Osteoporosis is a skeletal disorder characterised by weakened bone strength—due to reductions in bone mineral density, deterioration of the bone’s microarchitecture and impaired mineralisation—which dramatically raises the risk of fractures. Often silent until a low-impact injury occurs, it most commonly manifests as wrist, vertebral, hip, proximal humerus or pelvic fractures.
Throughout life, bone tissue undergoes continuous remodelling: old bone is removed by osteoclasts and new bone is laid down by osteoblasts. When resorption outpaces formation, the microstructural and mineral changes that define osteoporosis ensue. This delicate balance is influenced by hormones, growth factors and genetic predisposition—indeed, having a parent who suffered a hip fracture increases fracture risk independently of bone density.
Sex steroids are particularly important regulators: oestrogen deficiency after the menopause accelerates bone loss in women, while in men, rising levels of sex hormone–binding globulin with age diminish the availability of testosterone and oestrogen, similarly compromising bone strength. These age‑related changes underlie primary osteoporosis.
Secondary osteoporosis arises from other diseases and drugs. Excess glucocorticoids—whether from long‑term corticosteroid therapy or Cushing’s syndrome—are the most frequent culprits, doubling the risk of hip fractures in women and raising it 2.6‑fold in men. In men, hypogonadism and heavy alcohol use (more than four units per day) can also halve bone density. Lifestyle factors such as smoking, which further suppresses bone formation, inadequate dietary calcium and vitamin D, and long‑term proton pump inhibitor use (which impairs calcium absorption) compound fracture risk. Low body weight and rapid weight loss—seen for example in some female athletes with hypothalamic amenorrhoea—similarly predispose to early bone loss.
Clinically, one low‑trauma fracture vastly increases the likelihood of subsequent fractures in the following five to ten years. Even modest annual height loss—more than 0.5 cm—signals elevated risk of hip and other fractures in middle‑aged and older adults.
A wide range of medical conditions may provoke secondary bone loss: endocrine disorders such as hyperthyroidism, hyperparathyroidism, hyperprolactinaemia and diabetes mellitus; malabsorption syndromes like coeliac disease and chronic pancreatitis; inflammatory diseases such as rheumatoid arthritis; haematological illnesses including multiple myeloma and haemoglobinopathies; chronic organ diseases affecting the liver, kidneys or lungs; and prolonged immobility. In women, roughly one‑third of osteoporosis cases stem from secondary causes, most often disturbances in calcium metabolism (for example hyperparathyroidism or vitamin D deficiency).
At the cellular level, bone remodelling is orchestrated by the RANK–RANKL pathway: osteoblasts produce RANK ligand, which binds to RANK on osteoclast precursors, driving their activation and bone‑resorbing activity. Parathyroid hormone (PTH) exerts a dual effect—intermittent PTH stimulates osteoblast proliferation and increases bone mass, whereas chronically elevated levels promote resorption. Conversely, calcitonin suppresses osteoclastic activity via specific G‑protein–coupled receptors, reducing cytosolic calcium and inhibiting bone breakdown.
Calcium, phosphate and vitamin D homeostasis is maintained through a feedback loop involving PTH, calcitonin and 1,25‑dihydroxyvitamin D. Low serum calcium triggers PTH secretion, enhancing renal calcium reabsorption, activating osteoclasts via RANKL to liberate skeletal calcium, and upregulating renal 1α‑hydroxylase to convert vitamin D into its active form, thereby increasing intestinal calcium uptake. Vitamin D itself is first hydroxylated in the liver to 25‑hydroxyvitamin D and then converted in the kidney to 1,25‑dihydroxyvitamin D—completing the cycle that sustains bone health.
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