Metabolic Bone Disorders

Question 1

Define Osteoporosis

Answer 1

Progressive disease caused by low bone mass and deterioration of microarchitecture of bone tissue

Question 2

What is the most common complication of Osteoporosis?

Answer 2

Hip fractures at 87%

Question 3

How is Osteoporosis classified?

Answer 3

Using the T-score. T-score is a number of SDs that a patient’s BMD is from

Normal
 T score >-1 
Osteopoenia
T score -1 to -2.5
Osteoporosis
T score  below -2.5
Established Osteoporosis
T score

Question 4

Name 9 risk factors of Osteoporosis

Answer 4

1. Age
2. Gender - 80% women
3. Low BMI <19kg/m2
4. Untreated premature menopause or male hypogonadism
5. Alcohol
6. Smoking
7. Corticosteroid use
8. Conditions associated with prolonged immobility
9. Family history of maternal hip fracture

Question 5

What prevention advise can be given against Osteo?

Answer 5

Life style modification:

• Regular weight bearing - reduce risk of hip fx by 50%
• Stop smoking - reduce risk of hip fx by 25%
• Maintain adequate dietary levels of Calcium and Vit D
• Reduce alcohol intake
• Maintain BMI>19kg/m2

Question 6

Level of Calcium/Vit D needed for regular intake?

Answer 6

700mg/day

Double the recommended = reduces rate of bone loss

Question 7

What does DEXA scan stand for?

Answer 7

DEXA Scan - Dual Energy X-ray Absorptiometry

low energy X-rays penetrate less dense bone better

Question 8

What are the treatment options of Osteoporosis? (6)

Answer 8

1. Bisphosphonates (first line therapy). If contraindicated/not effective then…
2. Calcitonin
3. Hormone Replacement therapy only if <50yrs
4. Selective Estrogen Receptor Modulator (SERM) Raloxifene
5. Stronium Ranelate
6. Teriparatide

Question 9

What is the mechanism of action of bisphosphonates

Answer 9

e.g. alendronic acid reduces vertebral, wrist and hip fractures by approx. 50%
Risedronate sodium

Enzyme-resistant analogues of pyrophosphate that inhibit bone resorption. Approx. 50% of dose accumulates at sites of bone mineralisation where they bind to bone minerals in bone matrix

Remain (months/years) until they are released and ingested by osteoclasts as they resorb the bone

Thus osteoclasts exposed to high concentrations
Simple bisphosphonates accumulate and cause apoptosis (etidronate)
Nitrogen-containing bisphosphonates (i.e. alendronic acid) also interfere with attachment of osteoclast to bone (formn of ruffled border)

Question 10

What are the cautions and counselling points of Bisphosphonates?

Answer 10

All cause gastrointestinal side effects.

Patients should not take dose at bedtime and should stay upright for at least 30 mins after taking dose (oesophageal stricture)

Should avoid food before and after dose as food impairs absorption
Must be avoided in patients with renal impairment

Osteonecrosis of jaw has been reported following bisphosphonates (most commonly if given IV, rare with oral dose).

Question 11

What drug class does Alendronic acid (alendronate) belong to?

Answer 11

bisphosphonate; nitrogen-containing, second generation

Question 12

What is the mechanism of action of Alendronic acid?

Answer 12

Accumulates in bone and prevents bone resorption by inhibiting osteoclast attachment and survival

Question 13

Indications and dose of alendronic acid? (3)

Answer 13

1. post-menopausal osteoporosis (10mg daily or 70mg once weekly)
2. osteoporosis in men (10mg daily)
3. prevention and treatment of corticosteroid-induced osteoporosis in post-menopausal women not taking HRT (10mg daily)

Question 14

Counselling points for Alendronic acid? (3)

Answer 14

1. Swallow tablets whole with plenty of water while sitting or standing.
2. Take on an empty stomach at least 30 minutes before breakfast (or another oral medicine)
3. patient should stand or sit upright for at least 30 minutes after taking tablet

Question 15

Explain Hormone Replacement Therapy and who can use it

Answer 15

Oestrogens important in maintenance of bone integrity by inhibiting cytokines that recruit osteoclasts and opposing the bone resorbing Ca2+-mobilising role of PTH

Not first line, used in women with early natural or surgically induced menopause if other therapies don’t work.

Question 16

Mechanism of action of Raloxifene (SERM)

Answer 16

Selective Oestrogen Receptor Modulator (SERM)
Raloxifene has selective agonist activity on bone and cardiovascular system and antagonist activity on mammary tissue and the uterus
Inhibits bone resorption by preventing osteoclast recruitment without problem side effects of HRT

Question 17

What are the cautions, contra-indications and side effects of Raloxifene?

Answer 17

Increased risk of venous thromboembolism (discontinue if immobilised), breast cancer (?), hypertriglyceridaemia/heart disease
Contra-indications: thromboembolism, uterine bleeding, endometrial cancer, liver or renal impairment, pregnancy, breast feeding
Side effects: venous thromboembolism, menopausal symptoms (hot flushes, sweats, headache), leg cramps, peripheral oedema, gastrointestinal disturbances, hypertension

Question 18

Mechanism of action of Strontium ranelate?

Answer 18

Licensed for post-menopausal osteoporosis
Inhibits bone resorption and stimulates bone formation but exact mechanism is not clear
Strontium is adsorbed onto hydroxyapatite crystals in bone, is exchanged for Ca2+ in mineralised bone

Question 19

Strontium ranelate should be used in caution in which group of people?

Answer 19

those with predisposition to thromboembolism, renal impairment or requiring Ca2+ monitoring

Question 20

What are the guidelines and counselling points by the Scottish Medicine Consortium on the use of Strontium ranelate

Answer 20

Scottish Medicine Consortium advised that strontium ranelate should be restricted to use in women with high fracture risk (i.e. over 75 yrs with previous fracture) and if bisphosphonates are contra-indicated or not tolerated

2g granules in water given daily, preferably at bedtime

Food must be avoided for 2 hours before and after granules are taken, esp. Ca2+ containing foods

Antacids should also be avoided for 2hrs after taking

Question 21

What two substances play a key role in regulating/maintaining Calcium homeostasis and bone

Answer 21

Calcitonin and Parathyroid hormone (PTH)

Question 22

What is the function of Calcitonin?

Answer 22

Calcitonin inhibits osteoclast action directly and decreases plasma [Ca2+] by decreasing reabsorption of Ca2+ and phosphate in kidney.

Question 23

What is the function of PTH (parathyroid hormone) ?

Answer 23

PTH and its fragments can increase osteoblast number and stimulate their activity and increase bone mass, integrity and strength. Also decrease osteoblast apoptosis

Question 24

What is the dose regime for PTH and its fragments?

Answer 24

Human recombinant PTH:
subcutaneous injection, 100 micrograms daily for 24 mths max.

Teriparatide (PTH fragment 1-34):
subcutaneous injection, 20 micrograms daily for 18 mths max.

Question 25

How can corticosteroids induce osteoporosis?

Answer 25

The term corticosteroids encompasses both glucocorticoids (eg cortisol) and mineralocorticoids (eg aldosterone) Physiological concentrations of glucocorticoids are required for osteoblast differentiation Excessive pharmacological concentrations inhibit bone formation by inhibiting osteoblast differentiation and their activity and might also stimulate osteoclast action

Question 26

How can we reduce the risk of corticosteroid induced osteoporsis?

Answer 26

Doses of oral corticosteroids should be as low as possible AND shortest course of treatment possible Risk increases due to cumulative dose so even intermittent doses increase risk Greatest bone loss due to corticosteroids occurs in first 6-12 months of use so early steps to prevent development of osteoporosis is required Advise patients to take calcium/Vit D supplements

Question 27

Prophylaxis and treatment options for corticosteroid-induced osteoporosis are the same. What does it include?

Answer 27

a bisphosphonate (alendronic acid, risedronate etc) Bisphosphonate if >65yrs and taking oral/high dose inhaled steroids for > 3 mths If <65yrs, refer for DEXA scan and add bisphosphonate if T score is less than -1.5 Calcitriol (Vitamin D3 analogue) Hormone treatment (HRT in women or testosterone in men)

Question 28

What is Paget's disease of bone? and who does it affect?

Answer 28

Chronic bone disorder where areas of bone undergo accelerated bone remodeling due to hyperactivity of osteoblasts and osteoclasts Affects 1 in 10 elderly (3:1 male:female) but only minority are symptomatic

Question 29

Which bones are commonly affected by Paget's bone disease?

Answer 29

commonly pelvis, femur, skull, tibia, vertebrae, clavicle or humerus) enlarge, become structurally abnormal and weaker than normal

Question 30

What are the symptoms of Paget's disease of bone?

Answer 30

1. Bone pain - deep aching pain 2. Bone Enlargement - 3. Deformity 4. Hyercalcaemia (might lead to hypertension, kidney stones and muscle weakness) Increased blood flow through the bone might lead to heart failure. Increased incidence of cancer in affected bone.

Question 31

What are the treatment options for Paget's disease of bone?

Answer 31

1. Bisphosphonates - slows the progression of disease 2. Calcitonin: from 50 units 3 times wekly to 100 units daily by subcutaneous or IM injection 3. NSAIDs for pain

Question 32

Which bispohsphonates can be used for Pagets disease and what is their dose regime?

Answer 32

1. Disodium etidronate, single daily dose by mouth, 5mg/kg for up to 6mths (10mg/kg might be used with caution for up to 3 months). If reactivation occurs, treatment might be repeated after interval of no less than 3 mths. 2. Disodium pamidronate, 30mg once weekly for 6 weeks or 30mg in first week then 60mg every other week. Maximum dose/treatment 360mg. Can be repeated every 6mths. 3. Risedronate sodium, 30mg daily for 2 mths. Can be repeated after at least 2 mths 4. Tiludronic acid, 400mg daily as single dose for 12 weeks. Can be repeated after 6 mths 5. Zoledronic acid, single dose of 5mg IV infusion over 15 minutes. At least 500mg elemental calcium twice daily for 10 days recommended after infusion

Question 33

What is Osteomalacia and Rickets?

Answer 33

Osteomalacia (adults) and Rickets (children) is caused due to a lack of vit D Deficiency of vitamin D leads decreased plasma calcium and phosphate levels, which impacts on bone To increase plasma [Ca2+] levels caused by vitamin D deficiency, PTH levels increase, which leads to depletion of calcium stores in bone (de-mineralisation), which leads to their softening/weakening

Question 34

What are the 2 sources of Vit D?

Answer 34

Vitamin D2 (calcifediol) from diet Vitamin D3 (cholecalcifediol) from sunlight

Question 35

Symptoms of Osteomalacia and Rickets-?

Answer 35

Bone Pain/tenderness Skeletal deformity (bow legs, pigeon chest, spinal deformity (kyphosis, scoliosis) etc) Pathological Fx Dental deformities (delayed formation of teeth, increased cavities) Muscular problems (progressive weakness, decreased muscle tone, cramps) Impaired growth Low calcium leading to numbness of extremities, hand or feet spasms or arrhythmias

Question 36

Causes of Osteomalacia/Rickets? (5)

Answer 36

- Dietary deficiency Particularly children with dark-skin living in northern climes - Age-related deficiency Vitamin D metabolism decreases with age and many patients >80yrs are deficient - Secondary Rickets/osteomalacia Deficiency due to another condition (i.e. malabsorption, liver disease, renal failure) - Vitamin D dependent rickets Rare disorder arising due to lack of enzyme requires for metabolism of Vitamin D - Hypophosphataemic rickets (Vitamin D resistant rickets) Caused by decreased renal resorption of phosphate

Question 37

Treatment of Osteomalacia/Rickets

Answer 37

Calcium and Vitamin D supplements (except hypophosphataemic rickets which is treated with phosphate replacement and calcitriol)