Bone266
25.2 Joints270
25.3 Connective tissue diseases274
Within the osteoarticular system, the bones provide structural support for the body and have an important role in mineral homeostasis and haematopoiesis, and the joints permit movement. Disorders of the osteoarticular system can, therefore, cause significant disability and deformity. Most of the more common disorders such as osteoarthritis, osteoporosis and rheumatoid arthritis are chronic and progressive, causing significant morbidity among the general population, especially the elderly. Bone tumours affect all age groups, show marked diversity in their behaviour and different types target particular age groups and anatomic sites. Connective tissue diseases form an important group of multisystem disorders, and they are presented here because a feature common to most of them is their propensity to involve the joints and soft tissues. ‘Soft tissue tumours’ form a highly heterogeneous group of neoplasms that are important because benign tumours are relatively frequent and sarcomas are often highly aggressive.
25.1. Bone
Structure and function
The skeletal system is composed of 206 bones, and has a number of functions:
• Structural support.
• Protective. The skull and the vertebral column protect the brain and spinal cord respectively. The ribs protect the thoracic and upper abdominal organs to a lesser degree.
• Mineral homeostasis. Bone is a reservoir for the body’s calcium, phosphorus and magnesium.
• Haematopoiesis. Under normal conditions in the adult, bone is the sole site of haematopoietic marrow.
Bone is a special type of connective tissue, which is mineralised, and therefore has an organic and inorganic component. The organic component is the connective tissue matrix composed predominantly of type I collagen. The organic matrix undergoes mineralisation by the deposition of the mineral calcium hydroxyapatite. This mineral is the inorganic component of bone. Mineralisation gives bone its strength and hardness. Unmineralised bone is called osteoid. Bone formation, maintenance and remodelling is performed by the bone cells, of which there are three main types:
• Osteoblasts – these cells are responsible for bone formation. They synthesise the type I collagen that forms osteoid, and also initiate the process of mineralisation.
• Osteoclasts – these are multinucleate cells responsible for bone resorption.
• Osteocytes – evidence suggests that these cells have an important role in the control of the daily fluctuations in serum calcium and phosphorus levels and the maintenance of bone.
Bone can be formed quickly or slowly. When bone is formed quickly, such as in fracture repair or fetal development, the osteoblasts deposit the collagen in a random weave arrangement. This type of bone is called woven bone. Woven bone is replaced by lamellar bone, which is formed much more slowly.
In lamellar bone, the collagen is arranged in parallel sheets. Lamellar bone can also form without a woven bone framework. There are two types of mature lamellar bone:
• Cortical (compact) bone – this is composed of numerous units called haversian systems. In each haversian system the lamellar bone is arranged concentrically around a central canal called the haversian canal, through which arteries and veins run.
• Cancellous (spongy) bone – this consists of lamellar bone arranged in a meshwork of bone trabeculae.
Most bones are tubular, hollow structures that consist of a shaft, called the diaphysis, expanded end regions, called the epiphyses, and a region between the diaphysis and each epiphysis, called the metaphysis (Figure 69). The sleeve-like tube (or cortex) of each bone is composed of compact sheets of cortical bone. The inner portion of bone is not quite hollow and is called the medulla. The medulla contains cancellous bone, connective tissue, nerves, blood vessels, fat, and haematopoietic tissue. All bones are covered by a periosteum composed of connective tissue.
 |
| Figure 69 |
Development and growth of the skeleton
During fetal development, bone can be formed either directly in mesenchyme, as in the case of the skull and clavicles (intramembranous ossification), or on pre-existing cartilage (endochondral ossification). In intramembranous ossification, bone is laid down as woven bone that eventually matures into lamellar bone. In endochondral ossification, the cartilaginous template undergoes ossification at particular sites along the bone known as ossification centres. In long bones, the cartilage at the epiphysis persists until after puberty, allowing growth. This area of persisting cartilage is called the growth plate.
Once the bones are fully formed, further growth occurs by the laying down of further bone onto the pre-existing bone. The coordinated actions of the osteoblasts and osteoclasts are paramount in bone development and maintenance. In bone development, the action of osteoblasts predominates. When the skeleton has reached maturity, the bones are continually renewed and remodelled, which requires the actions of the osteoblasts and osteoclasts to be in equilibrium. By the third decade, osteoclastic resorption begins to predominate, with a resultant steady decrease in skeletal mass.
Developmental disorders
Achondroplasia
Achondroplasia is a major cause of dwarfism, and is due to mutation of a single gene. The condition can be familial, with autosomal dominant inheritance, or sporadic. The defective gene leads to abnormal ossification at the growth plates of bones formed by endochondral ossification. Intramembranous ossification is unaffected. Affected individuals have a characteristic appearance, with shortening of the proximal extremities, a relatively normal-sized trunk, and a disproportionately large head with typical bulging of the forehead and depression of the nasal bridge.
Osteogenesis imperfecta (‘brittle bone’ disease)
This is a rare group of genetic disorders that have in common the abnormal synthesis of type I collagen. In addition to bone, the other tissues rich in type I collagen are tendons, ligaments, skin, dentine and sclera. Affected individuals have brittle bones and spontaneous fractures may occur. The sclera appears blue because it is so thin that the underlying uveal pigment becomes visible. Some variants of osteogenesis imperfecta are fatal early in life while others are associated with survival.
Acquired disorders
Osteoporosis
Osteoporosis is characterised by reduced bone mass, making bone vulnerable to fracture. Trabecular bone is affected before cortical bone. Trabecular bone is found in the greatest amounts in the vertebral bodies and pelvis, and cortical bone is found in the greatest amounts in the long bones.
Aetiology and pathogenesis
Osteoporosis may be primary or secondary. Primary osteoporosis refers to senile osteoporosis and post-menopausal osteoporosis. Secondary osteoporosis is due to conditions other than age or menopause, such as reduced mobility (e.g. after fracture or associated with rheumatoid arthritis), smoking and alcohol consumption, endocrine disorders (e.g. Cushing’s syndrome, hyperthyroidism, diabetes) and corticosteroid therapy. Obesity and exercise appear to be protective against osteoporosis.
Senile osteoporosis There is a normal progressive loss of bone mass after around the age of 30years, and so all elderly people will have some degree of osteoporosis. Bone loss rarely exceeds 1% per year. The higher the initial bone density, the lower the risk of significant osteoporosis. Women are at higher risk than men, and white people are at higher risk than black people.
Post-menopausal osteoporosis Post-menopausal osteoporosis is characterised by hormone-dependent acceleration of bone loss. Post-menopausal women may lose up to 2% of cortical bone per year and up to 9% of trabecular bone per year for 8–10years, declining to the normal rate of bone loss after that. Oestrogen deficiency is thought to have a major role, and oestrogen replacement at the beginning of the menopause reduces the rate of bone loss.
Treatment
Women who take hormone replacement therapy have a reduced risk of developing post-menopausal osteoporosis. Also, oral bisphosphonates and vitamin D may be effective.
Metabolic bone disease
Rickets and osteomalacia
Osteomalacia is characterised by defective mineralisation of the osteoid matrix, and is associated with lack of vitamin D. When the condition occurs in the growing skeleton (children) it is called rickets. Vitamin D is important in the maintenance of adequate serum calcium and phosphorus levels, and deficiency impairs normal mineralisation of osteoid laid down in the remodelling of bone. The result is osteomalacia. In children, lack of vitamin D leads to inadequate mineralisation of the epiphyseal cartilage as well as the osteoid, resulting in rickets.
Aetiology
There are two main sources of vitamin D – dietary and endogenous. Consequently, there are four main causes of osteomalacia:
• Dietary deficiency of vitamin D – this used to be a common cause of rickets and osteomalacia. Improvements in diet and the addition of vitamin D to foodstuffs has drastically reduced the incidence of osteomalacia due to nutritional deficiency.
• Intestinal malabsorption – this is now the commonest cause of osteomalacia. Vitamin D is fat soluble. Any condition that causes malabsorption or poor absorption of fat (steatorrhoea) can cause osteomalacia. Causes include coeliac disease and Crohn’s disease.
• Deficiency of endogenous vitamin D due to defective synthesis in the skin – more than 90% of circulating vitamin D is photochemically synthesised in the skin. A steroid molecule precursor found in the epidermis is converted to vitamin D by UV light from the sun. Decreased exposure to sunlight or increased skin pigmentation hinders synthesis of vitamin D.
• Renal or liver disease – newly synthesised vitamin D is biologically inactive. A number of metabolic steps are required to convert vitamin D into its active form. The first of these steps is carried out by hepatocytes. The resulting compound is converted to the active form of vitamin D (1,25-dihydroxycalciferol) in the kidney. Hence, renal disease and, to a lesser extent, liver disease can lead to a deficiency in the active form of vitamin D.
Clinicopathological features
The basic abnormality is deficient mineralisation of the organic matrix of the skeleton. In children, the skeleton becomes deformed because there is reduced structural rigidity and inadequate ossification at the growth plates. In pre-ambulatory infants, there is flattening of the occipital bones, and in ambulatory children, bowing of the legs and lumbar lordosis are characteristic. A pigeon breast deformity may develop due to the forces incurred on the weakened bones of the chest during normal respiration. Excess osteoid may cause frontal bossing of the head. Inadequate calcification of the epiphyseal cartilage in long bones leads to cartilaginous overgrowth at the growth plates, resulting in localised enlargement, which is seen especially at the wrists, knees and ankles. Overgrowth of the cartilage at the costochondral junctions of the chest results in an appearance that is referred to as a ‘rachitic rosary’.
In adults, the osteoid that is laid down in the remodelling of bone is inadequately mineralised. The shape of the bone is usually not affected, but the bone becomes vulnerable to spontaneous fractures. Looser zones (pseudofractures) are the hallmark of osteomalacia, and they appear on X-rays as transverse linear lucencies perpendicular to the bone surface. Persistent inadequate mineralisation may eventually lead to generalised osteopenia.
Hyperparathyroidism and renal osteodystrophy
These are discussed in Chapter 19.
Paget’s disease (osteitis deformans)
The aetiology of Paget’s disease is uncertain. There is an initial phase of osteoclastic resorption of bone followed by a ‘reparative phase’ in which there is intense osteoblastic activity and overproduction of disordered and architecturally abnormal bone. Bones may become larger than normal, and are composed of structurally unsound cortical bone and thickened trabeculae with numerous prominent cement lines, which give the bone its characteristic ‘mosaic pattern’ on microscopy. Later, bone may become ivory hard (‘sclerosis’). The abnormal bone is vulnerable to fracture.
Clinical features and complications
The clinical features and complications of Paget’s disease are:
• bone pain
• fractures
• neuropathies
• deformities
• deafness
• high-output heart failure
• osteosarcoma and other bone tumours.
The spinal cord and nerve roots are also at risk of compression due to enlargement of the vertebral bodies. Distortion of the middle ear cavity and VIIIth nerve compression may lead to deafness. Other cranial nerves may be affected by compression. The bones in Paget’s disease are extremely vascular, and the subsequent increased blood flow can (rarely) lead to high-output heart failure. Paget’s disease may be complicated by the development of bone tumours, the most sinister being osteosarcoma.
Diagnosis and treatment
Paget’s disease may be detected incidentally on X-ray or become manifest through the development of typical clinical features. Intense osteoblastic activity means that affected individuals have raised serum alkaline phosphatase levels. Treatment is with calcitonin and bisphosphonates.
Osteomyelitis
Osteomyelitis refers to inflammation of the bone and marrow, and is usually the result of infection.
Aetiology
Organisms may gain access to the bone by bloodstream spread from a distant infected site, by contiguous spread from neighbouring tissues, or by direct access via a penetrating injury. Almost any organism can cause osteomyelitis, but those most frequently implicated are bacteria. Staphylococcus aureus is responsible for many cases. Patients with sickle cell disease are predisposed to Salmonella osteomyelitis. Mycobacterium tuberculosis is sometimes implicated.
Pathogenesis
The location of the lesions within a particular bone depends on the intraosseous vascular circulation, which varies with age. In infants less than a year old, the epiphysis is usually affected. In children the metaphysis is usually affected, and in adults the diaphysis is most commonly affected.
In acute osteomyelitis, once the infection has become localised in bone, an intense acute inflammatory process begins. The release of numerous mediators into the haversian canals leads to compression of the arteries and veins, resulting in localised bone death (osteonecrosis). The bacteria and inflammation spread via the haversian systems to reach the periosteum. Subperiosteal abscess formation and lifting of the periosteum further impairs the blood supply to the bone, resulting in further necrosis. The dead piece of bone is called the sequestrum. Rupture of the periosteum leads to formation of drainage sinuses, which drain pus onto the skin. If osteomyelitis becomes chronic, a rind of viable new bone is formed around the sequestrum and below the periosteum. This new bone is called an involucrum. An intraosseous abscess, called a Brodie abscess, may form.
Clinical features and treatment
Acute osteomyelitis presents with localised bone pain and soft tissue swelling. If there is systemic infection, patients may present with an acute systemic illness. Presentation may be extremely subtle in children and infants, who may present only with pyrexia (pyrexia of unknown origin, PUO). Characteristic X-ray changes consist of a lytic focus of bone surrounded by a zone of sclerosis. Treatment requires aggressive antibiotic therapy. Inadequate treatment of acute osteomyelitis may lead to chronic osteomyelitis, which is notoriously difficult to manage. Surgical removal of bony tissue may be required.
Avascular necrosis
This is necrosis of bone due to ischaemia. Ischaemia may result if the blood supply to a bone is interrupted, which may occur if there is a fracture particularly in areas where blood supply is suboptimal (e.g. the scaphoid and the femoral neck). Most other cases of avascular necrosis are either idiopathic or follow corticosteroid administration.
Bone tumours
Primary bone tumours are uncommon. They can generally be classified according to whether they are cartilage-forming or bone-forming.
Benign cartilage-forming tumours
Osteochondroma (exostosis)
Osteochondromas are cartilage-capped bony outgrowths, which most frequently occur near the metaphysis of long bones. Affected individuals are usually less than 20years of age. Exostoses are usually solitary. Malignant change is very rare.
Chondroma (enchondroma)
Chondromas are cartilaginous tumours that usually arise within the medullary cavity of the bones of the hands and feet. They occur most frequently in the third to fifth decades of life. The lesions can sometimes cause localised pain, swelling, tenderness or pathological fracture. X-rays show the characteristic ‘O-ring’ sign – oval-shaped radiolucent cartilage surrounded by a dense rim of bone. Most chondromas are solitary. Malignant change is extremely rare.
Other rare benign cartilage-forming tumours are chondroblastomas and chondromyxoid fibromas.
Benign bone-forming tumours
Osteoma
These are bosselated tumours of bone, which most frequently occur in the skull and facial bones. Symptoms depend on the site at which they occur, e.g. symptoms due to obstruction of paranasal sinuses, symptoms related to impingement on the brain.
Osteoid osteoma
These round tumours consist of a small central area (called the ‘nidus’) surrounded by dense sclerotic bone. Affected individuals are usually less than 25years old. The lesions are characteristically painful.
Malignant bone-forming tumours
Osteosarcomas
These are the commonest primary malignant tumour of bone, and they usually affect young adults. The metaphysis of long bones are the most frequently affected sites, particularly the distal femur. They present as painful enlarging masses. The tumours usually penetrate the bone cortex, causing elevation of the periosteum. This produces the characteristic triangular shadow (Codman triangle) seen on X-ray, formed by the bone cortex and the elevated ends of the periosteum. Patients with hereditary retinoblastoma are at significantly increased risk of developing osteosarcomas. Mutations in the p53 gene have also been implicated in some cases. A few cases are secondary to Paget’s disease or previous radiation. These aggressive tumours can metastasise widely, especially to the lungs, but due to advances in treatment, the 5-year survival has improved to around 50%.
Miscellaneous bone tumours
Ewing’s sarcoma
This tumour is composed of small, round, darkly staining cells, which are now believed to be neuroectodermal in origin. The tumour affects children and adolescents, the average age at presentation being 10–15years. The pelvis and the diaphysis of long bones are the most frequently affected sites. The tumour presents as a painful enlarging mass, and some patients may have systemic features such as a fever, raised white cell count, or raised erythrocyte sedimentation rate (ESR). Treatment with radiotherapy and chemotherapy has drastically improved survival rates.
Fibroblastic tumours
Although fibroblastic tumours such as malignant fibrous histiocytomas and fibrosarcomas more frequently arise within soft tissues, they can also occur in bones. A quarter of cases are secondary to pre-existing conditions such as Paget’s disease, radiation, or bone infarct. The prognosis for high-grade tumours is poor.
Secondary bone tumours
The commonest malignant tumours of bone are secondary deposits from other sites. Most skeletal secondary deposits originate from malignancies at the following sites:
• lung
• breast
• thyroid
• kidney
• prostate.
These deposits cause osteolytic lesions to the bone, with the exception of secondaries originating from prostate tumours, which cause osteosclerotic lesions.
25.2. Joints
Structure and function
Joints are of two types:
• Solid joints – these joints are fixed and rigid, and allow only minimal movement. Examples of solid joints include the skull sutures (where the skull bones are bridged by fibrous tissue) and the symphysis pubis (where the bones are joined by cartilage).
• Synovial joints – these joints have a joint space, which allows a wide range of movement. The articular cartilage in synovial joints is a specialised hyaline cartilage, which is an excellent shock absorber. The synovial membrane secretes synovial fluid into the joint space. Synovial fluid acts as a lubricant and provides nutrients for the articular hyaline cartilage (Figure 70).
 |
| Figure 70 |
Osteoarthritis (degenerative joint disease)
This is the most common type of joint disease, and is characterised by the progressive erosion of articular cartilage in weight-bearing joints. The incidence increases with age. Osteoarthritis can be primary or secondary to other bone or joint diseases, systemic diseases such as diabetes, a congenital or developmental deformity of a joint, or previous trauma including repetitive trauma.
Pathology and pathogenesis
Buy Membership for Pathology Category to continue reading. Learn more here
