Osteoporosis is a systemic skeletal disease characterised by low bone mass and microarchitectural deterioration, producing increased bone fragility and fracture susceptibility. It is defined as a T-score of -2.5 or below at the hip or lumbar spine on DEXA (WHO). A fragility fracture is one sustained from a fall from standing height or less. UK burden: 1 in 2 women and 1 in 5 men over 50 will sustain a fragility fracture; hip fractures alone account for around 65,000 UK presentations per year with 1-year mortality around 30%. Osteoporosis is preventable and treatable, yet many fragility-fracture patients are not on bone protection - a significant treatment gap. UK practice is anchored by NICE CG146 (risk assessment), NICE CG124 (hip fracture), relevant NICE technology appraisals (TA464, TA791, TA850, TA161), and the NOGG 2024 FRAX-linked treatment framework.
Bone remodels constantly through coordinated resorption (osteoclasts) and formation (osteoblasts). The RANK/RANKL/OPG system regulates this balance: osteoblast-derived RANKL drives osteoclast differentiation and resorption, while OPG is a decoy receptor that binds RANKL and protects bone. Osteocytes are the master regulators and produce sclerostin, which inhibits Wnt signalling and reduces bone formation. In osteoporosis, the balance shifts toward excess resorption.
Peak bone mass is achieved by the late 20s (genetics ~60-80%, plus nutrition, exercise, and hormones), with ~0.5-1% annual decline thereafter. Women lose 2-3% per year in the 5-10 years post-menopause because oestrogen normally suppresses RANKL and promotes OPG; postmenopausal oestrogen loss therefore accelerates osteoclast-mediated resorption.
Drug targets follow the biology: bisphosphonates trigger osteoclast apoptosis via the mevalonate pathway; denosumab is an anti-RANKL antibody mimicking OPG; romosozumab is an anti-sclerostin antibody with dual action (formation up, resorption down); teriparatide is a PTH analogue with anabolic effect.
Types: primary osteoporosis includes postmenopausal Type I (trabecular bone, vertebrae and distal radius) and senile Type II (hip, vertebrae, proximal humerus). Secondary causes include glucocorticoids (the most common drug cause - bone loss fastest in the first 3-6 months), hypogonadism (premature menopause under 45, androgen deprivation, hypothalamic amenorrhoea and RED-S in athletes), endocrine disorders (hyperthyroidism, hyperparathyroidism, Cushing's, type 1 diabetes), GI and nutritional causes (coeliac disease, IBD, anorexia nervosa, vitamin D deficiency), rheumatological disease (RA, SLE, AS), medications (aromatase inhibitors, GnRH agonists, anticonvulsants, long-term PPI, long-term heparin), CKD, liver disease, myeloma, immobility, excess alcohol, and smoking.
Mechanisms and drug targets:
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