metabolic bone disorders Flashcards
what is osteoporosis?
Is a progressive disease characterised by low bone density and the deterioration of bone microarchitecture which increases fracture risk.
Changes in bone lead to increased fragility and susceptibility to fracture:
~300,000 fragility fractures occur in UK/year.
Most common complication are hip fractures, but also see fractures of wrists, vertebrae and the humerus
50% of hip fractures could be avoided with regular physical activity
~3 million people in the UK have osteoporosis:
Prevalence of osteoporosis increases with age: 5% at 50 years, to >30% at 80 years.
what are the classifications of osteoporosis?
T-score: number of standard deviations (SDs) that a patient’s bone mineral density (BMD) is from the mean BMD of a healthy young woman (as assessed by Dual-energy X-ray absorptiometry [DEXA or DXA):
Normal:
T-score > -1.
Osteopenia (reduced BMD, i.e. bone is weaker):
T-score between -1 and -2.5 SD from mean.
Osteoporosis (greater risk of low-impact fractures):
T-score ≤ -2.5 SD from mean.
Severe osteoporosis:
T-score ≤ -2.5 SD from mean, and a history of previous fracture(s).
osteoporosis symptoms
Osteoporosis often has no symptoms. Usually, first sign is when a person breaks a bone in a minor fall or accident (i.e. a low-impact fracture).
Bone and (normal) ageing
In childhood and adolescence, new bone is quickly formed: Peak in bone density by mid-to-late 20s.
After 3rd decade of life, bone begins to decline at a rate of 0.3% per year.
40 years+, bone is broken down quicker than it is replaced: begin to lose bone mass and density.
Post-menopause: bone loss speeds up: oestrogen production stops.
what is bone mass
Bone mass is the total mass of calcium (in the skeleton) in grams.
what is the risks of osteoporosis ?
Age: Prevalence increases with age: 5% at 50 years, to >30% at 80 years.
Sex 1 in 2 women compared to 1 in 5 men over 50 years of age are expected to break a bone during their lifetime.
Low BMI: People with low BMI (<18.5kg/m2) are at increased fracture risk (i.e. those with eating disorders).
Untreated premature menopause (< age of 45), prolonged amenorrhoea or male hypogonadism:
After onset of menopause, women can lose ~2.5% of bone/year in first 5 years, due to decreased oestrogen production.
Alcohol: People who consume >2 alcoholic drinks/day are associated with higher risk of hip fracture.
Smoking: People who smoke are at 25% increased fracture risk.
Corticosteroid use (oral/long-term).
Conditions associated with prolonged immobility.
Genetics/family history of fractures/osteoporosis.
Other conditions/common comorbidities independently associated with bone loss (include: renal failure, inflammatory bowel or coeliac disease, hyperthyroidism, diabetes, rheumatoid
Other risk factors:
Low vitamin D and calcium levels.
Previous fracture.
Ethnicity (Caucasian have higher risk
Osteoporosis:non-pharmacological advice
modifiable and non-modifiable
Non-modifiable risk factors: previous fragility fracture, family history, untreated early (premature) menopause, etc.
Modifiable risk factors: smoking, alcohol intake, low BMI, etc:
Offer lifestyle advice to all:
Stop smoking.
Reduce alcohol intake.
Advice weight-bearing exercise (may slow bone density decline), balance training, stretching etc (may reduce risk of falls).
Balanced diet: achieve BMI between 20-25.
Maintain adequate dietary levels of calcium (aim for 700mg/day).
If vitamin D low/deficiency, discuss relevant supplements (prevention: 400IU daily; if deficient likely require higher doses).
Osteoporosis: definitionsand initial investigations
Fragility fracture (or low-impact fracture)
Primary prevention
Secondary prevention:
Fragility fracture (or low-impact fracture): fracture caused by injury that is insufficient to fracture a normal bone (e.g. fall from standing height or lower).
Primary prevention: detect those at risk of osteoporosis based on clinical risk factors; determine whether (1) DXA, and then (2) pharmacological treatment is required. Aim: identify modifiable risk factors, reduce future fracture risk.
Secondary prevention: those who have fragility fracture(s) history, and are diagnosed with osteoporosis.
Initial investigations may include:
Assessment of fracture probability (FRAX, Qfracture).
Blood test: check calcium and vitamin D levels; also parathyroid hormone levels.
Scan/imaging: ultrasound, X-ray/DXA.
Consider secondary causes that may require management (on steroid treatment?).
what is the fracture risk assessment tool
FRAX and QFRACTURE
Sign osteoporosis guidelines:fracture risk assessment
primary and secondary
check one note
Osteoporosis: drugs
Anti-resorptives: reduce bone turnover by inhibiting osteoclast activity:
Bisphosphonates: zoledronate (most potent), alendronate, risedronate, ibandronate, etidronate (least potent).
Monoclonal antibodies: denosumab (first biologic) is a human anti-RANKL Ab (stands for: receptor activator of the nuclear factor kappa-B ligand).
Hormonal modulators/therapies: HRT, tibolone (class: oestrogens), raloxifene (latter is an oestrogen agonist/antagonists, EAAs).
Anabolics: stimulate new bone formation by mobilising calcium from skeleton and re-depositing it; anabolics are given intermittently at small doses:
Parathyroid hormone (PTH): teriparatide (is a recombinant human PTH analogue).
Anti-resorptive & anabolic: stimulate osteoblasts and inhibit osteoclasts:
Strontium salts: strontium ranelate (discontinued August 2017: increased risk of venous thromboembolism and cardiovascular events).
what is the mechanism of biphosphate
side effect
avoid with?
BNF: bisphosphonates are adsorbed onto hydroxyapatite crystals in bone, slowing both rate of growth and dissolution, thus, reducing the rate of bone turnover (i.e. anti-resorptive):
Enzyme-resistant analogues of pyrophosphate; inhibit bone resorption.
~50% of dose accumulates at sites of bone mineralisation where they bind to bone minerals in bone matrix.
Remain (months/years) until they are released and ingested by osteoclasts as they resorb the bone.
Thus osteoclasts are exposed to high concentrations:
Simple bisphosphonates accumulate and cause osteoclast apoptosis (etidronate).
Nitrogen-containing bisphosphonates (i.e. alendronic acid) also interfere with attachment of osteoclast to bone (i.e. do not allow osteoclast ruffled border to form).
All bisphosphonates cause gastrointestinal side effects amongst others.
Alendronic acid and risedronate are associated with severe oesophageal reactions, including stricture, ulcers, etc
Patients should not take dose at bedtime and should stay upright for at least 30 mins after taking dose (minimise oesophageal stricture and/or reactions).
Should avoid food before and after dose as food impairs absorption:
Food should be avoided for at least 30 mins (check as time varies dep. on bisphosphonate, i.e. 2 hours before and after for etidronate).
Antacids, calcium salts and iron reduce absorption (see interactions).
Must be avoided in patients with renal impairment.
Osteonecrosis of jaw has been reported following bisphosphonates (most commonly if given IV [second line]; rare with oral dose):
Adequate oral hygiene should be maintained during and after treatment; any remedial dental work should be carried out prior to treatment.
Alendronic acid (alendronate)
drug class
moa
indication and dose
counselling
Drug class: bisphosphonate; nitrogen-containing, second generation.
Mechanism of action: Accumulates in bone and prevents bone resorption by inhibiting osteoclast attachment and survival (i.e. induces apoptosis in actively resorbing osteoclasts).
Indication and dose:
Post-menopausal osteoporosis (10mg daily or 70mg once weekly).
Osteoporosis in men (10mg daily).
Prevention and treatment of corticosteroid-induced osteoporosis in post-menopausal women not taking HRT (10mg daily).
Counselling:
Swallow tablets whole with plenty of water while sitting or standing.
Take on an empty stomach at least 30 mins before breakfast (or another oral medicine).
Patient should stand or sit upright for at least 30 mins after taking tablet.
Denosumab
drug class
moa
indication and dose
counselling
Drug class: biologic, human anti-Receptor Activator of NFkB ligand (RANKL) monoclonal antibody
Mechanism of action: Inhibits osteoclast formation, function, and survival, thereby decreasing bone resorption.
Indication and dose:
Osteoporosis in post-menopausal women, men at risk of fractures and for bone loss associated with long-term systemic glucocorticoid therapy in those at risk of fracture (60 mg every 6 months).
Counselling:
Patients should report any new or unusual thigh, hip, or groin pain during treatment as atypical femoral fractures have occurred in patients receiving denosumab for 2.5 or more years
Osteonecrosis of the jaw is common. Must see dentist before treatment for preventative dentistry. Must report any oral symptoms, maintain good oral hygiene and regular dental check-ups
Serious risk of hypocalcaemia so patients should report muscle spasms, twitches, cramps, numbness or tingling in the fingers, toes, or around the mouth
what are examples of hormone replacement therapy (HRT)
Hormone Replacement Therapy (HRT):
Oestrogens are important in maintenance of bone integrity by inhibiting cytokines that recruit osteoclasts and by opposing the bone resorbing calcium-mobilising role of PTH.
HRT (usually oestrogen and progestogen combo) is no longer first-line treatment of osteoporosis (used to be in 1990s the only treatment!) as it was found to increase the risk of breast cancer and stroke (when used for many years in older women):
However, HRT might be used in women with early/premature natural or surgically-induced menopause (<45-50 years of age) if other therapies are contra-indicated, not tolerated, or if there is no response.
HRT for ‘short-term’ treatment: no longer than 5 years.
Note: bone loss will resume upon stopping HRT.
