Open Access is an initiative that aims to make scientific research freely available to all. To date our community has made over 100 million downloads. It’s based on principles of collaboration, unobstructed discovery, and, most importantly, scientific progression. As PhD students, we found it difficult to access the research we needed, so we decided to create a new Open Access publisher that levels the playing field for scientists across the world. How? By making research easy to access, and puts the academic needs of the researchers before the business interests of publishers.
We are a community of more than 103,000 authors and editors from 3,291 institutions spanning 160 countries, including Nobel Prize winners and some of the world’s most-cited researchers. Publishing on IntechOpen allows authors to earn citations and find new collaborators, meaning more people see your work not only from your own field of study, but from other related fields too.
The extensive use of non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of severe pain associated with bone fractures raises concerns regarding their impact on fracture healing. While NSAIDs are favored for their anti-inflammatory properties, long-term administration has been associated with adverse effects on fracture healing. Despite the recognized risks, conflicting information exists regarding the effects of NSAIDs on fracture healing. Fracture healing is a complex process involving mechanisms of repair, including direct and indirect bone healing pathways. The inflammatory phase plays a crucial role in initiating the healing, with immune cells secreting cytokines and growth factors essential for healing. Prostaglandins, synthesized by COX enzymes, are key mediators, exerting stimulatory effects on bone formation and resorption. However, NSAIDs inhibit prostaglandin synthesis by blocking COX activity, disrupting the fracture-healing process. NSAIDs also have an inhibitory effect on the differentiation of chondrocytes into mature hypertrophied chondrocytes, crucial for endochondral ossification. Collagen X, expressed by hypertrophied chondrocytes, serves as a vital marker of fracture healing and has been implicated in the successful union of fractures. A comprehensive understanding of the interplay between NSAIDs, prostaglandins, and fracture healing mechanisms is essential for optimizing treatment strategies and minimizing adverse outcomes in patients with bone fractures.
*Address all correspondence to: shani3687@gmail.com
1. Introduction
Bone fractures are a public health issue affecting humans globally. In 2019, 178 million new fracture cases were seen globally, with an increase of 33.4%, and 455 million cases of acute or long-term symptoms of fracture were registered, which has increased to 70.1% since 1990. The chief complaint about bone fracture is chronic severe pain that results from damage to somatosensory nerve terminals, which innervates bones and muscles. For the treatment of severe pain, most used analgesics are non-steroidal anti-inflammatory drugs (NSAIDs). NSAIDs are preferred over different analgesics in fracture healing due to their anti-inflammatory effect in addition to pain relieving. However, long-term administration of NSAIDs is related to increased rates of delayed union, malunion, and non-union. Administration of NSAIDs can cause malunion, non-union, and delayed fracture healing due to inhibitory effects on cyclooxygenase-2 (COX-2) enzyme, which is essential for the synthesis of prostaglandins and interferes in the inflammatory phase of healing, which leads to an inhibitory effect on fracture healing [1, 2, 3, 4, 5, 6].
Controversial information exists regarding the effects of NSAIDs on the fracture healing process; at the same time, there is a lack of comparative information about fracture healing with the intake of non-selective COX and selective COX-2 inhibitors and localization of collagen X expressed by hypertrophied chondrocytes in the healing fracture.
The process of fracture healing occurs through a regenerative biological process that heals the loss of mechanical continuity in a bone resulting from the pathological mobility between the broken ends of a bone [7].
2.2 Factors that affect bone healing
The following factors play a vital role in bone healing process:
Delayed bone healing is seen in nutritional deficits and metabolic disorders, especially in diabetes mellitus.
Parathyroid hormones have a vital role in bone healing as they stimulate the proliferation and differentiation of osteoblasts and osteoclasts.
Aging
Infection of the fracture site delays the healing process [8].
2.3 Mechanisms of repair
The mechanism of fracture repair is divided into two categories, which are direct (primary) and indirect (secondary) bone healing, depending on differences in local motion between the fracture fragments.
2.3.1 Direct bone healing
In direct fracture healing, the cortex tries to bridge the continuity between the fracture fragments by regeneration, and this occurs only when the rigid internal fixation is established between fracture fragments. Fractured ends heal without the formation of a callus [9].
Direct healing of fractures exists through two processes: contact healing and gap healing. In both these processes, lamellar bone structure is formed between the fractured ends [10].
Contact healing occurs when the gap is less than 0.01 mm between fractured ends, and there is less than 2% of interfragmentary strain. In this process of contact healing at the ends of the osteons, cutting cones are formed, and the tips of these cutting cones cross the fracture line. These tips have osteoclasts that generate longitudinal cavities. These cavities are filled by new bone synthesized by osteoblasts, resulting in bony union and restoration of Haversian systems. The Haversian systems help in carrying osteoblasts to enter the area through blood vessels. In the end, bridging osteons mature into lamellar bone, leading to fracture healing without a callus formation [11].
In the gap healing process, the gap between fractured ends must be less than 800 μm between fractured fragments. The bone union and Haversian remodeling do not occur simultaneously. At the fracture site, a large amount of lamellar bone is present running perpendicular to the long axis, and this needs secondary reconstruction of osteonal tissue. Longitudinal revascularized osteons replace the primary bone structure and carry osteoprogenitor cells that differentiate into osteoblasts, which produce lamellar bone on each surface of the gap. This newly formed lamellar bone is laid down perpendicular to the long axis and is very weak in strength, which is then strengthened by Haversian remodeling without the formation of callus [11].
2.3.2 Indirect bone healing
Indirect fracture healing occurs due to the involvement of the periosteum and soft tissues surrounding the fracture site. This response is improved by restricted fracture fragment movement and is repressed by rigid fixation. This type of fracture healing comprises two processes: intramembranous and endochondral bone formation. Endochondral bone formation begins in a mechanically less stable region, which is near the fracture site outside the periosteum, whereas internal to the periosteum, a hard callus is formed by intramembranous ossification [12, 13].
2.4 Phases of fracture healing
The process of fracture healing comprises distinct phases, starting with an initial anabolic phase, in which local tissue size increases through inflammation and hematoma is formed (Figure 1). After hematoma formation, the inflammatory phase occurs, followed by the development of soft and hard callus, ultimately leading to bone remodeling [10].
Figure 1.
Different phases of fracture healing [14].
2.4.1 Hematoma formation
The impact force of trauma causing the fracture disturbs the normal bone structure with disruption of blood vessels at the site of contact, consequently leading to hematoma formation. The hematoma produced by vascular damage contains immune cells that migrate from the circulation and bone marrow to the injury site [15, 16].
2.4.2 Inflammatory phase
Hematoma formation triggers the early inflammatory phase, the role of which is most vital in initiating the process of the healing cascade. Inflammatory cells exert chemotactic effects and further recruit inflammatory and mesenchymal cells that are essential for fracture healing. These cells play a significant role in stimulating angiogenesis and extracellular matrix synthesis.
Inflammatory cells produce cytokines that affect fracture healing as the pro-inflammatory molecule interleukin 1(IL1) secreted by macrophages regulates the expression of cyclooxygenases (COX1 and COX2) enzymes which produce prostaglandins. During the inflammatory phase of fracture healing, inflammatory cells secrete several important growth factors including fibroblast growth factors (FGF), transforming growth factor-beta (TGF-beta), and platelet-derived growth factor (PDGF) which help and facilitate the process of fracture healing.
These factors after their secretion initiate the repair process as they promote and facilitate the stem cell proliferation and differentiation that results at the beginning of the formation of the fracture callus. Other principal factors released include tumor necrosis factor alpha, bone morphogenic protein, interleukin 6, interleukin 17F, and interleukin 23 [10, 14, 17].
2.4.3 Formation of cartilaginous callus
The next phase of fracture healing is the formation of a soft callus, also called cartilaginous callus. On a cellular level, chondrocytes and fibrocytes are predominant in the healing tissue. These cells form a soft callus (semi-solid) that provides mechanical support to the fracture. This soft callus acts as a stencil for the bony callus. Initially, the cartilaginous callus is avascular, but when the cartilaginous tissue is replaced by woven bone, vasculogenesis occurs, which results in vascular invasion of the healing tissue. The mesenchymal stem cells differentiate into chondrocytes in the central fracture area, leading to the formation of the soft callus and different growth factors expressed in soft callus including TGF-α2, PDGF, IGF-1, and BMPs. These growth factors stimulate the proliferation and differentiation of chondrocytes. The increased population of chondrocytes stabilizes the fracture zone [18, 19].
2.4.4 Formation of bony callus
The bony callus formation phase occurs after cartilaginous callus formation; chondrocytes present in the healing zone start to proliferate and mature to become hypertrophic. Chondrocytes, during the initial phase of bony callus formation, undergo a series of differentiation, leading to the formation of hypertrophic chondrocytes. This leads to an increase in the synthesis of collagen X that accumulates inside the extracellular matrix.
Mature hypertrophied chondrocytes are present adjacent to the tidemark within the deep layer of articular cartilage. COLX is a crucial factor in the successful union of fractures in the tissues going under endochondral ossification. The hypertrophic chondrocytes secrete angiogenic factors necessary for osteoclast and osteoblast recruitment, which is an essential step in bone formation.
Osteoclast acts to reabsorb the calcified matrix made by the hypertrophic chondrocytes whereas definitive bone formation is done by osteoblasts. Additional mesenchymal progenitor cells start to recruit and differentiate into osteoblasts, as chondrocytes undergo apoptosis, thus leading to the mineralization of the callus. This mineralized callus is called bony callus, which is composed of a thin layer of bone tissue around the periphery of soft callus [20, 21, 22, 23].
2.4.5 Angiogenesis and bone remodeling
New blood vessels continue to form with the action of vascular endothelial growth factor (VEGF). In the later phase, the bony callus grows through the action of osteoblasts, and bone resorption occurs by osteoclasts to reshape the callus. Both osteoblastic bone formation and osteoclastic bone resorption occur side by side, resulting in the regeneration of the original bone tissue architecture, which contains the outer cortical bone and inner trabeculae arrangement with a central space called the medullary cavity which contains the bone marrow [24].
2.5 Role of inflammatory cells in fracture healing
The key step in fracture healing is the inflammatory phase, as several immune cells are recruited to the injury site, which include neutrophils, platelets, and macrophages, and they are activated by cytokines. As immune cells invade the hematoma, they secrete cytokines and growth factors that help recruit mesenchymal cells. The growth factors (FGF, PDGF, TGFb, and FGF) and cytokines (IL-1, IL-6, and tumor necrosis factor (TNF)), which are released by inflammatory cells, influence prostaglandin production in the presence of pro-inflammatory stimuli. These cytokine and growth factors especially prostaglandins are produced by osteoblasts abundantly in fracture callus following fracture injury during the first 2 weeks [25, 26].
To understand the role of prostaglandins in bone healing process, we must know about their synthesis, mode of action, and how their inhibition affects the healing cascade in inflammatory process, which is discussed in the next section.
During the fracture healing process, prostaglandins are important lipid mediators that are synthesized by enzymes cyclooxygenase (COX-1 or COX-2) from arachidonic acid. These enzymes regulate inflammation and help in the synthesis of prostaglandins as they catalyze the early enzymatic stages. Prostaglandins are potent stimulators of bone formation as well as bone resorption. Their increased production stimulates vascular changes, chondrocyte differentiation, proliferation of osteogenic cells, and bone resorption in response to fracture. Prostaglandins increase collagen X expression with the help of bone morphogenetic protein 4 and growth/differentiation factor 5, which enhances chondrocyte growth and differentiation [27, 28, 29, 30].
3.1 Classification of prostaglandins
Prostaglandins belong to the family of eicosanoids which are composed of eicosa- (20-carbon) polyenoic fatty acids. Classes of eicosanoids comprise the prostanoid, leukotrienes (LTs), and lipoxins (LXs). Prostanoids include prostaglandins (PGs), prostacyclins (PGIs), and thromboxanes (TXs). There are four principal bioactive prostaglandins synthesized in vivo, which are prostaglandin (PG) E2 (PGE2), prostacyclin (PGI2), prostaglandin D2 (PGD2), and prostaglandin F2α (PGF2α) [31, 32].
3.2 Biosynthesis of prostaglandins
Prostaglandins are biosynthesized starting from the release of arachidonic acid from the plasma membrane phospholipids catalyzed by activated phospholipase A2 (Figure 2). Arachidonic acid is then converted to PGH2 by enzymes, cyclooxygenase, and peroxidase activities of PGH synthase, which is known as cyclooxygenase (COX) [34].
Figure 2.
Biosynthetic pathways of prostaglandins with their functions [33].
PGE2 is formed by the action of enzyme PGE synthase, PGD synthase acts to form PGD2, which is present in brain and mast cells, and prostaglandin F2α is produced by the enzyme Prostaglandin F (PGF) synthase present in the uterus. Thromboxane synthases present in platelets and macrophages act to produce thromboxane A2 and thromboxane B2, whereas prostacyclin synthase is found in endothelial cells, and prostacyclin synthase produces prostacyclin PGI2 [35].
3.2.1 Action of cyclooxygenase enzymes
Cyclooxygenase (COX) enzyme catalyzes the first two steps in the formation of prostaglandins. There are two main COX isoforms, COX-1 and COX-2. These two enzymes are the main targets of the commonly used NSAIDs, and they demonstrate the role of these enzymes in pain, fever, inflammation, and tumorigenesis. COX-1 is involved functionally in normal physiological functions, and COX-2 acts as an immediately acting agent produced rapidly induced by growth factors, oncogenes, carcinogens, and tumor-related substances [36, 37].
3.3 Functions of prostaglandins E2
Prostaglandins E2 has extensive spectrum actions on various organs, including inflammation, fracture healing, physiological bone formation, embryo implantation, vasodilation, and induction of labor. There are four G protein-coupled receptor subtypes, EP1R–EP4R (E-prostanoid receptor), which mediate the pharmacological activities of PGE2 [38].
3.3.1 Role in bone metabolism
Prostaglandin E2 plays either a stimulatory or an inhibitory role in bone metabolism, depending on the physiological or pathological conditions. Bone formation occurs in response to mechanical forces and bone fracture healing, whereas PGE2-mediated resorption contributes to bone loss in inflammatory diseases and prolonged immobilization. The binding of PGE2 to E-prostanoid receptor 2 appears to stimulate bone formation as it strongly acts on the osteoblastic lineage and stimulates bone formation, whereas PGE2 binding to E-prostanoid receptor 4 results in bone resorption due to the stimulation of osteoclast differentiation by cytokines and upregulation of the nuclear factor k-B ligand-receptor expression resulting in inhibition of osteoprotegerin expression in osteoblastic cells [39, 40].
3.4 Inhibition of prostaglandins synthesis
Prostaglandin synthesis is inhibited by the action of non-steroidal anti-inflammatory drugs (NSAIDs) as they inhibit the cyclooxygenase (COX) enzyme, which controls the biosynthesis of prostaglandins and thromboxane. The synthesis of PGE2 is inhibited by widely used non-steroidal anti-inflammatory drugs given in the treatment of inflammation, pain, and fever by blocking COX activity. Prostaglandins are essential for normal bone turnover and fracture healing. Therefore, the use of NSAIDs may affect bone healing by inhibiting the maturation of the callus [41, 42, 43].
So, the question here is why NSAIDs are still being administered in patients suffering from musculoskeletal conditions, especially in fracture healing. To answer this question, firstly, we need to understand NSAIDs and their benefits, discussed in the next section.
Non-steroidal anti-inflammatory drugs (NSAIDs) are the most common analgesics used for treating acute and chronic musculoskeletal disorders including traumas. NSAIDs decrease the increased pain threshold that is related to inflammation instead of elevating the normal pain threshold; therefore, its antinociceptive action is described as antihyperalgesic rather than analgesic [44, 45].
4.1 Classification of NSAIDs
4.1.1 Based on structure and selectivity
NSAIDs are divided into groups which are based on the chemical structure and their selectivity as non-selective, which are acetylated salicylates commonly known as aspirin, non-acetylated salicylates, acetic acids, propionic acids, which comprises naproxen, ibuprofen, diclofenac, and indomethacin, enolic acids, anthranilic acids (mefenamic acid), naphthylalanine, and selective COX-2 inhibitors (Figure 3; Table 1) [47].
Headache, dizziness, drowsiness, fatigue, and restless sleep Tinitus, Itching of skin Dizziness, rash, and tinnitus Dizziness, rash, and tinnitus Acidity, headache, and heartburn Dizziness, wheezing, and blurred vision
Anthranilic acid (fenemates)
Mefenamic acid Meclofenamic acid
500 mg daily initially, then 250 mg (6 hourly) 500 mg daily initially, then 250 mg (6 hourly)
Diarrhea, nausea, and hypertension Abdominal pain, nausea, and rash
Enolic acid derivatives (oxicams)
Piroxicam Tenoxicam Meloxicam
20 mg (6 hourly) 20 mg daily 10 mg daily
Black tarry stools, decreased urination, and severe stomach pain Headache, nausea, vomiting, and epigastric pain Headache, dizziness, and abdominal pain
Table 1.
Classification of NSAIDs according to structure.
4.1.2 Based on COX enzyme inhibition
Based on their effect on cyclooxygenase enzymes (COX-1 and COX-2), NSAIDs are classified as COX-1 selective, non-selective, COX-2 preferential, and COX-2 selective [48].
4.2 Function of NSAIDs
The main function of NSAIDs is to halt the synthesis and action of important inflammatory mediators which are synthesized during inflammation. These mediators include prostaglandins, coagulation cascade-derived peptides, interleukins (IL-2 and IL-6), and tumor necrosis factor (TNF). In the synthesis of prostaglandins, COX-1 and COX-2 are the rate-limiting enzymes that convert arachidonic acid into prostaglandins (Figure 4). So, the mechanism of NSAIDs is to act on these cyclooxygenase (COX) enzymes and inhibit them [50, 51].
Figure 4.
Schematic of the mechanism of action of NSAIDs [49].
NSAIDs not only inhibit the production of prostaglandins but also prolong the inflammatory and cartilaginous stage of bone healing by affecting the lineage of chondrocytes, which is written in detail in the following section.
5. Relation of NSAIDs and mature hypertrophied chondrocytes
5.1 Inhibitory effect on differentiation of chondrocytes
The use of NSAIDs in certain patients and in vitro studies linked with suppression of chondrocyte proliferation and differentiation [52]. The proliferation and differentiation of chondrocytes and osteoblasts is a critical component of fracture healing from the bone marrow stem cells (BMSCs).
The chondrogenic differentiation in fracture healing undergoes six phases. These phases are mesenchymal cells (chondroprogenitors), condensed mesenchymal cells, chondrocytes, proliferating chondrocytes, pre-hypertrophic chondrocytes, and hypertrophic chondrocytes. The process of chondrogenic differentiation undergoes generalized steps of chondrogenesis, cartilage hypertrophy, and ossification. For the maturation of chondrocytes into mature hypertrophied chondrocytes (MHCs), COX-2 activity is required, but NSAIDs inhibit the formation of MHCs by blocking the COX-2 enzyme (Figure 5) [21, 53].
Figure 5.
Role of COX-2 in the formation of hypertrophic chondrocytes [21].
5.2 Negative effect on expression of collagen X
5.2.1 Synthesis, structure, and location of collagen X
Mature Hypertrophied Chondrocytes synthesize collagen X in endochondral ossification. Type X collagen is present within the deep layer of articular cartilage adjacent to the tidemark. Collagen type X is a crucial factor in the successful union of fractures in the tissues going under endochondral ossification [22].
Type X collagen is non-fibrillar collagen consisting of three identical alpha 1 chains, and each chain has three domains: a short triple helix domain flanked by a bigger globular domain at the carboxyl end and a short non-collagenous domain at the amino end [54].
5.2.2 Bone healing marker
COLX is the major marker of hypertrophic chondrocytes, which can be detected within the first few days of bone formation. It plays several important roles contributing to the structural support of the pericellular network that is essential during matrix remodeling and helps in initiating biomineralization [55].
5.2.3 Effects of NSAID
The effects of NSAIDs on collagen type X expression, which is secreted by hypertrophic chondrocytes and an important marker of endochondral ossification during fracture healing, have been investigated in numerous studies. In one previous study, after administration of non-selective NSAIDs (diclofenac sodium and ketorolac) and selective COX-2 NSAIDs, low expression of collagen type X was observed as inhibition of COX enzymes negatively influenced the first phase of chondrogenic differentiation and affect chondrocyte hypertrophy [56]. In another study, a contradicted finding was observed as NSAID treatment did not affect the collagen X expression [57].
6. Relation of NSAIDs and delayed fracture healing
The administration of the NSAIDs during fracture healing can inhibit the formation of PGE2, and the mechanism of action might affect the fracture healing process. Taking into consideration the mechanism of action of NSAIDs, it can be inferred that taking NSAIDs might affect the fracture healing process. However, controversial results were observed when different studies were done on animals and humans.
6.1 Animal studies
Numerous studies have been done in the past in which different results were observed when performed on small animals with the administration of different NSAIDs (Table 2) [30].
Marginal effect with the concentrations of 2 and 10 μm but 50 μM reduced cell viability and Osteoprotegerin (OPG) secretion and stimulated oxygen consumption and GLUT-1 expression
No effect on ALP and calcium content in the absence of interleukin 1β, while in its presence, ALP and calcium were reduced only with the highest studied concentration
Several animal studies in rodents concluded the negative effect of NSAIDs on fracture repair, bone density, and strength [55]. In an animal experimental study on rat ulna, it was concluded that selective COX-2 inhibitor decreases the area of resorption along the fracture line, and non-selective NSAID administration altered the bone formation and resorption that lead to reduced length decreased remodeling and lamellar bone formation may occur [51]. In another experimental study on rat femur, fracture healing was delayed due to inhibition of COX-2 activity by selective COX-2 inhibitors [76].
Soft callus was seen in the fibula of rabbits due to an increased amount of cartilage and less amount of newly formed bone in callus, indicating delayed fracture healing when treated with non-selective and selective COX-2 inhibitors in a previous study [77]. In another study, it was appreciated that administration of COX-2 inhibitors in rats resulted in delayed healing with poorly developed callus and decreased bone strength [78].
A previous study that examined the effects of non-selective NSAIDs on bone repair in rats concluded that NSAIDs delayed or even completely inhibited fracture healing [79]. Similarly, bone healing was seen delayed with negative effects of systemic inflammation on the repair process in the mice which were given non-selective NSAIDs for 2 weeks after surgery [80].
6.1.2 No effect of NSAIDs
In contrast, in a few other animal studies, there was minor to zero effect on the fracture healing process [70, 71, 81, 82]. NSAIDs-treated groups showed no significant effect on fracture healing and remodeling in the animals [81]. The administration of NSAIDs did not affect fracture healing when given to rats after closed diaphyseal fibula fractures [73].
6.2 Human studies
Numerous previous studies have been done in humans, with the administration of different NSAIDs for certain time durations, and different results have been obtained (Table 3).
Randomized study involving 50 patients undergoing total knee replacement
Celecoxib (200 mg BD)
No differences in prosthesis migration, pain scores, range of motion, and subjective outcome were found after 2 years
Table 3.
Studies analyzing the effect of NSAIDs on bone healing in humans [30].
6.2.1 Negative effect of NSAIDs
In human studies, the administration of NSAIDs also resulted in controversial effects on the fracture healing process. In one human study, it was concluded that prolonged high-dose exposure to NSAIDs inhibits osteogenesis, leading to malunion and non-union in adults [74].
In another human retrospective study, malunion and non-union were seen in patients treated with both non-selective and selective COX-2 NSAIDs administration for more than 1 week, whereas delayed bone healing was seen in patients who had taken NSAIDs for 1 week, confirming the relationship between the duration of the treatment and fracture healing process [93].
6.2.2 No effect of NSAIDs
There are also a few studies that concluded NSAIDs have no effect on the fracture healing process. As in one previous study, no effect on fracture healing was seen between patients of Colles fracture who had been treated with ibuprofen and placebo for 2 week [94].
The conclusion drawn from the preceding discussion underscores the critical impact of non-steroidal anti-inflammatory drugs (NSAIDs), both non-selective and selective COX-2 inhibitors, on the process of fracture healing. Through their mechanism of action, these medications have been shown to detrimentally affect the expression of collagen X during the initial phases of fracture healing. This downregulation of collagen X expression is strongly associated with decreased new bone formation, leading to an increased presence of bone defects and fibrous tissue at the fracture site. As such, NSAIDs, particularly non-selective COX inhibitors, pose a significant risk to the optimal progression of bone healing.
The implications of this finding are profound, especially in clinical settings where fracture healing is of paramount importance. Patients who are administered NSAIDs, especially non-selective COX inhibitors, may experience delayed healing processes, prolonged recovery times, and increased susceptibility to complications associated with inadequate bone regeneration. It is imperative, therefore, for healthcare providers to exercise caution when prescribing NSAIDs, particularly in individuals deemed to be at considerable risk for impaired bone healing.
Furthermore, this conclusion underscores the need for a nuanced approach to pain management in patients with fractures, particularly in those who are vulnerable to compromised bone healing. While NSAIDs are often prescribed for their analgesic and anti-inflammatory properties, their potential adverse effects on bone metabolism and healing cannot be overlooked. Healthcare providers must weigh the benefits of pain relief against the potential risks of impaired fracture healing when making treatment decisions for their patients.
Considering these findings, it is recommended that alternative pain management strategies be considered for patients at risk of impaired bone healing. This may include the use of alternative analgesic medications or adjunctive therapies that do not interfere with the process of bone regeneration.
Additionally, close monitoring of patients who require NSAID therapy for other medical conditions is essential to promptly detect any signs of delayed fracture healing. Moving forward, further research is warranted to elucidate the precise mechanisms by which NSAIDs modulate fracture healing and to identify potential strategies to mitigate their adverse effects. A better understanding of these mechanisms will enable healthcare providers to optimize pain management strategies while minimizing the risk of impaired bone healing in vulnerable patient populations.
In the end, the use of non-selective and selective COX-2 NSAIDs has been shown to negatively impact fracture healing by decreasing the expression of collagen X and impairing new bone formation. Healthcare providers must exercise caution when prescribing NSAIDs, particularly in patients at risk of impaired bone healing. Alternative pain management strategies should be considered, and close monitoring of patients receiving NSAID therapy is essential to ensure optimal outcomes in fracture healing. Further research is needed to elucidate the underlying mechanisms and develop targeted interventions to mitigate the adverse effects of NSAIDs on bone healing.
References
1.McVeigh LG et al. Assessment, quantification, and Management of Fracture Pain: From animals to the clinic. Current Osteoporosis Reports. 2020;18(5):460-470. DOI: 10.1007/s11914-020-00617-z
2.Murphy PB et al. Efficacy and safety of non-steroidal anti-inflammatory drugs (NSAIDs) for the treatment of acute pain after orthopedic trauma: A practice management guideline from the eastern Association for the Surgery of trauma and the orthopedic trauma association. Trauma Surgery & Acute Care Open. 2023;8(1):e001056. DOI: 10.1136/tsaco-2022-001056
3.Peng J et al. Bulleyaconitine a reduces fracture-induced pain and promotes fracture healing in mice. Frontiers in Pharmacology. 2023;14:1046514. DOI: 10.3389/fphar.2023.1046514
4.Wibowo H, Widiyanti P. The effect of diclofenac sodium on callus formation in white male rat (Rattus norvegicus) cruris fracture healing. Journal of Folia Medica Indonesiana. 2022;58(2):108-112. DOI: 10.20473/fmi.v58i2.25212
5.Wu A-M et al. Global, regional, and national burden of bone fractures in 204 countries and territories, 1990-2019: A systematic analysis from the global burden of disease study 2019. The Lancet. 2021;2(9):e580-e592. DOI: 10.1016/S2666-7568(21)00172-0
6.Zhao Y et al. Chronic pain after bone fracture: Current insights into molecular mechanisms and therapeutic strategies. Brain Sciences. 2022;12(8):1056. DOI: 10.3390/brainsci12081056
7.Shenoy R, Pillai A. Biology of fracture healing-an overview. Journal of Thoracic Oncology. 2017;05(2):283-293. Available from: www.researchgate.net/publication/318573942_Biology_of_fracture_healing__an_overview
8.Kostenuik P, Mirza FM. Fracture healing physiology and the quest for therapies for delayed healing and nonunion. Journal of Orthopaedic Research. 2017;35(2):213-223. DOI: 10.1002/jor.23460
9.Bigham-Sadegh A, Oryan A. Basic concepts regarding fracture healing and the current options and future directions in managing bone fractures. International Wound Journal. 2015;12(3):238-247. DOI: 10.1111/iwj.12231
10.Ghiasi MS et al. Bone fracture healing in mechanobiological modeling: A review of principles and methods. Bone Reports. 2017;6:87-100. DOI: 10.1016/j.bonr.2017.03.002
11.Marsell R, Einhorn TA. The biology of fracture healing. Injury. 2011;42(6):551-555. DOI: 10.1016/j.injury.2011.03.031
12.Ghimire S et al. The investigation of bone fracture healing under intramembranous and endochondral ossification. Bone Reports. 2021;14:100740. DOI: 10.1016/j.bonr.2020.100740
13.Wang W, Yeung KWK. Bone grafts and biomaterials substitutes for bone defect repair: A review. Bioactive Materials. 2017;2(4):224-247. DOI: 10.1016/j.bioactmat.2017.05.007
14.Bahney CS et al. Cellular biology of fracture healing. Journal of Orthopaedic Research. 2019;37(1):35-50. DOI: 10.1002/jor.24170
15.Auer JA, Stick JA. Equine Surgery-E-Book. Elsevier Health Sciences; 2018. DOI: 10.1111/j.1751-0813.2012.00923.x. Available from: https://www.academia.edu/43994994/Equine_Surgery
16.Kolar P et al. The early fracture hematoma and its potential role in fracture healing. Tissue Engineering Part B: Reviews. 2010;16(4):427-434. DOI: 10.1089/ten.TEB.2009.0687
17.Ho-Shui-Ling A et al. Bone regeneration strategies: Engineered scaffolds, bioactive molecules and stem cells current stage and future perspectives. Biomaterials. 2018;180:143-162. DOI: 10.1016/j.biomaterials.2018.07.017
18.Oryan A, Monazzah S, Bigham-Sadegh A. Bone injury and fracture healing biology. Biomedical and Environmental Sciences. 2015;28(1):57-71. DOI: 10.3967/bes2015.006
19.Schindeler A et al. Bone remodeling during fracture repair: The cellular picture. Seminars in Cell & Developmental Biology. 2008;19(5):459-466. DOI: 10.1016/j.semcdb.2008.07.004
20.Bahrambeigi S et al. Metformin; an old antidiabetic drug with new potentials in bone disorders. Biomedical and Pharmacology Journal. 2019;109:1593-1601. DOI: 10.1016/j.biopha.2018.11.032
21.Su B, O’Connor JP. NSAID therapy effects on healing of bone, tendon, and the enthesis. Journal of Applied Physiology. 2013;115(6):892-899. DOI: 10.1152/japplphysiol.00053.2013
22.Topping RE, Bolander ME, Balian G. Type X collagen in fracture callus and the effects of experimental diabetes. Clinical Orthopaedics and Related Research. 1994;308:220-228. DOI: 10.1097/00003086-199411000-00032
23.Yang L et al. Hypertrophic chondrocytes can become osteoblasts and osteocytes in endochondral bone formation. Proceedings of the National Academy of Sciences. 2014;111(33):12097-12102. DOI: 10.1073/pnas.1302703111
24.Runyan CM, Gabrick KS. Biology of bone formation, fracture healing, and distraction osteogenesis. The Journal of Craniofacial Surgery. 2017;28(5):1380-1389. DOI: 10.1097/SCS.0000000000003625
25.Baht GS, Vi L, Alman BA. The role of the immune cells in fracture healing. Current Osteoporosis Reports. 2018;16(2):138-145. DOI: 10.1007/s11914-018-0423-2
26.Poniatowski Ł, A., et al., Transforming growth factor beta family: Insight into the role of growth factors in regulation of fracture healing biology and potential clinical applications. Mediators of Inflammation, 2015. 2015: p. 137823. DOI: 10.1155/2015/137823
27.Dekel S, Lenthall G, Francis M. Release of prostaglandins from bone and muscle after tibial fracture. An experimental study in rabbits. Journal of Bone and Joint Surgery. 1981;63(2):185-189. DOI: 10.1302/0301-620X.63B2.7217139
28.Hatakeyama Y, Tuan RS, Shum L. Distinct functions of BMP4 and GDF5 in the regulation of chondrogenesis. Journal of Cellular Biochemistry. 2004;91(6):1204-1217. DOI: 10.1002/jcb.20019
29.O’Connor JP et al. Fracture healing and lipid mediators. Bonekey Reports. 2014;3:517. DOI: 10.1038/bonekey.2014.12
30.Pountos I et al. Do nonsteroidal anti-inflammatory drugs affect bone healing? A critical analysis. Scientific World Journal. 2012;2012:606404. DOI: 10.1100/2012/606404
31.Mayes PA, Botham KM. Lipids of physiologic significance 14. In: Harper’s Illustrated Biochemistry. Lange; 2003. p. 111. Available from: https://www.academia.edu/41472638/Harpers_Illustrated_Biochemistry_a_LANGE_medical_book_twenty_sixth_edition_Medical_Publishing_Division
32.Ricciotti E, FitzGerald GA. Prostaglandins and inflammation. Arteriosclerosis, Thrombosis, and Vascular Biology. 2011;31(5):986-1000. DOI: 10.1161/ATVBAHA.110.207449
33.Graham S et al. Prostaglandin EP2 and EP4 receptor agonists in bone formation and bone healing: In vivo and in vitro evidence. Expert Opinion on Investigational Drugs. 2009;18(6):749-766. DOI: 10.1517/13543780902893051
34.Hubich A, Sholukh MJB. Biochemistry of prostaglandins A. Biochemistry (Mosc.). 2006;71(3):229-238. DOI: 10.1134/s0006297906030011
35.Funk CD. Prostaglandins and leukotrienes: Advances in eicosanoid biology. Science. 2001;294(5548):1871-1875. DOI: 10.1126/science.294.5548.1871
36.Rouzer CA, Marnett LJ. Cyclooxygenases: Structural and functional insights. Journal of Lipid Research. 2009;50 Suppl(Suppl):S29-S34. DOI: 10.1194/jlr.R800042-JLR200
37.Sales KJ, Jabbour HN. Cyclooxygenase enzymes and prostaglandins in pathology of the endometrium. Reproduction. 2003;126(5):559-567. DOI: 10.1530/rep.0.1260559
38.Li M, Thompson DD, Paralkar VM. Prostaglandin E(2) receptors in bone formation. International Orthopaedics. 2007;31(6):767-772. DOI: 10.1007/s00264-007-0406-x
39.Fracon RN et al. Prostaglandins and bone: Potential risks and benefits related to the use of nonsteroidal anti-inflammatory drugs in clinical dentistry. Journal of Oral Science. 2008;50(3):247-252. DOI: 10.2334/josnusd.50.247
40.Geusens P et al. NSAIDs and fracture healing. Current Opinion in Rheumatology. 2013;25(4):524-531. DOI: 10.1097/BOR.0b013e32836200b8
41.Bacchi S et al. Clinical pharmacology of non-steroidal anti-inflammatory drugs: A review. Anti-Inflammatory & Anti-Allergy Agents in Medicinal Chemistry. 2012;11(1):52-64. DOI: 10.2174/187152312803476255
42.Chen L. Current trends in PGE2 targeting for anti-inflammatory therapy. Pharmaceutical Bioprocessing. 2016;4(3):52-53. Available from: https://www.openaccessjournals.com/articles/current-trends-in-pge2-targeting-for-antiinflammatory-therapy.html
43.Wheeler P, Batt ME. Do non-steroidal anti-inflammatory drugs adversely affect stress fracture healing? A short review. British Journal of Sports Medicine. 2005;39(2):65-69. DOI: 10.1136/bjsm.2004.012492
44.Burian M, Geisslinger G. COX-dependent mechanisms involved in the antinociceptive action of NSAIDs at central and peripheral sites. Pharmacology & Therapeutics. 2005;107(2):139-154. DOI: 10.1016/j.pharmthera.2005.02.004
45.Tomić M et al. Chapter 1 - clinical uses of nonsteroidal anti-inflammatory drugs (NSAIDs) and potential benefits of NSAIDs modified-release preparations. In: Čalija B, editor. Microsized and Nanosized Carriers for Nonsteroidal Anti-Inflammatory Drugs. Boston: Academic Press; 2017. pp. 1-29. DOI: 10.1016/B978-0-12-804017-1.00001-7
46.Rao CV, Reddy BS. NSAIDs and chemoprevention. Current Cancer Drug Targets. 2004;4(1):29-42. DOI: 10.2174/1568009043481632
47.Ghlichloo I, Gerriets V. Nonsteroidal Anti-Inflammatory Drugs (NSAIDs). Treasure Island (FL): StatPearls Publishing LLC; 2022. Available from: https://www.ncbi.nlm.nih.gov/books/NBK547742/
48.Prior C, Eisen D, Herlands L. Use of NSAIDs for Prevention and Treatment of Cellular Abnormalities of the Female Reproductive Tract. World Intellectual Property Organization. Google Patents; 2003, Available from: https://patents.google.com/patent/US20030004143A1/en; https://patentscope.wipo.int/search/docs2/pct/WO2002085327/pdf/Mbg6jVcvLeByL7V3VzkmedZKlh89dRevNCf6f7TWv38
49.Ishiguro H, Kawahara T. Nonsteroidal anti-inflammatory drugs and prostatic diseases. BioMed Research International. 2014;2014:436123. DOI: 10.1155/2014/436123
50.Gunaydin C, Bilge SS. Effects of nonsteroidal anti-inflammatory drugs at the molecular level. The Eurasian Journal of Medicine. 2018;50(2):116-121. DOI: 10.5152/eurasianjmed.2018.0010
51.Kidd LJ et al. Selective and non-selective cyclooxygenase inhibitors delay stress fracture healing in the rat ulna. Journal of Orthopaedic Research. 2013;31(2):235-242. DOI: 10.1002/jor.22203
52.Karaarslan N et al. Effect of naproxen on proliferation and differentiation of primary cell cultures isolated from human cartilage tissue. Experimental and Therapeutic Medicine. 2018;16(3):1647-1654. DOI: 10.3892/etm.2018.6351
53.Jin F et al. The role of chondrocytes in fracture healing. Journal of Spine. 2016;5(4):1-8. DOI: 10.4172/2165-7939.1000328
54.He Y et al. Type X collagen levels are elevated in serum from human osteoarthritis patients and associated with biomarkers of cartilage degradation and inflammation. BMC Musculoskeletal Disorders. 2014;15(1):1-10. DOI: 10.1186/1471-2474-15-309
55.Knuth C et al. Collagen type X is essential for successful mesenchymal stem cell-mediated cartilage formation and subsequent endochondral ossification. European Journal of Cell Biology. 2019;38:106-122. DOI: 10.22203/eCM.v038a09
56.Merkely G et al. Do nonsteroidal anti-inflammatory drugs have a deleterious effect on cartilage repair? A systematic review. Cartilage. 2021;13(1_suppl):326s-341s. DOI: 10.1177/1947603519855770
57.Kalaszczynska I, Ferdyn K. Wharton’s jelly derived mesenchymal stem cells: Future of regenerative medicine? Recent findings and clinical significance. BioMed Research International. 2015;2015:430847. DOI: 10.1155/2015/430847
58.Tornkvist B et al. Lack of effect of indomethacin on mesenchymal limb-bud cells in vitro. Acta Orthopaedica Scandinavica. 1984;55(3):378-380. DOI: 10.3109/17453678408992379
59.Ho ML et al. Effects of nonsteroidal anti-inflammatory drugs and prostaglandins on osteoblastic functions. Biochemical Pharmacology. 1999;58(6):983-990. DOI: 10.1016/s0006-2952(99)00186-0
60.Evans CE, Butcher C. The influence on human osteoblasts in vitro of non-steroidal anti-inflammatory drugs which act on different cyclooxygenase enzymes. The Journal of Bone and Joint Surgery. British Volume. 2004;86(3):444-449. DOI: 10.1302/0301-620X.86B3.14592
61.Wang JL et al. Effect of celecoxib on Ca2+ movement and cell proliferation in human osteoblasts. Biochemical Pharmacology. 2004;67(6):1123-1130. DOI: 10.1016/j.bcp.2003.11.004
62.Chang JK et al. Nonsteroidal anti-inflammatory drug effects on osteoblastic cell cycle, cytotoxicity, and cell death. Connective Tissue Research. 2005;46(4-5):200-210. DOI: 10.1080/03008200500344025
63.Wang Y et al. Growth inhibition of mesenchymal stem cells by aspirin: Involvement of the WNT/beta-catenin signal pathway. Clinical and Experimental Pharmacology and Physiology. 2006;33(8):696-701. DOI: 10.1111/j.1440-1681.2006.04432.x
64.Wiontzek M et al. Effects of dexamethasone and celecoxib on calcium homeostasis and expression of cyclooxygenase-2 mRNA in MG-63 human osteosarcoma cells. Clinical and Experimental Rheumatology. 2006;24(4):366-372. Available from: https://www.clinexprheumatol.org/article.asp?a=2889
65.Wolfesberger B et al. In vitro effects of meloxicam with or without doxorubicin on canine osteosarcoma cells. Journal of Veterinary Pharmacology and Therapeutics. 2006;29(1):15-23. DOI: 10.1111/j.1365-2885.2006.00704.x
66.Chang JK et al. Effects of anti-inflammatory drugs on proliferation, cytotoxicity and osteogenesis in bone marrow mesenchymal stem cells. Biochemical Pharmacology. 2007;74(9):1371-1382. DOI: 10.1016/j.bcp.2007.06.047
67.Kellinsalmi M et al. Inhibition of cyclooxygenase-2 down-regulates osteoclast and osteoblast differentiation and favours adipocyte formation in vitro. European Journal of Pharmacology. 2007;572(2-3):102-110. DOI: 10.1016/j.ejphar.2007.06.030
68.Arpornmaeklong P, Akarawatcharangura B, Pripatnanont P. Factors influencing effects of specific COX-2 inhibitor NSAIDs on growth and differentiation of mouse osteoblasts on titanium surfaces. The International Journal of Oral & Maxillofacial Implants. 2008;23(6):1071-1081. Available from: http://medlib.yu.ac.kr/eur_j_oph/ijom/IJOMI/ijomi_23_1071.pdf
69.Abukawa H et al. Effect of ibuprofen on osteoblast differentiation of porcine bone marrow-derived progenitor cells. Journal of Oral and Maxillofacial Surgery. 2009;67(11):2412-2417. DOI: 10.1016/j.joms.2009.05.434
70.Hak DJ et al. The effect of cox-2 specific inhibition on direct fracture healing in the rabbit tibia. Journal of Orthopaedic Science. 2011;16(1):93-98. DOI: 10.1007/s00776-010-0016-0
71.Karachalios T et al. The effects of the short-term administration of low therapeutic doses of anti-COX-2 agents on the healing of fractures: An experimental study in rabbits. Journal of Bone and Joint Surgery. 2007;89(9):1253-1260. DOI: 10.1302/0301-620X.89B9.19050
72.Al-Waeli H et al. Non-steroidal anti-inflammatory drugs and bone healing in animal models-a systematic review and meta-analysis. Systematic Reviews. 2021;10(1):201. DOI: 10.1186/s13643-021-01690-w
73.Inal S et al. Comparison of the effects of dexketoprofen trometamol, meloxicam and diclofenac sodium on fibular fracture healing, kidney and liver: An experimental rat model. Injury. 2014;45(3):494-500. DOI: 10.1016/j.injury.2013.10.002
74.Wheatley BM et al. Effect of NSAIDs on bone healing rates: A meta-analysis. The Journal of the American Academy of Orthopaedic Surgeons. 2019;27(7):e330-e336. DOI: 10.5435/JAAOS-D-17-00727
75.Pountos I et al. NSAIDS inhibit in vitro MSC chondrogenesis but not osteogenesis: Implications for mechanism of bone formation inhibition in man. Journal of Cellular and Molecular Medicine. 2011;15(3):525-534. DOI: 10.1111/j.1582-4934.2010.01006.x
76.Simon AM, Manigrasso MB, O’Connor JP. Cyclo-oxygenase 2 function is essential for bone fracture healing. Journal of Bone and Mineral Research. 2002;17(6):963-976. DOI: 10.1359/jbmr.2002.17.6.963
77.O’Connor JP et al. A comparison of the effects of ibuprofen and rofecoxib on rabbit fibula osteotomy healing. Acta Orthopaedica. 2009;80(5):597-605. DOI: 10.3109/17453670903316769
78.Herbenick MA et al. Effects of a cyclooxygenase 2 inhibitor on fracture healing in a rat model. The American Journal of Orthopedics. 2008;37(7):E133-E137. Available from: https://cdn.mdedge.com/files/s3fs-public/Document/September-2017/037070133e.pdf
79.Lu LY et al. Pro-inflammatory M1 macrophages promote osteogenesis by mesenchymal stem cells via the COX-2-prostaglandin E2 pathway. Journal of Orthopaedic Research. 2017;35(11):2378-2385. DOI: 10.1002/jor.23553
80.Ramirez-Garcia-Luna JL et al. Defective bone repair in diclofenac treated C57Bl6 mice with and without lipopolysaccharide induced systemic inflammation. Journal of Cellular Physiology. 2019;234(3):3078-3087. DOI: 10.1002/jcp.27128
81.Brown KM et al. Effect of COX-2-specific inhibition on fracture-healing in the rat femur. Journal of Bone and Joint Surgery. 2004;86(1):116-123. DOI: 10.2106/00004623-200401000-00017
82.Goodman SB et al. Temporal effects of a COX-2-selective NSAID on bone ingrowth. Journal of Biomedical Materials Research Part A. 2005;72(3):279-287. DOI: 10.1002/jbm.a.30231
83.Davis TR, Ackroyd CE. Non-steroidal anti-inflammatory agents in the management of Colles’ fractures. British Journal of Clinical Pharmacology. 1988;42(5):184-189. DOI: 10.1111/j.1742-1241.1988.tb08548.x
84.Adolphson P et al. No effects of piroxicam on osteopenia and recovery after Colles’ fracture. A randomized, double-blind, placebo-controlled, prospective trial. Archives of Orthopaedic and Trauma Surgery. 1993;112(3):127-130. DOI: 10.1007/bf00449987
86.Wurnig C et al. Six-year results of a cementless stem with prophylaxis against heterotopic bone. Clinical Orthopaedics and Related Research. 1999;8:150-158. DOI: 10.1097/00003086-199904000-00020
87.Giannoudis PV et al. Nonunion of the femoral diaphysis. The influence of reaming and nonsteroidal anti-inflammatory drugs. The Journal of Bone and Joint Surgery. 2000;82:655-658. DOI: 10.1302/0301-620x.82b5.9899
88.Bhandari M et al. Predictors of reoperation following operative management of fractures of the tibial shaft. Journal of Orthopaedic Trauma. 2003;17:353-361. DOI: 10.1097/00005131-200305000-00006
89.Burd TA et al. Heterotopic ossification prophylaxis with indomethacin increases the risk of long-bone nonunion. The Journal of Bone and Joint Surgery. 2003;85:700-705. DOI: 10.1302/0301-620X.85B5.13970
90.Sculean A et al. The effect of postsurgical administration of a selective cyclo-oxygenase-2 inhibitor on the healing of intrabony defects following treatment with enamel matrix proteins. Clinical Oral Investigations. 2003;7:108-112. DOI: 10.1007/s00784-003-0200-0
91.Bhattacharyya T et al. Nonsteroidal anti-inflammatory drugs and nonunion of humeral shaft fractures. Arthritis & Rheumatology. 2005;53:364-367. DOI: 10.1002/art.21170
92.Meunier A et al. Celecoxib does not appear to affect prosthesis fixation in total knee replacement: A randomized study using radiostereometry in 50 patients. Acta Orthopaedica. 2009;80:46-50. DOI: 10.1080/17453670902804976
93.Lisowska B, Kosson D, Domaracka K. Positives and negatives of nonsteroidal anti-inflammatory drugs in bone healing: The effects of these drugs on bone repair. Drug Design, Development and Therapy. 2018;12:1809-1814. DOI: 10.2147/DDDT.S164565
94.Aliuskevicius M, Østgaard SE, Rasmussen S. No influence of ibuprofen on bone healing after Colles’ fracture - a randomized controlled clinical trial. Injury. 2019;50(7):1309-1317. DOI: 10.1002/jor.24498
Written By
Rana Muhammad Zeeshan
Submitted: 26 February 2024Reviewed: 27 February 2024Published: 18 June 2024
Open access peer-reviewed chapter - ONLINE FIRST
