Doi:10.1016/j.injury.2007.10.035Injury, 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.
Bisphosphonates are widely used bone anabolic 1. Abu EO, Horner A, Kusec V, et al. The localization of the agents inhibiting bone resorption. Based on this prin- functional glucocorticoid receptor alpha in human bone. J ciple, several authors suggested that bisphospho- Clin Endocrinol Metab 2000;85:883—9.
Pharmacological agents and impairment of fracture healing 2. Adolphson P, Abbaszadegan H, Jonsson U, et al. No effects 21. Claes LE, Wilke HJ, Augat P, et al. Effect of dynamization on of piroxicam on osteopenia and recovery after Colles' gap healing of diaphyseal fractures under external fixation.
fracture. A randomized, double-blind, placebo-controlled, Clin Biomech (Bristol Avon) 1995;10:227—34.
prospective trial. Arch Orthop Trauma Surg 1993;112: 22. Cruess RL, Dumont J. Fracture healing. Can J Surg 3. Alkan A, Erdem E, Gunhan O, Karasu C. Histomorphometric 23. Davis TR, Ackroyd CE. Non-steroidal anti-inflammatory evaluation of the effect of doxycycline on the healing of agents in the management of Colles' fractures. Br J Clin bone defects in experimental diabetes mellitus: a pilot study. J Oral Maxillofac Surg 2002;60:898—904.
24. Day SM, DeHeer DH. Reversal of the detrimental effects of 4. Amanat N, Brown R, Bilston LE, Little DG. A single systemic chronic protein malnutrition on long bone fracture healing.
dose of pamidronate improves bone mineral content and J Orthop Trauma 2001;15:47—53.
accelerates restoration of strength in a rat model of fracture 25. Deguchi M, Rapoff AJ, Zdeblick TA. Posterolateral fusion for repair. J Orthop Res 2005;235:1029—34.
isthmic spondylolisthesis in adults: analysis of fusion rate 5. Arikawa T, Omura K, Morita I. Regulation of bone morpho- and clinical results. J Spinal Disord 1998;11:459—64.
genetic protein-2 expression by endogenous prostaglandin 26. Dekel S, Lenthall G, Francis MJ. Release of prostaglandins E2 in human mesenchymal stem cells. J Cell Physiol from bone and muscle after tibial fracture. An experi- mental study in rabbits. J Bone Joint Surg Br 1981;63- 6. Aslan M, Simsek G, Yildirim U. Effects of short-term treat- ment with systemic prednisone on bone healing: an experi- 27. Dimitriou R, Tsiridis E, Giannoudis PV. Current concepts of mental study in rats. Dent Traumatol 2005;21:222—5.
molecular aspects of bone healing. Injury 2005;36: 7. Augat P, Margevicius K, Simon J, et al. Local tissue proper- ties in bone healing: influence of size and stability of the 28. Dodds RA, Catterall A, Bitensky L, Chayen J. Effects on osteotomy gap. J Orthop Res 1998;16:475—81.
fracture healing of an antagonist of the vitamin K cycle.
8. Augat P, Merk J, Ignatius A, et al. Early, full weightbearing Calcif Tissue Int 1984;36(2):233—8.
with flexible fixation delays fracture healing. Clin Orthop 29. Duck HJ, Mylod Jr AG. Heterotopic bone in hip arthroplas- Relat Res 1996;328:194—202.
ties. Cemented versus noncemented. Clin Orthop Relat Res 9. Beck A, Krischak G, Sorg T, et al. Influence of diclofenac (group of nonsteroidal anti-inflammatory drugs) on fracture 30. Duthie RB, Barker AN. The histochemistry of the preosseous healing. Arch Orthop Trauma Surg 2003;123:327—32.
stage of bone repair studied by autoradiography; the effect 10. Beck A, Salem K, Krischak G, et al. Nonsteroidal anti- of cortisone. J Bone Joint Surg Br 1955;37-B:691—700.
inflammatory drugs (NSAIDs) in the perioperative phase in 31. Ehrilch P, Harold T, Hunt TK. Effects of vitamin A and traumatology and orthopedics effects on bone healing. Oper glucocorticoids upon inflammation and collagen synthesis.
Orthop Traumatol 2005;17:569—78.
Ann Surg 1973;177:222—7.
11. Beljan JR. Osseous malrepair in calcium-deficient states.
32. Ehrlich P, Hunt T. Effects of cortisone & vit A on wound Life Sci Space Res 1974;12:133—9.
healing. Ann Surg 1968;167:324—8.
12. Blasingame JP, Resnick D, Coutts RD, Danzig LA. Extensive 33. Einhorn TA. The cell and molecular biology of fracture spinal osteophytosis as a risk factor for heterotopic bone healing. Clin Orthop Relat Res 1998;355:S7—21.
formation after total hip arthroplasty. Clin Orthop Relat Res 34. Elves MW, Bayley I, Roylance PJ. The effect of indomethacin upon experimental fractures in the rat. Acta Orthop Scand 13. Blunt JW, Plotz CM, Lattes R, et al. Effect of cortisone on experimental fractures in the rabbit. Proc Soc Exp Biol Med 35. Endo K, Sairyo K, Komatsubara S, et al. Cyclooxygenase-2 inhibitor delays fracture healing in rats. Acta Orthop 14. Brown KM, Saunders MM, Kirsch T, et al. Effect of COX-2- specific inhibition on fracture-healing in the rat femur. J 36. Endo K, Sairyo K, Komatsubara S, et al. Cyclooxygenase-2 Bone Joint Surg Am 2004;86-A:116—23.
inhibitor inhibits the fracture healing. J Physiol Anthropol 15. Burchardt H, Glowczewskie Jr FP, Enneking WF. The effect Appl Hum Sci 2002;21:235—8.
of adriamycin and methotrexate on the repair of segmental 37. Friedlaender GE, Tross RB, Doganis AC, et al. Effects of cortical autografts in dogs. J Bone Joint Surg Am chemotherapeutic agents on bone. I. Short-term metho- trexate and doxorubicin (adriamycin) treatment in a rat 16. Burd TA, Hughes MS, Anglen JO. Heterotopic ossification model. J Bone Joint Surg Am 1984;66:602—7.
prophylaxis with indomethacin increases the risk of long- 38. Gajraj NM. The effect of cyclooxygenase-2 inhibitors on bone nonunion. J Bone Joint Surg Br 2003;85(5):700—5.
bone healing. Reg Anesth Pain Med 2003;28:456—65.
17. Burssens A, Thiery J, Kohl P, et al. Prevention of heterotopic 39. Gebuhr P, Sletgard J, Dalsgard J, et al. Heterotopic ossifica- ossification with tenoxicam following total hip arthroplasty: tion after hip arthroplasty: a randomized double-blind mul- a double-blind, placebo-controlled dose-finding study. Acta ticenter study tenoxicam in 147 hips. Acta Orthop Scand Orthop Belg 1995;61:205—11.
18. Camu F, Beecher T, Recker DP, Verburg KM. Valdecoxib, a 40. Gerstenfeld LC, Thiede M, Seibert K, et al. Differential COX-2-specific inhibitor, is an efficacious, opioid-sparing inhibition of fracture healing by non-selective and cycloox- analgesic in patients undergoing hip arthroplasty. Am J Ther ygenase-2 selective non-steroidal anti-inflammatory drugs.
J Orthop Res 2003;21:670—5.
19. Castella FB, Garcia FB, Berry EM, et al. Nonunion of the 41. Giannoudis PV, MacDonald DA, Matthews SJ, et al. Nonunion humeral shaft: long lateral butterfly fracture–—a nonunion of the femoral diaphysis. The influence of reaming and non- predictive pattern? Clin Orthop Relat Res 2004;424: steroidal anti-inflammatory drugs. J Bone Joint Surg Br 20. Chahal J, Stephen DJ, Bulmer B, et al. Factors associated 42. Giordano V, Giordano M, Knackfuss IG, et al. Effect of with outcome after subtalar arthrodesis. J Orthop Trauma tenoxicam on fracture healing in rat tibiae. Injury I. Pountos et al.
43. Glassman SD, Rose SM, Dimar JR, et al. Puno RM. The effect 65. Keller J, Kjaersgaard-Andersen P, Bayer-Kristensen I, Melsen of postoperative nonsteroidal anti-inflammatory drug F. Indomethacin and bone trauma. Effects on remodelling of administration on spinal fusion. Spine 1998;23:834—8.
rabbit bone. Acta Orthop Scand 1990;61:66—9.
44. Goodman SB, Ma T, Mitsunaga L, et al. Temporal effects of a 66. Keller J, Klamer A, Bak B, Suder P. Effect of local prosta- COX-2-selective NSAID on bone ingrowth. J Biomed Mater glandin E2 on fracture callus in rabbits. Acta Orthop Scand Res A 2005;72:279—87.
45. Goodman S, Ma T, Trindade M, et al. COX-2 selective NSAID 67. Key JA, Odell RT, Taylor LW. Failure of cortisone to delay or to prevent the healing of fractures in rats. J Bone Joint Surg 46. Goodship AE, Walker PC, McNally D, et al. Use of a bispho- 68. Khoo DB. The effect of chemotherapy on soft tissue and sphonate (pamidronate) to modulate fracture repair in bone healing in the rabbit model. Ann Acad Med Singapore ovine bone. Ann Oncol 1994;5:S53—5.
47. Gravel CA, Le TT, Chapman MW. Effect of neoadjuvant 69. Kim SG, Chung TY, Kim MS, Lim SC. The effect of high local chemotherapy on distraction osteogenesis in the goat concentrations of antibiotics on demineralized bone induc- model. Clin Orthop Relat Res 2003;412:213—24.
tion in rats. J Oral Maxillofac Surg 2004;62:708—13.
48. Guarniero R, de Barros Filho TE, Tannuri U, et al. Study of 70. Kock HJ, Werther S, Uhlenkott H, Taeger G. Influence fracture healing in protein malnutrition. Rev Paul Med of unfractionated and low-molecular-weight heparin on bone healing: an animal model. Unfallchirurg 2002;105: 49. Gudmundson C. Oxytetracycline-induced disturbance of fracture healing. J Trauma 1971;11:511—7.
71. Krischak GD, Augat P, Sorg T, et al. Effects of diclofenac on 50. Gullihorn L, Karpman R, Lippiello L. Differential effects of periosteal callus maturation in osteotomy healing in an nicotine and smoke condensate on bone cell metabolic animal model. Arch Orthop Trauma Surg 2007;127:3—9.
activity. J Orthop Trauma 2005;19:17—22.
72. Lamparter S, Slight SH, Weber KT. Doxycycline and tissue 51. Gurpinar AN, Balkan E, Kilic N, et al. The effects of a repair in rats. J Lab Clin Med 2002;139:295—302.
fluoroquinolone on the growth and development of infants.
73. Lee OK, Coathup MJ, Goodship AE, Blunn GW. Use of Int Med Res 1997;25:302—6.
mesenchymal stem cells to facilitate bone regeneration 52. Hak DJ, Stewart RL, Hazelwood SJ. Effect of low molecular in normal and chemotherapy-treated rats. Tissue Eng weight heparin on fracture healing in a stabilized rat femur fracture model. J Orthop Res 2006;24(4):645—52.
74. Leonelli SM, Goldberg BA, Safanda J, et al. Effects of a 53. Haleem AA, Rouse MS, Lewallen DG, et al. Gentamicin and cyclooxygenase-2 inhibitor (rofecoxib) on bone healing. Am vancomycin do not impair experimental fracture healing.
J Orthop 2006;35:79—84.
Clin Orthop Relat Res 2004;427:22—4.
75. Li J, Law HK, Lau YL, Chan GC. Differential damage and 54. Hausman MR, Schaffler MB, Majeska RJ. Prevention of frac- recovery of human mesenchymal stem cells after exposure ture healing in rats by an inhibitor of angiogenesis. Bone to chemotherapeutic agents. Br J Haematol 2004;127: 55. Hazan EJ, Hornicek FJ, Tomford W, et al. The effect of 76. Li J, Mori S, Kaji Y, et al. Effect of bisphosphonate (inca- adjuvant chemotherapy on osteoarticular allografts. Clin dronate) on fracture healing of long bones in rats. J Bone Orthop Relat Res 2001;385:176—81.
Miner Res 1999;14:969—79.
56. Hellewell AB, Beljan JR, Goldman M. Effect of chronic 77. Long J, Lewis S, Kuklo T, et al. The effect of cyclooxygenase- administration of glucocorticoid (prednisolone) on the rate 2 inhibitors on spinal fusion. J Bone Joint Surg Am of healing of experimental osseous defects. Clin Orthop Relat Res 1974;100:349—55.
78. Luppen CA, Blake CA, Ammirati KM, et al. Recombinant 57. Hilibrand AS, Fye MA, Emery SE, et al. Impact of smoking on human bone morphogenetic protein-2 enhances osteotomy the outcome of anterior cervical arthrodesis with inter- healing in glucocorticoid-treated rabbits. J Bone Miner Res body or strut-grafting. J Bone Joint Surg Am 2001;83- 79. Ma YF, Li XJ, Jee WS, et al. Effects of prostaglandin E2 and F2 58. Hogevold HE, Grogaard B, Reikeras O. Effects of short-term alpha on the skeleton of osteopenic ovariectomized rats.
treatment with corticosteroids and indomethacin on bone healing. A mechanical study of osteotomies in rats. Acta 80. Madsen JE, Berg-Larsen T, Kirkeby OJ, et al. No adverse Orthop Scand 1992;63:607—11.
effects of clodronate on fracture healing in rats. Acta 59. Hornicek FJ, Gebhardt MC, Tomford WW, et al. Factors Orthop Scand 1998;69:532—6.
affecting nonunion of the allograft-host junction. Clin 81. Mashiba T, Hirano T, Turner CH, et al. Suppressed bone Orthop Relat Res 2001;382:87—98.
turnover by bisphosphonates increases microdamage accu- 60. Huddleston PM, Steckelberg JM, Hanssen AD, et al. Cipro- mulation and reduces some biomechanical properties in dog floxacin inhibition of experimental fracture healing. J Bone rib. J Bone Miner Res 2000;15:613—20.
Joint Surg Am 2000;82:161—73.
82. Matta J, Siebenrock K. Does indomethacin reduce hetero- 61. Isefuku S, Joyner CJ, Simpson AH. Gentamicin may have an topic bone formation after operation for acetabular frac- tures–—a prospective randomized study? J Bone Joint Surg 62. Jee WS, Ma YF. The in vitro anabolic actions of prostaglan- 83. Mont MA, Mathur SK, Frondoza CG, Hungerford DS. The dins in bone. Bone 1997;21:297—304.
effects of ciprofloxacin on human chondrocytes in cell 63. Jee WS, Park HZ, Roberts WE, Kenner GH. Corticosteroid and culture. Infection 1996;24:151—5.
bone. Am J Anat 1970;129:477—9.
84. Muir JM, Andrew M, Hirsh J, et al. Histomorphometric 64. Ke HZ, Jee WS, Mori S, et al. Effects of long-term daily analysis of the effects of standard heparin on trabecular administration of prostaglandin-E2 on maintaining elevated bone in vivo. Blood 1996;88:1314—20.
proximal tibial metaphyseal cancellous bone mass in male 85. Muir JM, Hirsh J, Weitz JI, et al. A histomorphometric rats. Calcif Tissue Int 1992;50:245—52.
comparison of the effects of heparin and low-molecular- Pharmacological agents and impairment of fracture healing weight heparin on cancellous bone in rats. Blood 1997;89: 105. Ritter MA, Vaughan RB. Ectopic ossification after total hip arthroplasty. Predisposing factors, frequency, and effect on 86. Murakami H, Kowalewski K. Effects of cortisone and an results. J Bone Joint Surg Am 1977;59:345—51.
anabolic androgen on the fractured humerus in guinea pigs: 106. Sato S, Kim T, Arai T, et al. Comparison between the effects clinical and histological study over a six-week period of of dexamethasone and indomethacin on bone wound heal- fracture healing. Can J Surg 1966;9:425—34.
ing. Jpn J Pharmacol 1986;42:71—8.
87. Neal BC, Rodgers A, Clark T, et al. A systematic survey of 107. Sawin PD, Dickman CA, Crawford NR, et al. The effects of 13 randomized trials of non-steroidal anti-inflammatory dexamethasone on bone fusion in an experimental model of drugs for the prevention of heterotopic bone formation posterolateral lumbar spinal arthrodesis. J Neurosurg after major hip surgery. Acta Orthop Scand 2000;71: 108. Sell S, Teschner M, Gaissmaier C, et al. Effect of diclo- 88. Nilsson OS, Bauer FC, Brostrom LA, Nilsonne U. Effect of the fenac on human osteoblasts and their stromal precursors antineoplastic agent methotrexate on experimental hetero- in vitro in relation to arthroplasty. Z Rheumatol 1999;58: topic new bone formation in rats. Cancer Res 1984;44: 109. Shaughnessy SG, Hirsh J, Bhandari M, et al. A histomorpho- 89. O'Brien CA, Jia D, Plotkin LI, et al. Glucocorticoids act metric evaluation of heparin-induced bone loss after directly on osteoblasts and osteocytes to induce their apop- discontinuation of heparin treatment in rats. Blood tosis and reduce bone formation and strength. Endocrinol- 110. Simmons DJ, Chang SL, Russell JE, et al. The effect 90. Paralkar VM, Grasser WA, Mansolf AL, et al. Regulation of of protracted tetracycline treatment on bone growth BMP-7 expression by retinoic acid and prostaglandin E(2). J Cell Physiol 2002;190:207—17.
91. Parker MJ, Raghavan R, Gurusamy K. Incidence of fracture- 111. Sisson HA, Hadfield GJ. The influence of cortisone on the healing complications after femoral neck fractures. Clin repair of experimental fracture in rabbit. Br J Surg Orthop Relat Res 2007;458:175—9.
92. Perry AC, Prpa B, Rouse MS, et al. Levofloxacin and trova- 112. Sommer-Tsilenis E, Sauer HD, Kruse HP. Delaying effect floxacin inhibition of experimental fracture-healing. Clin of cyclophosphamide on bone fracture healing chemical Orthop Relat Res 2003;14:95—100.
analyses of rat femora. Arch Orthop Trauma Surg 93. Persson PE, Sisask G, Nilsson O. Indomethacin inhibits bone formation in inductive allografts but not in autografts: 113. Stinchfield FE, Sankaran B, Samilson R. The effect of antic- studies in rat. Acta Orthop 2005;76:465—9.
oagulant therapy on bone repair. J Bone Joint Surg Am 94. Peter CP, Cook WO, Nunamaker DM, et al. Effect of alen- dronate on fracture healing and bone remodeling in dogs. J 114. Street JT, McGrath M, O'Regan K, et al. Thromboprophylaxis Orthop Res 1996;14:74—9.
using a low molecular weight heparin delays fracture repair.
95. Petri WH. Osteogenic activity of antibiotic-supplemented Clin Orthop Relat Res 2000;381:278—89.
bone allografts in the guinea pig. J Oral Maxillofac Surg 115. Subasi M, Kapukaya A, Kesemenli C, et al. Effect of che- motherapeutic agents on distraction osteogenesis. An 96. Pountos I, Georgouli T, Jones E, et al. The effect of NSAIDs on experimental investigation in rabbits. Arch Orthop Trauma the proliferation of mesenchymal stem cells and bone healing. Injury 2006;37:3.
116. Sudmann E, Bang G. Indomethacin-induced inhibition of 97. Pritchett JW. Ketorolac prophylaxis against heterotopic haversian remodelling in rabbits. Acta Orthop Scand ossification after hip replacement. Clin Orthop Relat Res 117. Tortolani PJ, Park AE, Louis-Ugbo J, et al. The effects of 98. Puzas JE, O'Keefe RJ, Schwarz EM, Zhang X. Pharmacologic doxorubicin (adriamycin) on spinal fusion: an experimental modulators of fracture healing: the role of cyclooxygenase model of posterolateral lumbar spinal arthrodesis. Spine J inhibition. J Musculoskelet Neuronal Interact 2003;3: 118. Tuncay I, Ozbek H, Kosem M, Unal O. A comparison of 99. Radi ZA, Khan NK. Effects of cyclooxygenase inhibition on effects of fluoroquinolones on fracture healing (an experi- bone, tendon, and ligament healing. Inflamm Res 2005;54: mental study in rats). Ulus Travma Acil Cerrahi Derg 100. Reikeraas O, Engebretsen L. Effects of ketoralac trometha- 119. Turner DM, Warson JS, Wirt TC, et al. The use of ketorolac in mine and indomethacin on primary and secondary bone lumbar spine surgery: a cost-benefit analysis. J Spinal Disord healing. An experimental study in rats. Arch Orthop Trauma 120. Vigorita JV. Orthopaedic pathology. 1st ed. Lippincott & 101. Reuben SS, Ablett D, Kaye R. High dose nonsteroidal anti- Wilkins. p. 85—97.
inflammatory drugs compromise spinal fusion. Can J 121. Wahlstrom O, Risto O, Djerf K, Hammerby S. Heterotopic bone formation prevented by diclofenac. Prospective study 102. Reuben SS, Ekman EF. The effect of cyclooxygenase-2 inhi- of 100 hip arthroplasties. Acta Orthop Scand 1991;62: bition on analgesia and spinal fusion. J Bone Joint Surg Am 122. Waters RV, Gamradt SC, Asnis P, et al. Systemic corticoster- 103. Reuben SS, Fingeroth R, Krushell R, Maciolek H. Evaluation oids inhibit bone healing in a rabbit ulnar osteotomy model.
of the safety and efficacy of the perioperative administra- Acta Orthop Scand 2000;71:316—21.
tion of rofecoxib for total knee arthroplasty. J Arthroplasty 123. Weinstein RS, Jilka RL, Parfitt AM, Manolagas SC. Inhibition of osteoblastogenesis and promotion of apoptosis of osteo- 104. Riew KD, Long J, Rhee J, et al. Time-dependent inhibitory blasts and osteocytes by glucocorticoids. Potential mechan- effects of indomethacin on spinal fusion. J Bone Joint Surg isms of their deleterious effects on bone. J Clin Invest Am 2003;85:632—4.
I. Pountos et al.
124. Weiss R, Ickowich M. The influence of cortisone on the 126. Wurnig C, Schwameis E, Bitzan P, Kainberger F. Six-year healing of experimental fractures in rats. Acta Anat (Basel) results of a cementless stem with prophylaxis against heterotopic bone. Clin Orthop Relat Res 1999;361: 125. Wiancko KB, Kowalewski K. Strength of callus in fractured humerus of rat treated with anti-anabolic and anabolic 127. Yamaji T, Ando K, Wolf S, et al. The effect of micromove- compounds. Acta Endocrinol (Copenh) 1961;36:310—8.
ment on callus formation. J Orthop Sci 2001;6(6):571—5.
A herbal formula, comprising panax ginseng and bee-pollen, inhibits development of testosterone-induced benign prostatic hyperplasia in male wistar rats
King Saud University Saudi Journal of Biological Sciences A herbal formula, comprising Panax ginseng andbee-pollen, inhibits development of testosterone-induced benign prostatic hyperplasia in male Wistarrats Hyun Kyung Park , Su Kang Kim ,, Sang Won Lee , Joo-Ho Chung Byung-Cheol Lee , Sae Won Na , Chun Gun Park Young Ock Kim a Kohwang Medical Research Institute, School of Medicine, Seoul 130-701, Republic of Koreab Development of Ginseng and Medical Plants Research Institute, Rural Administration, Eumseong 369-873, Republic of Koreac Department of Internal Medicine, College of Oriental Medicine, Seoul 130-702, Republic of Koread Department of Veterinary Internal Medicine, College of Veterinary Medicine, Konkuk University, Seoul, Republic of Korea
General Quality and Testing Regulations for Furniture Protection of the Environment and Personal Health Quality Assurance RAL-GZ 430 Dated: January 2016 DEUTSCHES INSTITUT FÜR GÜTESICHERUNG UND KENNZEICHNUNG E.V. Protection of the Environment and Personal Health (RAL-GZ 430) Quality and Testing Regulations for Furniture RAL-GZ 430