Disorders of Bone Health Including Osteoporosis

Question 1

What is Osteoporosis?

Answer 1

Progressive systemic skeletal disease characterised by low bone mass and micro-architectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture

Question 2

Bone physiology?

Answer 2

Bone undergoes a continual remodelling cycle at distinct sites called bone remodelling units. This contributes to calcium homeostasis and also to skeletal repair.

~10% of the adult skeleton is remodelled each year

Question 3

Three cell types contribute to bone homeostasis

Answer 3

• osteoblasts are bone forming cells
• osteoclasts are responsible for bone breakdown/resorption
• osteocytes are mature bone cells within the bone matrix, help to maintain bone and act as mechanosensors

With increasing age, there is increased osteocalst activity which is not matched by increased osteoblast activity. This imbalance of bone breakdown and formation leads to osteoporosis.

Question 4

Bone Microarchitecture Influences Bone Strength. how does this associate with age?

Answer 4

Question 5

What are the factors for Peak bone mass vs Bone loss?

Answer 5

Peak Bone Mass:
Genetics (70-80 %)
Body Weight
Sex hormones
Diet
Exercise

Bone Loss:
Sex hormone deficiency
Body weight
Genetics
Diet
Immobility
Diseases ( eg rheumatoid arthritis)
Drugs especially glucocorticoids, aromatase inhibitors

Question 6

Who is at risk and who to treat?

Answer 6

Target therapeutic intervention
at those at high risk of low impact fracture. Assess fracture risk.

Question 7

How to use risk factor assessment?

Answer 7

Who to assess?

• Anyone >age 50 years with risk factors
• Anyone under 50 years with very strong clinical risk factors eg
  -Early menopause
  -Glucocorticoids

When to refer for DXA?
* Anyone with a 10 year risk assessment for any OP fracture of at least 10%

Question 8

Clinical Risk Factors for Fragility Fracture?

Answer 8

Non-modifiable
Age
Gender
Ethnicity
Previous fracture
Family history
Menopause ≤ 45 years
co-existing disease

Modifiable:
BMD
Alcohol
Weight
Smoking
Physical inactivity
Pharmacological risk factors

Question 9

SIGN Guideline 142?

Answer 9

Guideline based around fracture risk and not bone mineral density

• Address risk factors for fracture
  Non-modifiable
  Modifiable
• Assessment of fracture risk
  Which tool to use

Question 10

Fracture Risk Calculators?

Answer 10

• Allow calculation of absolute risk by incorporating additional risk factors rather than just BMD.
• Prediction of 10 year fracture risk of major osteoporotic fracture or hip fracture
• Some limitations

Question 11

Who to refer for DEXA?

Answer 11

Patients over 50 y with low trauma fracture – often identified through Fracture Liaison Service (FLS) – “Stop at One”

Patients at increased risk of fracture based on risk factors – calculated using risk assessment tool eg FRAX or Qfracture. > 10% risk of fracture over 10 years

Question 12

Assessing Bone Density

Answer 12

BMD predicts fracture risk independently of other risk factors

DXA scans (Dual Energy Xray Absorptiometry) are most widely used method of measuring BMD

Normal : BMD within 1 SD of the young adult reference mean

Osteopenia (low bone mass) :BMD >1 SD below the young adult mean but <2.5 SD below this value

Osteoporosis : BMD ≥ 2.5 SD below the young adult mean

Severe osteoporosis : BMD ≥2.5 SD below the young adult mean with fragility fracture

If younger than 20 y, only Z score reported

Question 13

The lower the BMD the higher bone fx

Answer 13

T

Question 14

Drug treatments?

Answer 14

Calcium & vitamin D supplementation
Bisphosphonates
Denosumab
Teriparatide
Romosozumab
HRT
Testosterone

Question 15

Diet Mx?

Answer 15

Have high calcium diet
RNI 700mg calcium (2-3 portions from milk and dairy foods group)
Postmenopausal women aim dietary intake 1000 mg calcium per day to reduce fracture risk (3-4 portion calcium rich foods)
Non-dairy sources include
bread and cereals (fortified)
fish with bones, nuts,
green vegetables, beans

Question 16

Bisphosphonates therapy?

Answer 16

analogues of pyrophosphate that adsorb onto bone within the matrix

ingested by osteoclasts leading to cell death thereby inhibiting bone resorption

filling of resorption sites by new bone increases BMD by 5-8%

Anti-resorptive agents – alendronate and risedronate

for 5 years (10 years for vertebral fx)
Long term- consider “bone holday” for it

Prevent bone loss at all sites vulnerable to osteoporosis

Reduce risk of hip and spine fracture

Question 17

Zoledronic Acid?

Answer 17

Once yearly IV infusion for 3 years

1 in 3 acute phase reaction with first infusion – paracetamol

~ 70% reduction in vertebral fracture, 40% reduction in hip fracture

Consider if intolerant of oral bisphosphonates or unable to comply with dosing regime

Question 18

Denosumab

Answer 18

Denosumab – fully human monoclonal antibody that targets and binds with high affinity and specificity to RANKL (receptor activator of nuclear factor-kB ligand)

This prevents activation of its receptor, RANK, inhibiting development and activity of osteoclasts, decreasing bone resorption and increasing bone density.

Subcutaneous injection 6 monthly

Compared to placebo, reduces risk of vertebral fracture by ~68%, hip fracture by 40% and non-vertebral fracture by ~20%.

Adverse effects: Hypocalcaemia, eczema, cellulitis

No contraindication in severe renal impairment

Question 19

Denosumab

Answer 19

Denosumab – fully human monoclonal antibody that targets and binds with high affinity and specificity to RANKL (receptor activator of nuclear factor-kB ligand)

This prevents activation of its receptor, RANK, inhibiting development and activity of osteoclasts, decreasing bone resorption and increasing bone density.

Subcutaneous injection 6 monthly

Compared to placebo, reduces risk of vertebral fracture by ~68%, hip fracture by 40% and non-vertebral fracture by ~20%.

Adverse effects: Hypocalcaemia, eczema, cellulitis

No contraindication in severe renal impairment

Question 20

Teriparatide

Answer 20

Recombinant parathyroid hormone (1-34)

Stimulates bone growth rather than reducing bone loss – anabolic agent

Consider if severe osteoporosis - particularly if high risk of vertebral fracture

Question 21

Romosozumab

Answer 21

Wnt signaling pathway plays a role in skeletal homeostais and bone remodelling. Sclerostin is an inhibitor of this pathway
Romosozumab is a humanised monoclonal antibody that binds to sclerostin, preventing it from having this inhibitory effect
Acts as an anabolic agent, increasing bone mineral density, also reduces bone resorption
Given as a monthly injection for 12 months
Contraindication - previous MI/CVA

Question 22

When to treat?

Answer 22

Majority of patients, consider treatment with antiresorptive therapy when T score </= - 2.5

If ongoing steroid requirement >/=7.5mg prednisolone for 3 months or more or if there is a prevalent vertebral fracture, consider treatment with T score < -1.5 as fracture risk increased

Question 23

what is the impact of steroid (corticosteroids) on bones?

Answer 23

Direct: Reduction of osteoblast activity and lifespan
Suppression of replication of osteoblast precursors
Reduction in calcium absorption

Indirect: Inhibition of gonadal and adrenal steroid production

Question 24

Paget’s disease of bone?

Answer 24

Uncertain aetiology: may be a viral/environmental/biomechanical trigger in genetically predisposed individual

Affects long bones, pelvis, lumbar spine and skull predominantly

Rare < 40 y; incidence increases with age

Presents with bone pain, deformity, deafness, compression neuropathies
Osteosarcoma is a rare complication
May be incidental finding on X-ray (XR) or isolated high alkaline phosphatase
Diagnose on XR; isotope bone scan shows the distribution of disease; biochemistry shows raised alkaline phosphatase with otherwise normal LFTs
Treat with bisphosphonates if pain not responding to analgesia

Abnormal osteoclastic activity followed by increased osteoblastic activity
Abnormal bone structure with reduced strength and increased fracture risk
May be single site (monostotic) or multiple sites (polyostotic)

Question 25

Osteogenesis Imperfecta?

Answer 25

Rare group of genetic disorders mainly affecting bone

Most are secondary to mutations of type 1 collagen genes (COL1A1, COL1A2)

Most are autosomal dominant inheritance

May be associated with blue sclerae and dentinogenesis imperfecta

The more severe forms present with fractures in childhood
The mild form may not present until adulthood
There is no cure –only fracture fixation, surgery to correct deformities, bisphosphonates
Important differential diagnosis for suspected non-accidental injury