Lecture 27; Metabolic Bone diseases Flashcards
What are the types of bone?
Spongy (trabecular)
Compact (osteon) (cortical bone)
What sort of tissue is bone?
- Connective Tissue
- Dynamic balance between reabsoprtion and deposition
What happens to bone with age?
Menopause / really old (60) age in men results in bone reabsoprtion > Deposition
Give a brief description of bone?
Made of collagen fibres that have become part of a calcified matrix.
When looking macroscopically at bone what can be seen?
Smooth = Bone covered in lining cells derived from osteobasts
Rough = Osteoclast activity / bone remodelling site
How do osteoclasts function?
Release HCl = removes mineral structures
Releases proteolytic enzymes = removes collagenous structures
What do osteoblasts do?
Deposit collagen (osteoid) this becomes mineralised
How often is the entire skeleton replaced?
~10 years
What happens in osteoporosis?
When bone reabsoprtion exceeds bone deposition
- Less bone
- Less robust plates
- If a trabeculae rod is punched through the middle then the remaining partial rods will waste away as they are not load bearing.
What is the actual definition of osteoporosis?
Thinning of bone and destruction of the micro architecture.
What have clinical trials shown regarding trying to manipulate osteoclast activity in osteporosis?
Huge clinical trial that pharmacologically switched off osteoclasts reduced the number of fractures compared to the placebo group
- but no increase in bone density
However the microarchitecture was preserved.
Therefore prevention is better overall than a cure and it is never too late to intervene.
What does age do to bone?
Reduces its density and porosity esp. in women.
Bone, trabeculae thin, eventually reduction in trabeculae numbers.
What does the thinning of bone of age lead to?
Vertebral compression fractures are common as the bone can no longer bear load
This can result in kaposis (curved back) as front of vertebrae break more than back
When looking at bone density across a population what is it important to note?
- Bone density is normally distributed and remains this way with age even though whole population at older age has lower bone density
- Young adults / most people are not osteoporotic
- 50 = hardly any changes
When looking at the bone density on a population scale what is seen at 50-90?
- Ongoing bone loss
- Females by 80, 50% will have bone densities in the osteoporotic range
- Doesnt guarantee fracture but increases risk.
Describe the fracture risk of women in the us;
- Colles fracture risk inc. @50-60 then plateaus
- Spine fracture risk inc. throughout life
- Hip osteoporotic fractures at 75+ rapidly increases in risk
Describe the fracture risk of men in the US
Hip + Spine 80+ fracture risk increases rapidly
What is a hip fracture associated with?
- loss of independence
- 20% mortality
How many women will have an osteoportic fracture by death?
50%
How do we access fracture risk?
Bone densitometry
Clinical Risk Factors
What are the clinical risk features for fractures?
Age
Weight (low weight
What is a major osteoporotic fracture?
Major osteoporotic fracture is hip fracture, clinically evident vertebral fracture, proximal humerus fracture and distal forearm fracture. This is about half of total fractures
Does being physically active prevent fractures?
Mixed evidence
Reality might be that fit people are better are preventing falls.
What do osteocytes monitor and how do they regulate osteoclasts and osteoblasts?
Osteocytes = Have processes to monitor degree of bone loading, then can regulate osteoclasts (RANKL - turns them on) and osteoblasts (Sclerosin-turns them off)
= ALL IN RELATION TO LOAD BEARING
Describe the role of PTH in bone regulation;
PTH is secreted in response to lowered serum Ca levels and increases osteocyte secretion of RANKL
i.e it boosts Ca release form bone to increase sCa
Drugs can be used to inhibit PTH
What does exercise do to osteocytes?
Inhibits Sclerosin release.
Can an increase in dietary Ca increase bone density?
No Ca is homeostatically regulated such that an increase in dietary intake does not correlate with increased bone density.
What happened to bone density when ca supplementation was given?
Yes at 1 year there was a 1.5% increase in bone density but this was the same at 3 years.
Thus doesnt prevent fractures nor decrease the relative risk
What are activated Vit D levels assocated with?
UV exposure
How does PTH regulate vit D activation?
PTH regulates Vit D (1,25 D) activation to increase ca absorption in gut
What happens when people were given Vit D supplementation?
No net benefit of giving vit D supplementation in terms of spinal bone density and no significant changes in fracture risk.
When was vit D supplementation effective?
When supplementing people who were deficient it increased bone density
i.e those people who dont see much sun
What are the non-pharmacal interventions for addressing fracture risk?
Address risk factors for bone loss (smoking, low weight, alcohol)
Address risk factors for falls (hazards, vision, pills)
Exercise
Minimize impact (hip protectors, soft floors)
What are the pharmacological interventions for osteoclasts?
Principle treatment of osteoporosis = bisphosphonates
-ve charge makes it very attracted to bone but only 4% absorption (it poisons the osteoclasts)
However injected into the bone the 50% of it remains in the bone for years as it is not metabolised.
How could we treat osteoporosis?
Ca supplements (not really) Vit D supplements (to those deficient) PTH inhibition Bisphosphonates Exercise (inhibits sclerosin release)
Denosumab (inhibits RANKL)
Cathepsin K inhibitor (inhibits osteoclasts)
Antisclerosis antibodies
What are the conclusions of Ca supplementaiton?
Calcium supplements reduce bone turnover
Effects on fracture remain uncertain
Poor compliance with supplements limits their effectiveness
Calcium supplements increase risk of vascular events, stones, and GI events
What are the implications for Ca homeostasis practise?
Aim for dietary calcium intake of >400 mg/day
Use interventions with proven anti-fracture efficacy if fracture prevention is the goal
Calcium supplements are NOT a safe way to promote bone health
What are some side effects of bisphosphonates?
Common AEs:
Gastrointestinal
APR (acute phase reaction (ill))
IV BPs require satisfactory vitamin D and renal status
Rare AEs: ONJ (osteo necrosis jaw) Sub-trochanteric fractures AF Oesophageal cancer Mortality
What does bisphosphonates do to bone density and fracture risk?
- Rapid decrease in bone reabsorption
- Dose related
- Increase bone density
50% decrease in hip frac. risk
~50% decrease in vert. frac. risk
Not particular 20-30 reduction in no vertebral fracture risks
How do new drugs target RANKL?
RANKL regulates the development of osteoclasts
Denosumab ; Directs ABs against RANKL = decreased osteoclast development
How is TeriparatidePTH used?
Teriparatide PTH regulates osteoblast and osteoclast activity to stimulate bone formation.
What does anti-sclerosin AB do?
Antisclerosin AB
- Increased Bone density (best yet)
- Decreased fractures
