title: Pretreatment levels of bone turnover and the antifracture efficacy of alendronate: the fracture intervention trial.
abstract: The influence of pretreatment bone turnover on alendronate efficacy is not known. In the FIT, we examined the effect of pretreatment bone turnover on the antifracture efficacy of daily alendronate given to postmenopausal women. The nonspine fracture efficacy of alendronate was significantly greater among both osteoporotic and nonosteoporotic women with higher baseline levels of the bone formation marker PINP.
  
  
  BACKGROUND
  Previous trials have shown that high bone turnover is associated with greater increases in BMD among bisphosphonate-treated women. The influence of pretreatment bone turnover levels on antifracture efficacy has not been well studied.
  
  
  METHODS
  We randomized women 55-80 years of age with femoral neck BMD T scores < or = -1.6 to alendronate (ALN), 5-10 mg/day (n = 3105), or placebo (PBO; n = 3081). At baseline, 3495 women were osteoporotic (femoral neck BMD T score < or = -2.5 or prevalent vertebral fracture), and 2689 were not osteoporotic (BMD T score > -2.5 and no prevalent vertebral fracture). Pretreatment levels of bone-specific alkaline phosphatase (BSALP), N-terminal propeptide of type 1 collagen (PINP), and C-terminal cross-linked telopeptide of type 1 collagen (sCTx) were measured in all participants using archived serum (20% fasting). The risk of incident spine and nonspine fracture was compared in ALN- and PBO-treated subjects stratified into tertiles of baseline bone marker level.
  
  
  CONCLUSIONS
  During a mean follow-up of 3.2 years, 492 nonspine and 294 morphometric vertebral fractures were documented. Compared with placebo, the reduction in nonspine fractures with ALN treatment differed significantly among those with low, intermediate, and high pretreatment levels of PINP levels (p = 0.03 for trend). For example, among osteoporotic women in the lowest tertile of pretreatment PINP (<41.6 ng/ml), the ALN versus PBO relative hazard for nonspine fracture was 0.88 (95% CI: 0.65, 1.21) compared with a relative hazard of 0.54 (95% CI: 0.39, 0.74) among those in the highest tertile of PINP (>56.8 ng/ml). Results were similar among women without osteoporosis at baseline. Although they did not reach statistical significance, similar trends were observed with baseline levels of BSALP. Conversely, spine fracture treatment efficacy among osteoporotic women did not differ significantly according to pretreatment marker levels. Spine fracture treatment efficacy among nonosteoporotic women was related to baseline BSALP (p = 0.05 for trend). In summary, alendronate nonspine fracture efficacy is greater among both osteoporotic and nonosteoporotic women with high pretreatment PINP. If confirmed in other studies, these findings suggest that bisphosphonate treatment may be most effective in women with elevated bone turnover.
authors.affiliation: Department of Medicine, Epidemiology and Biostatistics, University of California, San Francisco, California 94107, USA. dbauer@psg.ucsf.edu
authors.forename: Douglas C
authors.initials: DC
authors.lastname: Bauer
authors.forename: Patrick
authors.initials: P
authors.lastname: Garnero
authors.forename: Marc C
authors.initials: MC
authors.lastname: Hochberg
authors.forename: Art
authors.initials: A
authors.lastname: Santora
authors.forename: Pierre
authors.initials: P
authors.lastname: Delmas
authors.forename: Susan K
authors.initials: SK
authors.lastname: Ewing
authors.forename: Dennis M
authors.initials: DM
authors.lastname: Black
mesh_terms: D015502:Absorptiometry, Photon; D000368:Aged; D000369:Aged, 80 and over; D019386:Alendronate / Q000008:administration & dosage*; D015415:Biomarkers / Q000097:blood; D015519:Bone Density / Q000187:drug effects*; D016723:Bone Remodeling / Q000187:drug effects*; D005260:Female; D005272:Femur Neck / Q000528:radiation effects; D050723:Fractures, Bone / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy*; D006801:Humans; D008875:Middle Aged; D015663:Osteoporosis, Postmenopausal / Q000150:complications*; D016103:Spinal Fractures / Q000150:complications / Q000000981:diagnostic imaging / Q000188:drug therapy*; D016896:Treatment Outcome
chemical_list: D015415:Biomarkers; D019386:Alendronate