Percutaneous lovastatin accelerates bone healing but is associated with periosseous soft tissue inflammation in a canine tibial osteotomy model

Experimental studies have shown the ability of statins to stimulate bone formation when delivered locally or in large oral doses, however most have been studied in rodents. This anabolic effect is through the selective activation of BMP‐2. Our purpose was to determine the effects of local treatment with lovastatin on bone healing in mammals as a preclinical animal model. We administered lovastatin (6 mg/kg) by percutaneous injection to a canine tibial osteotomy stabilized with external fixation. We found that lovastatin improved bone healing after a single injection into the fracture site assessed by serial radiography and histology at bone union. However, lovastatin treatment resulted in adverse local soft tissue inflammation. These results suggest that percutaneous lovastatin injection may be a useful adjuvant treatment over the course of bone healing to augment fracture repair, although further investigation into the mechanism of soft tissue adverse effects is warranted. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 32:210–216, 2014.     

Surgery for chronic symptoms after whiplash injury: Follow-up of 20 cases

Whereas continuous exposure to PTH results in bone resorption, administration at intermittent doses results in bone formation by increasing osteoblast number and activity. The anabolic action of PTH has also been demonstrated in clinical trials, in which PTH increased the bone mass and reduced fracture rate in patients with osteoporosis. In animal models of fracture healing and fixation of orthopedic implants, PTH increases the bone density in a dose-dependent manner, leading to faster repair and better fixation. The effect appears to be stronger on the new forming bone than on pre-existing bone. Based on these preclinical studies, we suggest that intermittent PTH treatment may also benefit fracture healing and implant fixation in patients.     

Parathyroid hormone--a drug for orthopedic surgery?

Whereas continuous exposure to PTH results in bone resorption, administration at intermittent doses results in bone formation by increasing osteoblast number and activity. The anabolic action of PTH has also been demonstrated in clinical trials, in which PTH increased the bone mass and reduced fracture rate in patients with osteoporosis. In animal models of fracture healing and fixation of orthopedic implants, PTH increases the bone density in a dose-dependent manner, leading to faster repair and better fixation. The effect appears to be stronger on the new forming bone than on pre-existing bone. Based on these preclinical studies, we suggest that intermittent PTH treatment may also benefit fracture healing and implant fixation in patients.     

Impaired bone healing in rabbits with steroid-induced osteonecrosis

Corticosteroids are prescribed for the treatment of many medical conditions and their adverse effects on bone, including steroid-associated osteoporosis and osteonecrosis, are well documented. Core decompression is performed to treat osteonecrosis, but the results are variable. As steroids may affect bone turnover, this study was designed to investigate bone healing within a bone tunnel after core decompression in an experimental model of steroid-associated osteonecrosis. A total of five 28-week-old New Zealand rabbits were used to establish a model of steroid-induced osteonecrosis and another five rabbits served as controls. Two weeks after the induction of osteonecrosis, core decompression was performed by creating a bone tunnel 3 mm in diameter in both distal femora of each rabbit in both the experimental osteonecrosis and control groups. An in vivo micro-CT scanner was used to monitor healing within the bone tunnel at four, eight and 12 weeks postoperatively. At week 12, the animals were killed for histological and biomechanical analysis. In the osteonecrosis group all measurements of bone healing and maturation were lower compared with the control group. Impaired osteogenesis and remodelling within the bone tunnel was demonstrated in the steroid-induced osteonecrosis, accompanied by inferior mechanical properties of the bone. We have confirmed impaired bone healing in a model of bone defects in rabbits with pulsed administration of corticosteroids. This finding may be important in the development of strategies for treatment to improve the prognosis of fracture healing or the repair of bone defects in patients receiving steroid treatment.     

A meta-analysis of bisphosphonates for periprosthetic bone loss after total joint arthroplasty

Background

Periprosthetic bone loss, which is common after joint arthroplasty, may cause bone loosening and lead to failed prosthetic fixation. Two previous meta-analyses have confirmed the mid-term effect of bisphosphonates (BPs) in preventing bone loss after arthroplasty. To determine long-term efficacy and gender bias of BPs after joint arthroplasty, we conducted a meta-analysis based on 17 RCTs involving 781 patients to evaluate the effect of BPs.

Methods

Meta-analysis was conducted after a systematic search of Medline, Embase, the Cochrane Collaboration Central Register of Controlled Clinical Trials, CINAHL, and ISI Web of Science, and manual examination of references in selected articles and conference abstracts of key orthopedic journals. Methodological quality and abstracted relevant data were evaluated. In addition to analysis of bone mineral density (BMD), we also conducted systematic analysis of clinically relevant outcomes and bone biochemical markers.

Results

Seventeen trials involving a total of 781 patients were assessed. Significantly less periprosthetic bone loss occurred in the BP-treated group than in the control group at 6 and 12 months (p < 0.0001). This protective effect was not noted at 3 months (p = 0.11) nor from 24–72 months (p = 0.14). The efficacy of BPs in the gender balance, shorter duration, and the non-nitrogenous BPs groups was no different from that for controls. Biochemical bone markers were suppressed in the BPs group. However, clinically relevant outcomes in the BPs group and controls were similar at all times.

Conclusions

The overall moderate-quality evidence from the RCTs confirmed the significant mid-term efficacy of BPs on periprosthetic bone loss after joint arthroplasty. Long-term efficacy of BPs was not observed, and the therapy was of more benefit to women, especially postmenopausal women. To achieve better efficacy, nitrogenous BPs and long duration of treatment may be recommended.     

Bisphosphonates for periprosthetic bone loss after joint arthroplasty: a meta-analysis of 14 randomized controlled trials

Summary

The present meta-analysis aimed to evaluate the middle-term efficacy of bisphosphonates on maintaining periprosthetic bone mass after joint arthroplasty and the potential influential factors. It was found that the protective effect of bisphosphonates, probably modified by its generation and the prosthesis location, could persist in a middle-term follow-up after surgery and after drug discontinuation.

Introduction

A previous meta-analysis of 6 RCTs with follow-up of 12?months suggested that bisphosphonates (BPs) could prevent bone loss after arthroplasty up to 6?months. Our meta-analysis based on 14 RCTs involving 671 patients with follow-up up to 72?months aimed to evaluate the middle-term efficacy of BPs, understand the sources of heterogeneity, and comprehensively identify the potential influential factors.

Methods

Electronic databases searching and hand searching of conference proceedings were conducted. We evaluated the methodological quality and abstracted relevant data. With fixed effect model we calculated the weighted mean differences to evaluate bone mineral density at different time points. We also conducted a systematic review for BP-related adverse effects.

Results

The significantly less periprosthetic bone loss occurred in the BP-treated group than in the control group at 3, 6, and 12?months, and between 24 and 72?months after the index surgery. The protective effect persisted during 18 to 70?months after discontinuation of BPs. The heterogeneity was minimized with the separation of hip and knee trials during the analysis. The efficacy was more potent for the second and the third generation of BPs than the first generation. None of the trials noted serious or fatal adverse effects related to BPs.

Conclusions

The overall moderate evidence from the RCTs confirmed the significantly short-term and middle-term efficacy of BPs on periprosthetic bone loss after joint arthroplasty. To obtain a better efficacy, the second and the third generation of BPs may be the choice.     

Potential uses of cytokines and growth factors in treatment of osteonecrosis

Osteonecrosis of the femoral head remains a devastating disease for young patients. As the normal process of bone formation, bone destruction, and fracture healing becomes more clearly understood, molecular agents--including cytokines, bone morphogenetic proteins, and angiogenic factors--will be identified as potential therapeutic agents for the treatment of osteonecrosis. As the pathology of osteonecrosis and repair of osteonecrotic lesions becomes clear, the potential combination of these molecular factors to influence the outcome of the disease in its repair process should become evident. With the myriad of agents and combinations of agents which may be beneficial in the treatment of osteonecrosis, a reproducible animal model is urgently needed to determine which of these combinations is most effective. Despite the lack of an animal model, progress in the use of cytokines for osteonecrosis treatment in conjunction with traditional treatment methods is possible in human subjects. This is due to the extremely low incidence of adverse reactions when these cytokines are used locally in nanogram to microgram quantities.     

Effect of osteoporosis medications on fracture healing

Antiosteoporotic medications are often used to concurrently treat a patient’s fragility fractures and underlying osteoporosis. This review evaluates the existing literature from animal and clinical models to determine these drugs’ effects on fracture healing. The data suggest that these medications may enhance bone healing, yet more thorough prospective studies are warranted. Pharmacologic agents that influence bone remodeling are an essential component of osteoporosis management. Because many patients are first diagnosed with osteoporosis when presenting with a fragility fracture, it is critical to understand how osteoporotic medications influence fracture healing. Vitamin D and its analogs are essential for the mineralization of the callus and may also play a role in callus formation and remodeling that enhances biomechanical strength. In animal models, antiresorptive medications, including bisphosphonates, denosumab, calcitonin, estrogen, and raloxifene, do not impede endochondral fracture healing but may delay repair due to impaired remodeling. Although bisphosphonates and denosumab delay callus remodeling, they increase callus volume and result in unaltered biomechanical properties. Calcitonin increases cartilage formation and callus maturation, resulting in improved biomechanical properties. Parathyroid hormone, an anabolic agent, has demonstrated promise in animal models, resulting in accelerated healing with increased callus volume and density, more rapid remodeling to mature bone, and improved biomechanical properties. Clinical data with parathyroid hormone have demonstrated enhanced healing in distal radius and pelvic fractures as well as postoperatively following spine surgery. Strontium ranelate, which may have both antiresorptive and anabolic properties, affects fracture healing differently in normal and osteoporotic bone. While there is no effect in normal bone, in osteoporotic bone, strontium ranelate increases callus bone formation, maturity, and mineralization; forms greater and denser trabeculae; and improves biomechanical properties. Further clinical studies with these medications are needed to fully understand their effects on fracture healing in order to simultaneously treat fragility fractures and underlying osteoporosis.     

Harmful lifestyles on orthopedic implantation surgery: a descriptive review on alcohol and tobacco use

Alcohol abuse and smoking habits have adverse effects on bone health and are a risk factor for osteoporosis, fractures and impaired fracture repair. Osteointegration processes around implanted biomaterials involve a coordinated cascade of complex events that are very similar to those occurring during fracture repair and require a suitable microenvironment and the coordinated action of cells and signal molecules. Therefore, diseases and harmful lifestyles that impair the normal bone healing process can reduce the success of implant surgery and may negatively influence the osteointegration of prostheses and implant devices for fracture fixation such as screws, nails and plates. Understanding the effects of harmful lifestyles on bone implant osteointegration is important for successful implant therapy, orthopedic reconstructive surgery and tissue-engineered-based therapies. However, the mechanisms by which smoking and alcoholism affect bone metabolism, bone mass and the balance of bone resorption and formation, also in the presence of an orthopedic implant, are not completely understood and remain inadequately elucidated. This review aims to analyze in vitro and in vivo studies regarding orthopedic implant integration in the presence of tobacco smoking and alcohol consumption with a focus on pathophysiology and local or systemic mechanisms of action on bone.     

Biomaterial Scaffolds for Treating Osteoporotic Bone

Healing fractures resulting from osteoporosis or cancer remains a significant clinical challenge. In these populations, healing is often impaired not only due to age and disease, but also by other therapeutic interventions such as radiation, steroids, and chemotherapy. Despite substantial improvements in the treatment of osteoporosis over the last few decades, osteoporotic fractures are still a major clinical challenge in the elderly population due to impaired healing. Similar fractures with impaired healing are also prevalent in cancer patients, especially those with tumor growing in bone. Treatment options for cancer patients are further complicated by the fact that bone anabolic therapies are contraindicated in patients with tumors. Therefore, many patients undergo surgery to repair the fracture, and bone grafts are often used to stabilize orthopedic implants and provide a scaffold for ingrowth of new bone. Both synthetic and naturally occurring biomaterials have been investigated as bone grafts for repair of osteoporotic fractures, including calcium phosphate bone cements, resorbable polymers, and allograft or autograft bone. In order to re-establish normal bone repair, bone grafts have been augmented with anabolic agents, such as mesenchymal stem cells or recombinant human bone morphogenetic protein-2. These developing approaches to bone grafting are anticipated to improve the clinical management of osteoporotic and cancer-induced fractures.     

Minocycline-induced black bone disease encountered during total knee arthroplasty

Finding discolored bone intraoperatively can be confusing and concerning to orthopedic surgeons. Multiple causes of pigmented bone exist, including ochronosis, metabolic bone diseases, metal deposits, sequestrum, metastatic disease, and minocycline use. Bone quality is an important consideration in intraoperative decision making with respect to components and fixation options in total joint arthroplasty. Abnormal bone encountered in routine arthroplasty can raise concerns over the integrity and healing potential of the bone when the etiology is uncertain.Minocycline is a drug routinely used for the treatment of acne, rosacea, and rheumatoid arthritis. Pigmentation is a commonly recognized adverse reaction associated with most of the drugs in the tetracycline family, affecting the skin, nails, teeth, oral mucosa, bones in the oral cavity, ocular structures, cartilage, thyroid, and other visceral structures.This article describes a case of pigmented bone secondary to minocycline use in a 55-year-old woman undergoing total knee arthroplasty. This entity has rarely been documented in the orthopedic literature; however, orthopedic surgeons should be aware of this side effect secondary to the widespread use of minocycline. Questions concerning the effect of minocycline on bone metabolism and structural integrity have yet to be fully answered, but an understanding and recognition of the entity will help guide surgeons with intraoperative decision making.     

Hydroxyapatite-coated orthopedic implants

Hydroxyapatite (HA)-coated metal implants were developed in order to capitalize on the excellent biological properties of HA, and minimize the potential for mechanical failure of the HA in vivo. Results of implantation studies suggest that synthetic HA is osteoconductive (enhances local bone healing) and becomes osteointegrated (forms an intimate bond with bone). HA-coated prostheses are currently being evaluated for use in cementless total joint arthroplasty. The purpose of this article is to review the experimental studies leading to the development of HA-coated orthopedic devices, and to summarize the current status of clinical studies. Finally, the concerns and future directions for HA-coated implants are addressed.     

Effects of Anti-osteoporosis Medications on Fracture Healing

A number of fractures are complicated by impaired healing. This is prevalent in certain risk groups such as elderly, osteoporotics, postmenopausal women, and in people with malnutrition. At present, no pharmacologic treatments are available. Thus, there is an unmet need for medications that can stimulate bone healing. Parathyroid hormone (PTH) is the first bone anabolic drug approved for the treatment of osteoporosis and, intriguingly, a number of animal studies prove the ability of PTH to induce fracture healing. PTH may therefore be a potential novel treatment option in humans with impaired healing. However, more randomized clinical trials documenting the clinical efficacy of PTH as a promoter of fracture healing in the clinical setting are warranted. Also, strontium ranelate seems to have beneficial effects on fracture healing under conditions with impaired healing. However, no clinical studies are available so far, and such studies are warranted before any conclusions can be drawn. In contrast, bisphosphonates—which are the most widely used drug for treating osteoporosis—delay the healing process slightly, although apparently not clinically relevant. Finally, a number of newer antiresorptive agents are available, but very few studies have addressed their effects on bone healing.     

Inflammation,fracture and bone repair

The reconstitution of lost bone is a subject that is germane to many orthopedic conditions including fractures and non-unions, infection, inflammatory arthritis, osteoporosis, osteonecrosis, metabolic bone disease, tumors, and periprosthetic particle-associated osteolysis. In this regard, the processes of acute and chronic inflammation play an integral role. Acute inflammation is initiated by endogenous or exogenous adverse stimuli, and can become chronic in nature if not resolved by normal homeostatic mechanisms. Dysregulated inflammation leads to increased bone resorption and suppressed bone formation. Crosstalk among inflammatory cells (polymorphonuclear leukocytes and cells of the monocyte–macrophage–osteoclast lineage) and cells related to bone healing (cells of the mesenchymal stem cell-osteoblast lineage and vascular lineage) is essential to the formation, repair and remodeling of bone. In this review, the authors provide a comprehensive summary of the literature related to inflammation and bone repair. Special emphasis is placed on the underlying cellular and molecular mechanisms, and potential interventions that can favorably modulate the outcome of clinical conditions that involve bone repair.     

Nichtsteroidale Antirheumatika (NSAR) in der perioperativen Phase in Traumatologie und Orthopädie

OBJECTIVE: To achieve analgesic, anti-inflammatory and antipyretic effects in traumatology and orthopedic surgery without side effects or with the least possible side effects, with special emphasis on bone healing. INDICATIONS: Acute and chronic inflammatory conditions, e. g., rheumatoid arthritis, ankylosing spondylitis. Degenerative joint disease. Posttraumatic and postoperative pain, edema, or fever. Prevention of heterotopic bone formation. CONTRAINDICATIONS: Hypersensitivity. Gastrointestinal ulceration or bleeding. Severe hepatic or renal impairment. RESULTS: Nonsteroidal anti-inflammatory drugs (NSAIDs) are invaluable in treating a variety of musculoskeletal conditions. As well as their excellent analgesic potency their anti-inflammatory effects are beneficial in treating posttraumatic and postoperative edema. In addition, NSAIDs inhibit heterotopic bone formation after hip arthroplasty. Animal studies, however, have demonstrated that they cause delayed fracture healing. Although clinical studies have not yet supplied unequivocal evidence of this effect in human subjects, the authors recommend that in the presence of other risk factors which may adversely affect fracture healing, such as smoking, diabetes mellitus or peripheral arterial occlusive disease, the indication of NSAID use for analgesia should be strictly limited. Therapeutic alternatives such as centrally acting agents (e. g., weak opioids) should be considered in these patients.     

Inhibition of sclerostin by monoclonal antibody enhances bone healing and improves bone density and strength of nonfractured bones

Therapeutic enhancement of fracture healing would help to prevent the occurrence of orthopedic complications such as nonunion and revision surgery. Sclerostin is a negative regulator of bone formation, and treatment with a sclerostin monoclonal antibody (Scl‐Ab) results in increased bone formation and bone mass in animal models. Our objective was to investigate the effects of systemic administration of Scl‐Ab in two models of fracture healing. In both a closed femoral fracture model in rats and a fibular osteotomy model in cynomolgus monkeys, Scl‐Ab significantly increased bone mass and bone strength at the site of fracture. After 10 weeks of healing in nonhuman primates, the fractures in the Scl‐Ab group had less callus cartilage and smaller fracture gaps containing more bone and less fibrovascular tissue. These improvements at the fracture site corresponded with improvements in bone formation, bone mass, and bone strength at nonfractured cortical and trabecular sites in both studies. Thus the potent anabolic activity of Scl‐Ab throughout the skeleton also was associated with an anabolic effect at the site of fracture. These results support the potential for systemic Scl‐Ab administration to enhance fracture healing in patients. © 2011 American Society for Bone and Mineral Research.     

小肠黏膜下层修复骨关节损伤的研究进展

作为天然细胞外基质生物衍生材料,小肠黏膜下层(small intestinal submucosa,SIS)可用作组织工程的理想支架,在修复组织缺损和实现组织重塑方面具有广阔的应用前景。近年来,SIS在修复骨关节损伤方面的应用逐渐增多,研究发现SIS对骨、半月板、韧带或肌腱均表现出良好的修复效果,但是在关节软骨、腱骨愈合等方面的具体作用还有待进一步探索。新型SIS修复材料的开发,也将是亟待解决的焦点问题和进一步研究的热点。     

Effects of calcitonin on animal and in vitro models of skeletal metabolism

During the 40 years since its discovery, calcitonin (CT) has been regarded primarily as an inhibitor of bone resorption and its therapeutic applications have been based on this property. A significant body of literature also indicates additional anabolic effects in animal and in vitro models. In a variety of bone loss histomorphometric models in the rat, CT, especially the salmon species, prevents or retards bone loss. In other species, similar results have been obtained, except in the beagle given human CT, in which a recent study reported increased bone resorption and bone loss. Consonant with the histomorphometric effects in several different species, bone mass (density) measured by a variety of methods increases, reversing the bone loss induced by the model. In related studies of mechanical properties, bone strength is increased by CT except in the beagle study which utilized human CT. In other species, experimentally induced fractures show either accelerated healing or heal normally, and there is no effect of CT to impair healing. Finally, studies of bone formation/mineralization strongly suggest an anabolic effect on cartilage formation, bone matrix synthetic activity, and bone growth. These animal effects are reflected by recent fracture prevention studies in humans. If its anabolic effects are ultimately found to be separable and additive to CT's basic action to inhibit bone resorption, new approaches to osteoporosis prevention, and possibly other treatment situations such as cartilage regeneration, may evolve using novel CT-like molecules.     

The challenges of promoting osteogenesis in segmental bone defects and osteoporosis

Conventional clinical management of complex bone healing scenarios continues to result in 5–10% of fractures forming non‐unions. Additionally, the aging population and prevalence of osteoporosis‐related fractures necessitate the further exploration of novel ways to augment osteogenesis in this special population. This review focuses on the current clinical modalities available, and the ongoing clinical and pre‐clinical research to promote osteogenesis in segmental bone defects, delayed unions, and osteoporosis. In summary, animal models of fracture repair are often small animals as historically significant large animal models, like the dog, continue to gain favor as companion animals. Small rodents have well‐documented limitations in comparing to fracture repair in humans, and few similarities exist. Study design, number of studies, and availability of funding continue to limit large animal studies. Osteoinduction with rhBMP‐2 results in robust bone formation, although long‐term quality is scrutinized due to poor bone mineral quality. PTH 1‐34 is the only FDA approved osteo‐anabolic treatment to prevent osteoporotic fractures. Limited to 2 years of clinical use, PTH 1‐34 has further been plagued by dose‐related ambiguities and inconsistent results when applied to pathologic fractures in systematic human clinical studies. There is limited animal data of PTH 1‐34 applied locally to bone defects. Gene therapy continues to gain popularity among researchers to augment bone healing. Non‐integrating viral vectors and targeted apoptosis of genetically modified therapeutic cells is an ongoing area of research. Finally, progenitor cell therapies and the content variation of patient‐side treatments (e.g., PRP and BMAC) are being studied. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1559–1572, 2018.     

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.