Diseases of Bone Epidemiology and Diagnosis

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Osteoporosis is defined as a chronic skeletal disorder characterized by compromised bone strength. The latter is caused by, or associated with, low bone mass and changes in bone size and geometry, bone turnover, and microarchitecture. Compromised bone strength leads to enhanced bone fragility, which predisposes to an increased risk of fracture. 'Minimal-trauma fractures' are the hallmark and major complication of osteoporosis, causing substantial morbidity, excess mortality, and high cost.

Amongst the metabolic bone diseases, osteoporosis is by far the most frequent one. The World Health Organization defines osteoporosis as a BMD of 2.5 standard deviations (SD) or more below the mean for young healthy individuals. According to this definition, approximately 30% of all postmenopausal women and 20% of all men older than 60 years of age have osteoporosis. The incidence of osteoporosis and of osteoporotic fractures increases with age: while only 4-5% of all women 60-70 years of age are found to have low BMD, this proportion rises to 50% in women aged 80 years or older. Similarly, according to the Dubbo Osteoporosis Epidemiological Study (DOES), the incidence of osteoporotic fractures is approximately 2000 per 100 000 person-years in the age group 60-70 years, but rises to almost 8000 per 100 000 person-years in women aged 80 years or more. One-third of women and one-sixth of men at age 90 years are estimated to have suffered a hip fracture.22

In the US, more than 1.3 million osteoporotic fractures occur each year. In 2001, the annual incidence of osteoporotic fractures in Australia was 64 500, which means that, every 8 min, one patient was being hospitalized for an osteoporotic fracture, resulting in a prevalence of ~ 1.9 million (present population: 20 million). Fifty percent of these fractures occur in the spine, while 25% are wrist and another 25% are hip fractures.23 Clearly, the latter are by far the most significant complications of the disease, with a 12-month mortality of 25-30%, and lasting morbidity requiring long-term care for another 50% of patients who have suffered a hip fracture. Fewer than one-third of all hip fracture patients will return to their home, and even these individuals have been shown to experience lasting disabilities and a loss in quality of life.24

Apart from fractures, low BMD is one of the major features of osteoporosis. There is a relatively stringent relationship between BMD and fracture risk, where statistically 1 SD decrease in BMD is associated with a twofold increase in fracture risk. Absolute fracture risk, however, is determined by a host of other factors, including age, gender, nutritional status, body composition, fracture status, and others. Not surprisingly, the majority of women who experience a minimal-trauma fracture have normal (7-score > — 1.0 SD) or osteopenosteopenic (7-score between — 1.0 and — 2.5 SD) peripheral bone density, and only 7% have osteoporosis as defined by bone densitometry measurement.25

The pathogenesis of osteoporosis is complex, even in those cases where a single cause is considered to be responsible for the bone damage (secondary osteoporosis). However, an imbalance in bone turnover and, therefore, in remodeling is currently considered the central process that ultimately may lead to a reduction in bone strength. The classical example is postmenopausal osteoporosis, where both bone resorption and bone formation are accelerated (high-turnover). A relative predominance of bone resorption over bone formation, maintained over many years, results in ongoing net loss not only of bone mass, but, more importantly, of mechanically viable bone (micro)structure. This will eventually result in mechanical failure of the bone.

The change in bone turnover, as seen in postmenopausal women, is most likely due to the rapid decline in endogenous estrogen levels around and shortly after menopause. Premenopausal estrogen levels inhibit osteoclast activity, reduce the activation frequency of the BMU, and promote apoptosis of mature osteoclasts via a mechanism that is not well understood. Low levels of circulating estrogen prolong osteoclast survival and stimulate the recruitment and differentiation/activation of osteoclasts. Some of the actions of estrogens are mediated through growth factors and cytokines (see Section

The situation is somewhat different in glucocorticoid-induced osteoporosis. Chronic treatment with glucocorticoids results in rapid and profound bone loss, with most of the change occurring during the first 6-12 months of treatment. Fracture risk is greatly increased amongst long-term hypercortisolemic patients. While the precise mechanisms of how glucocorticoids affect bone are still obscure, it is obvious that treatment with exogenous or excess of endogenous glucocorticoids results in a profound suppression of osteoblasts (bone formation) and a transient increase in bone resorption (osteoclasts). These catabolic effects of glucocorticoids on bone are in direct contrast to their known anabolic actions, where glucocorticoids promote the differentiation, maturation, and function of osteoblasts. Thus, while glucocorticoids appear to exert their effects on the skeleton through a number of pathways (e.g., suppression of sex steroids, muscle wasting, changes in renal/intestinal calcium handling), it appears that the most important catabolic skeletal actions directly target the osteoblast.12

Osteoporosis is a multifactorial, complex disease with a strong genetic determinant26 (see Section Identifying the patient at high risk for osteoporosis (and preventing the disease) is one of the major clinical aims. Existing (prevalent) osteoporotic fractures are amongst the strongest risk factors for future fractures. Compared to patients without prevalent fractures, subjects with one osteoporotic fracture have a three- to fivefold increased risk for further fractures. This relative risk increases to 10 in patients with three or more prevalent fractures.27

Other risk factors for osteoporosis include: advanced age, female gender, ethnic background, a family history of fracture, a low body mass index, early menopause/hypogonadism, low calcium intake, vitamin D deficiency, relative immobilization/sedentary lifestyle, previous hyperthyroidism, low BMD, high bone turnover, smoking, systemic inflammatory disease (e.g., rheumatoid arthritis, inflammatory bowel disease), celiac disease, prior or current therapy with glucocorticoids, anticonvulsant or neuroleptic drugs.28

Importantly, some of the above risk factors also affect falls risk. Particularly in the elderly, falls constitute a specific problem in that they predispose to fracture. Most peripheral fractures and, in particular, hip and forearm fractures, result from falls, even though the minority of falls actually results in a broken bone. Again, the association between falls and fracture is complex, but important factors include fall mechanics, bone geometry, neuromuscular coordination and body height, as well as fat mass. Primary hyperparathyroidism

Primary hyperparathyroidism (pHPT) is a frequent disorder characterized by hypercalcemia and inappropriately elevated serum levels of intact PTH. In 80% of cases with pHPT, a solitary parathyroid adenoma is found. However, in approximately 15% of patients presenting with typical pHPT, hyperplasia of all four parathyroid glands is found and these patients often exhibit signs and symptoms of hereditary syndromes, such as multiple endocrine neoplasia (types 1 and 2a).

Before the introduction of automated multichannel chemistry autoanalyzers, the diagnosis of pHPTwas difficult to make and patients often progressed to advanced disease stages, which regularly comprised symptoms such as nephrocalcinosis, fractures, osteitis fibrosa cystica, and muscle weakness or neuromuscular dysfunction ('stones, bones, and groans'). Today, patients with pHPTare often asymptomatic or very mildly symptomatic, and the diagnosis often follows the incidental finding of hypercalcemia during routine biochemistry checks. Subsequently, the correct diagnosis of pHPT is made by demonstrating inappropriately elevated serum PTH levels. The term 'inappropriately elevated' is clinically relevant, as up to 20% of patients with pHPT may present with normal or high normal serum PTH concentration in the presence of abnormally high serum calcium values. As hypercalcemia physiologically results in suppressed serum PTH levels, any patient with nonsuppressed serum PTH levels and hypercalcemia should be considered as having pHPT until proven otherwise. The only differential diagnosis in this situation is that of familial (benign) hypocalciuric hypercalcemia, although patients on long-term thiazides or lithium may present with similar constellations.

Due to the phosphaturic action of PTH, patients with pHPT often exhibit low normal or frankly reduced serum phosphorus concentrations. The urinary excretion of calcium (24-h urine) is high in about 40-50% of cases; low values are often observed in mild cases, as the primary renal effect of PTH is to increase calcium reabsorption. Serum 25-hydroxy vitamin D levels are usually low or low normal, while those of 1,25-dihydroxyvitamin D are often high normal or frankly elevated due to the stimulatory action of PTH on 1a-hydroxylase activity. Patients presenting with vitamin D deficiency and pHPT are considered to suffer from more severe skeletal disease, such as osteitis fibrosa cystica.

While most patients are oligo- or asymptomatic, a history of kidney stones is not uncommon and, together with osteopenia, nephrolithiasis is one of the more frequent manifestations of symptomatic pHPT. In long-standing pHPT, bone mass and density are typically reduced at predominantly cortical sites (e.g., distal radius), while at sites of cancellous bone (e.g., lumbar spine), bone density may be normal or only slightly reduced. These observations are attributed to the fact that pHPT has different effects on cortical and cancellous bone. However, approximately 15% of patients with pHPT present with osteopenia at the lumbar spine, and some patients may have osteoporosis. Of note, severe pHPT always results in global bone loss, and in these patients, fractures are not uncommon. Careful analysis of the patient with pHPT will reveal other symptoms, such as nonspecific neurological symptoms, fatigue, or depression.29 Paget's disease of bone

Paget's disease of bone is a chronic disease of unknown etiology, characterized by accelerated bone remodeling, abnormal bone structure, and hypertrophy of the affected bones. A number of factors, such as geographic distribution, secular changes, and familial occurrence, suggest that both genetic susceptibility and additional environmental factors play a role in the pathogenesis of the disease, Susceptibility loci for Paget's disease have been identified on chromosomes 18q21 (PDB2), 5q35 (PDB3), 5q31 (PDB4), and 2p36l (PDB5), and this list is still expanding. Furthermore, gene mutations involving sequestosome, a component of the ubiquitin signaling pathways, have been described in a common familial form of Paget's disease. The viral etiology of Paget's disease is still controversial, but there is good evidence to support the concept of viral protein cellular modulators.

The prevalence of the disease in the adult population ( >40 years) is around 1-3%, increases with age, and varies by geographic location (common in the UK, Australia, New Zealand, and South Africa, but rare in Asia, the Middle East, Africa, and, surprisingly, in Scandinavia). Recent investigations indicate that the incidence of Paget's disease of bone is in decline, particularly in countries with traditionally high prevalence.

The disease may occur in any part of the skeleton and may affect only a single (monostotic) or several bones (polyostotic). Clinically, patients present with skeletal pain, nerve compression syndromes, deformities (often resulting in severe osteoarthritis), and fractures. Rarely, neoplastic transformation into osteosarcoma-like tumors may occur.

The diagnosis of Paget's disease is based upon the clinical presentation, increased skeletal uptake on whole-body bone scans, and typical radiographic changes in the corresponding bones. The latter include bulging of affected bones, cortical thickening, and a mix of osteolytic and sclerotic bone changes. Distinctive abnormalities in bone turnover (mainly serum total and/or bone specific alkaline phosphatase) are used to define the activity of the disease.30

Today, almost all patients with Paget's disease of bone are treated with oral or intravenous bisphosphonates. The treatment aim is to mitigate pain and to prevent the typical complications of the disease. Whether this is best achieved by reducing bone turnover, or, as suggested lately, by completely suppressing bone remodeling for extended periods of time remains unclear. The treatment response is usually assessed by changes in clinical presentation, radionucleotide/ radiographic imaging, and biochemistry, although biochemical markers of bone turnover have proven to be of most use in the follow-up of these patients.31 Cancer-Induced Bone Disease Bone tumors

Skeletal tumors are histologically classified according to the cell or tissue type from which they seemingly originate, such as from bone (osteosarcomas) and from cartilage (chondrosarcomas). They are broadly classified as benign or malignant but can exhibit characteristics of both (transitional), and their aggressive and metastatic behaviors also range widely. In addition to a physical examination and complete history, determining tumor type and staging of the tumor are assisted by imaging techniques such as radiography, computed tomography, and magnetic resonance imaging, and by histological analysis of biopsied material (reviewed by Whyte32). Giant cell tumor of bone

Giant cell tumors (GCTs) of bone, also known as osteoclastomas, are benign locally lytic bone lesions that occur most commonly in men aged 20-40 years of age. The tumor mass is comprised of large multinucleated osteoclast-like cells and mononuclear macrophages within a mononuclear cell population of stromal cell appearance. The latter cells are the proliferative component of these tumors. By the time of presentation, GCTs have often produced chronic pain and pathological fracture. GCTs are mainly treated either by curettage or by excision followed by reconstructive surgery.33 Osteogenic sarcoma

Primary malignant bone tumors vary considerably in their clinical, pathological, and histological presentation. The most common primary bone tumor, typically occurring in male patients younger than 30 years of age, is osteosarcoma, or osteogenic sarcoma. Most are classic osteosarcomas, which present in the metaphysis of long bones, usually in the distal femur or proximal tibia, although they can form in any bone. They are aggressive and exhibit a wide phenotypic spectrum, producing osteolytic, mixed, or osteoblastic lesions. They are characterized by their rapid growth and metastasis to other areas of the bone or other organs, often causing pathological fracture and intractable pain. Treatment usually involves chemotherapy followed by limb-salvage surgery.34 Skeletal metastasis

The vast majority of bone tumors are metastasized solid tumors. The skeleton is a common site for the metastasis of solid tumors, including cancers of the prostate, breast, lung, kidney, and thyroid: other cancers, including bladder cancer, melanoma, and neuroblastoma, can also metastasize to the bone, but this is comparatively rare. Most metastases to the skeleton are lytic in nature, such as the majority of breast cancer bone metastases; however, some are mixed or osteosclerotic, as in the majority of prostate cancer bone metastases. Both the lytic and sclerotic effects of these cancers result from the dysregulation of normal bone remodeling, with relative excess in osteoclastic bone resorption mediating osteolysis and a relative excess of osteoblastic bone formation mediating osteosclerosis. However, even osteosclerotic metastases typically show increased bone resorption.35

Cancer cells induce bone resorption and formation by expressing bone active factors that act locally or systemically. Parathryroid hormone related protein (PTHrP) is a primary factor inducing bone resorption. The factors increasing bone formation are not clearly identified but candidates are endothelin-1, prostate-specific antigen, BMP6, TGF(b and IGF-1 and -2. It is likely that the increased bone resorption supports further growth of the tumor cells through the release of active proliferative factors from the bone matrix, thus establishing a vicious cycle, accelerating both bone destruction and tumor growth.36

Cancer bone metastases, regardless of phenotype, can cause insurmountable pain, pathological fractures, vertebral compressions, and hypercalcemia or hypocalcemia. Detectable bone metastasis, particularly in the case of prostate cancer bone metastasis, is correlated with significantly decreased survival. Treatment options are mainly palliative, although therapeutic strategies combining an antiresorptive approach, chemotherapy, and radiotherapy are showing promise. Multiple myeloma

Multiple myeloma is a disease in which B cells are transformed and proliferate to fill bone marrow spaces. The majority of multiple myeloma patients show predominantly lytic lesions, though sclerotic or mixed lesions are occasionally seen. Multiple myeloma cells are able to induce osteoclastic bone resorption through cell-cell interactions and through macrophage inflammatory protein-1 alpha (MIP1a) secretion, and also can inhibit bone formation through secretion of dickkopf 1. These dual actions lead to both local and systemic bone loss. Multiple myeloma is associated with a high risk of skeletal complications, including fracture, bone pain, and hypercalcemia. Treatment of patients with bisphosphonates to block bone resorption has been found to be of benefit in reducing these complications.37 Inflammation Rheumatic disease

This category encompasses a wide range of diseases that affect joint structures, including osteoarthritis, rheumatoid arthritis, systemic lupus erythematosus, and spondyloarthropathies. Osteoarthritis is typically limited to the articular structures, whereas the other disorders can also manifest systemic disease. Rheumatoid arthritis and other inflammatory diseases of joints are associated with local bone erosions, periarticular osteoporosis and systemic bone loss. These patterns of bone loss can contribute significantly to the progressive joint destruction that leads to permanent impairment of joint function and the loss of motility and independence associated with severe arthritis. The effects of inflammation on bone remodeling have been most studied in rheumatoid arthritis. Infiltration of the bone by proliferating synovial lining cells and inflammatory cells stimulates osteoclast formation, which stimulates osteolysis and produces radiographically apparent focal bone erosions. Osteopenic effects, both adjacent to the inflamed joint and systemic, are mainly mediated by stimulation of bone resorption brought about by increased numbers of osteoclasts.38 Periodontal disease

Periodontitis is diagnosed by erosion of the alveolar bone and a loss of soft-tissue attachment to the tooth, which can eventually result in abscesses and tooth loss. Some evidence of loss of attachment has been found in 90% of juveniles and adults, although only 15% of people exhibited clinically severe disease. Plaque bacteria are thought to initiate periodontitis and the presence of inflammatory factors, such as prostaglandins and cytokines, is correlated with alveolar bone loss, most likely by stimulating osteoclastogenesis and osteoclast activity.39 Wear particle foreign-body reactions (prostheses)

Joint replacement, particularly hip replacement, can fail in the long term due to aseptic loosening, requiring complex revision operations. This can occur due to the release from the articulating surfaces of wear particles from the prosthesis: these particles activate macrophages, which in turn induce inflammation at the implant and concomitantly stimulate osteolysis at the bone-implant interface. Anti-inflammatory and antiresorptive therapeutics and novel prosthesis materials are different approaches for the treatment or prevention of wear particle-induced bone loss.40 Genetic Diseases of Bone Metabolism

There are many congenital disorders affecting the skeleton either through direct impairment of cells involved in skeletal development or bone remodeling or through indirect effects mediated by endocrine or other metabolic abnormalities. These can result in bone of increased or decreased bone density, poorly mineralized bone, or disorganized bone undergoing excessive remodeling. Genetic basis of bone diseases

Genetic predisposition is a significant factor in the development of primary bone diseases, including osteoporosis and Paget's disease of bone. Of greater interest is the genetic basis of osteoporosis. A family history of osteoporosis is a significant risk factor for developing osteoporosis. Twin studies indicate a strong inherited component in peak BMD. For this reason, there is considerable interest in identifying polymorphisms or other genetic markers that could predict an individual's risk of developing osteoporosis. However, inheritance of peak bone mass, bone architecture, and fracture risk has so far proved to be complex, with many genes and chromosomal loci currently implicated. Studies in two inbred strains of mice revealed multiple genetic associations with bone mass, with different bone sites and indices showing different associations.56

Interest in polymorphisms as predictors of risk of developing osteoporosis was initiated by findings of association between polymorphisms in the vitamin D receptor gene and BMD.57 Large numbers of candidate genes have now been assessed for their association with various skeletal attributes and many positive associations reported. Unfortunately, many of these findings are not reproducible and no polymorphism is sufficiently predictive on its own to be clinically useful in an individual. Two genes with polymorphisms showing more robust association with BMD and fracture are the genes coding collagen 1 a and the vitamin D receptor, but each of these exhibits inadequate predictive power to be useful in individual patients.58,59 If useful diagnostic tools are to be developed for osteoporosis based on genetic testing, it is apparent that multiple genes will need to be assessed and interpreted based on extensive epidemiological data on how these genes interact to determine bone quality. Congential osteoporosis

Osteogenesis imperfecta is the most common form of congenital childhood osteoporosis. As with forms of osteoporosis, it is marked by decreased BMD and increased bone fragility. Osteogenesis imperfecta can be of varying severity and of either dominant or recessive inheritance. Osteogenesis imperfecta results from mutations in collagen type 1 genes that cause insufficient or disrupted collagen content in bone matrix. The most severe forms are postnatally lethal and less severe forms can produce multiple minimal-trauma fractures, growth impairment, and inability to walk.41 Recently, treatment with repeated infusions of pamidronate has been shown to be of benefit in these patients.42 Osteoporosis can result from mutations in genes related to osteoblast regulation, e.g., osteoporosis pseudoglioma syndrome, which results from an inactivating mutation in LRP5 that inhibits Wnt signaling in osteoblasts.43 Osteopetrosis

Osteopetrosis is a congenital condition resulting from a failure of bone resorption due to defects in the generation or function (more commonly) of osteoclasts. It is marked clinically by dense bones and increased bone fragility. In severe cases, there is also impaired growth and tooth eruption, club-shaped long bones, deafness, nerve compression, immune deficiency, and anemia. The marrow spaces are occluded by dense trabecular structures containing mineralized cartilage rests that result from failure to remove mineralized cartilage and bone formed during endochondral bone formation. Mutations in genes encoding carbonic anhydrase II, the chloride channel CLCN7, and the a3 subunit of vaculolar H + pump have been identified as causes of osteopetrosis and would all impair the ability of osteoclasts to generate acid required for bone demineralization. Treatment is by marrow transplant or with interferon-g. Pycnodysostosis is a similar bone disease with osteopetrotic phenotype, in this case due to mutations in cathepsin K, an osteoclast enzyme required for proteolytic breakdown of bone collagen.44 Osteosclerosis

Excessive bone formation can also produce bones of increased bone density. Mutations activating Wnt signaling have been found in the gene encoding LRP6 and in the gene encoding SOST; each produces a high-bone-mass phenotype.45,46 The increased bone strength in these subjects has led to active research into Wnt signaling as a therapeutic target for the development of anabolic factors. Skeletal dysplasias

Some genetic bone diseases are marked by high bone remodeling rate, disorganized bone structure, and, in some cases, fibrous replacement of bone marrow. This can be due to congenital hyperparathyroidism, mutations affecting osteoblast regulation (Gs-alpha subunit gene, GNAS1, in fibrous dysplasia), or in osteoclast regulation (RANK in familial expansile osteolysis, or OPG in familial hyperphosphatasia). Some of these conditions can be treated by reducing the impetus for high bone remodeling by parathyroidectomy or with antiresorptive treatments, e.g., calcitonin or bisphosphonates.47 Congenital rickets

This condition is marked skeletally by the failure of bone mineralization. Bone matrix remains as unmineralized osteoid and bone strength and rigidity are impaired. Congenital rickets can be induced by mutations affecting phosphate or calcium homeostasis, and by mutations in alkaline phosphatase, which are required for osteoblasts to induce matrix mineralization.

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