Osteoporosis and osteopenia
Description
- Reduced bone mass + microarchitectural deterioration -> inc fragility
- Cortical thinning + inc cortical porosity
- Trabecular thinning + loss of connectivity (not recoverable by any drug)
- Bone is qualitatively normal - distinguishes from osteomalacia (defective mineralisation)
| T-score | |
|---|---|
| Normal | >= -1.0 |
| Osteopenia | -1.0 to -2.5 |
| Osteoporosis | <= -2.5 |
| Established/severe | <= -2.5 + minimal-trauma fracture |
- Minimal-trauma fracture after age 50 = osteoporosis regardless of T-score
- Most fragility fractures occur in the osteopenic range - absolute risk, not T-score, drives treatment
Epidemiology
- ~1 in 2 women, 1 in 3 men >60 will sustain a minimal-trauma fracture
- >1 million Australians with osteoporosis
- Hip fracture: 12-month mortality ~20-25%, only ~40% regain prior independence
- Vertebral fractures ~2/3 clinically silent
Aetiopathogenesis
Primary
- Postmenopausal - oestrogen deficiency
- inc RANKL, dec OPG -> inc osteoclast recruitment and survival
- -> inc remodelling rate, resorption > formation
- Trabecular bone preferentially lost -> vertebral and distal radius
- Age-related - dec osteoblast function, dec calcium absorption, secondary hyperparathyroidism
- Cortical loss -> hip
Secondary
- Endocrine - hypogonadism (commonest secondary cause in men), thyrotoxicosis, Cushing, primary hyperparathyroidism, T1DM
- GI/nutritional - coeliac, IBD, bariatric surgery, vitamin D deficiency, anorexia, alcohol
- Marrow/malignant - myeloma, mastocytosis
- Inflammatory - RA, ankylosing spondylitis
- Organ failure - CKD-MBD, chronic liver disease
- Drugs - glucocorticoids, aromatase inhibitors, ADT/GnRH agonists, anti-epileptics, SGLT2i (canagliflozin), long-term heparin, thiazolidinediones, high-dose PPI
- Genetic - osteogenesis imperfecta
BMD loss by cancer therapy - 1 year, lumbar spine
| Chemo-induced ovarian failure | ~7.7% |
|---|---|
| AI + GnRH agonist | ~7.0% |
| ADT | ~4.6% |
| BMT | ~3.3% |
| AI alone | ~2.6% |
| Natural early menopause | ~2.0% |
Diagnosis
DEXA
- Lumbar spine and femoral neck/total hip
- Spine falsely elevated by degenerative change, aortic calcification, vertebral fracture, prior fusion
- Forearm if hyperparathyroidism or spine/hip unusable
- T-score vs young adult peak - use in postmenopausal women and men >50
- Z-score vs age-matched - use in premenopausal women, men <50, children
- Z < -2.0 -> mandatory secondary-cause workup
Fracture identification
- Lateral spine imaging (VFA or X-ray) if height loss >3 cm, kyphosis, or back pain
- Finding a silent vertebral fracture changes the patient to established osteoporosis
Absolute risk
- FRAX or Garvan - 10-year probability
- FRAX underestimates with recent fracture, glucocorticoids >7.5 mg, falls, and multiple fractures - it counts prior fracture yes/no only
Secondary-cause screen
- Ca, PO4, ALP, UEC, LFT, 25-OH vitamin D, PTH, TSH
- Testosterone (men), coeliac serology, SPEP/serum free light chains, 24h urinary calcium and cortisol if indicated
Management
A. Who to treat
- Minimal-trauma fracture (incl. asymptomatic vertebral) in a woman postmenopausal or man >50 - treat, no further risk calculation
- Confers 3-5x risk of another fracture within 12 months - the imminent-risk window
- NNT ~20 with prior fracture vs >100 without
- T-score <= -2.5
- High absolute risk on FRAX/Garvan without fracture
- Drug-induced:
- Glucocorticoids >=7.5 mg prednisolone for >3 months
- Aromatase inhibitor: treat if T < -2.0 or fracture
- ADT: treat if T < -2.5 or fracture
B. Non-pharmacological - everyone
- Calcium 1300 mg/day total, dietary first; supplement only to close the gap (~500-600 mg)
- Vitamin D to 25-OH >50 nmol/L (>75 if on treatment)
- Weight-bearing + progressive resistance and balance training
- Cease smoking, limit alcohol, falls and medication review
- Falls programmes reduce falls; fracture reduction not demonstrated
C. Drug choice - by risk tier
| Standard risk | Oral bisphosphonate (alendronate 70 mg weekly, risedronate 35 mg weekly) |
| Poor adherence, GI intolerance, upper GI disease | Zoledronic acid 5 mg IV yearly, or denosumab 60 mg SC 6-monthly |
| Very high risk (multiple/recent vertebral fractures, T <= -3.0, fracture on therapy) | Anabolic first - romosozumab or teriparatide |
| Premenopausal / early postmenopausal with vasomotor symptoms | MHT; raloxifene if breast-cancer risk reduction also wanted |
- Anabolic-before-antiresorptive is the current sequence in very high risk
- Larger BMD and fracture gains than the reverse order
- Antiresorptive first blunts the subsequent anabolic response
- Build bone, then lock it in - every anabolic course must be followed by an antiresorptive
- Romosozumab (anti-sclerostin, dual action) - 12 months only
- Contraindicated with MI or stroke in the preceding 12 months (ARCH cardiovascular signal)
- Teriparatide - 18 months (PBS), daily SC
- PBS: T <= -3.0 with >=2 minimal-trauma fractures, or a new fracture after >=12 months of antiresorptive
- PTH paradox: continuous exposure resorbs bone, intermittent daily dosing builds it
- Avoid: Paget, prior skeletal irradiation, unexplained inc ALP, active malignancy
D. Duration and stopping
- Denosumab must NEVER simply stop
- Rebound inc bone turnover -> rapid BMD loss -> multiple spontaneous vertebral fractures
- Give strictly 6-monthly; if delayed >1 month, chase it
- Ceasing requires transition to a bisphosphonate (zoledronic acid, timed ~6 months after the last dose)
- Bisphosphonate drug holiday after 5 years oral / 3 years IV, if low risk and stable BMD
- Continue in high risk to 10 years / 6 years
- Skeletal retention permits a holiday - denosumab has none, hence the contrast
E. Efficacy
| Vertebral | Hip | |
|---|---|---|
| Alendronate | ~47% | ~51% |
| Zoledronic acid | ~70% | ~41% |
| Denosumab | ~68% | ~40% |
| Raloxifene | ~36% | No effect |
Associations
- Coeliac disease, IBD, bariatric surgery
- RA, ankylosing spondylitis, SLE
- Hypogonadism, anorexia nervosa, athletic amenorrhoea (RED-S)
- Myeloma, mastocytosis
- COPD, chronic liver disease, CKD, transplantation
- Falls syndrome, sarcopenia, vitamin D deficiency
Natural history & complications
- Silent until fracture
- Vertebral fracture -> height loss, kyphosis, restrictive lung defect, chronic pain, inc mortality
- Fracture cascade: each fracture raises the risk of the next, greatest in the first 12 months
Complications of therapy
- Osteonecrosis of the jaw - ~1 in 2,260 to 1 in 8,470 in Australian osteoporosis populations; far higher at oncology doses
- Usually after >=2 years; mandible ~2/3
- Risk: extraction, poor dentition, glucocorticoids, smoking, malignancy
- Dental review before starting; do not delay urgent treatment for it
- Staged: antimicrobial rinse -> culture-directed antibiotics -> debridement
- Atypical femoral fracture - subtrochanteric/diaphyseal, transverse, lateral cortex
- Median ~7 years of bisphosphonate; prodromal thigh/groin pain in ~70%, bilateral in 28%
- Stop the antiresorptive; image the contralateral femur
- Progression to complete fracture ~50% if continued vs ~20% if stopped
- Zoledronic acid: acute-phase reaction (first infusion, paracetamol cover), AF signal, hypocalcaemia
- Correct vitamin D and calcium before any potent antiresorptive
- Raloxifene: VTE, vasomotor symptoms
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