Is inflammation harmless to loaded tendons?
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Animals↗
Biomedical subjects
Per Aspenberg
Publications and source records attributed to Per Aspenberg.
Systemic zoledronate treatment both prevents resorption of allograft bone and increases the retention of new formed bone during revascularization and remodelling. A bone chamber study in rats.
BACKGROUND: In osteonecrosis the vascular supply of the bone is interrupted and the living cells die. The inorganic mineral network remains intact until ingrowing blood vessels invade the graft. Accompanying osteoclasts start to resorb the bone trabeculae and gradually replace the bone. If the osteonecrosis occurs in mechanically loaded parts, like in the subchondral bone of a loaded joint, the remodelling might lead to a weakening of the bone and, in consequence to a joint collapse. Systemic bisphosphonate treatment can reduce the resorption of necrotic bone. In the present study we investigate if zoledronate, the most potent of the commercially available bisphosphonates, can be used to reduce the amount or speed of bone graft remodeling. METHODS: Bone grafts were harvested and placed in a bone chamber inserted into the tibia of a rat. Host tissue could grow into the graft through openings in the chamber. Weekly injections with 1.05 microg zoledronate or saline were given subcutaneously until the rats were harvested after 6 weeks. The specimens were fixed, cut and stained with haematoxylin/eosin and used for histologic and histomorphometric analyses. RESULTS: By histology, the control specimens were almost totally resorbed in the remodeled area and the graft replaced by bone marrow. In the zoledronate treated specimens, both the old graft and new-formed bone remained and the graft trabeculas were lined with new bone. By histomorphometry, the total amount of bone (graft+ new bone) within the remodelled area was 35 % (SD 13) in the zoledronate treated grafts and 19 % (SD 12) in the controls (p = 0.001). Also the amount of new bone was increased in the treated specimens (22 %, SD 7) compared to the controls (14 %, SD 9, p = 0.032). CONCLUSION: We show that zoledronate can be used to decrease the resorption of both old graft and new-formed bone during bone graft remodelling. This might be useful in bone grafting procedure but also in other orthopedic conditions, both where necrotic bone has to be remodelled i.e. after osteonecrosis of the knee and hip and in Perthes disease, or in high load, high turnover conditions like delayed union, periprosthetic osteolysis or bone lengthening operations. In our model an increased net formation of new bone was found which probably reflects that new bone formed was retained by the action of the bisphosphonates rather than a true anabolic effect.
Animals↗
Parecoxib impairs early metaphyseal bone healing in rats.
INTRODUCTION: Cox2 inhibitors decrease prostaglandin production and therefore influence bone healing especially in unstable long bone models. It is unclear to what extent implant fixation in stable metaphyseal bone is impaired. METHOD: Male rats numbering 30 and female rats numbering 40 received a stainless steel screw in the metaphyseal bone of the proximal tibia. Half of the rats were treated with 6.4 mg/kg BW parecoxib by continuous release from a subcutaneous mini pump during 7 or 14 days. After treatment, the pull out force, stiffness, and pull out energy of the screw were measured. RESULTS: No effect of parecoxib on the pull out force was found for male rats. In female rats the pull out force was decreased by 16% (P = 0.03) after 7 days treatment with parecoxib. This effect had disappeared after 14 days. CONCLUSION: Adverse effects of parecoxib on the early phase healing of metaphyseal bone in female rats are small and were not detectable after 14 days. No effect was seen in male rats, possibly due to a faster metabolic elimination of the drug.
Animals↗
Osteonecrosis: what does it mean? One condition partly caused by bisphosphonates--or another one, preferably treated with them?
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Bone Density Conservation Agents↗
How can one platelet injection after tendon injury lead to a stronger tendon after 4 weeks? Interplay between early regeneration and mechanical stimulation.
BACKGROUND: Mechanical stimulation improves the repair of ruptured tendons. Injection of a platelet concentrate (platelet-rich plasma, PRP) can also improve repair in several animal models. In a rat Achilles tendon transection model, 1 postoperative injection resulted in increased strength after 4 weeks. Considering the short half-lives of factors released by platelets, this very late effect calls for an explanation. METHODS: We studied the effects of platelets on Achilles tendon regenerates in rats 3, 5 and 14 days after transection. The tendons were either unloaded by Botulinum toxin A (Botox) injections into the calf muscles, or mechanically stimulated in activity cages. No Botox injections and ordinary cages, respectively, served as controls. Repair was evaluated by tensile testing. RESULTS: At 14 days, unloading (with Botox) abolished any effect of the platelets and reduced the mechanical properties of the repair tissue to less than half of normal. Thus, some mechanical stimulation is a prerequisite for the effect of platelets at 14 days. Without Botox, both activity and platelets increased repair independently of each other. However, at 3 and 5 days, platelets improved the mechanical properties in Botox-treated rats. INTERPRETATION: Platelets influence only the early phases of regeneration, but this allows mechanical stimulation to start driving neo-tendon development at an earlier time point, which kept it constantly ahead of the controls.
Achilles Tendon↗
Systemic zoledronate precoating of a bone graft reduces bone resorption during remodeling.
BACKGROUND: Cartilage degeneration often occurs after osteosynthesis of a devascularized intermediary fragment in a joint fracture, in mosaicplasty or in whole-joint toe-to-finger transplantation. Hypothetically, the degeneration is secondary to a collapse of the transferred subchondral bone as it remodels during high mechanical load. Bisphosphonates are used to reduce resorption of necrotic bone. We tested a systemic pretreatment before harvesting the graft in order to protect the bone and cartilage against collapse and secondary arthrosis. METHODS: Rats were given one zoledronate injection and bone grafts were harvested. The grafts were frozen, thawed and placed into bone chambers, and implanted into another batch of rats. Graft resorption and new bone formation was measured by histomorphometric analysis and compared with untreated grafts. RESULTS: In the remodeled area of the controls, the graft was almost totally resorbed and replaced by bone marrow. In the zoledronate-treated specimens, the graft remained and the graft trabeculas were lined with new bone. By histomorphometry, the total amount of bone (graft plus new bone) within the remodeled area was 16% in the zoledronate-treated grafts and 5% in the controls (p = 0.003). INTERPRETATION: A bone graft can be pretreated with bisphosphonate and remain protected against resorption once implanted again.
Animals↗
Pharmacological treatment of osteonecrosis.
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Bone Density Conservation Agents↗
High doses of OP-1 inhibit fibrous tissue ingrowth in impaction grafting.
A major concern in using growth factors in impaction grafting is the potential stimulation of the osteoclastic lineage. A solution would be using an osteoconductive material resistant to resorption and providing initial stability after reconstruction. Growth factors may promote bone formation in combination with such graft materials. We determined whether OP-1 would promote the incorporation of impacted morselized allografts and tricalcium phosphate/hydroxyapatite (TCP/HA) into host bone, whether bone formation would be preceded by an initial process of accelerated resorption, and whether the response to OP-1 remodeling/incorporation would be dose-related. We performed two bone chamber studies in goats to ascertain the early effects of OP-1 dose on resorption and incorporation of impacted morselized allografts and TCP/HA. After 4 weeks, the incorporation process of impacted morselized allografts and TCP/HA was not promoted by OP-1. We observed no signs of accelerated resorption preceding bone formation. An increase in OP-1 dose resulted in an inhibition of fibrous tissue formation but OP-1 did not promote bone formation. Early failures in impaction grafting, using mixes with OP-1, might be explained by the lack of fibrous tissue ingrowth and not by increased resorption and remodeling.
Animals↗
Osteonecrosis of the jaw: what do bisphosphonates do?
Osteonecrosis of the jaw is a new disease, partly caused by bisphosphonates. It is commonly assumed that the bisphosphonates somehow cause cell death (osteocyte necrosis) within the jawbone, which makes it prone to chronic infection. In this article, an alternative pathogenetic theory is suggested, based on the normal effect of bisphosphonates. According to the new theory, the bone is alive until it is injured and infected, and the reduced resorptive ability due to bisphosphonates hinders the formation of a fresh bone surface for re-establishment of bone cell coverage. The theories are compared, based on the recent, very scarce literature. None of them can be completely refuted, but the demonstration of living osteocytes within the lesion and the number of necessary assumptions speak against the theory of a primary, bisphosphonate-induced necrosis.
Diphosphonates↗
The total costs of a displaced femoral neck fracture: comparison of internal fixation and total hip replacement. A randomised study of 146 hips.
We randomised 143 patients--age 75 years or older--with displaced femoral neck fracture to either internal fixation or total hip replacement (THR) and compared the socio-economic consequences. In the internal fixation group, 34 of 78 hips underwent secondary surgery. In the THR group, 12 of 68 hips dislocated, the majority in mentally impaired patients. We calculated the total hospital costs for two years after operation. When secondary surgery was included, there was no difference in costs between the internal fixation and THR groups, or between the mentally impaired and lucid subgroups. The costs to the community were calculated comparing the baseline cost before surgery with the average cost per month during the first postoperative year. No difference was found between the treatment groups. The Harris hip scores were higher in the THR group, and pain was more common in the internal fixation group. In lucid patients, THR gives a better clinical result at the same cost.
Aged↗
Development of a large titanium bone chamber to study in vivo bone ingrowth.
In the bone conduction chamber (BCC) various materials and factors have been tested for their effect on bone graft incorporation and bone healing. However, biomaterials often have to be crushed to fit in this small chamber. Since cellular responses to biomaterials are influenced by the size and shape of particles, research concerning the evaluation of biomaterials is limited by the dimensions of this bone chamber. We enlarged and modified the BCC in order to be able to investigate the in vivo influences of biomaterials, growth factors and bone graft processing on tissue and bone ingrowth. Seven goats received four bone chambers each, three modified models and a BCC. The first model (BCC+) had two ingrowth openings, similar to that of the BCC. The second model had two round ingrowth openings (ROU). The third model had a open bottom for bone ingrowth (BOT). After 12 weeks, bone ingrowth distances were measured on histological sections and using muCT. Bone ingrowth was significantly higher (p=0.009 and 0.008) in the ROU compared to the BCC+ and the BOT, respectively. Similar results were found using muCT. The ROU model performed most similar to the BCC (gold standard) and is considered to be a promising new tool in biomaterials research.
Animals↗
Stimulation of implant fixation by parathyroid hormone (1-34)-A histomorphometric comparison of PMMA cement and stainless steel.
Whereas continuous exposure to PTH results in bone resorption, PTH administration at intermittent doses results in bone formation by increasing osteoblast number and activity. PTH leads to faster fracture repair and better fixation of orthopaedic implants in animal models. The present study evaluates if PTH is able to increase the contact surface between bone and implant and whether the effect of PTH is dependent on implant material characteristics. The implants were made as rods, either of stainless steel or Palacos R bone-cement. The steel rods had a surface roughness of R(a) 0.1 microm and the cement rods R(a) 2.2 microm. In 40 adult male rats, one cement rod was inserted in the left tibia and one steel rod in the right tibia. After implantation, the rats were divided into groups by random. One group was injected three times a week with human PTH (1-34) at a dose of 60 microg/kg BW/injection. The second group was injected with the vehicle only. Both groups were then divided into groups for 2 and 4 weeks time till tibial harvest. The tibial segments around the hole of the rods were then prepared by standard histological techniques. The linear tissue surfaces, that had been in contact with the surface of the rod, were analyzed in a blind fashion. PTH increased the bone contact fraction compared with the vehicle in the steel group from 7.4 (SD 7.6) to 21.1 (SD 10.7) % after 2 weeks and from 9.8 (SD 8.1) to 47.1 (SD 13.3) % after 4 weeks. In the cement group PTH increased the contact index again compared with the vehicle from 7.8 (SD 10.2) to 53.6 (SD 26.3) % already after 2 weeks and from 14.3 (SD 15) to 65.6 (SD 15.7) % after 4 weeks. The bone trabeculae adjacent to the implant had become fewer and thicker after the treatment with PTH (1-34), with an increase of the bone mass in the area next to the bone-implant-interface. The earlier onset of PTH effects in the rougher cement group suggests that intermittent PTH treatment might lead to an increased micro-interlock between implant and bone, and might therefore be considered as a possible drug to enhance incorporation of orthopedic implants.
Animals↗
Postoperative Cox inhibitors and late prosthetic loosening--suspicion increases!
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Arthroplasty, Replacement, Hip↗
Drugs and fracture repair.
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Adrenal Cortex Hormones↗
Topical, single dose bisphosphonate treatment reduced bone resorption in a rat model for prosthetic loosening.
Fluid pressure, instability or particles have been suggested to cause peri-prosthetic bone resorption. High intracapsular pressures have been reported in hip joints with loose prosthetic components, and oscillating fluid pressure has been shown to cause dramatic bone resorption in animal models. Resorption can be reduced by systemic bisphosphonate treatment in rat models with oscillating fluid pressure, but this has required higher doses than needed to inhibit normal remodelling. Bisphosphonates have high affinity to bone mineral. Topical application of the drug is therefore feasible. We used a previously described rat model where oscillating fluid pressure causes bone resorption. Before pressurization, a 1 mg/ml solution of alendronate was applied onto the bone surface for 1 min, after which excess bisphosphonate was rinsed away. Bone resorption was measured on histological slides as soft tissue area at the interface. Rats treated with topical alendronate had soft tissue areas reduced by half. Topical bisphosphonate treatment before cementing a joint implant could possibly reduce the risk of later loosening.
Administration, Topical↗
Systemic and local ibandronate enhance screw fixation.
The trauma involved with inserting implants into bone leads to an activation of the inflammatory response and an activation of osteoclasts. In addition, apoptosis of osteocytes in the surrounding area has been implicated in further activation of osteoclasts. If the balance between resorption and bone formation shortly after implantation favours resorption, an impairment of early fixation might ensue. Because bisphosphonates inhibit resorption, this study analyses whether they can improve early fixation. Stainless steel screws (M 1.7) were inserted into the tibiae of 76 male Sprague-Dawley rats. Daily subcutaneous injections of ibandronate (3 microg) or saline were given to 20 rats. The remaining rats received ibandronate or saline directly applied into the drill hole before the screw was inserted. Tibiae were harvested at 14 days. Mechanical tests were performed on 50 tibiae. Systemically treated tibiae were tested for pull-out strength alone. Locally treated tibiae were tested for either pull-out or torque resistance. The remaining 18 tibiae were prepared for histology. Systemic ibandronate increased the pull-out force at failure by 30% (p=0.04). Local treatment increased the force at failure by 15% (p=0.02) and stiffness by 28% (p=0.01). In the removal torque measurements, local ibandronate increased the torque-moment at failure by 60% (p=0.04), and the maximum friction moment by 51% (p=0.04). Energy for turning the screw 1/4 revolution was increased by 68% (p=0.02). These results demonstrate that early remodeling events plays an important role in screw fixation, and that systemic or local bisphosphonate treatment could be an effective pharmacological path to improve early implant fixation.
Animals↗
Platelet concentrate injection improves Achilles tendon repair in rats.
BACKGROUND: Blood platelets release a cocktail of growth factors when activated, some of which are thought to initiate and stimulate repair. EXPERIMENT AND FINDINGS: We studied whether a platelet concentrate injection would improve Achilles tendon repair in an established rat model. The Achilles tendon was transected and a 3 mm segment removed. After 6 h, a platelet concentrate was injected percutaneously into the hematoma. This increased tendon callus strength and stiffness by about 30% after 1 week, which persisted for as long as 3 weeks after the injection. At this time, the mechanical testing indicated an improvement in material characteristics--i.e., greater maturation of the tendon callus. This was confirmed by blinded histological scoring. INTERPRETATION: Platelet concentrate may prove useful for the treatment of Achilles tendon ruptures.
Achilles Tendon↗
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.
Animals↗