Bisphosphonates for Fracture
Prevention in Males:
A Systematic Review and Meta-
Analysis
Tina Willson
Yan Cheng, Tianze Ji...
BACKGROUND
Osteoporosis and Osteopenia in Men
• Characterized by
decreased bone
mineral density and
increased risk of
fragility fract...
Osteoporosis and Osteopenia in Men
• One in four men over age 50 will develop at
least one osteoporosis-related fracture
•...
Fracture Prevention
• Non-pharmacological interventions
– Calcium, Vitamin D, weight bearing exercise
• Pharmacological tr...
Bisphosphonates
• Prescribed as the first line treatment to
prevent fracture
• Oral bisphosphonates
– Alendronate (Fosamax...
Motivation
• Anti-fracture efficacy has mostly been studied in postmenopausal women
• Alendronate, risedronate, and zoledr...
OBJECTIVE
Objective
• To assess the efficacy of bisphosphonate
therapy in the prevention of vertebral and
non-vertebral fractures in...
METHODS
Methods
• Study Design
– Systematic Review and Meta-Analysis
• Developed protocol outlining
– Search Strategy
– Inclusion ...
PubMed Search Strategy
Inclusion Criteria
• RCT
• Adult male
• Fracture outcome
• Medication administered at licensed osteoporosis dosage
• Study...
Data Extraction
• Two reviewers independently extracted all data from each study.
• Data extracted:
– Study population
– S...
Analysis
• Stata used for all analyses
– Assessment of publication bias
• Funnel plots (including Egger’s test)
– Data syn...
Analyses
• Primary Analyses
– Assess effect of bisphosphonates on VF, NVF, and HIP
fracture at end of study, 12 months, an...
RESULTS
Study Selection
Databases searches: 649
Pubmed: 263
Scopus: 315
Cochrane: 50
Clinical.gov: 21
Included abstracts: 470
Incl...
Study Characteristics
• Therapies
– ALN: 22
– RIS: 10
– ZOL: 4
– IBAN: 2
• Outcome
– VF: 33
– NVF: 21
– HIP: 9
• Study dur...
Primary Results Male: Vertebral Fractures
Male Primary Results
Outcome
Number
of Studies
Number of
participants RR 95% CI
End of Study
Vertebral fracture- male stud...
Subgroup Results: Vertebral Fracture by Drug
Primary Results All Studies: Vertebral Fractures
Meta Regression Results: Male Proportion
-2-1
012
logRR
0.00 0.20 0.40 0.60 0.80 1.00
Male_Pop_%
Vertebral fracture
coeffi...
Subgroup Results by Select Study Quality
Characteristics
Summary of Findings
• Bisphosphonates significantly reduce vertebral fractures,
but effect size is not related to the prop...
DISCUSSION
Implications
• Results show bisphosphonates reduce vertebral
fracture risk as early as 12 months
– earlier than currently ...
Limitations
• Publication bias
– Conference proceedings
– Gray literatures
– Unpublished articles
• Language bias
– Includ...
QUESTIONS?
tina.willson@utah.edu
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Bisphosphonates for Fracture Prevention in Males: A Systematic Review and Meta- Analysis

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  • Large randomized controlled trials of osteoporosis treatments with a fracture endpoint are rare in men; studies in men tend to be small with changes in BMD or bone turnover markers as the primary outcome with fracture incidence usually reported as a secondary outcome
  • Treatments, Conditions, RCTs, Comparators, not cancer, humans, males
  • Alendronate: 10mg/daily; 70mg/weekly (ORAL);Risedronate: 35mg/weekly (ORAL);Zoledronic acid: 5mg/yearly (IV);Ibandronate: 3mg/quarterly (IV); 150mg/monthly (ORAL)
  • A total of 38 studies are included in this meta-analysis; 14 of them report separate fracture outcomes for males.
  • ----- Meeting Notes (4/23/14 14:09) -----check references
  • Only 1 study, zoledronic 2 studies
  • No significant effect for hip and non vertbral. Results were same for 12 and 24 month duration----- Meeting Notes (4/23/14 13:53) -----Add nvf, hip
  • ----- Meeting Notes (4/23/14 14:09) -----More discussion of met regressionsTake that outShow results on biasTake out objective/methods things not presenting
  • Bisphosphonates for Fracture Prevention in Males: A Systematic Review and Meta- Analysis

    1. 1. Bisphosphonates for Fracture Prevention in Males: A Systematic Review and Meta- Analysis Tina Willson Yan Cheng, Tianze Jiao, Greg Stoddard, Joanne LaFleur
    2. 2. BACKGROUND
    3. 3. 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 osteopenia Images: http://www.fore.org/patients/osteo_and_osteo.htm National Osteoporosis Foundation (NOF) www.nof.org
    4. 4. 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.org von Friesendorff et al. Journal of the American Geriatrics Society. 2011. 59(5):806-813
    5. 5. 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
    6. 6. 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)
    7. 7. 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
    8. 8. OBJECTIVE
    9. 9. 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
    10. 10. METHODS
    11. 11. 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
    12. 12. PubMed Search Strategy
    13. 13. 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
    14. 14. 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
    15. 15. 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
    16. 16. 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
    17. 17. RESULTS
    18. 18. Study Selection Databases searches: 649 Pubmed: 263 Scopus: 315 Cochrane: 50 Clinical.gov: 21 Included abstracts: 470 Included for full text review: 123 Data extraction: 38 Excluded: 85 No male fracture: 41 Not standard dosage: 12 Not RCT:10 No placebo group: 6 The same population as other study: 6 Short period of treatment/follow-up: 4 Unable to transfer the result: 3 Duplicates: 2 Not report fracture: 1 Excluded: 347 Not drug of interest: 140 Not RCT: 99 No males in study population: 43 Not placebo comparison: 35 No fracture reported: 21 Other reasons: 9 Duplicates: 179
    19. 19. 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
    20. 20. Primary Results Male: Vertebral Fractures
    21. 21. Male Primary Results Outcome Number of Studies Number of participants RR 95% CI End of Study Vertebral fracture- male studies 8 2060 0.38 (0.23, 0.62) Non-vertebral fracture- male studies 4 671 0.69 (0.30, 1.59) 12 weeks Vertebral fracture- male studies 5 1501 0.41 (0.22, 0.77) Non-vertebral fracture- male studies NA NA NA NA 24 weeks Vertebral fracture- male studies 4 1686 0.33 (0.17, 0.62) Non-vertebral fracture- male studies 3 544 0.59 (0.25, 1.44)
    22. 22. Subgroup Results: Vertebral Fracture by Drug
    23. 23. Primary Results All Studies: Vertebral Fractures
    24. 24. Meta Regression Results: Male Proportion -2-1 012 logRR 0.00 0.20 0.40 0.60 0.80 1.00 Male_Pop_% Vertebral fracture coefficient=-0.64, 95%CI=-1.98 to 0.69
    25. 25. Subgroup Results by Select Study Quality Characteristics
    26. 26. 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.
    27. 27. DISCUSSION
    28. 28. 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.
    29. 29. Limitations • Publication bias – Conference proceedings – Gray literatures – Unpublished articles • Language bias – Included only English or Chinese • Heterogeneity • Un-extractable data
    30. 30. QUESTIONS? tina.willson@utah.edu

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