Osteoporosis Practical approach to Treatment

Learning Objectives
At the end of this lecture you should be able to:
 Describe the basic process of bone remodelling and how defects in this system leads
to osteoporosis
 Define osteoporosis and how it is diagnosed
 Have an understanding of T scores and how they are used to determine if treatment
is needed
 Describe the common drugs used to treat osteoporosis, the mechanism of drug
action and side effects

Definition of Osteoporosis (WHO)

Systemic skeletal disease of men and women characterised by:
 Low bone mass
 Microarchitectural bone tissue deterioration
 Decreased bone strength
 Increased fracture risk

Fracture Risk
 Distance to fall
 Fat for protection
 Risky behaviours
 Disease

Bone strength & fracture risk

 Bone mass
 Microarchitecture
 Connectivity
 Intrasic property

Structure of bone
 Bone is a dynamic and complex composite structure, ranging in scale from
nanometres at the cellular level, to hundreds of microns at organic matrix and
mineral level to millimetres at the whole bone level
 Every 7 years all the bones in our bodies have been re-modelled

Relative proportions of cortical & trabecular bone at various sites

- Vertebral body (75% trabecular; 25% cortical)
- 1/3 distal radius (75% cortical; 25% trabecular)
- Femoral neck (75% cortical; 25% trabecular)

Bone remodelling
Bone remodelling:
 Localised process of removing bone and laying newly formed bone
 Constant ongoing process
Purpose:
  Maintenance of calcium homeostasis
 Removal and replacement of ageing bone
3 major cell types
 Osteoblasts (they form bone)
 Osteoclasts (resorb bone)
 Osteocyte (maintain bone and contribute to the regulation of ostroblasts and
osteoclasts

Communication between osteoblasts and osteoclast

• Bone remodelling is a finely balanced process
• Osteoblasts secretes:
– RANK-L (required for osteoclast maturation)
– OPG (binds RANK-L)

Wnt signalling
• Wnt: family of 19 glycoproteins
• Wnt signalling: critical role in skeletal development and adult skeletal homeostasis
• Regulated by a family of secreted Wnt antagonists
• Canonical Wnt signalling
– Enhancing osteoblastogenesis and bone formation
– Decreases osteoclastogenesis and bone resorption

Diagnosis (DXA)
- Spine (L1- L4)
- Hip (femoral neck)
- For diagnosis use T-score: Number of SD’s patient’s BMD is above or below the average
BMD of young adult
- To assess the need for further evaluation use Z-score: number of SD’s patient’s BMD is
above or below average for age

Diagnosis (DXA) – WHO criteria

- Normal bone density: T-score > -1
- Osteopenia: T-score between -1 and -2.5
- Osteoporosis: T-score < -2.5
- 1 SD equals a 10% decrease in bone density

When to start treatment - Any one of the following:

- T-score < 2.5
- Fracture

Treatment
Treatment for osteoporosis can be divided into antiresorptive and anabolic
• Antiresorptive (bone formation exceeds resorption):
– Bisphosphonates
– Estrogen
– Selective estrogen receptor modulators
– Denosumab
• Anabolic (increases osteoblast activity):
– Parathyroid hormone (PTH)

Treatment – bisphosphonates (gold standard)

 Include alendronate, risedronate and zoledronic acid
 Antiresorptive: inhibits bone resorption
 Prevent bone loss (first line treatment)
 Incorporated into bone and prevent cytokine release that activates osteoclasts and
osteoblasts apoptosis
 Reduction in both vertebral and hip fracture risk, especially with IV zoledronic acid
 Side effects:
– Gastrointestinal
– Atypical femoral fractures
– Osteonecrosis of the jaw

Treatment - estrogen
 After menopause bone resorption is uncoupled from bone formation (net loss of
bone)
 Trabecular bone is more affected than cortical
 Women who took a standard dose of estrogen had 56 fewer total fractures per
10,000 patients years
 But due to potential harm (increased risk of breast cancer and stroke) it is no longer
indicated for treatment or prevention of postmenopausal osteoporosis

Treatment – selective estrogen receptor modulators

 Lack the steroid structure of estrogen
  But bind to estrogen receptor (agonist or antagonist effects: In terms of bone, it is an
agonist. In breast tissue, it represses and shut down gene transcription)
 Raloxifene is approved for the treatment of osteoporosis
 Raloxifene reduces the risk of vertebral fractures by 40% and also reduced the
incidence of estrogen-positive breast cancer

Treatment – denosumab
 Human IgG2 monoclonal antibody with affinity and specificity for human RANKL
 It binds to RANKL decreasing bone resorption and reducing bone turnover
 Bone mass as well as strength in cortical and trabecular bone increase
 Used to treat osteoporosis
 Given every 6 months (subcutaneous injection)
 Side effects:
– Hypocalcaemia
– Atypical femoral fractures
– Osteonecrosis of the jaw

Treatment – parathyroid hormone (PTH)

 PTH regulates calcium and phosphate in the kidneys as well as bone metabolism
 PTH given intermittently stimulates osteoblasts
 PTH given continuously stimulates osteoclasts
 Teriparatide has shown to increase trabecular and cortical bone turnover by
increasing osteoblast activity of osteoclast activity
 Teriparatide increases BMD in all sites
 In postmenopausal women teriparatide decreased vertebral fractures from 14% to
4%
 Side effects:
– Nausea
– Hypercalcemia
– Dizziness

Exercise
 Physical activity has been shown to increase BMD
 Strength training with non-weight bearing exercise (swimming) has no effect of BMD
 Walking also has no effect of BMD
 For fracture prevention, pull on muscle seems to be the determining factor in
building bone
 In a 10-year follow-up, study of 2 years of back exercises showed an incidence of
vertebral compression fracture of 1.6% in the exercise group and 4.3 % in the control
group (Bone 2002)
 But some research shows no evidence that exercise prevents fractures

Conclusion
 Maintaining bone mass is a high dynamic process involving a number of signalling
pathways that regulate the function specialised bone cells
 When this process is defective this can lead to bone loss and increased risk of
fractures
 A number of drugs with varied mechanism of action have been development
 Exercise (weigh bearing) with drugs may improve bone mass?