Arthroscopic Optical Coherence Tomography The development of fiberoptic cameras that could be incorporated into arthroscopes in the latter decades of the twentieth century revolutionized orthopaedic diagnosis and treatment. The use of arthroscopy has progressed from the knee to smaller and more complex joints to arthroscopic soft-tissue removal and repair, now performed in virtually all appendicular joints. The basic imaging technology of conventional arthroscopes remains limited to acquisition of surface images. Cross-sectional imaging technologies utilized in orthopaedics include computed tomography, magnetic resonance imaging, ultrasound, and histologic analysis of tissue biopsies. The advantages of these technologies include diagnosis of complex fracture patterns and identification of subtle pathologies of the bone and soft tissues, such as stress fractures and ligament sprains. Obtaining cross-sectional images at microscopic resolutions traditionally has required histologic sectioning and processing of tissue specimens removed from the body. Optical coherence tomography (OCT) is a new imaging technology that provides high-resolution cross-sectional images of human tissues in near real time without damaging or removing the tissue. First introduced clinically for imaging the eye, OCT uses echographs of infrared light to generate high-resolution cross-sectional images of human tissues, including articular cartilage.1 This technology therefore permits the study of opaque tissues in situ at microscopic resolution. Han et al2 used OCT for nondestructive, high-resolution structural analysis of articular repair tissue following chondrocyte implantation in a rabbit model. The OCT images were compared with histologic images and evaluated for qualitative and quantitative features of surface roughness, repair tissue integration, and tissue microarchitecture. Close correlation was observed between OCT and histologic analysis of morphologic features important to the assessment of articular cartilage repair. This new technique, if integrated with an arthroscope, could potentially be used in longitudinal studies of articular cartilage repair in vivo. A handheld sterilizable probe of suitable dimensions for insertion into mammalian joints for real-time cross-sectional imaging was developed and used arthroscopically to image porcine articular cartilage.3 The transverse and axial resolutions of this OCT arthroscope were roughly 17 μm and 10 μm, respectively. Two-dimensional cross-sectional images of cartilage tissue with 500 × 1,000 pixels covering an area 6 mm in length × 1.5 to 2 mm in depth were acquired at nearly five frames per second. Successful application of in vivo OCT arthroscopy to porcine articular cartilage demonstrated sufficient resolution and practicality to move toward use in human joints. In human cadaveric studies, OCT identified early cartilage damage with nearperfect correlation to histology.4 Arthroscopic imaging of the medial and lateral femoral condyles and trochlea was readily accomplished using the OCT probe. This systematic arthroscopic evaluation of human articular cartilage also highlighted a major limitation of OCT in that high-resolution imaging was limited to the top 1 to 1.5 mm of opaque tissues, such as articular cartilage. Given the depth limitation of OCT and the fact that conventional arthroscopic surface imaging readily identifies fibrillated and fissured articular cartilage, a series of studies was then conducted to determine whether OCT could be used to identify subsurface cartilage degeneration in human articular cartilage with intact surfaces. The earliest pathologic changes to articular cartilage frequently occur before breakdown of the articular surface.5 Using OCT, a distinct banding pattern or multilaminar appearance known as OCT form birefringence was observed in young, healthy porcine articular cartilage and in some, but not all, human articular cartilage specimens. Grossly intact-appearing human knee cartilage obtained at the time of total knee replacement was scanned via OCT to identify regions retaining OCT form birefringence as well as regions that had lost CT form birefringence. The tissue was segregated into two groups based on whether form birefringence was retained or not and was assessed for proteoglycan synthetic activity following stimulation with anabolic growth factors.6 Human cartilage specimens without OCT form birefringence demonstrated early metabolic incompetence. 6 Although basal proteoglycan synthetic levels were similar, specimens without OCT form birefringence exhibited insensitivity to the anabolic effects of insulin-like growth factor-1 (IGF-1). Nitric oxide, a substance that has been implicated in chondrocyte insensitivity to IGF-1, was found in higher levels in cartilage without OCT form birefringence. Although chondrocyte insensitivity to IGF-1 cannot be reversed in severely diseased articular cartilage, incubation of specimens without OCT form birefringence with an inhibitor of nitric oxide synthase restored the ability of these specimens to respond to IGF-1 stimulation. These new data demonstrate that OCT potentially identified cartilage pathologies sufficiently early to restore an anabolic response to IGF-1. A recent clinical study using OCT during arthroscopic surgery in 19 human subjects following joint injury confirmed that OCT can be successfully used arthroscopically to identify differences in OCT birefringence patterns found in the laboratory that are consistent with early cartilage degeneration. 6 Further clinical and laboratory studies regarding whether OCT can be used to identify potentially reversible early human cartilage degeneration are underway. Constance R. Chu MD Denosumab: An Anti-RANKL Monoclonal Antibody Receptor activator of nuclear factor-κB ligand (RANKL) is a protein expressed by osteoblasts that binds to the surface of osteoclasts, leading to their activation and differentiation. This cytokine is the final principal mediator of bone resorption.7,8 in a broad range of conditions, including osteoporosis, rheumatoid arthritis, and metastatic cancer. In the process of bone metastasis, the primary mechanism responsible for bone destruction is cancer cell-mediated stimulation of osteoclastic bone resorption, with subsequent invasion of cancer cells into bone.9 Denosumab is a human monoclonal antibody that binds to RANKL with high affinity and specificity. By inhibiting the action of RANKL, denosumab reduces the differentiation, activity, and survival of osteoclasts.8 Early studies in humans have shown it to reduce bone turnover and improve bone density while also having a very rapid onset of action, sustained effects for several months after a single injection, and good tolerability.10 In July 2004, researchers at Amgen (Thousand Oaks, CA) published the results of the phase I clinical trial of Denosumab (AMG 162).11 The safety and bone antiresorptive effect of a single subcutaneous dose was investigated in 49 postmenopausal women. The study was randomized, doubleblind, and placebo-controlled. A rapid, profound (up to 84%), and sustained decrease in urinary N-telopeptide/ creatinine was observed. The drug was well tolerated; no serious adverse events occurred. In addition, a randomized, doubleblind, multicenter study was performed to determine the safety and efficacy of denosumab in patients with breast cancer or multiple myeloma with radiologically confirmed bone lesions.12 Following a single subcutaneous dose of denosumab, levels of N-telopeptides decreased within 1 day; this decrease lasted up to 84 days. The decrease in bone turnover markers was similar in magnitude but more sustained than with intravenous pamidronate. Injections were once again well tolerated. Additionally, subcutaneously administered denosumab was evaluated over 12 months in 412 postmenopausal women with low bone mineral density.13 Results showed an increase in bone mineral density of the lumbar spine of 3.0% to 6.7%, compared with an increase of 4.6% with alendronate and a loss of 0.8% with placebo. In the distal radius, there was a 0.4% to 1.3% increase in bone mineral density in the denosumab-treated patients compared with a decrease of 0.5% in the alendronate-treated patients and a decrease of 2.0% in the patients given placebo. Near-maximal reductions in mean levels of serum C-telopeptide from baseline were evident 3 days after administration of denosumab. A global phase III clinical trial of denosumab in patients with bone metastases is currently underway.9 The drug may become part of the treatment regimen in patients with metastases, in combination with chemotherapy and/or hormone therapy. 9 In addition, denosumab may well become a first-line treatment in postmenopausal osteoporosis and other skeletal diseases characterized by increased osteoblastic activity. Mark S. McMahon MD Yasuyoshi Ueki MD, PhD Bone Tissue Engineering A recent session of the Sun Valley Workshop on Skeletal Biology (held August 5-8, 2007, in Sun Valley, ID) provided an outstanding review of new advances in tissue engineering. In particular, a presentation given by Andres Garcia, PhD, of the Georgia Institute of Technology, reported results that could change the surgical use of bone allografts and further the development of artificial bone substitutes in the relatively near future. Garcia showed not only that the interaction of bone cells with an implant or matrix is mechanical but also that the integrin connections between cell and surface have fundamental importance to signaling and cell differentiation. Garcia built an artificial molecule (GFOGER) that contains an α2β1 binding site and tested its ability to improve osseointegration in a rat titanium implant model.14–16 In the model, a small titanium implant is press-fit laterally into a long bone either with or without coating with GFOGER. One result of the study was that the GFOGER-treated implants had approximately double the bony apposition and double the pull-out strength of the untreated implants. An interesting feature of the GFOGER molecule is that it attaches passively to the implant. This aspect of GFOGER could be a key feature in the potential clinical relevance of molecules such as this because passive attachment is essentially dipping the implant into a solution. This easy method of treatment potentially could be used with existing implants. As a further test of the ability of the new molecule to enhance bone growth, Garcia collaborated with Robert Guldberg, PhD, of the Georgia Institute of Technology, to test whether polymer scaffolds passively treated with GFOGER can bridge a defect of critical size in a rat longbone model. The results, not yet published, indicate that the scaffold alone was not efficacious and that treatment of the scaffold with GFOGER (ie, dipping) resulted in healing. Also at the Sun Valley Workshop, Adam Engler, PhD, of Princeton University, described a dose-response curve between matrix stiffness and the differentiation pathway of mesenchymal stem cells.17–20 At low matrix, stiffness cells differentiated into muscle, and at intermediate matrix, into cartilage; when cultured on a high-stiffness matrix, cells differentiated into an osteoblastic phenotype. David P. Fyhrie PhD