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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_2826_Библиотеки_им_академика_М_И_Перельмана.pdf
Diseases of Bone 313
Glucocorticoid-induced osteoporosis
Individuals requiring continuous oral glucocorticoid therapy for 3 months or more
(at any dose) should be assessed for osteoporotic risk factors. Post-menopausal
women, men aged over 50 years and anyone with a previous fragility fracture
should receive bisphosphonate treatment without waiting for DXA scanning.
Fracture risk assessment and DXA results guide treatment for other patients.
Where possible, glucocorticoid doses should be minimized and consideration
given to use of steroid-sparing immunosuppressants and alternative routes of
steroid administration (e.g. rectal steroids for distal ulcerative colitis).
Osteonecrosis
Osteonecrosis (avascular, aseptic or ischaemic necrosis) is death of bone
and marrow cells due to a reduced blood supply. The many causes include
medication (glucocorticoids in over 8% of cases, bisphosphonates), alcohol
abuse, sickle cell disease, trauma, radiation and HIV infection. The femoral
neck is the most common 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,
but joint replacement may be required.
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
(e.g. measles or respiratory syncytial virus) in osteoclasts in a genetically
susceptible host (increased risk in family members, susceptibility genes
identified).
Clinical features
The most common sites are the pelvis, femur, lumbar spine, skull and tibia,
although any bone can be involved. Most cases are asymptomatic, but features include the following:
• Pain in the bone 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.
314 Rheumatology
Investigations
• Serum alkaline phosphatase concentration is raised (reflects level of
bone formation), often >1000 U/L, with a normal calcium and phosphate
(see Table 7.12). Urinary hydroxyproline excretion is raised and may be
used as a marker of disease activity.
• X-rays show localized bony enlargement and distortion, sclerotic changes
(increased density) and osteolytic areas (loss of bone and reduced density).
• Radionuclide bone scans show increased uptake of bone-seeking
radionuclides. Appearances are similar to metastatic sclerotic carcinoma,
especially from breast and prostate.
Treatment
Bisphosphonates (mainly intravenous zoledronate p. 317) 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
phosphatase 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 manifestations of profound vitamin D deficiency. The major source of vitamin D is from
skin photosynthesis following ultraviolet B sunlight exposure (see Fig. 7.6).
A small amount is obtained from dietary sources (oily fish, egg yolks, supplemented breakfast cereals, margarine).
Aetiology
Risk factors for vitamin D deficiency include pigmented skin, use of sunscreen or concealing clothing, old age and institutionalization (particularly
nursing home residents), malabsorption, short bowel, renal disease (inadequate conversion of 25-(OH)D3 to 1,25-(OH)2D3), cholestatic liver disease
and treatment with anticonvulsants, rifampicin or highly active antiretroviral
treatment.
Clinical features
Proximal muscle weakness and pain are the common symptoms, but
osteomalacia may be asymptomatic. Low bone density on DXA scanning or
osteopenia on plain X-rays may also be a manifestation 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.
Therapeutics 315
Investigations
• Vitamin levels: serum 25-hydroxyvitamin D3 (OHD) is low (<25 nmol/L,
10 μg/L) in osteomalacia. Serum OHD concentrations between 25 and
50nmol/L suggest vitamin D insufficiency.
• Serum biochemistry: alkaline phosphatase is usually high. Phosphate and
calcium may be normal or low. PTH is raised.
• Radiology: X-ray appearance is characteristic, showing defective
mineralization and Looser’s pseudofractures (low-density bands running
perpendicular to the cortex, most commonly seen in the femur and
pelvis).
Management
Treatment of vitamin D deficiency involves an initial loading stage to replenish stores and a subsequent maintenance phase to avoid repeat deficiency.
Patients should also receive supplementary calcium of 1000–1200 mg/
day. In nutritional deficiency, recommended initial replacement is with oral
vitamin D 50 000 units per week for 8 weeks. Vitamin D is also available as
an intramuscular injection; two doses of 300 000 units are usually enough
to replenish stores. This should be followed by regular supplementation with
800–1000 units of vitamin D per day.
THERAPEUTICS
Anti-inflammatories and pain relief
Aspirin is indicated for transient musculoskeletal pain and pyrexia. In
inflammatory conditions, NSAIDs are usually given. Paracetamol is similar in
efficacy to aspirin, but has no demonstrable anti-inflammatory activity. It is
first-line treatment in pain relief where anti-inflammatories are not routinely
indicated. Codeine may be added when paracetamol alone is insufficient.
Paracetamol (acetaminophen)
Paracetamol inhibits synthesis of prostaglandins in the central nervous
system and peripherally blocks pain impulse generation. It reduces pyrexia
by inhibition of the hypothalamic heat-regulating centre. It is indicated for
mild to moderate pain and pyrexia. NSAIDs are preferred for pain relief in the
inflammatory arthritides.
Non-steroidal anti-inflammatory drugs
Mechanism of action
This mechanism is by inhibition of cyclo-oxygenase (COX), the enzyme which
catalyses the synthesis of cyclic endoperoxidases from arachidonic acid to
form prostaglandins. Inhibition of the COX-1 isoform in the gastrointestinal
316 Rheumatology
tract leads to a reduction in protective prostaglandins and predisposes to
gastroduodenal damage. COX-2 is the form mainly induced in response to
pro-inflammatory cytokines. The selective inhibitors of COX-2 (‘coxibs’ –
etoricoxib and celecoxib) have a lower risk of gastroduodenal damage than
the non-selective NSAIDs (e.g. ibuprofen, diclofenac).
Indications
Treatment is given in the smallest dose necessary for the shortest time.
• Pain and inflammation associated with inflammatory arthritides and
severe osteoarthritis
• Crystal synovitis
• Transient musculoskeletal pain
• Pain caused by secondary bone tumours.
Examples of preparations and doses
There are many different NSAIDs. They vary in their anti-inflammatory properties and tolerability, e.g. ibuprofen has fewer side effects than other NSAIDs
but anti-inflammatory activity is weaker. Indometacin is more potent, with
a higher incidence of side effects. Diclofenac and naproxen lie somewhere
between these two in potency and side effects.
Side effects
Gastrointestinal toxicity. The highest risk is in the elderly. Inflammation
and ulceration can occur throughout the gut but clinically is most apparent
in the stomach and duodenum (dyspepsia, erosions, ulceration, bleeding,
perforation). Of the non-selective NSAIDs, ibuprofen is associated with the
lowest risk, and piroxicam, indometacin and diclofenac with intermediate
risk. NSAIDs associated with the lowest risk are generally preferred, and the
lowest NSAID dose compatible with symptom relief should be prescribed.
Co-prescribe proton pump inhibitors with non-selective NSAIDs in high-risk
patients (>65 years, previous peptic ulceration, serious comorbidity, other
medication that increases gastrointestinal risk: warfarin, aspirin, corticosteroids) to reduce gastroduodenal damage.
Other side effects are hypersensitivity reactions (particularly rashes,
bronchospasm, angio-oedema), blood disorders, fluid retention (may precipitate cardiac failure in the elderly), acute kidney injury, hepatitis, pancreatitis
and exacerbation of colitis.
Cautions/contraindications
They are contraindicated in patients with a history of hypersensitivity to aspirin or any other NSAID – which includes those in whom attacks of asthma,
angio-oedema, urticaria or rhinitis have been precipitated by aspirin or any
other NSAID. They are also contraindicated in severe heart failure. Selective
COX-2 inhibitors are contraindicated in ischaemic heart disease, cerebrovascular disease, peripheral arterial disease and moderate or severe heart failure.
Therapeutics 317
Drugs affecting bone metabolism
Bisphosphonates
Mechanism of action
These synthetic analogues of bone pyrophosphate are adsorbed onto
hydroxyapatite crystals in bone and inhibit growth and activity of osteoclasts,
thereby reducing the rate of bone turnover.
Indications
Prophylaxis and treatment of osteoporosis in combination with calcium
(700–1000 mg daily, 1500 mg post-menopausally) and vitamin D (800 IU/
day) supplements if dietary intake inadequate. Treatment of Paget’s disease
and hypercalcaemia of malignancy, treatment of osteolytic lesions and bone
pain in bone metastases associated with breast cancer or multiple myeloma.
Examples of preparations and doses
Alendronic acid. Tablets: daily 10 mg; once weekly: 70 mg.
Treatment and prevention of osteoporosis: 10 mg daily at least 30 minutes
before breakfast or 70 mg once weekly.
Because of severe oesophageal reactions (oesophagitis, oesophageal
ulcers and strictures), patients should be advised to take the tablets with
a full glass of water on rising, to take them on an empty stomach at least
30 minutes before the first food or drink of the day and to stand or sit for at
least 30 minutes.
Pamidronate disodium. Injection: 15 mg, 30 mg, 60 mg, 90 mg.
Patients should be hydrated first.
Hypercalcaemia of malignancy: serum calcium <3.0 mmol/L, give 15–30 mg;
serum calcium >4.0 mmol/L, give 90 mg. Give as single infusion or in multiple
infusions over 2–4 consecutive days.
Osteolytic lesions and bone pain in bone metastases associated with
breast cancer or multiple myeloma: 90 mg every 4 weeks (or every 3 weeks
to coincide with chemotherapy in breast cancer).
Paget’s disease: 30 mg once a week for 6 weeks; may be repeated every
6 months.
Zoledronic acid. 4 mg/100 mL solution for infusion.
Patients should be hydrated first.
Hypercalcaemia of malignancy: give as single infusion of 4 mg zoledronic
acid over at least 15 minutes.
Prevention of skeletal events (e.g. pathological fractures, spinal compression)
associated with advanced malignancies involving bone: 4 mg every 3–4 weeks.
Side effects
Gastrointestinal side effects (dyspepsia, nausea, vomiting, abdominal pain,
diarrhoea, constipation), influenza-like symptoms, oesophageal reactions
318 Rheumatology
(see above), musculoskeletal pain. With intravenous pamidronate disodium: biochemical abnormalities (hypophosphataemia, hypocalcaemia,
hyper- or hypokalaemia, hypernatraemia), anaemia, thrombocytopenia, lymphocytopenia, seizures, acute kidney injury, conjunctivitis. Osteonecrosis of
the jaw– greatest risk is in patients receiving intravenous bisphosphonates
for cancer indications. Atypical femoral fractures are reported rarely and
mainly in association with long-term treatment.
Calcium
Reference nutrient intake is 700 mg.
Indications
Hypocalcaemia, osteomalacia, when dietary calcium intake (with or without
vitamin D) is deficient in the prevention and treatment of osteoporosis.
Examples of preparations and doses
Calcium carbonate. Chewable tablets (calcium 500 mg or Ca2+ 12.6 mmol).
Dispersible tablets: 400 (calcium 400 mg or Ca2+ 10 mmol), 1000 (calcium 1 g or
Ca2+ 25 mmol). Syrup (calcium 108.3 mg or Ca2+ 2.7 mmol/5 mL).
Osteoporosis and calcium deficiency: 700–1000 mg daily, syrup
55–75 mL daily.
Osteomalacia: 1000–3000 mg daily, syrup 55–155 mL daily.
Calcium gluconate. Injection: 10% (calcium 89 mg or Ca2+ 2.2 mmol/10 mL).
10–20 mL over 10 minutes for acute hypocalcaemia.
Side effects
Gastrointestinal disturbances; with injection, peripheral vasodilatation, fall in
blood pressure, injection-site reactions.
Vitamin D
Mechanism of action
Fat-soluble vitamin whose main action is to promote intestinal absorption of
calcium. An oral supplement of 10 μg (400 units) prevents deficiency.
Indications
• Prevention of vitamin D deficiency in those at risk, e.g. Asians consuming
unleavened bread and in elderly patients, particularly those who are
housebound or live in residential or nursing homes.
• As an adjunct in the prevention and treatment of osteoporosis where
dietary intake of vitamin D (and calcium) is suboptimal.
• Vitamin D deficiency caused by intestinal malabsorption, chronic liver
disease and severe renal impairment.
• Hypocalcaemia of hypoparathyroidism.
Therapeutics 319
Examples of preparations and doses
Cholecalciferol. Capsules: 800 units (equivalent to 20 ng of vitamin D3).
Prevention of vitamin D deficiency: one to two capsules (800–1600 units)
daily.
Vitamin D deficiency: one to four capsules (800–3200 units) daily.
Alfacalcidol. 1α-Hydroxycholecalciferol capsules: 250 ng, 500 ng, 1 μg.
Vitamin D treatment in patients with chronic kidney disease: 0.25–1 μg
daily.
Calcitriol. 1,25-Dihydroxycholecalciferol: 250 ng, 500 ng.
Vitamin D treatment in patients with chronic kidney disease: 250–1000
ng daily.
Side effects
Symptoms of overdosage include anorexia, lassitude, nausea and vomiting,
polyuria, thirst, headache and raised concentrations of calcium and phosphate in plasma and urine. All patients on pharmacological doses of vitamin
D should have plasma calcium concentration checked at intervals (initially
weekly) and if nausea and vomiting are present.
Water, electrolytes
8
andacid–base balance
WATER AND ELECTROLYTE REQUIREMENTS
In health, the volume and biochemical composition of both extracellular and
intracellular fluid compartments in the body remain remarkably constant.
Maintenance of the total amount depends on the balance between intake
and loss. Water and electrolytes are taken in as food and water, and lost in
urine, sweat and faeces. In addition, about 500 mL of water is lost daily in
expired air (insensible losses). The reference maintenance fluid, electrolyte
and nutrient intake in adults is given in Table 8.1. In certain disease states the
intake and loss of water and electrolytes is altered, and this factor must be
taken into account when providing fluid replacements. For instance, a patient
who is losing gastric secretions via a nasogastric tube will be losing additional sodium (25–80 mmol/L), potassium (5–20 mmol/L), chloride (100–150
mmol/L) and hydrogen ions (40–60 mmol/L) each day, which will need to be
replaced together with the normal daily requirements.
BODY FLUID COMPARTMENTS
In a normal adult man, 50%–60% of body weight is water; females have proportionately more body fat than males and total body water is about 45%–50%
of body weight. In a healthy 70 kg male, total body water is approximately
42 L. This is contained in three major compartments:
• Intracellular fluid: 28 L; about 35% of lean body weight
• Extracellular fluid:
• Interstitial fluid that bathes the cells: 9.4 L; about 12% of lean body
weight
• Plasma: 4.6 L; about 4%–5% of lean body weight.
The intracellular and interstitial fluids are separated by the cell membrane;
the interstitial fluid and plasma are separated by the capillary wall.
Osmotic pressure. Osmotic pressure is the primary determinant of
the distribution of water among the three major compartments. Osmolality
is determined by the concentration of osmotically active particles. Thus 1
mole of sodium chloride dissolved in 1 kg of water has an osmolality of
2 mmol/kg, as sodium chloride freely dissociates into two particles, the
sodium ion Na+ and the chloride ion Cl−. One mole of urea (which does not
dissociate) in 1 kg of water has an osmolality of 1 mmol/kg. Osmolarity
refers to the osmoles of solute per litre of solution (mmol/L) and for dilute
aqueous solutions is essentially equivalent to osmolality.
Body Fluid Compartments 321
Table 8.1 Routine fluid and electrolyte requirements
Daily requirement
Water 25–30 mL/kg/day
Sodium 1 mmol/kg/day
Potassium 1 mmol/kg/day
Chloride 1 mmol/kg/day
Glucose 50–100 mg/day*
*For example, 5% glucose contains 5 mg glucose per 100 mL.
Table 8.2 Normal adult electrolyte concentrations of
intracellular and extracellular fluids
+
Na
+
K
2+
Ca
2+
Mg
−
Cl
-
HCO
3
2-
PO
4
2-
SO
4
Organic acid
Protein
Plasma
(mmol/L)
142 144
4 4
2.5 2.5
1.0 0.5
102 114
26 30
1.0 1.0
0.5 0.5
3 4
16 0
Interstitial fluid
(mmol/L)
Intracellular
fluid (mmol/L)
10
160
1.5
13
2
8
57
10
3
55
The intracellular fluid contains mainly potassium (K+). Most of the
intracellular magnesium (Mg2+) is bound and osmotically inactive. In the
extracellular compartment, sodium (Na+) salts predominate in the interstitial
fluid and proteins in the plasma. Body Na+ stores are the primary determinant
of extracellular fluid volume but plasma volume is determined by both oncotic
pressure as well as protein concentration. The composition of intracellular
and extracellular fluids is shown in Table 8.2. The cell membrane separates
the intracellular and extracellular fluid compartments and maintains the
different electrolyte compositions within each compartment by active and
passive transport mechanisms. A change in osmolality in one compartment
will trigger water movement across the cell membrane to re-establish
osmotic equilibrium.
322 Water, electrolytes and acid–base balance
Protein
molecule
Hydrostatic
Lymphatic
Distribution of extracellular fluid
The capillary wall separating the intravascular (plasma) and interstitial spaces
is freely permeable to Na+, K+ and glucose and, therefore, these solutes do not
contribute to fluid distribution between these spaces. However, plasma proteins (e.g. albumin) have a limited ability to traverse the capillary bed, and act
to hold water in the intravascular space. The distribution of extracellular water
between intravascular and extravascular (interstitial) space is determined by
the equilibrium between hydrostatic pressure (i.e. intracapillary blood pressure), which tends to force fluid out of the capillaries, and oncotic pressure
(i.e. osmotic pressure exerted by plasma proteins), which acts to retain fluid
within the vessel. The net flow of fluid outwards is balanced by ‘suction’ of
fluid into the lymphatics, which returns it to the bloodstream (Fig. 8.1).
Oedema is defined as an increase in interstitial fluid and results from:
• Increased hydrostatic pressure, e.g. sodium and water retention in
cardiac failure
• Reduced oncotic pressure, e.g. hypoalbuminaemia associated with
nephrotic syndrome
• Obstruction to lymphatic flow
• Increased permeability of the blood vessel wall, e.g. at a site of
inflammation, the cytokines lead to an increase in vascular permeability.
pressure
s
drainage
Oncotic
pressure
Capillary lumen
Fig. 8.1 Distribution of water between the vascular and extravascular (interstitial)
spaces. This is determined by the equilibrium between hydrostatic pressure, which
tends to force fluid out of the capillaries, and oncotic pressure, which acts to retain
fluid within the vessel. The net flow of fluid outwards is balanced by ‘suction’ of fluid
into the lymphatics, which returns it to the bloodstream. Similar principles govern
the volume of the peritoneal and pleural spaces.
Interstitial
space