Negative effect of zoledronic acid on tendon-to-bone healing

Background and purpose — Outcome after ligament reconstruction or tendon repair depends on secure tendon-to-bone healing. Increased osteoclastic activity resulting in local bone loss may contribute to delayed healing of the tendon–bone interface. The objective of this study was to evaluate the effect of the bisphosphonate zoledronic acid (ZA) on tendon-to-bone healing.

Methods — Wistar rats (n = 92) had their right Achilles tendon cut proximally, pulled through a bone tunnel in the distal tibia and sutured anteriorly. After 1 week animals were randomized to receive a single dose of ZA (0.1?mg/kg IV) or control. Healing was evaluated at 3 and 6 weeks by mechanical testing, dual-energy X-ray absorptiometry and histology including immunohistochemical staining of osteoclasts.

Results — ZA treatment resulted in 19% (95% CI 5–33%) lower pullout strength and 43% (95% CI 14–72%) lower stiffness of the tendon–bone interface, compared with control (2-way ANOVA; p = 0.009, p = 0.007). Administration of ZA did not affect bone mineral density (BMD) or bone mineral content (BMC). Histological analyses did not reveal differences in callus formation or osteoclasts between the study groups.

Interpretation — ZA reduced pullout strength and stiffness of the tendon–bone interface. The study does not provide support for ZA as adjuvant treatment in tendon-to-bone healing.     

Detecting early bone changes using in vivo micro-CT in ovariectomized, zoledronic acid-treated, and sham-operated rats

Summary  

This study monitored in vivo the effect on bone microarchitecture of initiating antiresorptive treatment with zoledronic acid in rats at 2 weeks following ovariectomy, an early phase at which major degenerative bone changes have been found to occur. The treatment still facilitated the full reversal of cancellous bone loss in rat tibia, highlighting the importance of the time point of initiation of antiresorptive treatment.     

Expression of adenovirally delivered gene products in healing osseous tissues

Gene therapy has moved from the promise of laboratory investigation to the reality of clinical practice in just the last decade. Various methods for delivery of genes to host cells have been developed and utilized both in vitro and in vivo. From the perspective of the plastic surgeon, gene therapy holds the promise to augment healing in clinical situations that remain difficult to treat, such as chronic wounds, osteoradionecrosis, or possibly to expedite current clinical practices, such as distraction osteogenesis. The authors chose to investigate the potential for gene therapy in osseous tissues using a replication-deficient adenovirus vector to deliver the marker transgene beta-galactosidase. An adenovirus vector is ideal for use in situations in which transgene expression is desired for only a relatively short period of time, such as wound and fracture healing. Utilizing a rat mandibular osteotomy model, they demonstrated that, using an adenoviral vector, foreign genes can be delivered in a simple fashion and can be expressed in a reliable manner within and around the osteotomy site for at least 10 days. Furthermore, there was no evidence of transfection of distant tissues associated with local application of the adenovirus vector. With this information, clinicians may now attempt to deliver osteogenic and angiogenic genes in a site-specific fashion to improve and expedite osseous healing.     

The healing sternum: a comparison of osseous healing with wire versus rigid fixation

Although median sternotomy is used for most cardiac procedures, postoperative dehiscence remains a serious and persistent problem. This investigation was designed to assess new bone formation and sternal healing across the linear osteotomy of the sternum and to determine if rigid fixation would enhance bony healing and thus decrease unfavorable sequelae. To test this hypothesis, 14 skeletally mature baboons (Papio anubis) underwent standard median sternotomy; seven sternotomies were closed with interrupted 24-gauge cerclage wires, and seven, with thin Vitallium compression miniplates and transverse lag screws. The sterna from each group were harvested en bloc at 4 and 8 weeks, radiographed, processed, and serially sectioned and stained for histomorphometry to assess the quantity of new bone across the linear osteotomy. Clinical stability was superior with the plated and lag screw group at 4 weeks; however, by 8 weeks, no clinical difference between treatments was apparent. Histomorphometric analysis indicated that the linear osteotomy gap treated with plates and screws was less than the gap associated with the wire group. Rigid fixation of the sternum resulted in earlier union with primary osseous healing, suggesting greater inherent stability. these factors may decrease adverse sequelae for this procedure.     

Association between timing of zoledronic acid infusion and hip fracture healing

Summary

Patients in the Health Outcomes and Reduced Incidence with Zoledronic Acid Once Yearly (HORIZON) Recurrent Fracture Trial were assessed for evidence of delayed hip fracture healing. No association was observed between zoledronic acid (ZOL) and delayed healing. We conclude that ZOL has no clinically evident effect on fracture healing, even when the drug is infused in the immediate postoperative period.

Introduction

Intravenous zoledronic acid 5?mg (ZOL) given after a hip fracture reduces secondary fracture rates and mortality. It has been postulated that bisphosphonates may affect healing if given soon after a fracture. We sought to determine whether the timing of ZOL infusion affected the risk of delayed hip fracture healing.

Methods

In the HORIZON Recurrent Fracture Trial, patients were randomized within 90?days of a low-trauma hip fracture to receive either once-yearly ZOL (n?=?1,065) or placebo (n?=?1,062). Clinical symptoms of delayed hip fracture healing were sought at randomization, 6?months and 12?months after fracture; if present, a central adjudication committee blinded to treatment assignment reviewed radiographs and clinical records. Median follow-up was 1.9?years.

Results

The overall incidence of delayed healing was 3.2% (ZOL) and 2.7% (placebo; odds ratio [OR], 1.17; 95% confidence interval [CI], 0.72?C1.90; p?=?0.61). Logistic regression models revealed no association between ZOL and delayed healing even after adjusting for other risk factors (OR, 1.21; 95% CI, 0.74?C1.99; p?=?0.44). There was no interaction by timing of infusion, and nonunion rates were similar even when ZOL was given within 2?weeks of hip fracture repair. NSAID use was significantly associated with delayed fracture healing (OR, 2.55; 95% CI, 1.49?C4.39; p?<?0.001).

Conclusions

ZOL has no clinically evident effect on fracture healing, even when the drug is infused in the immediate postoperative period.     

The healing of femoral neck fractures in dogs

Summary This study evaluates healing fractures of the femoral neck in dogs by using standard radiography, intraosseous venography, India ink staining and histology.The 45 animals were divided into three groups, one of which was not treated, but in the other two the fracture was fixed with a screw or two Kirschner wires.Our results suggest that, when intraosseous venography was positive, India ink injection was also positive, and the late phase of fracture healing was reached.

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Résumé Etude de la consolidation des fractures du col fémoral chez le chien à l'aide des radiographies standard, de la phlébographie osseuse, de la coloration par l'encre de Chine et de l'examen anatomopathologique. Les animaux ont été divisés en trois groupes, dans l'un la fracture n'a pas été traitée, dans les deux autres elle a été fixée soit par une vis, soit par deux broches de Kirschner. Les résultats tendent à montrer que lorsque la phlébographie est positive, la coloration par l'encre de Chine l'est également et que la phase ultime de la consolidation est atteinte.

     

Effect of EHDP on fracture healing in dogs

Ethane-1-hydroxy-1,1-diphosphonate (EHDP) was administered subcutaneously to mature beagle dogs at dose levels of 0.1, 0.5, and 5.0 mg/kg/day for a 20 week period to determine the drug's effects on fracture healing. Uniform, transverse fractures of the midshaft radius were created in one limb and treated by external splintage. Drug-induced effects on fracture healing were monitored radiographically, histologically, and histomorphometrically; mechanical properties of the healing bones were determined in 4-point bending tests. At a dose of 0.1 mg/kg/day, ultimate load at failure and flexural rigidity of the fractured limbs equaled or exceeded that of saline control animals, and radiographic healing was normal. At a dose of 0.5 mg/kg/day ultimate load at failure and flexural rigidity of the fractured limbs proved inferior to saline control values, and radiographic healing appeared delayed. At a dosage of 5.0 mg/kg/day, there was obvious radiographic nonunion, and the callus of fractured radii had little inherent flexural rigidity or strength. Histomorphometrically, no differences were noted between control animals and the 0.1 or 0.5 mg/kg/day groups; however, mineralization activity appeared totally disrupted at the higher dosage level (5.0 mg/kg/day). In the 5.0 mg/kg/day group, EHDP-induced effects proved reversible with mineralization evident as early as 3 weeks following drug withdrawal. In mature beagle dogs EHDP proved to have dose-dependent and reversible inhibitory effects on secondary fracture healing.     

Structural and biomechanical responses of osseous healing: a novel murine nonunion model

Background

Understanding the biological mechanisms of why certain fractures are at risk for delayed healing or nonunion requires translational animal models that take advantage of transgenic and other genetic manipulation technologies. Reliable murine nonunion models can be an important tool to understand the biology of nonunion. In this study, we report the results of a recently established model for creating critical defects that lead to atrophic nonunions based on a unique fracture fixation technique.

Materials and methods

Subcritical (0.6 mm long) and critical (1.6 mm long) defects were created in femurs of 10-week-old double transgenic (Col1/Col2) mice and stabilized using a custom-designed plate and four screws. Four groups were used: normal, sham, subcritical, and critical. Histology (n = 3 for each group) was analyzed at 2 and 5 weeks, and micro-computed tomography (μCT) and torsional biomechanics (n = 12 for each group) were analyzed at 5 weeks.

Results

Subcritical defects showed healing at 2 weeks and were completely healed by 5 weeks, with biomechanical properties not significantly different from normal controls. However, critical defects showed no healing by histology or μCT. These nonunion fractures also displayed no torsional stiffness or strength in 10 of 12 cases.

Conclusions

Our murine fracture model creates reproducible and reliable nonunions and can serve as an ideal platform for studying molecular pathways to contrast healing versus nonhealing events and for evaluating innovative therapeutic approaches to promote healing of a challenging osseous injury.     

Early effects of parathyroid hormone on bisphosphonate/steroid-associated compromised osseous wound healing

Summary

Administration of intermittent parathyroid hormone (PTH) promoted healing of tibial osseous defects and tooth extraction wounds and prevented the development of necrotic lesions in rats on a combined bisphosphonate and steroid regimen.

Introduction

Osteonecrosis of the jaw (ONJ) has emerged in association with antiresorptive therapies. The pathophysiology of ONJ is unknown and no established cure currently exists. Our objective was to determine the effect of intermittent PTH administration on early osseous healing in the jaw and long bones of rats receiving bisphosphonate and steroid treatment.

Methods

Ovariectomized rats received the combination therapy of alendronate and dexamethasone (ALN/DEX) for 12 weeks. Osseous wounds were created in the jaw and tibia. PTH was administered intermittently and healing at 2 weeks post-op was compared between the jaw and tibia by microcomputed tomography and histomorphometric analyses.

Results

ALN/DEX treatment was associated with necrotic open wounds in the jaw but had no negative effects on healing and promoted bone fill in tibial defects. PTH therapy prevented the development of necrotic lesions in the jaw and promoted healing of the tibial defects. PTH therapy was associated with the promotion of osteocyte survival in osseous wounds both in the jaw and tibia.

Conclusions

Wound healing was impaired in the jaw in rats on a combined bisphosphonate and steroid regimen, and PTH therapy rescued necrotic lesions. These findings suggest that PTH therapy could be utilized to prevent ONJ from occurring in patients on combination antiresorptive and steroid therapy.     

Gap healing enhanced by hydroxyapatite coating in dogs.

During prosthetic implantation, gaps between the implant surface and the surrounding bone may occur resulting in reduced implant stability. In these instances bone-conductive materials might augment the formation of hosting bone into the pores of the implant and insure earlier implant stabilization and fixation by bony ingrowth. Titanium-alloy cylinders with a porous-titanium-alloy plasma spray coating were implanted into the medial femoral condyles in six mature dogs. In another group of six dogs, matched in age, weight, and gender, hydroxyapatite (HA) coated implants were used. All implants were surrounded by a 1-mm gap. Unilateral osteopenia of the knee, with a 20% reduction of bone density as judged by computed tomography scanning, was induced by 12 weekly intraarticular injections of carrageenin into the right knee before surgery. Four weeks after implantation, the HA-coated implants were compared to the parent porous-titanium implants by mechanical testing and histomorphometry. A marked positive influence of HA coating on bone mineralization and the strength of the interfacial bone between the bone and implant was found. The increment in interface shear strength and shear stiffness was three- to fivefold in osteopenic bone and two-fold in control bone. Coating of an unloaded porous-titanium-coated implant with HA accelerates the rate of bone ingrowth and thereby provides relatively high, early interfacial shear strengths in the presence of an initial gap between bone and implant even in the presence of osteopenic host bone.     

Effect of urinary extravasation on renal wound healing in dogs

It is frequently stated that extravasation of urine after intrarenal surgery is deleterious to renal wound healing causing fibrosis or granulation tissue. A study using dogs was designed to test the hypothesis that the contact of urine with incised renal parenchyma may cause altered wound healing. This study showed that exposure of the renal parenchyma to extravasated urine from open collecting structures did not alter renal healing.     

Cyanoacrylate sealing of pancreatic biopsy sites in dogs.

The ability of ethyl cyanocrylate monomer adhesive in preventing leaks following pancreatic surgery dogs was evaluated. Seventeen of 18 dogs in the control group had evidence of pancreatic leak following biopsy. There was no evidence of leak in 17 of 18 dogs on which the adhesive was used to seal the cut surface of the pancreas. Similar successful use of ethyl cyanoacrylate in patients would provide a safe method of taking a specimen from a mass for biopsy in the pancreas.     

Effect of alendronate on fracture healing and bone remodeling in dogs

To examine the effect of alendronate (4-amino-1-hydroxybutylidene bisphosphonate) on fracture repair, the drug was given to mature beagle dogs orogastrically at 2 mg/kg/day for 9 weeks preceding fracture, 16 weeks after fracture, or both before and after fracture (25 weeks). A transverse mid-diaphyseal fracture of the right radius was surgically induced and was stabilized by external coaptation splinting. Fracture healing and bone remodeling were evaluated by radiography, gross and histological examination, and bone histomorphometry. The mechanical properties of the fracture callus were determined by a four-point bending test. Radiographs and gross and microscopic examination demonstrated normal bone healing at the fracture site in all dogs. In dogs that received alendronate during the fracture healing period, at 16 weeks the calluses were approximately 2–3 times larger than those in dogs that received a placebo during the healing period. This is consistent with slower callus bone remodeling, an expected pharmacological effect of the compound. Bone histomorphometry demonstrated that treatment with alendronate did not inhibit bone formation or mineralization. Mechanical testing showed that the ultimate load at failure and the flexural rigidity of both the fractured and contralateral intact bone were unaffected by treatment with alendronate. Therefore, in this study, treatment with alendronate before or during fracture healing, or both, resulted in no adverse effects on the union, strength, or mineralization of bone in mature beagle dogs.     

Bisphosphonate administration prior to tooth extraction delays initial healing of the extraction socket in rats

Bisphosphonates (BPs) are clinically used for the treatment of bone metabolic abnormalities because they are powerful inhibitors of bone resorption. Osteonecrosis of the jaw has been observed after tooth extraction in a considerable number of BP-treated cancer patients, but the reason for this is not known. We studied the effects of BP on extraction socket healing in rats that were pretreated with BP prior to tooth extraction. Male Wistar rats (approximately 5 weeks old) were divided into experimental (BP) and control groups. In both groups, maxillary right second molars were extracted under general anesthesia. BP group rats were injected with 50 μl (1.0 mg/kg) alendronate into the right buccal alveolar bone every 4 days for 14 days, starting 2 days before tooth extraction. Control group rats were injected with physiological saline instead of alendronate. Rats were euthanized 3, 7, 10 or 14 days after tooth extraction, and maxillary bones were collected. Bone morphometric analysis using microfocus X-ray CT images and calculation of bone-resorption parameters based on hematoxylin and eosin or TRAP-stained pathological sections of the molar region showed that new bone formation in the extraction socket was delayed in the BP group relative to the control group during the first 7 days after extraction. A subsequent increase in new bone formation showed that bone resorption in the BP rats was eventually inhibited. This delay in initial healing may explain the jaw osteonecrosis observed in some BP-treated cancer patients.     

不同部位糖尿病足溃疡愈合情况分析

目的了解不同部位糖尿病足溃疡愈合情况。方法采用前瞻性研究方法,对142例Wagner分级2~4级的糖尿病足溃疡患者采取多学科协作的综合治疗方法,收集入院首次临床检查资料,留取入院每次清创后足溃疡照片,比较治疗30d内不同部位的足溃疡创面缩小率。结果发生在足背、足踝、足弓、足趾、足前掌及足跟的Wagner分级为2级的溃疡创面缩小率比较,差异有统计学意义(P0.01),发生在足趾的糖尿病足溃疡创面缩小率最小,足踝部及足背部溃疡创面缩小率较大。Wagner分级为2、3级的非受压组溃疡创面缩小率显著大于受压组(均P0.01)。结论不同部位糖尿病足溃疡愈合存在差异,治疗糖尿病足过程中采取适当的减压措施有利于糖尿病足溃疡的愈合。     

Experimental evaluation of free-tissue transfer to promote healing of infected wounds in dogs

An experimental model was designed to evaluate the course of healing and the changes in bacterial concentrations of infected forelimb wounds with devascularized bone in dogs. Infected leg wounds were allowed to heal by secondary intention or were covered with a full-thickness or split-thickness skin graft, an epigastric skin/fat flap, or a gracilis musculocutaneous flap. All skin grafts failed. Gracilis muscle flaps were superior to epigastric skin/fat flaps in decreasing soft-tissue bacterial concentrations. Quantitative bone cultures, however, were positive at reexploration 6 weeks later in 33% of all legs covered with a flap. X-ray films were successful in predicting the presence or absence of bone infection in 70% of all legs. Postmortem arteriograms of legs covered with muscle flaps showed neovascularity to bone. This study suggests muscle flap coverage of wounds debrided of contaminated, necrotic, or infected bone and soft tissue to be an excellent method of providing well-vascularized soft tissue promoting healing and resolution of infection.