DISEASES OF BONE - Clinical features, Investigations

Bone normally consists of 70% mineral and 30% organic matrix (mostly type 1 collagen fibres). The mineral component consists mostly of a complex crystalline salt of calcium and phosphate called hydroxyapatite. Although major skeletal growth occurs in childhood, adult bone is continuously being remodelled, with bone formation and resorption. Two major cell types are involved in bone remodelling:

■ Osteoblasts produce type 1 collagen and regulate its mineralization.

■ Osteoclasts produce hydrogen ions and lysosomal enzymes, which remove and resorb the mineral phase and collagen matrix.

Control of calcium and bone metabolism

Vitamin D and parathyroid hormone (PTH) are the major factors that control plasma calcium concentration and bone turnover. Bone metabolism is also controlled by calcitonin, glucocorticoids, sex hormones, growth hormone and thyroid hormone.

Vitamin D

The metabolism and actions of vitamin D are shown in Fig. 7.6.

Parathyroid hormone (PTH)

PTH is secreted from chief cells of the parathyroid gland. Plasma levels rise in response to a fall in serum ionized calcium. The effects are several, all serving to increase plasma calcium and decrease plasma phosphate:

Fig. 7.6 The metabolism and actions of vitamin D. The primary sources of vitamin D in humans is photoactivation in the skin of 7-dehydrocholesterol to cholecalciferol, which is then converted first in the liver to 25-hydroxyvitamin D and subsequently in the kidney to the much more active form, 1,25-dihydroxycholecalciferol (1,25(OH)2D3) . Regulation of the latter step is by PTH, phosphate and feedback inhibition by 1,25(OH)2D3. This step can also occur in lymphomatous and sarcoid tissue, resulting in the hypercalcaemia that may complicate these diseases.

■ Increased osteoclastic resorption of bone

■ Increased intestinal absorption of calcium

■ Increased synthesis of 1,25-(OH)2D3 (Fig. 7.6)

■ Increased renal tubular reabsorption of calcium.

Osteoporosis

This is a reduction in bone mass and micro-architectural deterioration of bone tissue, leading to bone fragility and an increased risk of fracture. Osteoporotic fractures (fragility fractures, low-trauma fractures) occur without major trauma. Osteoporosis is defined as a bone mineral density (BMD) more than 2.5 standard deviations (SDs) below the young adult mean value (T-score ≤-2.5). Values between 1 and 2.5 SDs below the young adult mean are termed ‘osteopenia'. There are additional risk factors identifiable from the history and examination which increase the fracture risk independently of BMD (Table 7.12) and thus assessment of fracture risk based solely on BMD will miss individuals at risk for fracture.

Aetiology

Osteoporosis is related to either inadequate peak bone mass and/or ongoing bone loss. Peak bone mass is achieved in early adult life and depends on

Table 7.12 Risk factors for osteoporosis and fragility fracture

BMD-dependent

BMD-independent

Female sex

Increasing age

Caucasian/Asian

Previous fragility fracture

Hypogonadism

Family history of hip fracture

Immobilization

Low body mass index

Chronic liver disease

Smoking

Chronic renal disease

Alcohol abuse

Chronic obstructive pulmonary disease

Glucocorticoid therapy

Gastrointestinal disease

High bone turnover

Low dietary calcium intake

Increased risk of talling

Vitamin D insufficiency

Rheumatoid arthritis

Drugs (corticosteroids, heparin, ciclosporin, anticonvulsants)

Endocrine disease (Cushing’s syndrome, hyperthyroidism, hyperparathyroidism)

Other diseases (diabetes mellitus, mastocytosis, multiple myeloma, osteogenesis imperfect)

genetic factors, nutritional factors, sex hormone status and physical activity. Then age-related bone loss occurs with an accelerated loss in women start-ing around the time of the menopause. The risk factors for osteoporosis are those that cause a reduction in peak bone mass attained in adult life or those that cause increased bone loss (Table 7.12).

Clinical features

Symptoms of osteoporosis are the result of fractures, which typically occur at four sites: the thoracic and lumbar vertebrae, proximal femur and distal radius (Colles' fracture). Thoracic vertebral fractures may lead to kyphosis and loss of height (‘widow's stoop').

Investigations

■ Dual-energy X-ray absorptiometry (DXA) is the gold standard in measure-ment of bone density usually of the lumbar spine and proximal femur. Osteoporosis is diagnosed when the BMD T-score falls below -2.5.

■ Radiology. X-rays demonstrate fractures but are insensitive for detecting osteopenia.

■ Serum biochemistry. Calcium, phosphate and alkaline phosphatase are normal.

■ Secondary causes of osteoporosis (thyrotoxicosis, myeloma, primary hyperparathyroidism, hypogonadism, coeliac disease) should be looked for by appropriate blood tests in men and premenopausal women.

Assessment of fracture risk

This should take into account both BMD and clinical risk factors (Table 7.12). Indications for DXA scanning are listed in Table 7.13. The Risk Factor Assess-ment Tool (World Health Organization [WHO] 2008) estimates the 10-year probability of hip fracture or major osteoporotic fractures combined for an

Table 7.13 Indications for dual-energy X-ray absorptiometry scanning
Radiographic osteopenia
Previous fragility fracture (in those aged less than 75 years)
Glucocorticoid therapy (in those aged less than 65 years)
Body mass index below 19 kg/m2
Maternal history of hip fracture
BMD-dependent risk factors in Table 7.12
In patients presenting with height loss and/or kyphosis, lateral thoracic spine X-ray is the initial investigation and shows loss of anterior vertebral body height and wedging due to fracture.
BMD, bone mineral density.

untreated patient between the ages of 40 and 90 years (www.shef.ac.uk/ FRAX/). It integrates clinical risk factors with femoral neck BMD (hip BMD may also be used in women). It is a guide only, and will not be helpful in all patients e.g. those with low spinal BMD but normal femoral neck. In patients >75 years with a fragility fracture DXA scanning is often not neces-sary prior to treatment for osteoporosis. FRAX does not identify the level of fracture risk at which treatment should be started and this will vary depending partly on the medical resources of the country. In the UK, osteoporosis treat-ment is cost-effective for a 4% 10-year risk of hip fracture and 3% in the USA.

Management

Prevention and treatment New vertebral fractures require bed rest for 1-2 weeks and strong analgesia. Muscle relaxants (e.g. diazepam 2 mg three times daily), subcutaneous calcitonin (50 IU daily) or intravenous pamidronate (single dose 60-90 mg) are also given for pain relief. Non-spinal fractures are treated by conventional orthopaedic means. Lifestyle advice includes stopping smoking, reducing alcohol intake, adequate intake of calcium (700-1000 mg/day, 1500 mg post-menopausally) and vitamin D (400800 IU/day) and regular weight-bearing exercises. In the elderly, physio-therapy and assessment of home safety are done to reduce the risk of falls. Hip protectors may reduce the risk of hip fracture in residential care.

Pharmacological intervention

■ Bisphosphonates (e.g. alendronate, risedronate, zoledronate, p. 319) are first-line treatment in most patients with osteoporosis. They inhibit bone resorption through inhibition of osteoclast activity, increase bone mass at the hip and spine, and most have been shown to reduce fracture incidence. Optimal duration of therapy is unknown.

■ Strontium ranelate (2 g daily) is a useful alternative to oral bisphospho-nates particularly in the frail elderly who have difficulty in complying with the dosage regimen. Its mechanism of action is uncertain.

■ Raloxifene (60 mg daily), a selective oestrogen-receptor modulator (SERM), activates oestrogen receptors on bone while having no stimula-tory effect on endometrium (cf: hormone replacement therapy [HRT], p. 314). It has been shown to reduce BMD loss at spine and hip, though fracture rates are reduced only in the spine. Side-effects are leg cramps, flushing, increased risk of thromboembolism (similar to HRT) and stroke.

■ Recombinant human parathyroid peptide 1-34 (teriparatide) and recom-binant human parathyroid hormone 1-84 stimulate bone formation and are both given by daily subcutaneous injection. They are indicated for severe cases of osteoporosis or in women who are intolerant of, or fail to respond to other therapies. A side-effect is hypercalcaemia.

■ Oestrogen therapy as HRT is second-line therapy because of adverse effects e.g. breast cancer and increased cardiovascular disease risk with long-term use (see p. 319). It is used for postmenopausal women who are at high risk of fracture and also have perimenopausal symptoms.

■ Testosterone is given to men with biochemical evidence of hypogonadism.

Glucocorticoid-induced osteoporosis

Oral corticosteroids are associated with a significant fracture risk at the hip and spine. General measures to reduce the fracture risk include reduction of the dose of corticosteroids to a minimum, an alternative route of administra-tion (e.g. rectal steroids in distal ulcerative colitis) and prescription of alterna-tive immunosuppressive agents. All patients should be given calcium and vitamin D supplements and lifestyle advice as above. In addition all patients over the age of 65 years or with a previous fragility fracture are given drug treatment for osteoporosis. Bisphosphonates and teriparatide are licensed in the UK for this purpose. Drug treatment is given to younger patients based on the results of a DXA scan and clinical risk factors.

Osteonecrosis

Osteonecrosis (avascular necrosis, ischaemic necrosis) is death of bone and marrow cells due to a reduced blood supply (vascular damage, increased intraosseous pressure, mechanical stresses). The many causes include medi-cation (glucocorticoids, bisphosphonates), alcohol abuse, sickle cell disease, trauma, radiation and HIV infection. The femoral neck is the commonest site affected and presents with pain and arthropathy and bony collapse if untreated. Diagnosis is by MRI; plain X-ray will not show early changes. Treatment depends on the cause and the site affected.

Paget’s disease

This is a focal disorder of bone remodelling in which there is increased osteoclastic bone resorption followed by formation of weaker new bone, increased local bone blood flow and fibrous tissue. The incidence increases with age; it is rare in the under-40s and affects up to 10% of adults by the age of 90 years.

Aetiology

The aetiology is unknown. The disease may result from a latent viral infection (canine distemper virus, measles or respiratory syncytial virus) in osteoclasts in a genetically susceptible host (increased risk in family members, suscep-tibility genes identified).

Clinical features

The most common sites are the pelvis, lumbar spine, femur, thoracic spine, skull and tibia, although any bone can be involved. Most cases are asymp-tomatic, but features include the following:

■ Pain in the bone pain or nearby joint (cartilage or adjacent bone is damaged).

■ Deformities: enlargement of the skull, bowing of the tibia

■ Complications: nerve compression (deafness, paraparesis), pathological fractures, rarely high-output cardiac failure (due to increased bone blood flow) and osteogenic sarcoma.

Investigations

■ Serum alkaline phosphatase concentration is raised (reflects level of bone formation), often >1000 U/L, with a normal calcium and phosphate. Urinary hydroxyproline excretion is raised and may be used as a marker of disease activity.

■ X-rays show characteristic changes in affected bone. There is localized bony enlargement and distortion, sclerotic changes (increased density) and osteolytic areas (loss of bone and reduced density).

■ Radionuclide bone scans showing increased uptake of bone-seeking radionuclides. Appearances are similar to metastatic sclerotic carcinoma, especially from breast and prostate.

Treatment

Bisphosphonates (intravenous zoledronate or oral, p. 319) inhibit bone resorption by decreasing osteoclastic activity, and form the mainstay of treatment. They are indicated for symptomatic patients and asymptomatic patients at risk of complications (e.g. fracture, nerve entrapment). Disease activity is monitored by symptoms and measurement of serum alkaline phos-phatase or urinary hydroxyproline.

Osteomalacia and vitamin D deficiency

Inadequate mineralization of the osteoid framework, leading to soft bones, produces rickets during bone growth in children and osteomalacia following epiphyseal closure in adults. Osteomalacia and rickets are the clinical mani-festations of profound vitamin D deficiency. The major source of vitamin D is from skin photosynthesis following ultraviolet B sunlight exposure (Fig. 7.6). A small amount is obtained from dietary sources (oily fish, egg yolks, supplemented breakfast cereals, margarine).

Individuals at risk for vitamin D deficiency are those with pigmented skin, use of sunscreen or concealing clothing, the elderly and institutionalized (particularly nursing home residents), malabsorption, short bowel, renal disease (inadequate conversion of 25-(OH)D3 to 1,25-(OH)2D3), cholestatic liver disease and patients taking anticonvulsants, rifampicin or highly active antiretroviral treatment.

Clinical features

Proximal muscle weakness and pain are the common symptoms. Low bone density on DXA scanning or osteopenia on plain X-rays may also be a mani-festation of vitamin D deficiency. Severe vitamin D deficiency may present with hypocalcaemia, tetany and seizures. Rickets in children presents with bony deformity (knock knees, bowed legs) and impaired growth.

Investigations

■ Serum 25-hydroxyvitamin D3 (IHD) is low (<25 nmol/L, 10 μg/L) in osteo-malacia. Serum OHD concentrations between 25 and 50 nmol/L suggest vitamin D insufficiency.

■ Serum biochemistry: alkaline phosphatase is usually high. Phosphate and calcium may be normal or low.

■ Radiology. X-ray appearance is characteristic, showing defective miner-alization and Looser's zones (low-density bands extending from the cortex inwards in the shafts of the long bones).

Management

Treatment of vitamin D deficiency is with oral calciferol 10 000 IU daily or 60 000 IU weekly for 8-12 weeks and then a maintenance dose of 1000 IU daily (10 000 IU weekly). Patients with severe malabsorption are treated with intramuscular calciferol 300 000 IU monthly for 3 months and then yearly maintenance doses. Vitamin D insufficiency is associated with adverse health effects (increased risk of type 2 diabetes mellitus, several cancers, cardio-vascular disease) and should also be treated (1000 IU daily).

Ebook Essentials of Kumar and Clark's Clinical Medicine, 5e

1. Ethics and communication

Ethics and communication

2. Infectious diseases

Infectious diseases

3. Gastroenterology and nutrition

Gastroenterology and nutrition

4. Liver, biliary tract and pancreatic disease

Liver, biliary tract and pancreatic disease
LIVER BIOCHEMISTRY AND LIVER FUNCTION TESTS
SYMPTOMS AND SIGNS OF LIVER DISEASE
JAUNDICE
HEPATITIS
NON - ALCOHOLIC FATTY LIVER DISEASE (NAFLD)
CIRRHOSIS
COMPLICATIONS AND EFFECTS OF CIRRHOSIS
LIVER TRANSPLANTATION
TYPES OF CHRONIC LIVER DISEASE AND CIRRHOSIS
PRIMARY SCLEROSING CHOLANGITIS
BUDD - CHIARI SYNDROME
LIVER ABSCESS
LIVER DISEASE IN PREGNANCY
LIVER TUMOURS
GALLSTONES
THE PANCREAS
CARCINOMA OF THE PANCREAS
NEUROENDOCRINE TUMOURS OF THE PANCREAS

5. Haematological disease

Haematological disease
ANAEMIA
Assessment and treatment of suspected neutropenic sepsis
HAEMOLYTIC ANAEMIA
INHERITED HAEMOLYTIC ANAEMIAS
ACQUIRED HAEMOLYTIC ANAEMIA
MYELOPROLIFERATIVE DISORDERS
THE SPLEEN
BLOOD TRANSFUSION
THE WHITE CELL
HAEMOSTASIS AND THROMBOSIS
THROMBOSIS
THERAPEUTICS

6. Malignant disease

Malignant disease
MYELOABLATIVE THERAPY AND HAEMOPOIETIC STEM CELL TRANSPLANTATION
THE LYMPHOMAS
THE PARAPROTEINAEMIAS
PALLIATIVE MEDICINE AND SYMPTOM CONTROL

7. Rheumatology

Rheumatology
COMMON INVESTIGATIONS IN MUSCULOSKELETAL DISEASE
COMMON REGIONAL MUSCULOSKELETAL PROBLEMS
BACK PAIN
OSTEOARTHRITIS
INFLAMMATORY ARTHRITIS
THE SERONEGATIVE SPONDYLOARTHROPATHIES
Clinical features, Investigations
INFECTION OF JOINTS AND BONES
AUTOIMMUNE RHEUMATIC DISEASES
SYSTEMIC INFLAMMATORY VASCULITIS
DISEASES OF BONE
THERAPEUTICS

8. Water, electrolytes and acid–base balance

WATER AND ELECTROLYTE REQUIREMENTS
BODY FLUID COMPARTMENTS
REGULATION OF BODY FLUID HOMEOSTASIS
PLASMA OSMOLALITY AND DISORDERS OF SODIUM REGULATION
DISORDERS OF POTASSIUM REGULATION
DISORDERS OF MAGNESIUM REGULATION
DISORDERS OF ACID - BASE BALANCE
THERAPEUTICS

9. Renal disease

Renal disease
INVESTIGATION OF RENAL DISEASE
GLOMERULAR DISEASES
NEPHROTIC SYNDROME
URINARY TRACT INFECTION
TUBULOINTERSTITIAL NEPHRITIS
HYPERTENSION AND THE KIDNEY
RENAL CALCULI AND NEPHROCALCINOSIS
URINARY TRACT OBSTRUCTION
ACUTE RENAL FAILURE/ACUTE KIDNEY INJURY
CHRONIC KIDNEY DISEASE
RENAL REPLACEMENT THERAPY
CYSTIC RENAL DISEASE
TUMOURS OF THE KIDNEY AND GENITOURINARY TRACT
DISEASES OF THE PROSTATE GLAND
TESTICULAR TUMOUR
URINARY INCONTINENCE

10. Cardiovascular disease

COMMON PRESENTING SYMPTOMS OF HEART DISEASE
INVESTIGATIONS IN CARDIAC DISEASE
CARDIAC ARRHYTHMIAS
HEART FAILURE
ISCHAEMIC HEART DISEASE
RHEUMATIC FEVER
VALVULAR HEART DISEASE
PULMONARY HEART DISEASE
MYOCARDIAL DISEASE
CARDIOMYOPATHY
PERICARDIAL DISEASE
SYSTEMIC HYPERTENSION
ARTERIAL AND VENOUS DISEASE
ELECTRICAL CARDIOVERSION
DRUGS FOR ARRHYTHMIAS
DRUGS FOR HEART FAILURE
DRUGS AFFECTING THE RENIN - ANGIOTENSIN SYSTEM
NITRATES, CALCIUM - CHANNEL BLOCKERS AND POTASSIUM - CHANNEL ACTIVATORS

11. Respiratory disease


Respiratory disease
TUBERCULOSISnd
DIFFUSE DISEASES OF THE LUNG PARENCHYMA
OCCUPATIONAL LUNG DISEASE
CARCINOMA OF THE LUNG
DISEASES OF THE CHEST WALL AND PLEURA
DISORDERS OF THE DIAPHRAGM

12. Intensive care medicine

Intensive care medicine

13. Drug therapy, poisoning, and alcohol misuse

Drug therapy, poisoning, and alcohol misuse

14. Endocrine disease

Endocrine disease
PITUITARY HYPERSECRETION SYNDROMES
THE THYROID AXIS
MALE REPRODUCTION AND SEX
FEMALE REPRODUCTION AND SEX
THE GLUCOCORTICOID AXIS
THE THIRST AXIS
DISORDERS OF CALCIUM METABOLISM
DISORDERS OF PHOSPHATE CONCENTRATION
ENDOCRINOLOGY OF BLOOD PRESSURE CONTROL
DISORDERS OF TEMPERATURE REGULATION
THERAPEUTICS

15. Diabetes mellitus and other disorders of metabolism

DIABETES MELLITUS
DIABETIC METABOLIC EMERGENCIES
COMPLICATIONS OF DIABETES
SPECIAL SITUATIONS
HYPOGLYCAEMIA IN THE NON - DIABETIC
DISORDERS OF LIPID METABOLISM
THE PORPHYRIAS

16. The special senses

THE EAR
THE NOSE AND NASAL CAVITY
THE THROAT
THE EYE

17. Neurology

COMMON NEUROLOGICAL SYMPTOMS
COORDINATION OF MOVEMENT
THE CRANIAL NERVES
COMMON INVESTIGATIONS IN NEUROLOGICAL DISEASE
UNCONSCIOUSNESS AND COMA
STROKE AND CEREBROVASCULAR DISEASE
EPILEPSY AND LOSS OF CONSCIOUSNESS
NERVOUS SYSTEM INFECTION AND INFLAMMATION
HYDROCEPHALUS
HEADACHE, MIGRAINE AND FACIAL PAIN
SPINAL CORD DISEASE
DEGENERATIVE NEURONAL DISEASES
DISEASES OF THE PERIPHERAL NERVES
MUSCLE DISEASES
MYOTONIAS
DELIRIUM
THERAPEUTICS

18. Dermatology

Dermatology

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