Osteoporosis & Fragility Fractures

A systemic skeletal disorder of low bone mass plus microarchitectural deterioration leading to bone fragility and fracture. This is a perennial NEET PG favourite: examiners love DEXA T-score cut-offs, the FRAX tool, the bisphosphonate–denosumab–teriparatide trio, atypical femoral fractures, and the classic osteoporosis-versus-osteomalacia distinction.

Definition & classification

Osteoporosis is defined as bone mineral density (BMD) 2.5 standard deviations or more below the young adult mean (T-score ≤ −2.5) by DEXA, or the occurrence of a fragility fracture irrespective of BMD. A fragility fracture is one resulting from a fall from standing height or less (low-energy trauma) — the bone is so weak it fails under loads that a normal skeleton would tolerate.

It is fundamentally a disease of reduced bone quantity with normal mineralisation (the bone present is fully mineralised but there is simply too little of it). Contrast this with osteomalacia, where there is defective mineralisation of normal osteoid.

Classification:

Type	Subtype	Cause / mechanism	Bone affected	Classic fracture
Primary	Type I (postmenopausal)	Oestrogen deficiency → ↑osteoclast activity	Trabecular bone	Vertebral crush, Colles
Primary	Type II (senile)	Ageing, ↓osteoblast function, age >70	Trabecular + cortical	Hip (femoral neck), vertebral wedge
Secondary	—	Drugs, endocrine, GI, marrow disease	Both	Variable
Idiopathic	Juvenile / young adult	Unknown	Both	Vertebral

High-yield: Type I (postmenopausal) osteoporosis preferentially affects trabecular (cancellous) bone — hence vertebrae and the distal radius fracture first. Type II (senile) affects both trabecular and cortical bone — hence the hip is classic.

Etiology & pathophysiology

Bone is in constant turnover via the basic multicellular unit (BMU): osteoclasts resorb, osteoblasts form. Peak bone mass is reached around age 30; thereafter a slow net loss occurs. Osteoporosis develops when resorption outpaces formation.

Key mechanism — the RANK / RANKL / OPG axis:

• Osteoblasts express RANKL, which binds RANK on osteoclast precursors → osteoclast differentiation, activation, survival → resorption.
• Osteoprotegerin (OPG), also from osteoblasts, is a decoy receptor that mops up RANKL → inhibits resorption.
• Oestrogen upregulates OPG and suppresses RANKL. Menopausal oestrogen withdrawal therefore unleashes osteoclasts → rapid trabecular loss in the first 5–10 post-menopausal years.

High-yield: Denosumab is a monoclonal antibody against RANKL — it functionally mimics OPG. This single fact links the pathophysiology directly to a drug, and is frequently asked.

Major risk factors (modifiable & non-modifiable):

• Non-modifiable: female sex, increasing age, Caucasian/Asian ethnicity, family history of hip fracture, early/surgical menopause, small body frame.
• Modifiable: smoking, excess alcohol, low calcium/vitamin D, sedentary lifestyle, low body weight (BMI < 19).

Secondary causes — mnemonic "SHATTERED":

• S — Steroids (glucocorticoids — the commonest drug cause)
• H — Hyperthyroidism, Hyperparathyroidism, Hypogonadism
• A — Alcohol & smoking
• T — Thin (low BMI)
• T — Testosterone low
• E — Early menopause
• R — Renal/liver failure
• E — Erosive/inflammatory disease (rheumatoid arthritis, myeloma)
• D — Dietary Ca/vit D deficiency, Diabetes, malabsorption

High-yield: Glucocorticoid-induced osteoporosis is the most common form of secondary osteoporosis. Steroids suppress osteoblasts, increase osteoblast/osteocyte apoptosis, reduce intestinal calcium absorption and increase renal calcium loss. Bone loss is fastest in the first 3–6 months. Consider bone protection if prednisolone ≥ 7.5 mg/day for ≥ 3 months.

Clinical features

Osteoporosis itself is silent — there is no pain until a fracture occurs ("the silent thief of bone"). Presentations:

• Vertebral compression (crush) fractures — the commonest osteoporotic fracture overall. May be asymptomatic (found incidentally) or cause acute back pain. Cumulative wedging → progressive height loss, thoracic kyphosis ("dowager's hump"), and a protuberant abdomen.
• Hip fracture (femoral neck / intertrochanteric) — the most morbid; presents with a shortened, externally rotated limb and inability to weight-bear. Carries ~20–30% one-year mortality.
• Distal radius (Colles) fracture — classic in postmenopausal women after a fall on the outstretched hand; "dinner-fork" deformity.
• Other sites: proximal humerus, pelvis, ribs.

High-yield: The three classic fragility fracture sites are vertebra, hip, and distal radius (Colles). A fragility fracture at any of these in an older patient = osteoporosis until proven otherwise, and warrants DEXA.

Diagnosis & investigation of choice

Investigation of choice: Dual-energy X-ray absorptiometry (DEXA / DXA) of the lumbar spine and hip (femoral neck). It is low-radiation, precise, and the basis of the WHO definition.

WHO BMD criteria (T-scores):

Category	T-score	Note
Normal	≥ −1.0	—
Osteopenia (low bone mass)	−1.0 to −2.5	"borderline"
Osteoporosis	≤ −2.5	diagnostic threshold
Severe / established osteoporosis	≤ −2.5 plus a fragility fracture	—

High-yield: T-score compares the patient to a young adult of the same sex (peak bone mass) and is used for diagnosis in postmenopausal women and men ≥ 50. Z-score compares the patient to age- and sex-matched controls — a Z-score ≤ −2.0 suggests a secondary cause and is used in premenopausal women, men < 50, and children.

• Each 1 SD fall in BMD roughly doubles the fracture risk.
• DEXA is reported per skeletal site; the lowest T-score governs the diagnosis.

FRAX tool (WHO Fracture Risk Assessment Tool): Calculates the 10-year probability of a major osteoporotic fracture (spine, hip, forearm, proximal humerus) and of hip fracture alone, using clinical risk factors ± femoral-neck BMD. Inputs include age, sex, weight, height, prior fracture, parental hip fracture, smoking, glucocorticoids, rheumatoid arthritis, secondary osteoporosis, and alcohol. FRAX can be calculated without a DEXA, making it useful for triaging who needs scanning and who needs treatment.

High-yield: FRAX gives a 10-year fracture probability. Treatment is generally recommended when 10-year major osteoporotic fracture risk is ≥ 20% or hip fracture risk ≥ 3% (NOF thresholds).

Laboratory work-up is to exclude secondary causes and mimics (osteomalacia, myeloma, hyperparathyroidism). In primary osteoporosis the routine biochemistry is normal — serum calcium, phosphate, and alkaline phosphatase are all normal (ALP may rise transiently after a fresh fracture). Order: serum Ca, PO₄, ALP, 25-OH vitamin D, PTH, TFTs, testosterone (men), renal/liver function, and serum/urine electrophoresis if myeloma is suspected.

Bone turnover markers (research/monitoring): formation — serum P1NP, osteocalcin, bone-specific ALP; resorption — urinary/serum CTX (C-telopeptide), NTX.

Plain radiograph is insensitive (≥ 30–40% bone loss needed before osteopenia is visible) — features include cortical thinning, increased radiolucency, vertebral wedging/biconcavity ("codfish" vertebrae). Not used to diagnose osteoporosis but often the first clue.

Osteoporosis vs Osteomalacia — the classic distinction

Feature	Osteoporosis	Osteomalacia
Defect	↓ bone quantity, normal mineralisation	Defective mineralisation of osteoid (excess unmineralised osteoid)
Bone composition	Normal mineral : matrix ratio	↑ unmineralised osteoid
Serum calcium	Normal	Low or low-normal
Serum phosphate	Normal	Low
Alkaline phosphatase	Normal	Raised
PTH	Normal	Raised (secondary hyperparathyroidism)
Vitamin D	Usually normal	Low
Pain	Painless until fracture	Diffuse bone pain, proximal myopathy
X-ray hallmark	Generalised lucency, wedge fractures	Looser's zones (pseudofractures)
Treatment	Antiresorptives/anabolics + Ca/D	Vitamin D + calcium replacement

High-yield: Looser's zones (Milkman's pseudofractures) — ribbon-like translucent bands perpendicular to the cortex, classically at the medial femoral neck, pubic rami, scapula, ribs — are pathognomonic of osteomalacia, NOT osteoporosis. A raised ALP with low Ca/PO₄ points to osteomalacia.

Management & drug of choice

Approach: Assess risk (DEXA ± FRAX) → exclude/treat secondary causes → lifestyle + calcium/vitamin D baseline → pharmacotherapy → reassess at intervals.

Stepwise treatment flow:

1. General/lifestyle → weight-bearing & resistance exercise, smoking cessation, limit alcohol, fall-prevention (vision, home hazards, balance), adequate protein.
2. Calcium + vitamin D → ensure ~1000–1200 mg elemental calcium/day and 800–1000 IU vitamin D/day. This is adjunctive to, not a substitute for, specific therapy.
3. First-line specific therapy → Bisphosphonate (oral alendronate or risedronate; IV zoledronic acid if intolerant).
4. Second-line / specific situations → denosumab, teriparatide/abaloparatide (anabolic), raloxifene, romosozumab.
5. Monitor → repeat DEXA at ~2 years; assess adherence; consider a drug holiday after 3–5 years of bisphosphonates in low-risk patients.

Drug classes

1. Bisphosphonates — first-line drug of choice.

• Mechanism: analogues of pyrophosphate that bind hydroxyapatite; ingested by osteoclasts. Nitrogen-containing bisphosphonates (alendronate, risedronate, ibandronate, zoledronate) inhibit farnesyl pyrophosphate synthase in the mevalonate pathway → disrupt osteoclast cytoskeleton → apoptosis. Non-nitrogenous (etidronate, clodronate) form cytotoxic ATP analogues.
• Net effect: antiresorptive — reduce bone turnover.
• Administration: oral alendronate (weekly) taken on an empty stomach with a full glass of water, remaining upright for 30 minutes (to prevent pill oesophagitis); zoledronic acid is a once-yearly IV infusion.
• Adverse effects: oesophagitis (oral), acute-phase reaction (IV), osteonecrosis of the jaw (ONJ), atypical femoral fractures (AFF), hypocalcaemia. Avoid if eGFR < 30–35 ml/min.

High-yield: Atypical femoral fractures are transverse/short-oblique fractures of the subtrochanteric or femoral shaft region with a medial spike and lateral cortical beaking, associated with long-term (> 3–5 yr) bisphosphonate use (over-suppressed turnover). They are often bilateral and preceded by prodromal thigh/groin pain. Always X-ray the contralateral femur. Management: stop the bisphosphonate; prophylactic/therapeutic intramedullary nailing.

2. Denosumab.

• Mechanism: human monoclonal antibody to RANKL → blocks osteoclast formation/function (antiresorptive). Given as 60 mg SC every 6 months.
• Useful in renal impairment (not renally cleared) — a key advantage over bisphosphonates.
• Adverse effects: hypocalcaemia (check Ca/vit D first), ONJ, AFF. Rebound vertebral fractures if stopped abruptly — must transition to a bisphosphonate, never simply discontinue.

3. Teriparatide (recombinant PTH 1–34) / Abaloparatide (PTHrP analogue).

• Mechanism: anabolic — intermittent (daily SC) PTH paradoxically stimulates osteoblasts and bone formation (continuous PTH would be catabolic). The only widely used bone-forming agents.
• Indications: severe osteoporosis, very low T-scores, multiple/recurrent fragility fractures, glucocorticoid-induced osteoporosis, failure of antiresorptives.
• Limit: maximum 2 years lifetime use; black-box warning for osteosarcoma (seen in rats) → contraindicated in Paget's disease, prior skeletal radiation, open epiphyses, hypercalcaemia.

High-yield: Teriparatide is anabolic (builds bone) because PTH is given intermittently; all the others in routine use (bisphosphonates, denosumab, raloxifene) are antiresorptive. After stopping an anabolic agent, follow with an antiresorptive to preserve gains.

4. Raloxifene (SERM). Oestrogen agonist on bone (↑BMD, ↓vertebral fractures) and antagonist on breast (↓breast cancer risk), but increases venous thromboembolism risk and worsens hot flushes. Does not reduce hip fracture risk.

5. Romosozumab. Monoclonal antibody to sclerostin → dual action (↑formation + ↓resorption); monthly SC for 12 months. Black-box warning for cardiovascular events (MI/stroke).

6. Hormone replacement therapy (HRT) — effective for prevention in early postmenopausal women but breast cancer/VTE/CV risks limit its role to those with menopausal symptoms.

Drug	Class	Route/frequency	Key caveat
Alendronate	N-bisphosphonate (antiresorptive)	Oral weekly	Oesophagitis; stay upright 30 min
Zoledronate	N-bisphosphonate	IV yearly	Acute-phase reaction; avoid eGFR<35
Denosumab	Anti-RANKL mAb	SC 6-monthly	Rebound fractures if stopped; OK in CKD
Teriparatide	Anabolic (PTH 1-34)	SC daily	Max 2 yr; osteosarcoma warning
Raloxifene	SERM	Oral daily	↑VTE; no hip protection
Romosozumab	Anti-sclerostin mAb	SC monthly ×12	Cardiovascular warning

Complications

• Hip fracture — the dreaded outcome; high one-year mortality (~20–30%), loss of independence, deep vein thrombosis, pneumonia, pressure sores from immobility.
• Vertebral fractures — chronic back pain, kyphosis, restrictive lung impairment, early satiety, increased subsequent fracture risk (a vertebral fracture quintuples risk of another).
• Fracture cascade — one fragility fracture markedly increases the risk of the next.
• Drug-related — ONJ, atypical femoral fractures, hypocalcaemia, rebound fractures (denosumab withdrawal).

High-yield: A prior fragility fracture is the single strongest predictor of future fracture — independent of BMD. "Fracture begets fracture."

Key differentials

• Osteomalacia / rickets — defective mineralisation; low Ca/PO₄, high ALP, Looser's zones (see table above). The single most-tested differential.
• Multiple myeloma — older patient, bone pain, lytic "punched-out" lesions, anaemia, ↑ESR, ↑calcium, monoclonal band; can present as vertebral collapse. Always exclude in osteoporosis with red flags.
• Metastatic bone disease — breast, prostate, lung, thyroid, kidney; pathological fractures, often raised ALP/Ca.
• Primary hyperparathyroidism — high Ca, high PTH, subperiosteal resorption, "salt-and-pepper" skull, osteitis fibrosa cystica.
• Paget's disease — markedly raised ALP, bone enlargement/deformity, mosaic lamellar pattern.
• Osteogenesis imperfecta — young patient, blue sclerae, recurrent fractures, defective type I collagen.

Recently asked / exam angle

• DEXA T-score thresholds — "T-score ≤ −2.5 = osteoporosis" and the osteopenia band (−1 to −2.5) are repeatedly tested. Know that the lumbar spine and hip are the standard sites and the lowest value is diagnostic.
• T-score vs Z-score — which population each compares against; Z-score for premenopausal women/young men/children and a clue to secondary causes.
• Denosumab = anti-RANKL, teriparatide = anabolic intermittent PTH, romosozumab = anti-sclerostin — direct mechanism-to-drug matching is a favourite single-best-answer format.
• Atypical femoral fracture — site (subtrochanteric/shaft), transverse pattern, prodromal thigh pain, link to long-term bisphosphonates; bilateral imaging.
• Osteoporosis vs osteomalacia biochemistry table — normal Ca/PO₄/ALP in osteoporosis vs low Ca/PO₄, high ALP and Looser's zones in osteomalacia.
• Glucocorticoid-induced osteoporosis as the commonest secondary cause and earliest bone loss in the first few months.
• FRAX — 10-year fracture probability, can be used without BMD; treatment thresholds (~20% major / 3% hip).
• First drug of choice = bisphosphonate; denosumab preferred in renal impairment; rebound fractures on stopping denosumab.

Rapid revision

1. Osteoporosis = low bone mass + microarchitectural decay; bone present is normally mineralised (vs osteomalacia).
2. Diagnosis = T-score ≤ −2.5 on DEXA or any fragility fracture.
3. Osteopenia = T-score −1.0 to −2.5.
4. T-score vs young adult (diagnosis); Z-score vs age-matched (secondary cause if ≤ −2.0).
5. Three classic fragility sites: vertebra, hip, distal radius (Colles).
6. Type I = postmenopausal, trabecular, oestrogen-loss; Type II = senile, cortical+trabecular, hip.
7. RANKL ↑ resorption; OPG/oestrogen inhibit it; denosumab blocks RANKL.
8. Commonest secondary cause = glucocorticoids ("SHATTERED" mnemonic).
9. In primary osteoporosis, Ca, PO₄, ALP are all normal.
10. First-line drug = bisphosphonate; teriparatide is the only routine anabolic (max 2 yr, osteosarcoma warning).
11. Atypical femoral fracture = subtrochanteric/shaft transverse fracture from long-term bisphosphonates; check both femurs.
12. Looser's zones = osteomalacia, not osteoporosis; raised ALP + low Ca/PO₄ point away from osteoporosis.