Pharmacological agents and impairment of fracture healing

Injury, Int. J. Care Injured (2008) 39, 384—394

www.elsevier.com/locate/injury
REVIEW
Pharmacological agents and impairment of fracture healing: What is the evidence?
Ippokratis Pountos a, Theodora Georgouli a, Taco J. Blokhuis b, Hans Chistoph Pape c, Peter V. Giannoudis a,*
a Academic Department of Trauma & Orthopaedics, School of Medicine, University of Leeds, UK b Department of Surgery & Traumatology, University Medical Center Nijmegen, The Netherlands c Academic Department, Pittsburgh Medical School, Pittsburgh, USA
Accepted 31 October 2007

KEYWORDS Bone healing; Inhibition; Pharmacological agents

Summary 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 corticosteroids, chemotherapeutic agents, non-steroidal anti-inflammatory drugs (NSAIDs), antibiotics, anticoagulants and drugs which reduce osteoclastic activity have been shown to affect bone healing. This review article presents our current understanding on this topic, focusing on data illustrating the effect of these drugs on fracture healing and bone regeneration. # 2007 Elsevier Ltd. All rights reserved.

Contents
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385 Chemotherapy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 385 Corticosteroids . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 386 Antibiotics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 387 Anticoagulants . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388 NSAIDS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 388 Bisphosphonates . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390 Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390 Disclosure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390 Conflicts of interest . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390 References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 390

* 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: [email protected] (P.V. Giannoudis).
0020–1383/$ — see front matter # 2007 Elsevier Ltd. All rights reserved. doi:10.1016/j.injury.2007.10.035

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385

Introduction
Bone healing is one of the most complex cascades of events resulting in the repair of fractured bone without scar formation, and a final outcome that resembles the previous state of an unbroken bone.
This process involves the coordinated action of several cells types, along with signal pathways and local changes in the biochemical content. It includes a variety of biological changes, starting with disruption of blood supply, haematoma formation, local hypoxia and inflammation.27 Cytokine and growth factor release, together with pro-inflammatory stimuli, result in a high production of prostaglandins.99 This environment seems to force mesenchymal stem cells (MSCs) to migrate, accumulate and proliferate, reaching adequate numbers to support differentiation.33,98 Neovasculogenesis in association with further growth factor and prostaglandin production, promotes differentiation of MSCs towards chondrogenic or osteogenic lineages, initially forming woven bone and in continuity with the hard callus.27,38,99 Finally, this process is followed by an extended period of remodelling characterised by resorption and new bone formation resulting in restoration of mechanical strength and stability.22
The outcome of this process is regulated by a diversity of local and systemic factors with varying degrees of involvement (Table 1).7,8,11,19— 21,24,41,48,55,73,86,91,118,120,127 Local inhibitory factors include the presence of a fracture gap, disturbances of blood flow, concomitant infection and extensive soft tissue damage.7,120 The surgical technique, the type of fixation and the success of the fixation are also factors which influence the fracture healing responce.19,21,120,127 Insufficient mechanical stability has a negative effect on healing, resulting either in excessive or diminutive callus formation, leading to hypertrophic or hypotrophic non-unions.21,127 In addition, the metabolic and nutritional state of the
Table 1 Factors that affect fracture healing
 Type of the fracture 19  Fracture gap 7  Poor technique, inadequate reduction, abnormal
position 120  Type of fixation and mechanical stability of
fracture21,127  Infection and debris, dead tissue in wound 120  Extensive soft tissue damage 120  Blood supply-smoking 73  Metabolic and nutritional state of the patient11,24,48  Age and gender of the patient20,91  Early mobilisation 8  Accompanying diseases11,20,24,48  Drug administration41,55,86,118

patient, together with the age, gender, smoking and accompanying pathologies, contribute to the delay or diminution of healing.11,20,24,48,57,73,91 As far as smoking is concerned, delayed healing does not appear to be due to a direct effect of nicotine on bone cells, which was found to up-regulate their activity, but probably due to vascular responses to nicotine or due to the effect on bone cells of other components absorbed during smoking.50
Another important factor that is known to have an effect on the fracture healing process is the administration of different pharmacological agents.
The aim of this review article is to provide a brief overview of the current evidence of the inhibitory effect of various drugs on the fracture healing response.
Chemotherapy
Chemotherapeutic agents are widely used for the treatment of malignant lesions. Fracture healing and limb-salvage procedures including vascularised bone grafts, autografts and allografts are significantly affected by these drugs (Table 2).15,37,47,54,55,68,75,88,112,117 Their anti-proliferative and cytotoxic properties have a great effect on neovasculogenesis,54 proper callus formation and host bone-allograft incorporation resulting in higher non-union rates.55,59 Similarly, anti-angiogenesis agents have a detrimental effect on fracture healing and the outcome resembles atrophic non-union.54
Several animal models have illustrated the effect of chemotherapy drugs on bone healing. Studies with the use of doxorubicin, cyclophosphamide, adriamycin and methotrexate reported diminution of bone formation.15,37,112 Chemical analysis of the callus showed diminished calcium and phosphatase deposition with the use of cyclophosphamide.108 Nilsson et al. showed that the inhibitory effects of methotrexate on bone formation persisted for at least three weeks after administration.88 In an animal model of spinal fusion, a single dose of adriamycin during surgery resulted in a significant inhibitory effect on the process of fusion.117
Distraction osteogenesis could be an alternative limb-salvage procedure as it does not seem to be affected by chemotherapy agents.47,115 Alternatively, approaches with tissue-engineering with the use of MSCs could be used.73 In rats receiving chemotherapy, the application of MSCs into an experimentally induced femoral defect produced bone formation similar to the non-chemotherapy treated animals.73 Such approaches may be beneficial for treatment of bone defects in patients undergoing chemotherapy.

386

I. Pountos et al.

Table 2 Chemotherapeutic agents’ effect on fracture healing

Year/study

Model used Drug

1983/Burchardt 15

Dogs

Doxorubicin and Methotrexate

1983/Sommer-Tsilenis 112 Rats

Cyclophosphamide

1984/Nilsson 88

Rats

1984/Friedlaender37

Rats

Methotrexate Doxorubicin and Methotrexate

1992/Khoo 68 2001/Hausman 54
2001/Hazan 55 2001/Subasi 115
2003/Gravel 47 2004/Li 75

Rabbits Rats
Humans Rabbits
Goats In vitro (MSCs)

Doxorubicin
TNP-470
na Methotrexate (osteosarcoma regimen) Doxorubicine
Arsenic trioxide, Busulphan, Cyclophasphomide, Methotrexate, Cytarabine, Etoposide, Dexamentasone, Vincristine, Pacilitaxel

Outcome
 Decrease of bone formation
 Inhibition of collagen formation  Delayed mineralisation
 Inhibition of bone formation
 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
 Variability of affection
 Paclitaxel, vincristine, etoposide and cytarabine had higher degree of affection

2004/Tortolani 117 na: not available.

Rabbits

Doxorubicin

 Inhibition of spinal fusion

Corticosteroids
The effect of corticosteroids on bone metabolism has been well documented. Corticosteroids induce osteoporosis, and they are the most common cause of secondary osteoporosis. Steroid administration leads to osteoblast apoptosis, osteocyte apoptosis, and inhibition of osteoblastogenesis89,123 resulting in

a decreased bone density. The inhibitory effect of
corticosteroids on fracture healing seems logical, but
not all animal studies have shown consistent results.
A number of studies have been conducted on the
effect of corticosteroids on bone healing (Table 3).6,13,31,32,58,67,78,86,106,107,111,122,124 In the
1950s, Blunt et al. first studied the effect of corticosteroids on bone healing.13 They reported that

Table 3 The effect of steroids on fracture healing

Year/study 1951/Blunt 13

Model used Rabbits

Drug Cortisone

1951/Sissons 111

Rabbits

Cortisone

1952/Key67 1964/Weiss 124 1966/Murakami 86 1972/Ehrlich31,32 1986/Sato 106 1992/Hogevold 58
2000/Waters 122

Rats Rats Guinea pigs Rats Rats Rats
Rabbits

Cortisone Cortisone Cortisone Prednisone Dexamethasone Methylprednisolone
Prednisone

2001/Sawin 107 2002/Luppen 78
2005/Aslan 6

Rabbits Rabbits
Rats

Dexamethasone Prednisolone
Prednisone

Outcome
 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
strength  No inhibitory effect encountered

Pharmacological agents and impairment of fracture healing

387

callus formation was decreased in rabbits receiving cortisone.13 In addition, absence of periosteal bone
and abnormal histological processes were described by Sisson and Hadfield.111 Thereafter, a number of
controversial studies were published presenting dif-
ferent results. Several rat studies failed to prove any inhibitory effect,6,58,67,124 whereas others
described a detrimental effect on bone healing.56,122,125 Waters et al., in a rabbit model of
fracture healing treated with prednisone, found
decreased callus volume, decreased mineral content and weaker repair of the fracture.122 Similarly,
in an experimental model of posterolateral lumbar
spinal arthrodesis in rabbits, dexamethasone inhib-
ited graft incorporation and had a higher rate of non-union.107 In wound healing the treatment of
rats with glucocorticoids seemed to decrease the
rate of fibroblasts and collagen accumulation, and as consequence the tensile strength.31,32
The reason for these differing results is still
unknown. Jee and co-workers stated that cortisone has a dose dependant effect on bone.63 In addition,
Duthie and Barker found that endochondral ossifica-
tion was clearly retarded in rats treated with corti-
sone but membranous ossification was not affected.30 Recent data suggest that the presence
of glucocorticoid receptors GRa at osteoblasts,
chondrocytes and osteocytes might play a role in endochondral bone formation.1 Therefore, the ani-
mal model, the duration and dosage of drugs admi-
nistered as well as the traumatic extent of the
experimentally induced fracture seems to have an
effect on the outcome.

Antibiotics
Several studies support the adverse effects of antibiotics on bone healing (Table 4).3,49,53,60,69,72, 83,92,118 Cartilage is mainly affected by alteration of the process of endochondral ossification. Quinolones are thought to cause chondrocyte death and degeneration of articular cartilage resulting in fissure formation and cartilage erosions. Their use in children was discouraged by some authors due to their effects on growing cartilage,83 whereas others did not observe any osteoarticular problem or joint deformity.51 Mont et al. suggested that ciprofloxacin decreased cellular proliferation and DNA synthesis, therefore newly differentiated cells are the most affected cell types.83 Ciprofloxacin administration in rats produced diminution of fracture healing during the early stages of repair, decreased chondrocyte number and abnormalities in cartilage morphology.60 Levofloxacin and trovafloxacin had also the same adverse outcome.92
Gentamicin in high concentrations seems to decrease proliferation of osteoblastic progenitors and therefore interfere with the normal healing of bone.61 Prolonged treatment with high doses of tetracycline impairs bone growth and maturation of bone in monkeys.110 In addition, in a rat model of bone repair induced by demineralised bone both gentamycin and tetracycline inhibited new bone formation.69
Other antibiotics such as doxycycline had no effect on bone healing.3 Similarly, cephalothin and tobramycin had no effect on the osteogenic activity of allografts in guinea pigs.95

Table 4 The effect of antibiotics on fracture healing

Year/Study

Model used Drug

1971/Gudmundson 49 Mice

Oxytetracycline

1996/Mont 83

In vitro

Ciprofloxacin

2000/Huddleston 60 Rats

2002/Alkan 3

Rats

2002/Lamparter72

Rats

2003/Perry92

Rats

2004/Kim 69

Rats

2004/Haleem 53

Rats

2005/Tuncay118

Rats

Ciprofloxacin
Doxycycline Doxycycline Levofloxacin and Trovafloxacin
Gentamicin and Tetracycline Gentamicin and Vancomycin Norfloxacin, Ofloxacin, Pefloxacin and Ciproxacin

Outcome
 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
 No effect  Inhibition of matrix metalloproteinases
 Decrease in strength  Inferior quality of callus
 Decreased bone formation  No effect encountered
 Retardation of healing occurred in all fluoroquinolone treated animals
 Differences in terms of healing inhibition were encountered

388

I. Pountos et al.

Table 5 The effect of anticoagulants on fracture healing

Year/study

Model used

Drug

1955/Stinchfield 113 Rabbits and dogs Heparin and Dicumarol

1996/Muir84

Rats

Heparin

1997/Muir85 2000/Street 114 2002/Kock 70

Rats Rabbits Rabbits

Heparin and LMWH LMWH Heparin and LMWH

LMWH: low-molecular-weight heparin.

Outcome
 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

It is clear from these studies that quinolones have a detrimental effect on cartilage formation and maintenance. In addition, local application of several antibiotics delivers high concentrations of the drugs which have toxic effect on the growing bone.
Anticoagulants
The effect of anticoagulant therapy on fracture healing was first studied as early as 1955 by Stinchfield et al.113 The stimulus was a high rate of pseudoarthrosis in patients receiving postoperative anticoagulant therapy for thrombophlebitis. In their study, delayed union was observed in animals receiving anticoagulant therapy. Thereafter several authors studied the effect of anticoagulants on bone healing (Table 5).70,84,85,113,114 Several studies observed that heparin causes decreased trabecular volume through increased resorption and decreased rate of bone formation.84,85,109 This 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-phosphate dehydrogenase and of alkaline phosphatase around the fracture in rats, indicating that Vitamin K-antagonists influence the bone metabolism in fresh callus tissue.28 Street et al. showed that the administration of the newer generation anticoagulants, the low-molecular-weight heparins, resulted in the development of less mature bone with reduced torsional strength,114 but this effect was milder compared to that of heparin.85 More recent studies have not been able to reproduce the effect of LMWH on fracture healing.52,70
NSAIDS
NSAIDs are frequently used for pain relief due to their pronounced analgesic potency, anti-inflammatory effects and lesser side effects compared with

opioids.10,38,103 They also improve the quality of analgesia and decrease hospital stay.18,119
Prostaglandin E-2 (PGE-2) and Prostaglandin F-2a
(PGF-2a) are both known to stimulate bone formation and increase bone mass.62,79 A fracture leads to high local prostaglandin production and release26
and experimental models showed that local admin-
istration of exogenous prostaglandins can stimulate bone formation.64,66 In rabbits a dose-dependent stimulation of callus formation was observed.66
Our in vitro results suggested that MSCs proliferation
is not affected by the quantity of prostaglandins
present, therefore we speculate that prostaglandins
may have an effect at a later stage of bone healing.96 Furthermore, PGE-2 has been shown to reg-
ulate both BMP-2 and BMP-7 expression suggesting a
potential role in modulation of bone metabolism.5,90
Various publications using several animal
models suggested that NSAIDs, due to their effect
on prostaglandin production, correlated with
various degrees of bone healing impairment (Table 6).2,9,14,23,33,35,40—44,65,71,74,77,93,96,100—102, 104,108,116,126 They produced delayed healing,
decreased mineral content and matrix of the callus and inhibited haversian remodelling.45,100,116 In rat
models treated with NSAIDs, bone density appeared decreased,9 bone stiffness and strength were reduced9,35,36 and histological evidence of
increased fibrous tissue accumulation was apparent.34 Goodman et al. studied the effect of short-
term Cox-2 inhibitor administration after fracture on a rabbit model.44 Their results indicated that if
Cox-2 was administered in the first two weeks after
fracture the bone ingrowth was not affected. In
contrast, if Cox-2 was administered continuously
for six weeks bone ingrowth was substantially
decreased.
On the other hand, several authors demonstrated
in animal models that NSAIDS have little or no effect on fracture healing.14,40,65,93,100 It should be pointed
out that although their findings provided evidence that ketorolac,100 celecoxib,14 and parecoxib40 do

Pharmacological agents and impairment of fracture healing

389

Table 6 The effect of NSAIDs on fracture healing

Year/study 1979/Sudmann 116

Model used Drug

Rabbits

Indomethacin

1982/Elves 34

Rats

Indomethacin

1988/Davis 23 1990/Keller65 1993/Adolphson 2 1998/Reikeraas 100

Humans Rabbits Humans Rats

1998/Glassman 43 1999/Sell 108

Humans In vitro

1999/Wurnig 126

Humans

2000/Giannoudis 41 Humans

2003/Beck 9

Rats

2002/Long 77 2003/Gerstenfeld 40

Rabbits Rats

2003/Giordano 42 2003/Riew104 2004/Brown 14 2004/Goodman 44
2005/Reuben 101

Rats Rabbits Rat Rabbits
Humans

2005/Reuben 102 2005/Endo 35 2005/Persson 93

Human Rats Rats

Fluriprophen Indomethacin Piroxicam Ketorolac Trom. and Indomethacin Ketorolac Diclofenac
Indomethacin
Ibuprophen and Diclofenac Diclofenac
Celecoxib Ketorolac, Parecoxib
Tenoxicam Indomethacin Celecoxib Rofecoxib
Celecoxib, Rofecoxib and Ketorolac
Celecoxib Etodolac Indomethacin

2006/Pountos 96

In vitro

Diclofenac, Ketorolac, Parecoxib, Ketoprofen, Piroxicam, Meloxicam and Lornoxicam

Outcome
 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 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
hip arthroplasty  Increased risk for non-union
 Impaired bone healing, low bending stiffness and bone strength
 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 no effect 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 osteogenesis

2006/Krischak 71

Rats

2006/Leonelli 74

Rats

Diclofenac Rofecoxib and Ibuprophen

 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-
strate similar effects after administration of indomethacin.14,100 Indomethacin in a rat model was also
found to have no effect on bone formation on auto-

grafts but to affect bone formation in demineralised allogeneic bone matrix.93 In addition, indomethacin
was found not to influence bone growth in small
defects but its effect was proportional to the extent

390
of traumatised bone.55 Spinal fusion in rabbits was not inhibited by celecoxib.77
In humans very few data exist demonstrating a potential relationship between bone healing and NSAIDs. Davis and Ackroyd studied the effect of two weeks administration of flurbiprophen on Colles’ fractures.23 No impairment on fracture healing union was encountered. Giannoudis et al. showed a strong association between long-term NSAIDs administration and non-union development.41 In patients undergoing spinal fusion the short-term administration of either low dose of ketorolac, celecoxib and rofecoxib had no effect on the rate of non-union.101,102 High or long-term postoperative doses of NSAIDS had an increased risk of developing non-union.25,43,101 In addition, the relation between administration of NSAIDs and both osteopenia after Colles’ fracture and aseptic loosening after hip replacement was studied,.2,126 and no correlation was seen. A significant effect was found by Burd et al. in a retrospective study on patients receiving indomethacin for prevention of heterotopic bone formation in acetabular fractures.16 Patients who did not receive indomethacin had significantly fewer non-unions of associated long bone fractures than patients who received it.16
Heterotopic bone formation (HBF) after major hip surgery seems to be connected with male gender,105 operative techniques29 and idiopathic hyperostosis of the skeleton.12 NSAIDs appear to prevent this process.87 Neal et al. in a systematic survey of 13 trials reported an overall decrease of HBF of 57%.87 The duration of NSAIDs administration seems unrelated to the development of HBF. Pritchett and Gebuhr et al. administered NSAIDs for two and five days postoperatively.39,97 They reported a reduction of HBF of 48— 50%. In contrast, great variability existed in similar studies with administration of NSAIDs varying from 10 to 92 days and HBF reduction from 7 to 97%.16,17,82,121
NSAIDs have a clear benefit in everyday clinical practice, and the contradictory results from these various animal models, as well the absence of well randomised clinical data, suggest that more research should be conducted on this topic; the animal studies may not reflect the clinical setting. In addition, the exact biology of heterotopic bone formation, where NSAIDs play a preventive role, remains unclear and cannot be considered as a reflection of bone healing. We believe that clinicians should weigh up their potential risks and benefits.38

I. Pountos et al.
nates might be candidates to up-modulate bone healing.4,46 Increased mineral content, volume and strength of callus were observed in animal models after bisphosphonate administration.4,46,80,94 Although these observations have been confirmed by several studies, concern exists as some authors suggest that the arrest of bone remodelling may produce osteoporotic, weak bone.76,81 Still, the available data on the use of bisphosphonates underline their importance in the prevention of additional fractures in osteoporotic patients, who are often diagnosed after a fracture has occurred. The possible negative effects on bone remodelling do not seem to outweigh their beneficial effects at this point.
Conclusion
Intensive research is currently focused on the treatment of fractures by the application of cells, scaffolds, growth factors or by development and design of new implants. Today’s knowledge on the effect of several drugs on bone healing is characterised by inconclusive and controversial results from several animal models, together with absence of univocal clinical data. It is clear, however, that some pharmacological agents impair the bone healing process, and small changes in medication of patients can contribute to a better outcome. This should be borne in mind by all physicians involved in the treatment of bone disorders, whether dealing with fractures or degenerative diseases. Further research in the foreseeable future may allow clinicians to understand better the inhibitory effect of several pharmacological agents on the fracture healing process and the mechanisms governing bone repair and regeneration.
Disclosure
No benefits in any form have been received or will be received from a commercial party related directly or indirectly to the subject of this article. No funds were received in support of this study.
Conflicts of interest
There are no conflicts of interest.

Bisphosphonates
Bisphosphonates are widely used bone anabolic agents inhibiting bone resorption. Based on this principle, several authors suggested that bisphospho-

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