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Is Cortical Bone Hip? What determines Cortical Bone Properties?
Bone 41 (2007) S3 – S8 www.elsevier.com/locate/bone
Is Cortical Bone Hip? What determines Cortical Bone Properties? Sol Epstein ⁎ Medicine and Geriatrics, Mount Sinai School of Medicine, New York, USA Doylestown Hospital, Doylestown, PA, USA Received 12 March 2007; accepted 12 March 2007 Available online 19 March 2007
Abstract Increased bone turnover may produce a disturbance in bone structure which may result in fracture. In cortical bone, both reduction in turnover and increase in hip bone mineral density (BMD) may be necessary to decrease hip fracture risk and may require relatively greater proportionate changes than for trabecular bone. It should also be noted that increased porosity produces disproportionate reduction in bone strength, and studies have shown that increased cortical porosity and decreased cortical thickness are associated with hip fracture. Continued studies for determining the causes of bone strength and deterioration show distinct promise. Osteocyte viability has been observed to be an indicator of bone strength, with viability as the result of maintaining physiological levels of loading and osteocyte apoptosis as the result of a decrease in loading. Osteocyte apoptosis and decrease are major factors in the bone loss and fracture associated with aging. Both the osteocyte and periosteal cell layer are assuming greater importance in the process of maintaining skeletal integrity as our knowledge of these cells expand, as well being a target for pharmacological agents to reduce fracture especially in cortical bone. The bisphosphonate alendronate has been seen to have a positive effect on cortical bone by allowing customary periosteal growth, while reducing the rate of endocortical bone remodeling and slowing bone loss from the endocortical surface. Risedronate treatment effects were attributed to decrease in bone resorption and thus a decrease in fracture risk. Ibandronate has been seen to increase BMD as the spine and femur as well as a reduced incidence of new vertebral fractures and non vertebral on subset post hoc analysis. And treatment with the anabolic agent PTH(1-34) documented modeling and remodelling of quiescent and active bone surfaces. Receptor activator of nuclear factor κ B ligand (RANKL) plays a key role in bone destruction, and the human monoclonal antibody denosumab binds to RANKL, inhibiting its action and thus improving BMD significantly. © 2007 Elsevier Inc. All rights reserved. Keywords: Cortical; Trabecular; Osteocyte; Periosteal; Bone marker
In order to understand the pathophysiology of osteoporosis and treatment, the anatomy and basic makeup of cortical bone need to be emphasized. Recent information into crucial aspects of cortical bone (i.e., the osteocyte, its life cycle, and more importantly, its death) provides vital information into the purpose of these cells while they were alive [1]. Osteocytes are the most abundant and evenly distributed, longest-lived, and best-connected cell types in the mineralized matrix [1,2]. However, it is the cannicular system through which these osteocytes communicate that is of particular interest [2]. Radiating dendritic processes from each osteocyte are extensive and run through the canaliculi, similar to that of dendritic
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processes in other systems [2]. Solute transport through the bone lacunar–canalicular system is believed to be essential for osteocyte survival and function [2]. However, this is not the only method of signaling these cells utilize. Osteocyte apoptosis can influence the mechanosensory function of the osteocyte network [1,2]. Though there is little conclusive data to demonstrate the relationship between mechanical loading and sensing of these cells, it is thought that through this interstitial fluid that osteocyte activity is triggered and also cell-signaling molecules and nutrient waste products [3]. The highly interconnective system appears to be 1 reason why osteocytes are responsive to mechanical strain, as well as translating that strain accordingly to the intensity of strain signals [1–3]. Mechanical strain is translated in vivo either as deformation of the extracellular matrix or as fluid shear stress along the cells which indicates that osteocytes have close contact with the bone matrix [4]. This
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mechanical sensor ability has also been indicated in the mechanosensing process in which osteocytes directly sense the deformation of the substrate to which they are attached [4,5]. Osteocytes make contact with the extracellular matrix through attachments points that colocalize with vinculin [4]. This connection is important in translating mechanical strain from extracellular signals into intracellular messages [4,5]. Age has always been a strong indicator in the determination of fracture risk independent of bone mineral density (BMD). With respect to osteocytes and increase in age, osteocyte lacunar density has been documented to decrease exponentially with age [6–7]. Osteocyte density has also recently been identified as a fracture indicator more accurate than bone mineral density alone (BMD) [6]. Studies in mice at both 8 and 16 months have concluded that even in the absence of any detectable decreases in BMD, an increased prevalence in osteocyte apoptosis was observed [1,6]. Decline in osteocyte lacunar density in cortical bone is correlated with increase in microcracks as well as increase in porosity with age [6]. Cyclic loading of bone during normal activity can lead to microcrack formation within the tissue matrix of compact bone [6]. Alteration to local material properties of bone tissue or alterations in the local tissue repair responses may play a role in the accumulation of microdamage in bone with aging [6,7]. This increase in porosity and microcrack density coincides with the decline of osteocyte number [7,8]. There must be a certain minimum in osteocyte number to maintain the network; moreover, the spatial organizational changes in osteocyte density, due to formation of composite osteons, reduce fluidity with age, indicating an increase in microfracture potential with increasing age [6–8]. The periosteum contains osteogenic cells that regulate the outer shape of bone and regulate cortical thickness, size, and position of the bone [9]. Osteoblasts in the cambium layer become fewer in number with age, and this reduction in number is speculated to contribute to the thinning and decreasing in layer thickness of the cambium layer [8,9]. Age-related changes to the periosteal cells, including their decline in reaction to circulating hormonal influences, need to be further examined [9]. Periosteal stimulation may provide better antifracture efficacy than agents that primarily target endosteal and trabecular cellular populations [9]. Targeting the osteogenic response on periosteal surfaces can increase bone circumference and reduce the risk of osteoporotic fracture. Analysis of the variations between periosteal cells and endosteal cells responses to external pharmacological influences is key to understanding how to combat osteoporosis [9,10]. The link between increases in endocortical resorption and reduction of periosteal bone formation has been examined in both perimenopausal and postmenopausal women [11]. Loss of bone from the inner, endocortical surface has been demonstrated to contribute to bone fragility, and the compensatory action of deposition of bone on the outer periosteal surface is believed to be an adaptive response as a resistance to bending [11]. Changes in bone mass and bone geometry and strength of the one-third distal radius, bone marker turnovers, and fracture incidences were measured in women (n = 821) between the ages of 30 and 89. Each woman was receiving hormone replacement therapy, and results
indicated an accelerated endocortical resorption, while periosteal apposition declined [11]. Women that had experienced the greatest loss of bone mass and strength had the highest level of remodeling activity [11]. With aging women, periosteal apposition does not increase after menopause to compensate for bone loss, instead it decreases. It can be speculated that stimulation of periosteal apposition to increase bone width will improve bone strength [11]. Expanding the periosteal parameter could dramatically improve bone strength and decrease fracture risk, without the influences of bone density [10]. Sex steroiddeficient animals and periosteal bone turnover in the femoral neck relating to osteoclast number were examined to further identify the relationship between osteocytes and periosteal formation [9,10]. Bone turnover in the periosteum of the femoral neck in controls was more rapid than at the femoral shaft, but slower than in the femoral neck cancellous bone [10]. Animals that were sex steroid-deficient resulted in an increase in osteoclast number on the periosteal surface when compared to controls [10]. With bone size being such an important determinant of bone strength, cellular activities at the periosteal surface may alter bone dimensions. As mentioned before, this chain of events starting with increased osteoclast activity results in an increase in bone resorption [1]. Structural properties of bone modify with age as well [11]. Several age-related physical changes include: decreased cortical thickness, increased cortical porosity, and changes in bone geometry [11–13]. These structural changes translate to alterations in strength and risk for fracture [12,13]. Each change is a start of a series of changes. For instance, an increase in bone turnover results in an increase in cortical porosity [12]. This in turn has implications in increased fracture risk. Structural properties are classified into 2 areas: modifiable and nonmodifiable [13,14]. Non-modifiable factors, i.e., hip axis length, femoral neck angle, and femoral neck length, are genetic bone traits. Modifiable factors, i.e., cortical thickness and cortical porosity, have been shown to improve with some antiresorptive therapies [14,15]. It has been suggested that in hip fractures, the cortex has thinned and shows increased porosity. In the femoral neck cortex, the remodeling defect associated with hip fractures was specific to composite osteons [15]. The data suggests that generation of composite osteons may be a mechanism leading to increasing porosity and trabecularization of the cortex [13]. The importance of separate androgen and estrogen receptor activation on trabecular and cortical bone has been documented in several mice studies [16]. Androgen receptor activation dominates normal trabecular bone development and cortical bone modeling in male mice. However, periosteal bone expansion is only observed with both androgen and estrogen receptor activation [16]. Loss of estrogen or androgen receptors increases the rate of bone remodeling by removing the restraining effects on osteoblastogenesis and osteoclastogenesis [17,18]. This loss also causes imbalance between resorption and formation by elongating the life span of osteoclasts while shortening the life span of osteoblasts [18]. In studies conducted on the estrogenmediated effects on trabecular and cortical bone, ovariectomized mice were subject to estrogen treatment [18]. Female
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estrogen receptor β-deficient mice had an increased total bone mineral content as a resultant of increased cortical bone mineral content, specifically the cortical cross-sectional area, and radial cortical growth associated with increased periosteal circumference of the bones [19]. However, in male estrogen receptor βdeficient mice, no effect was observed. The effect of estrogen receptor-β on cortical bone mass may include direct effects on bone tissue [19]. In trabecular bone, though seemingly unaffected by the estrogen receptor-β deficiency, there was a decrease in trabecular volumetric BMD, demonstrating that there must be another mechanism, inducing this type of volumetric reduction [19]. Speculation into the activity of estrogen α alone or in correlation with estrogen receptor β needs to be further researched. These observations indicate a sexually differentiated phenotype in females and an estrogen receptor β role in osteoblast function [19]. In studies that isolate androgen effects on bone, in correlation with aromatizable testosterone, male-specific findings were discovered [17]. In male and female androgen receptor knockout mice, androgen effects were discovered on the male skeleton. When aromatized testosterone was administered to orchidectomized androgen receptor knockout mice, only partial prevention of bone loss was observed [17]. This finding indicates the function of the androgen receptor in male bone remodeling. Testosterone increased trabecular BMD, volume, number, and width in orchidectomized mice. In testicular feminized male mice, testosterone had less effect on trabecular BMD and no effect on bone structure [16]. In male mice specifically, androgen receptor-mediated testosterone action is pertinent in periosteal bone formation with some contribution to trabecular bone maintenance [20]. Hormonal influences on skeletal modeling and remodeling are new targets of research. By understanding this complex relationship, controlling hormonal changes might aid in the maintenance of bone quality [21]. Sex hormone-binding globulin (SHBG) is a glycoprotein specifically binding to estradiol and testosterone, and both hormones have high binding affinities for SHBG. Therefore, the sex-steroids bound to SHBG cannot readily access target tissues [21]. SHBG concentrations double with age increases in men, therefore limiting the availability of sex steroids. This limitation impacts the observed decline in bone mass experienced in aging men [21]. In studies examining the effects of serum levels of SHBG, hormone levels, and BMD in elderly and young adult males, a definite link was discovered [21]. In elderly men, SHBG was associated with testosterone and BMD at all hip bone sites. This same pattern was discovered in male mice overexpressing human SHBG, which correlated to an increased cortical bone mineral content in the femur. It can be suggested that elevated SHBG levels cause increased bone mass [21]. The complex, parallel pathway of SHBG-mediated entry of sex steroids into cells must be further studied, as results indicate that SHBG acts as both an inhibitor and facilitator [21]. Growth hormone (GH) is a major regulator of postnatal skeletal growth, and androgens have been considered to be important in the regulation of male periosteal bone expansion [22]. To further examine the impact of hormones on bone, male
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mice during puberty were studied [22]. Interactions between androgens/GH and Insulin-like Growth Factor 1 (IGF-I), with their Growth Hormone Receptor (GHR) gene disrupted, or knocked out were used in this study [22]. Dihydrotestosterone or testosterone was administered to orchidectomized male GH receptor gene knockout mice. Results indicated that GHR inactivation and low serum IGF-I did not affect trabecular bone modeling, because of trabecular BMD [22]. Those administered with dihydrotestosterone or testosterone had full prevention of trabecular bone loss. In addition to preventing trabecular bone loss, dihydrotestosterone and testosterone stimulated periosteal bone formation in all mice within the study [22]. The stimulation of periosteal bone resulted in an increase in cortical thickness, without any treatment of IGF-1 and or skeletal IGF-1 expression. It can be concluded that androgens stimulate trabecular and cortical bone modeling independent of any IGF-1 production [22]. GHR activation maintains radial bone expansion [22]. Trabecular structure has been indicated as a determinant of bone strength, independent of bone mass, leading to investigations into assessing the microstructure of bone [23]. To identify the relationship between hormonal and bone turnover variables and trabecular microstructure, using a high-resolution peripheral quantitative computed tomography (QCT), bone volume and tissue and trabecular number (TbN), thickness (TbTh), and separation (TbSp) were all used as parameters for measures of change. The importance of bioavailable estradiol (bio E2) and bioavailable testosterone (bio T) in men and women, young, middle-aged, and elderly, were analyzed using the above trabecular parameters [23]. There were expected hormonal changes as a result of aging, with progressive decreases in both bio E2 and bio T, increases in parathyroid hormone (PTH), and decreases in IGF-1 and IGFBP-3. Bone volume and tissue volume were lower in middle-aged and elderly men in compared with younger men. TbN was higher, with TbTh decreased in middle-aged men when compared to young men [23]. Elderly men had lower TbN and increased TbSp in comparison to middle-aged men, with TbTh similar in elderly and middle-aged men [23]. The indications of this study into the correlations between IGF-1 and IGFBP-3 levels in men and conversion of thick trabeculae to thinner still remain unclear [23]. However, it can be hypothesized that high IGF-1/GH levels in puberty and young adulthood in men, in conjunction with high androgen levels, lead to the formation of thick trabeculae [23]. There is direct evidence to the link between increased bone turnover and deterioration of trabecular microstructure [23]. In women, similar expected changes to hormone levels were also documented [23]. Decreases in bone volume and tissue volume as well as trabecular number and separation occurred with age. However, TbTh had the most statistically significant decrease out of the bone parameters [23]. When analyzing the hormonal and bone turnover markers, bio E2 was most strongly correlated with these trabecular parameters in elderly men. However, with elderly women, both bio E2 and bio T were correlated with trabecular parameters and subsequent changes [23]. When assessing the importance of either bio E2 vs. bio T, there was variations depending on age and gender of the
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individual. In young men and women, neither bio E2 nor bio T was significant [23]. In middle-aged men, bio E2 was independently associated with TbN and with TbSp. Bio T was independently associated with TbN and TbTh [23]. In elderly men, bio E2 was independently associated with bone volume and tissue volume, TbTh [23]. Again; bio T was not independently associated with these parameters. This finding was similar in elderly women, with bio E2 independently associated with TbN and TbSp, and bio T having no independent effect [23]. Due to the varying interactions of IGF-1/GH on androgen vs. estrogen, a sexual dimorphism of changes in TbTh and TbN in young men vs. young women that were observed [23]. Again, as observed with the men in this study, there was a link between increased bone turnover and deterioration of trabecular microstructure [21]. Bone turnover and antiresorptive treatment measures have induced several paradoxes in how BMD is measured [24]. Modest increases in BMD by antiresorptive therapies decrease fracture risk by almost the same extent as more potent antiresorptive agents that increase BMD by greater amounts [24]. In trabecular bone, this leads to the question as to why small increases in BMD observed after these therapies translate to larger decreases in vertebral fractures than initially predicted [24]. Studies have indicated that antiresorptive agents reduce fracture risk primarily by reducing bone turnover, since cortical bone is weakened by high bone turnover due to the increase in porosity, but this does not produce major microarchitectural disruptions within the system [24]. From this, it can be assumed that both a reduction in bone turnover combined with increase in hip BMD are required to reduce hip fracture risk [24]. In QCT studies, the influence of microstructural parameters in correlation between cortical bone strength was analyzed [24,25]. Significant correlations were found between BMD and all mechanical parameters, the elastic modulus, and yield stress. Parameters related to pore-diameter and for fraction of porous structures correlated significantly with parameters describing porous structures for the mechanical parameters of cortical bone [25]. Porosity was closely associated with parameters describing porous structures and haversian canal dimensions. The relevance of osteon density and osteonal structures was also made apparent during this study [25]. Recent studies have been focusing specifically on biochemical markers of bone turnover, bone-specific alkaline phosphatase (BSAP); and BMD of the spine and hip after 1 year of treatment in postmenopausal women with the bisphosphonate alendronate [26]. Alendronate-treated women who had a 30% reduction in bone BSAP also had a reduced risk of non-spine and hip fractures [26]. There were greater reductions in bone turnover with alendronate, versus placebo, and this translated to fewer hip, non-spine, and vertebral fracture [26]. The level of biochemical markers in bone resorption may also be a determinant for the decrease in fracture risk [26,27]. Greater decreases in bone resorption markers were associated with greater decreases in vertebral and non-vertebral fractures. Two bone markers were used; type 1 collagen (CTX) and the Ntelopeptide of type 1 collagen (NTX) in osteoporotic women with risedronate vertebral fractures [27]. There was lessened
improvement in vertebral fracture benefit below a decrease of 55%-60% for CTX and 35%–40% for NTX. The changes in NTX and CTX for non-vertebral, osteoporosis-related fractures were between 54%–77%, respectively [27]. These changes are similar to that observed in vertebral fractures [27]. Risedronate treatment effects were due to the decrease in bone resorption occurring in patients, leading to a decrease in fracture risk [27]. In an abstract further examining risedronate treatment specifically on cortical vs. trabecular bone mass on canine, vertebral bodies were examined [28]. Female T-10 vertebral bodies were obtained from canines and were treated with either oral saline or oral risedronatem for 1 year. Finite element models generated from a micro-CT scan were taken and the models were subjected to compressive loading [28]. The shell mass fraction was not altered by treatment, and more importantly, the maximum shell and trabecular load fractions were not significantly different between control and treatment groups [28]. These results indicate that the amount of cortical vs. trabecular bone mass was unchanged by treatment, resulting in unaltered loading sharing between cortical and trabecular compartments [28]. This further implies that risedronate treatment may not fundamentally alter load sharing between cortical shell and trabecular bone [28]. Specifically focusing on the therapeutic effects of bisphosphonates and cortical bone, several studies have examined a variety of bisphosphonates, isolating the various sites of therapy [29]. The overall desired effects of bisphosphonate treatments are to decrease bone turnover rate. This translates to structural improvements in the hip inclusive of decreased cortical porosity and increased cortical thickness [29,15]. All these factors will reduce the overall risk of a hip fracture. One particular bisphosphonate, alendronate, has been documented in the reduction of cortical porosity [15]. Alendronate 10 mg was administered to postmenopausal women over the course of 3 years. The illiac bone biopsies indicated significant differences in alendronate vs. placebo treatment [15]. Relative calcium content of the osteoporotic bone was significantly lower than that of controls. Mineralization was significantly higher and more uniform after the treatment with alendronate as well [15]. Moreover, the porosity of cortical bone was significantly reduced with this treatment. All of these factors overall result in a reduction of fracture risk [27,16]. To examine the structural benefits of alendronate treatment, hip structural geometry and BMD were analyzed with DXA technology [15]. Women undergoing hormone replacement therapy, alendronate, or a combination therapy were included in this study. After 3 years of treatment, alendronate treatment significantly improved cortical thickness at the narrow neck and trochanteric and femoral shaft regions compared to placebo [15,16]. It was determined that distribution of bone mass-improved density with antiresorptive agents in combination, or alone, has a positive impact on structural strength and stability at the proximal femur [15]. In studies to determine whether alendronate treatment produced positive changes in structural geometry by affecting the periosteal vs. endocortical surfaces of bone, postmenopausal women with osteoporosis were evaluated [30]. Transilial biopsy specimens were obtained from 137 women at the end of
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treatment following double fluorochrome labeling [30]. The specimens were examined for total surface, single- and doublelabeled surface, and mineral apposition rate in the periosteal and endocortical envelopes. Results indicated that there were differences in the way bone envelopes behaved during treatment. The periosteal envelope had a lower rate of bone formation than the endocortical envelope. Alendronate treatment decreased endocortical envelope formation, but not the periosteal envelope [30]. The results suggest that alendronate positively affects cortical bone by allowing for periosteal expansion as well as slowing the rate of endocortical bone remodeling, therefore slowing bone loss from the endocortical surface [30]. Another bisphosphonate that has correlated with alendronate, in the respect that bone strength is contingent on bone geometry, is ibandronate [29]. Previous studies into the oral bisphosphonate ibandronate have documented increased BMD at the spine and femur as well as reduced incidence of new vertebral fractures in the United States 50% when compared to placebo. Osteoporotic women were administered 2.5 mg of oral ibandronate daily for 3 years, intermittent oral ibandronate (20 mg every other day), or placebo [29]. Results indicated that, relative to placebo, oral ibandronate improved resistance to axial loads at all aforementioned regions and bending loads at the intertrochanter and shaft regions [29]. A lower buckling ratio at all regions suggests an improved buckling resistance under compressive loads as well [29]. Anabolic treatments, such as PTH and strontium ranelate, have proved their efficacy in improving both cortical and cancellous bone structures [31]. Instead of increasing bone strength by reducing bone resorption, this form of treatment stimulates bone formation [32]. Biopsies from the iliac crest of women treated with injected teriparatide improved both cancellous and cortical bone. Two-dimensional histomorphometry and 3D microcomputed tomography (microCT) scans were utilized to examine the bone biopsies [32]. The 2D histomorphometric analyses revealed an increase in cancellous bone volume by 14%. There was no significant change in mineral appositional rate or wall thickness [32]. By the 3D scans, cancellous density and cortical thickness were both increased significantly. Not only was there an increase in volume, but the connectivity also improved with a shift toward a more plate-like structure. When anabolic treatment is concurrently used with alendronate treatment, no evidence of synergy was discovered [32]. Studies that examine the periosteal bone formation, after treatment with teriparatide (PTH (1–34)), documented a reactivation of periosteal bone formation [33]. Periosteal bone formation occurs at lower levels during adulthood, especially in women, and can be reactivated with the treatment of teriparatide [33]. IGF-II was found to be twice as high on periosteal surfaces in teriparatide-treated patients than placebo-treated patients, which may play a role in the creation of a positive bone balance, as well as improved trabecular and cortical bone architecture [33]. Receptor activator of nuclear factor κ B ligand (RANKL) plays a key role in bone destruction [33]. This is the final mediator that regulates bone remodeling and primary mediator
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in osteoclast formation, function, and survival [32–34]. RANKL is naturally inhibited by osteoprogestrin and is important in determining the balance of osteoclost activity [34]. Recent studies have examined the relationship between the polymorphisms in receptor activator RANK and RANKL with BMD in postmenopausal women (n = 412) [34]. The human monoclonal antibody denosumab binds to RANKL and inhibits RANKL action. RANKL is an essential component of osteoclast differentiation, activation, and survival [35]. Treatment with denosumab resulted in an increase in bone mineral density at the lumbar spine, at the total hip, and at the distal third of the radius. In postmenopausal women with low bone mass, denosumab was proven to be an effective treatment for osteoporosis [35]. Another secondary treatment that reduces hip fractures (post hoc analysis) and spine fractures is strontium ranelate. This drug's mode of action has a dual nature, in that it increases bone formation and reduces bone resorption [36]. To further determine the effect of strontium ranelate on the cortical and trabecular microstructure in postmenopausal women, a microCT scan was utilized [36]. Biopsies of women treated with strontium ranelate of the iliac crest were compared to placebo for increased bone density [36]. Strontium ranelate treatment improved the trabecular structural model by changing the trabeculae rod-like model to a plate-like pattern [36]. Increased cortical thickness and increased trabecular volume and number were also observed. This treatment moreover stimulated 3D trabecular and cortical bone formation, improved bone biomechanical competence, which may account for the decrease of fracture risk [36]. References [1] Manolagas SC. Choreography from the tomb: an emerging role of dying osteocytes in the purposeful, and perhaps not so purposeful, targeting of bone remodeling. BoneKEY Osteovision 2006;3:5–14. [2] Wang L, Wang Y, Han Y, et al. In situ measurement of solute transport in the bone lacunar–canalicular system. Proc Natl Acad Sci U S A 2005; 33:11911–6. [3] Bonewald L. Mechanosensation and transduction in osteocytes. BoneKEY Osteovision 2006;10:7–15. [4] Aarden EM, Nijweide PJ, Van der Plas A, et al. Adhesive properties of isolated chick osteocytes in vitro. Bone 1996;18:305–13. [5] You LD, Weinbaum S, Cowin SC, et al. Ultrastructure of the osteocyte process and its pericelluar matrix. Anat Rec, A Discov Mol Cell Evol Biol 2004;278:505–13. [6] Frank JD, Ryan M, Kalscheur VL, Ruaux-Mason CP, Hozak RR, Muir P. Aging and accumulation of microdamage in canine bone. Bone 2002;30: 201–6. [7] Qiu S, Rao DS, Palnitkar S, Parfitt AM. Reduced iliac function cancellous osteocyte density in patients with osteoporotic vertebral fractures. J Bone Miner Res 2003;18:1657–63. [8] Vashishth D, Verborgt O, Divine G, Schaffler MB, Fyhrie DP. Decline in osteocyte lacunar density in human cortical bone is associated with accumulation of microcracks with age. Bone 2000;26:375–80. [9] Allen MR, Hock JM, Burr DB. Periosteum: biology, regulation, and response to osteoporosis therapies. Bone 2004;35:1003–12. [10] Bliziotes M, Sibonga JD, Turner RT, Orwoll E. Periosteal remodelling at the femoral neck in nonhuman primates. J Bone Miner Res 2006: 1060–7. [11] Szulc P, Seeman R, Duboeuf F, Sornay-Rendu E, Delmas PD. Bone fragility: failure of periosteal apposition to compensate for increased
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S. Epstein / Bone 41 (2007) S3–S8 endocortical resorption in postmenopausal women. J Bone Miner Res 2006;12:1863–5. Bousson V, Bergot C, Meunier A, et al. CT of the middiaphyseal femur: cortical bone mineral density and relation to porosity. Radiology 2000;217: 179–87. Bell KL, Loveridge N, Jordan GR, Power J, Constant CR, Reeve J. Superosteons (remodeling clusters) in the cortex of the femoral shaft: Influence of age and gender. Bone 2000;27:297–304. Greenspan SL, Beck TJ, Resnick NM, Bhattacharya R, Parker RA. Effect of hormone replacement, alendronate, or combination therapy on hip structural geometry: a 3-year, double-blind, placebo-controlled clinical trial. J Bone Miner Res 2005;20:1525–32. Roschger P, Rinnerthaler S, Yates J, Rodan GA, Fratzl P, Klaushofer K. Alendronate increases degree and uniformity of mineralization in cancellous bone and decreases the porosity in cortical bone of osteoporotic women. Bone 2001;29:185–91. Vandenput L, Swinnen JV, Boonen S, et al. Role of the androgen receptor in skeletal homeostasis: and androgen-resistant testicular feminized male mouse model. J Bone Miner Res 2004;19:1462–70. Venken K, De Gendt K, Boonen S, et al. Relative impact of androgen and estrogen receptor activation in the effects of androgens on trabecular and cortical bone in growing male mice: a study in the androgen receptor knockout mouse model. J Bone Miner Res 2006;21:576–85. Kawano H, Takashi S, Takashi Y, et al. Suppressive function of androgen receptor in bone resorption. Proc Natl Acad Sci U S A 2003;100:9416–21. Vanderschueren D, Vandenput L, Boonen S, Lindberg MK, Bouillon R, Ohlsson C. Androgens and bone. Endocr Rev 2004;25:389–425. Windhal SH, Vidal O, Andersson G, Gustafsson JA, Ohlsson C. Increased cortical bone mineral content but unchanged trabecular bone mineral density in female ERβ/-mice. J Clin Invest 1999;104:895–901. Khosla S. Sex hormone binding globulin: inhibitor or facilitator (or both) of sex steroid action? J Clin Endocrinol Metab 2006;12:4764–6. Venken K, Moverare-Skrtic S, Kopchick JJ. Impact of androgens, growth hormones, and igf-I on bone and muscle in male mice during puberty. J Bone Miner Res 2007;1:72–82. Khosla J, Melton J, Achenbach S, Oberg A, Riggs B. Hormonal and biochemical determinants of trabecular microstructure at the ultradistal radius in women and men. J Clin Endocrinol Metab 2006;91:885–91. Riggs K, Melton LJ. Bone turnover matters: the raloxifene treatment paradox of dramatic decreases in vertebral fracture without commensurate increases in bone density. J Bone Miner Res 2002;17:11–4.
[25] Wachter NJ, Krischak GD, Mentzel M, et al. Correlation of bone mineral density with strength and microstructural parameters of cortical bone in vivo. Bone 2002;31:90–5. [26] Bauer DC, Black DM, Garnero P, et al. Change in bone turnover and hip, non-spine, and vertebral fracture in alendronate-treated women: the fracture intervention trial. J Bone Miner Res 2004;19:1250–8. [27] Eastell R, Barton I, Hannon RA, Chines A, Garnero P, Delmas PD. Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate. J Bone Miner Res 2003;18:1051–6. [28] Eswaran SK, Bevill G, Allen MR, Burr DB, Keaveny TM. Effect of risedronate on cortical and trabecular load sharing characteristics of the canine vertebral body. Presented at the American Society of Bone and Mineral 2006. Presented at the American Society for Bone and Mineral Research; September 2006; Philadelphia, PA. Abstract M341. [29] Fuerst T, Beck TJ, Gaither K, Kothari M, Genant HK. Effect of oral ibandronate on hip structure: results from the BONE study. In: The 28th Annual Meeting of the American Society of Bone and Mineral Research; September 2006; Philadelphia, PA. Abstract SU323. [30] Bare S, Recker S, Recker R, Kimmel D. Influence of alendronate on perisoteal and endocortical bone formation in the ilium of osteoporotic women. Abstract SA414. Presented at the 28th Annual Meeting of the American Society for Bone and Mineral Research; Philadelphia, PA. [31] Eghbali-Fatourechi G, Khosla S, Sanyal A, Boyle WJ, Lacey DL, Riggs BL. Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J Clin Invest 2003;111:1221–30. [32] Boyle WJ, Simonet WS, Lacey DL. Osteoclast differentiation and activation. Nature 2003;423:337–42. [33] Meunier P, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. NEJM 2004;350:459–68. [34] Ma YL, Zeng Q, Donley D. Teriparatide increases bone formation in modeling and remodeling osteons and enhances IGF-II immunoreactivity in postmenopausal women with osteoporosis. J Bone Miner Res 2006;21: 855–64. [35] Jiang Y, Genant H, Zhao J. Effect of strontium ranelate on 3D cortical and trabecular microstructure in postmenopausal osteoporosis in multicenter, double-blind, and placebo controlled studies. In: The 28th Annual Meeting of the American Society of Bone and Mineral Research; September 2006; Philadelphia, PA. Abstract 1160. [36] McClung MR, Lewiecki EM, Cohen SB, et al. Denosumab in postmenopausal women with low bone mineral density. NEJM 2006;8:821–31.
Is Cortical Bone Hip? What determines Cortical Bone Properties? Sol Epstein ⁎ Medicine and Geriatrics, Mount Sinai School of Medicine, New York, USA Doylestown Hospital, Doylestown, PA, USA Received 12 March 2007; accepted 12 March 2007 Available online 19 March 2007
Abstract Increased bone turnover may produce a disturbance in bone structure which may result in fracture. In cortical bone, both reduction in turnover and increase in hip bone mineral density (BMD) may be necessary to decrease hip fracture risk and may require relatively greater proportionate changes than for trabecular bone. It should also be noted that increased porosity produces disproportionate reduction in bone strength, and studies have shown that increased cortical porosity and decreased cortical thickness are associated with hip fracture. Continued studies for determining the causes of bone strength and deterioration show distinct promise. Osteocyte viability has been observed to be an indicator of bone strength, with viability as the result of maintaining physiological levels of loading and osteocyte apoptosis as the result of a decrease in loading. Osteocyte apoptosis and decrease are major factors in the bone loss and fracture associated with aging. Both the osteocyte and periosteal cell layer are assuming greater importance in the process of maintaining skeletal integrity as our knowledge of these cells expand, as well being a target for pharmacological agents to reduce fracture especially in cortical bone. The bisphosphonate alendronate has been seen to have a positive effect on cortical bone by allowing customary periosteal growth, while reducing the rate of endocortical bone remodeling and slowing bone loss from the endocortical surface. Risedronate treatment effects were attributed to decrease in bone resorption and thus a decrease in fracture risk. Ibandronate has been seen to increase BMD as the spine and femur as well as a reduced incidence of new vertebral fractures and non vertebral on subset post hoc analysis. And treatment with the anabolic agent PTH(1-34) documented modeling and remodelling of quiescent and active bone surfaces. Receptor activator of nuclear factor κ B ligand (RANKL) plays a key role in bone destruction, and the human monoclonal antibody denosumab binds to RANKL, inhibiting its action and thus improving BMD significantly. © 2007 Elsevier Inc. All rights reserved. Keywords: Cortical; Trabecular; Osteocyte; Periosteal; Bone marker
In order to understand the pathophysiology of osteoporosis and treatment, the anatomy and basic makeup of cortical bone need to be emphasized. Recent information into crucial aspects of cortical bone (i.e., the osteocyte, its life cycle, and more importantly, its death) provides vital information into the purpose of these cells while they were alive [1]. Osteocytes are the most abundant and evenly distributed, longest-lived, and best-connected cell types in the mineralized matrix [1,2]. However, it is the cannicular system through which these osteocytes communicate that is of particular interest [2]. Radiating dendritic processes from each osteocyte are extensive and run through the canaliculi, similar to that of dendritic
⁎ Fax: +1 215 345 2157. E-mail address: [email protected]. 8756-3282/$ - see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.bone.2007.03.006
processes in other systems [2]. Solute transport through the bone lacunar–canalicular system is believed to be essential for osteocyte survival and function [2]. However, this is not the only method of signaling these cells utilize. Osteocyte apoptosis can influence the mechanosensory function of the osteocyte network [1,2]. Though there is little conclusive data to demonstrate the relationship between mechanical loading and sensing of these cells, it is thought that through this interstitial fluid that osteocyte activity is triggered and also cell-signaling molecules and nutrient waste products [3]. The highly interconnective system appears to be 1 reason why osteocytes are responsive to mechanical strain, as well as translating that strain accordingly to the intensity of strain signals [1–3]. Mechanical strain is translated in vivo either as deformation of the extracellular matrix or as fluid shear stress along the cells which indicates that osteocytes have close contact with the bone matrix [4]. This
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mechanical sensor ability has also been indicated in the mechanosensing process in which osteocytes directly sense the deformation of the substrate to which they are attached [4,5]. Osteocytes make contact with the extracellular matrix through attachments points that colocalize with vinculin [4]. This connection is important in translating mechanical strain from extracellular signals into intracellular messages [4,5]. Age has always been a strong indicator in the determination of fracture risk independent of bone mineral density (BMD). With respect to osteocytes and increase in age, osteocyte lacunar density has been documented to decrease exponentially with age [6–7]. Osteocyte density has also recently been identified as a fracture indicator more accurate than bone mineral density alone (BMD) [6]. Studies in mice at both 8 and 16 months have concluded that even in the absence of any detectable decreases in BMD, an increased prevalence in osteocyte apoptosis was observed [1,6]. Decline in osteocyte lacunar density in cortical bone is correlated with increase in microcracks as well as increase in porosity with age [6]. Cyclic loading of bone during normal activity can lead to microcrack formation within the tissue matrix of compact bone [6]. Alteration to local material properties of bone tissue or alterations in the local tissue repair responses may play a role in the accumulation of microdamage in bone with aging [6,7]. This increase in porosity and microcrack density coincides with the decline of osteocyte number [7,8]. There must be a certain minimum in osteocyte number to maintain the network; moreover, the spatial organizational changes in osteocyte density, due to formation of composite osteons, reduce fluidity with age, indicating an increase in microfracture potential with increasing age [6–8]. The periosteum contains osteogenic cells that regulate the outer shape of bone and regulate cortical thickness, size, and position of the bone [9]. Osteoblasts in the cambium layer become fewer in number with age, and this reduction in number is speculated to contribute to the thinning and decreasing in layer thickness of the cambium layer [8,9]. Age-related changes to the periosteal cells, including their decline in reaction to circulating hormonal influences, need to be further examined [9]. Periosteal stimulation may provide better antifracture efficacy than agents that primarily target endosteal and trabecular cellular populations [9]. Targeting the osteogenic response on periosteal surfaces can increase bone circumference and reduce the risk of osteoporotic fracture. Analysis of the variations between periosteal cells and endosteal cells responses to external pharmacological influences is key to understanding how to combat osteoporosis [9,10]. The link between increases in endocortical resorption and reduction of periosteal bone formation has been examined in both perimenopausal and postmenopausal women [11]. Loss of bone from the inner, endocortical surface has been demonstrated to contribute to bone fragility, and the compensatory action of deposition of bone on the outer periosteal surface is believed to be an adaptive response as a resistance to bending [11]. Changes in bone mass and bone geometry and strength of the one-third distal radius, bone marker turnovers, and fracture incidences were measured in women (n = 821) between the ages of 30 and 89. Each woman was receiving hormone replacement therapy, and results
indicated an accelerated endocortical resorption, while periosteal apposition declined [11]. Women that had experienced the greatest loss of bone mass and strength had the highest level of remodeling activity [11]. With aging women, periosteal apposition does not increase after menopause to compensate for bone loss, instead it decreases. It can be speculated that stimulation of periosteal apposition to increase bone width will improve bone strength [11]. Expanding the periosteal parameter could dramatically improve bone strength and decrease fracture risk, without the influences of bone density [10]. Sex steroiddeficient animals and periosteal bone turnover in the femoral neck relating to osteoclast number were examined to further identify the relationship between osteocytes and periosteal formation [9,10]. Bone turnover in the periosteum of the femoral neck in controls was more rapid than at the femoral shaft, but slower than in the femoral neck cancellous bone [10]. Animals that were sex steroid-deficient resulted in an increase in osteoclast number on the periosteal surface when compared to controls [10]. With bone size being such an important determinant of bone strength, cellular activities at the periosteal surface may alter bone dimensions. As mentioned before, this chain of events starting with increased osteoclast activity results in an increase in bone resorption [1]. Structural properties of bone modify with age as well [11]. Several age-related physical changes include: decreased cortical thickness, increased cortical porosity, and changes in bone geometry [11–13]. These structural changes translate to alterations in strength and risk for fracture [12,13]. Each change is a start of a series of changes. For instance, an increase in bone turnover results in an increase in cortical porosity [12]. This in turn has implications in increased fracture risk. Structural properties are classified into 2 areas: modifiable and nonmodifiable [13,14]. Non-modifiable factors, i.e., hip axis length, femoral neck angle, and femoral neck length, are genetic bone traits. Modifiable factors, i.e., cortical thickness and cortical porosity, have been shown to improve with some antiresorptive therapies [14,15]. It has been suggested that in hip fractures, the cortex has thinned and shows increased porosity. In the femoral neck cortex, the remodeling defect associated with hip fractures was specific to composite osteons [15]. The data suggests that generation of composite osteons may be a mechanism leading to increasing porosity and trabecularization of the cortex [13]. The importance of separate androgen and estrogen receptor activation on trabecular and cortical bone has been documented in several mice studies [16]. Androgen receptor activation dominates normal trabecular bone development and cortical bone modeling in male mice. However, periosteal bone expansion is only observed with both androgen and estrogen receptor activation [16]. Loss of estrogen or androgen receptors increases the rate of bone remodeling by removing the restraining effects on osteoblastogenesis and osteoclastogenesis [17,18]. This loss also causes imbalance between resorption and formation by elongating the life span of osteoclasts while shortening the life span of osteoblasts [18]. In studies conducted on the estrogenmediated effects on trabecular and cortical bone, ovariectomized mice were subject to estrogen treatment [18]. Female
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estrogen receptor β-deficient mice had an increased total bone mineral content as a resultant of increased cortical bone mineral content, specifically the cortical cross-sectional area, and radial cortical growth associated with increased periosteal circumference of the bones [19]. However, in male estrogen receptor βdeficient mice, no effect was observed. The effect of estrogen receptor-β on cortical bone mass may include direct effects on bone tissue [19]. In trabecular bone, though seemingly unaffected by the estrogen receptor-β deficiency, there was a decrease in trabecular volumetric BMD, demonstrating that there must be another mechanism, inducing this type of volumetric reduction [19]. Speculation into the activity of estrogen α alone or in correlation with estrogen receptor β needs to be further researched. These observations indicate a sexually differentiated phenotype in females and an estrogen receptor β role in osteoblast function [19]. In studies that isolate androgen effects on bone, in correlation with aromatizable testosterone, male-specific findings were discovered [17]. In male and female androgen receptor knockout mice, androgen effects were discovered on the male skeleton. When aromatized testosterone was administered to orchidectomized androgen receptor knockout mice, only partial prevention of bone loss was observed [17]. This finding indicates the function of the androgen receptor in male bone remodeling. Testosterone increased trabecular BMD, volume, number, and width in orchidectomized mice. In testicular feminized male mice, testosterone had less effect on trabecular BMD and no effect on bone structure [16]. In male mice specifically, androgen receptor-mediated testosterone action is pertinent in periosteal bone formation with some contribution to trabecular bone maintenance [20]. Hormonal influences on skeletal modeling and remodeling are new targets of research. By understanding this complex relationship, controlling hormonal changes might aid in the maintenance of bone quality [21]. Sex hormone-binding globulin (SHBG) is a glycoprotein specifically binding to estradiol and testosterone, and both hormones have high binding affinities for SHBG. Therefore, the sex-steroids bound to SHBG cannot readily access target tissues [21]. SHBG concentrations double with age increases in men, therefore limiting the availability of sex steroids. This limitation impacts the observed decline in bone mass experienced in aging men [21]. In studies examining the effects of serum levels of SHBG, hormone levels, and BMD in elderly and young adult males, a definite link was discovered [21]. In elderly men, SHBG was associated with testosterone and BMD at all hip bone sites. This same pattern was discovered in male mice overexpressing human SHBG, which correlated to an increased cortical bone mineral content in the femur. It can be suggested that elevated SHBG levels cause increased bone mass [21]. The complex, parallel pathway of SHBG-mediated entry of sex steroids into cells must be further studied, as results indicate that SHBG acts as both an inhibitor and facilitator [21]. Growth hormone (GH) is a major regulator of postnatal skeletal growth, and androgens have been considered to be important in the regulation of male periosteal bone expansion [22]. To further examine the impact of hormones on bone, male
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mice during puberty were studied [22]. Interactions between androgens/GH and Insulin-like Growth Factor 1 (IGF-I), with their Growth Hormone Receptor (GHR) gene disrupted, or knocked out were used in this study [22]. Dihydrotestosterone or testosterone was administered to orchidectomized male GH receptor gene knockout mice. Results indicated that GHR inactivation and low serum IGF-I did not affect trabecular bone modeling, because of trabecular BMD [22]. Those administered with dihydrotestosterone or testosterone had full prevention of trabecular bone loss. In addition to preventing trabecular bone loss, dihydrotestosterone and testosterone stimulated periosteal bone formation in all mice within the study [22]. The stimulation of periosteal bone resulted in an increase in cortical thickness, without any treatment of IGF-1 and or skeletal IGF-1 expression. It can be concluded that androgens stimulate trabecular and cortical bone modeling independent of any IGF-1 production [22]. GHR activation maintains radial bone expansion [22]. Trabecular structure has been indicated as a determinant of bone strength, independent of bone mass, leading to investigations into assessing the microstructure of bone [23]. To identify the relationship between hormonal and bone turnover variables and trabecular microstructure, using a high-resolution peripheral quantitative computed tomography (QCT), bone volume and tissue and trabecular number (TbN), thickness (TbTh), and separation (TbSp) were all used as parameters for measures of change. The importance of bioavailable estradiol (bio E2) and bioavailable testosterone (bio T) in men and women, young, middle-aged, and elderly, were analyzed using the above trabecular parameters [23]. There were expected hormonal changes as a result of aging, with progressive decreases in both bio E2 and bio T, increases in parathyroid hormone (PTH), and decreases in IGF-1 and IGFBP-3. Bone volume and tissue volume were lower in middle-aged and elderly men in compared with younger men. TbN was higher, with TbTh decreased in middle-aged men when compared to young men [23]. Elderly men had lower TbN and increased TbSp in comparison to middle-aged men, with TbTh similar in elderly and middle-aged men [23]. The indications of this study into the correlations between IGF-1 and IGFBP-3 levels in men and conversion of thick trabeculae to thinner still remain unclear [23]. However, it can be hypothesized that high IGF-1/GH levels in puberty and young adulthood in men, in conjunction with high androgen levels, lead to the formation of thick trabeculae [23]. There is direct evidence to the link between increased bone turnover and deterioration of trabecular microstructure [23]. In women, similar expected changes to hormone levels were also documented [23]. Decreases in bone volume and tissue volume as well as trabecular number and separation occurred with age. However, TbTh had the most statistically significant decrease out of the bone parameters [23]. When analyzing the hormonal and bone turnover markers, bio E2 was most strongly correlated with these trabecular parameters in elderly men. However, with elderly women, both bio E2 and bio T were correlated with trabecular parameters and subsequent changes [23]. When assessing the importance of either bio E2 vs. bio T, there was variations depending on age and gender of the
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individual. In young men and women, neither bio E2 nor bio T was significant [23]. In middle-aged men, bio E2 was independently associated with TbN and with TbSp. Bio T was independently associated with TbN and TbTh [23]. In elderly men, bio E2 was independently associated with bone volume and tissue volume, TbTh [23]. Again; bio T was not independently associated with these parameters. This finding was similar in elderly women, with bio E2 independently associated with TbN and TbSp, and bio T having no independent effect [23]. Due to the varying interactions of IGF-1/GH on androgen vs. estrogen, a sexual dimorphism of changes in TbTh and TbN in young men vs. young women that were observed [23]. Again, as observed with the men in this study, there was a link between increased bone turnover and deterioration of trabecular microstructure [21]. Bone turnover and antiresorptive treatment measures have induced several paradoxes in how BMD is measured [24]. Modest increases in BMD by antiresorptive therapies decrease fracture risk by almost the same extent as more potent antiresorptive agents that increase BMD by greater amounts [24]. In trabecular bone, this leads to the question as to why small increases in BMD observed after these therapies translate to larger decreases in vertebral fractures than initially predicted [24]. Studies have indicated that antiresorptive agents reduce fracture risk primarily by reducing bone turnover, since cortical bone is weakened by high bone turnover due to the increase in porosity, but this does not produce major microarchitectural disruptions within the system [24]. From this, it can be assumed that both a reduction in bone turnover combined with increase in hip BMD are required to reduce hip fracture risk [24]. In QCT studies, the influence of microstructural parameters in correlation between cortical bone strength was analyzed [24,25]. Significant correlations were found between BMD and all mechanical parameters, the elastic modulus, and yield stress. Parameters related to pore-diameter and for fraction of porous structures correlated significantly with parameters describing porous structures for the mechanical parameters of cortical bone [25]. Porosity was closely associated with parameters describing porous structures and haversian canal dimensions. The relevance of osteon density and osteonal structures was also made apparent during this study [25]. Recent studies have been focusing specifically on biochemical markers of bone turnover, bone-specific alkaline phosphatase (BSAP); and BMD of the spine and hip after 1 year of treatment in postmenopausal women with the bisphosphonate alendronate [26]. Alendronate-treated women who had a 30% reduction in bone BSAP also had a reduced risk of non-spine and hip fractures [26]. There were greater reductions in bone turnover with alendronate, versus placebo, and this translated to fewer hip, non-spine, and vertebral fracture [26]. The level of biochemical markers in bone resorption may also be a determinant for the decrease in fracture risk [26,27]. Greater decreases in bone resorption markers were associated with greater decreases in vertebral and non-vertebral fractures. Two bone markers were used; type 1 collagen (CTX) and the Ntelopeptide of type 1 collagen (NTX) in osteoporotic women with risedronate vertebral fractures [27]. There was lessened
improvement in vertebral fracture benefit below a decrease of 55%-60% for CTX and 35%–40% for NTX. The changes in NTX and CTX for non-vertebral, osteoporosis-related fractures were between 54%–77%, respectively [27]. These changes are similar to that observed in vertebral fractures [27]. Risedronate treatment effects were due to the decrease in bone resorption occurring in patients, leading to a decrease in fracture risk [27]. In an abstract further examining risedronate treatment specifically on cortical vs. trabecular bone mass on canine, vertebral bodies were examined [28]. Female T-10 vertebral bodies were obtained from canines and were treated with either oral saline or oral risedronatem for 1 year. Finite element models generated from a micro-CT scan were taken and the models were subjected to compressive loading [28]. The shell mass fraction was not altered by treatment, and more importantly, the maximum shell and trabecular load fractions were not significantly different between control and treatment groups [28]. These results indicate that the amount of cortical vs. trabecular bone mass was unchanged by treatment, resulting in unaltered loading sharing between cortical and trabecular compartments [28]. This further implies that risedronate treatment may not fundamentally alter load sharing between cortical shell and trabecular bone [28]. Specifically focusing on the therapeutic effects of bisphosphonates and cortical bone, several studies have examined a variety of bisphosphonates, isolating the various sites of therapy [29]. The overall desired effects of bisphosphonate treatments are to decrease bone turnover rate. This translates to structural improvements in the hip inclusive of decreased cortical porosity and increased cortical thickness [29,15]. All these factors will reduce the overall risk of a hip fracture. One particular bisphosphonate, alendronate, has been documented in the reduction of cortical porosity [15]. Alendronate 10 mg was administered to postmenopausal women over the course of 3 years. The illiac bone biopsies indicated significant differences in alendronate vs. placebo treatment [15]. Relative calcium content of the osteoporotic bone was significantly lower than that of controls. Mineralization was significantly higher and more uniform after the treatment with alendronate as well [15]. Moreover, the porosity of cortical bone was significantly reduced with this treatment. All of these factors overall result in a reduction of fracture risk [27,16]. To examine the structural benefits of alendronate treatment, hip structural geometry and BMD were analyzed with DXA technology [15]. Women undergoing hormone replacement therapy, alendronate, or a combination therapy were included in this study. After 3 years of treatment, alendronate treatment significantly improved cortical thickness at the narrow neck and trochanteric and femoral shaft regions compared to placebo [15,16]. It was determined that distribution of bone mass-improved density with antiresorptive agents in combination, or alone, has a positive impact on structural strength and stability at the proximal femur [15]. In studies to determine whether alendronate treatment produced positive changes in structural geometry by affecting the periosteal vs. endocortical surfaces of bone, postmenopausal women with osteoporosis were evaluated [30]. Transilial biopsy specimens were obtained from 137 women at the end of
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treatment following double fluorochrome labeling [30]. The specimens were examined for total surface, single- and doublelabeled surface, and mineral apposition rate in the periosteal and endocortical envelopes. Results indicated that there were differences in the way bone envelopes behaved during treatment. The periosteal envelope had a lower rate of bone formation than the endocortical envelope. Alendronate treatment decreased endocortical envelope formation, but not the periosteal envelope [30]. The results suggest that alendronate positively affects cortical bone by allowing for periosteal expansion as well as slowing the rate of endocortical bone remodeling, therefore slowing bone loss from the endocortical surface [30]. Another bisphosphonate that has correlated with alendronate, in the respect that bone strength is contingent on bone geometry, is ibandronate [29]. Previous studies into the oral bisphosphonate ibandronate have documented increased BMD at the spine and femur as well as reduced incidence of new vertebral fractures in the United States 50% when compared to placebo. Osteoporotic women were administered 2.5 mg of oral ibandronate daily for 3 years, intermittent oral ibandronate (20 mg every other day), or placebo [29]. Results indicated that, relative to placebo, oral ibandronate improved resistance to axial loads at all aforementioned regions and bending loads at the intertrochanter and shaft regions [29]. A lower buckling ratio at all regions suggests an improved buckling resistance under compressive loads as well [29]. Anabolic treatments, such as PTH and strontium ranelate, have proved their efficacy in improving both cortical and cancellous bone structures [31]. Instead of increasing bone strength by reducing bone resorption, this form of treatment stimulates bone formation [32]. Biopsies from the iliac crest of women treated with injected teriparatide improved both cancellous and cortical bone. Two-dimensional histomorphometry and 3D microcomputed tomography (microCT) scans were utilized to examine the bone biopsies [32]. The 2D histomorphometric analyses revealed an increase in cancellous bone volume by 14%. There was no significant change in mineral appositional rate or wall thickness [32]. By the 3D scans, cancellous density and cortical thickness were both increased significantly. Not only was there an increase in volume, but the connectivity also improved with a shift toward a more plate-like structure. When anabolic treatment is concurrently used with alendronate treatment, no evidence of synergy was discovered [32]. Studies that examine the periosteal bone formation, after treatment with teriparatide (PTH (1–34)), documented a reactivation of periosteal bone formation [33]. Periosteal bone formation occurs at lower levels during adulthood, especially in women, and can be reactivated with the treatment of teriparatide [33]. IGF-II was found to be twice as high on periosteal surfaces in teriparatide-treated patients than placebo-treated patients, which may play a role in the creation of a positive bone balance, as well as improved trabecular and cortical bone architecture [33]. Receptor activator of nuclear factor κ B ligand (RANKL) plays a key role in bone destruction [33]. This is the final mediator that regulates bone remodeling and primary mediator
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in osteoclast formation, function, and survival [32–34]. RANKL is naturally inhibited by osteoprogestrin and is important in determining the balance of osteoclost activity [34]. Recent studies have examined the relationship between the polymorphisms in receptor activator RANK and RANKL with BMD in postmenopausal women (n = 412) [34]. The human monoclonal antibody denosumab binds to RANKL and inhibits RANKL action. RANKL is an essential component of osteoclast differentiation, activation, and survival [35]. Treatment with denosumab resulted in an increase in bone mineral density at the lumbar spine, at the total hip, and at the distal third of the radius. In postmenopausal women with low bone mass, denosumab was proven to be an effective treatment for osteoporosis [35]. Another secondary treatment that reduces hip fractures (post hoc analysis) and spine fractures is strontium ranelate. This drug's mode of action has a dual nature, in that it increases bone formation and reduces bone resorption [36]. To further determine the effect of strontium ranelate on the cortical and trabecular microstructure in postmenopausal women, a microCT scan was utilized [36]. Biopsies of women treated with strontium ranelate of the iliac crest were compared to placebo for increased bone density [36]. Strontium ranelate treatment improved the trabecular structural model by changing the trabeculae rod-like model to a plate-like pattern [36]. Increased cortical thickness and increased trabecular volume and number were also observed. This treatment moreover stimulated 3D trabecular and cortical bone formation, improved bone biomechanical competence, which may account for the decrease of fracture risk [36]. References [1] Manolagas SC. Choreography from the tomb: an emerging role of dying osteocytes in the purposeful, and perhaps not so purposeful, targeting of bone remodeling. BoneKEY Osteovision 2006;3:5–14. [2] Wang L, Wang Y, Han Y, et al. In situ measurement of solute transport in the bone lacunar–canalicular system. Proc Natl Acad Sci U S A 2005; 33:11911–6. [3] Bonewald L. Mechanosensation and transduction in osteocytes. BoneKEY Osteovision 2006;10:7–15. [4] Aarden EM, Nijweide PJ, Van der Plas A, et al. Adhesive properties of isolated chick osteocytes in vitro. Bone 1996;18:305–13. [5] You LD, Weinbaum S, Cowin SC, et al. Ultrastructure of the osteocyte process and its pericelluar matrix. Anat Rec, A Discov Mol Cell Evol Biol 2004;278:505–13. [6] Frank JD, Ryan M, Kalscheur VL, Ruaux-Mason CP, Hozak RR, Muir P. Aging and accumulation of microdamage in canine bone. Bone 2002;30: 201–6. [7] Qiu S, Rao DS, Palnitkar S, Parfitt AM. Reduced iliac function cancellous osteocyte density in patients with osteoporotic vertebral fractures. J Bone Miner Res 2003;18:1657–63. [8] Vashishth D, Verborgt O, Divine G, Schaffler MB, Fyhrie DP. Decline in osteocyte lacunar density in human cortical bone is associated with accumulation of microcracks with age. Bone 2000;26:375–80. [9] Allen MR, Hock JM, Burr DB. Periosteum: biology, regulation, and response to osteoporosis therapies. Bone 2004;35:1003–12. [10] Bliziotes M, Sibonga JD, Turner RT, Orwoll E. Periosteal remodelling at the femoral neck in nonhuman primates. J Bone Miner Res 2006: 1060–7. [11] Szulc P, Seeman R, Duboeuf F, Sornay-Rendu E, Delmas PD. Bone fragility: failure of periosteal apposition to compensate for increased
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