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Fracture healing in osteoporotic fractures: Is it really different?
Injury, Int. J. Care Injured (2007) 38S1, S90—S99
www.elsevier.com/locate/injury
Fracture healing in osteoporotic fractures: Basic concepts relevant to the design and Is it really different? development of the Point Contact Fixator (PC-Fix) A basic science perspective Stephan M. Perren and Joy S. Buchanan Peter Giannoudis1, Christopher Tzioupis1, Talal Almalki2, 2 Richard Buckley AO/ASIF Research Institute, Clavadelerstrasse, 7270 Davos, Switzerland
AO/ASIF Research Institute, Clavadelerstrasse, 7270 Davos, Switzerland Academic Department of Trauma & Orthopaedic Surgery, School of Medicine, University of Leeds, Leeds, UK 2 Division of Orthopaedic Trauma, University of Calgary, Canada
1
KEyWORDS:
One silly fountain; Progressive dwarves; Umpteen mats; KEyWORDS: Five silly healing, Fracture trailers; acceleration, osteoporosis, mesenchymal stem cells, growth factors
Summary1 bla bla bla bla One aardvark marries the pawnbroker, even though five bourgeois cats tickled umpteen Macintoshes, but two obese elephants drunkenly towed umpteen almost irascible sheep. Two bureaux easily telephoned Paul, even 1 wart though Summary the Osteoporosis hogs gossips, is a major but onehealth elephant problem tastescharacterized partly putridby wart comprohogs, because mised bone umpteen strength purple thatbotulisms predisposes kisses patients Mark, although to an increased the subways risk of bought fracture. one extremely Osteoporotic angst-ridden patients differ lampstand, from normal even subjects though five in bone obesemineral televisions composition, perused subways, bone mineral thencontent, five progressive and crystallinity. mats auctioned Poor bone off the quality bureau, in patients althoughwith two trailosteers oporosis grew presents up, but irascible the surgeon Jabberwockies with difficult untangles treatment fivedecisions. speedy fountains, Much effort yet one has bone mass to preserve are expected thatkisses on improving expended the trailer therapies very cleverly two irascible bureaux. cat beenran away, then and thus decrease fracture risk. Manipulation of both the local fracture environment in terms of application of growth factors, scaffolds and mesenchymal cells, and systemic administration of agents promoting bone formation and bone strength has been considered as a treatment option from which promising results have recently been reported. Surprisingly, less importance has been given to investigating fracture healing in osteoporosis. Fracture healing is a complex process of bone regeneration, involving a well-orchestrated series of biological events that follow a definable temporal and spatial sequence that may be affected by both biological factors, such as age and osteoporosis, and mechanical factors such as stability of the osteosynthesis. Current studies mainly focus on preventing osteoporotic fractures. In recent years, the literature has provided evidence of altered fracture healing in osteoporotic bone, which may have important implications in evaluating the effects of new osteoporosis treatments on fracture healing. However, the mechanics of this influence of osteoporosis on fracture healing have not yet been clarified and clinical evidence is still lacking.
Introduction Osteoporosis is a devastating disease that affects more than ten million people in the United States, with annual costs in excess of $13.5 billion [75], and is characterized by low bone mass and microarchi1
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tectural deterioration of bone structure, resulting in bone fragility and an increase in susceptibility to fracture [61]. Worldwide, 100−200 million people are at risk of an osteoporotic fracture each year. Statistics predict that by the year 2012, 25% of the European population will be over the age of 65 and by the year 2020, 52 million will be over 65-years-old in the USA [21]. Based on changing demographics and
Fracture healing of osteoporotic fractures: Is it really different?—A basic science perspective the increase in life expectancy, there will be an 89% increase in the male osteoporotic population by 2025, resulting in 800 000 hip fractures per year; in women, numbers affected will rise by 69% with up to 1.8 million hip fractures [28]. Multinational surveys of osteoporotic fracture management [68] clearly indicate that many orthopedic surgeons still neglect to identify, assess, and treat patients with fragility fractures. Osteoporosis both increases the number of atraumatic fractures and contributes to the severity of traumatic fractures. The management of these fractures is difficult due to the poor bone stock involved, and there may be problems with inadequate fixation strength (purchase) of implants used to stabilize the fracture until union occurs. In particular, fixation of fractures affecting the metaphyseal region of long bones is associated with an increased rate of complications. Various reports suggest nonunion rates of 2−10%, rates of malalignment after surgery of 4−40%, metal work failure rates of 1−10%, and reoperation rates of 3−23% [69, 72]. Research in osteoporosis has focused so far on the epidemiology, pathophysiology, diagnosis, and monitoring of the disease, as well as on its metabolic and cellular basis and the effects of novel therapeutic concepts. Significant progress has been made in each of these areas. Only recently has attention been given to the diagnosis and treatment of osteoporosis in patients who have suffered a fracture. Trauma surgeons are coming to understand that treatment of patients with osteoporotic fractures need to address the underlying osteoporosis in order to reduce the incidence of further fractures [66]. Appropriate treatment of skeletal injuries secondary to osteoporosis requires an understanding of the effect of osteoporosis on the material and structural properties of bone, the mechanisms of fracture, and the mode of fracture healing. Sufficient stabilization of fractures in the weight-bearing extremities is the primary goal of treatment. However, those fractures present unique challenges, because stabilization is frequently complicated by fixation failure [71]. The ability of a bone fracture to heal and remodel depends on the ensuing microvascular and biomechanical conditions, therefore. The musculoskeletal system and the mechanical environment play a key role in repairing, maintaining, and remodeling the material property and structural strength [15, 51, 81]. Fracture healing is a complex process during which a cascade of gene expression drives the iterative formation and resorption of various tissues, eventually leading to bone formation that bridges the broken bone ends. The rate and efficacy of fracture repair depends on a variety of factors, including those
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related to the patient (eg, age); factors resulting from trauma (severity of trauma, fracture geometry and location) and factors operating during healing (nutritional status, hormonal milieu). The decline in the capacity for fracture repair has been shown to be age related [67]. Disturbance of the development of strength within fracture calluses in the elderly has been shown in experimental rat models [22], but little is known about the causes of osteoporosis and its effect on the fracture repair process in humans [44]. The relationship between fracture healing and osteoporosis is complex. The underlying etiology (which may include aging, hypogonadism, rheumatism, thyroid and parathyroid disorders, malignancy, and mastocytosis) and the therapies commonly used for osteoporosis (estrogens, vitamin D, and bisphosphonates) may all potentially affect fracture healing. Due to these complexities, animal osteoporotic models, such as the rat, rabbit, or dog, may be more appropriate to study the effects of osteoporosis and to test drugs on the fracture repair process [60]. Clinical experience is inconsistent regarding whether bone healing is delayed in the presence of osteoporosis. Too few studies are available on the differences of bone healing in normal and osteoporotic individuals to suggest a reduced capacity for bone remodeling and bone healing in osteoporosis [11, 13, 50]. The purpose of this paper is to present the current evidence regarding the influence of osteoporosis on fracture healing.
Properties and characteristics of osteoporotic bone Bone mass and the mechanical performance of the skeleton are affected by a variety of local and systemic factors. Systemic control results from a number of calcium-regulating hormones such as parathyroid hormone, calcitonin, and vitamin D as well as growth hormone and sex hormones. Local control is exerted primarily by mechanical demands that result from gravity and the stressing of bone by muscular contraction. Many studies have shown that bone, as a tissue, adapts to these mechanical demands by producing a structure optimized for mass and geometry [22]. Mechanical properties of bone can be described at different levels from the macroscopic to the ultramicroscopic levels, and under different mechanical basic assumptions, such as heterogeneous or homogeneous and isotropic or anisotropic assumptions [36].
S92 Bone mass diminishes with increasing age as a result of changes in circulating levels of hormones, particularly decreased estrogen levels after menopause, but possibly also because of the decreased anabolic effects of mechanical loading as a result of declining levels of physical activity [57, 76]. The cellular and biochemical deficiencies related to osteoporosis lead to structural bone alterations in bone structure which profoudly affect traumatic fractures and their repair. Loss of cortical bone occurs through a decrease in bone thickness and an increase in porosity, which compromises its strength. This thinner layer of cortex neighboring plentiful cancellous bone is weaker and predisposes to lowenergy fractures. Loss of trabecular bone results in thinning, perforation, and reduced connectivity among the trabecular plates. The abundance of cancellous bone also adversely affects the fixation of osteoporotic fractures [17]. Hagiwara et al analyzed the distribution of bone density and trabecular orientation in the osteoporotic human vertebral body [28]. The results illustrated a considerably higher vertical trabecular orientation in the anterior 1/3 regions of the osteoporotic vertebral body. This finding is consistent with the higher incidence of the vertebral fracture associated with osteoporosis in the anterior part of the vertebral body (a wedge-shaped fracture) [30]. While the overall diameter of the long bones may remain the same, the ratio of cancellous to cortical bone is increased [11]. Fracture resistance is determined by the strength of the bone, which in turn depends on its geometric properties (size, shape, and connectivity), the activities of the cells in the tissue, and the material properties of the tissue [18, 41]. Osteoporotic bone is characterized not only by a reduced amount of bone, but also by modifications in the composition and structure of the affected osseous tissues [2, 54]. Raman microscopic imaging has been used recently to analyze the mineral properties of osteoporotic tissues [12]. In general, the mineral content (degree of mineralization) of osteoporotic tissues is decreased, the HA crystal size and perfection is increased, the carbonate content is increased, and the acid phosphate content is decreased [8, 9], which subsequently affects bone microarchitecture. There is a decrease in cross-linking οf subchondral bone and a thinning of trabeculae from resorption, resulting in fewer, thinner connections. Subtle reduction in the bone mass in the transverse direction increases the intensity of the trabecular orientation in the loading axis. This structural change may effectively resist loading when the direction of the loading coincides with that of the trabecular orientation. However, such structural change narrows the toler-
P Giannoudis et al able loading directions, which in turn may increase the fracture risk [9]. Bone density appears to be the major factor linked to the biomechanical functioning of osteoporotic bone. Bone cells from osteoporotic donors were found to differ in their response to cyclic strain, measured as enhanced cell proliferation and the release of transforming growth factor (TGF-b) and nitric oxide (NO) [37, 56]. These results indicate that bone cells from osteoporotic patients may be impaired in their long-term response to mechanical stress [68]. The decreased thickness and increased porosity of the cortical bone, as well as the rarefaction of the trabecular network, are partially compensated for by a higher bone diameter—as long as the bone is intact. However, these factors also dramatically affect the fixation strength (primary stability) of implants used for fracture fixation [46], the postoperative complications, and the recovery times [33]. Studies have shown that density is directly related to the strength of bone. The loss of density is seen globally, and affects both cortical and cancellous bone, with the cancellous bone being affected to a much greater degree, which places the elderly at an increased risk of fractures [2, 33, 54].
Fracture healing in osteoporotic bone: what evidence do we have? Although a plethora of information exists documenting the influence of ovariectomy οn bone mass and metabolism [34, 48, 65], very little basic science or clinical research has been conducted that documents the effects of established osteoporosis on the healing of these fractures [55, 77]. This lack is surprising considering the clinical importance of osteoporotic fractures and the wealth of information regarding osteoporotic animal models. Table 1 summarizes the most recent findings regarding the effect of osteoporosis on bone healing. Fracture healing is a complex physiological process that involves the coordinated participation of hematopoietic and immune cells within the bone marrow in conjunction with vascular and skeletal cell precursors, including mesenchymal stem cells (MSCs), that are recruited from the surrounding tissues and the circulation. Multiple factors regulate this cascade of molecular events by affecting different points in the osteoblast and chondroblast lineage through various processes such as migration, proliferation, chemotaxis, differentiation, inhibition, and extracellular protein synthesis. An understanding of the fracture healing cellular and
34 2-month-old SD rats
14 female swiss mountain sheep
Lill et al43 2003
60 7-month-old female Wistar rats
Namkung et al53 2001
1999
Model
one- and 6month-old virgin female rats of the Sprague-Dawley strain
al37
Meyer et al51 2000
Kubo et
Study
Type of fracture
group 1 seven osteoporotic sheep (mean age 7.5 * 1.5 years. group 2 seven healthy animals (mean age 4.1 * 0.7 years
group A: ovariectomy-osteoporosis group OVX+LCD group B: sham operation group SO
one week after arrival, the 6month-old animals were randomly subjected to either ovariectomy or sham surgery.
A standardized transverse midshaft tibia1 osteotomy (with a fracture gap of 3 mm) stabilized with a special external fixator for 8 weeks
open right femoral midshaft fracture created and stabilized by intramedullary pins
small hole drilled into the intercondylar notch at 8,32 and 50 weeks of age
group A: Ovariecfemoral shaft fractomy-Osteoporosis ture 3 months afgroup+LCD (OVX+F) ter ovariectomy Group B: Control+F
Intervention
Increase of in vivo bending stiffness of the callus delayed approximately 2 weeks in osteoporotic animals. A significant difference (33%) in torsional stiffness was found between the osteotomized and contralateral intact tibia in osteoporotic animals In osteoporotic animals, ex vivo bending stiffness was reduced 21%) (P = .05).
40% reduction in fracture callus cross-sectional area and a 23% reduction in bone mineral density in the healing femur of the ovx rats on day 21 (P < .01). ovx rats: fivefold decrease in the energy required to break the fracture callus, a threefold decrease in peak failure load, a twofold decrease in stiffness and a threefold decrease in stress as compared with the sx group (P < .01, respectively). delay in fracture callus healing with poor development of mature bone in the ovx rats.
Youngest group 8-week-old female rats: regained normal femoral rigidity and breaking load by 4 weeks after fracture. Middle group 31 weeks of age: 6 weeks after fracture partial restoration of rigidity and breaking load. 12 weeks after fracture, the ovariectomized rats remained significantly lower in both rigidity and breaking load. Oldest group of rats 50 weeks old: neither sham-operated nor ovariectomized rats regained normal rigidity or breaking load in their fractured femora within the 24 weeks in which they were studied. In all fractured bones, there was a significant increase in BMD over the contralateral intact femora due to the increased bone tissue and bone mineral in the fracture callus.
6 weeks post fracture radiologic, histologic and biomechanical findings of the fracture areas almost identical in both the osteoporosis group and the control group. 12 weeks post fracture, newly generated bones in the osteoporosis group showed histological osteoporotic changes and their bone mineral density on the fracture site decreased.
Results
Fracture healing of osteoporotic fractures: Is it really different?—A basic science perspective S93
36 6-month-old ovariectomized SD rats randomized into 2 groups
Qiao et al57 2005
Type of fracture
group A: ovariectomy-osteoporosis group OVX group B: sham operation group SO
group A: ovariectomy osteoporosis group group B: sham operation group
group A: ovariectomy-osteoporosis group+LCD (OVX+F) group B: Control+F
femoral shaft fracture 2 months after ovariectomy
midshaft tibia model 10 weeks after ovariectomy
fracture of the right side of the mandibular ramus 3 months after ovariectomy
group A: ovariecfemoral shaft tomy-osteoporosis fracture 3 months group OVX after ovariectomy group B: sham operation group SO
Intervention
Table 1: Preclinical studies addressing the effect of osteoporosis on fracture healing.
84 4-month-old male sprague-dawley (SD) rats randomised into two groups
60 3-month-old female wistar rats randomized into 2 groups
Wang et al75 2005
2004
Model
40 3-month-old female wistar rats randomized into 2 groups
al79
Islam et al30 2005
Xu et
Study
Decreased callus density in OVX group. Increased number of osteoclasts on the surface of osseous trabecula. The osseous trabecula became thinner and disrupted obviously in OVX group, and it became massive, thicker and closer gradually 8 weeks after fracture in SHAM group. The area of osseous trabecula in the SHAM group was bigger than that in the OVX group.
Callus bone mineral density was 12.8%, 18.0%, 17.0% lower in osteoporosis group 6, 12, 18 weeks after fracture, respectively (P<0.05); Callus failure load was 24.3%, 31.5%, 26.6%, 28.8% lower in osteoporosis group Callus failure stress was 23.9%, 33.6%, 19.1%, 24.9% lower in osteoporosis group 4, 6, 12, 18 weeks after fracture, respectively (P < .05) In osteoporosis group, endochondral bone formation was delayed, more osteoclast cells could be seen around the trabecula, and the new bone trabecula arranged loosely and irregularly
Prolonged phase of endochondral ossification, with an increased number of osteoclasts (P < .01) in the osteoporotic group. Expressions of BMP-2 and TNFα more pronounced in the osteoporotic group. Increase in the number of osteoblasts and TNFα+ cells compared with the normal control (P < .01).
Reduction in callus and bone mineral density in the healing femur and a decrease of osteoblasts expressing TGF.β1 near the bone trabecula were observed in the OVX rats 3.4 weeks after fracture. Higher content of soft callus in the OVX rats than that in the SO rats. No remarkable difference in expression and distribution of BMP-2 and bFGF between the OVX and SO groups.
Results
S94 P Giannoudis et al
Fracture healing of osteoporotic fractures: Is it really different?—A basic science perspective molecular pathways is not only critical for the future advancement of fracture treatment, but may also be informative for our further understanding of the mechanisms of skeletal growth and repair as well as the mechanisms of aging [28, 43, 49]. Many scholars have investigated the hypothesis that osteoporosis can impair fracture healing. Lindholm et al prepared a bone fracture model using rats fed with a low calcium diet, and reported that bone mineral density in the repaired tibial bone was as low as in the nonfractured bones [47]. Langeland examined the tensile strength of fractured tibial bone in female rats five or two weeks after producing fractures, and found out that neither strength nor collagen content differed significantly between ovariectomized rats and normal controls [40]. However, age-related effects in fracture healing were demonstrated by Bak and Andreassen, who found considerable delay in regaining strength of fractured limbs in older rats [3]. Li and Nishimura showed that osteopenic bone may express an altered phenotypic expression of cells associated with bone formation and noted a different composition of calcified tissue within the fracture callus of osteoporotic animals [42]. Nordsletten et al produced tibial fractures in rats with and without sciatic neurectomy and immobilized the lower extremities with casts [58]. They examined the fracture healing 25 days later, and found that callus formation was accelerated and bone mineral density was high in the neurectomy legs, but tensile strength did not differ significantly between the legs with sciatic neurectomy and those without. Recently, Hill et al reported on three-month-old rats that underwent ovariectomy and fracture six weeks later that were tested to failure in torsion at one, two, three and four weeks after fracture [31]. A statistically significant reduction in torsional strength 30 days after fracture was observed that was not present at earlier points. The researchers concluded that ovariectomy in rats impaired fracture healing and this model of osteopenia could be useful for studying treatments if end points of more than 30 days are used. Kubo et al examined the effects of estrogen deficiency and a low-calcium diet on 30-week-old Wistar female rat models that were estrogen deficient for twelve weeks prior to fracturing [39]. Tensile mechanical testing, dual energy x-ray absorptiometry, and light histology were performed. These authors reported that estrogen deficiency and low-calcium conditions did not markedly affect the early healing process, but largely affected the bones in the later period of healing. Newly generated bone formed at twelve weeks after the fracture showed histological osteoporotic changes and
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a lower mineral density in the estrogen-deficient group compared to controls [39]. Investigating the impact of age and ovariectomy on the healing of femoral fractures in a osteoporotic rat model (ovariectomy and low calcium diet), Meyer Jr et al concluded that age and ovariectomy significantly impair the process of fracture healing in female rats as judged by measurements of rigidity and breaking load in three-point bending and by accretion of mineral into the fracture callus [53]. Namkung et al have demonstrated for the first time, the influence of bone loss on the early phase of fracture healing in a rat osteoporotic model induced by ovx and LCD [55]. A significant reduction in fracture callus size, BMD, and mechanical strength was seen in osteoporotic rats three weeks post fracture, which is indicative of early failure of the repair process. Lill et al performed in vivo bending stiffness measurements and found a delay of two weeks in their osteoporotic sheep model (ovariectomy, low calcium diet, and steroids), but no difference in final strength when compared to healthy sheep [45]. They concluded that ovariectomy significantly impairs the process of fracture healing in adult animals as also judged by measurements of rigidity and breaking load in 3-point bending and by accretion of mineral into the callus. Walsh et al reported on the histological and biomechanical properties of femora fractures following a six-week estrogen-deficient state in three-monthold female CD Ι COB rats with a normal diet using a standard closed fracture mode [77]. Tensile and 4four-point bending mechanical testing resu1ts revealed a significant impairment in fracture healing in the estrogen-deficient state. Histology revealed that the estrogen-deficient fractures lag behind in healing. Wang et al aimed to evaluate the influence of osteoporosis on the middle and late periods of fracture healing in rat osteoporotic models [78]. He found a lower callus bone mineral density and callus failure stress in the osteoporosis group, in which endochondral bone formation was delayed and in which the new bone trabeculae were arranged loosely and irregularly, demonstrating an histomorphological impairment of healing. Similar results were obtained by Qiao et al who concluded that fracture healing in the presence of osteoporosis results in poor bone quality [59]. Another source of information on osteopenic bone comes from the paraplegic literature, where clinical findings on fracture healing are controversial. Rapid healing with rare nonunion has been reported in osteopenic bone of paraplegics, as well as malunion and nonunion of simple long-bone fractures [26].
S96 When performing a study using an estrogen-deficient model, there are a number οf factors to be considered that have been shown to significantly influence the level οf osteopenia [74]. Furthermore, explanations for the diversity in biomechanical findings are complicated by the marked differences in the animal models in terms of age, length οf estrogen deficiency, fracture site, and biomechanical testing conditions. This area of research warrants further study and standardization of models and endpoints used to evaluate the effects of estrogen deficiency, as well as the methods of noninvasive and invasive therapy.
Discussion Fracture healing is the most remarkable of all repair processes in the body since it results in the actual reconstitution of the injured tissue. The relation between metabolic bone disease and fracture healing depends on the role of the skeleton as a metabolic resource. Even though delayed fracture healing is not obvious in patients, the decreased healing capacity in osteoporosis is reflected in a dramatically increased failure rate of implant fixation [16]. Various theories have been proposed to attempt to delineate the underlying mechanisms of impaired fracture healing in osteoporotic fractures. Extracellular matrix metabolism plays a central role in the development of skeletal tissues and in most orthopaedic diseases and trauma such as fracture healing [25]. Specific genes must be expressed to make or repair appropriate extracellular matrix. These genes are regulated by a balance of positive and negative factors in order to exhibit a strictly restricted expression. Runx2 is a vital transcription factor for skeletal mineralization that is expressed in osteoblasts at a high level as well as in hypertrophic chondrocytes and in mesenchymal cells in the periosteum/perichondrium. It stimulates osteoblast differentiation of mesenchymal stem cells, promotes chondrocyte hypertrophy, and contributes to endothelial cell migration and vascular invasion of developing bones [79]. Homozygous Runx2-mutant mice exhibit complete arrest of osteoblast differentiation, which results in severe developmental defects of osteogenesis [38]. With the loss of ovarian estrogen, menopausal women lose trabecular bone at several sites in the skeleton, including the spine [62]. Woven bone plays a key role in fracture healing. Most of the immediate hard callus is initially formed with woven bone,
P Giannoudis et al which stabilizes the healing bone while remodeling occurs to restore the cortical bone of the diaphysis. If this woven bone is also estrogen sensitive, as is the trabecular bone in the metaphysis, then it is not unreasonable to expect ovariectomy to delay fracture healing because of impairment in bone formation. However, direct experimental evidence for this expectation is limited [53]. The inferior mechanical properties of osteoporotic bone may reflect alterations in the moment of inertia or cross-sectional area, or bonding interactions between the mineral and organic constituents of the bone matrix. The alterations in healing observed may reflect compositional differences in terms of osteoinductive molecules present in the bone matrix compounded by delayed osseous differentiation. This proposal is supported by findings that the osteoinductive capacity of demineralized bone matrix may decrease with age and in ovariectomised (ovx) rats due to an alteration in the composition of the matrix [13, 73, 77]. It has also been shown that estrogen modulates the mechano-sensitivity of bone cells. In the presence of estrogen, the expression of prostaglandin as a response to mechanical strain was significantly enhanced, which indicates that fractures in postmenopausal women may react differently to the mechanical signal that occurs during fracture repair, compared to fractures in premenopausal women or men [34]. While bone resorption can increase, formation decreases, possibly because osteoblasts decrease with age [64]. Osteoblasts originate from MSCs [6, 80] that reside in bone marrow together with hematopoietic stem cells. These two stem cell types cooperate through direct cell-to-cell interactions and release of cytokines and growth factors [4, 23]. Since osteoblast numbers might relate to progenitor numbers, D’ippolito et al [20] hypothesized that the number of MSCs (with osteogenic potential) residing in the bone marrow of human thoracic/lumbar vertebrae—a skeletal site of high turnover in bone—could be associated with age-related osteoporosis [19]. They concluded that the bone-marrow microenvironment changes with age, resulting in cell-to-cell and cell-to-matrix interactions that may be unfavorable for MSC proliferation or that may favor MSC maturation toward a different lineage (eg, adipogenic). Total marrow fat increases with age, and there is an inverse relationship between marrow adipocytes and osteoblasts with aging [6, 10]. Bergman et al [7] also concluded that defects in the number and proliferative potential of MSCs may underlie age-related defects in osteoblast number and function. Rodriguez et al showed that MSCs derived from both control and osteoporotic postmenopausal
Fracture healing of osteoporotic fractures: Is it really different?—A basic science perspective women share some functional dynamic responses but differ importantly in others [63]. Some of the differences observed, like the differential mitogenic response to IGF-1 and the diminished ability of MSCs derived from osteoporotic donors to differentiate into the osteogenic lineage, suggest that these cells have a diminished ability to produce mature bone forming cells. Furthermore, osteoporotic cells present a lower proliferation rate and exhibit a differential response to IGF-1.Thus, clinical and in vitro observations document an inverse relationship between adipocytes and osteoblasts. In osteoporotic patients, increased bone marrow adipose tissue correlates with decreased trabecular bone volume [27]. Early histomorphometric observations suggested that a change in bone cell dynamics, causing osteoporosis, is the consequence of the adipose replacement of the marrow functional cell population [52]. These findings suggest that a mechanism that could account for the decrease in bone volume, and hence mechanical strength, may result from opposing effects on differentiation of the two cell lines. The commitment to the adipocyte differentiation pathway occurs at the expense of osteoblast numbers and osteogenic function [27]. This commitment may contribute to osteoporotic bone involution but may also negatively effect bone formation during fracture healing [1].
Conclusion The highly complex process of fracture repair is still not fully understood; however, research in recent years has identified various associations between factors that affect the repair process and healing outcome. Clinical experience is inconsistent regarding a possible delay of bone healing in osteoporosis and clinical studies that confirm delayed healing in elderly people are scarce. Patient-based research regularly suffers from limitations including that no control group can be attained, that it is difficult to create homogeneous study groups, and that there are ethical limitations. As a result, experimental studies on the effect of osteoporosis on fracture healing have been carried out on ovariectomized rats. These studies have shown that ovariectomy significantly reduces bone mass and that the mechanical strength of the bone after completion of healing appears to be reduced. Furthermore, fracture healing appears to be delayed with respect to callus mineralization and biomechanical properties. However, animal models have disadvantages such
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as differences in bone metabolism compared with humans, lack of prominent decrease of bone mass after ovariectomy, and animal protection aspects. Moreover, they permit the study of interventions and new treatment procedures that might not be appropriate in patients. The mechanical and biological factors that are involved in the healing process of bone are certainly affected by age and osteoporosis. Alterations in bone metabolism, like osteoporosis, seem to delay callus maturation and consequently decelerate fracture healing. Nevertheless, it still remains an unsolved question as to whether fracture healing is impaired by osteoporosis.
Bibliography 1. Augat P, Simon U, Liedert A, Claes L. Mechanics and mechanobiology of fracture healing in normal and osteoporotic bone. Osteoporos Int. 2005 16 Suppl 2:S36−43. 2. Bailey AJ, Sims TJ, Ebbesen EN et al. Age-related changes in the biochemical properties of human cancellous bone collagen: relationship to bone strength. Calcif Tissue Int. 1999 65:203−10. 3. Bak B, Andreassen T. The effect of aging on fracture healing in the rat. Calcif Tissue Int. 1989 45:292−297. 4. Benayahu D, Horowitz M, Zipori D, Wientroub S. Hemopoietic functions of marrow-derived osteogenic cells. Calcif Tissue Int. 1992 51:195−201. 5. Beresford JN. Osteogenic stem cells and the stromal system of bone and marrow. Clin Orthop Relat Res 1989;240:270−80. 6. Beresford JN, Bennett JH, Devlin C et al. Evidence for an inverse relationship between the differentiation of adipocytic and osteogenic cells in rat marrow stromal cell cultures. J Cell Sci. 1992 102:341−51. 7. Bergman RJ, Gazit D, Kahn AJ et al. Age-related changes in osteogenic stem cells in mice. J Bone Miner Res. 1996 11:568−77. 8. Boivin GY, Chavassieux PM, Santora AC, et al. Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women. Bone. 2000 27:687−694. 9. Boskey AL, DiCarlo E, Paschalis E, et al. Comparison of mineral quality and quantity in iliac crest biopsies from high-and lowturnover osteoporosis: an FT-IR microspectroscopic investigation. Osteoporos Int. 2005 16:2031−8. 10. Burkhardt R, Kettner G, Bohm W et al. Changes in trabecular bone, hematopoiesis and bone marrow vessels in aplastic anemia, primary osteoporosis, and old age: a comparative histomorphometric study. Bone. 1987 8:157−64. 11. Burr DB, Forwood MR. Fyhrie DP, et al. Bone microdamage and skeletal fragility in osteoporotic and stress fractures. J Bone Miner Res. 1997 12:6−15. 12. Carden A, Morris MD. Application of vibrational spectroscopy to the study of mineralized tissues (review). J Biomed Opt. 2000 5:259−268.
S98 13. Cesnjai M, Stavljenic A, Vukicevic S. Decreased osteoinductive potential of bone matrix from ovariectomized rats. Acta Orthop Scand. 1991 62:471−5. 14. Chao EY, Inoue N, Koo TK, Kim YH. Biomechanical considerations of fracture treatment and bone quality maintenance in elderly patients and patients with osteoporosis. Clin Orthop Relat Res. 2004 425:12−25. 15. Cowin SC. Bone stress adaptation models. J Biomech Eng. 1993 115:528−533. 16. Cranney A, Tugwell P, Zytaruk N, et al. Osteoporosis Methodology Group and the Osteoporosis Research Advisory Group. Meta-analyses of therapies for postmenopausal osteoporosis. IV. Meta-analysis of raloxifene for the prevention and treatment of postmenopausal osteoporosis. Endocr Rev. 2002 23:524−528. 17. Currey JD, Brear K, Zioupos P. The effect of ageing and changes in mineral content in degrading the toughness of human femora. J Biomech. 1996 29:257−260. 18. Dalle-Carbonare L, Giannini S. Bone microarchitecture as an important determinant of bone strength. J Endocrinol Invest. 2004 27:99−105. 19. Delling G, Amling M. Biomechanical stability of the skeleton-it is not only bone mass, but also bone structure that counts. Nephrol Dial Transplant. 1995 10:601−6. 20. D’Ippolito G, Schiller PC, Ricordi C. Age-related osteogenic potential of mesenchymal stromal stem cells from human vertebral bone marrow. J Bone Miner Res. 1999 14:1115−1119.
P Giannoudis et al 32. Islam AA, Rasubala L, Yoshikawa H, et al. Healing of fractures in osteoporotic rat mandible shown by the expression of bone morphogenetic protein-2 and tumour necrosis factor-alpha. Br J Oral Maxillofac Surg. 2005 43:383−91. 33. Ito K, Hungerbuhler R, Wahl D, Grass R. Improved intramedullary nail interlocking in osteoporotic bone. J Orthop Trauma. 2001 15:192−6. 34. Joldersma M, Klein-Nulend J, Oleksik AM, et al. Estrogen enhances mechanical stress-induced prostaglandin production by bone cells from elderly women. Am J Physiol Endocrinol Metab. 2001 280:E436−442. 35. Kalu DN, Liu CC, Hardin RR, Hollis BW. The aged rat model of ovarian hormone deficiency bone loss. Endocrinology. 1989 124:7−16. 36. Katz JL. Anisotropy of Young’s modulus of bone. Nature. 1980 283:106−107. 37. Klein-Nulend JJ, Sterck CM, Semeins P, et al. Aging and mechanosensitivity of human bone cells. J Bone Miner Res. 1996 11:S266. 38. Komori T, Yagi H, Nomura S, et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell. 1997 89:755−764. 39. Kubo T, Shiga T, Hashimoto J. Osteoporosis influences the late period of fracture healing in a rat model prepared by ovariectomy and low calcium diet. J Steroid Biochem Mol Biol. 1999 68:197−202.
21. Dreinhofer KE. Multinational survey of osteoporotic fracture management. Osteoporos Int. 2005 16 Suppl 2:S44−53
40. Langeland N. Effects of oestradiol-17 beta benzoate treatment on fracture healing and bone collagen synthesis in female rats. Acta Endocrinol. 1975 80:603−12.
22. Ekeland A, Engesoeter LB, Langeland N. Influence of age on mechanical properties of healing fractures and intact bones in rats. Acta Orthop Scand. 1982 53:527−534.
41. Lanyon L, Armstrong V, Ong D, et al. Is estrogen receptor alpha key to controlling bones’ resistance to fracture? J Endocrinol. 2004 182:183−191.
23. Friedenstein AJ, Latzinik NV, Gorskaya YF, et al. Bone marrow stromal colony formation requires stimulation by haemopoietic cells. Bone Miner. 1992 18:199−213.
42. Li X, Nishimura I. Altered bone remodeling pattern of the residual ridge in ovariectomized rats. J Bone Miner Res. 1994 72:324−330.
24. Frost HM. The role of changes in mechanical usage set points in the pathogenesis of osteoporosis. J Bone Miner Res. 1992 7:253−261.
43. Li X, Quigg RJ, Zhou J et al. Early signals for fracture healing. Cell Biochem. 2005 95:189−205.
25. Fukui N, Zhu Y, Maloney WJ, et al. Stimulation of BMP-2 expression by pro-inflammatory cytokines IL-1 and TNF-alpha in normal and osteoarthritic chondrocytes. J Bone Joint Surg. 2003 85-A(Suppl 3):59−66. 26. Garland D. Clinical observations on fractures and heterotopic ossification in the spinal cord and traumatic brain injured populations. Clin Orthop. 1988 233:86−101. 27. Gimble JM, Robinson CE, Wu X, Kelly KA. The function of adipocytes in the bone marrow stroma: An update. Bone. 1996 19:421−428. 28. Gullberg B, Johnell 0, Kanis JA. Worldwide projections for hip fracture. Osteoporos Int. 1997 407−413 29. Hadjiargyrou M, Lombardo F, Zhao S, et al. Transcriptional profiling of bone regeneration. Insight into the molecular complexity of wound repair. J Biol Chem. 2002 277:30177−30182. 30. Hagiwara H, Inoue N, Matsuzaki H, et al. Relationship between structural anisotropy of the vertebral body and bone mineral density. Trans Orthop Res Soc. 2000 25:738. 31. Hill EL, Kraus K, Lapierre KP, et al. Ovariectomy impairs fracture healing after 21 days. Trans Orthop Res Soc. 1995 20:230.
44. Lill CA, Fluegel AK, Schneider E. Sheep model for fracture treatment in osteoporotic bone: A pilot study about different induction regimens. J Orthop Trauma. 2000 14:559−566. 45. Lill CA, Hesseln J, Schlegel U, et al. Biomechanical evaluation of healing in a non-critical defect in a large animal model of osteoporosis. J Orthop Res. 2003 21:836−842. 46. Lim TH, An HS, Evanich C, et al. Strength of anterior vertebral screw fixation in relationship to bone mineral density. J Spinal Disord. 1995 8:121−125. 47. Lindholm TS. Effects of 1alpha-hydroxycholecalciferol on osteoporotic changes induced by calcium deficiency in bone fractures in adult rats. J Trauma 1978;18:336−40. 48. Liu CC, Kalu DN. Human parathyroid hormone-(1−34) prevents bone loss and augments bone formation in sexually mature ovariectomized rats. J Bone Miner Res. 1990 5:973−82. 49. Lombardo F, Komatsu D, Hadjiargyrou M. Molecular cloning and characterization of Mustang, a novel nuclear protein expressed during skeletal development and regeneration. FASEB J. 2004 18:52−61. 50. Marie PJ, Sabbagh A, de Vernejoul MC, Lomri A. Osteocalcin and deoxyribonucleic acid synthesis in vitro and histomorphometric indices of bone formation in postmenopausal osteoporosis. J Clin Endocrinol Metab. 1989 69:272−9.
Fracture healing of osteoporotic fractures: Is it really different?—A basic science perspective
S99
51. Meadows TH, Bronk JT, Chao EYS, Kelly PJ. Effect of weight bearing on healing of cortical defects in the canine tibia. J Bone Joint Surg. 1990 72A:1074−1080.
69. Sterck JG, Klein-Nulend J, Lips P, Burger EH. Response of normal and osteoporotic human bone cells to mechanical stress in vitro. Am J Physiol. 1998 274:E1113−20.
52. Meunier PJ, Aaron J, Edouard C, Vignon C. Osteoporosis and the replacement of cell populations of the marrow by adipose tissue. Clin Orthop Rel Res. 1971 80:147−154.
70. Stover M. Distal femoral fractures: current concepts, results and problems. Injury. 2001 32(Suppl 3):3−13.
53. Meyer RA Jr, Tsahakis PJ, Martin DF. Age and ovariectomy impair both the normalization of mechanical properties and the accretion of mineral by the fracture callus in rats. J Orthop Res. 2001 19:428−35. 54. Mosekilde L. Age-related changes in bone mass, structure, and strength—effects of loading. Z Rheumatol. 2000 59 Suppl 1:1−9. 55. Namkung-Matthai H, Appleyard R, Jansen J, et al. Osteoporosis influences the early period of fracture healing in a rat osteoporotic model. Bone. 2001 28:80−6. 56. Neidlinger-Wilke C, Stall I, Claes L, Human osteoblasts from younger normal and osteoporotic donors show differences in proliferation and TGF-release in response to cyclic strain. J Biomech. 1995 28:1411−1418. 57. Nordin BEC, Need AG, Chatterton BE, et al. The relative contributions of age and years since menopause to postmenopausal bone loss. J Clin Endocrinol Metab. 1990 70:83−88. 58. Nordsletten L, Madsen JE, Almaas R et al. The neural regulation of fracture healing: effects of sciatic nerve resection in rat tibia, Acta Orthop Scand. 1994 65:299−304. 59. Qiao L, Xu KH, Liu HW, Liu HQ. Effects of ovariectomy on fracture healing in female rats. Sichuan Da Xue Xue Bao Yi Xue Ban. 2005 36:108−11. 60. Raisz LG. Local and systemic factors in the pathogenesis of osteoporosis. N Engl J Med. 1988 318:818−828. 61. Richard D, Wasnich MD. Epidermiology of osteoporosis. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. New York: Lippincott-Raven. 1996 249−251. 62. Ritzel H, Amling M, Pösl M, et al. The thickness of human vertebral cortical bone and its changes in aging and osteoporosis: A histomorphometric analysis of the complete spinal column from thirty-seven autopsy specimens. J Bone Miner Res. 1997 12:89−95. 63. Rodriguez JP, Garat S, Gajardo H et al. Abnormal osteogenesis in osteoporotic patients is reflected by altered mesenchymal stem cells dynamics. J Cell Biochem. 1999 75:414−23. 64. Roholl PJ, Blauw E, Zurcher C, et al. Evidence for a diminished maturation of preosteoblasts into osteoblasts during aging in rats: An ultrastructural analysis. J Bone Miner Res. 1994 9:355−366. 65. Salih MA, Liu CC, Arjmandi BH, Kalu DN. Estrogen modulates the mRNA levels for cancellous bone protein of ovariectomized rats. Bone Miner. 1993 23:285−99. 66. Schneider E, Goldhahn J, Burckhardt P. The challenge: fracture treatment in osteoporotic bone. Osteoporos Int. 2005 16 (Suppl 2):S1−2. 67. Silver JJ, Einhorn TA. Osteoporosis and aging: Current update. Clin Orthop. 1995 316:10−20. 68. Smith D, Enderson B, Mauli K. Trauma in the elderly: Determinants of outcome. South Med J. 1990 83: 171−177
71. Swiontkowski MF, Harrington RM, Keller TS, Van Patten PK. Torsion and bending analysis of internal fixation techniques for femoral neck fractures: the role of implant design and bone density. J Orthop Res. 1987 5:433−444. 72. Syed AA, Agarwal M, Giannoudis PV, et al. Distal femoral fractures: long term outcome following stabilisation with the LISS. Injury. 2004 35:599−607. 73. Syftestad GT, Urist MR. Bone aging. Clin Orthop. 1982 162:288−297. 74. Thompson DD, Simmons HA, Pirie CM, Ke HZ. FDA Guidelines and animal models for osteoporosis. Bone. 1995 17:125S−133S
.
75. U.S. Department of Health and Human Services. Bone Health and Osteoporosis. A report of the US Surgeon General, Rockville MD, 2004. 76. Villareal DT, Morley JE. Trophic factors in aging: should older people receive hormonal replacement therapy? Drugs Aging. 1994 4:492−509. 77. Walsh WR, Sherman P, Howlett CR, et al. Fracture healing in a rat osteopenia model. Clin Orthop Relat Res. 1997 342:218−27. 78. Wang JW, Li W, Xu SW, et al. Osteoporosis influences the middle and late periods of fracture healing in a rat osteoporotic model. Chin J Traumatol. 2005 8:111−6. 79. Westendorf JJ. Transcriptional co-repressors of Runx2. J Cell Biochem. 2006 98:54−64. 80. Wlodarski KH. Properties and origin of osteoblasts. Clin Orthop Relat Res. 1990 252:276−93. 81. Wolff J. The Law of Bone Remodelling. Translated by Maquet P, Furlong R. Berlin, Springer-Verlag 1986. 82. Xu SW, Wang JW, Li W, Wang Y, Zhao GF. Osteoporosis impairs fracture healing of tibia in a rat osteoporotic model. Zhonghua Yi Xue Za Zhi. 2004 84:1205−9.
Correspondence Address P. Giannoudis MD, EEC (ortho) Professor Academic Department of Trauma & Orthopaedics, Clarendon Wing, Floor A Leeds General Infirmary Great George Street Leeds, LS1 3EX, United Kingdom Tel: 0044-113-3922750 email: [email protected] This paper has been written entirely by the authors, and has received no external funding. The authors have no significant financial interest or other relationship.
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Fracture healing in osteoporotic fractures: Basic concepts relevant to the design and Is it really different? development of the Point Contact Fixator (PC-Fix) A basic science perspective Stephan M. Perren and Joy S. Buchanan Peter Giannoudis1, Christopher Tzioupis1, Talal Almalki2, 2 Richard Buckley AO/ASIF Research Institute, Clavadelerstrasse, 7270 Davos, Switzerland
AO/ASIF Research Institute, Clavadelerstrasse, 7270 Davos, Switzerland Academic Department of Trauma & Orthopaedic Surgery, School of Medicine, University of Leeds, Leeds, UK 2 Division of Orthopaedic Trauma, University of Calgary, Canada
1
KEyWORDS:
One silly fountain; Progressive dwarves; Umpteen mats; KEyWORDS: Five silly healing, Fracture trailers; acceleration, osteoporosis, mesenchymal stem cells, growth factors
Summary1 bla bla bla bla One aardvark marries the pawnbroker, even though five bourgeois cats tickled umpteen Macintoshes, but two obese elephants drunkenly towed umpteen almost irascible sheep. Two bureaux easily telephoned Paul, even 1 wart though Summary the Osteoporosis hogs gossips, is a major but onehealth elephant problem tastescharacterized partly putridby wart comprohogs, because mised bone umpteen strength purple thatbotulisms predisposes kisses patients Mark, although to an increased the subways risk of bought fracture. one extremely Osteoporotic angst-ridden patients differ lampstand, from normal even subjects though five in bone obesemineral televisions composition, perused subways, bone mineral thencontent, five progressive and crystallinity. mats auctioned Poor bone off the quality bureau, in patients althoughwith two trailosteers oporosis grew presents up, but irascible the surgeon Jabberwockies with difficult untangles treatment fivedecisions. speedy fountains, Much effort yet one has bone mass to preserve are expected thatkisses on improving expended the trailer therapies very cleverly two irascible bureaux. cat beenran away, then and thus decrease fracture risk. Manipulation of both the local fracture environment in terms of application of growth factors, scaffolds and mesenchymal cells, and systemic administration of agents promoting bone formation and bone strength has been considered as a treatment option from which promising results have recently been reported. Surprisingly, less importance has been given to investigating fracture healing in osteoporosis. Fracture healing is a complex process of bone regeneration, involving a well-orchestrated series of biological events that follow a definable temporal and spatial sequence that may be affected by both biological factors, such as age and osteoporosis, and mechanical factors such as stability of the osteosynthesis. Current studies mainly focus on preventing osteoporotic fractures. In recent years, the literature has provided evidence of altered fracture healing in osteoporotic bone, which may have important implications in evaluating the effects of new osteoporosis treatments on fracture healing. However, the mechanics of this influence of osteoporosis on fracture healing have not yet been clarified and clinical evidence is still lacking.
Introduction Osteoporosis is a devastating disease that affects more than ten million people in the United States, with annual costs in excess of $13.5 billion [75], and is characterized by low bone mass and microarchi1
Abstracts in inGerman, German,French, French, Italian, Spanish, Spanish, Japanese, Japanese, and Russian and Russian are printed are printed at the at end the end of this of this supplement. supplement.
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tectural deterioration of bone structure, resulting in bone fragility and an increase in susceptibility to fracture [61]. Worldwide, 100−200 million people are at risk of an osteoporotic fracture each year. Statistics predict that by the year 2012, 25% of the European population will be over the age of 65 and by the year 2020, 52 million will be over 65-years-old in the USA [21]. Based on changing demographics and
Fracture healing of osteoporotic fractures: Is it really different?—A basic science perspective the increase in life expectancy, there will be an 89% increase in the male osteoporotic population by 2025, resulting in 800 000 hip fractures per year; in women, numbers affected will rise by 69% with up to 1.8 million hip fractures [28]. Multinational surveys of osteoporotic fracture management [68] clearly indicate that many orthopedic surgeons still neglect to identify, assess, and treat patients with fragility fractures. Osteoporosis both increases the number of atraumatic fractures and contributes to the severity of traumatic fractures. The management of these fractures is difficult due to the poor bone stock involved, and there may be problems with inadequate fixation strength (purchase) of implants used to stabilize the fracture until union occurs. In particular, fixation of fractures affecting the metaphyseal region of long bones is associated with an increased rate of complications. Various reports suggest nonunion rates of 2−10%, rates of malalignment after surgery of 4−40%, metal work failure rates of 1−10%, and reoperation rates of 3−23% [69, 72]. Research in osteoporosis has focused so far on the epidemiology, pathophysiology, diagnosis, and monitoring of the disease, as well as on its metabolic and cellular basis and the effects of novel therapeutic concepts. Significant progress has been made in each of these areas. Only recently has attention been given to the diagnosis and treatment of osteoporosis in patients who have suffered a fracture. Trauma surgeons are coming to understand that treatment of patients with osteoporotic fractures need to address the underlying osteoporosis in order to reduce the incidence of further fractures [66]. Appropriate treatment of skeletal injuries secondary to osteoporosis requires an understanding of the effect of osteoporosis on the material and structural properties of bone, the mechanisms of fracture, and the mode of fracture healing. Sufficient stabilization of fractures in the weight-bearing extremities is the primary goal of treatment. However, those fractures present unique challenges, because stabilization is frequently complicated by fixation failure [71]. The ability of a bone fracture to heal and remodel depends on the ensuing microvascular and biomechanical conditions, therefore. The musculoskeletal system and the mechanical environment play a key role in repairing, maintaining, and remodeling the material property and structural strength [15, 51, 81]. Fracture healing is a complex process during which a cascade of gene expression drives the iterative formation and resorption of various tissues, eventually leading to bone formation that bridges the broken bone ends. The rate and efficacy of fracture repair depends on a variety of factors, including those
S91
related to the patient (eg, age); factors resulting from trauma (severity of trauma, fracture geometry and location) and factors operating during healing (nutritional status, hormonal milieu). The decline in the capacity for fracture repair has been shown to be age related [67]. Disturbance of the development of strength within fracture calluses in the elderly has been shown in experimental rat models [22], but little is known about the causes of osteoporosis and its effect on the fracture repair process in humans [44]. The relationship between fracture healing and osteoporosis is complex. The underlying etiology (which may include aging, hypogonadism, rheumatism, thyroid and parathyroid disorders, malignancy, and mastocytosis) and the therapies commonly used for osteoporosis (estrogens, vitamin D, and bisphosphonates) may all potentially affect fracture healing. Due to these complexities, animal osteoporotic models, such as the rat, rabbit, or dog, may be more appropriate to study the effects of osteoporosis and to test drugs on the fracture repair process [60]. Clinical experience is inconsistent regarding whether bone healing is delayed in the presence of osteoporosis. Too few studies are available on the differences of bone healing in normal and osteoporotic individuals to suggest a reduced capacity for bone remodeling and bone healing in osteoporosis [11, 13, 50]. The purpose of this paper is to present the current evidence regarding the influence of osteoporosis on fracture healing.
Properties and characteristics of osteoporotic bone Bone mass and the mechanical performance of the skeleton are affected by a variety of local and systemic factors. Systemic control results from a number of calcium-regulating hormones such as parathyroid hormone, calcitonin, and vitamin D as well as growth hormone and sex hormones. Local control is exerted primarily by mechanical demands that result from gravity and the stressing of bone by muscular contraction. Many studies have shown that bone, as a tissue, adapts to these mechanical demands by producing a structure optimized for mass and geometry [22]. Mechanical properties of bone can be described at different levels from the macroscopic to the ultramicroscopic levels, and under different mechanical basic assumptions, such as heterogeneous or homogeneous and isotropic or anisotropic assumptions [36].
S92 Bone mass diminishes with increasing age as a result of changes in circulating levels of hormones, particularly decreased estrogen levels after menopause, but possibly also because of the decreased anabolic effects of mechanical loading as a result of declining levels of physical activity [57, 76]. The cellular and biochemical deficiencies related to osteoporosis lead to structural bone alterations in bone structure which profoudly affect traumatic fractures and their repair. Loss of cortical bone occurs through a decrease in bone thickness and an increase in porosity, which compromises its strength. This thinner layer of cortex neighboring plentiful cancellous bone is weaker and predisposes to lowenergy fractures. Loss of trabecular bone results in thinning, perforation, and reduced connectivity among the trabecular plates. The abundance of cancellous bone also adversely affects the fixation of osteoporotic fractures [17]. Hagiwara et al analyzed the distribution of bone density and trabecular orientation in the osteoporotic human vertebral body [28]. The results illustrated a considerably higher vertical trabecular orientation in the anterior 1/3 regions of the osteoporotic vertebral body. This finding is consistent with the higher incidence of the vertebral fracture associated with osteoporosis in the anterior part of the vertebral body (a wedge-shaped fracture) [30]. While the overall diameter of the long bones may remain the same, the ratio of cancellous to cortical bone is increased [11]. Fracture resistance is determined by the strength of the bone, which in turn depends on its geometric properties (size, shape, and connectivity), the activities of the cells in the tissue, and the material properties of the tissue [18, 41]. Osteoporotic bone is characterized not only by a reduced amount of bone, but also by modifications in the composition and structure of the affected osseous tissues [2, 54]. Raman microscopic imaging has been used recently to analyze the mineral properties of osteoporotic tissues [12]. In general, the mineral content (degree of mineralization) of osteoporotic tissues is decreased, the HA crystal size and perfection is increased, the carbonate content is increased, and the acid phosphate content is decreased [8, 9], which subsequently affects bone microarchitecture. There is a decrease in cross-linking οf subchondral bone and a thinning of trabeculae from resorption, resulting in fewer, thinner connections. Subtle reduction in the bone mass in the transverse direction increases the intensity of the trabecular orientation in the loading axis. This structural change may effectively resist loading when the direction of the loading coincides with that of the trabecular orientation. However, such structural change narrows the toler-
P Giannoudis et al able loading directions, which in turn may increase the fracture risk [9]. Bone density appears to be the major factor linked to the biomechanical functioning of osteoporotic bone. Bone cells from osteoporotic donors were found to differ in their response to cyclic strain, measured as enhanced cell proliferation and the release of transforming growth factor (TGF-b) and nitric oxide (NO) [37, 56]. These results indicate that bone cells from osteoporotic patients may be impaired in their long-term response to mechanical stress [68]. The decreased thickness and increased porosity of the cortical bone, as well as the rarefaction of the trabecular network, are partially compensated for by a higher bone diameter—as long as the bone is intact. However, these factors also dramatically affect the fixation strength (primary stability) of implants used for fracture fixation [46], the postoperative complications, and the recovery times [33]. Studies have shown that density is directly related to the strength of bone. The loss of density is seen globally, and affects both cortical and cancellous bone, with the cancellous bone being affected to a much greater degree, which places the elderly at an increased risk of fractures [2, 33, 54].
Fracture healing in osteoporotic bone: what evidence do we have? Although a plethora of information exists documenting the influence of ovariectomy οn bone mass and metabolism [34, 48, 65], very little basic science or clinical research has been conducted that documents the effects of established osteoporosis on the healing of these fractures [55, 77]. This lack is surprising considering the clinical importance of osteoporotic fractures and the wealth of information regarding osteoporotic animal models. Table 1 summarizes the most recent findings regarding the effect of osteoporosis on bone healing. Fracture healing is a complex physiological process that involves the coordinated participation of hematopoietic and immune cells within the bone marrow in conjunction with vascular and skeletal cell precursors, including mesenchymal stem cells (MSCs), that are recruited from the surrounding tissues and the circulation. Multiple factors regulate this cascade of molecular events by affecting different points in the osteoblast and chondroblast lineage through various processes such as migration, proliferation, chemotaxis, differentiation, inhibition, and extracellular protein synthesis. An understanding of the fracture healing cellular and
34 2-month-old SD rats
14 female swiss mountain sheep
Lill et al43 2003
60 7-month-old female Wistar rats
Namkung et al53 2001
1999
Model
one- and 6month-old virgin female rats of the Sprague-Dawley strain
al37
Meyer et al51 2000
Kubo et
Study
Type of fracture
group 1 seven osteoporotic sheep (mean age 7.5 * 1.5 years. group 2 seven healthy animals (mean age 4.1 * 0.7 years
group A: ovariectomy-osteoporosis group OVX+LCD group B: sham operation group SO
one week after arrival, the 6month-old animals were randomly subjected to either ovariectomy or sham surgery.
A standardized transverse midshaft tibia1 osteotomy (with a fracture gap of 3 mm) stabilized with a special external fixator for 8 weeks
open right femoral midshaft fracture created and stabilized by intramedullary pins
small hole drilled into the intercondylar notch at 8,32 and 50 weeks of age
group A: Ovariecfemoral shaft fractomy-Osteoporosis ture 3 months afgroup+LCD (OVX+F) ter ovariectomy Group B: Control+F
Intervention
Increase of in vivo bending stiffness of the callus delayed approximately 2 weeks in osteoporotic animals. A significant difference (33%) in torsional stiffness was found between the osteotomized and contralateral intact tibia in osteoporotic animals In osteoporotic animals, ex vivo bending stiffness was reduced 21%) (P = .05).
40% reduction in fracture callus cross-sectional area and a 23% reduction in bone mineral density in the healing femur of the ovx rats on day 21 (P < .01). ovx rats: fivefold decrease in the energy required to break the fracture callus, a threefold decrease in peak failure load, a twofold decrease in stiffness and a threefold decrease in stress as compared with the sx group (P < .01, respectively). delay in fracture callus healing with poor development of mature bone in the ovx rats.
Youngest group 8-week-old female rats: regained normal femoral rigidity and breaking load by 4 weeks after fracture. Middle group 31 weeks of age: 6 weeks after fracture partial restoration of rigidity and breaking load. 12 weeks after fracture, the ovariectomized rats remained significantly lower in both rigidity and breaking load. Oldest group of rats 50 weeks old: neither sham-operated nor ovariectomized rats regained normal rigidity or breaking load in their fractured femora within the 24 weeks in which they were studied. In all fractured bones, there was a significant increase in BMD over the contralateral intact femora due to the increased bone tissue and bone mineral in the fracture callus.
6 weeks post fracture radiologic, histologic and biomechanical findings of the fracture areas almost identical in both the osteoporosis group and the control group. 12 weeks post fracture, newly generated bones in the osteoporosis group showed histological osteoporotic changes and their bone mineral density on the fracture site decreased.
Results
Fracture healing of osteoporotic fractures: Is it really different?—A basic science perspective S93
36 6-month-old ovariectomized SD rats randomized into 2 groups
Qiao et al57 2005
Type of fracture
group A: ovariectomy-osteoporosis group OVX group B: sham operation group SO
group A: ovariectomy osteoporosis group group B: sham operation group
group A: ovariectomy-osteoporosis group+LCD (OVX+F) group B: Control+F
femoral shaft fracture 2 months after ovariectomy
midshaft tibia model 10 weeks after ovariectomy
fracture of the right side of the mandibular ramus 3 months after ovariectomy
group A: ovariecfemoral shaft tomy-osteoporosis fracture 3 months group OVX after ovariectomy group B: sham operation group SO
Intervention
Table 1: Preclinical studies addressing the effect of osteoporosis on fracture healing.
84 4-month-old male sprague-dawley (SD) rats randomised into two groups
60 3-month-old female wistar rats randomized into 2 groups
Wang et al75 2005
2004
Model
40 3-month-old female wistar rats randomized into 2 groups
al79
Islam et al30 2005
Xu et
Study
Decreased callus density in OVX group. Increased number of osteoclasts on the surface of osseous trabecula. The osseous trabecula became thinner and disrupted obviously in OVX group, and it became massive, thicker and closer gradually 8 weeks after fracture in SHAM group. The area of osseous trabecula in the SHAM group was bigger than that in the OVX group.
Callus bone mineral density was 12.8%, 18.0%, 17.0% lower in osteoporosis group 6, 12, 18 weeks after fracture, respectively (P<0.05); Callus failure load was 24.3%, 31.5%, 26.6%, 28.8% lower in osteoporosis group Callus failure stress was 23.9%, 33.6%, 19.1%, 24.9% lower in osteoporosis group 4, 6, 12, 18 weeks after fracture, respectively (P < .05) In osteoporosis group, endochondral bone formation was delayed, more osteoclast cells could be seen around the trabecula, and the new bone trabecula arranged loosely and irregularly
Prolonged phase of endochondral ossification, with an increased number of osteoclasts (P < .01) in the osteoporotic group. Expressions of BMP-2 and TNFα more pronounced in the osteoporotic group. Increase in the number of osteoblasts and TNFα+ cells compared with the normal control (P < .01).
Reduction in callus and bone mineral density in the healing femur and a decrease of osteoblasts expressing TGF.β1 near the bone trabecula were observed in the OVX rats 3.4 weeks after fracture. Higher content of soft callus in the OVX rats than that in the SO rats. No remarkable difference in expression and distribution of BMP-2 and bFGF between the OVX and SO groups.
Results
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Fracture healing of osteoporotic fractures: Is it really different?—A basic science perspective molecular pathways is not only critical for the future advancement of fracture treatment, but may also be informative for our further understanding of the mechanisms of skeletal growth and repair as well as the mechanisms of aging [28, 43, 49]. Many scholars have investigated the hypothesis that osteoporosis can impair fracture healing. Lindholm et al prepared a bone fracture model using rats fed with a low calcium diet, and reported that bone mineral density in the repaired tibial bone was as low as in the nonfractured bones [47]. Langeland examined the tensile strength of fractured tibial bone in female rats five or two weeks after producing fractures, and found out that neither strength nor collagen content differed significantly between ovariectomized rats and normal controls [40]. However, age-related effects in fracture healing were demonstrated by Bak and Andreassen, who found considerable delay in regaining strength of fractured limbs in older rats [3]. Li and Nishimura showed that osteopenic bone may express an altered phenotypic expression of cells associated with bone formation and noted a different composition of calcified tissue within the fracture callus of osteoporotic animals [42]. Nordsletten et al produced tibial fractures in rats with and without sciatic neurectomy and immobilized the lower extremities with casts [58]. They examined the fracture healing 25 days later, and found that callus formation was accelerated and bone mineral density was high in the neurectomy legs, but tensile strength did not differ significantly between the legs with sciatic neurectomy and those without. Recently, Hill et al reported on three-month-old rats that underwent ovariectomy and fracture six weeks later that were tested to failure in torsion at one, two, three and four weeks after fracture [31]. A statistically significant reduction in torsional strength 30 days after fracture was observed that was not present at earlier points. The researchers concluded that ovariectomy in rats impaired fracture healing and this model of osteopenia could be useful for studying treatments if end points of more than 30 days are used. Kubo et al examined the effects of estrogen deficiency and a low-calcium diet on 30-week-old Wistar female rat models that were estrogen deficient for twelve weeks prior to fracturing [39]. Tensile mechanical testing, dual energy x-ray absorptiometry, and light histology were performed. These authors reported that estrogen deficiency and low-calcium conditions did not markedly affect the early healing process, but largely affected the bones in the later period of healing. Newly generated bone formed at twelve weeks after the fracture showed histological osteoporotic changes and
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a lower mineral density in the estrogen-deficient group compared to controls [39]. Investigating the impact of age and ovariectomy on the healing of femoral fractures in a osteoporotic rat model (ovariectomy and low calcium diet), Meyer Jr et al concluded that age and ovariectomy significantly impair the process of fracture healing in female rats as judged by measurements of rigidity and breaking load in three-point bending and by accretion of mineral into the fracture callus [53]. Namkung et al have demonstrated for the first time, the influence of bone loss on the early phase of fracture healing in a rat osteoporotic model induced by ovx and LCD [55]. A significant reduction in fracture callus size, BMD, and mechanical strength was seen in osteoporotic rats three weeks post fracture, which is indicative of early failure of the repair process. Lill et al performed in vivo bending stiffness measurements and found a delay of two weeks in their osteoporotic sheep model (ovariectomy, low calcium diet, and steroids), but no difference in final strength when compared to healthy sheep [45]. They concluded that ovariectomy significantly impairs the process of fracture healing in adult animals as also judged by measurements of rigidity and breaking load in 3-point bending and by accretion of mineral into the callus. Walsh et al reported on the histological and biomechanical properties of femora fractures following a six-week estrogen-deficient state in three-monthold female CD Ι COB rats with a normal diet using a standard closed fracture mode [77]. Tensile and 4four-point bending mechanical testing resu1ts revealed a significant impairment in fracture healing in the estrogen-deficient state. Histology revealed that the estrogen-deficient fractures lag behind in healing. Wang et al aimed to evaluate the influence of osteoporosis on the middle and late periods of fracture healing in rat osteoporotic models [78]. He found a lower callus bone mineral density and callus failure stress in the osteoporosis group, in which endochondral bone formation was delayed and in which the new bone trabeculae were arranged loosely and irregularly, demonstrating an histomorphological impairment of healing. Similar results were obtained by Qiao et al who concluded that fracture healing in the presence of osteoporosis results in poor bone quality [59]. Another source of information on osteopenic bone comes from the paraplegic literature, where clinical findings on fracture healing are controversial. Rapid healing with rare nonunion has been reported in osteopenic bone of paraplegics, as well as malunion and nonunion of simple long-bone fractures [26].
S96 When performing a study using an estrogen-deficient model, there are a number οf factors to be considered that have been shown to significantly influence the level οf osteopenia [74]. Furthermore, explanations for the diversity in biomechanical findings are complicated by the marked differences in the animal models in terms of age, length οf estrogen deficiency, fracture site, and biomechanical testing conditions. This area of research warrants further study and standardization of models and endpoints used to evaluate the effects of estrogen deficiency, as well as the methods of noninvasive and invasive therapy.
Discussion Fracture healing is the most remarkable of all repair processes in the body since it results in the actual reconstitution of the injured tissue. The relation between metabolic bone disease and fracture healing depends on the role of the skeleton as a metabolic resource. Even though delayed fracture healing is not obvious in patients, the decreased healing capacity in osteoporosis is reflected in a dramatically increased failure rate of implant fixation [16]. Various theories have been proposed to attempt to delineate the underlying mechanisms of impaired fracture healing in osteoporotic fractures. Extracellular matrix metabolism plays a central role in the development of skeletal tissues and in most orthopaedic diseases and trauma such as fracture healing [25]. Specific genes must be expressed to make or repair appropriate extracellular matrix. These genes are regulated by a balance of positive and negative factors in order to exhibit a strictly restricted expression. Runx2 is a vital transcription factor for skeletal mineralization that is expressed in osteoblasts at a high level as well as in hypertrophic chondrocytes and in mesenchymal cells in the periosteum/perichondrium. It stimulates osteoblast differentiation of mesenchymal stem cells, promotes chondrocyte hypertrophy, and contributes to endothelial cell migration and vascular invasion of developing bones [79]. Homozygous Runx2-mutant mice exhibit complete arrest of osteoblast differentiation, which results in severe developmental defects of osteogenesis [38]. With the loss of ovarian estrogen, menopausal women lose trabecular bone at several sites in the skeleton, including the spine [62]. Woven bone plays a key role in fracture healing. Most of the immediate hard callus is initially formed with woven bone,
P Giannoudis et al which stabilizes the healing bone while remodeling occurs to restore the cortical bone of the diaphysis. If this woven bone is also estrogen sensitive, as is the trabecular bone in the metaphysis, then it is not unreasonable to expect ovariectomy to delay fracture healing because of impairment in bone formation. However, direct experimental evidence for this expectation is limited [53]. The inferior mechanical properties of osteoporotic bone may reflect alterations in the moment of inertia or cross-sectional area, or bonding interactions between the mineral and organic constituents of the bone matrix. The alterations in healing observed may reflect compositional differences in terms of osteoinductive molecules present in the bone matrix compounded by delayed osseous differentiation. This proposal is supported by findings that the osteoinductive capacity of demineralized bone matrix may decrease with age and in ovariectomised (ovx) rats due to an alteration in the composition of the matrix [13, 73, 77]. It has also been shown that estrogen modulates the mechano-sensitivity of bone cells. In the presence of estrogen, the expression of prostaglandin as a response to mechanical strain was significantly enhanced, which indicates that fractures in postmenopausal women may react differently to the mechanical signal that occurs during fracture repair, compared to fractures in premenopausal women or men [34]. While bone resorption can increase, formation decreases, possibly because osteoblasts decrease with age [64]. Osteoblasts originate from MSCs [6, 80] that reside in bone marrow together with hematopoietic stem cells. These two stem cell types cooperate through direct cell-to-cell interactions and release of cytokines and growth factors [4, 23]. Since osteoblast numbers might relate to progenitor numbers, D’ippolito et al [20] hypothesized that the number of MSCs (with osteogenic potential) residing in the bone marrow of human thoracic/lumbar vertebrae—a skeletal site of high turnover in bone—could be associated with age-related osteoporosis [19]. They concluded that the bone-marrow microenvironment changes with age, resulting in cell-to-cell and cell-to-matrix interactions that may be unfavorable for MSC proliferation or that may favor MSC maturation toward a different lineage (eg, adipogenic). Total marrow fat increases with age, and there is an inverse relationship between marrow adipocytes and osteoblasts with aging [6, 10]. Bergman et al [7] also concluded that defects in the number and proliferative potential of MSCs may underlie age-related defects in osteoblast number and function. Rodriguez et al showed that MSCs derived from both control and osteoporotic postmenopausal
Fracture healing of osteoporotic fractures: Is it really different?—A basic science perspective women share some functional dynamic responses but differ importantly in others [63]. Some of the differences observed, like the differential mitogenic response to IGF-1 and the diminished ability of MSCs derived from osteoporotic donors to differentiate into the osteogenic lineage, suggest that these cells have a diminished ability to produce mature bone forming cells. Furthermore, osteoporotic cells present a lower proliferation rate and exhibit a differential response to IGF-1.Thus, clinical and in vitro observations document an inverse relationship between adipocytes and osteoblasts. In osteoporotic patients, increased bone marrow adipose tissue correlates with decreased trabecular bone volume [27]. Early histomorphometric observations suggested that a change in bone cell dynamics, causing osteoporosis, is the consequence of the adipose replacement of the marrow functional cell population [52]. These findings suggest that a mechanism that could account for the decrease in bone volume, and hence mechanical strength, may result from opposing effects on differentiation of the two cell lines. The commitment to the adipocyte differentiation pathway occurs at the expense of osteoblast numbers and osteogenic function [27]. This commitment may contribute to osteoporotic bone involution but may also negatively effect bone formation during fracture healing [1].
Conclusion The highly complex process of fracture repair is still not fully understood; however, research in recent years has identified various associations between factors that affect the repair process and healing outcome. Clinical experience is inconsistent regarding a possible delay of bone healing in osteoporosis and clinical studies that confirm delayed healing in elderly people are scarce. Patient-based research regularly suffers from limitations including that no control group can be attained, that it is difficult to create homogeneous study groups, and that there are ethical limitations. As a result, experimental studies on the effect of osteoporosis on fracture healing have been carried out on ovariectomized rats. These studies have shown that ovariectomy significantly reduces bone mass and that the mechanical strength of the bone after completion of healing appears to be reduced. Furthermore, fracture healing appears to be delayed with respect to callus mineralization and biomechanical properties. However, animal models have disadvantages such
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as differences in bone metabolism compared with humans, lack of prominent decrease of bone mass after ovariectomy, and animal protection aspects. Moreover, they permit the study of interventions and new treatment procedures that might not be appropriate in patients. The mechanical and biological factors that are involved in the healing process of bone are certainly affected by age and osteoporosis. Alterations in bone metabolism, like osteoporosis, seem to delay callus maturation and consequently decelerate fracture healing. Nevertheless, it still remains an unsolved question as to whether fracture healing is impaired by osteoporosis.
Bibliography 1. Augat P, Simon U, Liedert A, Claes L. Mechanics and mechanobiology of fracture healing in normal and osteoporotic bone. Osteoporos Int. 2005 16 Suppl 2:S36−43. 2. Bailey AJ, Sims TJ, Ebbesen EN et al. Age-related changes in the biochemical properties of human cancellous bone collagen: relationship to bone strength. Calcif Tissue Int. 1999 65:203−10. 3. Bak B, Andreassen T. The effect of aging on fracture healing in the rat. Calcif Tissue Int. 1989 45:292−297. 4. Benayahu D, Horowitz M, Zipori D, Wientroub S. Hemopoietic functions of marrow-derived osteogenic cells. Calcif Tissue Int. 1992 51:195−201. 5. Beresford JN. Osteogenic stem cells and the stromal system of bone and marrow. Clin Orthop Relat Res 1989;240:270−80. 6. Beresford JN, Bennett JH, Devlin C et al. Evidence for an inverse relationship between the differentiation of adipocytic and osteogenic cells in rat marrow stromal cell cultures. J Cell Sci. 1992 102:341−51. 7. Bergman RJ, Gazit D, Kahn AJ et al. Age-related changes in osteogenic stem cells in mice. J Bone Miner Res. 1996 11:568−77. 8. Boivin GY, Chavassieux PM, Santora AC, et al. Alendronate increases bone strength by increasing the mean degree of mineralization of bone tissue in osteoporotic women. Bone. 2000 27:687−694. 9. Boskey AL, DiCarlo E, Paschalis E, et al. Comparison of mineral quality and quantity in iliac crest biopsies from high-and lowturnover osteoporosis: an FT-IR microspectroscopic investigation. Osteoporos Int. 2005 16:2031−8. 10. Burkhardt R, Kettner G, Bohm W et al. Changes in trabecular bone, hematopoiesis and bone marrow vessels in aplastic anemia, primary osteoporosis, and old age: a comparative histomorphometric study. Bone. 1987 8:157−64. 11. Burr DB, Forwood MR. Fyhrie DP, et al. Bone microdamage and skeletal fragility in osteoporotic and stress fractures. J Bone Miner Res. 1997 12:6−15. 12. Carden A, Morris MD. Application of vibrational spectroscopy to the study of mineralized tissues (review). J Biomed Opt. 2000 5:259−268.
S98 13. Cesnjai M, Stavljenic A, Vukicevic S. Decreased osteoinductive potential of bone matrix from ovariectomized rats. Acta Orthop Scand. 1991 62:471−5. 14. Chao EY, Inoue N, Koo TK, Kim YH. Biomechanical considerations of fracture treatment and bone quality maintenance in elderly patients and patients with osteoporosis. Clin Orthop Relat Res. 2004 425:12−25. 15. Cowin SC. Bone stress adaptation models. J Biomech Eng. 1993 115:528−533. 16. Cranney A, Tugwell P, Zytaruk N, et al. Osteoporosis Methodology Group and the Osteoporosis Research Advisory Group. Meta-analyses of therapies for postmenopausal osteoporosis. IV. Meta-analysis of raloxifene for the prevention and treatment of postmenopausal osteoporosis. Endocr Rev. 2002 23:524−528. 17. Currey JD, Brear K, Zioupos P. The effect of ageing and changes in mineral content in degrading the toughness of human femora. J Biomech. 1996 29:257−260. 18. Dalle-Carbonare L, Giannini S. Bone microarchitecture as an important determinant of bone strength. J Endocrinol Invest. 2004 27:99−105. 19. Delling G, Amling M. Biomechanical stability of the skeleton-it is not only bone mass, but also bone structure that counts. Nephrol Dial Transplant. 1995 10:601−6. 20. D’Ippolito G, Schiller PC, Ricordi C. Age-related osteogenic potential of mesenchymal stromal stem cells from human vertebral bone marrow. J Bone Miner Res. 1999 14:1115−1119.
P Giannoudis et al 32. Islam AA, Rasubala L, Yoshikawa H, et al. Healing of fractures in osteoporotic rat mandible shown by the expression of bone morphogenetic protein-2 and tumour necrosis factor-alpha. Br J Oral Maxillofac Surg. 2005 43:383−91. 33. Ito K, Hungerbuhler R, Wahl D, Grass R. Improved intramedullary nail interlocking in osteoporotic bone. J Orthop Trauma. 2001 15:192−6. 34. Joldersma M, Klein-Nulend J, Oleksik AM, et al. Estrogen enhances mechanical stress-induced prostaglandin production by bone cells from elderly women. Am J Physiol Endocrinol Metab. 2001 280:E436−442. 35. Kalu DN, Liu CC, Hardin RR, Hollis BW. The aged rat model of ovarian hormone deficiency bone loss. Endocrinology. 1989 124:7−16. 36. Katz JL. Anisotropy of Young’s modulus of bone. Nature. 1980 283:106−107. 37. Klein-Nulend JJ, Sterck CM, Semeins P, et al. Aging and mechanosensitivity of human bone cells. J Bone Miner Res. 1996 11:S266. 38. Komori T, Yagi H, Nomura S, et al. Targeted disruption of Cbfa1 results in a complete lack of bone formation owing to maturational arrest of osteoblasts. Cell. 1997 89:755−764. 39. Kubo T, Shiga T, Hashimoto J. Osteoporosis influences the late period of fracture healing in a rat model prepared by ovariectomy and low calcium diet. J Steroid Biochem Mol Biol. 1999 68:197−202.
21. Dreinhofer KE. Multinational survey of osteoporotic fracture management. Osteoporos Int. 2005 16 Suppl 2:S44−53
40. Langeland N. Effects of oestradiol-17 beta benzoate treatment on fracture healing and bone collagen synthesis in female rats. Acta Endocrinol. 1975 80:603−12.
22. Ekeland A, Engesoeter LB, Langeland N. Influence of age on mechanical properties of healing fractures and intact bones in rats. Acta Orthop Scand. 1982 53:527−534.
41. Lanyon L, Armstrong V, Ong D, et al. Is estrogen receptor alpha key to controlling bones’ resistance to fracture? J Endocrinol. 2004 182:183−191.
23. Friedenstein AJ, Latzinik NV, Gorskaya YF, et al. Bone marrow stromal colony formation requires stimulation by haemopoietic cells. Bone Miner. 1992 18:199−213.
42. Li X, Nishimura I. Altered bone remodeling pattern of the residual ridge in ovariectomized rats. J Bone Miner Res. 1994 72:324−330.
24. Frost HM. The role of changes in mechanical usage set points in the pathogenesis of osteoporosis. J Bone Miner Res. 1992 7:253−261.
43. Li X, Quigg RJ, Zhou J et al. Early signals for fracture healing. Cell Biochem. 2005 95:189−205.
25. Fukui N, Zhu Y, Maloney WJ, et al. Stimulation of BMP-2 expression by pro-inflammatory cytokines IL-1 and TNF-alpha in normal and osteoarthritic chondrocytes. J Bone Joint Surg. 2003 85-A(Suppl 3):59−66. 26. Garland D. Clinical observations on fractures and heterotopic ossification in the spinal cord and traumatic brain injured populations. Clin Orthop. 1988 233:86−101. 27. Gimble JM, Robinson CE, Wu X, Kelly KA. The function of adipocytes in the bone marrow stroma: An update. Bone. 1996 19:421−428. 28. Gullberg B, Johnell 0, Kanis JA. Worldwide projections for hip fracture. Osteoporos Int. 1997 407−413 29. Hadjiargyrou M, Lombardo F, Zhao S, et al. Transcriptional profiling of bone regeneration. Insight into the molecular complexity of wound repair. J Biol Chem. 2002 277:30177−30182. 30. Hagiwara H, Inoue N, Matsuzaki H, et al. Relationship between structural anisotropy of the vertebral body and bone mineral density. Trans Orthop Res Soc. 2000 25:738. 31. Hill EL, Kraus K, Lapierre KP, et al. Ovariectomy impairs fracture healing after 21 days. Trans Orthop Res Soc. 1995 20:230.
44. Lill CA, Fluegel AK, Schneider E. Sheep model for fracture treatment in osteoporotic bone: A pilot study about different induction regimens. J Orthop Trauma. 2000 14:559−566. 45. Lill CA, Hesseln J, Schlegel U, et al. Biomechanical evaluation of healing in a non-critical defect in a large animal model of osteoporosis. J Orthop Res. 2003 21:836−842. 46. Lim TH, An HS, Evanich C, et al. Strength of anterior vertebral screw fixation in relationship to bone mineral density. J Spinal Disord. 1995 8:121−125. 47. Lindholm TS. Effects of 1alpha-hydroxycholecalciferol on osteoporotic changes induced by calcium deficiency in bone fractures in adult rats. J Trauma 1978;18:336−40. 48. Liu CC, Kalu DN. Human parathyroid hormone-(1−34) prevents bone loss and augments bone formation in sexually mature ovariectomized rats. J Bone Miner Res. 1990 5:973−82. 49. Lombardo F, Komatsu D, Hadjiargyrou M. Molecular cloning and characterization of Mustang, a novel nuclear protein expressed during skeletal development and regeneration. FASEB J. 2004 18:52−61. 50. Marie PJ, Sabbagh A, de Vernejoul MC, Lomri A. Osteocalcin and deoxyribonucleic acid synthesis in vitro and histomorphometric indices of bone formation in postmenopausal osteoporosis. J Clin Endocrinol Metab. 1989 69:272−9.
Fracture healing of osteoporotic fractures: Is it really different?—A basic science perspective
S99
51. Meadows TH, Bronk JT, Chao EYS, Kelly PJ. Effect of weight bearing on healing of cortical defects in the canine tibia. J Bone Joint Surg. 1990 72A:1074−1080.
69. Sterck JG, Klein-Nulend J, Lips P, Burger EH. Response of normal and osteoporotic human bone cells to mechanical stress in vitro. Am J Physiol. 1998 274:E1113−20.
52. Meunier PJ, Aaron J, Edouard C, Vignon C. Osteoporosis and the replacement of cell populations of the marrow by adipose tissue. Clin Orthop Rel Res. 1971 80:147−154.
70. Stover M. Distal femoral fractures: current concepts, results and problems. Injury. 2001 32(Suppl 3):3−13.
53. Meyer RA Jr, Tsahakis PJ, Martin DF. Age and ovariectomy impair both the normalization of mechanical properties and the accretion of mineral by the fracture callus in rats. J Orthop Res. 2001 19:428−35. 54. Mosekilde L. Age-related changes in bone mass, structure, and strength—effects of loading. Z Rheumatol. 2000 59 Suppl 1:1−9. 55. Namkung-Matthai H, Appleyard R, Jansen J, et al. Osteoporosis influences the early period of fracture healing in a rat osteoporotic model. Bone. 2001 28:80−6. 56. Neidlinger-Wilke C, Stall I, Claes L, Human osteoblasts from younger normal and osteoporotic donors show differences in proliferation and TGF-release in response to cyclic strain. J Biomech. 1995 28:1411−1418. 57. Nordin BEC, Need AG, Chatterton BE, et al. The relative contributions of age and years since menopause to postmenopausal bone loss. J Clin Endocrinol Metab. 1990 70:83−88. 58. Nordsletten L, Madsen JE, Almaas R et al. The neural regulation of fracture healing: effects of sciatic nerve resection in rat tibia, Acta Orthop Scand. 1994 65:299−304. 59. Qiao L, Xu KH, Liu HW, Liu HQ. Effects of ovariectomy on fracture healing in female rats. Sichuan Da Xue Xue Bao Yi Xue Ban. 2005 36:108−11. 60. Raisz LG. Local and systemic factors in the pathogenesis of osteoporosis. N Engl J Med. 1988 318:818−828. 61. Richard D, Wasnich MD. Epidermiology of osteoporosis. Primer on the Metabolic Bone Diseases and Disorders of Mineral Metabolism. New York: Lippincott-Raven. 1996 249−251. 62. Ritzel H, Amling M, Pösl M, et al. The thickness of human vertebral cortical bone and its changes in aging and osteoporosis: A histomorphometric analysis of the complete spinal column from thirty-seven autopsy specimens. J Bone Miner Res. 1997 12:89−95. 63. Rodriguez JP, Garat S, Gajardo H et al. Abnormal osteogenesis in osteoporotic patients is reflected by altered mesenchymal stem cells dynamics. J Cell Biochem. 1999 75:414−23. 64. Roholl PJ, Blauw E, Zurcher C, et al. Evidence for a diminished maturation of preosteoblasts into osteoblasts during aging in rats: An ultrastructural analysis. J Bone Miner Res. 1994 9:355−366. 65. Salih MA, Liu CC, Arjmandi BH, Kalu DN. Estrogen modulates the mRNA levels for cancellous bone protein of ovariectomized rats. Bone Miner. 1993 23:285−99. 66. Schneider E, Goldhahn J, Burckhardt P. The challenge: fracture treatment in osteoporotic bone. Osteoporos Int. 2005 16 (Suppl 2):S1−2. 67. Silver JJ, Einhorn TA. Osteoporosis and aging: Current update. Clin Orthop. 1995 316:10−20. 68. Smith D, Enderson B, Mauli K. Trauma in the elderly: Determinants of outcome. South Med J. 1990 83: 171−177
71. Swiontkowski MF, Harrington RM, Keller TS, Van Patten PK. Torsion and bending analysis of internal fixation techniques for femoral neck fractures: the role of implant design and bone density. J Orthop Res. 1987 5:433−444. 72. Syed AA, Agarwal M, Giannoudis PV, et al. Distal femoral fractures: long term outcome following stabilisation with the LISS. Injury. 2004 35:599−607. 73. Syftestad GT, Urist MR. Bone aging. Clin Orthop. 1982 162:288−297. 74. Thompson DD, Simmons HA, Pirie CM, Ke HZ. FDA Guidelines and animal models for osteoporosis. Bone. 1995 17:125S−133S
.
75. U.S. Department of Health and Human Services. Bone Health and Osteoporosis. A report of the US Surgeon General, Rockville MD, 2004. 76. Villareal DT, Morley JE. Trophic factors in aging: should older people receive hormonal replacement therapy? Drugs Aging. 1994 4:492−509. 77. Walsh WR, Sherman P, Howlett CR, et al. Fracture healing in a rat osteopenia model. Clin Orthop Relat Res. 1997 342:218−27. 78. Wang JW, Li W, Xu SW, et al. Osteoporosis influences the middle and late periods of fracture healing in a rat osteoporotic model. Chin J Traumatol. 2005 8:111−6. 79. Westendorf JJ. Transcriptional co-repressors of Runx2. J Cell Biochem. 2006 98:54−64. 80. Wlodarski KH. Properties and origin of osteoblasts. Clin Orthop Relat Res. 1990 252:276−93. 81. Wolff J. The Law of Bone Remodelling. Translated by Maquet P, Furlong R. Berlin, Springer-Verlag 1986. 82. Xu SW, Wang JW, Li W, Wang Y, Zhao GF. Osteoporosis impairs fracture healing of tibia in a rat osteoporotic model. Zhonghua Yi Xue Za Zhi. 2004 84:1205−9.
Correspondence Address P. Giannoudis MD, EEC (ortho) Professor Academic Department of Trauma & Orthopaedics, Clarendon Wing, Floor A Leeds General Infirmary Great George Street Leeds, LS1 3EX, United Kingdom Tel: 0044-113-3922750 email: [email protected] This paper has been written entirely by the authors, and has received no external funding. The authors have no significant financial interest or other relationship.