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.
Schulthess Clinic Zurich and Clinical Priority Program "Fracture Fixation in Osteoporotic, Bone" of AO Foundation, Davos, Switzerland. Electronic address: joerg.goldhahn@kws.ch.
Jörg
J
Goldhahn
Wyeth Research, Cambridge, MA, USA.
Wim H
WH
Scheele
Eli Lilly and Company, Indianapolis, IN, USA.
Bruce H
BH
Mitlak
Département de l'Enregistrement et des Etudes Cliniques, AFSSAPS, Saint Denis, France.
Eric
E
Abadie
Division of Orthopedics and Sports Medicine, Department of Neuroscience and Locomotion, Faculty of Health Sciences, Linköping University, Linkoping, Sweden.
Per
P
Aspenberg
Biomechanics Laboratory Paracelsus Medical University, Salzburg, Austria; Biomechanics Laboratory Paracelsus Medical University, Salzburg, Austria.
Peter
P
Augat
Metabolic Bone Unit, Laboratory of Molecular Genetics, Department of Internal Medicine, University of Florence, Florence, Italy.
Maria-Luisa
ML
Brandi
International Osteoporosis Foundation, Nyon, Switzerland.
Nansa
N
Burlet
Wyeth Research, Cambridge, MA, USA.
Arkadi
A
Chines
Hôpital Edouard Herriot, Lyon, France.
Pierre D
PD
Delmas
IRIS-Servier, Paris, France.
Isabelle
I
Dupin-Roger
Clinical Development, GSK, Philadelphia, PA, USA.
Dominique
D
Ethgen
AO Clinical Investigation and Documentation, Davos Platz, Davos, Switzerland.
Beate
B
Hanson
F. Hoffmann-La Roche AG, Basel, Switzerland.
Florian
F
Hartl
Centre for Metabolic Bone Diseases (WHO Collaborating Centre), University of Sheffield Medical School, Sheffield, UK.
John A
JA
Kanis
Amgen Inc., Thousand Oaks, CA, USA.
Reshma
R
Kewalramani
AGES PharmMed, Vienna, Austria.
Andrea
A
Laslop
Queen's University Belfast, Division of Surgery and Perioperative Care, Department of Orthopaedic Surgery, Musgrave Park Hospital, Stockman's Lane, Belfast, Ulster, UK.
David
D
Marsh
Senior Expert, Icelandic Medicines Control Agency, Seltjarnarnes, Iceland.
Sif
S
Ormarsdottir
Centre Collaborateur de l'Oms pour la prevention de l'osteoporose, Geneva, Switzerland.
René
R
Rizzoli
Merck & Co., Whitehouse Station, NJ, USA.
Art
A
Santora
Center for Musculoskeletal Surgery, Charité-Universitätsmedizin Berlin, Germany.
Gerhard
G
Schmidmaier
Novartis Pharma AG, Basel, Switzerland.
Michael
M
Wagener
Department of Public Health Sciences, University of Liège, Liège, Belgium, Chairman GREES, President ESCEO.
Jean-Yves
JY
Reginster
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