Bones

chapter 23 Bones



INTRODUCTION AND OVERVIEW


Bones are complex organs with many important functions, the most obvious being structural. They provide support for the body and the means by which muscles can insert into fixed structures in order to allow movement. They are also important in hearing, through the transduction of sound via the ear’s ossicles, and they protect other soft organs that are easily damaged, such as the brain, eyes, kidneys, lungs and spleen. Bone marrow, which is largely within the medulla of the long bones, is the centre for production of blood cells (haematopoesis) and an important site for storage of fatty acids. Bones also have important metabolic functions, including:






Bone strength depends not only on the hardness of the minerals within bone, but also the structure and organisation of the connective tissue—largely collagen. Despite the brittleness of bone, the network of collagen fibres gives it some flexibility. It is the movement of bone and the action of forces through the harder layer of compact or cortical bone as it grows and repairs that tells bone how to lay down and organise its structure. Weight-bearing exercise, particularly for the long bones, is vital for maintenance of bone strength and structure, whereas physical inactivity and immobilisation of bones will lead to weakening of those bones. The interior of bone—the medulla or trabecular bone—is far more porous and provides an environment for the bone marrow.


Bone is in a continual process of rebuilding itself through the action of osteoblasts and osteocytes, which lay down and maintain new bone, and osteoclasts, which resorb bone. The balance between these cells gives bone the capacity to repair itself and to remodel itself over time. Imbalances between the activity of these cells can predispose to development of bone pathology, such as osteoporosis. Maintenance of healthy bones requires vitamin D (dietary and from sunlight), a balanced diet with adequate fruit, vegetables, protein, calcium and other minerals, growth hormone, and thyroid and sex hormones. The resorption of bone by osteoclasts is inhibited by calcitonin secreted by the parafollicular cells in the thyroid gland.


Bones develop from cartilage, and by the time of birth only the metaphyses of the long bones are visible on X-ray. Bone growth throughout childhood takes place at the epiphyses or the growth plate of the long bones, which slowly narrow. By the time they fuse, at the end of adolescence, no further growth is possible and the person will have attained their adult height. The eventual height of a person depends on many factors including genetics, nutrition, hormonal status and injuries. Injuries such as fractures (e.g. involving the epiphysis) can lead to premature fusion and reduced growth of that bone. Height can also be reduced when there is inherited short stature, significant malnutrition, inadequate sex hormones, growth hormone deficiency or hypothyroidism.


This chapter describes the following conditions affecting bones:








OSTEOPOROSIS



DEFINITION


In 1991, osteoporosis was defined as a metabolic bone disease characterised by ‘low bone mass, microarchitectural deterioration of bone tissue leading to enhanced bone fragility and a consequent increase in fracture risk’.1 However, the current conception of osteoporosis is as a disease of compromised bone strength that predisposes an individual to an increased risk of fracture.2 In this new definition, osteoporosis is a dynamic, rather than an anatomical, condition. The disease is thus low bone mass and deteriorated bone quality, and fracture is the clinical consequence of the disease.


The ‘bone strength’ component of the definition refers to the integration of bone mass and bone quality. ‘Bone quality’ primarily refers to bone architecture, metabolic turnover, damage accumulation (e.g. microfractures) and demineralisation. At present, the most clinically relevant indicator of bone quality is a history of personal fracture. The current definition of osteoporosis represents it as both a disease and a risk factor, and this has important implications for the pathogenesis, prevention and treatment of the disease.


Osteoporosis is highly prevalent in the general population. Using the operational definition of osteoporosis (based on measurement of bone mineral density (BMD)), the prevalence of osteoporosis in Australian men and women aged 60 years and above was estimated to be 11% and 27% respectively.3 As expected, the prevalence of osteoporosis increases with advancing age, from approximately 5% (men) and 13% (women) at 60 years of age to over 28% (men) and 63% (women) at age 80 or above.4 With a rapidly ageing population, it is expected that osteoporosis will be an even greater problem in the next 20 years or so.


The outcome of osteoporosis is fragility fracture. Fractures are a major public health problem because of their high incidence rate in the population, and because individuals with fracture are at increased risk of mortality and morbidity and reduced quality of life, and incur significant healthcare costs. In several population-based epidemiological studies, all major fractures were associated with increased mortality, especially in men.5 Even in healthy older women, clinical vertebral fractures, commonly manifested as asymptomatic fracture, and hip fractures, are substantially associated with increased mortality.6,7 A more recent study demonstrated that asymptomatic vertebral deformity is a major risk factor for subsequent fracture and mortality.8


The increase in fracture cases will result in a significant increase in healthcare costs. The annual cost of treatment of fractures and associated sequelae has been estimated at $10–20 billion in the United States and £3 billion in England and Wales. Within the next 50 years the cost of hip fracture alone in the United States may exceed $240 billion.9 In Canada, the annual cost of hip fracture is estimated at $650 million and is expected to rise to $2.4 billion by 2041.10 In Australia, the direct and indirect costs of fracture have been estimated at $7.5 billion.11



EPIDEMIOLOGY OF FRACTURES


Theoretically, any fracture related to low bone density may be considered an osteoporotic fracture. Fractures of the spine (vertebrae), hip and wrist (distal forearm) have long been regarded as typical osteoporotic fractures.1216 Most types of fracture occur more often in patients with low BMD,17,18 and therefore most types of age-related fractures are osteoporotic in nature. According to this definition, the following fracture types are considered osteoporotic:




In both women and men, fractures occurring at the skull and face, hands and fingers, feet and toes, ankle and patella are classified as not due to osteoporosis.19


Because fragility or osteoporotic fracture is defined as fracture-related with minimal trauma (i.e. a fall from standing height or less),20,21 in the research setting, fractures clearly due to major trauma (such as motor vehicle accidents) or due to underlying diseases (such as cancer or bone-related diseases) were excluded from analysis.5,16,18,2226


Overall, the incidence of any fracture in women and men increases with advancing age, and is greater in women than in men. The incidence of fracture also varies according to geographic variations between and within countries. Fracture rates in women aged 60 or older are six times higher than those in women aged 35–59 years; in men aged 60 or older the rate is 1.4-fold greater than in men less than 60 years of age.27


Overall fracture rates are greater in urban than in rural areas.28,29 The difference is more pronounced in those aged 60 years or over, suggesting that environmental factors have an impact on bone health.


The magnitude of osteoporosis-related fracture can be quantified by the lifetime risk of fracture. In developed countries it is estimated that the residual lifetime risk of any fracture for men and women from age 60 is approximately a quarter and just under a half respectively.16 For individuals with osteoporosis, the mortality-adjusted lifetime risk of any fracture is probably over 40% for men and 65% for women.3 The three most common sites are hip, vertebral and Colles’ fracture.



TYPES OF FRACTURE




Vertebral fracture


Osteoporosis has sometimes been referred to as a ‘silent disease’ because individuals often do not have apparent symptoms and pain until a fracture occurs. Asymptomatic vertebral fracture can be considered a silent disease, because patients do not realise that they have a fracture and do not seek medical attention. Currently, there is no ‘gold standard’ for the identification of vertebral fracture34,35; estimates of its overall prevalence and incidence rate in elderly women and men depends in part on the definition used.36


Asymptomatic vertebral fracture can be detected by conventional radiology, but it is not an attractive means of large-scale screening, because of cost and radiation exposure. In a large-scale study,37 vertebral fracture was present in 12% of women and men. As expected, the prevalence of vertebral fracture increases with age, more sharply in women.38 The use of corticosteroid therapy doubles the risk.39 Studies have found that about 33% of vertebral fractures or deformities are symptomatic40 and that only 23% of vertebral deformities in women were diagnosed clinically.41 In other words, there are many ‘silent’ vertebral fractures that produce no obvious symptoms. Vertebral deformities, whether clinically recognised or not, are related to an increase in chronic back pain and disability,42,43 and to low health-related quality of life44 and an increase in mortality.8,45



Distal forearm fracture


A fracture of the distal forearm is one that occurs through the distal third of the radius and/or ulna. It is frequently and typically seen in women.46,47 Although its consequence is less serious than that of a hip fracture, it is associated with significant pain and may be associated with severe and long-term complications.48,49 The incidence increases rapidly with advancing age in women (but less so with men), for up to 10 years following menopause, and tends to slow thereafter.50



CLINICAL ASSESSMENT OF OSTEOPOROSIS


The clinical assessment of osteoporosis and fracture risk is based on assessment of:





Risk factors


Risk factors can be broadly classified into modifiable and non-modifiable risk factors (listed in Box 23.1). Of these, the four key risk factors are:







A prior fragility fracture substantially elevates an individual’s risk of future fracture.5,8,51,52 The elevated risk is 1.5- to 9.5-fold depending on age at assessment, number of prior fractures and the site of the incident fracture. A pre-existing asymptomatic vertebral fracture increases the risk of a second vertebral fracture and non-vertebral fracture at least four-fold.8 A study of a placebo group showed that 20% of those who experienced a vertebral fracture during the period of observation had a second vertebral fracture within 1 year. Patients with a hip fracture are at increased risk of a second hip fracture. The risk of subsequent fracture among those with a prior fracture at any site is 2.2 times that of people without a prior fragility fracture.52 A family history of osteoporotic fracture is also a major risk factor for fracture.


Although most studies have focused on the index person’s mother or other female family members, the genetic influence on risk of osteoporosis is multifactorial, and one should not ignore a history of osteoporotic fracture in first- or second-degree male relatives. Therefore, other family members should be included during assessment of genetic contribution to osteoporosis risk.



Bone strength


At present there is no direct method for reliably measuring bone strength. However, BMD, measured by dual-energy X-ray absorptiometry (DXA), provides a benchmark for bone strength. BMD measurement could account for up to 70–75% of variance in bone strength.53 BMD is often standardised by expressing it as a T-score, i.e. the number of standard deviations (SD) from the young normal mean, taken as aged between 20 and 30 years.


There is a strong, continuous and consistent relationship between BMD and fracture risk, such that each SD lowering in BMD is associated with a 1.6-fold increase in fracture risk in both men and women.54 In Chinese women, the relative risk of fracture for each SD lowering in femoral neck BMD was two-fold.55 There is evidence that the magnitude of association between BMD and hip fracture risk (with relative risk being 2.256 to 3.657) is equivalent to or even stronger than the association between serum cholesterol and cardiovascular disease. Measurement of BMD is therefore considered the gold standard for diagnosis of osteoporosis in elderly men and postmenopausal women.


An operational definition of osteoporosis, by which a postmenopausal woman is considered to have osteoporosis, is if her femoral neck BMD (which is more reliable than lumbar spine measurements) is decreased by at least 2.5 SD compared with the mean value in young adults.58 The WHO classification also includes definitions of osteopenia and normal BMD (Table 23.1). The operational criteria of osteoporosis for women has also been adopted for men.59 These classifications do not apply to children.


TABLE 23.1 WHO diagnostic categories for BMD in postmenopausal women


















Category Projected proportion of population*
Normal BMD not more than 1 SD below peak BMD in young adult mean
(T-score > −1)
Osteopenia BMD 1–2.5 SD below young adult mean
(T-score −1 to −2.5)
Osteoporosis BMD 2.5 SD or more below young adult mean
(T-score at or below −2.5)
Established osteoporosis BMD 2.5 SD or more below young adult mean, and the presence of one or more fragility fractures

* Urban, 2020 (%). SD: standard deviation. BMD: bone mineral density.


Source: Nolla et al. 200260




Bone turnover markers


Bone is a net result of two counteracting processes of bone resorption and bone formation, often referred to as bone remodelling.





Bone turnover rate in postmenopausal women correlates negatively with BMD, and markers of bone resorption are associated with fracture risk.66 A reduction in biochemical markers appears to be correlated with a decrease in vertebral fracture incidence67 in some studies, but is not necessarily always predictive of response to therapies. Nevertheless, the predictive value of biomarkers in assessing an individual patient can be limited by their high variability within individuals.68



Assessment of absolute fracture risk


At any given level of BMD, fracture risk varies widely in relation to the burden of other risk factors56 (some modifiable), such as:












Thus, for any one individual, the likelihood of fracture depends onavv a combination of risk factors. This means that two individuals, both with osteoporosis, can have different risks of fracture because they have different non-BMD risk profiles. Likewise, an osteoporotic individual can have the same risk of fracture as a non-osteoporotic individual. A logical and appropriate assessment of fracture risk for an individual should therefore take into account the individual’s risk profile, including BMD and a history of fracture. A multivariable-based nomogram such as the one developed by Nguyen and colleagues69,70 and the WHO’s FRAX model71 can be used to estimate an individual’s absolute risk of fracture, and help select patients suitable for intervention.


The critical question of who should be treated can only be answered by a complete evaluation of an individual’s risk profile. Treatment is cost-effective if an individual’s 10-year risk of hip fracture is between 1.2% and 9.0%, depending on age.72 To facilitate the estimation of this threshold, a nomogram (Figure 23.1) is used to estimate the probability of fracture based on age, BMD and history of fractures and falls.


image

FIGURE 23.1 Nomogram for predicting 5-year and 10-year probability of hip fracture.69 To use, mark the age of an individual on the ‘Age’ axis and take a vertical line up to the ‘Points’ axis. Repeat this process for each additional risk factor, then sum the points. Locate the final sum on the ‘Total points’ axis and take a vertical line down to the 5-year and 10-year risk lines to determine the individual’s probability of sustaining a hip fracture within these timeframes



TREATMENT




Nutrition and supplements




Calcium and vitamin D


A combination of calcium and vitamin D reduces the incidence of hip and non-vertebral fractures.7577 Elderly women (aged 69+ years) taking calcium (1200 mg/day) and vitamin D (800 IU) for 18 months had their risk of hip fracture reduced by 43% and non-vertebral fracture by 32%, although in a recent meta-analysis it was shown that the use of calcium or calcium plus vitamin D reduced fracture risk by 12%.55 In summary, calcium and vitamin D appear to be efficacious in reducing the risk of hip fracture and non-vertebral fractures. There is some evidence, however, that calcium supplements can lead to a moderately increased risk of myocardial infarction. Regular moderate sun exposure should also be remembered as a valuable way of maintaining adequate vitamin D levels. If vitamin D levels are very low (< 50 nmol/L2), a large loading dose of vitamin D of up to 50,000 IU per month until the level is at least > 75 nmol/L2 and then a maintenance dose of 2000 IU daily with 3-monthly monitoring.78 Some advocate a larger loading dose of 100,000 IU as being helpful in bringing up the levels more quickly, followed by a supplement of 1000–5000 IU daily, monitored at 3-monthly intervals until normal range is achieved. Then maintenance of 1000 IU daily if sun exposure has not increased.



Pharmacological


During the past two decades, several major advances in the treatment of osteoporosis have been made. There are now more therapeutic options available than at any time before. Anti-fracture therapies can be broadly divided into two groups: anti-resorptive and bone-forming (anabolic) agents. The former reduces bone turnover, while the latter increases bone formation. Both agents have been shown to reduce fracture risk for some, although not necessarily all, fragility fractures. It is difficult to assess the relative anti-fracture efficacy of the various therapies, as there have not been any head-to-head comparative trials.




Selective oestrogen receptor modulators


In postmenopausal women suffering from osteoporosis, raloxifene (at the dose of 60 mg/day) has been shown to significantly reduce the risk of vertebral fracture by as much as 50%.83,84 However, its effects on hip and non-vertebral fractures have not been consistent. Raloxifene could also reduce the risk of non-vertebral fractures in women with severe osteoporosis. The drug is mostly used in younger postmenopausal women who have bone loss predominantly at the spine, not the hip.



Calcitonin


Calcitonin (generally given as a nasal spray), due to its antiresorptive properties, has been used in the treatment of osteoporosis for many years, with significant beneficial effects in reducing bone loss and fracture risk, possibly up to 33% when combined with calcium (1000 mg/day) and vitamin D (400 IU per day).85 Similar risk reduction was also observed in those with a pre-existing vertebral fracture.85 A meta-analysis including four studies conducted between 1966 and 2000 found that calcitonin reduced vertebral fracture risk by 54%. However, its effect on non-vertebral fractures has not been shown. Calcitonin is also associated with pain relief in patients following acute osteoporotic vertebral fractures.



Bisphosphonates


Bisphosphonates are currently a mainstay of pharmacological therapy for the treatment of osteoporosis in both postmenopausal women and elderly men. Bisphosphonates inhibit bone resorption through their effects on osteoclasts, and other complex cellular mechanisms that are not well understood. Their potential benefits need to be weighed against the risk of side effects, including jaw necrosis in long-term use.


There are a number of agents in this class, and based on their mode of action they can be classified into two main groups: those that closely resemble pyrophosphate (clodronate and etidronate), and nitrogen-containing bisphosphonates (alendronate, risedronate and ibandronate). Currently, alendronate (Fosamax®), risedronate (Actonel®) and ibandronate (Boniva®) are FDA-approved for osteoporosis treatment.


Alendronate—has been extensively studied in the treatment and prevention of fracture. In a three-year study of postmenopausal women86 it significantly reduced the incidence of new fractures, possibly by up to 47% over three years.87 In this group of patients it also reduced the risk of hip fracture and wrist fracture. It is effective in the treatment of glucocorticoid-induced osteoporosis, increases BMD88,89 and decreases the incidence of vertebral fractures at 2 years (6.8% vs 0.7%) in glucocorticoid-treated men and women.89 It also has beneficial effects in men.90

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Jun 3, 2017 | Posted by in GENERAL SURGERY | Comments Off on Bones

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