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George P. LYRITIS
MD, PhD
University of Athens
Laboratory for the Research
of Musculoskeletal System
KAT Hospital, Athens
GREECE
G. P. Lyritis ,Greece
Fracture healing is an extremely important biological process that is necessary for the survival of the animal. Fracture healing failure is associated with serious impairment of the locomotor systemas well as a decline in quality of life. Postfracture deformities after poor reduction of the fractured extremity, eg, leg shortening or angulations, are associated with serious functional incapacity. Fracture healing should ideally fully return bone strength to its prefracture state. Fracture healing is a unique biological event that takes a considerably long period of time to complete. A short phase of endochondral external callus formation is followed by a prolonged remodeling period. There is a danger of nonunion and possible refracture occurring during the endochondral callus formation phase. As fractures are more common in people with osteoporosis who may already be undergoing long-term treatment with antiosteoporotic medication, it is of great clinical importance to know whether these drugs have a positive or negative effect on the biological process of fracture repair. Surprisingly, the existing literature, especially clinical studies, is limited. Prospective trials in patients receiving antiosteoporotic medications prior to and/or after a fracture would be helpful, especially for orthopedic surgeons, and would aid their care of osteoporotic patients before and following fracture. In this review, the existing knowledge is presented with an emphasis on the practical issues related to the clinical applications in orthopedic surgery.
Fracture healing: a three-step process
Fracture healing is an important biological process that is necessary for the survival of the injured animal.1 Bone is a unique tissue and its repair process of great biological importance, as it aims to fully restore lamellar bone to its original condition thereby regaining initial bone strength.2 Fracture is usually understood as being the complete disruption of a long bone after a fall, but many people ignore the fact that trabecular bones, especially in osteopenic patients, may suffer microfractures, which are automatically restored by minicallus formation,3 as shown in Figure 1 (page 80). Repair of a fractured long bone typically progresses in three consequent stages.
_ Stage 1 (inflammatory phase)
This follows immediately after fracture and is associated with the activation of wound healing pathways usually observed after a soft tissue injury (bleeding, development of a hematoma with macrophages and other inflammatory cells) and the gradual development of capillary clotting.4 Several cytokines and growth factors, including transforming growth factor β (TGF-β) and vascular endothelial growth factor (VEGF), facilitate the recruitment of additional inflammatory cells and the invasion of multipotent mesenchymal stem cells from the periosteum and the bone marrow. During this stage, a primitive callus develops, reducing uncontrolled mobility at the fracture site.4 The inflammatory stage of fracture healing is fast and lasts up to a week after fracture.
Figure 1. Trabecular microfractures.
_ Stage 2 (reparative phase)
This phase starts within the first days of the inflammatory one and continues for several weeks. A gradually developing hard callus is formed—usually around the fracture site—that imitates a large internal splint around the fractured bone. The formation of the external callus is stimulated by instability at the fracture site. Micromotion enhances callus maturation and its transformation froma cartilaginous to a harder osseous model, while local strains become gradually smaller.2 The simultaneous removal from the injured area of avascular dead bone and the production of fresh bone occur during the reparative phase, with the action of cartilage and differentiated osteoblasts coming directly from precursor cells (intramembranous ossification).Within the fracture gap and at its periphery, abundant cartilage formation occurs in a manner similar to the endochondral ossification observed at the growth plate. Chondrocyte proliferation and differentiation are stimulated by the expression of growth factors including TGF-β2, platelet-derived growth factor (PDGF), insulinlike growth factor 1 (IGF-1), and some bone morphogenetic proteins (BMPs), ie, BMP-2, –4, –5, and –6).5 The reparative external callus, which is typically composed of woven bone, now connects the fragment ends, offering limited mechanical strength at the fracture site. The first two stages of fracture healing (inflammatory and reparative) and external callus formation are considered mechanisms necessary for the survival of the injured animal, which after a reasonable consolidation of the fracture can partially return to its usual activities. Of course, this solution by no means offers bone strength equal to that in the prefracture period, and the possibility of a refracture is still high. The full restoration of the initial mechanical condition occurs after a prolonged period of time through the well-known mechanism of bone remodeling. During the callus remodeling phase, woven bone is gradually replaced by lamellar bone, according to the laws of the mechanostat that Frost described many years ago.2,3
_ Stage 3 (remodeling phase)
This is a nonemergency phase and can be considered as a gradual adaptation of the fractured bone to the usual strains of everyday life. As a paradigm for the adaptive biological mechanism of fracture remodeling, we have taken the story of the restoration of the walls of the Acropolis of Athens6 following the destruction of the city during the PersianWars and their urgent rebuilding with the ruins of the walls destroyed by the Persians (Figure 2).
_ Does osteoporosis affect fracture healing?
Fractures in the osteoporotic elderly are more frequently associated with complications and invalidity during the period of rehabilitation.7 Experimental studies on the effect of osteoporosis on fracture repair in the ovariectomized rat model have shown delayed fracture healing8 and a diminution of the mechanical strength of bone after the completion of the healing process. The final outcome is the union of the fracture; nonunion is very uncommon. On the other hand, there is only anecdotal evidence that osteoporosis may delay fracture healing in humans.9 Taking into consideration that bone modeling and fracture healing have similar mechanisms and that osteoblastic modeling is usually suppressed in advanced age and in osteoporotic patients, it seems normal that fracture repair in elderly people should take longer.10 In the corticosteroid-induced osteoporosis animal model, fracture healing was found to be delayed.11 In conclusion, there is still a question mark over whether postmenopausal and senile osteoporosis affects fracture healing in humans. Nevertheless, mechanical and biological factors involved in the healing process of bone are influenced by age and osteoporosis, in the way estrogen deficiency has a biological effect on bone.12
_ Does high bone turnover affect fracture healing?
It is well known that posttraumatic osteopenia is the result of high bone turnover and that fracture healing is associated with increased biochemical bone markers, especially those of bone resorption.13 Women who have recently sustained fracture have higher levels of bone markers, in particular serum tartrate-resistant acid phosphatase 5b (S-TRACP-5b) and urine osteocalcin. Even two years after fracture, biochemical formation and resorption markers such as serum bone alkaline phosphatase and serum collagen C-telopeptide (S-CTX) are elevated, compared to prefracture period levels.13 Scintigraphy also demonstrates hot areas at fracture sites, presumably a result of existing long-term high bone turnover at the fracture site. This is a possible explanation as to why a history of preexisting fracture is an indicator of high risk for a new fracture.14
Figure 2. An ancient Greek metaphor for the inflammatory, reparative, and remodeling phases of fracture healing.
Pharmaceutical treatment of osteoporosis and its effect on fracture healing
Fractures are common in osteoporotic patients. According to epidemiologic studies, the incidence of fractures of long bones exponentially increases with age, representing a major cause of morbidity and mortality in elderly people.15 While antiosteoporotic therapies significantly lower the risk of a fracture, almost half of elderly people experience a new fracture in their lifetime.16 Fracture healing in patients already being treated is therefore a problem of clinical importance. The effect of osteoporotic therapies on fracture healing has been studied experimentally, but the existing clinical studies are rather limited. Osteoporosis treatments are nowadays classified into three groups: anticatabolic, anabolic,17 and dual action (anabolic and anticatabolic, mainly represented by strontium ranelate) categories. Each group of antiosteoporotic therapy has different mechanisms of action on bone cells, but it is true that most of them also influence other bone cells, either directly or indirectly, via the coupling phenomenon.18 Based on the characteristics of fracture repair and the type of fixation, an antiosteoporotic drug may be chosen to accelerate fracture healing, to assist the recovery of the patient, or to avoid any fracture complications. An evaluation of the complication rates after fracture fixation of the proximal femur shows that patients with suspected osteoporosis have an increased rate of refracture or fixation failure.19 While preclinical studies support the fact that pharmacological agents can augment fracture union,20 it is not clear if this translates into clinical benefit and offers patients with osteoporosis or at high risk of delayed union a better chance of fracture healing.21 To ensure that antiosteoporotic agents have a beneficial effect on fracture healing (especially for diaphyseal and metaphyseal fractures of long bones), biomechanical, histologic, and radiographic differences must be shown between individual patients and nontreated injured persons.18 This means that prospective clinical studies should be designed to demonstrate a positive medicinal effect.
_ Preclinical evaluation of the effect of osteoporosis therapies
A reduced capacity in osteoporosis to heal a fracture has been shown in several animal models. Experimental data show a 40% reduction in the cross-sectional area of fracture callus as well as a 23% reduction in bone mineral density (BMD) in healing ovariectomized rat femoral fractures.22 Mechanical properties of callus are impaired, and the fixation stability of the implants deteriorates dramatically.23 Some drugs, in particular corticosteroids, decrease the healing process remarkably.11 It would be of great interest to know the effect of osteoporosis therapies on the fracture healing process. For convenience, both preclinical and clinical data will be presented.
_ Clinical studies and experience of the effect of bisphosphonate treatment on fracture healing
Bisphosphonates have a marked inhibitory effect on osteoclasts and bone resorption, especially in the case of high bone turnover conditions. The effect of bisphosphonates on fracture healing depends on the type of substance as well as the duration and the prefracture administration dosage. In a canine model of closed, transverse radial fracture treated with alendronate, increased callus formation was found, due to slower callus formation, and no inhibition of bone formation or decrease of callus strength was observed.24 A larger callus with increased bone mineral content was also found in a sheep animal fracture model treated with pamidronate, but again no effect on the mechanical properties of the callus was detected.25 Incadronate given to growing rats with a femoral shaft fracture, which also produced a larger callus, increased stiff- ness and ultimate load of the callus, too.26 A similar effect (larger callus and increased torsional mechanical strength) was also found after the administration of ibandronate in ovariectomized rat.27 Zoledronic acid administered in rats that sustained a closed femoral fracture and that were examined using different methods (nanoindentation,28 histology,29 and biomechanical30 after local application of zoledronic acid) suffered no delay of callus formation and no effect on the mechanical properties of the callus. By the absence of interference with mechanical status, one can speculate that in animal models, different bisphosphonates do no practical harm to the fracture healing outcome, but delay endochondral ossification.31
Figure 3. The healing process in a subtrochanteric fracture.
There is a surprising lack of evidence and prospective clinical studies on fracture healing in patients treated with bisphosphonates, especially over a long period of time. One year of alendronate treatment did not alter fracture healing at the distal radius in a small group of postmenopausal osteoporotic women.32 In another small group of patients, one in 9 patients treated with alendronate who had sustained a fracture had a problem with fracture healing.33 All these 9 patients were found to have histological evidence of severe depression of bone formation. It was speculated from this small amount of evidence that alendronate treatment in osteoporotic patients who had sustained a fracture of the appendicular skeleton does not delay fracture union.34 As it is possible that bisphosphonate treatment may suppress bone turnover and promote microfracture accumulation, it is questionable whether this type of treatment can also facilitate the development of stress fractures.35 Bone microdamage is critical in the understanding of bone quality. Assessment of microdamage is technically difficult, especially in humans. The clinical impact of microdamage accumulation, potentially induced by bone drugs, has been demonstrated in experimental studies, but is still controversial in humans. In clinical practice, orthopedic surgeons with concerns about the depression of bone turnover during the period of fracture healing may wish to stop bisphosphonates in order to avoid impairment of the bone healing process. But on the other hand, initiating antiosteoporotic treatment in untreated people who have suffered a fracture could prevent consequent macrofracture.36
_ Atypical subtrochanteric fractures and bisphosphonates
During the last few years, a series of case reports have drawn our attention to an unusual type of subtrochanteric or diaphyseal femoral fracture,37-41 especially in alendronate patients. The high number of reported cases in a short period of time suggests that many similar fractures were treated previously by orthopedic surgeons, who either did not notice the association with alendronate treatment or never reported it. All these fracture have some common clinical and radiological features. The majority of the patients received alendronate for a long period of time, some of them had atypical pain in the broken thighmonths before femoral fracture, and someof them were taking additional drugs, commonly corticosteroids.41 Radiologically, all these fractures are surprisingly almost identical to unusually thick femoral cortices with a transverse fracture line and a cortical peak at the medial distal femoral fragment. Because of the longstanding preexisting femoral pain, some patients were examined and, in the prefracture radiograph, there was a suspicion of a stress fracture of the medial cortex (Figure 3). Scintigraphy in some prefracture cases also revealed a hot spot at the site of the future fracture.40 The biggest retrospective controlled study of the atypical fractures37 reports a long prefracture period with alendronate. As this category of fractures is a new scientific finding, more epidemiologic39 and laboratory studies are needed. Suppressed (frozen) bone turnover could be speculated, but high levels of active osteoclasts were detected in one case with bone biopsy at the fracture site.40
_ Effect of PTH (1-34) and strontium ranelate on fracture healing
The amino terminal active form of human parathyroid hormone (PTH [1-34], teriparatide) has an anabolic effect on both cortical and trabecular bone. Animal studies on fracture healing suggest that PTH signaling improves the biomechanical properties of fracture callus and accelerates callus formation, endochondral ossification, and bone remodeling.42,43 Based on these data, PTH (1-34) is likely to be a potent agent for enhancing fracture healing in patients with poor fracture healing potential, such as those with osteoporosis, prolonged steroid use, or recalcitrant nonunion.43 It is also recognized that daily PTH administration is an effective therapy for increasing BMD and preventing fractures in both male and female osteoporosis patients. More recently, a growing body of evidence supports the conclusion that PTH would also be an effective anabolic therapy for the enhancement of bone repair following fracture.42 Treatment with PTH results in significant increases in BMD, production of bone matrix proteins, new bone formation, and increased mechanical strength, indicating that PTH can enhance and accelerate normal fracture healing.
Several animal studies have demonstrated that PTH therapy consisting of daily subcutaneous injections during bone repair leads to increased callus volumes and a more rapid return of bone strength. Although no human clinical trial data are yet available, the role of PTH and of teriparatide in fracture healing is currently under investigation. The magnitude of the increase in the animal group treated with teriparatide was found to be two times higher than at the nonosteotomy site.42 It is difficult to extrapolate a positive effect to humans, as there is no evidence in humans suffering recent fracture and because the doses administered to animals are several times higher than the human dosage (20 ìg/day). Theoretically, its anabolic effect on bone formation could explain the significant decrease in vertebral fractures observed in clinical studies.
Strontium ranelate was found to stimulate bone formation and inhibit bone resorption.44 This dual-action (formation and resorption) medication can also be considered as a possible therapeutic agent for accelerating fracture healing and increasing itsmechanical properties. In an intact, closed femoral fracture male rat model, healing was studied radiologically and histologically. Both studies showed an increase in effect with time.45 Local application of strontium salts in implants used in fracture fixation has been suggested for fracture repair promotion.46 Prospective studies in humans are necessary to show this healing acceleration also occurs in man.18 Recently, it was reported that strontium ranelate as well as teriparatide can increase the callus volume in a closed femoral fracture experimental rat model, while callus torsional strength is improved by strontium alone.47 However, further studies are necessary to confirm these encouraging results in humans.
_ Effects of estrogen, raloxifene, and vitamin D and its analogues on fracture healing
The effect of estrogens and raloxifene on fracture healing was studied in the ovariectomized closed tibial fracture rat model. It was found that both medications improve fracture healing histologically and mechanically.48 Apart from the animal study, there is no evidence for the clinical use of estrogens and raloxifene in fracture healing in humans, especially over a prolonged period of time.
Several animal studies have shown that vitamin D3 treatment promotes both fracture healing and mechanical strength in the callus.49 However, no adequate studies on the role of vitamin D and calcium treatment in fracture healing are currently available in humans. One study focused on the healing process in osteoporotic/osteopenic fractures and investigated the potential of an oral calcium and vitamin D3 supplement at mitigating some of the problems associated with the osteoporotic fracture healing process, such as delayed or insufficient healing.50
The increase in BMD in the fracture region was interpreted as a positive impact by vitamin D3 and calcium on the fracture healing process, thanks to a higher concentration in the cellular environment of these agents. The supplement potentially facilitates osteoblasts in building Ca2+ and producing callus via an increase in the rate of osteoblast/osteoclast turnover from osteogenic cells. Despite a high concentration of calcium in the animal study, the callus had little bending strength, so it is therefore possible that although vitamin D3 and calcium increase the calcium concentration in the fracture area, it still yields brittle bone.More investigation is necessary, but it seems likely that osteoporotic women might benefit from oral calcium plus vitamin D3 supplementation during the fracture healing process.
Calcitonin is found to promote the cartilaginous phase of fracture healing.51 However, examination of the innervation of callus reveals an extensive distribution of sensory fibers containing calcitonin gene–related peptide (CGRP), a neuropeptide with potent vasodilatory actions. In a rabbit animal model with a defect of the mandible, there was a positive correlation between the expression and activity of CGRP and nitric oxide synthase (NOS) and fracture healing. It has therefore been speculated that CGRP may promote fracture healing via the regulation of the expression and activity of NOS.52
New strategies for the evaluation of antiosteoporotic treatments are needed
Therapeutic strategies for the prevention and treatment of the nontraumatic fractures, especially those of the appendicular skeleton, must seriously consider the importance of the high incidence of fracture healing delay or failure in the elderly, especially, as well as the increased incidence of refracture after a fracture. Both the disturbance of fracture healing as well as the possibility of fracture reoccurrence at the site of the mechanically immature callus are important for osteoporotic patients, especially those of advanced age. Antiosteoporosis medication enhances the healing process in general, but it is surprising that there is a lack of evidence in prospective clin- ical studies to support this notion. New studies must be designed and performed with better quality methodology18 to prove the efficacy and safety of antiosteoporotic medication in humans. The extrapolation of positive findings found in experimental studies to human biology is, in many aspects, unsafe. Dosing in experimental studies is different to that in humans, the duration of the fracture process in animals is shorter, and the side effects of drugs in humans and animals are different. Another important point is that prospective clinical studies in osteoporotic patients in the fracture repair or rehabilitation period would be helpful for the orthopedic surgeons who have to look after osteoporotic patients before and following fracture. It is well known that a history of fracture is a major risk factor for future bone injury.14 Patients with recent trauma remain under orthopedic observation and care for a considerably long period of time (up to 2 years) and may possibly undergo orthopedic intervention to remove implants. Orthopedic surgeons should therefore get seriously involved with osteoporosis and metabolic bone diseases, in general. _
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Keywords: antiosteoporotic treatment; fracture healing; bone remodeling; bisphosphonate; strontium ranelate
