Osteoporosis — Pathophysiology and Management

Osteoporosis is a systemic skeletal disease characterised by reduced bone mineral density (BMD) and deterioration of bone microarchitecture, leading to increased bone fragility and fracture risk. It is the most common metabolic bone disease worldwide, affecting approximately 200 million people globally and causing over 8.9 million fractures annually. The disease is largely asymptomatic until a fragility fracture occurs — by which point significant bone loss has already accumulated. The orthopaedic surgeon is often the first clinician to encounter osteoporosis through the fragility fracture presentation, and has a critical role in initiating fracture liaison service (FLS) referral and secondary prevention of further fractures.

• Definition (WHO, 1994): osteoporosis is defined by a T-score ≤ −2.5 on dual-energy X-ray absorptiometry (DEXA) scan; the T-score compares the patient`s BMD to the young adult reference mean (peak bone mass); osteopenia = T-score between −1.0 and −2.5; normal = T-score > −1.0; the Z-score compares the patient`s BMD to an age-matched reference population — a Z-score ≤ −2.0 = below expected range for age (suggests secondary osteoporosis); the T-score is used to diagnose and treat; the Z-score is used to identify secondary causes
• Epidemiology: women are disproportionately affected (oestrogen withdrawal at menopause causes accelerated bone loss — up to 3–5% per year in the first 5–10 years post-menopause); 1 in 2 women and 1 in 5 men over 50 will suffer an osteoporotic fracture in their lifetime; the most clinically significant fragility fractures are: hip fractures (highest mortality — 20–30% 1-year mortality), vertebral fractures (1/3 symptomatic; 2/3 incidental; cause height loss, kyphosis, and significant morbidity), distal radius fractures (most common fragility fracture in women under 75), and proximal humerus fractures
• FRAX (Fracture Risk Assessment Tool — WHO): the internationally validated tool for calculating a patient`s 10-year probability of a major osteoporotic fracture (hip, spine, forearm, humerus) and hip fracture separately; inputs include age, sex, weight, height, prior fragility fracture, parental hip fracture, smoking, alcohol, corticosteroid use, rheumatoid arthritis, secondary osteoporosis, and BMD T-score (optional but improves accuracy); FRAX score guides treatment decisions; NICE recommends treatment if FRAX 10-year major fracture risk exceeds the age-dependent intervention threshold (available via the NOGG — National Osteoporosis Guideline Group — online tool)

• Bone remodelling cycle: bone is in a continuous state of turnover; osteoclasts (bone-resorbing cells) resorb bone in `resorption pits`; osteoblasts (bone-forming cells) fill these pits with new osteoid; the cycle is tightly coupled — formation follows resorption; the key regulatory pathway is the RANK/RANKL/OPG axis: RANKL (Receptor Activator of NF-κB Ligand) is produced by osteoblasts and stromal cells; it binds to RANK on osteoclast precursors, activating osteoclastogenesis (osteoclast differentiation and activation); OPG (osteoprotegerin) — produced by osteoblasts — acts as a decoy receptor for RANKL, blocking osteoclast activation; in osteoporosis, the balance is disrupted in favour of resorption; increased RANKL activity or decreased OPG = accelerated bone loss
• Hormonal influences: oestrogen inhibits osteoclast activity (via reducing RANKL and promoting osteoclast apoptosis); at menopause, oestrogen withdrawal → disinhibition of osteoclasts → accelerated trabecular bone loss (particularly in the lumbar spine and femoral neck); testosterone has a similar effect in men — hypogonadism causes male osteoporosis; PTH (parathyroid hormone) in excess (hyperparathyroidism) stimulates osteoclastic bone resorption; 1,25-OH vitamin D is essential for calcium absorption from the gut; deficiency leads to secondary hyperparathyroidism → accelerated bone resorption
• Types of osteoporosis: (1) Primary — postmenopausal (Type I — oestrogen withdrawal); age-related (Type II — senile osteoporosis, affects both sexes after age 70); (2) Secondary — glucocorticoid-induced (most common secondary cause — systemic steroids reduce osteoblast activity and increase osteoclast activity; even short courses ≥3 months of prednisolone ≥7.5 mg/day require consideration of bone protection); other causes: hypogonadism, hyperparathyroidism, hyperthyroidism, malabsorption (coeliac disease), renal failure, multiple myeloma, rheumatoid arthritis, immobility, alcohol excess, smoking

• The `imminent fracture risk` concept: the risk of a subsequent fracture is highest in the first year after an index fragility fracture — 20–25% of patients sustain a second fracture within 12 months; this `imminent risk` window is the most important opportunity for intervention; early initiation of osteoporosis treatment (within 4–12 weeks of the index fracture) dramatically reduces the risk of re-fracture; the Fracture Liaison Service (FLS) is the model of care for identifying fragility fracture patients, performing DEXA, calculating FRAX, and initiating treatment; all patients presenting with a fragility fracture should be referred to the FLS
• Orthopaedic surgeon`s role: all patients presenting with a fragility fracture (wrist, hip, vertebra, humerus, ankle — from a fall from standing height or less) should be: (1) assessed for secondary causes (routine bloods); (2) prescribed calcium and vitamin D at the time of fracture; (3) referred to FLS or bone clinic; (4) have DEXA arranged; (5) started on bone protection if indicated — the orthopaedic team should not wait for the GP to initiate treatment after fracture

• DEXA T-score: ≤ −2.5 = osteoporosis; −1.0 to −2.5 = osteopenia; > −1.0 = normal; Z-score ≤ −2.0 = below age-matched reference = investigate secondary causes
• RANK/RANKL/OPG axis: RANKL (from osteoblasts) activates osteoclasts via RANK; OPG (from osteoblasts) decoys RANKL = inhibits osteoclasts; denosumab = anti-RANKL antibody = inhibits osteoclast activation; bisphosphonates = incorporated into bone → osteoclast apoptosis via mevalonate pathway inhibition
• Bisphosphonate side effects: oesophageal irritation (oral — upright 30 min after dose); ONJ (rare — mainly IV bisphosphonates + dental); atypical femoral fractures (AFF — thigh/groin pain + beaking cortical thickening on X-ray after >3–5 years); drug holiday at 5 years in low-risk patients
• Denosumab CRITICAL: do NOT stop abruptly — rebound multiple vertebral fractures occur on stopping without bisphosphonate transition; must transition to bisphosphonate 6 months after last denosumab dose
• Teriparatide: anabolic (intermittent PTH = osteoblast stimulation); for severe osteoporosis or bisphosphonate failure; 24-month maximum course; followed by anti-resorptive therapy; contraindicated in Paget`s, prior radiotherapy, hypercalcaemia
• FRAX: WHO tool; 10-year major fracture and hip fracture probability; inputs = age, sex, BMI, clinical risk factors ± DEXA T-score; compared against NOGG age-specific intervention threshold; above threshold = treat
• Glucocorticoid-induced osteoporosis: most common secondary cause; systemic steroids ≥7.5 mg prednisolone for ≥3 months = bone protection (bisphosphonate + calcium + vitamin D); reduces BMD and fracture risk; DEXA at baseline and after 1 year of treatment
• Vitamin D correction before bisphosphonates: treat vitamin D deficiency before starting bisphosphonates — risk of hypocalcaemia with bisphosphonates in vitamin D-deficient patients; correct to >50 nmol/L before starting treatment