GIM Journal Club

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GIM Journal Club

• Effects of Atorvastatin on Bone in Postmenopausal
  Women with Dyslipidemia A Double-Blind, Placebo
  Controlled, Dose-Ranging Trial
• Uha Reddy, M.D.
• January 22, 2008

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Osteoporosis

• Major public health risk
• Osteoporosis related fractures
• 1.5 Million fractures annually
• 1 in 2 women over the age of 50 and 1 in 4 men
  over the age of 50 will have a fracture related
  to osteoporosis in his/her lifetime
• Healthcare costs 14 billion/year!

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HMG-CoA reductase inhibitors

• Or statins, known to effectively treat
  dyslipidemia
• Positive effect on bone remodeling
• In vitro and animal studies
• Increase bone formation by osteoblasts
• Decrease bone resorption by osteoclasts

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Studies so far

• Mostly observational studies and secondary
  analyses
• Inconsistent results regarding the effect of
  statins on bone density and fracture risk
• No large scale, double blind, placebo controlled
  trial

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Importance for Primary Care

• Osteoporosis and dyslipidemia
• High prevalence
• Often found in the same patient
• Clinically important
• Treated by primary care doctors
• Obvious benefit to finding one medication that
  can help with both problems

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Study Inclusion Criteria

• 626 women, age 40-75
• LDL levels of at least 130 mg/dl and less than
  190 mg/dl
• Lumbar spine BMD between 0.0 and 2.5 SD below the
  mean
• All postmenopausal
• serum estradiol levels less than 110 pmol/liter
  and FSH levels more than 30 IU/liter

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Study Exclusion Criteria

• Treatment with lipid lowering meds, hormone
  therapy, or other drugs affecting bone metabolism
• History of DM, CAD, or any medical disease
  associated with development of metabolic bone
  disease
• 2 or more CV risk factors and LDL 160 or greater

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Study Design

• 2 week screening period
• 52 weeks of randomized therapy
• Participants randomly assigned
• Placebo
• Or daily doses of atorvastatin (10, 20, 40, or 80
  mg)
• All received calcium/Vitamin D

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Study Design (cont)

• Dual energy x-ray absorptiometry (DXA) performed
  at baseline, at 26 wks, and at completion (52
  wks)
• Lumbar spine BMD
• Femoral neck, trochanter, total proximal femoral
  area BMD

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Study Design (cont)

• Biochemical markers of bone metabolism
• Serum N-telopeptide of type I collagen, serum
  C-telopeptide of type I collagen, osteocalcin,
  N-terminal, bone specific alkaline phosphatase,
  N-terminal propeptide of procollagen type 1,
  urinary deoxypyridinoline
• Serum lipid markers
• Total cholesterol, LDL, TGs, and HDL

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Participants
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Primary endpoint

• Percent change in areal lumbar spine BMD from
  baseline to end of study between the placebo
  group and each atorvastatin group
• Secondary endpoints
• Femoral BMD change
• Biochemical marker change

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Results

• Please see Table 2
• No significant differences
• For all measures in table, p value was not
  significant (Dunnetts method) for any difference
  btw placebo and any of the atorvastatin groups
• Confidence intervals lower limits are all below
  0

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Results

• No significant difference
• Primary endpoint lumbar BMD
• Femoral BMD
• Biochemical markers
• Lipid profile
• Total cholesterol, LDL, and TGs levels decreased
  (in atorvastatin groups) in a statistically
  significant manner
• HDL no significant change

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Adverse Effects

• Serious AEs in 12 patients
• Not related to study treatment
• Only 1 (hemorrhagic stroke) led to
  discontinuation
• No deaths, no rhabdomyolysis
• Elevated LFTs
• Leading to 2 discontinuations

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Adverse Effects (cont)

• Frequently reported AEs listed in Table 3
• Most frequent treatment related AE
• Myalgia
• No complete list of AEs leading to
  discontinuation

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Discussion

• No evidence that systemic atorvastatin
  significantly effects BMD or biochemical markers
• Cannot exclude the possibility of subtle effects
  over many years
• But, all other meds proven beneficial for
  osteoporosis have produced results within the 52
  week timeframe

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Discussion (cont)

• Statins are biotransformed in the liver with high
  first-pass clearance ? low systemic exposure to
  active drug ? lack of effect may be secondary to
  low statin uptake into bone tissue
• Higher doses of statins unlikely to be clinically
  feasible

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About the study

• Well-designed study
• Clinically significant objective
• Primary and secondary endpoints were concrete and
  able to be objectively obtained

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About the article

• Thorough presentation of study design/participants
  and thoughtful discussion
• More information about reasons for
  discontinuation (30-36 participants in each group
  were discontinued)

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Overall

• Useful information obtained
• Statins are still important meds, will continue
  to be prescribed for dyslipidemia
• First double-blind, placebo-controlled, dose
  ranging trial of this kind, so future trials
  would be useful . . .

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References

• Bone, HG, et al. Effects of Atorvastatin on Bone
  in Postmenopausal Women with Dyslipidemia A
  Double-Blind, Placebo-Controlled, Dose-Ranging
  Trial. J Clin Endocrinol Metab, December 2007,
  92(12) 4671-4677.
• Osteoporosis. National Institute of Arthritis and
  Musculoskeletal and Skin Diseases. Retrieved 17
  Jan 2008 from http//www.niams.nih.gov/Health_Info
  /Bone/Osteoporosis/

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Thank you!