title: Vitamin D, osteoprotegerin/receptor activator of nuclear factor-kappaB ligand (OPG/RANKL) and inflammation with alendronate treatment in HIV-infected patients with reduced bone mineral density.
abstract: OBJECTIVE
  The aim of the study was to determine the effect of alendronate (ALN) on inflammatory markers and osteoprotegerin (OPG)/receptor activator of nuclear factor-kappaB ligand (RANKL), and to explore the associations of baseline systemic inflammation and vitamin D status on the bone mineral density (BMD) response to ALN.
  
  
  METHODS
  Eighty-two HIV-positive patients with lumbar spine T-score ≤ -1.5 were randomized to ALN 70 mg weekly or placebo for 48 weeks; all received calcium carbonate 500 mg/vitamin D3 200 IU twice daily. Serum C-telopeptide (CTx) and BMD were assessed at baseline and week 48. Stored plasma samples in 70 subjects were assayed for levels of 25-hydroxyvitamin D (25(OH)D), OPG, RANKL, interleukin (IL)-6 and soluble receptors for tumour necrosis factor (TNF)-α 1 and 2 (sTNFR 1 and 2).
  
  
  RESULTS
  ALN increased BMD more than placebo at both the lumbar spine (difference ALN - placebo 2.64%; P = 0.011) and the total hip (difference 2.27%; P = 0.016). No within- or between-arm differences in OPG, RANKL or inflammatory markers were observed over 48 weeks. High baseline CTx and sTNFR2 were associated with a more robust BMD response to ALN over 48 weeks at the lumbar spine [difference 5.66%; 95% confidence interval (CI) 3.50, 7.82; P < 0.0001] and total hip (difference 4.99%; 95% CI 2.40, 7.57; P = 0.0002), respectively. Baseline 25(OH)D < 32 ng/mL was associated with larger increases in total hip BMD over 48 weeks, independent of ALN treatment (P = 0.014).
  
  
  CONCLUSIONS
  Among HIV-positive patients, higher baseline bone resorption and TNF-α activity were associated with an increased BMD response to ALN. The greater BMD response in those with lower vitamin D reinforces the importance of vitamin D supplementation with bisphosphonate treatment.
authors.affiliation: Division of Endocrinology, Diabetes & Metabolism, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: J
authors.initials: J
authors.lastname: Natsag
authors.affiliation: Center for Biostatistics in AIDS Research, Harvard School of Public Health, Boston, MA, USA.
authors.forename: M A
authors.identifier: http://orcid.org/0000-0001-9160-4544
authors.initials: MA
authors.lastname: Kendall
authors.affiliation: Metabolic Bone Center, Johns Hopkins Bayview Medical Center, Baltimore, MD, USA.
authors.forename: D E
authors.initials: DE
authors.lastname: Sellmeyer
authors.affiliation: Division of Pediatric Infectious and Rheumatology Diseases, Case Western Reserve University, Cleveland, OH, USA.
authors.forename: G A
authors.initials: GA
authors.lastname: McComsey
authors.affiliation: Division of Endocrinology, Diabetes & Metabolism, Johns Hopkins University, Baltimore, MD, USA.
authors.forename: T T
authors.initials: TT
authors.lastname: Brown
mesh_terms: D000328:Adult; D019386:Alendronate / Q000008:administration & dosage* / Q000627:therapeutic use; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000627:therapeutic use; D001862:Bone Resorption / Q000188:drug therapy* / Q000378:metabolism; D002762:Cholecalciferol / Q000008:administration & dosage* / Q000494:pharmacology; D004311:Double-Blind Method; D004359:Drug Therapy, Combination; D005260:Female; D015658:HIV Infections / Q000150:complications* / Q000378:metabolism; D006801:Humans; D008159:Lumbar Vertebrae / Q000187:drug effects / Q000473:pathology; D008297:Male; D008875:Middle Aged; D053245:RANK Ligand / Q000378:metabolism*; D016896:Treatment Outcome
chemical_list: D050071:Bone Density Conservation Agents; D053245:RANK Ligand; C505688:TNFSF11 protein, human; D002762:Cholecalciferol; D019386:Alendronate
keywords: alendronate; bone turnover marker; inflammation; low bone mineral density; vitamin D