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Locomotor > Pain & Analgesia: Drugs affecting bone metabolism > Flashcards

Pain & Analgesia: Drugs affecting bone metabolism Flashcards

1
Q

What are the basic components of human bone?

A

-Types: 80% cortical (long bones), trabecular bone (vertebrae, epiphyses: large surface area, metabolically more active)
-Constituents: cells (osteoblasts, osteoclasts), osteoid (Unmineralised organic matrix secreted by osteoblasts, collagen type 1 main component, 15
% body mass), hydroxyapatite crystals, mineralised bone (99% of Ca2+ body stores, PO4/3-)

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2
Q

What are the important bone cells in bone metabolism?

A
  • Osteoblasts= secrete new bone matrix

- Osteoclasts= break the matrix down (resorption)

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3
Q

Describe the physiological behaviour of bone metabolism

A
  • Bone turnover is constant allowing for ‘remodelling’ in responses to changed mechanical stresses, maintain calcium homeostasis
  • 10% remodelled every year
  • Bone resorption and formation normally balanced in healthy young adults (imbalance in rates= bone loss)
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4
Q

Describe the structure of cortical bone

A

Concentric rings of the Haversian system based around central blood vessels
-Strength

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5
Q

What are the major influences on bone metabolism/ turnover?

A
  • Mineral requirements (Ca2+, PO4/3- absorbed from diet)
  • Hormones (PTH, vitamin D, calcitonin, oestrogens)
  • Diet
  • Drugs
  • Physical factors (exercise, loading)
  • Cytokines (bone morphogenic proteins, IL-6, IGF-1, breaking down bone)
  • Age: young= new bone formation predominates, old= bone loss (0.5-1% per year from 40 both sexes), menopause= acceleration (trabecular osteoclast activity)
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6
Q

What happens to the ageing skeleton?

A
  • Childhood and youth= active growth and mineralising
  • Peak bone mass/ stable adult skeleton/ skeletal maturity= 30 years
  • Slow loss both sexes 40
  • Rapid loss at menopause
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7
Q

Why is there a close relationship between calcium and bone metabolism?

A
  • Bone contains 99% body Ca2+ as hydroxyapatite crystals
  • Daily turnover 700 mg Ca2+ significant for Ca homeostasis
  • Physiological roles of calcium: cells signalling and contraction mechanism
  • Cytoplasmic [Ca2+] = 0.1 micro mol/l
  • Extracellular [Ca2+] = 2.5 mmol/l
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8
Q

How is calcium concentration controlled?

A

Interaction of:

  • Parathyroid hormone (PTH)
  • Vitamin D
  • Calcitonin
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9
Q

How is PTH related to bone metabolism?

A
  • Increases Ca2+ release from bone
  • Decreases calcium excretion
  • Key defence of Ca concentration in extracellular fluids
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10
Q

How is Vitamin D related to bone metabolism?

A
  • Increases bone mineralisation
  • Increases Ca2+ (+PO4/3-) uptake from GIT
  • Decreases calcium excretion
  • Protect bone and promote mineralisation
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11
Q

How is calcitonin related to bone metabolism?

A

-Decreases Ca2+ release from bone
-Increases calcium excretion
so decrease in Ca serum concentration

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12
Q

Which are the important disease affecting bone?

A
  • Osteoporosis: decreased bone mass with distorted micro-architecture (increase fractures)
  • Renal osteodystrophy: decreased renal vitamin D activation, increased PTH activity
  • Paget’s Disease: distortion of bone resorption and remodelling
  • Osteomalacia: defective bone mineralisation due to vitamin D deficiency (adult)
  • Rickets: defective bone mineralisation due to vitamin D deficiency (child)
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13
Q

What are drugs that affect bone metabolism?

A 
Therapeutic:
-Bisphosphates
-Oestrogens and analogues (HRT, supplements)
-Calcium salts
-Vitamin D
-Other drugs active on the bone= calcitonin, PTH analogues, strontium
Adverse effects:
-Corticosteroids
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14
Q

What is osteoporosis?

A
  • Reduction in bone density (local/ general) and osteoid
  • Bone mass decreases with age (women >40)
  • Accelerates after menopause (endogenous oestrogens protective)
  • Clinical relevance increased risk of pathological fractures
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15
Q

What are the causes of osteoporosis?

A 
Primary
-Old-age, post-menopausal status
Secondary
-Immobilisation/ lack of exercise
-Malnutrition or malabsorption
-Endocrine disease (thyrotoxicosis, Cushing's syndrome- over secretion of endogenous glucocorticoids)
-Drugs (corticosteroids, heparin)
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16
Q

Which sites does osteoporosis occur at?

A
  • More than 50% trabecular
  • Neck of femur, vertebral bodies
  • Can lead to perforation in trabecular plates
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17
Q

How can osteoporosis be diagnosed?

A
  • X-rays show loss of trabeculae and cortical (increased translucence)
  • Photon absorptiometry may confirm loss of bone density (uptake of photons passed through the bone)
  • Serum Ca2+, PO4/3- and alkaline phosphatase usually normal
  • Often diagnosed after first presentation with a pathological fracture
18
Q

Describe the epidemiology of fracture risk

A
  • Increases with age
  • Higher for females at all ages (I in 2 vs 1 in 6)
  • Male= hip most likely, vertebra, wrist
  • Females= vertebra, hip, wrist
19
Q

Which drugs cause osteoporosis?

A

Corticosteroids

Bone: decreases osteoblast differentiation, increases osteoclast, decreases Ca absorption

20
Q

Describe Heparin

A
  • Other similar drugs: warfarin is an oral anticoagulant (takes time to work- heparin lasts a few days)
  • A glycosaminoglycan anticoagulant that interferes with the activity of the intrinsic coagulation cascade
  • Thromboembolism (DVT/ pulmonary), Thromboprophylaxis, short term except pregnancy
  • Parenteral (IV/SC) administration necessary (large complex molecule broken down by gastric acid)
  • Bleeding, osteoporosis only when long term and in pregnancy (increase osteoclast, decrease osteoblasts)
  • Partial thromboplastin time (PTT)
21
Q

What drugs are used for primary prevention of osteoporosis?

A

-Bisphosphonates (alendronate)
-Calcium and Vitamin D
-Exercise
=Physical (hip protectors, safer flooring)

22
Q

What are the drugs used for secondary prevention (fractures)?

A 
Antiresorptive drugs
-Bisphosphonates
-Oestrogens
-Raloxifene
-Calcitonin
Bone forming drugs
-Parathyroid hormone
-Strontium ranelate
23
Q

Describe bisphosphonates

A
  • Similar structure to hydroxyapatite crystals
  • Alendronic acid
  • Industrial use= corrosion prevention, textile, fertiliser, washing powder, oil industry
  • Analogues of pyrophosphate
  • Reduce bone resorption by osteoclasts= hinder recruitment, stimulate osteoblasts to produce inhibitor of osteoclast formation
  • Given continuously
24
Q

Describe Alendronic acid

A
  • Similar drugs= alendronate sodium (Fosamax), Risedronate, pamidronate
  • Decreases osteoclast activity so decrease bone loss, decrease risk of spine and hip fractures
  • Postmenopausal osteoporosis (70% market), prevention of corticosteroid-induced OP, Paget’s disease, malignant bone metastases
  • 70 mg orally weekly, one tablet- empty stomach morning, 8 ounces water, 30 mins before eating/ drinking, upright
  • GI upset, oesophagus irritation, osteonecrosis of jaw, oesophagitis, rupture of oesophagus- damages lower oesophageal mucosa
25
Q

Describe oestrogens in Hormone Replacement Therapy

A
  • Similar= selective oestrogen receptor modulators (tamoxifen)
  • Interacts with intra-cellular receptors, inhibits bone resorption by osteoclasts, reduces hip and spinal fractures in postmenopausal women
  • Menopausal symptoms, osteoporosis (not first-line),- prophylaxis
  • 0.3-0.625 mg daily
  • Tablets/ skin patch, often combined with progesterone
26
Q

What are the adverse effects of HRT?

A 
Minor
-Vaginal bleeding
-Breast tenderness
-Mood disturbances
Major
-Increased risk of: endometrial cancer= 200% (minimised by combining oestrogen and progesterone 40%), breast cancer= 20% (60% for oestrogen and progestin), venous thromboembolism=100%, stroke (30%)
27
Q

Summarise oestrogens for osteoporosis

A
  • Endogenous oestrogens have a major impact on skeleton and are a natural influence on preventing OP
  • Endogenous treatment moderately effective in reducing fractures
  • Major adverse effects
  • Rarely used now
28
Q

Describe Raloxifene

A
  • Similar= Selective Estrogen Receptor Modulators (SERMs), tamoxifen, tibolone
  • Oestrogen receptor agonists at some tissues (bone) and antagonsist at breast
  • OP, increase bone mass and decreased risk of vertebral fractures only (30-50%), decrease oestrogen dependent breast cancer 65% over 4 years and cardiovascular LDL cholesterol
  • Oral once daily
  • Hot flushes, thromboembolism (DVT)
29
Q

What is calcitonin?

A
  • Naturally occurring hormone (thyroid C cells) involved in calcium regulation and bone metabolism
  • Inhibits osteoclasts, slows bone loss, increases spinal bone density
  • Unlicensed but used as pain relief after vertebral fractures when other analgesic measures are unsuccessful
  • Protein so no oral bioavailability, injection (50-100 IU daily), nasal spray (200 IU daily)
  • Allergic reaction at injection sites
30
Q

Describe PTH (parathyroid hormone)

A
  • Teriparatide (1-34 fragments of PTH)- actual hormone stimulate Ca release from bone to regulate extracellular concentration
  • High risk fracture osteoporosis
  • Stimulates new bone formation by osteoblasts and bone mineral density, decreases 70% vertebral fractures, 50% non-vertebral
  • Daily injection up to 24 months (peptide molecule not bioavailable)
  • Nausea, leg cramps, dizziness
31
Q

How can osteoporosis be prevented?

A
  • Balanced diet rich in calcium and vitamin D (sunlight)
  • Weight-bearing exercise
  • Avoid smoking and excessive alcohol use
  • Drugs (Alendronic acid when appropriate)= women > 70 risk factors- family history of fracture, alcohol, RA, premature OP/ women < 70 confirmed OP or low bone mineral density
32
Q

Describe calcium supplements

A
  • Key mineral required for bone formation (heart, muscle, nerves)
  • 1000 to 1300 mg per day
  • Oral calcium lactate often given with vitamin D
  • Hypercalcaemia- anorexia, vomiting, polyuria, constipation, weak
33
Q

Describe vitamin D

A
  • Needed for body to absorb calcium and phosphate
  • 400 and 800 IU daily
  • Dairy products, egg yolks, saltwater fish and liver
  • Oral ergocalciferol or alfacalcidol (hydroxylated- do not require patients to go out into sun to activate)
  • Hypothyroidism, renal bone disease, rickets/ osteomalacia indications
  • Hypercalcaemia (nausea, constipation, fatigue, weakness, depression)
34
Q

What is renal bone disease/ osteodystrophy?

A

-Bone demineralisation accompanies chronic kidney disease

35
Q

What are the causes of renal osteodystrophy?

A
  • Failure of 1-alpha hydroxylation required to activate vitamin D leading to low serum calcium and activation of parathyroid glands
  • Phosphate retention tending to reduce free calcium ions
36
Q

What is the diagnosis and treatment of renal osteodystrophy?

A
  • Blood tests showing decreased calcium and vitamin D and increased phosphate and parathyroid hormone
  • Calcium and vitamin D supplementation (1-alphacalcidol so kidneys dont need to hydroxylate to activate)
  • Restriction of dietary phosphate
  • Phosphate binders (calcium carbonate)
  • Renal replacement (transplantation, haemodialysis)
37
Q

What is Paget’s disease of the bone?

A
  • Aetiology unknown (viral infection), genetic/ environmental
  • Often incidental X-ray finding in asymptomatic patient
  • Disordered turnover of bone, disrupts normal cycle- weakened and deformed, easily fractured
  • Lone bone, skull, pelvis
  • Symptomatic= bone pain
  • Characteristic skull and long bone deformities
38
Q

What are the complications of Paget’s disease?

A
  • Pathological fractures- complete or incomplete
  • Hypercalcaemia
  • Heart failure (hypermetabolic state)
  • Neurological effects= cranial nerve lesions, (bone around skull grows and compresses nerves) spinal cord lesions
  • OA (disordered shape)
  • Osteosarcomas (disordered metabolism)
39
Q

What is the treatment for Paget’s disease?

A
  • Analgesia (non-steroidal anti-inflammatory agents)
  • Bisphosphonates will reduce bone turnover
  • Neurological complications and fractures may require surgical intervention
40
Q

What is rickets?

A
  • Lack of vitamin D in childhood years (growth of skeleton)
  • Growing edge of long bone= epiphyseal growth
  • Curved structure, deformity, cupping, splaying
41
Q

What is osteomalacia?

A
  • Softening of the bones caused by defective bone mineralisation
  • Secondary to adequate available calcium and phosphorus
  • Overactive resorption of calcium from the bone (hyperparathyroidism)
  • Adult vitamin D deficiency
  • Pseudo fracture, Looser’s zone= band of bone material of decreased bone density= reaction in surrounding bone= creates fracture
  • Overlap with osteoporosis presentation- loss of mineral content of bone
42
Q

What is the treatment for rickets and osteomalacia?

A
  • Vitamin D replacement therapy
  • If malabsorption is the case then may require treatment by injection
  • Phosphate supplements in familial hypophosphatemic rickets

Locomotor (20 decks)

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