Abstract: Osteoporosis is a bone disease that leads to enhanced bone fragility and thus an increased risk of fracture. Osteoporotic fractures are a major cause of suffering, disability and death in the older population and their costs to healthcare services exceed those of many other chronic diseases (Johnell and Kanis, 2006). In the UK, around 230,000 people every year suffer a fracture because of osteoporosis at an estimated cost to the NHS of £1.8billion a year. Hormones and the RANKL/RANK/OPG signalling system have been shown to have a significant effect on bone remodelling. Oestrogen is the main hormone that affects bone. In post-menopausal women, oestrogen deficiency has been shown to lead to an increase in bone resorption due to excessive osteoclast activity (Jilka, 2003). Parathyroid Hormone (PTH) and calcitonin have also been shown to have an effect on bone, although the role of calcitonin is less clear (Raisz, 2005). It has been shown that RANKL/RANK signalling regulates osteoclast formation, activation and survival in normal bone modelling and remodelling. OPG protects bone from excessive resorption by binding to RANKL, thus acting as an inhibitor, preventing it from binding to RANK. Therefore, the relative concentration of RANKL and OPG in bone is a major determinant of bone mass and strength (Boyce and Xing, 2008). There are a number of different pharmacological and non-pharmacological ways of treating osteoporosis. However, their efficacy is not as great as they should be due to a high non-compliance rate (Rizzoli et al., 2010). Being able to treat patients with a less inconvenient treatment will prove vital in reducing the number of patients that suffer fragility fractures. As the UK population ages, there will be an increased burden on the NHS with regards to osteoporosis sufferers. It is therefore important that various measures are implemented to identify at risk patients and to improve the effectiveness of care. By 2015 the NHS hopes to have saved £20 billion through improvements in the quality and efficiency of treatment (UK Osteoporosis Report, 2010).
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Osteoporosis is a bone disease that leads to enhanced bone fragility and thus an increased risk of fracture. In osteoporosis, bone mineral density (BMD) is reduced along with a degradation in bone microarchitecture and an alteration in the amount and variety of proteins in bone. Although fragility fractures can occur throughout the skeleton, they are most common at the wrist, spinal vertebrae and hip. The incidence of vertebral and hip fractures increases exponentially with advancing age while that of wrist fractures levels off after the age of 60 years (Prentice, 2004). Osteoporotic fractures are a major cause of suffering, disability and death in the older population and their costs to healthcare services exceed those of many other chronic diseases. In Europe the disability due to osteoporosis is greater than that caused by many cancers, with the exception of lung cancer. It also causes at least as much, if not more, disability than that caused by a variety of chronic non-infectious diseases such as asthma and high blood-pressure related heart disease (Johnell and Kanis, 2006). In the UK, around 230,000 people every year suffer a fracture because of osteoporosis at an estimated cost to the NHS of £1.8billion a year.
The WHO defines osteoporosis as a value for bone mineral content (BMC) or bone mass density (BMD), that can be measured through a variety of techniques such as dual-energy x-ray absorptiometry (DXA), being 2.5 standard deviations or more below the young adult mean (WHO, 1994). It has been shown that a low BMC or BMD in the elderly correlates with a sub-optimal bone mass in young adulthood when peak bone mass is achieved, greater bone loss in later life or both (Prentice, 2004). It is therefore important that one stimulates the bone forming mechanisms in the body through various means, such as exercise, and avoid factors, such as smoking and alcohol, which can cause a decline in bone formation and remodelling. Bone loss is also not a phenomenon that is confined to Earth alone. It is one of the most serious medical problems associated with prolonged weightlessness and therefore a stumbling block with a view to a future long duration space flight mission to Mars. As the human skeleton has evolved in an environment where the force of Earth's gravity has been a continual presence, the removal of gravity during long-duration space flight results in a loss of homeostasis in the skeleton (Lang et al., 2004). Therefore, being able to reduce bone loss through pharmacological or other ways remains vital as it has the potential to save significant amounts of money and also be beneficial in space exploration.
2.0 The Effect of Hormones on Bone Homeostasis
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Hormones play a crucial role in bone homeostasis. They strongly determine the rate of bone resorption; low levels of oestrogen lead to increased bone resorption as well as decreasing the deposition of new bone that normally takes place in weight-bearing bones. The parathyroid glands also contribute to increased bone resorption by secreting parathyroid hormone (PTH) in response to low calcium levels, which increases bone resorption to ensure sufficient calcium in the blood. However, it has also been shown that PTH can have a beneficial role in bone with studies showing that once a day, subcutaneous injection of PTH increases bone mass and formation. The role of calcitonin, a hormone generated by the thyroid that increases bone deposition, is less clear and probably not as significant as that of PTH (Raisz, 2005). Although it has been shown to inhibit bone resorption, further work is required to fully establish its effects and the mechanisms by which it brings these about.
2.1 The Effect of Oestrogen on Bone
Oestrogen has a major role to play in the regulation of bone turnover during the different phases of life. During puberty, there is an increase in oestrogen that leads to a bisphasic effect on growth. This stimulates the secretion of growth hormone resulting in an increase in growth whilst also promoting the closure of the growth plate. It also has an effect on modelling to stimulate endosteal apposition and inhibit periosteal apposition. Finally, it causes a decrease in the rate of bone remodelling. The effects of oestrogen on modelling and remodelling persist until the menopause (Eastell, 2004).
Oestrogen brings about a change in bone remodelling by causing a decrease in activation frequency that leads to a decrease in numbers of osteoclasts and osteoblasts. It is thought that oestrogen affects osteoclasts indirectly through products that are secreted by the osteoblast. Binding of different cytokines to their receptors in osteoblasts is believed to result in the release of soluble factors that act directly on osteoclasts to modulate their recruitment or activity. Thus, it is thought that oestrogen could inhibit the release of osteoclast stimulatory factors or, alternatively, could enhance the release of osteoclast inhibitory factors (Krassas and Papadopoulou, 2001). These products include RANKL (the ligand of the receptor activator of nuclear factor kappa B) and colony stimulating factor 1 (CSF-1). They regulate the differentiation of osteoclast precursors to osteoclasts and, once differentiated, the activity of the mature osteoclast and its rate of apoptosis (Eastell, 2005). It is still not known the exact mechanism of action that oestrogen has on osteoblasts. Some experiments have provided evidence for oestrogen increasing osteoblast formation, differentiation, proliferation and function. More recently, it has been demonstrated that oestrogen antagonises glucocorticoid-induced osteoblast apoptosis and thus, extends osteoblast lifespan resulting in prolonged bone formation (Riggs et al., 2002). However, more work is required to look into this further and to establish the exact mechanisms behind such an effect.
As originally pointed out by Frost, 1966, the activities of osteoclasts and osteoblasts are combined into functional assemblies called basic multicellular units (BMUs) that are responsible for bone remodelling. This remodelling increases in sex steroid deficiency, which may account for the initial decrease in bone mineral density. This is due to expansion of the remodelling space caused by a prolonged resorption phase and a reduced formation phase, resulting in an incapability of osteoblasts to refill the increased volume of the resorption cavity caused by increased osteoclast activity (Riggs et al, 2002). However, it cannot explain the imbalance between formation and resorption that leads to progressive bone loss. A possible explanation can be linked to oestradiol. This sex hormone promotes osteoclast apoptosis but prevents that of osteoblasts, leading to increased bone being laid down. In oestrogen deficiency, these complementary processes are lost; there is a decrease in the death of osteoclasts leading to deeper than normal erosion cavities and a reduction in wall thickness of bone due to a reduced number of osteoblasts (Jilka, 2003).
2.2 Parathyroid Hormone (PTH) and its Effects on Bone
Parathyroid Hormone (PTH) is a circulating hormone comprised of 84 amino acids that is produced in the parathyroid glands. The overall function of endogenous PTH is to maintain normal extracellular calcium levels by enhancing gastrointestinal calcium absorption, renal calcium and phosphate reabsorption, and osteoclastic bone resorption, which in turn leads to the release of calcium from the skeleton (Ellegaard et al, 2010).
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PTH binds to osteoblasts to produce both an anabolic or catabolic effect, depending on its route of administration. The anabolic properties of PTH can be seen when PTH is given in a low dosage, intermittently. There is a rapid increase in bone formation markers that is later followed by an increase in bone resorption markers (Girotra et al, 2006). The mechanisms behind this response are unknown. However, it has been hypothesised that the increased bone formation can be attributed to a rise in osteoblast number as a result of increased proliferation and differentiation of osteoblasts in vitro and in vivo, a decrease in osteoblast apoptosis and activation of bone lining cells (Datta and Abou-Samra., 2009).
However, continuous administration of PTH has the opposite effect. Continuous infusion of PTH results in severe hypercalcaemia and a net decrease in trabecular bone volume (Bergenstock and Partridge, 2007). It most likely induces this bone resorption by activating osteoclasts indirectly through its actions on osteoblastic cells (Teitelbaum, 2000). Osteoblasts possess specific surface receptors for parathyroid hormone and parathyroid hormone-related protein (PTHrP). However, there was little evidence for the presence of these receptors on osteoclasts (Zaidi et al., 1993). This was initially supported by studies that used isolated cultures of osteoclast cells which showed that parathyroid hormone does not directly increase osteoclastic activity. However, it was shown that the reintroduction of osteoblast-like cells to these cultures restored the effect of parathyroid hormone (Zaidi et al., 1993). More recently, however, Langub et al., 2001 suggested that osteoclasts do possess the parathyroid 1 receptor (PTH1R) when they documented mRNA and protein of PTH1R in osteoclasts of iliac crest bone samples from humans. This was supported by Faucheaux et al., 2002 who found that PTHrP stimulates osteoclast differentiation in regenerating skeletal tissues of deer antlers and that its effects on osteoclastogenesis are independent of RANKL synthesis, possibly through the documented PTH1R in the cytoplasmic and nuclear compartments of the osteoclasts.
Several groups have suggested that PTH stimulates osteoclastogenic action by altering the levels of RANKL and OPG gene expression. As will be explained later, OPG binds to RANKL, thus inhibiting it from binding to RANK and so preventing excessive bone resorption. In 2004, Huang et al., showed that RANKL is maximally increased by PTH 1-2 h after treatment. This observation supported the results of Lee and Lorenzo, 1999 who had demonstrated a rapid RANKL response in PTH-treated osteoblasts. Huang et al., 2002 also found that PTH had a rapid effect to reduce OPG mRNA levels, with its effects becoming evident as early as two hours after exposure to PTH.
The activation of osteoclasts and the differentiation of osteoclast precursors are promoted by PTH-induced increases in the level of RANKL and/or decreases in the level of OPG (Huang et al., 2004). From the reports by Lee and Lorenzo in 1999 and 2002 that have used in vitro primary bone cells from mouse long bone and calvaria to assess PTH effects on RANKL and OPG, it has been suggested that PTH treatment affects RANKL/OPG mRNA levels in short 6-day cell cultures after stromal cell isolation. However, this data may not be reflective of cellular function at later stages of osteoblast differentiation. The results from the experiment carried out by Huang et al., 2004 suggest that there is a switch in the regulatory mechanism of osteoclastogenesis induced by PTH, whereby OPG is dominant in the earlier stages of osteoblast differentiation and RANKL dominates the effects on osteoclastogenesis during the latter stages of osteoblast differentiation.
2.3 Calcitonin and its Effects on Bone
Calcitonin is a naturally occurring, 32-amino acid hormone that is produced primarily by the parafollicular cells of the thyroid. It plays an important physiological role in mineral and skeletal homeostasis (Wallach et al., 1993) and also acts to reduce blood calcium (Ca2+), by opposing the effects of parathyroid hormone (Boron and Boulpaep, 2004).
The effects of calcitonin are mediated by the calcitonin receptor, which belongs to family B of the G protein-coupled receptor superfamily (Sexton et al., 1999). It acts directly on osteoclast calcitonin receptors to inhibit bone resorption. When calcitonin binds to its receptor, it causes a change in the cytoskeleton of the osteoclast that is followed by inhibition of osteoclast motility and subsequent bone resorption (Komarova et al., 2003). The response of osteoclasts to calcitonin has been attributed to distinct signalling pathways. For example, the activation of adenylate cyclase upon binding leads to a rise in intracellular levels of cAMP. It is these cAMP-dependent mechanisms that mediate the initial loss of motility in osteoclasts (Komarova et al., 2003). Since bone resorption requires motile processes, the inhibition of osteoclast motility by calcitonin may play an important role in its ability to inhibit bone resorption by osteoclasts. Another example is the coupling of the calcitonin receptor to the PLC pathway. The activation of this pathway causes the release of Ca2+ from intracellular stores which results in a rise in extracellular calcium leading to an increase in deposition of calcium in the bone which is of benefit in preventing the compression fractures resulting from osteoporotic thinning (Pondel, 2000).
Furthermore, calcitonin also inhibits osteoclast secretion, especially that of tartrate-resistant acid phosphatise (TRAP) and Na+/K+-ATPase. It also alters the localisation of carbonic anhydrase and thus acid secretion in osteoclasts (Bilezikian et al., 2002). The release of TRAP at sites of osteoclast attachment to bone, that is, the extracellular bone resorption compartment, may be an important mechanism contributing to mineral and matrix dissolution. This relationship between TRAP and bone resorption has been supported by Yumita et al., 1991, whose study on isolated rat osteoclasts showed that calcitonin inhibited the release of TRAP and thus also bone resorption. The numerous effects that calcitonin has and the fact that it opposes the action of PTH, which can at times be to increase bone resorption, means that it could be an even more effective treatment in preventing excessive loss of BMD than ones that focus on PTH and its related causes. To establish this effect, further research is required to fully elucidate the actions and mechanisms by which calcitonin reduces bone resorption, in particular the most important pathways that are inhibited which result in the greatest decrease in resorption, so that treatments can be developed which target these.
3.0 The Function of RANKL/RANK/OPG in Bone Modelling
The discovery of the OPG/RANK-L/RANK system, which began with a seminal paper published in 1997 by Simonet et al., is one of the outstanding events in bone biology (Khosla, 2001). It has been shown that RANKL/RANK signalling regulates osteoclast formation, activation and survival in normal bone modelling and remodelling and in a variety of pathologic conditions that are characterised by increased bone turnover. OPG protects bone from excessive resorption by binding to RANKL, thus acting as an inhibitor, preventing it from binding to RANK. Therefore, the relative concentration of RANKL and OPG in bone is a major determinant of bone mass and strength (Boyce and Xing, 2008).
RANKL is a 317-amino acid polypeptide with a cytoplasmic N-terminal domain, a transmembrane domain and an extracellular C-terminal domain (Pérez-Sayáns et al., 2010). RANKL expression is primarily induced by osteoblastic stromal cells, which leads to osteoclast formation and activity. However, it is also expressed in lymph nodes, thymus and mammary glands, lungs and at low levels in a variety of other tissues, including the spleen and bone marrow (Boyce and Xing, 2008). RANKL exists as a cell surface molecule and binding to its cognate receptor RANK on the surface of osteoclast precursors is essential for generating new osteoclasts (Romas, 2009). In addition, binding of it to RANK on mature osteoclasts promotes their adherence to bone and suppresses osteoclast apoptosis, therefore prolonging bone resorption (Romas, 2009).
Human RANK is a 616-amino acid peptide, with a 28-amino acid signal peptide, an N-terminal extracellular domain, a short transmembrane domain of 21 amino acids, and a large C-terminal cytoplasmic domain (Khosla, 2001). It is expressed primarily on cells of the macrophage/monocytic lineage, including preosteoclastic cells, T and B cells, dendritic cells, and fibroblasts (Khosla, 2001).
To date, no humans have been identified with inactivating mutations or deletions of RANK. However, a deletion mutation was found to have occurred spontaneously in a line of transgenic mice, which bore all of the characteristics of mice with targeted deletion of RANK (Boyce and Xing, 2007). These knockout mice had profound osteopetrosis due to an absence of osteoclasts which confirmed the importance of RANK for osteoclast formation as these mutations proved that RANK is expressed on preosteoclastic cells and that it was the sole receptor on these cells for RANKL (Khosla, 2001). Therefore, without RANK, RANKL could not bind and activate osteoclastogenesis. It has been shown that activating mutations in exon 1 of RANK causes an increase in RANK-mediated nuclear factor-ÎºB (NF-ÎºB) signalling, resulting in an increase in osteoclast formation and activity. This is thought to account for the increased osteolysis seen in some patients with familial Paget's disease and has therefore confirmed the importance of this system in humans (Hughes et al., 2000).
Osteoprotegerin (OPG), also known as "bone protector", belongs to the TNF receptor family. It is a soluble glycoprotein, consisting of 380 amino acids and seven domains. It is expressed in many types of cells such as osteoblasts, heart, kidney, liver, spleen and bone marrow (Klejna et al., 2009). OPG expression is influenced by many of the factors that also induce RANKL expression (Boyce and Xing, 2008). In times of increased osteoclast activity, in general 'when RANKL expression is up-regulated, OPG expression is down-regulated or not induced to the same degree as RANKL, such that the RANKL/OPG ratio changes in favour of osteoclastogenesis' (Boyce and Xing, 2008). Anything that leads to an increase in the ratio of RANKL to OPG will result in higher osteoclast activity.
A number of treatments that target ways of increasing BMD do so by increasing OPG production. As mentioned earlier, oestrogen deficiency in postmenopausal women is one of the major causes of osteoporosis. In vitro studies have shown increased OPG production by primary human osteoblasts when treated with oestrogen (Reid and Holen, 2009). This was further supported by several studies that showed that Raloxifene, a selective-oestrogen receptor modulator (SERM) caused an increase in BMD by stimulating OPG production in osteoblasts. Another group of drugs that treat osteoporosis are bisphosphonates that inhibit osteoclast-mediated bone resorption by increasing OPG levels in primary trabecular osteoblasts, providing further evidence for the protective role of OPG in osteoporosis (Reid and Holen, 2009).
4.0 Current Treatment
There are a number of different pharmacological and non-pharmacological ways of treating osteoporosis. Some of the non-phamacological treatments include having supplements of calcium and vitamin D which have been found to be vital in achieving optimal peak bone mass (Nieves et al., 1995). A recent study by Boonen et al., 2007, suggested that oral vitamin D only appeared to reduce the risk of hip fractures when taken with calcium. Having a healthy diet and good lifestyle are also very important in helping to prevent the onset of osteoporosis. Regular physical activity is known to have a positive effect on bone mass and can also improve agility, strength and balance which may reduce the risk of falls (National Osteoporosis Foundation, 2008). Smoking and alcohol consumption can also have a detrimental effect on BMD. Evidence suggests that smoking causes increased hepatic metabolism of oestrogens which results in lower oestrogen levels among postmenopausal smokers (Jensen et al., 1985). As stated earlier, oestrogen has a protective role in bone and a reduced level may contribute to the greater risk that smokers have of suffering from osteoporosis. Therefore, patients should be counselled on the damaging effects of smoking and encouraged to follow smoking cessation programs. Likewise excessive intake of alcohol also has a negative effect on bone health, it increases the risk of falling and requires intervention when identified (National Osteoporosis Foundation, 2008).
The main pharmacological treatments for osteoporosis are bisphosphonates, raloxifene, strontium ranelate and parathyroid hormone, known as teriparetide. Due to their relatively low cost, the first line of treatment recommended by the National Institute for Health and Clinical Excellence (NICE) are oral bisphosphonates (UK Osteoporosis Report, 2010). The high cost of teriparetide means that its use is mainly intended for those that have a very high fracture risk, particularly of the vertebrae (National Osteoporosis Guideline Group, 2009). Hormone Replacement Therapy (HRT) is not specifically recommended as a treatment for osteoporosis and is now almost never used. This is because there is a risk that HRT slightly raises the chance of developing certain conditions, such as breast cancer, endometrial cancer, ovarian cancer and stroke, more than it lowers the risk of osteoporosis (NHS Choices).
Denosumab, a fully human monoclonal antibody that mimics the activity of OPG, is able to prevent RANKL from interacting with RANK, thus reducing osteoclast activity. It has recently been approved by NICE who concluded that treatment with denosumab, when oral bisphosphonates are unsuitable, was a cost-effective use of NHS resources for the secondary prevention of osteoporotic fragility fractures in postmenopausal women at increased risk of fractures (NICE, 2010). As previously stated, the interaction between RANKL/RANK/OPG is an important determinant of bone mass and strength. Studies such as that by Cummings et al., 2009, have shown a decrease in the risk of vertebral, nonvertebral and hip fractures when Denosumab is given subcutaneously twice yearly for 36 months (Cummings et al., 2009). Their trial also showed that there was no increase in the risk of cancer, infection, cardiovascular disease, delayed fracture healing, or hypocalcemia when taking Denosumab and that its use led to neither cases of osteonecrosis of the jaw nor any other adverse reactions (Cummings et al., 2009).
A major problem in the treatment of osteoporosis is the low adherence to treatment. For example, adherence to oral formulations of bisphosphonates is less than 50% within a year after starting therapy. This is of significance as there is no reduction in fracture risk from treatment when compliance is this low (Rizzoli et al., 2010). Therefore the recent approval of denosumab may prove to be highly beneficial as a treatment. As it is given subcutaneously every 6 months, it avoids the inconvenience that is encountered when taking oral or intravenous formulations and will thus lead to higher compliance.
The mechanisms of bone loss in the elderly are beginning to be unravelled. Our knowledge into the different disease pathways has increased vastly over the past three to four decades. This can be down to the ever changing and more sophisticated imaging techniques that have allowed clinicians and researchers to better understand the principles behind bone loss and where it occurs, leading them to make accurate predictions about future loss of bone. An improvement in microscopy and laboratory techniques has also enabled scientists to study the mechanisms that are contributing to skeletal homeostasis. This increased knowledge into the different cells and pathways implicated in the pathogenesis of osteoporosis has led to more improved treatments being available that have greatly reduced the loss of BMD in patients. It is important that this progress is continued. With increasing affluence, populations all over the world are growing older. The UK in particular is expected to see a rise in people over the age of 50 from 20 million to 25 million by 2020 (UK Osteoporosis Report, 2010). Therefore, a greater number of people will be at risk from suffering a fragility fracture. The impact that this has on later life is highly significant. When looking at the global burden of osteoporosis by calculating the Disability Adjusted Life Years (DALYs), it was found that, osteoporosis accounted for more DALYs lost than most types of cancer, with the exception of lung cancer (Johnell and Kanis, 2006).
It is important that different measures are taken to help prevent fracture occurrence. There are various frameworks, guidelines and screening initiatives in place by the NHS to identify at risk patients. Not only will this improve an elderly person's quality of life, it will also save the NHS money that can be used in other areas. By 2015 the NHS hopes to have saved £20 billion through improvements in the quality and efficiency of treatment (UK Osteoporosis Report, 2010). There is plenty of evidence to show that effective management of fragility fractures can be cost-effective without impacting on quality. Care that is prompt and effective - minimising delay, maximising recovery, and promoting early return home - is not only better care, but is also less costly (BOA-BGS, 2007). As stated by the British Orthopaedic Association & British Geriatrics Society: "Looking after hip fracture patients well is a lot cheaper than looking after them badly" (BOA-BGS, 2007).