Marys Medicine

Doi:10.1016/j.injury.2007.10.035

Injury, Int. J. Care Injured (2008) 39, 384—394 Pharmacological agents and impairment offracture healing: What is the evidence? Ippokratis Pountos , Theodora Georgouli , Taco J. Blokhuis ,Hans Chistoph Pape Peter V. Giannoudis a Academic Department of Trauma & Orthopaedics, School of Medicine, University of Leeds, UKb Department of Surgery & Traumatology, University Medical Center Nijmegen, The Netherlandsc Academic Department, Pittsburgh Medical School, Pittsburgh, USA Accepted 31 October 2007 Bone healing is an extremely complex process which depends on the coordinated action of several cell lineages on a cascade of biological events, and has always been a major medical concern. The use of several drugs such as corticoster- Pharmacological agents oids, chemotherapeutic agents, non-steroidal anti-inflammatory drugs (NSAIDs),antibiotics, anticoagulants and drugs which reduce osteoclastic activity have beenshown to affect bone healing. This review article presents our current understandingon this topic, focusing on data illustrating the effect of these drugs on fracture healingand bone regeneration.
# 2007 Elsevier Ltd. All rights reserved.
* Corresponding author at: Academic Department of Trauma & Orthopaedics, Leeds General Infirmary, Great George Street, Leeds LS1 3EX, UK. Tel.: +44 113 3922750; fax: +44 113 3923290.
E-mail address: (P.V. Giannoudis).
0020–1383/$ — see front matter # 2007 Elsevier Ltd. All rights reserved.
Pharmacological agents and impairment of fracture healing patient, together with the age, gender, smoking andaccompanying pathologies, contribute to the delay Bone healing is one of the most complex cascades of or diminution of heaAs far as events resulting in the repair of fractured bone smoking is concerned, delayed healing does not without scar formation, and a final outcome that appear to be due to a direct effect of nicotine on resembles the previous state of an unbroken bone.
bone cells, which was found to up-regulate their This process involves the coordinated action of activity, but probably due to vascular responses to several cells types, along with signal pathways and nicotine or due to the effect on bone cells of other local changes in the biochemical content. It includes components absorbed during smoking.
a variety of biological changes, starting with disrup- Another important factor that is known to have tion of blood supply, haematoma formation, local an effect on the fracture healing process is the hypoxia and inflammCytokine and growth administration of different pharmacological agents.
factor release, together with pro-inflammatory sti- The aim of this review article is to provide a brief muli, result in a high production of prostaglandins.
overview of the current evidence of the inhibitory This environment seems to force mesenchymal stem effect of various drugs on the fracture healing cells (MSCs) to migrate, accumulate and proliferate, reaching adequate numbers to support differentia-tion.Neovasculogenesis in association withfurther growth factor and prostaglandin production, promotes differentiation of MSCs towards chondro-genic or osteogenic lineages, initially forming woven Chemotherapeutic agents are widely used for bone and in continuity with the hard callus.
the treatment of malignant lesions. Fracture Finally, this process is followed by an extended healing and limb-salvage procedures including period of remodelling characterised by resorption vascularised bone grafts, autografts and allografts and new bone formation resulting in restoration of mechanical strength and stability.
).Their anti-prolif- The outcome of this process is regulated by a erative and cytotoxic properties have a great effect diversity of local and systemic factors with varying on neovasculogenesisproper callus formation and host bone-allograft incorporation resulting in higher Local inhibitory factors non-union ratSimilarly, anti-angiogenesis include the presence of a fracture gap, disturbances agents have a detrimental effect on fracture healing of blood flow, concomitant infection and extensive and the outcome resembles atrophic non-union soft tissue damaThe surgical technique, the Several animal models have illustrated the effect type of fixation and the success of the fixation are of chemotherapy drugs on bone healing. Studies also factors which influence the fracture healing with the use of doxorubicin, cyclophosphamide, respoInsufficient mechanical stabi- adriamycin and methotrexate reported diminution lity has a negative effect on healing, resulting either of bone formatChemical analysis of the in excessive or diminutive callus formation, leading callus showed diminished calcium and phosphatase to hypertrophic or hypotrophic non-uIn deposition with the use of cyclophosphamide.
addition, the metabolic and nutritional state of the Nilsson et al. showed that the inhibitory effects ofmethotrexate on bone formation persisted for at Factors that affect fracture healing least three weeks after administration.In an ani-mal model of spinal fusion, a single dose of adria-  Type of the fracture mycin during surgery resulted in a significant  Fracture gap  Poor technique, inadequate reduction, abnormal inhibitory effect on the process of Distraction osteogenesis could be an alternative  Type of fixation and mechanical stability of limb-salvage procedure as it does not seem to be affected by chemotherapy agents.Alterna-  Infection and debris, dead tissue in wound tively, approaches with tissue-engineering with  Extensive soft tissue damage the use of MSCs could be useIn rats receiving  Blood supply-smoking chemotherapy, the application of MSCs into an  Metabolic and nutritional state of the patient experimentally induced femoral defect produced  Age and gender of the patient bone formation similar to the non-chemotherapy  Early mobilisation treated Such approaches may be bene-  Accompanying diseases ficial for treatment of bone defects in patients  Drug administration I. Pountos et al.
Chemotherapeutic agents' effect on fracture healing Doxorubicin and Methotrexate  Decrease of bone formation  Inhibition of collagen formation Delayed mineralisation  Inhibition of bone formation Doxorubicin and Methotrexate  Diminished bone formation The number of osteoblasts and osteoclasts was unaffected  Impairment of bone healing  Result resembles atrophic non-union Suppressed callus and woven bone  High increase of non-union rates  This regimen had no effect on distraction osteogenesis  No effect on distraction osteogenesis Arsenic trioxide, Busulphan,  Variability of affection Cyclophasphomide, Methotrexate,  Paclitaxel, vincristine, etoposide Cytarabine, Etoposide, and cytarabine had higher degree  Inhibition of spinal fusion na: not available.
a decreased bone density. The inhibitory effect ofcorticosteroids on fracture healing seems logical, but The effect of corticosteroids on bone metabolism has not all animal studies have shown consistent results.
been well documented. Corticosteroids induce A number of studies have been conducted on the osteoporosis, and they are the most common cause of secondary osteoporosis. Steroid administration leads to osteoblast apoptosis, osteocyte apoptosis, 1950s, Blunt et al. first studied the effect of corti- and inhibition of osteoblastogeneresulting in costeroids on bone heaThey reported that The effect of steroids on fracture healing  Decreased callus formation  Retardation of healing Abnormal histological appearance  No inhibitory effect encountered  No inhibitory effect encountered  Retardation of bone healing  Inhibition of collagens synthesis  Retardation of mineralisation  No inhibitory effect encountered  Lower callus size and mineral content Chronic administration resulted in weaker bone  Inhibition of bone graft incorporation in spinal fusion  25% lower callus area and 55% inhibition of torsional  No inhibitory effect encountered Pharmacological agents and impairment of fracture healing callus formation was decreased in rabbits receiving cortisone.In addition, absence of periosteal boneand abnormal histological processes were described Several studies support the adverse effects of anti- by Sisson and HadfieThereafter, a number of biotics on bone healing controversial studies were published presenting dif- Cartilage is mainly affected by alteration ferent results. Several rat studies failed to prove any of the process of endochondral ossification. Quino- lones are thought to cause chondrocyte death and described a detrimental effect on bone heal- degeneration of articular cartilage resulting in fissure Waters et al., in a rabbit model of formation and cartilage erosions. Their use in chil- fracture healing treated with prednisone, found dren was discouraged by some authors due to their decreased callus volume, decreased mineral con- effects on growing cartilagewhereas others did tent and weaker repair of the frSimilarly, not observe any osteoarticular problem or joint in an experimental model of posterolateral lumbar deformity.Mont et al. suggested that ciprofloxacin spinal arthrodesis in rabbits, dexamethasone inhib- decreased cellular proliferation and DNA synthesis, ited graft incorporation and had a higher rate of therefore newly differentiated cells are the most non-union.In wound healing the treatment of affected cell types.Ciprofloxacin administration rats with glucocorticoids seemed to decrease the in rats produced diminution of fracture healing during rate of fibroblasts and collagen accumulation, and the early stages of repair, decreased chondrocyte as consequence the tensile strength.
number and abnormalities in cartilage morphology.
The reason for these differing results is still Levofloxacin and trovafloxacin had also the same unknown. Jee and co-workers stated that cortisone has a dose dependant effect on bone.In addition, Gentamicin in high concentrations seems to de- Duthie and Barker found that endochondral ossifica- crease proliferation of osteoblastic progenitors and tion was clearly retarded in rats treated with corti- therefore interfere with the normal healing of bone.
Prolonged treatment with high doses of tetracycline affected.Recent data suggest that the presence impairs bone growth and maturation of bone in mon- of glucocorticoid receptors GRa at osteoblasts, keys.In addition, in a rat model of bone repair chondrocytes and osteocytes might play a role in induced by demineralised bone both gentamycin and endochondral bone formatTherefore, the ani- tetracycline inhibited new bone format mal model, the duration and dosage of drugs admi- Other antibiotics such as doxycycline had no nistered as well as the traumatic extent of the effect on bone healing.Similarly, cephalothin experimentally induced fracture seems to have an and tobramycin had no effect on the osteogenic effect on the outcome.
activity of allografts in guinea The effect of antibiotics on fracture healing  No significant effect  Inhibition of cellular proliferation No effect on proteoglycans synthesis, morphology and stain pattern  Decreased torsional strength and stiffness Alternations of cartilage morphology  Inhibition of matrix metalloproteinases Levofloxacin and Trovafloxacin  Decrease in strength Inferior quality of callus Gentamicin and Tetracycline  Decreased bone formation Gentamicin and Vancomycin  No effect encountered Norfloxacin, Ofloxacin,  Retardation of healing occurred in all Pefloxacin and Ciproxacin fluoroquinolone treated animals  Differences in terms of healing inhibition I. Pountos et al.
The effect of anticoagulants on fracture healing Heparin and Dicumarol  Delayed healing Fibrous accumulation in callus  Decreased rates of bone formation Increased rates of resorption  LMWH has milder effect on bone formation  Retardation of bone healing  Heparin impaired the filling of bore holes whilst LMWH had no effect LMWH: low-molecular-weight heparin.
It is clear from these studies that quinolones have They also improve the quality of a detrimental effect on cartilage formation and analgesia and decrease hospital stay.
maintenance. In addition, local application of sev- Prostaglandin E-2 (PGE-2) and Prostaglandin F-2a eral antibiotics delivers high concentrations of the (PGF-2a) are both known to stimulate bone forma- drugs which have toxic effect on the growing bone.
tion and increase bone mass.A fracture leads tohigh local prostaglandin production and reand experimental models showed that local admin- istration of exogenous prostaglandins can stimulatebone formation.In rabbits a dose-dependent The effect of anticoagulant therapy on fracture stimulation of callus formation was healing was first studied as early as 1955 by Stinch- Our in vitro results suggested that MSCs proliferation field et The stimulus was a high rate of pseu- is not affected by the quantity of prostaglandins doarthrosis in patients receiving postoperative present, therefore we speculate that prostaglandins anticoagulant therapy for thrombophlebitis. In their may have an effect at a later stage of bone heal- study, delayed union was observed in animals Furthermore, PGE-2 has been shown to reg- receiving anticoagulant therapy. Thereafter several ulate both BMP-2 and BMP-7 expression suggesting a authors studied the effect of anticoagulants on bone potential role in modulation of bone metabo- healing ().Several studies observed that heparin causes decreased trabecular volume through increased resorption and decreased models suggested that NSAIDs, due to their effect rate of bone formThis effect was not reversible, as after the end of administration heparin was found sequestered in bone for an extended period of time. Dodds et al. showed a decrease in periosteal activities of glucose 6-phos- decreased mineral content and matrix of the callus phate dehydrogenase and of alkaline phosphatase and inhibited haversian remoIn rat around the fracture in rats, indicating that Vitamin models treated with NSAIDs, bone density appeared K-antagonists influence the bone metabolism in decrbone stiffness and strength were fresh callus tissue.Street et al. showed that the administration of the newer generation anticoagu- increased fibrous tissue accumulation was appar- lants, the low-molecular-weight heparins, resulted ent.Goodman et al. studied the effect of short- in the development of less mature bone with term Cox-2 inhibitor administration after fracture reduced torsional strengthbut this effect was on a rabbit model.Their results indicated that if milder compared to that of More recent Cox-2 was administered in the first two weeks after studies have not been able to reproduce the effect fracture the bone ingrowth was not affected. In of LMWH on fracture hea contrast, if Cox-2 was administered continuouslyfor six weeks bone ingrowth was substantiallydecreased.
On the other hand, several authors demonstrated in animal models that NSAIDS have little or no effect NSAIDs are frequently used for pain relief due to on fracture healinIt should be pointed their pronounced analgesic potency, anti-inflamma- out that although their findings provided evidence tory effects and lesser side effects compared with that ketorolacelecoxiand parecoxido Pharmacological agents and impairment of fracture healing The effect of NSAIDs on fracture healing  Inhibition of haversian remodelling  No effect on repairing drill holes Higher effect on older animals Histological evidence of increased fibrous accumulation with decrease of osteogenesis and remodelling  No effect on Colles' fracture  Effect depends on the extent of trauma  No effect on Colles' fracture Ketorolac Trom.
 Ketorolac Tromethamine had no effect on healing of rat osteotomy whilst indomethacin impaired healing  High rate of non-union in spinal fusion  MSCs proliferation decreased by 18% and osteoblastic proliferation by 2.5%  No effect on prosthetic loosening after cementless  Increased risk for non-union  Impaired bone healing, low bending stiffness and  No effect on spinal fusion  Cox-2 selective parecoxib has small effect on delaying fracture healing  Ketorolac had the highest effect  Delays in bone healing occurred  Inhibition in early phase of healing  No effect on fracture healing  Less bone ingrowth Lower effect if given short-term  Celecoxib, rofecoxib and low dose of ketorolac had no effect on spinal fusion  High dose of ketorolac increased the rate of non-union  Short-term administration had no effect on spinal fusion  Bone healing was impaired.
 The drug inhibited bone formation in heterotopic demineralised allogeneic bone matrix but had noeffect on autografts  No effect on MSCs proliferation when cellular medium was supplemented with expected plasma concentrations.
 Negative effect encountered when toxic concentrations used (over 100 mg/ml).
 NSAIDs in plasma concentrations had no effect on  Impairment of callus maturation  Non-union in 65% of rofecoxib treated and 17.6% of ibuprophen treated rats not affect fracture healing, they failed to demon- grafts but to affect bone formation in demineralised strate similar effects after administration of indo- allogeneic bone matrixIn addition, indomethacin methacin.Indomethacin in a rat model was also was found not to influence bone growth in small found to have no effect on bone formation on auto- defects but its effect was proportional to the extent I. Pountos et al.
of traumatised boSpinal fusion in rabbits was nates might be candidates to up-modulate bone not inhibited by celecoxi healinIncreased mineral content, volume and In humans very few data exist demonstrating a strength of callus were observed in animal models potential relationship between bone healing and NSAIDs. Davis and Ackroyd studied the effect of Although these observations have been confirmed two weeks administration of flurbiprophen on Colles' by several studies, concern exists as some authors fractureNo impairment on fracture healing union suggest that the arrest of bone remodelling may was encountered. Giannoudis et al. showed a strong produce osteoporotic, weak bonStill, the association between long-term NSAIDs administra- available data on the use of bisphosphonates under- tion and non-union development.In patients under- line their importance in the prevention of additional going spinal fusion the short-term administration of fractures in osteoporotic patients, who are often either low dose of ketorolac, celecoxib and rofecoxib diagnosed after a fracture has occurred. The possible had no effect on the rate of non-unionHigh or negative effects on bone remodelling do not seem to long-term postoperative doses of NSAIDS had an outweigh their beneficial effects at this point.
increased risk of developing non-unionInaddition, the relation between administration ofNSAIDs and both osteopenia after Colles' fracture and aseptic loosening after hip replacement wasstudied,and no correlation was seen. A signifi- Intensive research is currently focused on the treat- cant effect was found by Burd et al. in a retrospective ment of fractures by the application of cells, scaf- study on patients receiving indomethacin for preven- folds, growth factors or by development and design of tion of heterotopic bone formation in acetabular new implants. Today's knowledge on the effect of fracturePatients who did not receive indometha- several drugs on bone healing is characterised by cin had significantly fewer non-unions of associated inconclusive and controversial results from several long bone fractures than patients who received it.
animal models, together with absence of univocal Heterotopic bone formation (HBF) after major hip clinical data. It is clear, however, that some pharma- surgery seems to be connected with male gender, cological agents impair the bone healing process, and operative techniquand idiopathic hyperostosis of small changes in medication of patients can contri- the skeletNSAIDs appear to prevent this pro- bute to a better outcome. This should be borne in cess.Neal et al. in a systematic survey of 13 trials mind by all physicians involved in the treatment of reported an overall decrease of HBF of 57%The bone disorders, whether dealing with fractures or duration of NSAIDs administration seems unrelated to degenerative diseases. Further research in the fore- the development of HBF. Pritchett and Gebuhr et al.
seeable future may allow clinicians to understand administered NSAIDs for two and five days postopera- better the inhibitory effect of several pharmacolo- tively.They reported a reduction of HBF of 48— gical agents on the fracture healing process and the 50%. In contrast, great variability existed in similar mechanisms governing bone repair and regeneration.
studies with administration of NSAIDs varying from 10to 92 days and HBF reduction from 7 to 97 NSAIDs have a clear benefit in everyday clinical practice, and the contradictory results from thesevarious animal models, as well the absence of well No benefits in any form have been received or will be randomised clinical data, suggest that more research received from a commercial party related directly should be conducted on this topic; the animal studies or indirectly to the subject of this article. No funds may not reflect the clinical setting. In addition, the were received in support of this study.
exact biology of heterotopic bone formation, whereNSAIDs play a preventive role, remains unclear andcannot be considered as a reflection of bone healing.
Conflicts of interest We believe that clinicians should weigh up theirpotential risks and benefits There are no conflicts of interest.
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A herbal formula, comprising panax ginseng and bee-pollen, inhibits development of testosterone-induced benign prostatic hyperplasia in male wistar rats

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