[Frontiers in Bioscience S2, 468-482, January 1, 2010]
Bone remodeling, humoral networks and smart biomaterial technology for osteoporosis
Milena Fini1,2, Angelo Carpi3 , Veronica Borsari1, Matilde Tschon1, Andrea Nicolini4, Maria Sartori1, Jeffrey Mechanick5, Roberto Giardino1,6
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TABLE OF CONTENTS
1. ABSTRACT
One of the unfortunate sequelae of increased life expectancy is a growing number of age-related degenerative diseases, a prime example being osteoporosis. This form of metabolic bone disease and related co-morbidities consume tremendous resources and costs from a nation's health care system. Osteoporosis results from genetic, age-related, and hormone-dependent causes as well as a compendium of secondary pathophysiological states. The presence of osteoporosis as a comorbidity confers a significant negative prognostic element following orthopedic procedures. In vitro and in vivo studies of osteoporotic bone implicate microarchitectural bone rarefaction, microenvironmental and functional disturbance of osteoblast-osteoclast coupling, and abnormal tissue and signalling molecule repertoires, each having detrimental effects on the regenerative and osteointegration processes. This review explores the pathophysiology of bone remodeling from a macro- and micro- systems biology standpoint with a focus on cytokine interactions. Furthermore, therapeutic interventions exploiting vulnerable nodes in these physiological networks will be posited. One exciting development in this area is the use of novel biomaterials.
2. INTRODUCTION
Osteoporosis is caused by genetic, age-related, hormone-dependent, or iatrogenic (drug-related) factors as well as a host of pathophysiological states, including malabsorption and chronic kidney disease, and harmful life styles (e.g., smoking and alcoholism). Osteoporosis is associated with increased risk for fracture and also contributes to orthopedic implant or reconstructive surgery failures. As a negative prognosticator for many illnesses, osteoporosis confers significant quality of life compromise, economic burden and excess morbidity and mortality on health care systems globally.
Contemporary innovations for the treatment of musculoskeletal pathology include new surgical techniques, biological therapies and smart biomaterials. These so-called "smart" biomaterials are produced by modifying the physical properties of the scaffolds using peptide sequences, and most importantly, by developing materials that can deliver proteins to enhance tissue regeneration and actively participate in the formation of functional tissue (1, 2). Specifically, biological stimulators, such as cells, growth factors and signaling molecules, alone or in combination with bioactive and biomimetic materials have been studied in clinical trials. They have been shown to treat many traumatic or degenerative pathologies, such as fractures, congenital skeletal malformations, cartilage or ligament lesions, osteoporosis, and other bone remodeling disorders.
Biomaterials that are successfully cultured with healthy bone cells show reduced osteoconductive properties when cultured with pathological bone cells isolated from osteoporotic bone (3, 4). In vitro and in vivo studies of osteoporotic bone implicate microarchitectural bone rarefaction, microenvironmental and functional disturbance of osteoblast-osteoclast coupling, and abnormal tissue and signalling molecule repertoires, each having detrimental effects on the regenerative and osteointegration processes. It is proposed that achieving some threshold resonance between biological interventions and the complex interactions of humoral regulatory factors in the skeleton is necessary for therapeutic success (5).
Unfortunately, comorbid and patient idiosyncratic factors can mitigate the utility of biological therapies and biomaterials. What are these precise mitigating factors? How do they interact with physiological networks involving bone? What fashion can therapeutic skeletal interventions be tailored to optimize outcome?
This article will address these questions. First, bone remodeling physiology will be reviewed with an emphasis on humoral (cytokine and hormonal) regulatory networks. Then, the pathological state in osteoporosis will be discussed setting the stage for potential biological interventions. Third, biological therapies and various biomaterials tailored to exploit vulnerable nodes in the systems physiology of bone will be explored.
3. PHYSIOLOGIC BONE REMODELLING
3.1. General aspects
Bone is a dynamic tissue. It requires continuous remodeling to supply and fulfill structural and metabolic functions. There are several key physiological functions that bone remodeling subserves. Generally considered as the most important, bone provides the internal mechanical support of the body and anatomically, the sites of tendon and muscle attachment for locomotion. Accordingly, bone protects vital organs body and encases the bone marrow. However, bone also plays an important metabolic role. Bone is the main store of inorganic ions, calcium (Ca) and phosphorus (P) principally, and it is involved in mineral homeostasis (6-8). Additionally, recent evidence now implicates bone as a source of humoral factors that can affect pancreatic beta-cell function and insulin secretion, and via complex networking, other organs participating in the control of body composition and intermediary metabolism (9, 10).
The dynamic nature of bone was firstly proposed in 1892 and is widely referred as Wolff's law: "As bones are subjected to stress demands in weight bearing posture, they will model or alter their shape accordingly" (11). In other words, even though skeletal mass and histomorphology are well defined, bone will remodel in response to mechanical forces, biochemical changes, and biological signals.
Approximately 10% of the skeleton is renewed each year by remodelling (12). This process is necessary to repair skeletal microfractures of the skeleton, prevent accumulation of older and weaker bone, and maintain mineral homeostasis. This process is complex and characterized by the coordinated actions of osteoclasts and osteoblasts, organized in basic multicellular units (BMU) that follow a cycle of resorption, reversal, formation, and resting phases. Remodeling begins with the migration of partially differentiated mononuclear pre-osteoclasts to the bone surface where they form multinucleated osteoclasts (13,14). The signal that initiates the resorption phase is thought to be the mechanical stress that alters local bone architecture and is sensed and transduced by osteocytes (15). After osteoclastic resorption, which takes about 2 weeks, there is a reversal phase when mononuclear cells on the bone surface provide signals for osteoblast differentiation and migration. The reversal phase lasts up to 4-5 weeks. In the formation phase, osteoblast lay down bone until the resorbed bone is completely replaced by new bone; this phase may last for about 4-6 months. Eventually, bone surface is covered with flattened lining cells and a resting period follows (16). This dynamic process occurs in BMUs at multiple sites simultaneously throughout the skeleton and is a localized rather than a systemic process (17).
3.2. Systemic regulation: the role of hormones
There are several control points that are susceptible to systemic and local humoral factors and produce a specific skeletal phenotype (6). Direct systemic regulation of bone remodeling is carried out by various hormones. These include, but are not limited to, parathyroid hormone (PTH), calcitonin (CTN), insulin, insulin-like growth factors-1 and -2 (IGF-1 and -2), growth hormone (GH), pituitary glycoproteins (thyroid stimulating hormone (TSH), follicle-stimulating hormone (FSH)), glucocorticoids (cortisol), sex steroids (androgens and estrogens), thyroid hormones and 1,25-dihydroxyvitamin D (125-D) (13).
PTH is the primary regulator of calcium homeostasis. It maintains serum calcium concentrations by stimulating bone resorption, facilitating renal calcium absorption, and increasing renal production of 125-D. PTH stimulates bone formation when given intermittently and bone resorption when secreted continuously (18, 19).
CTN, a natural product of C-cells in the thyroid gland, in pharmacologic doses, is a potent osteotropic factor which blocks basal osteoclast activity by mediating loss of the osteoclast ruffled border, by retraction of cytoplasmic extensions and decreased motility, and secretion of proteolytic enzymes through its receptor on osteoclasts (20). Under normal physiological conditions, CTN exerts little regulatory control over bone remodeling.
The GH/IGF-1 and -2 systems are important for skeletal growth, especially at the cartilaginous end plates and during endochondral bone formation. They are among the major determinants of adult bone mass through their effect on regulation of both bone formation and resorption (21).
125-D, the active metabolite of vitamin D, is essential in enhancing the absorption of Ca and P from the gastrointestinal tract, and in this way, it promotes bone mineralization. 125-D also regulates renal Ca handling and can affect PTH secretion. In addition, 125-D possesses important anabolic effects on bone, thus exerting a dual effect on bone turnover (6).
Glucocorticoids exert both stimulatory and inhibitory effects on bone cells. They are essential for osteoblast maturation by promoting their differentiation from mesenchymal cells but they also decrease osteoblast activity. Furthermore, glucocorticoid excess sensitizes bone cells to other regulators of bone remodelling and augments osteoclast recruitment (22, 23).
Estrogens prevent osteclast formation and reduce osteoclast lifespan. They stimulate bone formation by enhancing osteoblast proliferation and by decreasing apoptosis. Estrogens affect gene expression for bone-specific enzymes, bone matrix proteins, hormone receptors, transcription factors, and they also up-regulate the local production of osteoprotegerin (OPG), IGF-1, IGF-2, and transforming growth factor-beta (TGF-beta) (24). Androgens are essential for skeletal growth and maintenance via their anti-resorptive effect via androgen receptor signal transduction, which is present in all types of bone cells (25).
The remodeling process is also influenced by the hypothalamic-pituitary-thyroid (HPT) axis. Osteoclast activity is increased by thyroid hormone but only through coupling with osteoblasts, which is mediated by cytokine signaling (interleukin-6 (IL-6), IL-8, prostaglandin E2, and IGF-1) (26). In addition, thyroid-stimulating hormone (TSH) reduces the formation, function and survival of osteoclasts and thus exerts an anti-resorptive effect. After ovariectomy, TSH can prevent bone loss and even restore lost bone (27). Thyroid hormone excess opposes the effects of TSH in bone remodeling and can cause secondary osteoporosis and fracture (28-33) Even when the effects of suppressed TSH occur with elevated thyroid hormone levels, there is increased bone turnover and decreased bone mass (34).
3.3. Local regulation: the role of cytokines
The role of cytokines as intermediaries in the control of bone remodeling stems from the observation that mature osteoclasts lack receptors for most hormone regulators, namely PTH and 125-D (35). This premise was validated by identification of the receptor activator of nuclear factor kB ligand (RANKL; a cytokine) as the principal intermediator of osteoblast-osteoclast coupling via binding with receptor activator of nuclear factor kB (RANK), which is highly expressed on the osteoclast membrane (36).
Cytokines are most often defined as a group of regulatory factors with the following attributes:
- low molecular weight (<80 kDa),
- very potent (acting in the 10-13 - 10-10 M range),
- generally glycosylated peptides,
- produced transiently by most nucleated cells,
- manifest pleiotropic, mainly autocrine or paracrine, overlapping biological activities.
Even though cytokines are primarily involved in the inflammatory response, they provide integration between immune and endocrine systems in many tissues or organs (25). The interconnected network between the skeletal and immune systems is referred to by the emerging interdisciplinary research field of osteoimmunology (37, 38).
Activation of the remodeling cycle starts with osteoblastic degradation of unmineralized osteoid between the osteoblastic cell layer and the mineralized bone. This is necessary since osteoclasts cannot adhere to unmineralized bone (12, 13). Then, osteoblasts increase their expression of RANKL and macrophage colony stimulating factor (M-CSF). M-CSF binds to its receptor c-Fms on preosteoclastic cells, which is necessary for osteoclastogenesis because it is the primary determinant of the pool of these precursors cells. RANKL binds to its cognate receptor RANK expressed on osteoclast progenitor cell. Together, this leads to expansion of the osteoclast progenitor pool, increased survival of these cells, differentiation into mononucleated progenitor cells, fusion into multinucleated osteoclasts, and then activation.
Simultaneously, osteoblasts decrease their expression of OPG, a secretory dimeric glycoprotein and soluble receptor belonging to the tumor necrosis factor (TNF) receptor superfamily. OPG is an inhibitor of RANK activation via decoy receptor binding to RANK. This reduces the effect of RANKL on osteoclastogenesis and in effect constitutes an efficient negative layer of control.
After the retraction of osteoblasts, activated osteoclasts attach to bone by vitronectin receptors, which have binding sites containing the amino acid sequence Arg-Gly-Asp (RGD) in osteopontin and bone sialoprotein on mineralized bone surfaces. The most common cell-binding domain used as a candidate peptide to improve cell adhesion onto biomaterial surfaces is the Arg- Gly-Asp (RGD) sequence. RGD recognition of the adhesive protein RGD sequence by cell integrins provides a signal for cell adhesion, spreading, and growth (39). Osteoclasts develop a ruffled border and, by means of a proton pump and a chloride channel, generate an acid environment in Howship's resorption lacunae. This dissolves hydroxyapatite crystals. The demineralized organic matrix of bone will subsequently be degraded by proteolytic enzymes, including highly collagenolytic cathepsin K.
Subsequently, osteoblast precursor cells are recruited to the lacunae, where they differentiate into fully active osteoblasts that will fill the resorption lacunae with new bone.
It has been suggested that IGF-I and TGF-beta superfamily members are also "coupling factors" that link bone formation to bone resorption since they are released during the resorption process and function in the recruitment and activation of osteoblasts in BMUs (12). In fact, TGF-beta peptides are chemotactic agents for bone cells and the exposure of osteoblast precursors to these factors induces proliferation. Since it is unlikely that the TGF-beta superfamily members act alone, other growth factors as IGF-1 and -2, fibroblast growth factor (FGF), and platelet-derived growth factor (PDGF), are known as bone growth stimulants. Lean et al. (15) demonstrated that IGF-I is the paracrine factor secreted by osteocytes in response to mechanical forces, thus acting as an initiator of the bone remodeling.
The RANKL-RANK-OPG system is essential for osteoclast differentiation. Their expression is regulated by hormones and other cytokines that stimulate or inhibit bone resorption. IL-1, TNF-alpha, and cytokines in the IL-6 family of cytokines, enhance RANKL expression (40). IL-6 is produced by osteoclasts in response to PTH and 125-D. PTH also inhibits OPG secretion (41). Although adequate levels of 125-D are necessary to provide calcium for bone formation via intestinal absorption, high levels induce bone resorption by increasing RANKL gene expression in osteoblasts (42). Estrogens also regulate RANKL and OPG expression indirectly via various cytokines. In fact, estrogens are a potent inhibitor of IL-1beta and TNF-alpha production in bone marrow cells and monocytes (43). Estrogens also inhibit the production of IL-6 in stromal cells and osteoblasts (44).
In general, cytokines exert regulatory control over bone remodeling by serving as intermediaries for the indirect effects of hormones while also mediating the complex cell-cell communications between osteoblasts and osteoclasts. Table 1 summarizes the principal cytokines involved in physiologic bone remodeling.
3.4. Integration of systemic and local factors with whole body function: a systems approach
Several recent discoveries involve complex physiological networks that involve bone remodeling. In addition to the more intuitive direct physiological relationships described in the above sections, body composition, intermediary metabolism, pancreatic beta-cell function, and intestinal endocrine function each participate in potentially important network connections. Fu et al. present a model wherein leptin production by adipocytes influences hypothalamic sympathetic nervous system activity (45). Downstream agonism of type-2 beta-adrenergic receptors on osteoblasts drives an incoherent feed-forward loop involving cyclic adenosine monophosphate (cAMP) response element binding (CREB), the clock genes per and cry, and activator protein-1 (AP-1) to modulate osteoblast proliferation. The integrative effects of fat and body composition (leptin production), brain (sympathetic nervous system) and bone (osteoblast proliferation) also impact pancreatic beta-cell activity since osteocalcin (from osteoblasts) promotes insulin production (46). Another mechanism that modulates osteoblast proliferation involves the production of serotonin by intestinal enterochromaffin cells (47). Furthermore, mathematical analysis of a multiorgan physiological network centered on bone can yield emergent, nonintuitive relationships that can prove to be useful in clinical medicine. More specifically, the full potential of biomaterial use in bone may require a systems approach to bone physiology.
4. BONE REMODELLING AND OSTEOPOROSIS
4.1. General considerations
Dysregulated bone remodeling (bone resorption > bone formation) can lead to bone loss, or osteoporosis (48). The currently accepted definition of osteoporosis is 'a systemic skeletal disease characterized by a reduction in bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture risk' (49).
Osteoporosis may be either a primary or a secondary form. Primary osteoporosis is the more common form and is due to the typical age-related loss of bone from skeleton. It is classified as type-1 and type-2. Type-1, or postmenopausal osteoporosis, affects women within 15 to 20 years of menopause. Women manifest two phases of type-1 age-related bone loss. The first, at menopause, is caused by estrogen deficiency and results in an uneven increase in bone resorption, as compared with formation, that mainly affects trabecular bone. This is called 'high-turnover' osteoporosis. After 4-8 years, 'low-turnover' osteoporosis begins, with a slower and constant loss of both trabecular and cortical bone, primarily caused by decreased bone formation (50).
Estrogen deficiency is thought to underlie type-1 osteoporosis, rendering the skeleton more sensitive to PTH, resulting in increased Ca resorption from bone. This in turn decreases PTH secretion, 125-D production, and Ca absorption. This ultimately causes loss of trabecular bone, leading to vertebral crush fractures and distal forearm fractures. Quantitative measurements of the amount of bone resorption in post-menopausal women is equal to 425 mg/day of calcium, while bone formation is only 387mg/day; this results in a net daily loss of 38 mg of Ca (49).
Type-2, or senile osteoporosis, occurs in women or men more than 70 years of age. Type-2 osteoporosis is generally referred to as a low-turnover osteoporosis and it is usually associated with decreased bone formation along with decreased ability of the kidney to produce 125-D. This vitamin D deficiency results in decreased Ca absorption, secondary hyperparathyroidism, and increased bone resorption. Cortical and trabecular bone is lost and this leads to increased risk of hip, long bone, and vertebral compression fractures (51).
Men exhibit only the slow phase of bone loss, most likely due to decreased levels of bio-available testosterone and estrogen associated with increased levels of sex-hormone binding globulin (SHBG). Decreased estrogen causes an increased bone resorption, while decreased testosterone is responsible for decreased bone formation (52).
Secondary osteoporosis results from the presence of other diseases or altered conditions that predispose to bone loss and is classified as type-3. This form of osteoporosis occurs equally in men and women and at any age. Secondary osteoporosis is associated with a variety of conditions, including endocrine imbalances (as Cushing's syndrome, hypo- and hyper-thyroidism, and hypogonadism); cancer (notably multiple myeloma); gastrointestinal disorders (especially celiac and inflammatory bowel diseases due to malabsorption); drug use (such as corticosteroids, cancer chemotherapy, anticonvulsants, heparin, barbiturates, benzodiazepines, valporic acid, gonadotropin-releasing hormone, and excessive use of aluminium-containing antacids); genetic disorders (cystic fibrosis and osteogenesi imperfecta); rheumatic and autoimmune diseases (lupus and rheumatoid arthritis); chronic kidney disease; and other specific conditions (alcoholism, depression, immobilization, and poor nutrition, including malnutrition due to eating disorders) (16, 53-56).
Among the parameters that can be measured today, bone mineral density (BMD) is the most used predictor of osteoporotic fractures. The World Health Organization, WHO, has defined osteoporosis as the state of having a BMD greater than 2.5 standard deviation below peak adult bone mass, whether or not a fragility fracture has occurred, based on epidemiological studies on the risk of osteoporotic fractures (57-59). Osteopenia is defined as a BMD between 1 and 2.5 SD below that of a young normal adult. Using standardized bone density measurements of the total hip, "normal" bone is greater than 833 mg/cm2, "osteopenia" is between 833 and 648 mg/cm2, and "osteoporosis" is lower than 648 mg/cm2. In order to distinguish the asymptomatic condition of having low bone mass without fractures, the WHO has suggested that the term "severe osteoporosis" has to be reserved for patients with a BMD and a fragility fracture (51). The current emphasis on BMD in the diagnosis and treatment of osteoporosis limits awareness of the importance of bone quality. It has been shown that loss of connectivity within the network of trabecular bone is also a fracture risk factor independent of BMD (60).
Currently the WHO is designing an absolute fracture-risk model that will help clinicians determine who is at risk and when drug therapy should be initiated. Secondary findings from the Improving Measurements of Persistence of Actonel Treatment (IMPACT) trial showed that 38 percent of subjects, ages 65-80, with a diagnosis of osteoporosis had no risk factors (61). Optimal fracture-risk assessment in the individual patient can be achieved by using diagnostic correlates from DXA and currently available biotechnology in a translational medicine approach. The use of bone-related biomarkers and other laboratory tests not traditionally associated with bone health can improve therapeutic management and identify individuals with elevated fracture risk independent of reduced BMD (62).
As the average age of the world's population shifts upward, the incidence and prevalence of osteoporosis increases. According to the ESOPO study (63), an epidemiological survey on osteoporosis in Italy, osteoporosis is an under-diagnosed and under-estimated disease. About 23% of women older than 40 and 14% of men over 60 are affected by osteoporosis, while osteopenia is present in 42% of women and 34% of men.
4.2. Local dysregulation: the role of cytokines
Bone hyperresorption during estrogen withdrawal is mediated by elevated FSH levels and activation of cytokine-induced increases in osteoclastogenesis (64). Activated osteoclasts are usually found in the presence of accessory (inflammatory) cells. Moreover, both human and animal studies demonstrate that hypogonadal bone loss may involve activation of osteoclasts by pro-inflammatory cytokines (65). Specifically, Pacifici et al. (66), showed that in women, ovariectomy was associated with an increase in IL-1 and TNF-alpha secretion by peripheral blood mononuclear cells, with a concomitant increase in bone resorption. In the women who received estrogen replacement therapy after ovariectomy, IL-1 and TNF-alpha secretion returned to pre-operative levels (66). It was also demonstrated that the production of IL-6 (67), IL-1, TNF-alpha (68), and M-CSF (macrophage-colony stimulating factor) (69) is enhanced in bone marrow stromal cells and osteoblasts from ovariectomized mice. IL-6 production can be directly regulated by hormones: its hepatic production is increased by PTH (70). Ovariectomy also leads to enhanced expression of IL-1 and TNF-alpha in bone marrow macrophages (69). It should be noted that the increased production of M-CSF in stromal cells from ovariectomized mice may be an indirect effect caused by increased IL-1 and TNF-alpha. Weitzmann et al. (71) also demonstrated that ovariectomy increases the TNF-alpha-producing subset of T lymphocytes by approximately twofold. Attesting to the relevance of T cells in estrogen-deficiency-induced bone loss, athymic T-cell deficient mice are completely protected against the bone loss induced by ovariectomy (71).
Data from Eghbali-Fatourechi et al. (72) showed enhanced RANKL expression in bone marrow stromal cells isolated from post-menopausal women, suggesting that upregulation of RANKL on bone marrow cells is an important determinant of increased bone resorption induced by estrogen deficiency. D'Amelio P et al. (64) recently found a similarly enhanced RANKL expression in peripheral blood mononuclear cells, including T cells of postmenopausal women with osteoporosis, compared with healthy postmenopausal and premenopausal women. This suggests that bone resorption induced by estrogen depletion is mediated by the immune system and supports the notion of a distinct osteoimmune dysregulation in postmenopausal osteoporosis
The neutralization of elevated levels of IL-1, TNF-alpha, and IL-6 reduces bone loss in ovariectomized animals. Several studies found that by administrating neutralizing specific antibodies, binding proteins, or receptor antagonists for IL-1, TNF-alpha, or IL-6, osteoclast formation and bone resorption were decreased after ovariectomy in mice and rats (68, 73, 74). This implicates IL-1, TNF-alpha and IL-6 in the mechanisms by which estrogen withdrawal induces an increased expression of RANKL and M-CSF, increased osteoclast activity, and increased bone resorption. Table 2 reports the cytokines and their mechanism of action in osteoporosis.
The role of the RANK-RANKL-OPG system in osteoclastogenesis, was demonstrated in a series of gene ablation studies. Mice lacking functional RANKL develop a form of osteopetrosis and lack osteoclasts (75). On the contrary, mice with the OPG-deficient gene develop osteoporosis with an increased number of osteoclasts (76) and mice with OPG-overexpressed gene develop osteopetrosis (77).
Other cytokines are also involved in the pathophysiology of bone remodeling. IL-7, IL-11, IL-15, IL-17, and prostaglandin E-2 (PGE-2) have been shown to stimulate bone resorption, while IL-4, IL-10, IL-13, TGF-beta, and interferon-gamma (IFN-gamma) to inhibit bone resorption (78,79). In addition, Shaughnessy et al. (80) demonstrated that the neutralization of IL-11 activity decreases osteoclast formation and increases cancellous bone volume in ovariectomized mice.
Steroid hormone receptors, are cytosolic proteins which dimerize after ligand binding and translocate into the nucleus where they induce or inhibit the transcription of genes. There are 2 different estrogen receptors (ER). ER-alpha is expressed in many cells including osteoblasts and osteoclasts, ER-beta is expressed in epithelial and mesenchymal tissues, including osteoblasts. Although most of the action of the two ERs are due to their function as ligand-dependent transcription factors, the promoters of IL-1, TNF-alpha, and IL-6 lack classic ER response elements.
Stein and Yang (81) reported that ERs are able to interfere at a molecular level with the transcription of the genes encoding various cytokines. For instance, the IL-6 promoter is inhibited by estrogen in the absence of a functional ER binding site (81). This inhibition is mediated by NF-kB and CCAAT/Enhancer binding protein beta (C/EBP beta) (81). However, it has been shown that ERs interact with several other transcription factors and it has been proposed that this is the mechanism by which the steroid hormone inhibits cytokine receptors. For example, it has been shown that ligand-activated ER-alpha and -beta can block the ability of NF-kB to bind to response elements in the IL-6 gene (81, 82). It is likely that this repression by ERs is also important for the control of the IL-1 gene, which contains several NF-kB sites in the promoter. It has also been shown that activation of ERs represses the stimulatory effect of the transcription factor AP-1 on the TNF-alpha gene (83). It is important to note that attempts to assess circulating levels of these cytokines in postmenopausal women and to then correlate them to clinical markers of osteoporosis have resulted in conflicting results. This most likely reflects the relevance of local cytokine production rather than circulating cytokine levels.
5. THERAPEUTIC CONSIDERATIONS: BIOLOGICAL THERAPY AND BIOMATERIALS
5.1. Current chemotherapeutics
Contemporary management of osteoporosis consists of nonpharmacological and pharmacological measures. Among the non-pharmacological, basic recommendations include changes in lifestyle, nutrition (for deficiencies or insufficiencies in calcium and vitamin D) and physical activity (84). Pharmacological therapies directly affect the bone tissue and can be divided into therapies that decrease bone resorption (antiresorptive therapies) and those that increase deposition of bone extracellular matrix (anabolic therapies) (85). Antiresorptive therapies alter osteoclast activity and diminish bone turnover; they include bisphosphonates, selective estrogen receptor modulators (SERMs), estrogen, and calcitonin. Anabolic therapies stimulate bone formation by promoting osteoblast activity and number; the only FDA approved anabolic agent is teriparatide, or human recombinant parathyroid hormone.
Bisphosphonates are the most commonly used treatments for osteoporosis. They are non-hormone phosphate-based compounds that increase bone mineral density by two key properties: their high chemical affinity for bone hydroxyapatite crystals and their inhibitory effects on osteoclast activity (85). Mineral binding affinities differ among the clinically used bisphosphonates and may influence their differential distribution within bone, their biological potency, and their duration of action (86). Bisphosphonates can reduce the pathological fracture risk by 50% after 1 year of oral administration (87).
SERMs are antiresorptive agents that activate estrogen receptors in bone. They are currently used in postmenopausal women with favorable effects on bone mineral density and bone mass (88). Their use has widely supplanted hormone (estrogen) replacement therapy for osteoporosis.
Synthetic CTN is administered in patients who are more than five years postmenopausal with low bone mass. It binds directly to osteoclasts and decreases their activity and number (85). CTN is also helpful in the treatment of bony pain secondary to fractures: although the analgesia mechanism is not well-understood, the neuroactivity of CTN may be cytokine-mediated (89).
Strontium ranelate is a recently developed drug with both antiresorptive and anabolic properties. It inhibits osteoclast activity and accelerates apoptosis, thus decreasing bone resorption. It also seems to increase preosteoblast differentiation. Strontium ranelate was recently approved for use in Europe, but is not currently available in the United States (90, 91).
5.2. Biological therapies
Biological therapies are those using compounds naturally found in the human body. For many human diseases, biological therapies are still under clinical investigation and hold great promise. Fortunately, in the management of osteoporosis, one biological therapy has already been FDA-approved for use in osteoporotic patients and has proven benefit (92). Teriparatide consists of an amino acidic sequence of human parathyroid hormone synthesized with recombinant DNA technology. It has been found to be a useful stimulator of bone formation, reflected by increasing BMD owing to improving both cortical and trabecular bone formation.
Nearly every known modulator of osteoclast activity exerts its effect through the RANK-RANKL-OPG system (65). It is therefore not surprising that this system represents an attractive therapeutic target for the treatment of osteoporosis. Eghbali-Fatourechi et al. (72) demonstrated that RANKL expression is significantly higher in post-menopausal women, compared with pre-menopausal women and post-menopausal women treated with estrogen. Estrogens are known to increase OPG secretion and estrogen depletion after menopause leads to a decrease in OPG and to an increase in RANKL, causing bone resorption and loss (17).
In recent years, agents currently under study include OPG, RANK and RANKL antibodies or inhibitors of RANKL, such as Denosumab (63). This biological agent is a specific antibody raised against RANKL that blocks the binding of RANKL to RANK. Denosumab has been tested in clinical trials with promising results (17). The Phase II trial showed an increase of bone mineral density in Denosumab-treated postmenopausal women compared with placebo-treated ones and a similar BMD to ones treated with bisphosphonate therapy (93).
Other biological therapies for osteoporosis under investigation include OPG and RANK receptors. In animal studies, recombinant OPG was shown to be highly effective in inhibiting bone loss by binding to RANKL and decreasing osteoclastogenesis (75). In human studies with OPG, a single dose was shown to reduce bone resorption markers by 80% (94). However, a problem with OPG therapy is that it has a short (20-30 minutes) half-life and is not specific for RANKL. OPG also binds TNF-related apoptosis-inducing ligand (TRAIL), which is important in natural immunity (94). Another promising target for inhibiting the activity of mature osteoclasts is the H+-ATPase pump, which is necessary for osteoclasts to secrete H+ and acidify the resorptive area (95). Thus, a reduction in osteoclastic resorption could be achieved by inhibiting H+-ATPase activity (95). Owing to the rapidity rate of discovery for anti-resorptive or anabolic therapy targets, it is expected that a library of novel biological agents will expand our armamentarium for the treatment of osteoporosis.
5.3. Biomaterials
When osteosynthesis devices or cementless implants are inserted in bone for fracture fixation, joint replacement and prosthetic dentistry, mechanisms underlying the osseointegration process involve a cascade of various cellular and extracellular events (96). The role of osteoporosis in the success of bone implants needs further investigations, however microarchitectural deterioration and biological drawbacks affecting cells of both osteoblastic and osteoclastic lineages, extracellular matrix proteins, local and systemic regulatory factors can negatively influence the early bone response and the bone remodelling processes around implants (3, 96, 97).
Many in vitro and in vivo experimental researches and clinical studies demonstrated that aging and estrogen deficiency cause a decrease of the osteointegration rate and bone density around common orthopaedic implant materials (3, 98-101). It is supposed that even the ideal clinically used biomaterial could fail if implanted in a compromised microenvironment. As an example, human Demineralized Bone Matrix (DBM) that is the gold standard of osteoinductive biomaterials, decrease the osteoinductive potential when implanted in female rats with low estrogen levels (102).
Therefore, new solutions acting on biomaterials are required to stimulate bone formation and osteofixation of implants and many strategies have been proposed to decrease failure risks of implantation surgery in patients affected by osteoporosis and needing reconstructive therapies because of fragility fractures, degenerative diseases or edentulism. These strategies could be divided into 2 main groups:
- strategies directly focused on modifying biomaterial features as design, surface chemistry and bioactivity, roughness and topography
- strategies focused on local and systemic substances/therapies delivered by biomaterials which can be used as adjuvants to stimulate endogenous tissue healing
Implant design may maximize the bone-implant interface, while chemical and topographical properties of the implant surface can be critical for protein adsorption which mediates cell adhesion, can recruit bone forming cells and stimulate cell proliferation and extracellular matrix protein synthesis. Cells interact with the environment (and also with biomaterial surfaces) through transmembrane and intracellular receptors that mediate cell division, maturation, gene expression, collagen and other extracellular matrix (ECM) protein synthesis (103). Regarding implant chemistry, the use of ceramic coatings (i.e. hydroxyapatite, tricalcium phosphate) on metallic materials is suggested to reverse the negative effects of osteoporotic conditions both in animal models and in patients (104, 105). Changes in cell-protein-material interface communications, dissolution and release of specific key ions that act on local cells to up regulate gene expression or influence cell differentiation have been advocated to explain the stimulatory effect of hydroxyapatite and other ceramic coatings (103). However, in some studies the use of an osteoconductive hydroxyapatite coating was not sufficient in restoring normal physiological bone ingrowth in estrogen deficient subjects (106, 107).
The sensitivity of bone cells is not limited to chemical phenomena but also to the surface topography (103). The implant surface roughness combined with a proper implant chemistry was demonstrated to be an important "geometrical mediator" of bioactivity for bone cells and tissue also in the case of aged and osteoporotic bone. In the cases of insufficient bone quantity implants with a high roughness profile have demonstrated superior outcomes compared to smooth surfaces (108). High roughness (Ra ~ 12-18um) biomaterials with and without HA coating, behaved similarly without differences in the osteointegration rate in young, aged and estrogen-deficient animals (109).
The amount of growth factors (GF) and the number of bone cells capable of being stimulated by a bioactive surface decrease as a consequence of patient aging and estrogen deficiency and at present many researchers are working also on the combination between biomaterials and drugs or signalling molecules such as ions, peptides and proteins (110).
Biphosphonates have been used locally applied or immobilized on the surface of implants or by systemically administered in osteoporotic animals and patients submitted to implantation surgery (107, 111-113). Also drugs capable of enhancing bone formation such as statins, were tested and improved bone healing around titanium in osteoporotic rats (114). It has been suggested that several statin drugs, including Simvastatin, increase the mRNA expression of bone morphogenetic protein 2 (BMP-2) in osteoblasts, with a subsequent increase in bone formation, when injected subcutaneously over the murine calvaria (115).
Strontium (Sr), that is an inorganic ion and a natural component of food and beverages, has the ability to enhance bone volume and prevent bone loss (116); thereby Sr has become increasingly attractive for the prevention and treatment of osteoporosis. There are in vitro and in vivo studies that elucidate the ability of Sr treatment to promote osteoblast-related gene expression and alkaline phosphatase of osteogenic-differentiating mesenchymal stem cells (117) and, when coadministered with calcium in ovariectomized goats, to increase new bone matrix formation in a dose-dependent manner (118). Thus, the growing evidence of the beneficial effect of Sr on bone justifies the increasing interest toward Sr incorporation in biomaterials, as calcium phosphate bioceramics and cements (119-121).
Combination of biomaterials with growth factors, mesenchymal stem cells, different forms of biophysical stimulation, hormones and other signalling molecules demonstrated to have a beneficial effect on the process of osteointegration due to the ability to induce osteoblast development, bone regeneration and vascularization (122-127). However, the effect on bone formation around implants inserted into osteoporotic bone was investigated in few studies on bFGF, BMP-2 and Prostaglandin E2 EP4 selective agonist (128-130).
During the last years also new strategies are growing thanks to the development of biotechnology. Biomimetic coating methods are inspired by the natural process of biomineralization. The deposition of calcium phosphates apatite crystals onto metallic surfaces with different techniques (electrodeposition, immersion in SBF or in supersaturated CaP solution) forms a biomimetic coating of biological apatite which serves as biomimetic matrix for osteogenic cell attachment and growth. Biomimetic innovative biomaterials were successfully tested in vitro and in vivo healthy preclinical models (108, 131, 132) but no data are available on the efficacy of these materials in osteoporotic bone of pathological animal models.
Future trends of innovative research investigate on nanomaterials that matching natural bone have been proposed as the next generation of orthopaedic implant materials with the aim to improve surface properties of the implant by possessing a greater surface area, to create an environment more conducive and to promote osteoblast function (133). Cells of our body are predisposed to interact with nanostructured surfaces, because all living systems are governed and are composed by molecular building blocks at nanometer scales, as proteins, nucleic acids, lipids and carbohydrates (134). Nanobiomaterials, possessing higher surface area to volume ratio than conventional microscale biomaterials, have demonstrated to provide advantageous interactions with the protein that control cellular function, in particular fibronectin, vitronectin, laminin and collagen (135). Although nanobiomaterials seem to be an attractive strategy, no data are available when implanted in compromised osteoporotic bone in preclinical studies; also understanding the molecular mechanism of healthy and pathological cell-nanomaterial interactions, with particular attention also at improving proper vascularization of the tissue ensuring adequate blood supply for successful biomaterial/tissue integration could be expected. Tissue engineering based therapies, by combining both smart biomaterials tailored for compromised bone tissue, cells and growth factors or drugs for rebalancing the bone remodelling process, could be an innovative tool to promote osteointegration in osteoporotic conditions, although, to date, few attempts are available on fracture healing of osteoporotic rats (136).
6. CONCLUSIONS
All the current available studies support the systems biology view that manipulating the implant biomaterial surface in the setting of bone growth, bone remodelling, and local microenvironment networks could lead to an enhanced and accelerated osteointegration rate in osteoporotic patients.
However, the high costs of these delivery systems, issues of release control, the uncertainty concerning the most effective dosage, and the possibility of collateral effects of the proposed signalling molecules, are still a limitation for the use of biomaterials in clinical trials. Furthermore, contemporary clinical strategies that demonstrate a beneficial effect on fracture healing and osteointegration in healthy conditions were not investigated in pathological animal models and clinical osteoporotic conditions. It is precisely these studies - the use of smart biomaterial technology in the setting of complex pathological networks involving bone - that need to be designed.
7. ACKNOWLEDGEMENTS
Authors equally contributed to this article. This study was partially supported by Rizzoli Orthopaedic Institute, Bologna-Italy.
8. REFERENCES
1. R. Stoop: Smart biomaterials for tissue engineering of cartilage. Injury 39 (Suppl 1), S77 -S87 (2008)
doi:10.1016/j.injury.2008.01.036
http://dx.doi.org/10.1016/j.injury.2008.01.036
2. M. E. Furth, A. Atala, M. E. Van Dyke: Smart biomaterials design for tissue engineering and regenerative medicine. Biomaterials 28, 5068-5073 (2007)
doi:10.1016/j.biomaterials.2007.07.042
http://dx.doi.org/10.1016/j.biomaterials.2007.07.042
3. M. Fini, G. Giavaresi, P. Torricelli, V. Borsari, R. Giardino, A. Nicolini, A. Carpi: Osteoporosis and biomaterial osteointegration. Biomed Pharmacother 58(9), 487-493 (2004)
4. A. Bigi, S. Panzavolta, L. Sturba, P. Torricelli, M. Fini, R. Giardino: Normal and osteopenic bone-derived osteoblast response to a biomimetic gelatin-calcium phosphate bone cement. J Biomed Mater Res A 78(4), 739-745 (2006)
doi:10.1002/jbm.a.30765
http://dx.doi.org/10.1002/jbm.a.30765
5. E. Galliera, M. Locati, A. Mantovani, M. M. Corsi: Chemokines and bone remodelling. Int J Immunopathol Pharmacol 21(3), 485-492 (2008)
6. D. J. Hadjidakis, I. I. Androulakis: Bone remodelling. Ann NY Acad Sci 1092, 385-396 (2006)
doi:10.1196/annals.1365.035
http://dx.doi.org/10.1196/annals.1365.035
7. K. Sato, H. Takayanagi: Osteoclasts, rheumatoid arthritis, and osteoimmunology. Curr Opin Rheumatol 18, 419-426 (2006)
doi:10.1097/01.bor.0000231912.24740.a5
http://dx.doi.org/10.1097/01.bor.0000231912.24740.a5
8. S-K. Lee, J. Lorenzo: Cytokines regulating osteoclast formation and function. Curr Opin Rheumatol 18, 411-418 (2006)
doi:10.1097/01.bor.0000231911.42666.78
http://dx.doi.org/10.1097/01.bor.0000231911.42666.78
9. N. K. Lee, H. Sowa, E. Hinoi, M. Ferron, J. D. Ahn, C. Confavreux, R. Dacquin, P. J. Mee, M. D. McKee, D. Y. Jung, Z. Zhang, J. K. Kim, F. Mauvais-Jarvis, P. Ducy, G. Karsenty: Endocrine regulation of energy metabolism by the skeleton. Cell 130(3), 456-469 (2007)
doi:10.1016/j.cell.2007.05.047
http://dx.doi.org/10.1016/j.cell.2007.05.047
10. T. Nomiyama, D. Perez-Tilve, D. Ogawa, F. Gizard, Y. Zhao, E. B. Heywood, K. L. Jones, R. Kawamori, L. A. Cassis, M. H. Tschöp, D. Bruemmer: Osteopontin mediates obesity-induced adipose tissue macrophage infiltration and insulin resistance in mice. J Clin Invest 117(10), 2877-2888 (2007)
doi:10.1172/JCI31986
http://dx.doi.org/10.1172/JCI31986
11. J. Wolff: Das Gesetz der Transformation des Knochens. Verlag von August Hirscwald, Berlin (1892)
12. U. H. Lerner: Bone remodelling in post-menopausal osteoporosis. J Dent Res 85(7), 584-595 (2006)
doi:10.1177/154405910608500703
http://dx.doi.org/10.1177/154405910608500703
13. P. A. Hill: Bone remodelling. Br J Orthod 25, 101-107 (1998)
doi:10.1093/ortho/25.2.101
http://dx.doi.org/10.1093/ortho/25.2.101
14. D. W. Sommerfeldt, C. T. Rubin: Biology of bone and how it orchestrates the form and function of the skeleton. Eur Spine J 10, S86-S95 (2001)
doi:10.1007/s005860100283
http://dx.doi.org/10.1007/s005860100283
15. J. M. Lean, A. G. Mackay, J. W. Chow, T. J. Chambers: Osteocytic expression of mRNA for c-fos and IGF-I: an immediate early gene response to an osteogenic stimulus. Am J Physiol 270, 937-945 (1996)
16. M. Lind, C. Bünger: Factors stimulating bone formation. Eur Spine J 10, S102-S109 (2001)
doi:10.1007/s005860100269
http://dx.doi.org/10.1007/s005860100269
17. C. J. Gallagher: Advances in bone biology and new treatments for bone loss. Maturitas 60, 65-69 (2008)
doi:10.1016/j.maturitas.2008.04.005
http://dx.doi.org/10.1016/j.maturitas.2008.04.005
18. J. P. Bilezikian: Clinical utility of anabolic therapy for osteoporosis. Bone 43(1), S13-16 (2008)
19. C. Rattanakul, Y. Lenbury, N. Krishnamara, D. J. Wollkind: Modeling of bone formation and resorption mediated by parathyroid hormone: response to estrogen/PTH therapy. Biosystems 70, 55-72 (2003)
doi:10.1016/S0303-2647(03)00040-6
http://dx.doi.org/10.1016/S0303-2647%2803%2900040-6
20. T. J. Chambers, C. J. Magnus: Calcitonin alters behaviour of isolated osteoclasts. J Pathol 136(1), 27-39 (2005)
doi:10.1002/path.1711360104
http://dx.doi.org/10.1002/path.1711360104
21. R. C. Olney: Regulation of bone mass by growth hormone. Med Pediatr Oncol 41(3), 228-234 (2003)
doi:10.1002/mpo.10342
http://dx.doi.org/10.1002/mpo.10342
22. S. Ito, N. Suzuki, S. Kato, T. Takahashi, M. Takagi: Glucocorticoids induce the differentiation of a mesenchymal progenitor cell line, ROB-C26 into adipocytes and osteoblasts, but fail to induce terminal osteoblast differentiation. Bone 40, 84-92 (2007)
doi:10.1016/j.bone.2006.07.012
http://dx.doi.org/10.1016/j.bone.2006.07.012
23. H-J. Kim, H. Zhao, H. Kitaura, S. Bhattacharyya, J. A. Brewer, L. J. Muglia, P. Ross, S. L. Teitelbaum: Glucocorticoids suppress bone formation via the osteoclas. J Clin Invest 116(8), 2152-2160 (2006)
doi:10.1172/JCI28084
http://dx.doi.org/10.1172/JCI28084
24. S. C. Manolagas, S. Kousteni, R. L. Jilka: Sex steroids and bone. Recent Prog Horm Res 57, 385-409 (2002)
doi:10.1210/rp.57.1.385
http://dx.doi.org/10.1210/rp.57.1.385
25. C. Joseph, A. M. Kenny, P. Taxel, J. A. Lorenzo, G. Duque, G. A. Kuchel: Role of endocrine-immune dysregulation in osteoporosis, sarcopenia, frailty and fracture risk. Mol Asp Med 26, 181-201 (2005)
doi:10.1016/j.mam.2005.01.004
http://dx.doi.org/10.1016/j.mam.2005.01.004
26. J. A. Wexler, J. Sharretts: Thyroid and bone. Endocrinol Metab Clin N Am 36, 673-705 (2007)
doi:10.1016/j.ecl.2007.04.005
http://dx.doi.org/10.1016/j.ecl.2007.04.005
27. L. Sun, S. Vukicevic, R. Baliram, G. Yang, R. Sendak, J. McPherson, L-L. Zhu, J. Iqbal, R. Latif, A. Natrajan, A. Arabi, K. Yamoah, B. S. Moonga, Y. Gabet, T. F. Davies, I. Bab, E. Abe, K. Sampath, M. Zaidi: Intermittent recombinant TSH injections prevent ovariectomy-induced bone loss. Proc Natl Acad Sci USA 105(11), 4289-4294 (2008)
doi:10.1073/pnas.0712395105
http://dx.doi.org/10.1073/pnas.0712395105
28. E. Murphy, G. R. Williams: The thyroid and the skeleton. Clin Endocrinol (Oxf) 61(3), 285-298 (2004)
doi:10.1111/j.1365-2265.2004.02053.x
ùhttp://dx.doi.org/10.1111/j.1365-2265.2004.02053.x
29. J. Iqbal, T. F. Davies, L. Sun, E. Abe, A. Carpi, J. Mechanick, M. Zaidi: Skeletal morphofunctional considerations and the pituitary-thyroid axis. Front Biosci S1, 92-107 (2009)
30. S. R. Cummings, M. C. Nevitt, W. S. Browner, K. Stone, K. M. Fox, K. E. Ensrud, J. Cauley, D. Black, T. M. Vogt: Risk factors for hip fracture in white women. Study of Osteoporotic Fracture Research Group. N Engl J Med 332(12), 767-773 (1995)
doi:10.1056/NEJM199503233321202
http://dx.doi.org/10.1056/NEJM199503233321202
31. J. A. Franklyn, P. Maisonneuve, M. C. Sheppard, J. Betteridge, P. Boyle: Mortality after the treatment of hyperparathyroidism with radioactive iodine. N Engl J Med 338(11), 712-718 (1998)
doi:10.1056/NEJM199803123381103
http://dx.doi.org/10.1056/NEJM199803123381103
32. P. Vestergaard, L. Mosekilde: Fractures in patients with hyperparathyroidism and hypothyroidism: a nationwide follow-up study in 16,249 patients. Thyroid 12(5), 411-419 (2002)
doi:10.1089/105072502760043503
http://dx.doi.org/10.1089/105072502760043503
33. P. Vestergaard, L. Rejnmark, J. Weeke, L. Mosekilde: Fracture risk in patients treated for hyperthyroidism. Thyroid 10(4), 341-348 (2000)
doi:10.1089/thy.2000.10.341
http://dx.doi.org/10.1089/thy.2000.10.341
34. E. Abe, L. Sun, J. Mechanik, J. Iqbal, Y. Kosj, R. Baliram, A. Arabi, B. Moonga, T. Davies, M. Zaidi: Bone loss in thyroid disease: role of low TSH and high thyroid hormone. Ann N Y Acad Sci 1116(1), 383-391 (2007)
doi:10.1196/annals.1402.062
http://dx.doi.org/10.1196/annals.1402.062
35. T. R. Arnett: Regulation of bone cell function by acid-base balance. Proc Nutr Soc 62, 511-520 (2003)
doi:10.1079/PNS2003268
http://dx.doi.org/10.1079/PNS2003268
36. M. C. Horowitz, Y. Xi, K. Wilson, M. A. Kacena: Control of osteoclastogenesis and bone resorption by members of the TNF family of receptors and ligands. Cytokine Growth Factors Rev 12, 9-18 (2001)
doi:10.1016/S1359-6101(00)00030-7
http://dx.doi.org/10.1016/S1359-6101%2800%2900030-7
37. J. R. Arron, Y. Choi: Bone versus immune system. Nature 408, 535-536 (2000)
doi:10.1038/35046196
http://dx.doi.org/10.1038/35046196
38. M. C. Walsh, N. Kim, Y. Kadono, J. Rho, S. Young Lee, J. Lorenzo, Y. Choi : Osteoimmunology : interplay between the immune system and bone metabolism. Ann Rev Immunol 24, 33-63 (2006)
doi:10.1146/annurev.immunol.24.021605.090646
http://dx.doi.org/10.1146/annurev.immunol.24.021605.090646
39. S. P. Massia, J. A. Hubbell: Covalent surface immobilization of Arg-Gly-Asp- and Try-Ile-Gly-Ser-Arg-containing peptides to obtain well-defined cell adhesive substrates. Anal Biochem 187, 292-301 (1990)
doi:10.1016/0003-2697(90)90459-M
http://dx.doi.org/10.1016/0003-2697%2890%2990459-M
40. S. Kwan Tat, M. Padrines, S. Théoleyre, D. Heymann, Y. Fortun: IL-6, RANKL, TNF-alpha/IL-1: interrelations in bone resorption pathophysiology. Cytokine Growth Factor Rev 15(1), 49-60 (2004)
doi:10.1016/j.cytogfr.2003.10.005
http://dx.doi.org/10.1016/j.cytogfr.2003.10.005
41. S-K. Lee, J. A. Lorenzo: Parathyroid hormone stimulates TRANCE and inhibits osteoprotegerin messenger ribonucleic acid expression in murine bone marrow cultures: correlation with osteoclast-like cell formation. Endocrinology 140, 3552-3561 (1999)
doi:10.1210/en.140.8.3552
http://dx.doi.org/10.1210/en.140.8.3552
42. S. Morony, C. Capparelli, R. Lee, G. Shimamoto, T. Boone, D. L. Lacey, C. R. Dunstan: A chimeric form of osteoprotegerin inhibits hypercalcemia and bone rsorption induced by IL-1beta, TNF-alpha, PTH, PTHrP, and 1,25(OH)2 D3. J Bone Miner Res 14, 1478-1485 (1999)
doi:10.1359/jbmr.1999.14.9.1478
http://dx.doi.org/10.1359/jbmr.1999.14.9.1478
43. R. Pacifici: Aging and cytokine production. Calcif Tissue Int 65(5), 345-351 (1999)
doi:10.1007/s002239900710
http://dx.doi.org/10.1007/s002239900710
44. G. Girasole, R. L. Jilka, G. Passeri, S. Boswell, G. Boder, D. C. Williams, S. C. Manolagas: 17 beta-estradiol inhibits interleukin-6 production by bone marrow-derived stromal cells and osteoblasts in vitro: a potential mechanism for the antiosteoporotic effect of estrogens. J Clin Invest 89(3), 883-891 (1992)
doi:10.1172/JCI115668
http://dx.doi.org/10.1172/JCI115668
45. L. Fu, M. S. Patel, A. Bradley, E. F. Wagner, G. Karsenty: The Molecular Clock Mediates Leptin-Regulated Bone Formation. Cell 122(5), 803-815 (2005)
doi:10.1016/j.cell.2005.06.028
http://dx.doi.org/10.1016/j.cell.2005.06.028
46. E. Hinoi, N. Gao, D. Young Jung, V. K. Yadav, T. Yoshizawa, M. Myers, S. C. Chua, J. K. Kim, K. H. Kaestner, G. Karsenty: The sympathetic tone mediates leptin's inhibition of insulin secretion by modulating osteocalcin bioactivity. J Cell Biol 183(7), 1235-1242 (2008)
doi:10.1083/jcb.200809113
http://dx.doi.org/10.1083/jcb.200809113
47. V. K. Yadav, J-H. Ryu, N. Suda, K. F. Tanaka, J. A. Gingrich, G. Schütz, F. H. Glorieux, C. Y. Chiang, J. D. Zajac, K. L. Insogna, J. Mann, R. Hen, P. Ducy, G. Karsenty: Lrp5 Controls Bone Formation by Inhibiting Serotonin Synthesis in the Duodenum. Cell 135(5), 825-837 (2008)
doi:10.1016/j.cell.2008.09.059
http://dx.doi.org/10.1016/j.cell.2008.09.059
48. M. M. Iqbal: Osteoporosis: Epidemiology, Diagnosis, and Treatment. South Med J 93, 2-18 (2000)
No DOI found
49. Consensus Development Conference. Diagnosis, prophylaxis and treatment of osteoporosis. Am J Med 94, 646-650 (1993)
doi:10.1016/0002-9343(93)90218-E
http://dx.doi.org/10.1016/0002-9343%2893%2990218-E
50. H. Tilg, A. R. Moschen, A. Kaser, A. Pines, I. Dotan: Gut, inflammation and osteoporosis: basic and clinical concepts. Gut 57(5), 684-694 (2008)
doi:10.1136/gut.2006.117382
http://dx.doi.org/10.1136/gut.2006.117382
51. World Health Organization. Assessment of fracture risk and its application to screening for postmenopausal osteoporosis. Report of a WHO study group. World Health Organ Tech Rep Ser 843, 1-129 (1994)
52. L. Riggs, S. Khosla, J. Melton 3rd: Sex steroids and the construction and conservation of the adult skeleton. Endocr Rev 23(3), 279-302 (2002)
doi:10.1210/er.23.3.279
http://dx.doi.org/10.1210/er.23.3.279
53. H. Duncan: Osteoporosis in rheumatoid arthritis and corticosteroid induced osteoporosis. Orthop Clin North Am 3, 571-583 (1972)
54. J. C. Gerster, R. Bossy, J. Dudler: Bone non-union after osteotomy in patients treated with methotrexate. J Rheumatol 26, 2695-2697 (1999)
55. P. Torricelli, M. Fini, G. Giavaresi, V. Borsari, L. Rimondini, R. Rimondini, A. Carassi, R. Giardino: Intermittent exposure to ethanol vapor affects osteoblast behaviour more severely than estrogen deficiency does in vitro study on rat osteoblasts. Toxicol 237(1-3), 68-76 (2007)
doi:10.1016/j.tox.2007.05.010
http://dx.doi.org/10.1016/j.tox.2007.05.010
56. P. Torricelli, M. Fini, G. Giavaresi, L. Rimondini, M. Tschon, R. Rimondini, A. Carassi, R. Giardino: Chronic alcohol abuse and endosseous implants: linkage of in vitro osteoblast dysfunction to titanium osseointegration rate. Toxicol 243(1-2), 138-144 (2008)
doi:10.1016/j.tox.2007.10.001
http://dx.doi.org/10.1016/j.tox.2007.10.001
57. S. R. Cummings, J. L. Kelsey, M. C. Nevitt, K. J. O'Dowd: Epidemiology of osteoporosis and osteoporotic fractures. Epidemiologic rewiews 7, 78-208 (1985)
58. S. R. Cummings, M. C. Nevitt: Epidemiology of hip fractures and falls. In: Clinical disorders of bone and mineral metabolism. Eds: Kleerekoper M, Krane SM, Mary Ann Liebert, NY 231-236 (1989); J. Melton 3rd: Epidemiology of fractures. In: Osteoporosis: etiology, diagnosis, and menagement. Eds: Riggs BL, Melton LJ III, Raven Press, NY 133-154 (1988)
59. J. Kanis, F.A. Pitt: Epidemiology of osteoporosis. Bone 31(suppl.1), S7-S15 (1992)
60. E. Legrand, D. Chappard, C. Pascaretti, M. Duquenne, S. Krebs, V. Rohomer, M. F. Basle, M. Audran: Trabecular bone microarchitecture, bone mineral density, and vertebral fractures in male osteoporosis. J Bone Miner Res 15(1), 13-19 (2000)
doi:10.1359/jbmr.2000.15.1.13
http://dx.doi.org/10.1359/jbmr.2000.15.1.13
61. T-P. Van Staa, H. G. M. Leufkens, C. Cooper: Detection of "unexpected" osteoporosis: insights from the "IMPACT" trial. Arthritis Rheum 44, S256 (2001)
62. K. McCormick: Osteoporosis: integrating biomarkers and other diagnostic correlates into the management of bone fragility. Altern Med Rev 12(2), 113-145 (2007)
63. S. Adami, S. Giannini, R. Giorgino, G. Isaia, S. Maggi, L. Sinigaglia, P. Filipponi, G. Crepaldi, O. Di Munno: The effect of age, weight, and lifestyle factors on calcaneal quantitative ultrasound: the ESOPO study. Osteoporos Int 14(3), 198-207 (2003)
64. P. D'Amelio, A. Grimaldi, S. Di Bella, S. Z. M. Brianza, M. A. Cristofaro, C. Tamone, G. Giribaldi, D. Ulliers, G. P. Pescarmona, G. Isaia: Estrogen deficiency increases osteoclastogenesis up-regulating T cells activity: A key mechanism in osteoporosis. Bone 43(1), 92-100 (2008)
doi:10.1016/j.bone.2008.02.017
http://dx.doi.org/10.1016/j.bone.2008.02.017
65. G. R. Mundy: Osteoporosis and inflammation. Nutrition Reviews 65(12), S147-151 (2007)
doi:10.1301/nr.2007.dec.S147-S151
http://dx.doi.org/10.1301/nr.2007.dec.S147-S151
66. R. Pacifici, C. Brown, E. Puscheck, E. Friedrich, E. Slatopolsky, D. Maggio, R. McCracken, L. V. Avioli: Effect of surgical menopause and estrogen replacement on cytokine release from human blood mononuclear cells. Proc Natl Acad Sci U S A 88(12), 5134-5138 (1991)
doi:10.1073/pnas.88.12.5134
http://dx.doi.org/10.1073/pnas.88.12.5134
67. G. Passeri, G. Girasole, R. L. Jilka, S. C. Manolagas: Increased interleukin-6 production by murine bone marrow and bone cells after estrogen withdrawal. Endocrinology 133(2), 822-828 (1993)
doi:10.1210/en.133.2.822
http://dx.doi.org/10.1210/en.133.2.822
68. R. Kitazawa, R. B. Kimble, J. L. Vannice, V. T. Kung, R. Pacifici: Interleukin-1 receptor antagonist and tumor necrosis factor binding protein decrease osteoclast formation and bone resorption in ovariectomized mice. J Clin Invest 94(6), 2397-2406 (1994)
doi:10.1172/JCI117606
http://dx.doi.org/10.1172/JCI117606
69. R. B. Kimble, S. Srivastava, P. Ross, A. Matayoshi, R. Pacifici: Estrogen deficiency increases the ability of stromal cells to support murine osteoclastogenesis via an interleukin-1and tumor necrosis factor-mediated stimulation of macrophage colony-stimulating factor production. J Biol Chem 271(46), 2890-2897 (1996)
70. M. A. Mitnick, A. Grey, U. Masiukiewicz, M. Bartkiewicz, L. Rios-Velez, S. Friedman, L. Xu, M. C. Horowitz, K. Insogna: Parathyroid hormone induces hepatic production of bioactive interleukin-6 and its soluble receptor. Am J Physiol Endocrinol Metab 280, E405-E412 (2000)
71. N. Weitzmann, R. Pacifici: T cells: unespected playes in the bone loss induced by estrogen deficiency and in basal bone homeostasis. Ann NY Acad Sci 1116, 360-375 (2007)
doi:10.1196/annals.1402.068
http://dx.doi.org/10.1196/annals.1402.068
72. G. Eghbali-Fatourechi, S. Khosla, A. Sanyal, W. J. Boyle, D. L. Lacey, L. Riggs: Role of RANK ligand in mediating increased bone resorption in early postmenopausal women. J Clin Invest 111(8), 1221-1230 (2003)
73. R. L. Jilka, G. Hangoc, G. Girasole, G. Passeri, D. C. Williams, J. S. Abrams, B. Boyce, H. Broxmeyer, S. C. Manolagas: Increased osteoclast development after estrogen loss: mediation by interleukin-6. Science 257(5066), 88-91 (1992)
doi:10.1126/science.1621100
http://dx.doi.org/10.1126/science.1621100
74. R. B. Kimble, S. Bain, R. Pacifici: The functional block of TNF but not of IL-6 prevents bone loss in ovariectomized mice. J Bone Miner Res 12(6), 935-941 (1997)
doi:10.1359/jbmr.1997.12.6.935
http://dx.doi.org/10.1359/jbmr.1997.12.6.935
75. Y-Y. Kong, H. Yoshida, I. Sarosi, H-L. Tan, E. Timms, C. Capparelli, S. Morony, A. J. Oliveira-dos-Santos, G. Van, A. Itie, W. Khoo, A. Wakeham, C. R. Dunstan, D. L. Lacey, T. W. Mak, W. J. Boyle, J. M. Penninger: OPGL is a key regulator of osteoclastogenesis, lymphocyte development and lymphnode organogenesis. Nature 397, 315-323 (1999)
doi:10.1038/16852
http://dx.doi.org/10.1038/16852
76. N. Bucay, I. Sarosi, C. R. Dunstan, S. Morony, J. Tarpley, C. Capparelli, S. Scully, H. L. Tan, W. Xu, D. L. Lacey, W. J. Boyle, S. Simonet: Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification. Genes Dev 12, 1260-1268 (1998)
doi:10.1101/gad.12.9.1260
http://dx.doi.org/10.1101/gad.12.9.1260
77. S. Simonet, D. L. Lacey, C. R. Dunstan, M. Kelley, M-S. Chang, R. Lüthy, H. Q. Nguyen, S. Wooden, L. Bennett, T. Boone, G. Shimamoto, M. DeRose, R. Elliott, A. Colombero, H. L. Tan, G. Trail, J. K. Sullivan, E. Davy, N. Bucay, L. Renshaw-Gegg, T. M. Hughes, D. Hill, W. Pattison, P. Campbell, S. Sander, G. Van, J. Tarpley, P. Derby, R. Lee, W. J. Boyle: Osteoprotegerin: a novel secreted protein involved in the regulation of bone density. Cell 89(2), 309-319 (1997)
doi:10.1016/S0092-8674(00)80209-3
http://dx.doi.org/10.1016/S0092-8674%2800%2980209-3
78. N. Horwood: Lymphocyte-derived cytokines in inflammatory arthritis. Autoimmunity 41(3), 230-238 (2008)
doi:10.1080/08916930701694766
http://dx.doi.org/10.1080/08916930701694766
79. Y. Gao, W-P. Qian, K. Dark, G. Toraldo, A. S. Lin, R. E. Guldberg, R. A. Flavell, N. Weitzmann, R. Pacifici: Estrogen prevents bone loss through transforming growth factor beta signalling in T cells. Proc Natl Acad Sci USA 101, 16618-16623 (2004)
doi:10.1073/pnas.0404888101
http://dx.doi.org/10.1073/pnas.0404888101
80. S. G. Shaughnessy, K. J. Walton, P. Deschamps, M. Butcher, S. M. Beaudin: Neutralization of interleukin-11 activity decreases osteoclast formation and increases cancellous bone volume in ovariectomized mice. Cytokine 20(2), 78-85 (2002)
doi:10.1006/cyto.2002.1981
http://dx.doi.org/10.1006/cyto.2002.1981
81. B. Stein, M. X. Yang: Repression of the interleukin-6 promoter by estrogen receptor is mediated by NF-kappa B and C/EBP beta. Mol Cell Biol 15(9), 4971-4979 (1995)
82. T. Pelzer, M. Neumann, T. de Jager, V. Jazbutyte, L. Neyses: Estrogen effects in the myocardium: inhibition of NF-kappaB DNA binding by estrogen receptor-alpha and -beta. Biochem Biophys Res Commun 286(5), 1153-1157 (2001)
doi:10.1006/bbrc.2001.5519
http://dx.doi.org/10.1006/bbrc.2001.5519
83. M. Schmitt, P. Bausero, P. Simoni, D. Queuche, V. Geoffroy, C. Marschal, J. Kempf, C. Quirin-Stricker: Positive and negative effects of nuclear receptor on transcription activation by AP-1 of the human choline acetyltransferase proximal promoter. J Neurosci Res 40, 152-164 (1995)
doi:10.1002/jnr.490400203
http://dx.doi.org/10.1002/jnr.490400203
84. S. Papapoulos, P. Makras: Selection of antiresorptive or anabolic treatments for postmenopausal osteoporosis. Nat Clin Pract Endocrinol Metab 4(9), 514-523 (2008)
doi:10.1038/ncpendmet0941
http://dx.doi.org/10.1038/ncpendmet0941
85. S. L. Kates, O. S. Kates, D. A. Mendelson: Advances in the medical management of osteoporosis. Injury 38(S3), S17-S23 (2007)
doi:10.1016/j.injury.2007.08.007
http://dx.doi.org/10.1016/j.injury.2007.08.007
86. G. Russell, Z. Xia, J. E. Dunford, U. Oppermann, A. Kwaasi, P. A. Hulley, K. L. Kavanagh, J. T. Triffitt, M. W. Lundy, R. J. Phipps, B. L. Barnett, F. P. Coxon, M. J. Rogers, N. B. Watts, F. H. Ebetino: Bisphosphonates: an update on mechanisms of action and how these relate to clinical efficacy. Ann N Y Acad Sci 1117, 209-257 (2007)
doi:10.1196/annals.1402.089
http://dx.doi.org/10.1196/annals.1402.089
87. A. Cranney, G. Wells, A. Willan, L. Griffith, N. Zytaruk, V. Robinson, D. Black, J. Adachi, B. Shea, P. Tugwell, G. Guyatt: Meta-analyses of therapies for post-menopausal osteoporosis. II. Meta-analysis of alendronate for the treatment of postmenopausal women. Endocr Rev 23, 508-516 (2002)
doi:10.1210/er.2001-2002
http://dx.doi.org/10.1210/er.2001-2002
88. M. Maricic, J. D. Adachi, S. Sarkar, W. Wu, M. Wong, K. D. Harper: Early effects of raloxifene on clinical vertebral fractures at 12 months in postmenopausal women with osteporosis. Arch Intern Med 162, 1140-1143 (2002)
doi:10.1001/archinte.162.10.1140
http://dx.doi.org/10.1001/archinte.162.10.1140
89. C. Gennai: Analgesic effect of calcitonin in osteoporosis. Bone 30 (S5), S67-70 (2002)
doi:10.1016/S8756-3282(02)00713-5
http://dx.doi.org/10.1016/S8756-3282%2802%2900713-5
90. P. D. Delmas: Clinical effects of strontium ranelate in women with postmenopausal osteoporosis. Osteoporosis Int 16(S1), S16-19 (2005)
doi:10.1007/s00198-004-1767-2
http://dx.doi.org/10.1007/s00198-004-1767-2
91. P. J. Marie: Strontium ranelate: a physiological approach for optimizing bone formation and resorption. Bone 38(2 S1), S10-14 (2006)
92. P. Chen, P. D. Miller, P. D. Delmas, D. A. Misurski, J. H. Krege: Change in lumbar spine BMD and vertebral fracture risk reduction in teriparatide-treated post-menopausal women with osteoporosis. J Bone Miner Res 21, 1785-1790 (2006)
doi:10.1359/jbmr.060802
http://dx.doi.org/10.1359/jbmr.060802
93. M. R. McClung, M. Lewiecki, S. B. Cohen, M. A. Bolognese, G. C. Woodson, A. H. Moffett, M. Peacock, P. D. Miller, S. N. Lederman, C. H. Chesnut, D. Lain, A. J. Kivitz, D. L. Holloway, C. Zhang, M. C. Peterson, P. J. Bekker: Denosumab in postmenopausal women with low bone mineral density. N Engl J Med 354, 821-831 (2006)
doi:10.1056/NEJMoa044459
http://dx.doi.org/10.1056/NEJMoa044459
94. J. G. Emery, P. McDonnel, M. B. Burke, K. C. Deen, S. Lyn, C. Silverman, E. Dul, E. R. Appelbaum, C. Eichman, R. DiPrinzio, R. A. Dodds, I. E. James, M. Rosemberg, J. C. Lee, P. R. Young: OPG is a receptor for the cytokine ligand TRAIL. J Biol Chem 273, 14363-14367 (1998)
doi:10.1074/jbc.273.23.14363
http://dx.doi.org/10.1074/jbc.273.23.14363
95. M. Zaidi, H. C. Blair, B. S. Moonga, E. Abe, C. L-H. Huang: Osteoclastogenesis, bone resorption and osteoclast-based therapeutics. J Bone Miner Res 18(4), 599-609 (2003)
doi:10.1359/jbmr.2003.18.4.599
http://dx.doi.org/10.1359/jbmr.2003.18.4.599
96. M. Franchi, M. Fini, G. Giavaresi, V. Ottani. Peri-implant osteogenesis in health and osteoporosis. Micron 26, 630-644 (2005)
97. P. Augat, U. Simon, A. Liedert, L. Claes: Mechanics of mechano-biology of fracture healing in normal and osteoporotic bone. Osteoporosis Int 16(S2), S36-S43 (2005)
doi:10.1007/s00198-004-1728-9
http://dx.doi.org/10.1007/s00198-004-1728-9
98. G. Alsaadi, M. Quirynen, A. Komárek, D. van Steenberghe: Impact of local and systemic factors on the incidence of oral implant failures, up to abutment connection. J Clin Periodontol 34(7), 610-617 (2007)
doi:10.1111/j.1600-051X.2007.01077.x
http://dx.doi.org/10.1111/j.1600-051X.2007.01077.x
99. K. Strømsøe: Fracture fixation problems in osteoporosis. Injury 35(2), 107-113 (2004)
doi:10.1016/j.injury.2003.08.019
http://dx.doi.org/10.1016/j.injury.2003.08.019
100. H. Zhang, C. G. Lewis, M. S. Aronov, G. A. Gronowicz: The effects of patient age on human osteoblasts response to Ti-6Al-4V implants in vitro. J Orthop Res 22, 30-38 (2004)
doi:10.1016/S0736-0266(03)00155-4
http://dx.doi.org/10.1016/S0736-0266%2803%2900155-4
101. V. Borsari, M. Fini, G. Giavaresi, L. Rimondini, R. Chiesa, L. Chiusoli, R. Giardino: Sandblasted titanium osteointegration in young, aged and ovariectomized sheep. Int J Artif Organs 30(2), 163-172 (2007)
102. J. McMillan, R. C. Kinney, D. M. Ranly, S. Fatehi-Sedeh, Z. Schwartz, B. B. Boyan: Osteoinductivity of demineralised bone matrix in immunocompromised mice and rats is decreased by ovariectomy and restored by estrogen replacement. Bone 40(1), 111-121 (2007)
doi:10.1016/j.bone.2006.07.022
http://dx.doi.org/10.1016/j.bone.2006.07.022
103. K. A. Hing: Bone repair in the twenty-first century: biology, chemistry or engineering? Phil Trans R Soc A 362(1825), 2821-2850 (2004)
104. A. Moroni, C. Faldini, F. Pegreffi, S. Giannini: Hydroxyapatite-coated screws decrease the incidence of fixation failure in osteoporotic trochanteric fractures. Clin Orthop Relat Res 425, 87-92 (2004)
doi:10.1097/01.blo.0000132405.30139.bb
http://dx.doi.org/10.1097/01.blo.0000132405.30139.bb
105. M. Fini, G. Giavaresi, T. Greggi, L. Martini, N. Nicoli Aldini, P. Parisini, R. Giardino: Biological assessment of the bone-screw interface after insertion of uncoated and hydroxyapatite-coated pedicular screws in the osteopenic sheep. J Biomed Mater Res A 66(1), 176-183 (2003)
doi:10.1002/jbm.a.10605
http://dx.doi.org/10.1002/jbm.a.10605
106. J. Pan, T. Shirota, K. Ohno, K. Michi: Effect of ovariectomy on bone remodelling and adjacent to hydroxyapatite-coated implants in the tibia of mature rats. J Oral Maxillofac Surg 58, 877-882 (2000)
doi:10.1053/joms.2000.8212
http://dx.doi.org/10.1053/joms.2000.8212
107. J. M. Steinacker, M.
107. A. H. A. Kurth, C. Eberhardt, S. Muller, Schwarz, F. Bauss: The biphosphonate ibandronate improves implant integration in osteopenic ovariectomized rats. Bone 37(2), 204-210 (2005)
doi:10.1016/j.bone.2004.12.017
http://dx.doi.org/10.1016/j.bone.2004.12.017
108. L. Le Guehennec, A. Soueidan, P. Layrolle, Y. Amouriq: Surface treatments of titanium dental implants for rapid osseointegration. Dent Mat 23(7), 844-854 (2007)
doi:10.1016/j.dental.2006.06.025
http://dx.doi.org/10.1016/j.dental.2006.06.025
109. V. Borsari, M. Fini, G. Giavaresi, M. Tschon, R. Chiesa, L. Chiusoli, A. Salito, L. Rimondini, R. Giardino: Comparative in vivo evaluation of porous and dense duplex titanium and hydroxyapatite coating with high roughnesses in different implantation environments. J Biomed Mater Res A 89(2), 550-560 (2009)
doi:10.1002/jbm.a.31995
http://dx.doi.org/10.1002/jbm.a.31995
110. M-E. Marquis, E. Lord, E. Bergeron, O. Drevelle, H. Park, F. Cabana, H. Senta, N. Faucheux: Bone cells-biomaterials interactions. Front Biosci 14, 1023-1067 (2009)
doi:10.2741/3293
http://dx.doi.org/10.2741/3293
111. M. Yoshinari, Y. Oda, T. Inoue, K. Matsuzaka, M. Shimono: Bone response to calcium phosphate coated and biphosphonate immobilized titanium implants. Biomaterials 23(14), 2879-2885 (2002)
doi:10.1016/S0142-9612(01)00415-X
http://dx.doi.org/10.1016/S0142-9612%2801%2900415-X
112. G. Giro, D. Goncalves, C. E. Sakakura, R. M. Rodrigues Pereira, E. Marcantonio Junior, S. Regina Perez Orrico: Influence of estrogen deficiency and its treatment with alendronate and estrogen on bone density around osseointegrated implants: radiographic study in female rats. Oral Surg Oral Pathol Oral Radiol Endod 105, 162-167 (2008)
doi:10.1016/j.tripleo.2007.06.010
http://dx.doi.org/10.1016/j.tripleo.2007.06.010
113. V. A. Stadelmann, A. Terrier, O. Gauthier, J-M. Bouler, D. P. Pioletti: Implants delivering biphosphonate locally increase periprosthetic bone density in an osteoporotic sheep model. A pilot study. Eur Cell Mater 16, 10-16 (2008)
114. Z. Du, J. Chen, F. Yan, Y. Xiao: Effects of Simvastatin on bone healing around titanium implants in osteoporotic rats. Clin Oral Impl Res 20, 145-150 (2009)
doi:10.1111/j.1600-0501.2008.01630.x
http://dx.doi.org/10.1111/j.1600-0501.2008.01630.x
115. G. Mundy, R. Garrett, S. Harris, J. Chan, D. Chen, G. Rossini, B. Boyce, M. Zhao, G. Gutierrez: Stimulation of bone formation in vitro and in rodents by statins. Science 286, 1946-1949 (1999)
doi:10.1126/science.286.5446.1946
http://dx.doi.org/10.1126/science.286.5446.1946
116. P. J. Marie: Strontium ranelate: new insights into its dual mode of action. Bone 40, S5-8 (2007)
doi:10.1016/j.bone.2007.02.003
http://dx.doi.org/10.1016/j.bone.2007.02.003
117. S. Peng, G. Zhou, K. D. Luk, K. M. Cheung, Z. Li, W. M. Lam, Z. Zhou, W. W. Lu: Strontium promotes osteogenic differentiation of mesenchymal stem cells through the Ras/MAPK signalling pathway. Cell Physiol Biochem 23(1-3), 165-174 (2009)
doi:10.1159/000204105
http://dx.doi.org/10.1159/000204105
118. Z. Li, W. W. Lu, P. K. Chiu, W. M. Lam, B. Xu, K. M. Cheung, J. C. Leong, K. D. Luk: Strontium-Calcium coadministration stimulates bone matrix osteogenic factor expression and new bone formation in a large animal model. J Orthop Res (epub of print) (2008)
119. L. Leroux, J. L. Lacout: Preparation of calcium strontium hydroxyapatites by a new route involving calcium phosphate cements. J Mater Res 16(1), 171-178 (2001)
doi:10.1557/JMR.2001.0028
http://dx.doi.org/10.1557/JMR.2001.0028
120. E. Landi, A. Tampieri, G. Celotti, S. Sprio, M. Sandri, G. Logroscino: Sr-substituted hydroxyapatites for osteoporotic bone replacement. Acta Biomater 3, 961-969 (2007)
doi:10.1016/j.actbio.2007.05.006
http://dx.doi.org/10.1016/j.actbio.2007.05.006
121. C. Cappuccini, P. Torricelli, E. Boanini, M. Gazzano, R. Giardino, A. Bigi: Interaction of Sr-doped hydroxyapatite nanocrystals with osteoclast and osteoblast-like cells. J Biomed Mater Res 89(3), 594-600 (2009)
doi:10.1002/jbm.a.31975
http://dx.doi.org/10.1002/jbm.a.31975
122. K-H. Frosch, A. Drengk, P. Krausse, V. Volker, N. Miosge, C. Werner, D. Schild, E. K. Sturmer, K. M. Sturmer: Stem cell-coated titanium implants for the partial joint resurfacing of the knee. Biomaterials 27, 2542-2549 (2006)
doi:10.1016/j.biomaterials.2005.11.034
http://dx.doi.org/10.1016/j.biomaterials.2005.11.034
123. K. Soballe, T. B. Jensen, O. Mouzin, L. Kidder, J. E. Bechtold: Differential effect of a bone morphogenetic protein-7 (OP-1) on primary and revision loaded, stable implants with allografts. J Biomed Mater Res 71A, 569-576 (2004)
doi:10.1002/jbm.a.30115
http://dx.doi.org/10.1002/jbm.a.30115
124. K. J. Kim, M. Iwase, S. Kotake, T. Itoh: Effects of bone marrow grafting on the titanium porous-coated implant in bilateral total knee arthroplasty. Acta Orthopaedica 78, 116-122 (2007)
doi:10.1080/17453670610013510
http://dx.doi.org/10.1080/17453670610013510
125. L. Peidro, J. M. Segur, D. Poggio, P. Fernandez de Retana: Use of freeze-dried bone allograft with platelet-derived growth factor for revision of a glenoid component. J Bone Joint Surg Br 88(9), 1228-1231 (2006)
doi:10.1302/0301-620X.88B9.17471
http://dx.doi.org/10.1302/0301-620X.88B9.17471
126. R. D. Sumner, T. M. Turner, R. M. Urban, A. S. Virdi, N. Inoue: Additive enhancement of implant fixation following combined treatment with rhTGF beta2 and rhBMP-2 in a canine model. J Bone Joint Surg Am 88(4), 806-817 (2006)
doi:10.2106/JBJS.E.00846
http://dx.doi.org/10.2106/JBJS.E.00846
127. D. Dallari, M. Fini, G. Giavaresi, N. Del Piccolo, C. Stagni, L. Amendola, N. Rani, S. Gnudi, R. Giardino: Effects of pulsed electromagnetic stimulation on patients undergoing hip revision prostheses: a randomized prospective double blind study. Bioelectromagnetics (epub of print) (2009)
128. Y. Gao, E. Luo, J. Hu, J. Xue, S. Zhu, J. Li: Effect of combined local treatment with zoledronic acid and basic fibroblast growth factor on implant fixation in ovariectomized rats. Bone 44, 225-232 (2009)
doi:10.1016/j.bone.2008.10.054
http://dx.doi.org/10.1016/j.bone.2008.10.054
129. A. Sachse, A. Wagner, M. Keller, O. Wagner, W. Wetzel, F. Layher, R. A. Venbrocks, P. Hortschanky, M. Pietraszczyk, B. Wiederanders, H. J. Hempel, J. Bossert, J. Horn, K. Schmuck, J. Mollenhauer: Osteointegration of hydroxyapatite-Titanium implants coated with nonglycosilated recombinant human bone morphogenetic protein 2 (BMP-2)
in aged sheep. Bone 37, 699-710 (2005)
doi:10.1016/j.bone.2005.06.011
http://dx.doi.org/10.1016/j.bone.2005.06.011
130. K. Hayashi, A. Fotovati, S. Abu-Ali, K. Oda, H. Oida, M. Naito: Prostaglandin EP4 receptor agonist augments fixation of hydroxyapatite-coated implants in a rat model of osteoporosis. J Bone Joint Surg Br 87-B(8), 1150-1156 (2005)
doi:10.1302/0301-620X.87B8.15886
http://dx.doi.org/10.1302/0301-620X.87B8.15886
131. A. Bigi, N. Nicoli-Aldini, B. Bracci, B. Zavan, E. Boanini, F. Sbaiz, S. Panzavolta, G. Zorzato, R. Giardino, A. Facchini, G. Abatangelo, R. Cortivo: In vitro culture of mesenchymal cells onto nanocrystalline hydroxyapatite-coated Ti13Nb13Zr alloy. J Biomed Mater Res 82A, 213-221 (2007)
doi:10.1002/jbm.a.31132
http://dx.doi.org/10.1002/jbm.a.31132
132. A. Bigi, M. Fini, B. Bracci, E. Boanini, P. Torricelli, G. Giavaresi, N. Nicoli Aldini, A. Facchini, F. Sbaiz, R. Giardino: The response of bone to nanocrystalline hydroxyapatite-coated Ti13Nb11Zr alloy in an animal model. Biomaterials 29, 1730-1736 (2008)
doi:10.1016/j.biomaterials.2007.12.011
http://dx.doi.org/10.1016/j.biomaterials.2007.12.011
133. L. H. Tasker, G. J. Sparey-Taylor, L. D. Nokes: Applications of nanotechnology in orthopaedics. Clin Orthop Rel Res 456, 243-249 (2007)
doi:10.1097/BLO.0b013e31803125f4
http://dx.doi.org/10.1097/BLO.0b013e31803125f4
134. E. M. Christenson, T. S. Anseth, J. van de Beuken, C. K. Chan, B. Ercan, J. A. Jansen, C. T. Laurencin, W-J. Li, R. Murugan, L. S. Nair, S. Ramakrisna, R. S. Tuan, T. J. Webster, A. G. Mikos: Nanobiomaterial applications in orthopaedics. J Orthop Res 25, 11-22 (2007)
doi:10.1002/jor.20305
http://dx.doi.org/10.1002/jor.20305
135. T. J. Webster, L. S. Schadler, R. W. Siegel: Mechanism of enhanced osteoblast adhesion on nanophase alumina involve vitronectin. Tissue Eng 7(3), 291-301 (2001)
doi:10.1089/10763270152044152
http://dx.doi.org/10.1089/10763270152044152
136. Y. Tang, W. Tang, J. Lin, Y. Jie, H. Wang, L. Liu, W. Tian: Combination of bone tissue engineering and BMP-2 gene transfection promotes bone healing in osteoporotic rats. Cell Biol Int 32, 1150-1157 (2008)
doi:10.1016/j.cellbi.2008.06.005
http://dx.doi.org/10.1016/j.cellbi.2008.06.005
Abbreviations: Ca: calcium; P: phosphorus; BMU: basic multicellular units; PTH: parathyroid hormone; CTN: calcitonin; IGF: insulin like growth factor; GH: growth hormone; TSH: thyroid stimulating hormone; FSH: follicle stimulating hormone; 125-D: 1,25 diihydroxyvitamin D; OPG: osteoprotegerin; TGF: transforming growth factor; HPT: hypothalamic-pituitary-thyroid; IL: interleukin; RANKL: receptor activator of nuclear factor kB ligand; RANK: receptor activator of nuclear kB; M-CSF: macrophage colony stimulating factor; TNF: tumor necrosis factor; RGD: Arg-Gly-Asp; FGF: fibroblast growth factor; PDGF: platelet-derived growth factor; cAMP: cyclic adenosine monophosphate; CREP: cAMP response element binding; SHBG: sex-hormone binding globulin; AP: activator protein; BMD: bone mineral density; IMPACT: improving measurements of persistence of actonel treatment; IFN: interferon; ER: estrogen receptors; NF-kB: nuclear factor-kappa B; C/EBPbeta: CCAAT/Enhancer binding protein beta; SERM: selective estrogen receptor modulators; TRAIL: tumor necrosis factor-related apoptosis-inducing ligand; DBM: demineralized bone matrix; ECM: extracellular matrix; BMP: bone morphogenetic protein; Sr: strontium.
Key Words: Bone, Osteoporosis, Hormones, Cytokines, Osteoblasts, Biomaterials, Review
Send correspondence to: Angelo Carpi, Department of Reproduction and Ageing University of Pisa Santa Chiara Hospital, Via Roma 67 56126 Pisa Italy, Tel: 39 050 992955, Fax: 39 050 992955, E-mail:a.carpi@med.unipi.it