Osteoporosis
Description
- Skeletal disorder of reduced bone mass and disrupted microarchitecture -> reduced strength -> fragility fracture
- Fragility (minimal-trauma) fracture = fracture from a fall from standing height or less
- *A fragility fracture is osteoporosis regardless of the T-score*
- Silent until it fractures - there are no symptoms of low bone density itself
Common fracture sites
- Vertebral (most are asymptomatic and found incidentally), hip (neck of femur), distal radius (Colles), humerus, pelvis, ribs
- *Skull, hands, feet, cervical spine - NOT osteoporotic. Fracture here means pathological or traumatic*
Epidemiology
- ~1 in 2 women and ~1 in 3 men over 50 will have a minimal-trauma fracture
- ~1.2 million Australians with osteoporosis; ~6.3 million with osteopenia
- ~165,000 minimal-trauma fractures/yr in Australia
- Hip fracture: ~25% mortality at 12 months, ~50% never regain prior function
- Massively under-treated: <20% of patients with a fragility fracture are investigated or treated
Aetiopathogenesis
Bone biology
- Peak bone mass ~25-30 yr, determined ~60-80% genetically
- Remodelling: osteoclast resorption then osteoblast formation, coupled by RANKL/OPG
- RANKL (osteoblast) binds RANK (osteoclast precursor) -> osteoclast maturation
- OPG is the decoy receptor that blocks RANKL - denosumab is a synthetic OPG equivalent
- Sclerostin (osteocyte) inhibits Wnt -> switches off osteoblasts - romosozumab blocks sclerostin
Primary osteoporosis
- Type I (postmenopausal) - oestrogen deficiency
- inc RANKL, dec OPG -> inc osteoclast activation -> accelerated resorption
- Trabecular bone predominantly -> vertebral and distal radius fracture
- Fastest loss in the first 5-10 years after menopause
- Type II (senile/age-related) - both sexes, >70
- dec osteoblast function, secondary hyperparathyroidism, vitamin D deficiency
- Cortical and trabecular -> hip fracture
Secondary causes
- Endocrine
- Glucocorticoid excess (exogenous or Cushing) - the commonest secondary cause
- Hypogonadism - early menopause, anorexia/athletic amenorrhoea, androgen deprivation therapy, aromatase inhibitors
- Hyperparathyroidism, hyperthyroidism (incl. over-replacement), diabetes (both types), acromegaly
- Non-endocrine
- CKD (CKD-MBD), chronic liver disease
- Coeliac disease, IBD, bariatric surgery, pancreatic insufficiency - malabsorption
- Rheumatoid arthritis, ankylosing spondylitis, SLE
- Myeloma, mastocytosis, haemochromatosis, thalassaemia
- COPD, transplantation, immobility, HIV
- Nutritional
- Vitamin D deficiency (bone pain + proximal myopathy), low dietary calcium, low body weight, excess alcohol, eating disorder
- Drugs
- Glucocorticoids (>=7.5 mg prednisolone for >=3 months), aromatase inhibitors, androgen deprivation
- Anticonvulsants (phenytoin, carbamazepine), heparin, excess thyroxine, PPIs, SSRIs, chemotherapy, ciclosporin/tacrolimus, thiazolidinediones, medroxyprogesterone
Glucocorticoid-induced osteoporosis - a distinct pathophysiology
- Bone loss is fastest in the FIRST 3-6 MONTHS
- Direct osteoblast apoptosis + prolonged osteoclast survival + dec intestinal calcium absorption + hypogonadism
- *Fractures occur at a HIGHER T-score than in postmenopausal osteoporosis - do not wait for -2.5*
Diagnosis
WHO diagnostic categories (DXA T-score)
| T-score | |
|---|---|
| >= -1.0 | Normal |
| -1.0 to -2.5 | Osteopenia (low bone mass) |
| <= -2.5 | Osteoporosis |
| <= -2.5 with fracture | Established/severe osteoporosis |
- T-score = SDs from young adult mean - the number that defines disease and drives PBS eligibility
- Z-score = SDs from age-matched mean - use in premenopausal women, men <50 and children; Z <= -2.0 = "below expected for age" and mandates a secondary-cause search
- Report the LOWEST of lumbar spine, femoral neck and total hip
DXA pitfalls
- Falsely HIGH lumbar spine: degenerative OA, syndesmophytes, vertebral fracture, aortic calcification, prior instrumentation
- In this situation trust the hip
- Requires the same machine for serial comparison
- Vertebral fracture assessment (VFA) or lateral spine X-ray adds occult fractures
Who to scan
- All women and men aged >=70
- Any minimal-trauma fracture after age 50
- Glucocorticoids >=7.5 mg prednisolone for >=3 months
- Any condition or drug from the secondary-cause list
- Premature menopause (<45), hypogonadism
Investigations - screen for a secondary cause in everyone
- Calcium, phosphate, ALP, albumin
- 25-OH vitamin D, PTH
- UEC/eGFR, LFT, TSH
- FBE, ESR
- Serum and urine protein electrophoresis + free light chains (myeloma)
- Testosterone in men
- Coeliac serology (tissue transglutaminase)
- 24-h urinary calcium (hypercalciuria, malabsorption)
- Lateral thoracolumbar spine X-ray for vertebral fracture if height loss >3 cm, kyphosis or back pain
Clinical assessment
- Fragility fracture history - vertebral, hip, wrist, rib, humerus; and parental hip fracture
- Falls history and falls risk factors - the other half of fracture risk
- Height loss and kyphosis
- Examination: bony tenderness, proximal myopathy (vitamin D), signs of CKD, thyroid disease, malnutrition, Cushing syndrome
Absolute fracture risk tools
- FRAX or Garvan - 10-year probability of major osteoporotic and hip fracture
- FRAX underestimates risk with recent fracture, multiple fractures, high glucocorticoid dose, or falls - adjust upward clinically
Management
Axis: risk stratification to decide WHO to treat, then therapy tier for WITH WHAT. Build bone then lock it in.**
Who to treat
- A. Any minimal-trauma fracture after age 50 - treat regardless of T-score
- B. T-score <= -2.5 on DXA
- C. High absolute fracture risk
- 10-yr major osteoporotic fracture risk >=20%, OR
- 10-yr hip fracture risk >=3%
- D. Glucocorticoid >=7.5 mg prednisolone/day expected for >=3 months - treat at a T-score of -1.5, not -2.5
Universal measures - every patient
- Calcium 1000-1300 mg/day, from diet where possible (supplements only if intake is inadequate)
- Vitamin D - target 25-OH vitamin D >50 nmol/L; 1000-2000 IU/day typical
- Weight-bearing and resistance exercise + balance training - the balance component prevents falls, which prevents fractures
- Falls prevention: medication review (sedatives, antihypertensives), vision, footwear, home hazards, postural hypotension
- Smoking cessation, alcohol <=2 standard drinks/day
- Minimise glucocorticoid dose and duration
Antiresorptive - "lock it in"
| Agent | Dose | Notes |
|---|---|---|
| Alendronate | 70 mg weekly oral | First-line. Upright 30 min, fasting |
| Risedronate | 35 mg weekly oral | |
| Zoledronic acid | 5 mg IV yearly | Best adherence. Reduces all-cause mortality after hip fracture (HORIZON). Acute phase reaction ~30% on first dose - pre-treat with paracetamol |
| Denosumab | 60 mg SC 6-monthly | RANKL monoclonal. Safe in CKD (no renal dose adjustment) - the agent of choice if eGFR <30. Most-prescribed in Australia |
| Raloxifene | SERM | Vertebral fracture only; dec breast cancer, inc VTE and hot flushes |
| MHT | For women with menopausal symptoms in early menopause |
- Check and correct vitamin D and calcium BEFORE any potent antiresorptive - severe hypocalcaemia otherwise, especially with zoledronic acid, denosumab and CKD
- Avoid bisphosphonates if eGFR <30-35
Anabolic - "build bone"
- Romosozumab (anti-sclerostin, 210 mg SC monthly for 12 months)
- Dual action: inc bone formation AND dec resorption
- Now available first-line on the PBS for severe osteoporosis: T-score <= -2.5 plus either a hip or symptomatic vertebral fracture in the last 24 months, or >=2 fractures including one new symptomatic fracture in the last 24 months
- *Contraindicated within 12 months of myocardial infarction or stroke* (ARCH cardiovascular imbalance)
- 12 months maximum, once in a lifetime
- Teriparatide (PTH 1-34, 20 microg SC daily)
- Anabolic when given intermittently (continuous PTH resorbs bone - the paradox)
- Superior to risedronate for vertebral fracture in glucocorticoid-induced and severe osteoporosis (VERO)
- PBS: very severe disease, T-score <= -3.0, >=2 fractures with one new fracture after >=12 months of antiresorptive therapy
- Lifetime maximum 18-24 months
Sequencing - the rule that is examined
- *Anabolic FIRST, then antiresorptive - build bone then lock it in*
- Anabolic gains are entirely lost within ~12 months unless followed by an antiresorptive
- Anabolic given AFTER a bisphosphonate produces a blunted response - the sequence is not interchangeable
- Never stop denosumab without transitioning to a bisphosphonate
- *Rebound: rapid bone loss and multiple spontaneous vertebral fractures within 6-18 months of a missed dose*
- Denosumab has no drug holiday - the effect is fully reversible
Drug holiday - bisphosphonates only
- Consider after 5 years oral or 3 years IV if:
- No fracture on treatment, AND
- T-score improved to > -2.5, AND
- Low falls risk
- Continue (no holiday) if: fracture on treatment, T-score still <= -2.5, ongoing glucocorticoid, high falls risk
- Reassess with DXA and clinical review every 2-3 years during the holiday
- Bisphosphonates persist in bone for years; denosumab, teriparatide and romosozumab do not
Monitoring
- DXA at 1-2 years after starting, then 2-yearly
- Calcium, vitamin D, renal function
- A stable or improved BMD is treatment success - waiting for a rise is the wrong endpoint
- Reassess adherence at every visit (<50% still on oral bisphosphonate at 1 year)
Special situations
- Glucocorticoid-induced: start bone protection at the same time as the steroid in anyone on >=7.5 mg for >=3 months; bisphosphonate first-line, teriparatide if severe
- Post-transplantation: DXA monitoring, calcium and vitamin D, bisphosphonate
- Men: check testosterone; treatment evidence and agents are the same
- Fracture liaison service - the single most effective system-level intervention
Rare adverse effects of potent antiresorptives
- Osteonecrosis of the jaw - ~1/10,000-100,000 in osteoporosis dosing (far higher at oncology doses). Dental assessment before starting; avoid elective extractions during therapy
- Atypical femoral fracture - subtrochanteric/diaphyseal, transverse, lateral cortical beaking; prodromal thigh pain; risk rises after >5 years. *Image the contralateral femur*
- The absolute risk of both is dwarfed by the fracture risk they prevent
Associations
- Rheumatoid arthritis, ankylosing spondylitis, SLE - inflammation, immobility, steroids
- Coeliac disease, IBD, bariatric surgery - malabsorption
- CKD-MBD, chronic liver disease, primary biliary cholangitis
- Hyperparathyroidism, hyperthyroidism, Cushing syndrome, hypogonadism, diabetes
- Myeloma - always exclude in a new vertebral fracture
- Anorexia nervosa, athletic amenorrhoea (RED-S)
- COPD, transplantation, HIV
- Falls, sarcopenia, frailty - the co-determinant of fracture
- Breast cancer on aromatase inhibitors; prostate cancer on androgen deprivation
Natural history & complications
- Bone loss is progressive and asymptomatic until fracture
- Treatment reduces vertebral fracture by ~50-70% and hip fracture by ~40%
The fracture cascade
- A fragility fracture roughly doubles the risk of the next one
- Vertebral fracture carries the highest risk of a subsequent fracture - the "vertebral fracture cascade"
- Risk is highest in the first 1-2 years after a fracture ("imminent fracture risk") - this is the window in which to start treatment, not later
Consequences
- Hip fracture: ~25% one-year mortality; ~50% never regain independence; ~25% enter residential care
- Vertebral fracture: height loss, kyphosis, chronic pain, restrictive lung disease, early satiety, and independent excess mortality
- Loss of independence, institutionalisation, depression, fear of falling
Complications of the disease and its treatment
- Recurrent fracture, chronic pain, disability
- Hypocalcaemia with potent antiresorptives in unrecognised vitamin D deficiency or CKD
- Oesophagitis and ulceration with oral bisphosphonates
- Rebound vertebral fractures after stopping denosumab
- Osteonecrosis of the jaw, atypical femoral fracture
- Under-treatment remains the dominant problem - fewer than 1 in 5 patients with a fragility fracture receive treatment
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