title: Morphea-like skin reactions in patients treated with the cathepsin K inhibitor balicatib.
abstract: BACKGROUND
  In a multicenter clinical trial in North America and Europe that tested the cathepsin K (catK) inhibitor balicatib for the treatment of osteoporosis, several patients developed hardening of the skin.
  
  
  OBJECTIVE
  We sought to characterize these observed adverse events.
  
  
  METHODS
  Patients with skin hardening were examined by a local dermatologist. All of those patients except one had at least one biopsy specimen taken from affected skin, which was read by local and two central dermatopathologists. Workup was directed for consideration of systemic scleroderma.
  
  
  RESULTS
  Nine patients of 709 treated with balicatib developed skin hardening and were given a diagnosis of morphea-like skin changes. No such events were observed in patients taking placebo or the lowest balicatib dose. After discontinuation of balicatib, skin changes resolved completely in 8 and partially in one patient.
  
  
  CONCLUSIONS
  Each patient was seen by a different dermatologist in 6 different countries.
  
  
  CONCLUSIONS
  These observations are likely dose-related adverse effects of balicatib. Although catK was originally thought to be expressed only in osteoclasts, it has more recently also been found in lung and dermal fibroblasts and been implicated in the degradation of the extracellular matrix in the lung and the skin. It is therefore plausible that the observed dermal fibrosis in balicatib-treated patients is a result of impaired degradation of extracellular matrix proteins and may represent a class effect of catK inhibitors. We recommend that further exploration of catK inhibition for the treatment of osteoporosis or cancer should include monitoring for similar adverse effects.
authors.affiliation: Department of Dermatology, Boston University School of Medicine, Boston, Massachusetts 02118, USA. truenger@bu.edu
authors.forename: Thomas M
authors.initials: TM
authors.lastname: Rünger
authors.forename: Silvano
authors.initials: S
authors.lastname: Adami
authors.forename: Claude-Laurent
authors.initials: CL
authors.lastname: Benhamou
authors.forename: Edward
authors.initials: E
authors.lastname: Czerwiński
authors.forename: Jordi
authors.initials: J
authors.lastname: Farrerons
authors.forename: David L
authors.initials: DL
authors.lastname: Kendler
authors.forename: Linda
authors.initials: L
authors.lastname: Mindeholm
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Realdi
authors.forename: Christian
authors.initials: C
authors.lastname: Roux
authors.forename: Vanessa
authors.initials: V
authors.lastname: Smith
mesh_terms: D000368:Aged; D001549:Benzamides / Q000008:administration & dosage / Q000009:adverse effects*; D056657:Cathepsin K / Q000037:antagonists & inhibitors* / Q000378:metabolism; D003094:Collagen / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000008:administration & dosage / Q000009:adverse effects*; D005260:Female; D005347:Fibroblasts / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D006801:Humans; D008875:Middle Aged; D015337:Multicenter Studies as Topic; D010024:Osteoporosis / Q000188:drug therapy*; D010879:Piperazines / Q000008:administration & dosage / Q000009:adverse effects*; D016032:Randomized Controlled Trials as Topic; D012594:Scleroderma, Localized / Q000139:chemically induced* / Q000473:pathology
chemical_list: D001549:Benzamides; D004791:Enzyme Inhibitors; D010879:Piperazines; D003094:Collagen; C529767:balicatib; C534130:CTSK protein, human; D056657:Cathepsin K