"A systemic skeletal disease characterised by low bone mass and microarchitectural deterioration of bone tissue, with a consequent increase in bone fragility and susceptibility to fracture." ^[1]

Why this matters: The definition captures two inseparable elements—quantity (low bone mass) and quality (microarchitectural deterioration). Both contribute to bone fragility. A normal-density bone with disrupted microarchitecture can still fracture, and vice versa. This is why BMD alone doesn't perfectly predict fracture risk—hence the development of FRAX.

"In the adult skeleton, bone is constantly remodelled at multiple sites by the coordinated and sequential actions of bone-resorbing osteoclasts and bone-forming osteoblasts to repair microdamage and to adapt bone structure to the mechanical and metabolic needs." ^[1]

The cycle:

• Activation → Resorption (osteoclasts dig out old/damaged bone) → Reversal → Formation (osteoblasts lay down new osteoid, which mineralizes) → Quiescence

• This is "coupled": resorption and formation are linked so that bone removed ≈ bone replaced in health.

• The resorption phase takes approximately 10 days; following resorption, macrophage-like cells appear at the reversal phase before osteoblast precursors are recruited, proliferate, differentiate, and secrete new bone matrix that then mineralises. ^[1]

"Osteocytes represent > 95% of all bone cells, are embedded in the mineral, function as mechanosensors and fine-tune bone remodelling by osteoblasts and osteoclasts." ^[1]

Key players:

RANK/RANKL/OPG axis (from lecture diagram): ^[1]

• Osteoblasts express RANKL on their surface
• RANKL binds RANK on osteoclast precursors → osteoclast differentiation & activation → bone resorption
• OPG (osteoprotegerin) is a decoy receptor produced by osteoblasts that binds RANKL and prevents it from activating RANK → inhibits resorption
• Denosumab is a monoclonal antibody that mimics OPG by binding RANKL

Sclerostin pathway:

• Osteocytes secrete sclerostin, which inhibits the Wnt signalling pathway in osteoblasts → suppresses bone formation
• Romosozumab blocks sclerostin → disinhibits Wnt → increases osteoblast activity (anabolic) AND decreases osteoclast activity (anti-resorptive) = dual effect ^[1]

Additional sclerostin biology (from lecture diagram): ^[1]

• Mechanical unloading and oestrogen deficiency upregulate sclerostin production by osteocytes
• Sclerostin also stimulates RANKL expression, thereby promoting osteoclast formation and activity — i.e., sclerostin is not only anti-anabolic but also pro-resorptive
• Sclerostin inhibits osteoblast differentiation and reduces mineralisation
• This explains why romosozumab (anti-sclerostin) has a dual effect: blocking sclerostin both disinhibits osteoblast-mediated formation and reduces RANKL-driven resorption

"Increased rate of bone remodelling in both cancellous and cortical bone" + "Negative remodelling balance." ^[1]

Why does this happen?

• Peak bone mass is reached around age 20–40 ^[3]
• After ~40, gradual bone loss occurs (~1% per year) ^[3]
• In postmenopausal women: oestrogen deficiency → increased RANKL, decreased OPG → accelerated osteoclast activity → resorption >> formation → rapid bone loss in first 5–10 years post-menopause
• In age-related (Type 2) osteoporosis: decreased calcium/vitamin D intake and absorption, decreased renal 1α-hydroxylase activity, secondary hyperparathyroidism → increased bone turnover ^[3]

What the remodelling images show: ageing recruits more remodelling units, but each osteoclast-cut resorption cavity is larger than the osteoblast-filled replacement packet. Repeated negative balance perforates and disconnects trabeculae and thins the cortex; this loss of connectivity explains why strength falls disproportionately to the reduction in bone mass. ^[1]

Role of oestrogen in bone remodelling (from lecture diagram): ^[1]

• With oestrogen: oestrogen enhances bone formation by stimulating osteoblast differentiation and function; suppresses osteoclast differentiation via direct cellular effects and reduced RANKL production by activated T cells, MSCs, osteoblasts, and osteocytes; promotes osteoclast apoptosis; suppresses sclerostin; and is required for adequate mechanosensing and mechanotransduction by osteocytes
• Oestrogen deficiency: RANKL production is upregulated (especially by activated T cells) → higher osteoclast number and activity (↑↑ bone resorption); individual osteoblast function is suppressed partly through upregulation of sclerostin (Wnt inhibitor), though total osteoblast number increases (↑ bone formation, but net bone loss); osteocyte mechanosensing is impaired (↓ mechanosensing)

Pathophysiology of glucocorticoid-induced osteoporosis ^[1]

Glucocorticoids cause osteoporosis through multiple mechanisms:

• Decrease osteoblast differentiation, function, and lifespan (apoptosis of osteoblasts and osteocytes)
• Increase osteoclast lifespan
• Decrease intestinal calcium absorption and increase renal calcium excretion → secondary hyperparathyroidism
• Decrease sex hormones (suppress GnRH)
• Myopathy → increased fall risk
• Fracture risk increases rapidly, even before significant BMD decline (because of bone quality deterioration)

Additional GIOP mechanisms (from lecture diagram): ^[1]

• Osteocyte apoptosis → decreased canalicular circulation → decreased bone quality → may lead to osteonecrosis
• Decreased muscle mass → decreased mechanosensing (compounds osteocyte dysfunction)
• Decreased sex steroids → increased RANKL and decreased OPG → drives the early, transient increase in osteoclast survival and bone resorption

Common sites: Wrist, Vertebra, Hip ^[1]

Radiograph recognition from the slide montage: the distal-radius image shows a metaphyseal wrist fracture, the lateral spine image shows anterior vertebral height loss/wedging, and the hip image shows a proximal-femoral fracture. The visual sequence also mirrors the typical age pattern: wrist fractures tend to appear earlier, vertebral fractures next, and hip-fracture incidence rises most steeply in the oldest age groups. ^[1]

Hip fractures: ^[1]

"One-year mortality rate: 20–30%" "40–60% of survivors cannot regain pre-fracture level of mobility within one year" "20–60% of previously independent patients require assistance with at least one ADL"

Vertebral fractures: ^[1]

"20% excess mortality 5-year post-fracture" "Acute and chronic back pain, deformity and height loss, diminished quality of life"

WHO Diagnostic Categories: ^[1]

"Low-trauma / low-energy fracture in a postmenopausal woman or elderly — defined as a fracture that occurs from a fall from standing height or lower." ^[1]

A low-trauma hip or vertebral fracture in the appropriate patient generally establishes osteoporosis and an indication for treatment irrespective of BMD. Other fragility fractures are powerful risk markers but should trigger DXA and a full clinical risk/secondary-cause assessment rather than being treated as an identical diagnostic shortcut in every patient. ^[15]

"Gold standard: the only means for diagnostic classification according to WHO diagnostic criteria." ^[1]

"Central DXA at hip and spine are the recommended sites." ^[1]

"BMD measurements at these regions of interest are the best predictor of fracture risk for the corresponding sites." ^[1]

"For every reduction of 1 SD, fracture risk increases by 1.5–2 times overall." ^[1]

T-score vs Z-score:

• T-score = number of SDs from a young-adult reference mean → used in postmenopausal women and men ≥ 50. Current ISCD/OSHK positions use the uniform White female, non-race-adjusted NHANES III reference for femoral-neck/total-hip T-scores in both women and men; lumbar-spine T-scores use the manufacturer's reference database. ^[15][16]
• Z-score = compared to age-matched population → used in premenopausal women and men < 50; Z-score ≤ −2.0 suggests secondary cause ^[3]

"Simple ethnic-specific web-based tool that integrates clinical information to predict a 10-year probability of major osteoporotic fracture and hip fracture." ^[1]

The lecture uses FRAX to guide treatment in untreated postmenopausal women and men aged ≥ 50 years. ^[1]

Why FRAX? BMD alone has poor sensitivity for predicting fractures. FRAX incorporates clinical risk factors (age, sex, BMI, prior fracture, parent hip fracture, glucocorticoid use, smoking, alcohol, rheumatoid arthritis, secondary osteoporosis) ± BMD to give a more clinically useful 10-year fracture probability.

Current-use nuance: the FRAX calculator accepts ages 40–90 years, but whether and how its result changes treatment depends on the population, indication and local guideline. It is country-specific, can be calculated without BMD or with femoral-neck BMD, and does not itself prescribe a universal intervention threshold. The 20% major-osteoporotic-fracture and 3% hip-fracture cut-offs shown later in the lecture are US-adapted examples, not universal Hong Kong thresholds. ^[15][22]

• The formula is correct, but the reference database is not simply sex- and ethnicity-matched: current central-DXA T-score conventions use a uniform young White female NHANES III reference for hip measurements in both sexes, as described above. ^[15][16]

Risk factors:

• Female sex
• Increasing age
• Low body weight ( < 45 kg)
• Family history of osteoporosis or fragility fracture
• Premature menopause (age < 40) or early menopause (age 40–45)
• Low calcium intake
• Lack of exercise or sedentary lifestyle
• Smoking
• Excessive alcohol intake ( > 3 standard drinks per day)
• Lack of sun exposure
• Prolonged immobilization

Medication entries in this broad screening list are not all equivalent in causality or effect size. Glucocorticoids, aromatase inhibitors and excess thyroid replacement are well-established hazards; associations for PPIs and anticoagulants depend on agent, dose, duration and confounding. Use the list to prompt medication review, not to assign causation automatically.

Detailed history of clinical risk factors for osteoporosis and/or fractures:

• Smoking and alcohol
• Personal / parental history of fracture(s)
• Fall risk
• Estimate daily dietary calcium intake
• Past health: prolonged sex hormone deficiency (age of menopause, use of HRT), type 1 diabetes, anorexia nervosa, rheumatological diseases, GI disease / malabsorption syndrome (gastrectomy, intestinal bypass, Crohn's disease, coeliac disease)
• Drug history: glucocorticoid, PPI, anticonvulsants, thiazolidinediones (osteoporosis risk); hypnotics, diuretics (fall risk)

"The objective of treating osteoporosis is to reduce the likelihood of fragility fractures by strengthening the skeleton or decreasing fall frequency, or both." ^[1]

Indications for therapy in postmenopausal women and men age ≥ 50: ^[1]

• Prior hip or vertebral fracture
• BMD T-score ≤ −2.5 at spine or proximal femur
• BMD T-score between −1 and −2.5 (low bone mass) AND:
  • 10-year risk of major fracture ≥ 20% (FRAX)
  • 10-year risk of hip fracture ≥ 3% (FRAX)

The 20%/3% cut-offs reproduce the lecture's US-adapted example. They are not universal FRAX thresholds; use the current local guideline and clinical context. Prior hip/vertebral fracture and a qualifying T-score remain treatment-defining findings, while recent/multiple fractures may justify an anabolic-first strategy. ^[15][22]

• Healthy balanced diet rich in calcium and vitamin D
• Regular weight-bearing and muscle-strengthening exercises
• Avoidance of smoking and excessive alcohol intake
• Adequate sunlight exposure

Calcium: ^[1]

• Target: 800–1200 mg/day, ideally through dairy products
• Supplements if dietary intake < 800 mg/day (calcium carbonate or calcium citrate)
• Calcium carbonate is best taken with food because it depends more on gastric acidity; calcium citrate may be taken with or without food and is often preferred when gastric acidity is reduced
• Side effects: dyspepsia, constipation

Vitamin D: ^[1]

• Promotes calcium absorption in gut, maintains serum Ca/PO4 for mineralization, important for neuromuscular function
• Major source: skin synthesis of cholecalciferol (D3) under UV light. There is no universally safe or sufficient fixed “10–15 minute” prescription: skin type, season, clothing, latitude and UV index all matter, and sunburn should be avoided
• For patients with established osteoporosis, the 2024 OSHK guideline supports supplementation tailored to intake, deficiency and risk; the lecture uses 800–1000 IU/day (sometimes up to 2000 IU/day in obesity, limited sun or malabsorption). Do not extrapolate this automatically to every healthy adult. ^[15][20]
• Major circulating form: 25(OH)D
• The Hong Kong osteoporosis guideline retains a target of 25(OH)D ≥ 75 nmol/L in this clinical context. By contrast, the 2024 Endocrine Society disease-prevention guideline found no universal outcome-specific serum target for generally healthy people; these recommendations address different populations. ^[15][20]

Exercise: ^[1]

• Weight-bearing exercises (brisk walking, jogging, Tai Chi, dancing, stair-climbing)
• Benefits: retards bone loss, increases muscle mass/strength, improves balance and reduces falls, improves QoL

Fracture Risk Stratification:

This table reproduces the lecture's relative treatment tiers: its “low risk” row still has densitometric osteoporosis and does not mean “no fracture risk” or “no treatment.” Current Hong Kong guidance broadly supports raloxifene/HRT for selected younger postmenopausal women at lower hip-fracture risk, potent bisphosphonate or denosumab for high risk, and a bone-forming agent first for imminent/very-high risk, followed by an antiresorptive. Individualise for fracture site/recency, renal function, cardiovascular/VTE risk and patient preference. ^[15]

"Occur in the subtrochanteric region or diaphysis of the femur with unique radiological features: predominantly transverse fracture line, periosteal callus formation, minimal comminution."

"More common with long-term bisphosphonate therapy ( > 7–8 years): 113 per 100,000 person-years."

"Also reported with denosumab, with even lower incidence."

Why? Prolonged suppression of bone remodelling → accumulation of microdamage → stress fracture in cortical bone of the femoral shaft. Patients often have prodromal thigh pain before complete fracture.

What the bilateral femur radiograph shows: one side has a complete, near-transverse diaphyseal fracture with little comminution and focal lateral-cortical “beaking”; the contralateral femur has lateral cortical thickening/periosteal reaction consistent with an incomplete stress lesion. AFF can be bilateral, so new thigh/groin pain warrants full-length femoral imaging and assessment of the opposite side. ^[1]

Current definition: exposed bone, or bone that can be probed through an intraoral or extraoral fistula, persisting for > 8 weeks in a patient with current/previous antiresorptive therapy alone or in combination with immune modulators or antiangiogenic drugs, with no jaw radiotherapy or metastatic disease to the jaw. ^[21]

Incidence: 1:10,000 to 1:100,000

Risk factors: Age > 65, periodontitis, bisphosphonate use > 2 years, smoking, denture wearing, diabetes mellitus, invasive dental procedures (e.g. extractions).

Clinical implication: perform an oral assessment and optimise dental health before antiresorptive therapy; arrange professional dental review when disease or planned invasive work warrants it. Coordinate elective extractions individually, but do not create unnecessary treatment delay in a patient at imminent fracture risk. ^[15][21]

• Conservative management: symptoms usually improve in 6–8 weeks
• Start with multimodal conservative care: analgesia, safe early mobilisation, rehabilitation/fall prevention and osteoporosis treatment. Routine vertebral augmentation is not supported: sham-controlled trials show no clinically important benefit from vertebroplasty, and evidence for kyphoplasty remains insufficient. Exceptionally, a carefully selected patient with severe, recent, imaging-confirmed fracture pain despite optimal care may discuss augmentation after full explanation of uncertain benefit and risk. ^[15]
• Open surgical intervention for:
  • Significant neurological deficits
  • Progressive and severe kyphotic deformity
  • Intractable pain

• Operative management: Geriatric hip fracture clinical pathway ^[1]
• Surgery types depend on fracture location and displacement: ^[4]
  • Intracapsular (femoral neck): undisplaced → cannulated screws / DHS; displaced → hemiarthroplasty or THR
  • Extracapsular (intertrochanteric): DHS or cephalomedullary nail

• Usually non-operative: manipulation and cast application for 4–6 weeks
• Operative management in selected patients (e.g. intra-articular, unstable)

• Treat the underlying osteoporosis (pharmacological + non-pharmacological)
• Fall prevention measures ^[4]
• Secondary fracture prevention: Fracture Liaison Service model

1. MCQ: An elderly woman with back pain and height loss. X-ray shows wedge compression fracture. What is the diagnosis? → Osteoporotic vertebral compression fracture
2. MCQ: What is the gold standard investigation for diagnosing osteoporosis? → DXA
3. MCQ: T-score of −2.8 — what category? → Osteoporosis
4. SAQ: List 4 risk factors for osteoporosis → Female sex, increasing age, low body weight, premature menopause, glucocorticoid use, smoking, alcohol, family history, low calcium, sedentary lifestyle
5. MCQ: How does CKD affect antiresorptive choice? → Bisphosphonate renal limits are agent-specific (e.g. zoledronic acid CrCl < 35 mL/min); denosumab is not renally cleared but can cause severe hypocalcaemia in advanced CKD/CKD-MBD
6. MCQ: Side effect of teriparatide → Hypercalcaemia
7. MCQ: Mechanism of denosumab → Anti-RANKL monoclonal antibody
8. SAQ/Minicase: Management of osteoporotic vertebral fracture → Conservative multimodal care is first-line; routine augmentation is unsupported; urgent specialist assessment/surgery for neurological compromise or instability
9. MCQ: Romosozumab contraindication → History of MI or stroke
10. MCQ: ALP is elevated with back pain in elderly → Think osteomalacia or Paget's, NOT osteoporosis