above or below the mean young adult peak bone density

as the reference group.[37]

1. Normal is a T-score +2.5 to –1.0

2. Low bone mass is a T-score of –1.1 to –2.4 inclusively

3. Osteoporosis is a T-score equal to or less than -2.5.

4. Severe osteoporosis is a T- score equal to or less than -2.5 and a fragility fracture.

6

The 2010 Canadian Practice Guidelines recommend that all individuals with a T-score of the

spine or hip ≤-2.5 should be considered as having at least moderate 10-year risk of osteoporotic

fractures.[38]

The BCCA’s Genito-urinary Tumour Group recommends if BMD, history or plain films identify

'osteoporosis' (defined here as a T-score

7

shown to modestly increase BMD at the hip and lumbar spine sites and was shown to reduce the

incidence of new vertebral fractures, but no statistical difference was found for hip fractures.[17,

43] Denosumab was also found to reduce pathological fractures in men with metastatic prostate

cancer.[44]

Toremifene, a selective estrogen receptor modulator (SERM), has been studied to reduce fracture

risks in men receiving ADT. It was found that the 2-year incidence of new vertebral fractures

had a significant relative risk reduction of 50%. Also, the incidence in all fractures was 10.1%

(47 patients) with placebo and 6.3% with toremifene, which is a significant relative risk

reduction of 38% (95% CI 2.2 to 60.2, p=0.036).[45] Toremifene is not currently available in

Canada.

All the treatments are effective in preventing bone loss and increasing bone mass and can help

reduce the risks of fragility fractures such as hip fractures.[43, 46, 47] However, osteoporosis

medications have known adverse effects which include osteonecrosis of the jaw (ONJ) with

bisphosphonate [48] or denosumab use,[49] and venous thromboembolism with long-term use of

SERMs, such as raloxifene.[50] Therefore, the use of osteoporosis treatments require balancing

benefit and risk. Osteoporosis treatments also vary widely in cost, with newer medications being

substantially more costly than older, off-patent medications.

1.5 Rationale for Analyses

The consequences of fracture are grave. Patients with hip fracture have increased morbidity,

mortality and cost. Hip fractures cause the most morbidity [51] and are associated with a higher

risk of death (HR 4.13) in the first year after a hip fracture compared to those without

fractures.[52] Loss of function and independence may be overwhelming, with 40% of affected

8

persons unable to walk independently, and 60% requiring assistance a year later.[51] The

economic burden of fractures in Canadian men was estimated at $570 million in the year 2007 to

2008.[53] Hospitalizations following hip fractures were most costly at approximately $20,163

per hospitalization. Over 70% of all fractures occurred in patients older than 70 years with the

highest number of hospitalizations observed in the 81 to 90-year old age group.[53]

There are published reviews on effectiveness of bisphosphonates [54, 55] in improving BMD in

men on ADT. There is, however, no review that includes newer agents (i.e., denosumab) even

though it has been studied in this setting. Furthermore, there is no head-to-head randomized

controlled trial (RCT) comparing two or more active treatments.

The economic attractiveness of reducing the risk of having a hip fracture using different

treatments with varying effectiveness and risks in men with locally advanced prostate cancer

treated with ADT is unknown.

Therefore, from a clinical and policy perspective, there is a potential benefit in treating prostate

cancer patients initiating on ADT who are at risks for osteoporosis; hence reducing risks of

fractures. Although screening of osteoporosis may be recommended in this population, it would

be of interest to treating physicians and policy makers to determine what treatment would be

most effective and cost-effectiveness in reducing hip fractures in prostate cancer patients on

continuous ADT.

9

2. Literature Review

Although studies were found on cost-effectiveness analyses of osteoporosis treatment in

reducing risks of fractures, they were mainly studied in women.[56, 57] At the time of the

systematic review, in men with prostate cancer, there was no systematic review that specifically

evaluated the effectiveness of all available osteoporosis treatments in improving BMD or

fracture risks. Recently, the Cancer Care Ontario working group published a systematic review

and a meta-analysis and found that bisphosphonates were found to be effective in increasing

BMD, but no benefit has been shown in preventing fractures among patients with non-metastatic

prostate cancer. Denosumab was shown to improve BMD and reduce the incidence of new

vertebral fractures in men with non-metastatic prostate cancer.[58]

Lastly, there is no cost-effectiveness analysis that was published between no treatment,

bisphosphonates, denosumab and raloxifene.

2.1 Cost-effectiveness Analysis of Screening for Osteoporosis in Men with

Prostate Cancer

There was one cost-effectiveness analysis that examined the prostate cancer population, but it

was related to screening patients. It evaluated the different screening strategies to prevent

fractures in men who were receiving ADT in the US.[59] A Markov state-transition model

simulated the progression of prostate cancer and the incidence of hip fractures was developed

with a hypothetical cohort of men aged 70 years with locally advanced or high-risk localized

prostate cancer starting a 2-year course of ADT after radiation therapy.

10

There were three arms to the model; 1) No BMD test or alendronate therapy, 2) a BMD test

followed by selective alendronate therapy for patients with osteoporosis, or 3) universal

alendronate therapy without a BMD test. It was found that in patients starting adjuvant ADT for

locally advanced or high-risk localized prostate cancer, a BMD test followed by selective

alendronate for those with osteoporosis is a cost-effective use of resources.

The incremental cost-effectiveness ratio (ICER) for the strategy of a BMD test and selective

alendronate therapy for patients with osteoporosis and universal alendronate therapy without a

BMD test were $66,800 per QALY gained and $178,700 per QALY gained, respectively.

Therefore, the authors concluded that, among patients who begin adjuvant ADT for locally

advanced or high-risk localized prostate cancer, BMD testing followed by selective alendronate

for those with osteoporosis is cost-effective; in addition, for patients at higher risk for hip

fractures (i.e., older patients and those with histories of fracture or low BMD before ADT),

routine use of alendronate without BMD testing is justifiable.

2.2 Current Gaps

The costs of managing hip fractures is quite significant to the healthcare system and reducing

risks in patients experiencing a hip fracture is important from a quantity and quality of life

perspective. A cost-effectiveness analysis on the use of bisphosphonates, denosumab or

raloxifene on the reduction of hip fracture in men treated with ADT with potential adverse event

from the osteoporosis treatment would be important from the perspective of the Ministry of

Health or treating physicians.

Furthermore, there is no relative effectiveness review on the different osteoporosis treatments in

this population on BMD improvement or reduction in fracture risks. The objective of the project

11

was to first, identify and synthesize evidence on the effectiveness of bisphosphonates,

denosumab and raloxifene in reducing the risks of hip fractures and/or having BMD

improvement in patients who were treated with ADT using LHRH agonists for at least 6 months.

A network meta-analysis (NMA) was then conducted, as there is no randomized controlled trial

that evaluated all active treatments in our population. Lastly, a cost-effectiveness analysis was

performed in the same population to inform the Ministry of Health on potential decisions on

reimbursement of these treatments.

12

3. Methods

3.1 Systematic Review - Background

A systematic review was completed with the goal of reducing bias by identifying, appraising,

and synthesizing all relevant studies.[60] It provided a detailed and comprehensive plan and

search strategy a priori to identify and synthesize evidence on the efficacy of the use of

bisphosphonates, denosumab and raloxifene in reducing risks of fragility (i.e., hip) fractures in

patients who were treated with ADT using LHRH agonists continuously for at least 6 months of

use. The data gathered was used to conduct a network meta-analysis (NMA).

3.2 Steps of the Systematic Review

3.2.1 Research Question

The research question that guided the study was: What is the most effective fragility fracture

prevention strategy (i.e., IV zoledronic acid, denosumab, oral bisphosphonates or toremifene) in

patients 65 years of age or older with locally advanced prostate cancer (stage T3/4 M0) who

were on adjuvant ADT for at least six months and are progressing through prostate cancer states

until death?

3.2.2 Data Sources and Searches

We developed comprehensive a priori search strategies in conjunction with an information

specialist. We searched MEDLINE (OVID, 1946-September 2015) and EMBASE (1970-

September 2015) for all RCTs assessing interventions of interest in patients with prostate cancer

13

(please refer to Appendix 1 for search strategies). No language restriction was applied. Two

reviewers (YP & MEH) independently screened citations from literature search and extracted

data. Conflicts between reviewers were resolved through consensus.

The Preferred Reporting Items for Systematic reviews and Meta-analyses (PRISMA) guided the

analysis [61].

3.2.3 Study Selection

3.2.3.1 Screening criteria

A study was considered to be not relevant if it met one of the following criteria:

• letter, editorial, review, or lay press article

• Non-human studies

• endpoints which did not include evaluation of fragility fractures, or BMD values

Inclusion criteria comprised of RCTs in patients with prostate cancer 18 years of age who

received ADT continuously for ≥6 months. Patients must be randomized to an active treatment

or placebo and have measured BMD at baseline and at end of study.

We excluded RCTs with endpoints which did not include evaluation of fragility fractures, or

BMD evaluation. We also excluded RCTs of patients with metastatic disease or of non-human

studies. Letters, editorials, reviews or other secondary research studies, cross over studies, and

lay press articles were also excluded.

All RCTs that met the eligibility criteria were included in this analysis.

14

Active treatments included bisphosphonates (of any strength or route of administration) such as

alendronate, clodronate, etidronate, pamidronate, risedronate or zoledronic acid (ZA), SERMs

such as raloxifene and toremifene, and denosumab.

Screening of articles was based on the titles, abstracts, and keywords of each study. The

screening criteria was applied as broadly as possible to ensure that only irrelevant studies were

excluded. The full-text reports of all potentially relevant articles and of articles that were

designated as “unclear” were retrieved for review.

Screening of articles was based on the titles, abstracts, and keywords of each study. The

screening criteria was applied as broadly as possible to ensure that only irrelevant studies were

excluded. The full-text reports of all potentially relevant articles and of articles that were

designated as “unclear” were retrieved for review.

3.2.3.2 Data Extraction

The data extraction form was tested on three included studies and modified as required. Data

extraction began when agreement was noted between the reviewers. Then the reviewers

independently extracted all of the data using the standardized data extraction form. Data were

stored and managed in Microsoft Excel tables. Discrepancies were resolved by discussion

amongst the reviewers.

From the included RCTs, data extractions were based on:

Study characteristics: year of conduct, sample size, study duration, intervention and comparator,

respective treatment dose and length of treatment

15

Patient characteristics: number of patients, mean age and standard deviation, BMD at baseline,

osteoporosis status (T-score), history and type of baseline fracture (if available)

Outcome results: binary outcomes (e.g., fracture or no fracture), or the number of fractures in

each treatment arm was extracted, if available. For continuous data (e.g., lumbar spine, femoral

neck and total hip BMD value), the percentage or absolute change from baseline in all

intervention groups were extracted. If the BMD change from baseline was not provided, then the

value at end of follow-up and the baseline value were used to calculate the change. Standard

errors (SEs) were used to calculate confidence intervals; the 95% confidence interval is equal to

1.96×SE on either side of the mean.

Possible modifiers included the dosages of each intervention, allowed cotreatment (combination

therapies), the length of follow up (1, 5, and 10 years+), duration of ADT treatment, age of

patients, and previous and types of fractures. Therefore, the year of study, interventions, dose,

concomitant therapy (vitamin D and calcium), sample size, duration of ADT use, baseline BMD,

duration of study and patients’ age were abstracted.

The primary outcome was percentage change in BMD compared to baseline or placebo. When

standard error or standard deviation of BMD was not reported, attempts were made to contact the

authors for missing data, and then established methods were used to impute values [62].

Otherwise, data were estimated from graphs, when possible, using WebPlotDigitizer.[63] The

percentage change in BMD was extracted at 12 months to provide consistency in data analysis.

The secondary outcome was fracture rates.

16

3.2.4 Quality of Study and Risk of Bias Appraisal

Bias is a systematic error that can be introduced into randomized controlled trials. Bias can occur

at any phase of the study, including study design, data collection, or process of data analysis.

Bias, therefore, can be reduced by rigorously following proper study design process and

implementation. As some degree of bias is nearly always present in a published study, assessing

bias can help determine how they can influence a study's conclusions.

The validity of individual trials was evaluated using the Risk of Bias instrument, endorsed by the

Cochrane Collaboration.[64, 65] This instrument was used to evaluate the following key

domains: 1) randomization generation; 2) allocation concealment; 3) blinding of participants,

personnel and outcome assessors; 4) incomplete outcome data (withdrawal); 5) selective

outcome reporting; and 6) other sources of bias such as potential for industry bias. The risk of

bias instrument was used to assign summary assessments of within study bias; low risk of bias

(low risk of bias for all key domains), unclear risk of bias (unclear risk of bias for one or more

key domains), or high risk of bias (high risk of bias for one or more key domains).

The quality of RCTs was assessed using the Jadad scale.[66] Three criteria: randomization,

blinding and accounting of all patients, were used for assessment. Randomization was evaluated

based on how randomization was generated (e.g., computer, random number list, coin toss or

well-shuffled envelopes); blinding was determined whether it was done appropriately (e.g.,

masking of tablets), and if all patients were accounted for in the study (e.g., discontinued,

dropped out). A high quality study would have a maximum score of five, with maximum of 2

points each for randomization and blinding, and 1 point for accountability for all patients.

17

3.3 Network Meta-Analysis

3.3.1 Network Meta-Analysis - Background

To compare outcomes between two interventions for which there is no direct evidence, a

network meta-analysis (NMA) was utilized. A NMA, also known as a multiple-treatment meta-

analysis or mixed-treatment comparison analysis, compares multiple treatments simultaneously

by combining direct and indirect evidence. It is an extension of meta-analysis and is a valuable

statistical tool for decision makers who need to determine the relative effectiveness across a set

of alternatives, rather than from just two treatments. The challenge of a meta-analysis is the lack

of evidence between two active treatments. NMA overcomes this challenge by applying an

evidence network that involves more than two RCTs and more than two interventions. It

incorporates indirect comparisons when there is no direct comparison between the interventions

of interest. By combining both direct and indirect evidence, the objective is to improve the

precision of estimates.[67]

The three underlying assumptions of NMA are similarity, consistency and homogeneity. In

assessing similarity, it was important to determine whether differences among studies may affect

the comparisons of treatments or make some comparisons inappropriate (i.e., patient populations,

dosages etc.) Similarity assumption means that studies should only be combined if they are

considered to be clinically and methodologically similar. For the consistency assumption, the

results of indirect and direct comparisons should be in general agreement. Finally, even though

trials may differ on study and patient characteristics, they can be homogeneous if these

characteristics are not modifiers of the relative treatment effect of different treatments.

18

Any kind of variability among studies in a systematic review may be termed heterogeneity.

There can be three different types of heterogeneity: 1) clinical heterogeneity (variability in the

subjects, interventions and outcomes studied); 2) methodological heterogeneity (variability in

study design, blinding, risk of bias); and 3) statistical heterogeneity (variability in the

intervention effects, and is a consequence of clinical or methodological diversity, or both, among

the studies).

3.3.2 Objective of the NMA

We conducted a Bayesian NMA [68] of RCTs to assess relative efficacy of bisphosphonates,

denosumab, raloxifene or toremifene in improving BMD as a surrogate endpoint of reducing

risk of hip fractures in patients treated with ADT for ≥6 months of continuous use. The main

outcome was assumed to be the percentage change in BMD versus placebo.

3.3.3 Analysis

The outcomes were conducted using a Bayesian random effects (RE) model. A RE model was

chosen because we assumed that each study within the analysis has its own true effect given that

the study characteristics may differ across studies.[69] Relative treatment effects assumed to

follow a normal distribution with mean 0 and variance 105. For between-trial standard deviation,

a uniform prior distribution was used with ranges from 0 to 5. Posterior means and 95% credible

intervals (CrI) for the relative effect of treatments on changes to BMD were estimated. A fixed

effects (FE) binomial model was used for fracture risk using WinBUGS (version 1.4.3).[70]

Models were estimated using Markov Chain Monte Carlo (MCMC) simulations, using three

MCMC chains of 150,000 iterations. Each of the three chains assumed different initial values to

19

assess sensitivity of the model parameters on the initial values assumed. Non-informative priors

were used throughout the NMA analysis. The included treatments were ranked by using the

surface under the cumulative ranking curve (SUCRA) to determine the treatment with the

highest probability of being most effective in improving BMD. SUCRA ranges between 0 and 1;

where 1 represents 100% of the time treatment is always ranked first versus 0% that the

treatment is always ranked last.

3.3.3.1 Evaluation of Heterogeneity and Similarity

In order to evaluate clinical and methodological heterogeneity, a tabular summary of studies and

patients’ characteristics for each pairwise comparison was completed. Conceptually,

heterogeneity can be assessed via the degree to which differences or similarities in these

characteristics vary and affect the outcomes (i.e., possible effect modifiers) [71].

3.3.3.2 Evaluation of Consistency

Before embarking on further analysis, the consistency assumption had to be met. This was to

evaluate whether the outcomes between direct and indirect comparisons were in concordance.

The structure diagram that was developed from the analysis helped to determine the number of

loops that existed.

In order to test consistency for single loop, the Bucher method could be used.[67] Inconsistency

was evaluated by comparing results of direct estimate with indirect estimate. For example, if

direct evidence existed between denosumab and zoledronic acid, the direct estimate of

denosumab vs zoledronic acid could be compared to the indirect estimate between denosumab vs

placebo and zoledronic acid vs placebo.

20

3.3.3.3 Evaluation of Convergence

Model convergence was assessed visually. When iteration graphs showed a random scatter

around a stable mean value, we inferred that convergence was achieved.

3.3.4 Evidence Presentation

The findings of the NMA were summarized with a network diagram to show the connections

between the different comparators; and the thickness of the lines represented the number of

studies between the comparators. Thicker connecting lines indicated higher numbers of studies

used for comparison. A table summarized the results of the NMA between the different

comparators.

3.4 Cost-Effectiveness Analysis

3.4.1 Cost-Utility Analysis – Background

Under a resource constrained healthcare system, economic evaluations help decision makers

evaluate funding choices. A health economics analysis assesses the expected costs of possible

treatments and resources consumed; i.e., the expected outcomes from each treatment.

A cost-utility analysis (CUA) is recommended by economics guidelines [72] as the primary form

of economic analysis as it estimates the costs and the outcomes of competing treatments

measured as quality-adjusted life-years (QALYs). Unlike cost-effectiveness analysis (CEA),

which documents costs per life saved, CUA captures costs per quality of life. Therefore, a CUA

accounts for both life years gained and the utility or impact of treatments on the quality of those

life years. Utility is a preference measurement, which suggests how much a population would

21

prefer to be in one health state (e.g., having locally advanced prostate cancer versus metastatic

prostate cancer). A utility of zero is the preference assigned to death and one applies to perfect

health. Therefore, metastatic prostate cancer health state would likely have a lower utility value

than locally advanced prostate cancer health state.

The final output of a CUA is an incremental cost-utility ratio (ICUR), which evaluates the

incremental costs and incremental utility of a treatment compared to a control or standard of

care. In our analysis, the standard of care is no treatment. There is usually an ICUR value above

which payers will decide not to fund a treatment. This is called the willingness-to-pay (WTP)

threshold. Payers would consider a treatment to be cost-effective when the ICUR is lower than

their pre-defined WTP. Ideally, for payers, the utility of a treatment would be higher and it

would be less costly than the standard of care.

3.4.2 Economic Assumptions

We conducted a cost-utility analysis from a third-party payer perspective. Drug costs and costs

related to prostate cancer and hip fracture were expressed in 2017 Canadian dollars adjusted for

inflation using the Bank of Canada’s Consumer Price Index (CPI). Health outcomes and costs

were discounted at 1.5% per year as per current Canadian guidelines.[73]

3.4.3 Population

We simulated a cohort of men with a mean age of 65, who were diagnosed with locally advanced

prostate cancer (stage T3/4 M0) and who were on continuous ADT. Simulated men entered the

model with no prior fragility fractures. While men were progressing through the prostate cancer

health states, as defined under the Model Structure section, they could also sustain a hip fracture.

22

3.4.4 Treatment Strategies

Treatments for ADT-induced bone loss included bisphosphonates, a human monoclonal antibody

(denosumab) and a SERM, e.g., raloxifene. All these treatments are effective in preventing bone

loss and increasing bone mass through different mechanisms of action. They can reduce risk of

hip fractures by improving BMD at the femoral neck site in men on ADT [43] and some have

shown a reduction in fractures in Phase III trials.[45, 47] The specific treatments evaluated in

this analysis were oral bisphosphonates such as alendronate and risedronate, denosumab,

zoledronic acid, raloxifene, and no treatment.

3.4.5 Model Structure

We created a state transition microsimulation model using TreeAge Pro 2017 [Figure 1].[74]

The model consisted of prostate cancer health states, hip fracture states, and adverse events due

to osteoporosis treatments. Patients progressed sequentially through a series of health states

related to prostate cancer:[75] locally advanced disease (T3/4, M0), biochemical failure (three

consecutive PSA increases after the nadir has been reached), metastatic castrate-sensitive cancer

(new metastatic disease that is responsive to hormonal therapy), metastatic castrate resistant

cancer (asymptomatic/minimally symptomatic cancer that has not been treated with

chemotherapy) and death [Figure 1]. Probabilistic analysis was used as a base case.

Deterministic sensitivity analyses were also performed. Variables tested included costs of

treatments, probability of adverse event, starting ages at 55 or 75, BMD percentage change,

utility of having hip fracture, and using BMD percentage change values from total hip site

instead of femoral neck site.

23

3.4.6 Model Parameters

Epidemiologic data inputs are described in Table 1.

3.4.6.1 Prostate Cancer Natural History

Prostate cancer progression was based on the natural history of the disease from locally advanced

prostate cancer, to biochemical failure cancer, to metastatic castrate sensitive cancer, to castrate

resistant cancer health states, and ultimately to death.[76-79] The progression rates were

estimated from the following sources: published studies, systematic review and other health

economics studies involving patients who closely resembled our population of patients with

prostate cancer on ADT, and who progressed from one health state to another.[76-79]

3.4.6.2 Incidence of Hip Fracture

Patients could sustain a hip fracture in any of the health states thereby accruing fracture-specific

costs and decrements in quality-of-life.

Patients were simulated with an average starting BMD value at the femoral neck site of 0.794

g/cm2 based on an average starting age of 65 years.[80] Patients could experience a new hip

fracture on a monthly rate based on the 10-year probability of having a hip fracture which were

dependent on the T-score and age.[27]

3.4.6.3 Effectiveness of Osteoporosis Treatments

Both BMD at the femoral neck site and patient age have been shown to be strong predictors of

hip fracture in prospective studies.[26, 81]

24

The treatment effects on reduction of BMD were derived from our network meta-analysis

comparing the relative efficacy of osteoporosis treatments on reducing risks of fragility

fractures.[46] BMD loss was modeled to be a function of age and the number of years on

ADT,[82] while osteoporosis treatments mitigated BMD loss. BMD values were updated

monthly based on age, years on ADT and the effect of treatment.[46, 82]

3.4.6.4 T-Score calculation

Monthly BMD value at femoral neck site for each treatment was calculated using a two-stage

approach with posterior samples from the Bayesian simulations [67] of a NMA.[46]

The percentage of BMD change for each treatment was generated from the output of the

Convergence Diagnostics and Output Analysis (CODA) for each iteration from the NMA.[46]

Each CODA represented the percentage of BMD change values for different treatments and they

were incorporated into the model for each simulated patient. The updated monthly BMD value

at the femoral neck site was calculated by accounting for the BMD loss from ADT and the

percentage improvement in BMD from each treatment as derived from the CODA outputs.[67]

Each patient’s T-score was estimated from the difference between the updated monthly BMD

value and the BMD reference (BMDref) divided by the BMD reference standard deviation

(BMDref_SD).[80] The ideal BMD reference was derived from a healthy 30-year old adult

female at the femoral neck site from the National Health and Nutrition Education Survey III

(NHANES III) reference database for white women.[80] The BMD value from white women is

the reference standard for both men and women to calculate the T-score .[37] A T-score of 0

means the BMD is equal to the norm for a healthy, young woman. The more negative the

calculated T-score, the higher the risk of fracture.[83]

25

3.4.7 Adverse Effects

Patients could suffer from ONJ while on bisphosphonates or denosumab [84, 85], and venous

thromboembolism with raloxifene [86]. These adverse events were selected because they could

have the most impact on patients’ quality of life and the costs to the healthcare system. The costs

and disutility of an adverse event were assumed to apply for a maximum of one year. Once

patients suffered an adverse event, the osteoporosis treatment was discontinued.

3.4.8 Mortality

Prostate cancer mortality rates were based on the rate of death associated with their respective

prostate cancer states.[75] The mortality rate from hip fractures was based on the hazard ratio

associated with sustaining a hip fracture [87] with the death rate of the normal Canadian male

population serving as the reference.[88]

Death from prostate cancer or hip fracture was possible at any time and in any health state. All

men made monthly transitions between the health states until they died or reached 100 years of

age. The inputs for the model are described below and are found in Table 1.

3.4.9 Quality of Life

Our preference was to use utilities estimated from direct methods such as standard gamble or

time trade off, but due to inconsistencies in measuring utilities, we used utilities values that were

available in the published literature that used standard gamble, EQ5D or values from the Cost-

Effectiveness Analysis Registry [89] for each prostate cancer health state.[90-92] For incident

and subsequent fracture utilities, we extracted information from systematic reviews on utility

values associated with osteoporotic fractures.[93, 94]

26

The disutility of experiencing ONJ with bisphosphonates or denosumab and deep vein

thrombosis from raloxifene were derived from studies using time trade off method [95] and

standard gamble [96], respectively. ONJ was defined as stage 3, which meant exposed or

necrotic bone with pain and infection in the jaw and one or more of: pathologic fracture, extra

oral fistula, or osteolysis.[95] The utility inputs for the model are reported in Table 2.

3.4.10 Costs

Drug costs included acquisition costs (i.e., 2018 Canadian Public Drug Programs Formulary [97]

price plus 8% wholesaler mark-up) and the dispensing fee ($6.11). Prostate cancer health state

costs were taken from an Ontario population-based costing study that considered factors such as

physician visits, potential homecare and diagnostic procedures.[6]

The hip fracture costs in the first and subsequent years were derived from Canadian data.[98, 99]

Included costs were hospitalization, homecare and physician services. We assumed that

treatment costs for prostate cancer were independent of hip fracture status. The costs input for

the model is provided in Table 3.

3.5 Analysis and Outcomes

Probabilistic analysis was used as a base case and included uncertainty in treatment effects,

patient characteristics and costs. Five hundred samples of 25,000 hypothetical patients were

performed, in which each input parameter value was drawn from a sampling distribution which

resulted in empirical output distributions of incremental cost and quality-adjusted life

expectancy.

27

Deterministic sensitivity analyses were also performed. Variables tested included costs of

treatments, probability of adverse events, starting age at 55 or 75 years, BMD percentage change,

and utility of having a hip fracture. We used BMD percentage change values from total hip site

instead of femoral neck site.

We measured both costs and health outcomes over a lifetime horizon, which provided

cumulative sample estimates of number of hip fractures, costs, life years (LYs) and QALYs. The

model’s main output was the incremental cost-effectiveness ratio or incremental cost-utility ratio.

Incremental net monetary benefit [100] at various willingness-to-pay thresholds was also

calculated to determine the extra net benefit of the different treatments compared to placebo. The

highest incremental net benefit was considered the most cost-effective.

The calculation was based on this formula:

Net benefit (NB) = (QALYs)*Willingness-to-pay - Costs

3.5.1 Expected Value of Perfect Information

Expected Value of Perfect Information (EVPI) was calculated to measure the highest costs of

making the wrong decision based on all parameter uncertainties. EVPI helps decision makers

answer the question on the maximum costs and value associated with funding additional to help

eliminate uncertainty in the decision.[101] The calculation for EPVI per person was dependent

on different willingness-to-pay thresholds, and was calculated as shown in Equation 1:

28

Equation 1: EVPI = average of the maximum net benefit for all samples with perfect

information (maximum net benefit) – maximum of the average net monetary benefit for each

treatment strategy with imperfect or present information (expected net benefit).

A simplified example is provided below:

ITERATION Net Benefit (based on willingness-to-pay of $50,000/QALY gained)

Maximum

Net

Benefit

Placebo Zoledronic

Acid Denosumab Risedronate Alendronate Raloxifene

1 $197,790 $180,530 $190,069 $198,573 $198,583 $196,576 $198,583

2 $227,796 $211,546 $220,314 $229,571 $229,694 $227,113 $229,694

…500 $434,818 $416,842 $426,620 $434,835 $435,261 $433,254 $435,261

Expected Net

Benefit $304,389 $286,877 $296,512 $305,057 $305,182 $302,993 $305,215

EVPI = $305,215 - $305,182 = $33 per patient

Population EVPI was determined by using the per patient EVPI, the annual incident of hip

fractures in our population (I), the lifetime horizon of the treatment (t), and the discount rate (r)

(Equation 2).

Equation 2: Population EVPI = EVPI It/(1+r)t t=1,2,3…

It was calculated by multiplying the an incident rate of 110.4 per 100,000 males [1] by the annual

prevalence of men with prostate cancer, which was estimated to be 21,300.[1] A discount rate of

1.5% was used.

The population EVPI was calculated based on three willingness-to-pay thresholds of $50,000,

$100,000 and $125,000 per QALY gained. The results provided information to decision makers

on the maximum value that should be placed on research to gain certainty in the funding

decisions.

29

Cumulative distribution plots were created to illustrate the uncertainty in the decision. The

calculations were based on the results of the probabilistic analyses of 500 samples of 25,000

iterations. Each iteration provided an incremental net health benefit based on the difference in

costs, QALY and willingness-to-pay thresholds for treatment options that were on the cost-

effectiveness frontier. By displaying the incremental net health benefit for each iteration, it

showed an overall percentage of times that a wrong decision could have been made. A wrong

decision would be if the incremental net health benefit was negative.

30

4. Results

4.1 Network Meta-Analysis

Studies were stratified by BMD test locations: total hip (TH), lumbar spine (LS), femoral neck

(FN) sites. A total of 13 RCTs [102-114] were used for analysis. Eleven studies [102-104, 106,

107, 109-114] evaluated outcomes at the TH site (1618 patients in treatment arm; 1649 patients

in placebo arm). Thirteen studies [102-114] evaluated outcomes at the LS site (1671 patients in

treatment arm; 1699 in placebo arm), of which 11 studies [102-106, 109-114] evaluated

outcomes at the FN site (1527 patients in treatment arm; 1540 patients in placebo arm). The

studies evaluated six (at TH and FN sites) and seven (at LS site) treatments versus placebo.

The PRISMA Flow Diagram is presented in Figure 2. The mutual comparator in the analysis was

placebo to allow us to compare treatments across the trials in the network. The network diagram

is shown in Figure 3.

4.1.1 Data Synthesis and Analysis

The mean age range of patients tested at TH, LS, and FN sites for intervention and placebo

groups ranged from 65 to 76 years. Nine of eleven TH [102-104, 106, 107, 109-111, 113] and

FN studies [102-106, 109-111, 113] and 11 of 13 LS [102-111, 113] studies had patients on ADT

12 months. Two studies that contributed data to all three site analyses had an unknown ADT

duration [112, 114].

At baseline, patients in 5 studies had unknown osteoporosis status [103, 104, 109, 112, 114], 4

studies included patients with normal bone status [102, 106, 110, 113] and 4 included both

31

normal and osteopenic patients [105, 107, 108, 110]. All patients were recommended to take

calcium and vitamin D daily, except in one study [103] where intake was unknown. Dosages of

osteoporosis treatments were consistent with their recommended dosages with the exception of

ZA, where four studies used 4mg IV every 3 months [104, 107, 110, 112], one study used 4mg

every 6 months [108] and one used 4mg at 12 months [110]. The characteristics of included

studies are found in Appendix 2.

Although the age, prostate cancer stage and co-treatment with calcium and vitamin D were

similar between the studies, there was some heterogeneity between studies based on duration of

ADT use and different dosing and frequency of zoledronic acid.

Formal testing [115] was not applied to test the consistency assumption since there was no direct

evidence between active treatments to test consistency with indirect evidence. A visual

inspection of iteration plots showed convergence. Figures 4 present visual plots for the BMD

change that compared between treatments and placebo at the femoral neck site.

Based on the Cochrane risk of bias assessment tool, the majority of the trials were at medium

risk of bias, which included those studies that were randomized and double blinded, but did not

discuss or report missing data. Most included studies, except one [106], had a Jadad score of at

least 3.

4.1.2 BMD Percentage Change Compared to Placebo

Overall, patients on active treatment had BMD improvements from baseline (Appendix 3).

Patients on placebo had worsening of their BMD. One exception was an alendronate study,

which reported that patients on placebo had a BMD improvement of 1.18% vs 0.23% (p=0.631)

32

for the alendronate arm. Another outlier was a toremifene study, in which BMD declined on

treatment (-0.1% vs -1.44%; p

33

p=0.004 at 24 months). Other studies reported fractures as adverse events where data were not

systematically gathered. The number of events was small, and statistical significance could not

be determined. One alendronate study [106] reported 1 fragility fracture in each arm vs placebo

and another [109] reported 3 patients had fractures on placebo and 1 patient while on alendronate

(p = 0.44). Israeli [107] reported two traumatic fractures with ZA and 1 with placebo, and

another reported [108] 1 bone fracture in each ZA and placebo arm.

Hence, a NMA was performed with only two studies on vertebral fracture risks, denosumab (679

patients) and toremifene (477 patients) [102, 103] as each treatment was compared to placebo at

24 months. Denosumab was ranked higher than toremifene based on SUCRA of 89.4% of having

lower risk of vertebral fractures.

4.1 Cost-Effectiveness Analysis

4.2.1 Model Validation

The incidence rate of hip fracture in the placebo arm was 360/100,000 person-years or 0.0036

per person year. Patients in the simulation generally experienced their first hip fracture between

age 72 to 77. Therefore, the modeled rate lied within the upper and lower bounds of an age-

specific hip fracture rate of 270 to 400 per 100,000 person-years during this age range in actual

patients with prostate cancer [116] The estimated mean overall undiscounted survival within the

placebo strategy of the model was 12.5 years and was within the observed 12 to 19 year life-

expectancy of a 65 year-old Canadian man with prostate cancer.[117]

34

4.2.2 Base Case Analysis

4.2.2.1 Hip Fracture

When 25,000 iterations were simulated, analysis showed that patients in the placebo strategy

sustained the most number of hip fractures, followed by those treated with denosumab and

raloxifene. Patients in the zoledronic acid strategy sustained the least number of hip fractures.

However, the differences in the incidence rates were very small, placebo at 0.0036 per person-

year, denosumab at 0.0030 per person-year, and raloxifene at 0.0029 per person-year. Zoledronic

acid had the lowest incidence rate at 0.0018 per person-year. Both alendronate and risedronate

were very similar at around 0.0021 per person-year.[Tables 1 to 3] The relative risk of hip

fracture for denosumab versus placebo was calculated to be approximately 0.80.

4.2.2.2 Osteonecrosis of the Jaw and Quality Adjusted Life Years

The risks of experiencing osteonecrosis of the jaw (ONJ) were highest with zoledronic acid,

followed by denosumab, and lowest with oral bisphosphonates. Hence, patients experienced

further decrements of quality of life and increased costs with the adverse event. The combined

decrements in patients experiencing ONJ and higher number of hip fractures contributed to its

lower quality adjusted life years (QALY) compared to oral bisphosphonates.

Expected QALY of the different treatments ranged from 8.8820 (placebo) to 8.9237 (zoledronic

acid). For all treatment strategies, the undiscounted life years were similar at approximately 12.5

years.

35

4.2.2.3 Costs

Although zoledronic acid was the most effective strategy, it also had the highest lifetime costs

($159,310) due to the highest drug cost per month. The factors which contributed to denosumab

having the second highest lifetime costs were: drug cost and ONJ treatment costs. Placebo had

the lowest lifetime costs ($139,712) due to lack of drug costs and lack of costs associated with

adverse events.

Zoledronic acid was effective in reducing the number of hip fractures, but this effect was not

sufficiently large to offset the differences in drug costs. Therefore, even though patients without

osteoporosis treatment experienced a higher number of hip fractures, the hip fracture savings was

smaller than the higher drug (and adverse event) costs.

4.2.2.4 Incremental Cost-Effectiveness Ratio

All treatment strategies were more effective, but more costly than placebo. Although risedronate

was less costly, it was also slightly less effective than alendronate. Hence, alendronate is the

most cost-effectiveness treatment strategy with an incremental cost-effectiveness ratio (ICER) of

$30,400 per QALY gained compared to placebo. Zoledronic acid was the most effective but also

most costly. The ICER for zoledronic acid was $14.8 million compared to alendronate, which

would not be a cost-effective option for a third-party payer. Other treatment arms, including

risedronate, denosumab and raloxifene strategies were all dominated, which meant they were less

effective and more costly than alendronate.[Table 5]

36

4.2.2.5 Net Monetary Benefit & Cost-Effectiveness Frontier

Net monetary benefit was also calculated to summarize the value of each treatment in monetary

terms based on the different willingness-to-pay (WTP) thresholds from $50,000 to $100,000

[Table 6]. Alendronate had the highest net monetary benefit for the WTP thresholds from

$50,000 to $100,000.

The cost-effectiveness frontier showed that risedronate, raloxifene and denosumab were not on

the cost-effectiveness frontier; therefore, they were not cost-effective. Alendronate and

zoledronic acid were on the frontier, and therefore were cost-effective options. However,

zoledronic acid had a much higher ICER compared to alendronate.[Figure 8]

4.2.3 Uncertainties

We represented parameter uncertainty in our model at various cost-effectiveness ratios using a

cost-effectiveness acceptability curve (CEAC). It used a joint distribution of costs and effects to

evaluate uncertainty by identifying where the ICER falls in relations to the cost-effectiveness

plane and the cost-effectiveness threshold.[118] The probabilities represented the proportion of

the iterations or scatter plot points that fall to the south and east region of the cost-effectiveness

plane; meaning the proportion of times that the strategy has the highest net benefit at various

levels of willingness-to-pay.[118]

The CEAC [Figure 9] showed that alendronate had 72% probability of being the most cost-

effective treatment in the model iterations at a $50,000 per QALY gained willingness-to-pay

threshold.[117] Results for other willingness-to-pay thresholds are provided in Figure 2. If the

willingness-to-pay threshold was at $30,000 per QALY gained, placebo has 70% probability to

37

be the most cost-effective strategy, while alendronate reduced to have 25% probability to be the

most cost-effective treatment. Lastly, the $40,000 per QALY gained threshold was the crossover

between placebo and alendronate strategies. At a willingness-to-pay threshold of $40,000, both

alendronate and placebo has about 50% probability of having the highest net benefit.

4.3 Sensitivity Analyses

4.3.1 Deterministic Sensitivity Analyses

One-way deterministic sensitivity analyses were performed varying costs of bisphosphonates and

denosumab, costs of treating hip fracture in the first year, BMD change affected by denosumab

or risedronate, rate of ONJ with denosumab, and utility of experiencing a hip fracture.[Appendix

4] These parameters were selected based on the potential costs and quality of life impact that

patients may experience during treatment. Given that the costs of generic medications can

decrease to 90% [119], and injectable to 65%,[120] reduced costs were tested. There were two

parameter values which made risedronate the most cost-effective strategy over the lifetime

horizon compared to its basecase value: 1) reduction in costs per month by at least 22.5%, which

equated to approximately less than $9.90 per month (included markup and dispensing fee); and

2) improvement of risedronate BMD change by about 45%.

If the BMD percentage change in denosumab was improved by 45% from baseline value, then its

ICER would be $194,000/QALY gained compared to alendronate. A detailed list of parameters

and summary of the results of the deterministic sensitivity analyses is provided in Table 8.

38

Starting ages of patients entering the model were also varied at 55 and 75 years. At age 55,

alendronate was found to be the most cost-effective strategy. However, at age 75, risedronate

was the most cost-effective strategy.

BMD percentage change from total hip site was used for re-analysis instead of femoral neck site.

A limitation was that in the network meta-analysis, risedronate was not evaluated because of its

lack of evidence at this bone site. The results showed alendronate was still a cost-effective

treatment strategy compared to placebo, followed by raloxifene with extended dominance.

Denosumab and zoledronic acid were also cost-effective, but with ICERs of $6 million and $14

million, respectively.

4.4 Expected Value of Perfect Information

In a budget constraint healthcare system, a decision that is made based on current information

and the payer’s willingness-to-pay threshold, has a cost associated with making the wrong

decision. Expected value of perfect information (EVPI) provided the costs associated with

making a decision if all uncertainties were removed.

For a willingness-to-pay threshold of $50,000, the costs of gaining perfect information was $33

per patient. If the threshold was lowered to $25,000, then the costs would increase to $272 per

patient.[Figure 10] The graph shows the various willingness-to-pay thresholds and the costs

associated with obtaining perfect information in order to make a decision with certainty.

Population expected value of perfect information were calculated to be between $710,000 and

$925,000 for willingness-to-pay thresholds of $50,000 to $125,000.

39

The full calculations for maximum and average net benefit for 500 samples with 25,000

iterations are presented in Appendix 5. It provided detailed information of maximum net

monetary benefit for each strategy at a $50,000 willingness-to-pay threshold.

The cumulative distribution plots illustrated the uncertainty around making a wrong decision

based on various willingness-to-pay thresholds. We found that at the $50,000 willingness-to-pay

threshold between placebo and alendronate, there was about 13% of the time that a wrong

decision was made to fund i.e., had a negative incremental net health benefit. At $100,000 or

$125,000 willingness-to-pay thresholds, there was no economic value in reducing uncertainty

since none of the sample iterations had a negative incremental net health benefit.[Figure 11]

Similarly, the results for the incremental net health benefit between alendronate and zoledronic

acid found no economic value in reducing uncertainty because no sample iteration showed a

negative incremental net health benefit.

40

5. Discussion and Conclusions

5.1 Network Meta-Analysis

We conducted a NMA evaluating all available preventive treatments for osteoporosis in men

with non-metastatic prostate cancer. Our results showed that all treatments were effective in

reducing the rate of bone loss when compared to placebo. Treated patients’ BMD change from

baseline ranged from -1.2% to 6.0%. Some treatments appeared to be supported by stronger

evidence. Denosumab and zoledronic acid showed improvement in BMD across all sites (~3% at

TH and FN, ~6% at LS sites). The lower bound of the 95% CrI did not include zero at all sites

for these two drugs. Similarly, when we used SUCRA to determine treatment rank probability,

we found that ZA consistently ranked amongst the top two treatments at all sites. Denosumab

was ranked amongst the top two at the LS and TH sites.

In the two studies that evaluated the effect of preventive therapy on fracture risk, denosumab and

toremifene were effective in reducing vertebral fracture risk. In a systematic review that

evaluated bisphosphonates to prevent fragility fractures, it was found that there was no evidence

of a difference in effect on fractures between treatments in this class of drugs [121].

Raloxifene was ranked highest based on SUCRA of 0.8628 compared to other treatments at the

total hip site. Although raloxifene was ranked highest, based on the relative comparison, there is

no evidence of significantly better BMD improvement compared to other treatments. A recent

study[122] evaluated the possible reasons for SUCRA’s uncertainty. The reasons for the

uncertainty in ranking raloxifene to be most effective could be that the data between the

comparisons were scarce from the limited number of patients in each arm (20 patients). Another

41

explanation could be that the population size is too small and did not have sufficient power to

show statistical difference.

Factors other than treatment efficacy, such as patient preferences, adverse events and costs are

also important when choosing a treatment. However, we did not systematically evaluate these in

this network meta-analysis.

In terms of patient preferences, ZA was given intravenously every several months (3 to 12

months) which required a visit to a hospital or clinic. This included travel, waiting, set up and

monitoring time, and a 15-minute infusion. Denosumab was given subcutaneously every 6

months. The advantage over ZA is that patients can inject themselves. However, some patients

may prefer not to self-administer, and some may need additional education by a healthcare

professional or through homecare. Other bisphosphonates can be taken orally.

The risk of adverse effects can also influence treatment choice. The relative risk of ONJ with

fewer ZA infusions per year (as in our population for prevention of bone loss) versus 4 mg every

4-weeks (for reducing risk of skeletal-related event in metastatic cancer) is 0.002 [123, 124]. The

incidence of ONJ with all frequencies of ZA is 0-90, with oral bisphosphonates is 1.04-69 [125]

and with denosumab is 0-30.2 [125], per 100,000 patient-years.

Out-of-pocket costs borne by patients for infusion therapy (i.e., travelling costs, parking fees,

time lost from work) and other costs assumed by payer (i.e., nursing time, drug costs, ancillary

equipment) should also be considered. With respect to drug costs, in the US [126], ZA 4mg/5mL

costs $60/infusion ($60 to $240/year), denosumab 60mg costs $1075/injection ($2150/year) and

oral risedronate 35mg costs $25/week ($1300/year) or alendronate 70mg costs $0.40/week

($21/year).

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Our analyses suggested that IV ZA was a reasonable alternative, followed by oral

bisphosphonates. Our results did not show that one drug was unequivocally more effective than

another. All drugs appeared to be effective in reducing the rate of bone loss. In fact, they were

almost universally shown to be associated with improved BMD, and credible intervals showed a

significant degree of overlap between agents. Therefore, we believe that the most important

policy implication of this work is that, because preventive therapy is effective, men who are at

risk for fracture should receive some form of osteoporosis treatment. Choosing the optimal drug

should be determined on the basis of efficacy, as reported here, but also on the basis of safety,

patient preferences, patient and health system costs, and local availability.

5.1.1 Strengths and Limitations

Our study has both strengths and limitations. Network meta-analysis facilitates comparison of

treatments that have not been evaluated in head-to-head trials. We used a well-documented

surrogate endpoint (i.e., BMD change) to estimate fracture risk, which allowed more studies to

be included in the NMA than would have been possible had we used fracture as our main

outcome. The limitations are the lack of direct comparisons, and that some of the indirect

comparisons were either based on single trials only or that they included few patients in the

studies. As a result, the credible intervals between comparisons were often wide. Lastly, we were

bound to draw inference on fracture risk based on BMD as a surrogate endpoint.

A comprehensive economic evaluation provided additional evidence supporting decision making

for men with prostate cancer receiving ADT.

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5.2 Cost-Effectiveness Analysis

We conducted a cost-utility analysis that evaluated the cost-effectiveness of alendronate,

risedronate, raloxifene, zoledronic acid, denosumab and no treatment to reduce the number of hip

fractures while experiencing an adverse event with osteoporosis treatments in patients 65 years

or older with prostate cancer who were on continuous ADT. Simulated patients experienced the

most number of incident hip fractures with placebo, and the least number with zoledronic acid,

followed by alendronate. Alendronate was found to be the most cost-effective strategy compared

to placebo. Zoledronic acid had a $14 million/QALY gained compared to alendronate, which is

far above a conventional payer’s willingness to pay. Even though zoledronic acid may be

marginally more effective, its costs seemed to outweigh its benefit. Both denosumab and

raloxifene were less effective and more costly than oral bisphosphonates; hence, these strategies

were dominated.

The major drivers of the model were costs and BMD improvements of risedronate and

denosumab. We tested several variables in one-way sensitivity analyses [Table 3] and

alendronate was no longer the dominant strategy if the monthly cost of risedronate was either

reduced or BMD change was improved within the plausible range. Similarly, when denosumab’s

cost was reduced by 90% to about $7 per month from $67 per month (including markup and

dispensing fee), its ICER was reduced to $57,600/QALY gained compared to alendronate. Since

the effectiveness of the treatments was dependent on the BMD improvements from a NMA,[46]

we tested the BMD change for denosumab as well. If BMD change was improved by at least

45% relative to its baseline value, denosumab had an ICER of $194,000/QALY gained compared

to alendronate.

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We also calculated the relative risk of denosumab in the simulation compared to the published

study.[47] The RCT found that fracture at any site happened in fewer patients in the denosumab

group (38 [5.2%]) than in the placebo group (53 [7.2%]), with a relative risk of 0.72 (95% CI,

0.48 to 1.07). The number of hip fractures in this simulation between placebo and denosumab led

to a calculated relative risk of 0.80 (95% CI 0.74 to 0.87). The relative risk was similar between

this simulation and the RCT. In the sensitivity analysis, we also varied the improvement of

percentage BMD change with denosumab by up to ±90%, and the result remained the same with

alendronate being the most cost-effective strategy.

Canadian and US Guidelines recommend that men who are receiving ADT should be assessed

for fracture risk, and that to prevent fractures, osteoporosis therapy should be considered.[34, 38,

127] Other factors to guide pharmacologic therapy selection is patient preference for

treatment.[38] Alendronate is the most cost-effective treatment and it is convenient to administer.

It is only taken once weekly orally versus denosumab, which is administered subcutaneously

every six months, or zoledronic acid, which was given intravenously every three months (as per

most studies in men with prostate cancer).[128-130] Other concerns for patients are potentially

the time and out of pocket costs (i.e., parking) to have an intravenous injection in a hospital, or

rarely, the fear of injection. However, for patients with potential compliance issues, bedridden

patients where injections are administered by a nurse or caregiver, or patients who cannot

swallow tablets, injections given every 3 months or longer may be preferred. From a patient’s

perspective, treatment convenience is a potentially important consideration.

The older, off-patent drugs such as oral bisphosphonates were most cost-effective. There is very

little efficacy difference between alendronate and risedronate.[46, 131] At the current prices, the

newer drugs such as denosumab or zoledronic acid were not cost-effective.

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5.2.1 Strengths and Limitations

The strength of this analysis was that we evaluated all potential treatment options for reducing

hip fracture incidences, and the potential serious adverse events that could impact quality of life

and costs.

One limitation of this analysis was excluding the impact of vertebral fractures. The calculations

used throughout this analysis were based on BMD at the femoral neck site; however, the use of

BMD at the lumbar spine site to calculate the reduction of vertebral fracture needs more

substantiation. This made it difficult to accurately account for vertebral fractures, especially with

up to one-half of vertebral fractures being radiographically detected but clinically asymptomatic.

Another analysis found alendronate to be cost-effective for reducing incidence of hip fractures,

and concluded that its analysis may have underestimated the benefits of alendronate given that