Definition of Osteoporosis
Osteoporosis (MIM 166710) is a metabolic bone disease characterised by a reduction in bone mineral density (BMD), deterioration of the micro-architecture of bone, with a consequent increased fragility and fracture risk. Osteoporotic fractures are most commonly observed at the wrist, vertebrae and hip and can also occur without any significant trauma. For diagnostic purposes the World Health Organisation (WHO) defined osteoporosis as a BMD of 2.5 standard deviations (SD) below the average of young adult females (t-score) (Kanis et al., 1994). It has been shown that the risk of fracture increases as bone mass decreases, with a 1.5 – 3 fold increase for each SD decrease in BMD (Marshall et al., 1996).
Fracture risk is not only determined by BMD but also by other factors that have an influence on bone strength such as bone geometry and microarchitecture (Wachter et al., 2002). All of these properties might affect the mechanical strength of cortical bone and so are important predictors of fracture risk.
Accurate estimation of affected individuals is very difficult to achieve as it depends on a number of factors including measurement differences between skeletal sites and technology used. Melton (2002) described how when taking measurements at different anatomical sites and using the WHO criteria one can find discrepancies in osteoporosis prevalence that imply important differences in the proportion of patients for whom treatment might be indicated.
Pathophysiology of Osteoporosis
Bone loss and osteoporosis will result when the balance between bone formation and resorption is lost and so there is either excess osteoclastic bone resorption and/or decreased osteoblast activity.
Peak Bone Mass and the Rate of Bone Loss
The pathogenesis of osteoporosis depends upon two important factors:
Adequate skeletal mass/density at different anatomical sites is reached by late adolescent age, in both trabecular and cortical bone. Immediately when peak bone mass is reached, trabecular bone starts declining although this does not seem to have any significant effect on bone strength (Matkovic et al., 1994). Peak bone mass reached is strongly determined by genetic factors together with a number of environmental factors including physical exercise and calcium intake (Aud`I et al., 1999; Stear et al., 2003). The higher the peak bone mass reached early in life the longer it takes for a fracture threshold to be reached later on in life.
Age related bone loss is brought about mainly by the various physiological changes occurring in the body with advancing age including the lack of oestrogen and low calcium absorption from the intestine that leads to persistent secondary hyperparathyroidism. These changes will bring about an increase in osteoclast activity and so bone resorption, which is observed with the onset of menopause in women. Increased osteoclastic bone resorption is the major factor in the deterioration of bone mass and a number of hormones including parathyroid hormone (PTH) and the lack of oestrogen are known to influence osteoclast numbers and activation.
In postmenopausal osteoporosis, bone volume decreases even though there is a very high overall turnover of both resorption and formation, showing that resorption exceeds formation. It is evident that a coupling mechanism exists between bone resorption and formation as many factors and hormones that increase bone resorption, as PTH, also stimulate bone formation. A recent study showed that OPG regulates bone formation through a coupling mechanism with bone resorption and so the decreased OPG levels with the onset of menopause also results in a decreased bone formation while resorption is increased (Nakamura et al., 2003). On the other hand, another study showed that OPG levels were higher in postmenopausal women suggesting that OPG might be secreted in response to the increase in bone resorption (Liu et al., 2005).
In age-related osteoporosis, decreased bone formation might be due to both the decreased activity of osteoblasts or else due to their reduced number. It was shown that an increase in adipose tissue results in a decrease in bone formation, supporting the hypothesis that a clonal switch in the differentiation of stromal cells to the adipocyte lineage might be partly responsible for osteoporosis (Byers et al., 2001). This mechanism highlights the importance of leptin, a small polypeptide secreted by adipocytes that was previously shown to inhibit bone formation through a central mechanism involving the hypothalamus (Ducy et al., 2000). Decreased synthesis or function of BMPs, insulin-like growth factor (IGF)-1 and of the transcriptional factor Cbfa-1, all of which are important for osteoblast differentiation, might all lead to decreased bone formation (Byers et al., 2001; Karsenty, 2001).
Oestrogen deficiency and osteo-immunology
Oestrogen (or the lack of it) plays a very important role in the pathogenesis of postmenopausal osteoporosis. The mechanisms by which oestrogen affects bone metabolism are complicated but it is well known that with the decrease in oestrogen levels brought about by the onset of menopause, there is an increased synthesis of a number of factors including inflammatory cytokines such as interleukins (IL)-1 and 6 (Pacifici, 1996). These inflammatory cytokines are known to increase osteoclast formation and activation. It was proposed that there is interplay of the immune system and bone physiology and that a sub-clinical inflammatory process might be triggered with advancing age (Ginaldi et al., 2005). Both systems share common molecules including various receptors and cytokines. IL-1 and IL-6, together with TNF-α are known to increase RANKL expression in osteoblast / stromal cells that lead to increased osteoclastogenesis and thus bone resorption. Besides the increased expression of RANK induced by these cytokines in these cells, activated T-cells are also known to express RANKL themselves. T-cells also down regulate osteoclastogenesis by producing interferon (IFN)-γ that binds to its receptor on osteoclasts and interfere with the RANKL-RANK signalling pathway. This suppression occurs as a result of TRAF6 degradation brought about by ubiquitin-proteosome system activated by IFN-γ (Takayanagi et al., 2000).
Oestrogen deficiency directly affects bone resorption by negatively affecting the expression of OPG and so osteoclast differentiation and activation is enhanced (Hofbauer et al., 2000). Indirectly, oestrogen deficiency can lead to an increased resorption by disrupting calcium metabolism leading to a persistent secondary hyperparathyroidism. This results from a decreased intestinal absorption of calcium, increased renal calcium wasting and also possibly due to effects on vitamin D metabolism leading to a net loss of calcium from the body (Riggs et al., 1998).
Osteoporosis is a complex disease and so both environmental and genetic factors play an important part in its pathogenesis and risk. These factors might affect peak bone mineral density reached early in life, the rate of bone loss, bone strength and the risk of falling. Table 1 shows a list of factors that increase the risk for osteoporosis and fractures.
Racial differences in the incidence and increased risk of osteoporosis might be due to genetic differences as well as environmental factors. The low incidence of hip fractures in Asia and Africa when compared to the western world might be related to differences in the diet. Although Asians and African populations have low calcium intake, they still have the lowest incidence of fractures and this may be due to compensation by increased intestinal calcium absorption and diets low in protein, phosphorus and acid ash that decrease urinary excretion of calcium. Also a higher intake of soy bean products protects the bone due to the presence of phyto-oestrogens (Fujita, 2001).
Table 1. Risk Factors for Osteoporosis and Fractures
Clinical Aspects and Diagnosis
From the clinical point of view, osteoporosis usually presents with fractures of the wrist, vertebrae and hip. These fractures usually result without any significant trauma during routine everyday activity.
The assessment and diagnosis of osteoporosis depends entirely on the measurement of skeletal mass using one of the several radiological techniques such as dual energy X-ray absorptiometry (DEXA). DEXA uses two X-ray photon beams and is the most commonly used technique to measure BMD at different anatomical sites as well as total body. Bone mineral content (BMC) is measured from the amount of photons that are not absorbed by bone, from which BMD is calculated. The accuracy of DEXA is more than 90% but depends not only on the technique itself but also on the way the measurement is done (Kanis, 2002). This technique does not give any information about the microarchitecture of bone, but only a two dimensional picture and not a true volumetric density. Measurement of DEXA is recommended for:
Other techniques used for measurement of BMD include ultrasound, computed tomography (CT) and radiography all of which have their own limitations and cannot be used for the diagnosis of osteoporosis. Combined measurements such as DEXA and CT can be used to assess an individual’s risk to fractures. The diagnosis of osteoporosis is done according to WHO criteria (described above). According to the latest recommendations of the International Society of Clinical Densitometry, z-scores (number of SDs below the average of a sex and age matched group of controls) instead of t-scores were suggested to be used for diagnosis in premenopausal women, children, and adolescents as well as in men without secondary causes of osteoporosis (Khan et al., 2004).
Biochemical Markers of Bone Turnover
There are various biochemical markers measured in plasma or urine that can be used to evaluate an increase in bone turnover, fracture risk, response to therapy and also any unexplained bone loss. Indices of bone formation that are measured in serum include:
Indices of bone resorption measured in urine and/or serum include:
Most of these biochemical markers are derived from the synthesis and degradation of collagen molecules measured by techniques such as high performance liquid chromatography (HPLC) and enzyme immunoassays (EIA). Until now there is no ideal marker that can be used for evaluation of bone turnover or diagnosis and studies are being carried out to evaluate the clinical utility of these markers (Watts, 1999).
Complex diseases like osteoporosis occur more frequently in populations than most monogenic disorders and so are of a greater burden on society. In the European Union, osteoporosis now costs more than €4.8 billion annually in hospital healthcare alone and this expense is expected to rise as the aging population continues to increase (European Parliament Osteoporosis Interest Group, 2003). According to the latest demographic review issued by the National Statistics Office of Malta in 2002, the population of males and females over the age of 65 years – the sector of the population most vulnerable to fractures – is going to increase from 12.7% to 21% by the year 2035 (National Statistics Office, 2003).
In 1995, Melton reported that in the United States (US) 70% of postmenopausal women aged 80 and over were osteoporotic, of which 60% have experienced one or more fractures of the proximal femur, vertebrae, distal forearm or pelvis (Melton, 1995). The high incidence of osteoporosis in postmenopausal women at the age of 80 years is an over-representation because the number of women that reach this age is low due to mortality by other causes. In the same report, Melton also reported that 30% of postmenopausal Caucasian women have osteoporosis, 16% of which have established osteoporosis (t-score <-2.5 and one or more fragility fractures).
For 2005, it was predicted that the total expenditure for incident fractures in the US would reach $17 billion and by the year 2025 it is expected to rise by 50%. More than 87% of this increase is expected to be for people between 65 – 74 years of age and 175% increase is projected for the Hispanic population (Burge et al., 2007).
Without any doubt osteoporotic fractures, especially those of the hip, have serious consequences on the individual and are a public health concern. Besides being a predominant cause of death, hip fractures render the affected individual functionally dependent in the activities of everyday life and also account for significant medical expenses. With the increase in the overall global population, it is projected that by the year 2050 the number of hip fractures worldwide will reach 6.3 million as compared to 1.7 million in 1990. This figure could go up to 21 million when assuming a 1% annual increase in age adjusted incidence and if incidence rates increase by 3% annually in the rest of the world excluding Europe and North America (Melton, 2002).
More than 10 – 20% of women that suffer from an osteoporotic hip fracture die within a year of the accident. Other osteoporotic fractures as those in the vertebra and wrist are to a lesser extent associated with increased mortality. It is also unclear whether this is a result of the fracture itself or else due to other underlying medical conditions. A relationship exists between low BMD and increased mortality in males which was independent of co-morbidity (Van der Klift et al., 2002). This relationship was not observed in women.