title: Are Changes in Composition in Response to Treatment of a Mouse Model of Osteogenesis Imperfecta Sex-dependent?
abstract: BACKGROUND
  Osteogenesis imperfecta (OI) is a genetic disease characterized by skeletal fragility and deformity. There is extensive debate regarding treatment options in adults with OI. Antiresorptive treatment reduces the number of fractures in growing oim/oim mice, an animal model that reproducibly mimics the moderate-to-severe form of OI in humans. Effects of long-term treatments with antiresorptive agents, considered for treatment of older patients with OI with similar presentation (moderate-to-severe OI) are, to date, unknown.
  
  
  OBJECTIVE
  Fourier transform infrared (FTIR) imaging, which produces a map of the spatial variation in chemical composition in thin sections of bone, was used to address the following questions: (1) do oim/oim mice show a sex dependence in compositional properties at 6.5 months of age; (2) is there a sex-dependent response to treatment with antiresorptive agents used in the treatment of OI in humans; and (3) are any compositional parameters in oim/oim mice corrected to wild-type (WT) values after treatment?
  
  
  METHODS
  FTIR imaging data were collected from femurs from four to five mice per sex per genotype per treatment. Treatments were 24 weeks of saline, alendronate, or RANK-Fc; and 12 weeks of saline+12 weeks RANK-Fc and 12 weeks of alendronate+RANK-Fc. FTIR imaging compositional parameters measured in cortical and cancellous bones were mineral-to-matrix ratio, carbonate-to-mineral ratio, crystal size/perfection, acid phosphate substitution, collagen maturity, and their respective distributions (heterogeneities). Because of the small sample size, nonparametric statistics (Mann-Whitney U- and Kruskal-Wallis tests with Bonferroni correction) were used to compare saline-treated male and female mice of different genotypes and treatment effects by sex and genotype, respectively. Statistical significance was defined as p<0.05.
  
  
  RESULTS
  At 6.5 months, saline-treated male cortical oim/oim bone had increased mineral-to-matrix ratio (p=0.016), increased acid phosphate substitution (p=0.032), and decreased carbonate-to-mineral ratio (p=0.016) relative to WT. Cancellous bone in male oim/oim also had increased mineral-to-matrix ratio (p=0.016) relative to male WT. Female oim/oim mouse bone composition for all cortical and cancellous bone parameters was comparable to WT (p>0.05). Only the female WT mice showed a response of mean compositional properties to treatment, increasing mineral-to-matrix after RANK-Fc treatment in cancellous bone (p=0.036) compared with saline-treated mice. Male oim/oim increased mineral-to-matrix cortical and cancellous bone heterogeneity in response to all long-term treatments except for saline+RANK-Fc (p<0.04); female oim/oim cortical mineral-to-matrix bone heterogeneity increased with ALN+RANK-Fc and all treatments increased cancellous female oim/oim bone acid phosphate substitution heterogeneity (p<0.04).
  
  
  CONCLUSIONS
  Both oim/oim and WT mice, which demonstrate sex-dependent differences in composition with saline treatment, showed few responses to long-term treatment with antiresorptive agents. Female WT mice appeared to be more responsive; male oim/oim mice showed more changes in compositional heterogeneity. Changes in bone composition caused by these agents may contribute to improved bone quality in oim/oim mice, because the treatments are known to reduce fracture incidence.
  
  
  CONCLUSIONS
  The optimal drug therapy for long-term treatment of patients with moderate-to-severe OI is unknown. Based on bone compositional changes in mice, antiresorptive treatments are useful for continued treatment in OI. There is a reported sexual dimorphism in fracture incidence in adults with OI, but to date, no one has reported differences in response to pharmaceutical intervention. This study suggests that such an investigation is warranted.
authors.affiliation: Musculoskeletal Integrity Program, Hospital for Special Surgery, 535 E 70th Street, New York, NY, 10021, USA, Boskeya@HSS.edu.
authors.forename: Adele L
authors.initials: AL
authors.lastname: Boskey
authors.forename: Josephine
authors.initials: J
authors.lastname: Marino
authors.forename: Lyudmila
authors.initials: L
authors.lastname: Spevak
authors.forename: Nancy
authors.initials: N
authors.lastname: Pleshko
authors.forename: Stephen
authors.initials: S
authors.lastname: Doty
authors.forename: Erin M
authors.initials: EM
authors.lastname: Carter
authors.forename: Cathleen L
authors.initials: CL
authors.lastname: Raggio
mesh_terms: D019386:Alendronate / Q000494:pharmacology*; D000818:Animals; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000494:pharmacology*; D001862:Bone Resorption / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004195:Disease Models, Animal; D005260:Female; D005269:Femur / Q000187:drug effects* / Q000378:metabolism; D050723:Fractures, Bone / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D008297:Male; D051379:Mice; D010013:Osteogenesis Imperfecta / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000494:pharmacology*; D012737:Sex Factors; D017550:Spectroscopy, Fourier Transform Infrared; D013997:Time Factors
chemical_list: D050071:Bone Density Conservation Agents; C517736:Rank-Fc; D011993:Recombinant Fusion Proteins; D003094:Collagen; D019386:Alendronate