Clinical Hemorheology and Microcirculation

 Critical-size bone defects after compound fractures, infection, or tumor resection are challenging to treat. The same is true for fractures in patients with impaired bone healing due to metabolic diseases and cancer. Despite considerable progress over the last decade in surgical techniques, material design, and dedicated imaging approaches, these scenarios represent unsolved clinical problems. The high socioeconomic burden of such conditions justifies increasing interest in novel osteoinductive drugs for adjuvant therapeutic approaches. There is an increasing body of experimental and clinical literature on potentially promising effects of growth factors, anti-resorptive, and anabolic agents. The true clinical efficacy of these, however, is discussed controversially. Therefore, we aimed to critically examine the hypothesis that targeted adjuvant therapies have the potential to enhance bone regeneration in critical-size bone defects and under systemic conditions that impair bone healing. This first approach to the topic deals with small molecule drugs and compounds that influence the immune response and inflammatory processes. In particular, literature reporting on selective cyclooxygenase-2 inhibitors has been reviewed with respect to their local and systemic mode of action and to stimulate further research on bone healing under critical conditions.

 The treatment of critical-size bone defects following complicated fractures, infections or tumor resections is a major challenge. The same applies to fractures in patients with impaired bone healing due to systemic inflammatory and metabolic diseases. Despite considerable progress in development and establishment of new surgical techniques, design of bone graft substitutes and imaging techniques, these scenarios still represent unresolved clinical problems. However, the development of new active substances offers novel potential solutions for these issues. This work discusses therapeutic approaches that influence angiogenesis or hypoxic situations in healing bone and surrounding tissue. In particular, literature on sphingosine-1-phosphate receptor modulators and nitric oxide (NO^•) donors, including bi-functional (hybrid) compounds like NO^•-releasing cyclooxygenase-2 inhibitors, was critically reviewed with regard to their local and systemic mode of action.

In this third in a series of reviews on adjuvant drug-assisted bone healing, further approaches aiming at influencing the healing process are discussed. Local and systemic modulation of bone metabolism is pursued with use of a number of drugs with completely different indications, which are characterized by a pleiotropic spectrum of action. These include drugs used to treat lipid disorders (HMG-CoA reductase inhibitors), hypertension (ACE inhibitors), osteoporosis (bisphosphonates), cancer (proteasome inhibitors) and others. Potential applications to enhance bone healing are discussed.