Susan V. Bukata

Teriparatide as a Chondroregenerative Therapy for Injury-Induced Osteoarthritis

Teriparatide is chondroprotective and chondroregenerative in a mouse model of injury-induced osteoarthritis of the knee. Extending the Service Life of Arthritic Joints Every year, millions of people with osteoarthritis are forced to scale back their physical activities hoping to alleviate pain and increase the longevity of their degenerating joints. The problem is serious: A decade from now, 25% or more of the U.S. population are predicted to suffer from osteoarthritis. The hallmark problem in osteoarthritis is the progressive and irreversible loss of cartilage. Ultimately, the only option is to surgically replace the lost cartilage with metal and plastic. But are there alternative strategies that could lead to cartilage replacement and reduce the cycle of pain and reduced quality of life? In this issue of Science Translational Medicine, Sampson and colleagues report that a naturally occurring hormone called parathyroid hormone (trade name Forteo), already approved by the Food and Drug Administration to build bone, can also boost the buildup of cartilage in a mouse model of injury-induced osteoarthritis. In this mouse model, injury to the meniscus and ligaments of the knee initiates a slow process of cartilage degeneration that is comparable to that seen in people suffering a similar injury. To approximate the clinical situation of treating someone with symptomatic osteoarthritis caused by a past trauma, the researchers administered parathyroid hormone to mice that were already osteoarthritic because of an injury to the medial meniscus and medial collateral ligament. Tissue and molecular analyses of the injured knee joints revealed that after 1 month of daily treatment with parathyroid hormone, the cartilage layer was 32% thicker than in injured mice that did not receive the hormone. In addition, the investigators noted an increase in production of matrix molecules by chondrocytes (the cells that produce cartilage), suppression of genes associated with inappropriate chondrocyte maturation, and a reduction in cartilage breakdown. The ability of parathyroid hormone to boost the addition of new cartilage matrix while blocking its degradation in osteoarthritic joints suggests that it may be a useful therapeutic for treating patients with osteoarthritis, a pervasive clinical condition with surgery as the only current solution. There is no disease-modifying therapy for osteoarthritis, a degenerative joint disease that is projected to afflict more than 67 million individuals in the United States alone by 2030. Because disease pathogenesis is associated with inappropriate articular chondrocyte maturation resembling that seen during normal endochondral ossification, pathways that govern the maturation of articular chondrocytes are candidate therapeutic targets. It is well established that parathyroid hormone (PTH) acting via the type 1 PTH receptor induces matrix synthesis and suppresses maturation of chondrocytes. We report that the PTH receptor is up-regulated in articular chondrocytes after meniscal injury and in osteoarthritis in humans and in a mouse model of injury-induced knee osteoarthritis. To test whether recombinant human PTH(1–34) (teriparatide) would inhibit aberrant chondrocyte maturation and associated articular cartilage degeneration, we administered systemic teriparatide (Forteo), a Food and Drug Administration–approved treatment for osteoporosis, either immediately after or 8 weeks after meniscal/ligamentous injury in mice. Knee joints were harvested at 4, 8, or 12 weeks after injury to examine the effects of teriparatide on cartilage degeneration and articular chondrocyte maturation. Microcomputed tomography revealed increased bone volume within joints from teriparatide-treated mice compared to saline-treated control animals. Immediate systemic administration of teriparatide increased proteoglycan content and inhibited articular cartilage degeneration, whereas delayed treatment beginning 8 weeks after injury induced a regenerative effect. The chondroprotective and chondroregenerative effects of teriparatide correlated with decreased expression of type X collagen, RUNX2 (runt-related transcription factor 2), matrix metalloproteinase 13, and the carboxyl-terminal aggrecan cleavage product NITEGE. These preclinical findings provide proof of concept that Forteo may be useful for decelerating cartilage degeneration and inducing matrix regeneration in patients with osteoarthritis.

Orthopedic Uses of Teriparatide

Teriparatide is a drug currently approved for treating patients with osteoporosis who are at high risk for future fracture. In the treatment of osteoporosis, teriparatide works as an anabolic agent stimulating bone formation throughout the skeleton by principally enhancing osteoblast-derived bone formation relative to osteoclast-derived bone resorption. The net effect is increased bone mass. For patients with a fracture, a similar process of increased bone formation is required transiently at the fracture site for repair. Teriparatide has been investigated in animal models and in patients as a potential agent to enhance fracture repair. In addition, evidence that teriparatide enhances chondrogenesis has generated interest in using the agent for articular cartilage repair. Research is currently underway to understand the effects teriparatide may have on mesenchymal stem cells, and on other effects that have been reported anecdotally in patients using the drug for osteoporosis care, including the healing of fracture nonunions and a decreased incidence of back pain. We review the current animal and human reports available on the uses of teriparatide in musculoskeletal diseases beyond osteoporosis.

PGE2 and IL-6 production by fibroblasts in response to titanium wear debris particles is mediated through a Cox-2 dependent pathway

Aseptic loosening of orthopaedic implants is precipitated by wear debris‐induced osteolysis. Central to this process are the pro‐inflammatory mediators that are produced in response to wear by the fibroblastic cells, which comprise the majority of periprosthetic membranes. Since this pro‐inflammatory cascade is mediated by a plethora of factors with redundant functions, it is imperative to establish a hierarchy. Two well‐known fibroblast derived pro‐inflammatory factors that stimulate wear debris‐induced osteoclastic resorption are prostaglandin E2 (PGE2) and IL‐6. However, their relationship to each other in this process is poorly defined. Here we show immunohistochemistry of retrieval membranes indicating that COX‐2 is the principal cyclooxygenase responsible for PGE2 production in fibroblasts around failed implants. We also performed in vitro experiments with fibroblasts derived from wild‐type (WT), COX‐1 (–/–) and COX‐2 (–/–) mice, which demonstrated that COX‐2 is required for Ti wear debris‐induced PGE2 production. Interestingly, COX‐2 was also required for IL‐6 production in these assays, which could be rescued by the addition of exogenous PGE2 (10−6 M). Pharmacology studies that utilized the COX‐1 selective inhibitor SC 560, the COX‐2 selective inhibitor celecoxib, and the nonselective COX inhibitor indomethacin confirmed these results. Taken together, these results indicate that selective inhibition of prostaglandin signaling could favorably impact aseptic loosening beyond its direct effects on PGE2 synthesis, in that it inhibits downstream pro‐inflammatory/pro‐osteoclastic cytokine production.

A Guide to Improving the Care of Patients With Fragility Fractures

This monograph is written as a guide for physicians, nurses, therapists, and students interested in ideal care for their patients with fragility fractures. The scope of fragility fractures in the United States is large and will grow over the next 20 years as the population ages. There is much that can be done currently to idealize the outcomes of these patients. Additional research in many areas is needed to further improve the quality of care for these patients. We plan to update this monograph as new information concerning the care of seniors with fragility fractures develops.

Differential effects of biologic versus bisphosphonate inhibition of wear debris-induced osteolysis assessed by longitudinal micro-CT.

Aseptic loosening of total joint replacements is caused by wear debris‐induced osteoclastic bone resorption, for which bisphosphonates (BPs) and RANK antagonists have been developed. Although BPs are effective in preventing metabolic bone loss, they are less effective for inflammatory bone loss. Because this difference has been attributed to the antiapoptotic inflammatory signals that protect osteoclasts from BP‐induced apoptosis, but not RANK antagonists, we tested the hypothesis that osteoprotegerin (OPG) is more effective in preventing wear debris‐induced osteolysis than zoledronic acid (ZA) or alendronate (Aln) in the murine calvaria model using in vivo micro‐CT and traditional histology. Although micro‐CT proved to be incompatible with titanium (Ti) particles, we were able to demonstrate a 3.2‐fold increase in osteolytic volume over 10 days induced by polyethylene (PE) particles versus sham controls (0.49 ± 0.23mm3 versus 0.15 ± 0.067mm3; p < 0.01). Although OPG and high‐dose ZA completely inhibited this PE‐induced osteolysis (p < 0.001), pharmacological doses of ZA and Aln were less effective but still reached statistical significance (p < 0.05). Traditional histomorphometry of the sagital suture area of calvaria from both Ti and PE‐treated mice confirmed the remarkable suppression of resorption by OPG (p < 0.001) versus the lack of effect by physiological BPs. The differences in drug effects on osteolysis were largely explained by the significant difference in osteoclast numbers observed between OPG versus BPs in both Ti‐ and PE‐treated calvaria; and linear regression analyses that demonstrated a highly significant correlation between osteolysis volume and sagittal suture area versus osteoclast numbers (p < 0.001).

Systemic administration of pharmacological agents and bone repair: What can we expect

Pharmacologic agents that modulate bone formation and bone remodelling are in broad use and development for the treatment of osteoporosis and other disorders of bone fragility. There is significant interest into the effect these agents may have on bone repair and fracture healing and whether these agents may be beneficial or detrimental to bone repair. Bisphosphonates delay callus remodelling, but increased callus volume seen during endochondral bone repair with bisphosphonate use allows for equivalent biomechanical properties for the fractured bone. Teripartide stimulates bone formation and in bone repair appears to have the potential to accelerate fracture callus formation and remodelling, potentially accelerating fracture healing. Animal models of fracture healing have demonstrated accelerated healing with larger callus volume, more rapid remodelling to mature bone, and improved biomechanical properties of the fractured bone. Clinical data with teriparatide has shown mixed results for its ability to stimulate fracture healing. Wnt signalling is one of the major pathways through which cartilage and bone formation is regulated during development. This same pathway has been identified as one of the ways that teriparatide stimulates bone formation. Antibodies to downstream proteins in this pathway, Dkk-1 and sclerostin, show significant promise of accelerating even normal fracture healing in preclinical animal models.

Endogenous tissue engineering: PTH therapy for skeletal repair

Based on its proven anabolic effects on bone in osteoporosis patients, recombinant parathyroid hormone (PTH1-34) has been evaluated as a potential therapy for skeletal repair. In animals, the effect of PTH1-34 has been investigated in various skeletal repair models such as fractures, allografting, spinal arthrodesis and distraction osteogenesis. These studies have demonstrated that intermittent PTH1-34 treatment enhances and accelerates the skeletal repair process via a number of mechanisms, which include effects on mesenchymal stem cells, angiogenesis, chondrogenesis, bone formation and resorption. Furthermore, PTH1-34 has been shown to enhance bone repair in challenged animal models of aging, inflammatory arthritis and glucocorticoid-induced bone loss. This pre-clinical success has led to off-label clinical use and a number of case reports documenting PTH1-34 treatment of delayed-unions and non-unions have been published. Although a recently completed phase 2 clinical trial of PTH1-34 treatment of patients with radius fracture has failed to achieve its primary outcome, largely because of effective healing in the placebo group, several secondary outcomes are statistically significant, highlighting important issues concerning the appropriate patient population for PTH1-34 therapy in skeletal repair. Here, we review our current knowledge of the effects of PTH1-34 therapy for bone healing, enumerate several critical unresolved issues (e.g., appropriate dosing regimen and indications) and discuss the long-term potential of this drug as an adjuvant for endogenous tissue engineering.

Dementia and hip fractures: development of a pathogenic framework for understanding and studying risk.

Dementia and hip fractures are 2 conditions that are seen primarily in older adults, and both are associated with substantial morbidity and mortality. An individual with dementia is up to 3 times more likely than a cognitively intact older adult to sustain a hip fracture. This may occur via several mechanisms, including (1) risk factors that are common to both outcomes; (2) the presence of dementia increasing hip fracture incidence via intermediate risk factors, such as falls, osteoporosis, and vitamin D; and (3) treatment of dementia causing side effects that increase hip fracture risk. We describe a model that applies these 3 mechanisms to explain the relationship between dementia and hip fractures. Comprehensive understanding of these pathways and their relative influence on the outcome of hip fracture will guide the development of effective interventions and potentially improve prevention efforts.

Reduction of particle-induced osteolysis by interleukin-6 involves anti-inflammatory effect and inhibition of early osteoclast precursor differentiation

The goal of this study was to define the anti-osteoclastogenic and/or anti-inflammatory role of IL-6 in inflammatory bone resorption using in vivo and in vitro methods. To this end, titanium particles were placed on murine calvaria, and bone resorption and osteoclast formation quantified in wild-type and IL-6(-/-) mice. In this model, calvarial bone loss and osteoclast formation were increased in titanium-treated IL-6(-/-) mice. Although basal numbers of splenic osteoclast precursors (OCP) were similar, IL-6(-/-) mice treated with particles in vivo had increased splenic OCP suggesting an enhanced systemic inflammatory response. In vitro osteoclastogenesis was measured using splenic (OCP) at various stages of maturation, including splenocytes from WT, IL-6(-/-) and TNFalpha transgenic mice. ELISA was used to measure TNFalpha production. IL-6 inhibited osteoclastogenesis in early OCP obtained from wild-type and IL-6(-/-) spleens. Pre-treatment of OCP with M-CSF for three days increased the CD11b(high)/c-Fms+ cell population, resulting in an intermediate staged OCP. Osteoclastogenesis was unaffected by IL-6 in M-CSF pre-treated and TNFalpha transgenic derived OCP. IL-6(-/-) splenocytes secreted greater concentrations of TNFalpha in response to titanium particles than WT; addition of exogenous IL-6 to these cultures decreased TNFalpha expression while anti-IL-6 antibody increased TNFalpha. While IL-6 lacks effects on intermediate staged precursors, the dominant in vivo effects of IL-6 appear to be related to strong suppression of early OCP differentiation and an anti-inflammatory effect targeting TNFalpha. Thus, the absence of IL-6 results in increased inflammatory bone loss.

Short-term and Long-term Orthopaedic Issues in Patients With Fragility Fractures

BackgroundPatients with impaired bone quality who suffer a fragility fracture face substantial challenges in both their short- and long-term care. In addition to poor bone quality, many of these patients have multiple medical comorbidities that alter their surgical risk and affect their ultimate functional recovery. Some medical issues can contribute to the altered bone quality and must be addressed to prevent future fractures.Questions/purposesThis review summarizes the modifications in perioperative management and fracture fixation in patients with common fragility fractures who have impaired bone quality. It also summarizes the postoperative diagnosis and treatment of secondary causes of impaired bone quality in these patients.MethodsWe performed a PubMed search, and literature published after 2000 was prioritized, with the exception of benchmark clinical trial studies published before 2000.ResultsPatients with altered bone quality require rapid perioperative management of multiple medical comorbidities. Implant selection in patients with poor quality bone should permit early weightbearing, and constructs should maximize surface area contact with the remaining bone. Long-term diagnosis and treatment of other disease states contributing to poor bone quality (vitamin D deficiency/insufficiency, hypothyroidism, hyperthyroidism, hyperparathyroidism, Cushing’s disease, and hypogonadism) must occur to minimize the chances of future fractures.ConclusionsRecognition of patients with impaired bone quality and proper treatment of their special needs in both the short and long term are essential for their best opportunity for maximal functional recovery and prevention of future fractures.