Metabolic Bone Disease Flashcards
Pre-osteoclasts are formed from what type of progenitor cell?
Myeloid progenitor cell
Pre-osteoblasts are formed from what type of progenitor cell?
Mesenchymal progenitor cell
Many Factors Stimulate Osteoblast Expression of RANK Ligand, name 3.
- Osteoblasts appear to be controlling cell of bone turnover
- Vitamin D
- Glucocorticoids
- IL-1, IL-11
- RANK ligand required for activated osteoclast
Where does vitamin D come from?
- Sunshine
* Diet - oily fish, egg yolk
What reaction occurs when UV rays hit the skin?
7DHC (hydrocholesterol) is transformed into a precursor of Vit D which circulates protein bound
What stage of Vit D pathway occurs at the liver?
Conversion of the Vit D precursor to 25(OH)vit D - MAIN STORAGE FORM OF VITAMIN D
What stage of Vit D pathway occurs at the kidney?
Conversion of 25(OH)vit D to 1,25(OH)2 vit D - ACTIVE FORM OF VITAMIN D
What is the main function of vit D?
•Absorption of calcium from the gut
What is another role of vit D?
•Works with parathyroid to move calcium in and out of tissues
What test is used to measure vit D status?
25-hydroxy vit D
What can caused vit D deficiency?
- Kidney and liver disease
- Darker skin - melanocytes competing for the UV radiation and prevent first reaction
- Older people have less 7DHC in skin
Why is regulation of calcium metabolism so important?
To maintain Ca2+ levels in the ECF (at expense of bon calcium)
What does parathyroid hormone do?
Regulates calcium levels (stimulates active vit d production etc.)
What is Paget’s disease?
- LOCALISED disorder of bone turnover
* Increased bone resorption followed by increased bone formation
What are the bone features of Paget’s?
- Disorganised bone
- Bigger
- Less compact
- More vascular
- More susceptible to deformity and fracture
What is the aetiology of Paget’s?
- Relatively common
- Strong genetic component - 15-30% are familial
- Loci of SQSTMI
- Restricted geographic distribution - those of Anglo-Saxon origins
- Environmental trigger - possibility of chronic viral infection within Osteoclast (in youth)
What are the symptoms of Paget’s?
- > 40s
- Bone pain
- Occasionally presents with bone deformity
- excessive heat over affected (Pagetic) bone
- Neurological complications such as deafness
What are the clinical signs of Paget’s?
- Isolated elevation of serum alkaline phosphatase - do not treat on this alone (incidental finding)
- Occasionally the development of osteosarcoma in the affected bone
- Do x-ray then isotope bone scan (for metabolic activity)
What is the treatment of Paget’s?
- No evidence to treat if asymptomatic unless in skull or an areas requiring surgical intervention
- Intravenous bisphosphonate therapy - one-off zoledronic acid infusion, oral option is also available
ZOLEDRONIC ACID
What are rickets and osteomalacia?
- Severe nutritional vit D or calcium deficiency causing insufficient mineralisation
- Vitamin D stimulates the absorption of calcium and phosphate from the gut and calcium and phosphate then become available for bone mineralisation
- Muscle function is also impaired in low vitamin D states
- Rickets - in growing child
- Osteomalacia - in adult when the epiphyseal lines are closed
How does rickets present?
- Stunted growth
- Large forehead
- Odd-shaped legs
- Odd-shaped ribs and breast bones
- Wide joint at elbow, wrist and ankle
- Odd curve to spine or back
- Wide bones
How does osteomalacia present?
- Particularly in elderly - housebound/institutionalised
- Bone pain
- Muscle weakness
- Increased falls risk
- More common in POC
- May see micro-fractures on x-rays
How are rickets and osteomalacia treated?
•Vit D and calcium supplementation
What is osteogenesis imperfecta?
- Genetic disorder of connective tissue characterised by fragile bones from mild trauma and even acts of daily life
- Defect in type 1 collagen
Which of the 28 types of type 1 collagen defect are most common?
1-4
How is type 1 characterised?
Milder form-when child starts to walk and can present in adults
How is type 2 characterised?
Lethal by age 1
How is type 3 characterised?
Progressive deforming with severe bone dysplasia and poor growth
How is type 4 characterised?
Similar to type 1 but more severe
What are other clinical features of osteogenesis imperfecta?
- Growth deficiency
- Defective tooth formation (dentigenesis imperfecta)
- Hearing loss
- BLUE SCLERA
- Scoliosis/Barrel Chest
- Ligamentous laxity - HYPERMOBILTIY (Beighton score)
- Easy bruising
How if OI treated?
- Surgical - treat fractures
- Medical - IV bisphophonates (to prevent fracture)
- Social - educational and social adaptations
- Genetic - genetic counselling for parent and next generation
What is osteoporosis?
- A metabolic bone disease characterised by low bone mass and micro architectural deterioration of bone tissue, leading to enhanced bone fragility and a consequent increase in fracture risk
- A result on DXA bone scanning
What are risk factors for fractures in osteoporosis?
- Age
- BMD - bone mineral density
- Falls
- Bone turnover
What is FRAX?
WHO fracture risk assessment tool
Q fracture is another risk assessment tool for fracture risk which was developed in the UK. What variables does it take into account?
- CV risk
- Falls
- TCA (tricyclic antidepressants)
- Does not have the ability to add BMD
When should a patient be referred for a DXA scan?
- When risk assessment score is greater than 10%
- When they are on oral steroids
- When they have had a previous scan
What does a DXA scan measure?
- BMD
- T-score - compares patient to young adult (only age is not the same)
- Z-score - compares patient to absolute peer group
Who is at risk of osteoporosis?
- I in 2 women over 50 will have an osteoporotic fracture before they die
- I in 5 men over 50 will suffer and osteoporotic fracture
- A 50 year old woman has a lifetime risk of 17% of a hip fracture
- If you suffer 1 vertebral fracture you are 5 times more likely to have another and twice as likely to have hip fracture than if you had no vertebral fractures
What are the endocrine causes of osteoporosis (7)?
- Thyrotoxicosis - hyperthyroidism
- Hyper and Hypoparathyroidim
- Cushings (hypercortisolism)
- Hyperprolactinaemia
- Hypopituitarism
- Low sex hormone levels
What are the rheumatic causes of osteoporosis (3)?
- Rheumatoid arthritis
- Ankylosing Spondylitis
- Polymyalgia Rheumatica
What are the gastroenterological causes of osteoporosis (3)?
- Inflammatory diseases - UC and crohns
- Liver diseases - PBC, CAH, Alcoholic cirrhosis, Viral cirrhosis (Hep C)
- Malabsorption - Cystic Fibrosis, chronic pancreatitis, coeliac disease, whipples disease, short gut syndromes and ischaemic bowel
Which medications cause osteoporosis?
- Steroids
- PPI
- Enzyme inducting antiepileptic medications
- Aromatase inhibitors - post-menopausal women
- GnRH inhibitors
- Warfarin
How does our bone mass change with time?
- Increases to ~30y
- Decreases >40y
- Accelerated loss after menopause
How do we prevent osteoporotic fractures?
- Minimise risk factors
- Ensure good calcium and Vitamin D status
- Falls prevention strategies
- Medications - HRT
What are the side effects of HRT?
- Increased risk of blood clots
- Increased risk of breast cancer with extended use into late 50s/early 60s
- Increased risk of heart disease and stroke - if used after large gap from menopause, would not start if 2-3 years have passed
- Increased risk of prostate cancer in men
- No HRT after 60 years
What are SERMs?
- Selective oEstrogen Receptor Modulators
- Raloxifene - reduce vertebral fracture rate but no effect on other bones
- Reduce breast cancer risk
RALOXIFENE
Negative effects of SERMs?
- Hot flushes if taken close to menopause
- Increased clotting risks
- Lack of protection at hip site
What is the main osteoporosis treatment?
- Bisphosphonates
- Oral Bisphosphonates generally the first line of treatment
- Adequate Renal function required
- Adequate Calcium and Vitamin D status
- Good Dental Health and Hygiene advised - Notify dentist on Bisphosphonates, Encourage regular check ups/well fitting dentures
How do bisphophonates work?
- Bisphosphonate binds to bone mineral
- When the osteoclast breaks down the bone, it takes the bisphosphonate too
- The bisphosphonate poisons the osteoclast
- The osteoclast becomes aware it is damaged at carries out apoptosis
- The bisphophonate and the bone it was secured to are both regurgitated by the osteoclast back onto the bone surface
What are the side effects of bisphosphonates?
- Oesophagitis
- Iritis/uveitis
- Not safe when eGFR<30 mls/min
Extremely rare:
•ONJ - osteonecrosis of the jaw
•Atypical femoral shaft fractures
When is a drug holiday taken from bisphosphonates?
- Drug Holiday for 1-2 years
- Usually after 10 years Oral Bisphosphonates
- 5 year course very safe
What is denosumab?
- Monoclonal antibody against RANKL
- Prevents any osteoclastic stimulation
- Reduces osteoclastic bone resorption
How is denosumab administered?
- Subcutaneous injection every 6 months
* Allows bone to break down
Why is denosumab beneficial?
- Safer in patients with significant renal impairment then bisphosphonates
- Reduce risk of hip fracture
- Use in older individual
What are the side effects of denosumab?
- Allergy/rash
- Symptomatic hypocalcaemia if given when vitamin D depleted
- Rebound fracture risk when treatment stopped
- ?ONJ
- ? Atypical femoral shaft fractures
What is teriparatide?
- Intermittent human parathyroid hormone (IHPT)
* Used in people having vertebral fractures despite other therapies
How is teriparatide administered?
•Daily injection
What are the side effects of teriparatide?
•Injection site irritation •Rarely hypercalcaemia •Allergy •Limited to one course due to osteosarcoma risk - seen in rats COST
