1. Bisphosphonates for Fracture
Prevention in Males:
A Systematic Review and Meta-
Analysis
Tina Willson
Yan Cheng, Tianze Jiao, Greg Stoddard, Joanne LaFleur

2. BACKGROUND

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. 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. 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. 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. 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. OBJECTIVE

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. METHODS

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. PubMed Search Strategy

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. 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. 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. 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. RESULTS

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. 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. Primary Results Male: Vertebral Fractures

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. Subgroup Results: Vertebral Fracture by Drug

23. Primary Results All Studies: Vertebral Fractures

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. Subgroup Results by Select Study Quality
Characteristics

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. DISCUSSION

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. Limitations
• Publication bias
– Conference proceedings
– Gray literatures
– Unpublished articles
• Language bias
– Included only English or Chinese
• Heterogeneity
• Un-extractable data

30. QUESTIONS?
tina.willson@utah.edu