Clinical evaluation of medicinal products for acceleration of fracture healing in patients with osteoporosis.
Pre-clinical studies indicate that pharmacologic agents can augment fracture union. If these pharmacologic approaches could be translated into clinical benefit and offered to patients with osteoporosis or patients with other risks for impaired fracture union (e.g. in subjects with large defects or open fractures with high complication rate), they could provide an important adjunct to the treatment of fractures. However, widely accepted guidelines are important to encourage the conduct of studies to evaluate bioactive substances, drugs, and new agents that may promote fracture union and subsequent return to normal function. A consensus process was initiated to provide recommendations for the clinical evaluation of potential therapies to augment fracture repair in patients with meta- and diaphyseal fractures. Based on the characteristics of fracture healing and fixation, the following study objectives of a clinical study may be appropriate: a) acceleration of fracture union, b) acceleration of return to normal function and c) reduction of fracture healing complications. The intended goal(s) should determine subsequent study methodology. While an acceleration of return to normal function or a reduction of fracture healing complications in and of themselves may be sufficient primary study endpoints for a phase 3 pivotal study, acceleration of fracture union alone is not. Radiographic evaluation may either occur at multiple time points during the healing process with the aim of measuring the time taken to reach a defined status (e.g. cortical bridging of three cortices or disappearance of fracture lines), or could be obtained at a single pre-determined timepoint, were patients are expected to reach a common clinical milestone (i.e. pain free full weight-bearing in weight-bearing fracture cases). Validated Patient Reported Outcomes (PRO's) measures will need to support the return to normal function co-primary endpoints. If reduction of complication rate (e.g. non-union) is the primary objective, the anticipated complications must be defined in the study protocol, along with their possible associations with the specified fracture type and fixation device. The study design should be randomized, parallel, double-blind, and placebo-controlled, and all fracture subjects should receive a standardized method of fracture fixation, defined as Standard of Care.
Goldhahn
Jörg
J
Schulthess Clinic Zurich and Clinical Priority Program "Fracture Fixation in Osteoporotic, Bone" of AO Foundation, Davos, Switzerland. Electronic address: joerg.goldhahn@kws.ch.
Scheele
Wim H
WH
Wyeth Research, Cambridge, MA, USA.
Mitlak
Bruce H
BH
Eli Lilly and Company, Indianapolis, IN, USA.
Abadie
Eric
E
Département de l'Enregistrement et des Etudes Cliniques, AFSSAPS, Saint Denis, France.
Aspenberg
Per
P
Division of Orthopedics and Sports Medicine, Department of Neuroscience and Locomotion, Faculty of Health Sciences, Linköping University, Linkoping, Sweden.
Augat
Peter
P
Biomechanics Laboratory Paracelsus Medical University, Salzburg, Austria; Biomechanics Laboratory Paracelsus Medical University, Salzburg, Austria.
Brandi
Maria-Luisa
ML
Metabolic Bone Unit, Laboratory of Molecular Genetics, Department of Internal Medicine, University of Florence, Florence, Italy.
Burlet
Nansa
N
International Osteoporosis Foundation, Nyon, Switzerland.
Chines
Arkadi
A
Wyeth Research, Cambridge, MA, USA.
Delmas
Pierre D
PD
Hôpital Edouard Herriot, Lyon, France.
Dupin-Roger
Isabelle
I
IRIS-Servier, Paris, France.
Ethgen
Dominique
D
Clinical Development, GSK, Philadelphia, PA, USA.
Hanson
Beate
B
AO Clinical Investigation and Documentation, Davos Platz, Davos, Switzerland.
Hartl
Florian
F
F. Hoffmann-La Roche AG, Basel, Switzerland.
Kanis
John A
JA
Centre for Metabolic Bone Diseases (WHO Collaborating Centre), University of Sheffield Medical School, Sheffield, UK.
Kewalramani
Reshma
R
Amgen Inc., Thousand Oaks, CA, USA.
Laslop
Andrea
A
AGES PharmMed, Vienna, Austria.
Marsh
David
D
Queen's University Belfast, Division of Surgery and Perioperative Care, Department of Orthopaedic Surgery, Musgrave Park Hospital, Stockman's Lane, Belfast, Ulster, UK.
Ormarsdottir
Sif
S
Senior Expert, Icelandic Medicines Control Agency, Seltjarnarnes, Iceland.
Rizzoli
René
R
Centre Collaborateur de l'Oms pour la prevention de l'osteoporose, Geneva, Switzerland.
Santora
Art
A
Merck & Co., Whitehouse Station, NJ, USA.
Schmidmaier
Gerhard
G
Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Germany.
Wagener
Michael
M
Novartis Pharma AG, Basel, Switzerland.
Reginster
Jean-Yves
JY
Department of Public Health Sciences, University of Liège, Liège, Belgium, Chairman GREES, President ESCEO.
D002986:Clinical Trials as Topic; D004353:Drug Evaluation, Preclinical; D017102:Fracture Healing; D006801:Humans; D010024:Osteoporosis / Q000188:drug therapy*; D004364:Pharmaceutical Preparations; D016896:Treatment Outcome
D004364:Pharmaceutical Preparations