Osteopontin-1 (OP-1) has demonstrated considerable clinical usefulness,
along with a strong record of safety, in a wide variety of musculoskeletal
disorders in more than 500 patients worldwide during the past decade. Specifically,
the outcomes of patients with tibial nonunions enrolled in a randomized,
prospective clinical trial in the United States and treated with OP-1
and intramedullary fixation were comparable with those of patients
treated with bone autograft and a rod. These, and the other carefully
observed cases, build on substantial preclinical evaluation and
begin the very important and practical process of clarifying the
unique role these molecules will play in the clinical arena.
As with many new directions in medicine, the earliest research raises
meaningful questions about study goals and design, including the
specific questions to be addressed, the appropriateness and limitations
of available methods of assessment, and the interpretation of data.
The scope and the funding of clinical trials, as well as management
of the partnership between academia and industry, are frequent issues encountered
and addressed in the conduct of novel and cutting-edge clinical
research.
The conduct of any well planned and scientifically rigorous clinical
study to assess a new therapeutic approach requires a clearly defined
clinical problem for which a hypothesis regarding the proposed treatment
can be articulated and tested. In this regard, clinical research
must build on both safety and efficacy data derived in a preclinical
setting. The research questions require methods of assessment that
are pertinent, reliable, accurate, and reproducible and are accomplished
without bias and in sufficient numbers of patients to provide interpretable
information.
Long-bone nonunions requiring the use of internal fixation were selected
for the initial clinical evaluation of OP-1 because these unequivocal
failures of biology represent an extremely difficult clinical dilemma
and there is general agreement concerning their definition.
Consequently, tibial nonunions, judged by treating surgeons as needing
intramedullary rod fixation and bone grafts, were chosen for this
study. These specific inclusion circumstances occur relatively infrequently;
however, such cases are often frustrating in terms of response to
currently available treatment. Furthermore, the majority of patients
in this study group had multiple prior procedures that failed to resolve
the nonunions, including the use of intramedullary rods and autografts.
By definition, they were all failures of conventional fracture care.
In effect, each patient acted as his or her own control, and each
success following intervention became incrementally important. Clearly, other
clinical procedures commonly accomplished with bone grafting are
worthy of investigation regarding the value of adding an osteoinductive
molecule, but tibial nonunions represent an especially challenging
circumstance. Success in this condition portends efficacy with other musculoskeletal
sites and disorders.
The present study was not designed to answer whether bone autograft
is required to heal a tibial nonunion but rather to demonstrate
the success rate of treatment with OP-1 plus internal fixation and
compare this with the commonly used approach of bone autograft plus internal
fixation in similar circumstances.
Several methods of evaluation were incorporated into the design
of this study, all noninvasive in nature. There are, however, certainly
limitations to the accuracy and sensitivity of noninvasive monitoring.
Of particular importance, it became clear that plain x-ray has limited
sensitivity in judging bone repair. For instance, in the majority
of published reports, radiographic outcome was established by the treating
orthopaedic surgeon as "healed" or "not
healed" rather than having independent radiologists blinded
to treatment determine the number of cortices bridged. Additionally,
most past studies did not use a prospectively determined endpoint
(such as 9 months) but rather listed patients as successfully treated
if the bone healed at any time point. Nonetheless, plain x-ray remains
one of several important and available measures of fracture repair
and plays a part in reaching an overall determination of success.
These patients, although homogeneous in the presence of a tibial
nonunion, have additional variations in their fracture configuration,
amount of bone loss, prior treatment, implant configuration, and
medical/social histories. Nonetheless, the achievement
of reasonable comparability between these groups must be sought
and, in this case, was achieved.
Perhaps the most impressive lessons learned in the clinical arena are
related to the recognition that patients and their disorders vary and
those patients and their surgeons may weigh differently the relative
risks and benefits of available (and future) therapeutic approaches.
Unique new therapies expand available choices. It is the obligation
and opportunity of science and medicine to provide patients with
predictably useful and safe alternatives that meet their needs.
It is furthermore necessary to provide physicians with sufficient
information concerning the nature and safety of these approaches
to help patients make good decisions about their care and to appropriately
use these new products and procedures. Well designed and properly
executed clinical research is a critical factor in developing these
advances and the related knowledge.