bisphosphonates for fracture prevention in males: a systematic review and meta- analysis

Bisphosphonates for Fracture Prevention in Males:

A Systematic Review and Meta-Analysis

Tina WillsonYan Cheng, Tianze Jiao, Greg Stoddard, Joanne LaFleur

BACKGROUND

Osteoporosis and Osteopenia in Men• Characterized by

decreased bone mineral density and increased risk of fragility fractures

• Prevalence in US Men:– 0.8 million with

osteoporosis– 11.8 million with

osteopeniaImages: http://www.fore.org/patients/osteo_and_osteo.htm

National Osteoporosis Foundation (NOF) www.nof.org

Osteoporosis and Osteopenia in Men

• One in four men over age 50 will develop at least one osteoporosis-related fracture

• Each 80,000 men will break a hip • One in three men will die in the first year after

a hip fracture and another 1/3 will fracture again

Sources: National Osteoporosis Foundation (NOF)l www.nof.orgvon Friesendorff et al. Journal of the American Geriatrics Society. 2011. 59(5):806-813

Fracture Prevention • Non-pharmacological interventions– Calcium, Vitamin D, weight bearing exercise

• Pharmacological treatments– Bisphosphonates, parathyroid hormone, denosumab

• Guidelines from the NOF and Endocrine Society recommend pharmacological treatment in men age 50+ with:– Hip or vertebral fracture– T score <-2.5– T score in the osteopenic range and high risk of fracture

based on clinical risk factors

Bisphosphonates• Prescribed as the first line treatment to

prevent fracture • Oral bisphosphonates– Alendronate (Fosamax)– Risedronate (Actonel)– Ibandronate (Boniva

• IV bisphosphonates– Ibandronate (Boniva)– Zoledronic Acid (Reclast)

Motivation• Anti-fracture efficacy has mostly been studied in postmenopausal women • Alendronate, risedronate, and zoledronic acid have been shown to reduce the

risk of vertebral fracture in men • Risedronate has demonstrated reductions in incidence of non-vertebral and

hip

• Overall lack of evidence of bisphosphonate efficacy on non-vertebral fractures• Limited sample size in clinical trials• Fracture incidence reported as secondary outcome

• Unclear• If patient characteristics influence the effects of bisphosphonates on fracture prevention• Whether a specific bisphosphonate is better than others for fracture prevention in males• If different bisphosphonates are better for the prevention of different types of fracture in men

• A review is needed to synthesize the evidence and summarize the efficacy of bisphosphonates for fracture prevention in males

OBJECTIVE

Objective• To assess the efficacy of bisphosphonate

therapy in the prevention of vertebral and non-vertebral fractures in males at risk for fracture compared to placebo

METHODS

Methods• Study Design

– Systematic Review and Meta-Analysis• Developed protocol outlining

– Search Strategy– Inclusion Criteria– Study Selection

• Title/Abstract Review• Full Text Review• Data Extraction

– Planned Analyses• Data Sources

– PubMed, Scopus, Cochrane Controlled Trials Register, ClinicalTrials.gov

PubMed Search Strategy

Inclusion Criteria• RCT• Adult male • Fracture outcome• Medication administered at licensed osteoporosis dosage • Study duration >=12 months• If Calcium/Vitamin D used, must be administered in both

study arms• Unique population (delete replications)• Extractable outcomes • Published abstract in English or Chinese• Human study

Data Extraction• Two reviewers independently extracted all data from each study. • Data extracted:

– Study population – Study duration– Study Drug (ALN, IBAN, RIS, ZOL)– Patient characteristics( age, BMI, T scores, prior fracture)– Fracture outcomes (VF, NVF, and HIP) at end of the study and any

intermediate time periods reported – Potential sources of bias (adequate, inadequate, unclear)

• Generation of allocation sequence• Concealment of allocation sequence• Blinding• Attrition• Funding source (pharmaceutical company, other)

ALN-Alendronate, IBAN-Ibandronate, RIS-Risedronate, ZOL-Zoledronic Acid, VF-Vertebral Fracture, NVF- Non-vertebral Fracture

Analysis• Stata used for all analyses– Assessment of publication bias• Funnel plots (including Egger’s test)

– Data synthesis• Fixed effects model

• Analyses were performed on– All studies– Subset of studies that report separate male

outcomes

Analyses• Primary Analyses– Assess effect of bisphosphonates on VF, NVF, and HIP

fracture at end of study, 12 months, and 24 months.• Subgroup Analyses– Assess effects of bisphosphonates on fracture outcomes at

end of study by• Drug • Potential sources of bias

• Heterogeneity – Meta regressions

• Proportion male

RESULTS

Study SelectionDatabases searches: 649

Pubmed: 263Scopus: 315

Cochrane: 50Clinical.gov: 21

Included abstracts: 470

Included for full text review: 123

Data extraction: 38Excluded: 85

No male fracture: 41Not standard dosage: 12

Not RCT:10No placebo group: 6

The same population as other study: 6Short period of treatment/follow-up: 4

Unable to transfer the result: 3Duplicates: 2

Not report fracture: 1

Excluded: 347Not drug of interest: 140

Not RCT: 99No males in study population:

43Not placebo comparison: 35

No fracture reported: 21Other reasons: 9

Duplicates: 179

Study Characteristics• Therapies

– ALN: 22– RIS: 10– ZOL: 4– IBAN: 2

• Outcome– VF: 33– NVF: 21– HIP: 9

• Study duration– 12 months: 27– 18 months: 1– 24 months: 9– 36 months: 1

• Primary Osteoporosis– Yes: 8– No: 30

• Secondary Osteoporosis– Steroid Induced: 5– HIV: 4– Cystic Fibrosis: 3– Renal Transplant: 3

• Mean Lumbar Spine T score– Normal: 7– Osteopenia: 14– Osteoporosis: 4

• Mean Femoral Neck T score– Normal: 2– Osteopenia: 14– Osteoporosis: 0

• Mean Total Hip T score– Normal: 3– Osteopenia: 8– Osteoporosis: 0

• Mean age– <=40: 7– 40-50: 8– 50-60: 9– 60-70: 7– >70: 3

• Mean BMI class– Underweight: 0– Normal: 13– Overweight: 6– Obese:0

ALN-Alendronate, IBAN-Ibandronate, RIS-Risedronate, ZOL-Zoledronic Acid, VF-Vertebral Fracture, NVF- Non-vertebral Fracture

Primary Results Male: Vertebral Fractures

Male Primary Results

Subgroup Results: Vertebral Fracture by Drug

Primary Results All Studies: Vertebral Fractures

Meta Regression Results: Male Proportion

-2-1

01

2logRR

0.00 0.20 0.40 0.60 0.80 1.00Male_Pop_%

Vertebral fracture

coefficient=-0.64, 95%CI=-1.98 to 0.69

Subgroup Results by Select Study Quality Characteristics

Summary of Findings• Bisphosphonates significantly reduce vertebral fractures,

but effect size is not related to the proportion of males in the study.

• We did not find a significant effect for bisphosphonates on non-vertebral or hip fractures in men.

• Zoledronic acid appears to have a greater effect than other bisphosphonates, but only two articles are included in this study.

• Significant results are more likely to be found in the studies that were financially supported by pharmaceutical industry or had unclear or inadequate quality characteristics.

DISCUSSION

Implications• Results show bisphosphonates reduce vertebral fracture

risk as early as 12 months– earlier than currently believed and has implications for older

men who may have been previously overlooked for treatment

• Effect size not related to proportion of male in the study – anti-fracture benefits of bisphosphonates may be the same

in males and females• Results highlight a need for better understanding of

baseline fracture risk and the effects of bisphosphonate therapy on fracture outcomes in males.

Limitations• Publication bias– Conference proceedings– Gray literatures– Unpublished articles

• Language bias– Included only English or Chinese

• Heterogeneity• Un-extractable data

QUESTIONS?

tina.willson@utah.edu