title: Bone safety with risedronate: histomorphometric studies at different dose levels and exposure.
abstract: This report describes bone safety and histomorphometric data across different dose levels and dosing frequencies of risedronate. Normal bone structure and histomorphometric data were observed, with ongoing bone remodeling and mineralization regardless of dose. These data are reassuring and do not suggest compromised bone remodeling during treatment with established risedronate regimens.
  
  
  BACKGROUND
  The efficacy and bone safety of risedronate 5 mg daily were established in pivotal phase III randomized, placebo-controlled clinical studies. Histomorphometric analysis of paired biopsies demonstrated bone safety as reflected by presence of fluorescent tetracycline double-labels in all evaluable biopsies. This report describes bone safety and histomorphometric data across studies of various dose regimens of risedronate.
  
  
  METHODS
  Bridging studies, with bone mineral density as the primary endpoint, demonstrated non-inferiority of risedronate 35 mg and 50 mg once a week, risedronate 150 mg once a month, and a risedronate 75-mg dose on two consecutive days a month versus risedronate 5 mg daily. The low oral bioavailability and known dosing limitations due to food interactions of bisphosphonates have led to development of an oral delayed-release dose form of risedronate 35 mg to be taken weekly, before or after breakfast. Bone biopsies were collected at 24 months in studies involving these risedronate dosing regimens; bone safety and histomorphometric data were evaluated.
  
  
  RESULTS
  Qualitative bone histology showed normal mineralization of newly formed bone without evidence of pathological findings, such as osteomalacia, bone marrow dyscrasia, or bone marrow fibrosis. Importantly, ongoing bone remodeling, based on fluorochrome labeling, was observed in all patients regardless of dose and exposure. Key histomorphometric variables were comparable to those observed with the risedronate 5 mg daily dose and were within the range seen in healthy pre- and post-menopausal women.
  
  
  CONCLUSIONS
  Overall, the results are reassuring with respect to bone safety and histomorphometric data, and do not suggest oversuppression of bone remodeling during treatment with these established risedronate regimens.
authors.affiliation: Osteoporosis Research Center, Creighton University School of Medicine, 601 N. 30th Street Suite 4820, Omaha, NE, 68131, USA, rrecker@creighton.edu.
authors.forename: R R
authors.initials: RR
authors.lastname: Recker
authors.forename: L-G
authors.initials: LG
authors.lastname: Ste-Marie
authors.forename: P
authors.initials: P
authors.lastname: Chavassieux
authors.forename: M R
authors.initials: MR
authors.lastname: McClung
authors.forename: M W
authors.initials: MW
authors.lastname: Lundy
mesh_terms: D000368:Aged; D001706:Biopsy; D015519:Bone Density / Q000187:drug effects; D050071:Bone Density Conservation Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D016723:Bone Remodeling / Q000187:drug effects; D001842:Bone and Bones / Q000473:pathology; D017326:Clinical Trials, Phase III as Topic; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D012968:Etidronic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy* / Q000473:pathology / Q000503:physiopathology; D016032:Randomized Controlled Trials as Topic; D000068296:Risedronic Acid
chemical_list: D050071:Bone Density Conservation Agents; D000068296:Risedronic Acid; D012968:Etidronic Acid