Osteoporosis Treatment Efficacy for Men: A Systematic Review and Meta-Analysis

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Nayak S, et al. "Osteoporosis Treatment Efficacy for Men: A Systematic Review and Meta-Analysis". Journal of the American Geriatrics Society. 2017. 65(3):490-495.
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Clinical Question

In male patients with a history of osteoporosis, low BMD, or past fragility fracture, which treatment option is most efficacious in reducing the risk of a vertebral and/or non-vertebral fracture?

Bottom Line

Based on a meta-analysis and systematic review, men with osteoporosis saw benefit from bisphosphonates for reduction in vertebral fractures. There is some evidence for the use of bisphosphonates to lower of risk of nonvertebral fractures in men with osteoporosis, but more studies are necessary. Likewise, non-bisphosphonate medications need more supporting evidence to establish their association with fracture risk reduction.

Major Points

  • Bisphosphonates are the drug of choice for men with osteoporosis to significantly reduce the chance of a vertebral fracture. (Nayak, et al.).
  • The meta-analysis initially showed that bisphosphonates significantly reduced nonvertebral fractures compared to non-bisphosphonates, but a subsequent sensitivity analysis revealed a risedronate study that had notable influence. Its removal led to non-significance and thus the ambiguity regarding bisphosphonate use in non-vertebral fractures.
  • The results regarding bisphosphonates pertain to men with a diagnosis of osteoporosis, low BMD, or a history of a fragility fracture.
  • More studies are needed to determine the benefit of medications in men with osteoporosis in relation to nonvertebral fractures.
  • Alendronate and risedronate were found to have a significant reduction in the incidence of vertebral fractures. Otherwise, it’s difficult to conclude which individual medication is more efficacious than another based on the lack of active comparator trials available in literature.
  • More randomized control trials with high power are necessary to better understand the benefits of zoledronic acid, denosumab, and teriparatide in males with osteoporosis.

Guidelines

  • “2014 Clinician’s Guide to Prevention and Treatment of Osteoporosis.”
    • Treatments function to reduce the chance of fracture in osteoporosis.
    • The following drugs are endorsed by the FDA for treatment of osteoporosis in men: bisphosphonates (i.e. alendronate, risedronate, zoledronic acid, but NOT ibandronate), teriparatide, and denosumab. Other organizations also offer treatment considerations.
    • Calcitonin has only been approved for women with osteoporosis.
    • Efficacy studies of FDA-approved drugs have mostly been conducted in women. Generally, patients are treated with a bisphosphonate first line.
    • Men qualify for treatment if they:
      • “Are >50 years of age and have a BMD t-score of ≤ -2.5 at the femoral neck, total hip, or lumbar spine.” OR
      • Present with a spine or hip fracture. OR
      • “T-score between -1 and -2.5 found at the femoral neck, total hip or lumbar spine by DXA and 10-year hip fracture probability > 3 percent or a 10-year major osteoporosis-related fracture probability > 20 percent.”
    • Monitoring of bisphosphonate therapy: serum calcium and 25(OH)D, BMD

Design and Methods

  • Systematic review and meta-analysis
    • 24 records (with 22 RCTs) were obtained from PubMed, Embase, and the Cochrane Library from August 2014-March 2016.
  • Articles were published from 1998-2013.
  • Quantity of male patients in a given study (low/high): 23/1199
  • N=4,868 males
  • Individual study length: anywhere from 1-3 years
  • Drug (# of articles included)
    • Alendronate (5)
    • Zoledronic acid (4)
    • Risedronate (3)
    • Ibandronate (1)
    • Calcitonin (2)
    • Denosumab (2)
    • Strontium ranelate (2)
    • Teriparatide (2)
    • Monoflourophosphate (1)
    • Calcitriol (1)
    • Parathyroid hormone (1)
  • Majority of studies had two treatment arms comparing a medication versus placebo, calcium/vitamin D, or both.
  • 2 studies compared drugs directly against another
    • Teriparatide versus alendronate
    • Zoledronic acid versus alendronate

Population

Inclusion Criteria

  • Trials assessing the effectiveness of treatment in adults whom had osteoporosis, low BMD, or past fragility fracture
  • Randomized clinical studies
  • Exclusive data outlined in the trials for males or had only male subjects enrolled
  • Outcomes included fracture incidence of men
  • Reported in any language
  • No regard to patient comorbidities

Exclusion Criteria

  • Studies where not all subjects had a history of osteoporosis or low BMD (i.e. t-score ≤ 1)

Baseline Characteristics

  • “Men with primary osteoporosis, hypogonadal osteoporosis, or both and did not include men with other causes of secondary osteoporosis.” (Nayak, et al.).
  • Mostly white males
  • Types of fractures considered
    • Vertebral fractures (most frequently assessed outcome)
      • X-ray revealed
      • Clinical, based on symptoms
    • Nonvertebral fractures
    • Clinical fractures, based on symptoms at any location

Intervention

N/A - meta-analysis and systematic review

Outcome

Relative risk (RR) was calculated from fracture incidence for each individual medication and the bisphosphonate class. Ibandronate, Monofluorophosphate, Calcitriol, Parathyroid hormone are not included because they each only had one study. Heterogeneity was determined for each meta-analysis.

Treatment

Fracture Type
RR (95% CI) I^2

Alendronate

Vertebral fractures
0.328 (0.155–0.692) I^2 = 29.4%
Nonvertebral fractures
0.751 (0.352–1.602) I^2 = 0.0%

Calcitonin

Vertebral fractures
0.272 (0.046–1.608) I^2 = 0.0%

Denosumab

Vertebral fractures
0.256 (0.029–2.238) I^2 = 0.0%

Risedronate

Vertebral fractures
0.428 (0.245–0.746) I^2 = 27.4%

Zoledronic acid

Clinical fractures
0.742 (0.436–1.263) I^2 = 0.0%

Bisphosphonates

i.e. alendronate, ibandronate, risedronate, and zoledronic acid

Vertebral fractures
0.368 (0.252–0.537) I^2 = 0.0%
Vertebral fractures (clinical)
0.398 (0.105–1.506) I^2 = 0.0%
Nonvertebral fractures
0.604 (0.404–0.904) I^2 = 0.0%
Clinical fractures
0.791 (0.500–1.253) I^2 = 0.0%

Sensitivity analysis - Bisphosphonates

Vertebral fractures
0.353-0.391 (0.215-0.265 to 0.518-0.594)
Vertebral fractures (clinical)
not significant
Nonvertebral fractures
0.715 (0.382-1.337)
Clinical fractures
not significant

Adverse Events

N/A

Criticisms

  • One author had a noted conflict of interest with Merck & Co.
  • There was limited study availability for non-bisphosphonate interventions.
  • Small sample sizes were selected. Of all the studies gathered for the meta-analysis, only one reported an adequate power. Testing was done primarily in white patients.
  • Uncertainty regarding the longevity of osteoporosis drugs. The longest trials that were included had continued for no more than 3 years.
  • Unclear or high risk of bias present in all studies in the meta-analysis. Trials were rated as having high, low, or unclear bias across five recommended categories.

Funding

  • Many trials (16 out of 22) gathered in the meta-analysis had documented financial support from pharmaceutical companies. See page 492 of article for citations.
  • The authors who completed the meta-analysis and systematic review received grants from the NIH.
  • “The sponsors had no role in the design, methods, data collection, analysis, or preparation of the paper” (Nayak, et al.).

Further Reading