Osteoporosis Flashcards
Characteristics of osteogenesis imperfecta
- Autosomal dominant inherited bone condition due to mutations in COL1A1 or COL1A2.
- Mutation in type 1 collagen gene results in decreased production of type 1 collagen
- Brittle bones prone to fracture, blue clera, progressing hearing loss due to abnormal ossicles
Mutations in COL1A1 and COL1A2 lead to what conditions?
Osteogenesis imperfecta
Osteoporosis
Ehlers Danlos Syndrome
What happens in mutations for WNT1 and LRP5
WNT: signals OSTEOBLASTS TO MAKE MORE BONE!
Mutations in WNT1 impair bone formation
- Heterozygous missense mutation in WNT1 = severe, early onset inherited osteoporosis
- Homozygous nonsense mutation lead to severe form of osteogenesis imperfecta.
Note: LRP5 is a coreceptor of WNT so mutations in LRP5 also cause OP
- Severe inactivating mutations: osteoporosis pseudoglioma
- Mild inactivating mutations: osteopenia
- Activating mutations: high bone mass
What are the stimulators and inhibitors of osteoclast generation.
Stimulators of osteoclast generation: calcitriol, PTH, TNF-a, prostaglandin E2, IL1, 6, 11, 17
Inhibitors of osteoclast generation: IL4,12,13,17
IFN gamma
What does RANKL activate?
- Binds to RANK receptor on osteoclast precursor and mature osteoclast cells and activates osteoclasts
- Production stimulated by PTH, Vitamin D
Effect of oestrogen and progesterone on bone?
- In late puberty, estrogen inhibits bone resorption, promotes osteoclast apoptosis but prevents osteoblast apoptosis
- Progesterone has an anabolic effect on bone, increasing osteoblastic activity and competing for osteoblastic receptors of the glucocorticoids
Which cytokines have osteoclastic activity vs osteoblastic activity
Osteoclastic activity
- IL-1 stimulate osteoclast differentiation
- Prostaglandin E2
- IL6 - role in myeloma
Osteoblastic activity
- TGFB
- IL 10
- insulin favours ostoeblastic activity
What are the causes of osteoporosis?
Primary OP (most common form)
- Type 1 post-menopausal as decreased estrogen leads to increased bone resoprtion
Type II senile OP, gradual loss of bone mass as patients age
Secondary OP
- Drug induced: steroids, anticonvulsants (phenytoin, carbamazepine), thyroxine, PPI, aromatase inhibitors (letrzole), immunosuppressants (cyclosporin, tacrolimus)
- MM
- Excessive alcohol use
- Immobilisation
- Endocrine: hypercortislism, hypogonadism, hyperthyroid, hyperparathyroid, renal disease, addisons, diabetes
- Lifestyle: smoking, alcohol. immobilisation
- GI: ceoliac, malabsoprtion, IBD
- Genetics: CF, osteogenesis imperfecta, Marfans, Ehler Danlos
- Post transplant bone loss is the most rapid in 3-6 months after transplantation, medication induced
Clinical features of OP
- Mostly asymptomatic
- Fragility fracture
- Common locations: vertebral > femoral neck > colles (distal radius) > long bones like humerus
- > 25% loss of height = compression fracture
Investigations for OP
- DEXA scan: measure lumbar spine and femoral neck.
Non dominant radius of forearm if hyperparathyroidism, obese, spine (osteophytes, vascular calcifications) or hip cannot be measured - Women > 65, Men > 70
- T score difference in SD between patient’s BD and BMD of a young adult reference mass for post menopausal women
OP: T score < 2.5SD
Osteopenia: T score between -1 and -2.5 SD
Normal: >-1 SD
OP is diagnosed if T score < -2.5SD OR fragility fracture present regardless of BMD OR osteopenia with high falls fractur risk
- Z score: compares a person’s bone density to what is expected in someone of equivalent age, sex, and weight matched controls
- Detects secondary causes of osteoporosis rather than occurring due to age, eg: steroids, malignancy, multiple myeloma
Worsening z score also correlates with increased fracture risk - use for premenopausal women and younger men (<50yo)
What are the effects of weight on BMD
- High BMI often associated with higher BMD
- Lower BMI often associated with lower BMD - mechanical effects on weight bearing bone stimulating osteoblasts
- Classically obesity suggested to be protective for fracture but some sites eg: upper arm increased+
In Australia, PBS subsidized meds available for OP if:
- minimal trauma fracture regardless of BMD
- 70 years or older with osteoporosis at hip or spine
- T score < -1.5 on 7.5 mg prednisolone equivalent for 3 months
What z score do you need to start investigating and what investigations.
- Determines need for investigations eg z < -2.0
- Initial Investigations:
FBE, U&Es, serum protein electrophoresis, serum free light chains/urine Bence Jones protein, LFTs, Ca, PO4, 25(0H) vitamin D, PTH, TSH, ESR/CRP and testosterone (in males only). - Further Investigations as needed:
Coeliac screen, E2, LH and FSH in women if premature menopause is suspected, hypercortisolism screen, 24-hour urine calcium and creatinine excretion.
?Role of bone turnover markers eg: C-terminal telopeptide of type 1 collagen (CTx), CrosslapS
What calculator can be used to assess fracture risk?
Fracture risk calculator (FRAX): 10 year probability of hip fracture and major osteoporotic fracture (hip/clinical spine, proximal humerus, foream) for untreated patients between 40-90yo
- Treatment should be considered if high 10 year risk of osteoporotic fracture is > 20% or hip fracture > 3%.
- So improves fracture prediction but relies on FN BMD
Trabecular bone score
Characteristics of osteomalacia.
DEFICIENCY OF MINERALISED BONE
Chronically LOW VIT D and hypophosphatemia can cause osteomalacia in adults and rickets in children. CLINICAL FEATURES - Bone pain - Fractures (usually stress type) - Proximal myopathy (→ waddling gait)
Condition characterised by impaired mineralisation and disrupted microarchitecture at the growth place. Can be caused by vitamin D deficiency (most common), proximal tubular acidosis, hypophosphatemia and low calcium intake. Manifestations include bone pain, pathological fractures and myopathy
Rickets can present as widening of the wrist joints due to an excess of non-mineralized osteoid at the growth plate
Osteomalacia describes softening of the bones secondary to low vitamin D levels that in turn lead to decreased bone mineral content. If this occurs in growing children it is referred to as rickets, with the term osteomalacia preferred for adults.
Causes vitamin D deficiency malabsorption lack of sunlight diet chronic kidney disease drug induced e.g. anticonvulsants inherited: hypophosphatemic rickets (previously called vitamin D-resistant rickets) liver disease: e.g. cirrhosis
Features bone pain bone/muscle tenderness fractures: especially femoral neck proximal myopathy: may lead to a waddling gait
Investigation bloods low vitamin D levels low calcium, phosphate (in around 30%) HIGH ALP x-ray translucent bands (Looser's zones or pseudofractures)
Treatment
vitamin D supplmentation
a loading dose is often needed initially
calcium supplementation if dietary calcium is inadequate
What vit D level do you aim for if on anti-resorptive therapy for OP
Vit D > 50
What is the role of PTH in bone
What is the role of calcitonin
- If given intermittently: bone formation by inhibiting osteoblast apoptosis, also inhibits collagen synthesis at high concentrations
- If given continuously: bone resorption
- Stimulates osteoclastic gene expression and production if IL6, IGF1, prostaglandins
Calcitonin: transiently inhibits osteoclasts
What medications are used for OP?
- Anti-resorptives: inhibit osteoclasts, reduce bone resorption and reduce born formation - reduce the remodelling rate and reduce osteoclast mediated resorption and thus reduced bone formation. Overall there is reduction in the amount of bone lost.
Examples: bisphosphonate (inhibit osteoclast activity), denosumab (RANK ligand inhibitor, prevents differentiation, maturation and activity of osteoclasts), SERMS (eg: raloxifene) - used in post menopausal. HRT safe in women <60yo.
Anabolic Agents: promote osteoblasts to increase bone formation
Used where there is high fracture risk
- Recent clinical/verebtal fracture
- Multiple prior fractures
- Low bone mass
- Treatment failure
Teriparatide and romosozumab listed for patients meeting 3/2/1 rule.
- Teriparatide (PTH analogue): increase bone resorption + formation, subcut daily injection for 18 months, activates osteoblast and stimulate bone formation and because it affects bone remodelling it also affects bone resorption.
- Romosozumab (monoclonal antibody against sclerostin): reduced bone resorption, increased bone formation. Acts on bone modelling, no resorption phase and bone resorption is reduce and bone formation is increased
VIt D: increase absorption of calcium and phosphate from the gastrointestinal tract
MOA of bisphosphonates + SE
- Bisphosphonates: e.g., alendronate, risedronate
- Mechanism of action: inhibition of osteoclasts → reduced bone resorption
Side Effects
- Hypocalcemia - need to be vitamin D and calcium replete before starting
- Esophagitis, esophageal cancer
- Osteonecrosis of the jaw (zoledronic acid > pamidronate)
- AF, uveitis
- Atypical femoral fracture (rare)
-
Bisphosphonates should be taken in the morning and evening at least 30 minutes before meals, with plenty of water, and the patient should maintain an upright position for at least 30 minutes following intake to prevent esophagitis.
- Not recommended in severe kidney disease
- Slow bone loss, improve BMD and reduce fracture rates
- increased risk of atypical stress fractures of the proximal femoral shaft in patients taking alendronate
- acute phase response: fever, myalgia and arthralgia may occur following administration
- hypocalcaemia: due to reduced calcium efflux from bone. Usually clinically unimportant
- Alendronate has been approved for treatment of men with osteoporosis as well as treatment of both women and men with glucocorticoid induced
osteoporosis. Alendronate has been shown to reduce
the incidence of spine and hip fractures by approximately SO%
over 3 years in patients with previous fractures. - Risedronate reduces the incidence of vertebral fracture by approximately
45% and nonvertebral fractures by one-third over 3 years. - Zoledronic acid has
been approved for secondary prevention of fractures in
patients who have had recent low-trauma hip fracture.
Reduce vertebral fractures by 70%, hip fractures by 41%
What medications can be used if patients don’t respond to bisphosphonates?
Teriparatide: parathyroid hormone analog
- Mechanism of action: Stimulates bone formation by inhibiting osteoblast apoptosis (also inhibits collagen synthesis at high concentrations). Also increase bone resorption. Net result is increased bone mass
- Mainly used for the treatment of osteoporosis and as an alternative for severe osteoporosis (T-score ≤ -3.5) or for patients with contraindications to bisphosphonates [17]
- Administered in a pulsatile fashion
- Side Effects
Hypercalcemia (usually transitory)
Calciphylaxis
Increased risk of osteosarcoma in patients with: Paget disease of the bone (or an unexplained elevation of alkaline phosphatase) or prior cancers or radiation therapy
- Reduces risk of vertebral and other fractures, but not hip fractures.
Alendronate blunts teliparatide effect.
Raloxifene: (selective estrogen receptor modulator, SERM): used in post menopausal patients
MOA: Inhibits osteoclast bone resorption and promoting of osteoclast apoptosis
SE: hot flushes, VTE
Not given in pre-menopausal women due to risk of ovarian stimulation, not effective in males
Only reduces risk of vertebral fractures
Denosumab (monoclonal antibody against RANKL)
- Mechanism of action: prevents RANKL from activating osteoclasts via the RANK receptor.
- Indicated in patients with impaired renal function or in whom bisphosphonates therapy failed
- Adherence to 6-monthly dosing regimen is essential to prevent loss of bone mineral density between doses
- Therapy must be either indefinite, or replaced by a bisphosphonate if stopped
- Withdrawal or interruption of treatment (dose delayed by more than 4 weeks) is associated with an increased risk of multiple spontaneous vertebral fracture
- Can cause hypocalcaemia (particularly in patients with impaired kidney function [creatinine clearance 30 mL/min or less], vitamin D deficiency or a malabsorption disorder
- Administration of denosumab is safe provided that:
serum 25-hydroxyvitamin D concentration is greater than 50 nanomol/L
serum total calcium concentration corrected for albumin is in the normal range (2.10 to 2.60 mmol/L)
creatinine clearance is greater than 30 mL/min.
- Calcitonin
Rarely used today due to the availability of more effective alternatives
Indicated in postmenopausal osteoporosis
Hormonal Therapy
- Estrogen: for women with intolerance to first-line or second-line treatment options or with persistent menopausal symptoms
- Usually in combination with progestin
- Contraindications: breast cancer, coronary heart disease, deep vein thrombosis
- Testosterone: for men with hypogonadism
- Calcitonin inhibits osteoclast activity and reduces renal and gastrointestinal resorption of calcium.
Strontium: activates osteoblasts and stimulates osteoclasts to promote osteoprotegerin which inhibits RANK-RANKL binding
What is the function of sclerostin and what is the function of romosozumab?
- Sclerostin is a negative regulator of bone formation. Inhibits WNT signalling (WNT signals osteoblasts to make more bone) and downregulate the stimulus for osteoblast development and function.
- Romosozumab is a monoclonal antibody (IgG2) that inhibits sclerostin.
Allows signalling down the WNT pathway leading to both bone formation and decrease in bone resorption (prevents osteoclast differentiation)
What are the effects of romosozumab?
In postmenopasual women with OP, Romo significantly increased BMD at the lumbar spine, hip and femoral neck. Reduces vertebral, hip and non vertebral fractures
Must be followed up by an antiresorptive where effects are reversible when ceased.
SE: increased risk of MI/stroke
What are the best medications for OP?
Least effective to most effective in improving BMD at lumbar and hip.
- Aledronate
- Zoledronic acid
- Denosumab
- Teriparatide
- Denosumab + Teriparatide
- Romosozumab and then alendronate
- Romosozumab and then denosumab
Indication for romosozumab
Used in treatment failure
- T score < -3 SD
- > 2 minimal trauma fractures
> 1 symptomatic new fracture after 12 months of continuous therapy with antiresorptive
What are born turnover markers
Monitor response to therapy
P1NP: synthesised by osteoblasts when procollagen is cleated by type 1 collage
CTX: synthesised by osteoclasts when type 1 collage is cleaved during resoprtion.
Characteristics of paget disease
Associated with increased bone remodelling - increase in both osteoclast + osteoblast activity leading to formation of disorganised (woven) bone which is weak and replaces the normal lamellar bone. Resulting in overgrowth of bone at single (monostatic) or multiple (polostotic) sites.
The skull, spine/pelvis, and long bones of the lower extremities are most commonly affected.
Where the paget disease normally affect and what are the clinical features?
Investigation findings
the stereotypical presentation is an older male with bone pain and an isolated raised ALP
A condition where uncontrollable bone turnover occurs, most likely due to a disorder of the osteoclast.
Bones of the axial skeleton
are most frequently affected, namely the pelvis (70%),femur (55%), lumbar spine (53%), skull (42%), and tibia (30%).
The skull, spine/pelvis, and long bones of the lower extremities are most commonly affected.
Bone pain
Pathological fractures - chalk stick fractures of long bone
Bone deformities, bowing of legs, saber shin
Skull enlargement - increasing hat size
Impaired hearing - due to ankylosis of the ossicles
High ALP, bone turnover markers
Normal CMP
Isolated ALP —> bone scan
- other markers of bone turnover include: procollagen type I N-terminal propeptide (PINP), serum C-telopeptide (CTx), urinary N-telopeptide (NTx), and serum and urinary hydroxyproline
Treatment of Paget disease
1st line: bisphosphonates as they suppress rapid born turnover
2nd line: calcitonin
Complications of paget’s
OA
Malignant degeneration into osteosarcoma (rare)
High output heart failure due to formation of ateriovenous shunts within the bone which leads to an increased overall blood flow
Complications deafness (cranial nerve entrapment) bone sarcoma (1% if affected for > 10 years) fractures skull thickening high-output cardiac failure
What is osteomalacia?
Disorder of decreased mineralisation of newly formed osteoid at site of bone turnover, caused by hypocalcaemia and hypophosphataemia associated with Vitamin D deficiency.
