• Osteoporosis is the most common metabolic bone disease ^[2]
• 1 osteoporotic fracture occurs every 3 seconds worldwide ^[2]
• Lifetime fracture risk:
  • 1 in 3 postmenopausal women ^[2][5]
  • 1 in 5 men aged ≥ 50 years ^[2]
  • Overall lifetime risk as high as 40% ^[2]

Prevalence in HK women (1995): 60–69 years: 1 in 6; 70–79 years: 1 in 5; ≥80 years: 1 in 4 ^[4]

• Hong Kong has an ageing population — the prevalence is expected to rise substantially
• Hip fracture is a major burden: Hong Kong reports approximately 4,000–5,000 hip fractures per year in the elderly
• Vertebral fractures are even more common but frequently undiagnosed (only ~1/3 come to clinical attention)

• Common sites of osteoporotic fractures: wrist, vertebrae, hip ^[2]
• Female predominance — loss of ovarian function at menopause leading to oestrogen deficiency precipitates rapid bone loss ^[3]

Normal bone is composed of trabecular bone (20% of mass, 80% of bone turnover) and cortical bone (80% of mass, 20% of bone turnover) ^[4]

Why does this matter? Because trabecular bone has a much higher turnover rate, it is the first to be affected by states that increase bone resorption (e.g., oestrogen deficiency). This is why:

• Vertebral fractures (trabecular-rich) occur earlier in postmenopausal women
• Distal radius (metaphysis = trabecular) is also affected early
• Hip fractures increase later because the femoral neck has a mix of cortical and trabecular bone

Bone remodelling occurs within basic multicellular units (BMUs) containing osteoclasts, osteoblasts, and osteocytes ^[4]

The remodelling cycle has two phases:

1. Osteoclastic resorption (30–40 days): Osteoclasts (derived from haematopoietic precursors) excavate bone, forming a resorption pit (Howship's lacuna). They signal osteoblasts to arrive ^[4].
2. Bone formation (≈150 days): Osteoblasts (derived from mesenchymal stem cells) lay down osteoid, which subsequently mineralises to form new bone ^[4].

Key point: Resorption is fast (~1 month) but formation is slow (~5 months). This asymmetry means anything that increases turnover rate will tip the balance towards net bone loss, because resorption outpaces formation.

Osteoporosis is a disease of bone turnover: resorption > production ^[5]

This is the master regulatory system of osteoclastogenesis and is the pharmacological target for several drugs:

• RANKL (Receptor Activator of Nuclear Factor κB Ligand): Expressed by osteoblasts/stromal cells; binds to RANK on osteoclast precursors → stimulates osteoclast differentiation, activation, and survival ^[4]
• Osteoprotegerin (OPG): A soluble decoy receptor secreted by osteoblasts; competitively inhibits the RANK–RANKL interaction → prevents osteoclastogenesis ^[4]
• M-CSF (Macrophage Colony-Stimulating Factor): Secreted by osteoblasts; promotes differentiation of osteoclast precursors ^[4]

The RANKL : OPG ratio determines net bone remodelling:

• High RANKL : OPG ratio → favours resorption → bone loss
• Low RANKL : OPG ratio → favours formation → bone preservation

Factors that ↑RANKL: dexamethasone, 1,25-(OH)₂D₃, PTH, PGE₂ → favours resorption ^[4]
Factors that ↓RANKL: 17β-oestradiol → favours formation ^[4]

Oestrogen acts to increase bone formation and decrease bone resorption by ^[4]:

• ↓ osteoblast apoptosis by ↓ TGF-β secretion
• ↓ osteoblast-induced osteoclastogenesis by ↓ cytokine secretion and ↓ RANKL expression
• ↑ osteoclast apoptosis by ↑ TNF-α secretion

So oestrogen does three things simultaneously:

1. Keeps osteoblasts alive longer → more bone formation
2. Prevents osteoblasts from activating osteoclasts → less resorption
3. Kills osteoclasts faster → less resorption

When oestrogen drops at menopause, all three protective mechanisms are lost simultaneously, leading to rapid bone loss in the first 5–10 years postmenopause (up to 2–3% per year at the spine).

• Peak bone mass is achieved at approximately age 25–30 ^[3][5]
• After peak, there is a slow, inevitable decline in BMD with age (~0.5–1% per year)
• In women, there is an accelerated phase of bone loss (2–3% per year) for 5–10 years after menopause, after which it decelerates
• Higher peak bone mass = larger "bone bank" = lower risk of osteoporosis later
• Factors that determine peak bone mass: genetics (60–80%), nutrition (calcium, vitamin D), physical activity, hormonal status

From the GC lecture slide ^[1]:

Clinical risk factors of osteoporosis:

• 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 immobilisation

Non-modifiable risk factors:

• Female sex — lower peak bone mass, plus oestrogen withdrawal at menopause
• Increasing age — cumulative bone loss; also increased fall risk
• Family history of osteoporosis or fragility fracture (genetics account for 60–80% of BMD variance)
• Ethnicity — Caucasian and Asian populations at higher risk than African populations (higher peak bone mass in African populations)
• Smaller bone frame — less reserve for bone mass ^[3]

Modifiable risk factors:

• Low body weight ( < 45 kg) — low mechanical loading stimulus; also low adipose tissue = less peripheral oestrogen conversion ^[1]
• Smoking — directly toxic to osteoblasts; anti-oestrogenic; reduces intestinal calcium absorption ^[1][3]
• Excessive alcohol intake ( > 3 standard drinks/day) — directly suppresses osteoblast function; increases fall risk ^[1]
• Low calcium intake / Lack of sun exposure — leads to vitamin D insufficiency → secondary hyperparathyroidism → increased resorption ^[1]
• Lack of exercise or sedentary lifestyle — bone responds to mechanical loading (Wolff's law); immobility leads to disuse osteoporosis ^[1]
• Prolonged immobilisation — extreme example of above (e.g., bedbound patients, spinal cord injury) ^[1]

Initial evaluation of osteoporosis — Drug history: ^[1]

• Increased risk of osteoporosis: glucocorticoid, PPI, anticonvulsants, thiazolidinediones
• Increased risk of fall: hypnotics, diuretics

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) ^[1]

Organised systematically:

Osteoporosis causes fragile bones, but fractures require a force — most commonly a fall. Therefore, fall prevention is equally important as treating bone density.

Fall risk assessment is critical in the elderly ^[4]:

• Agility, hearing, eyesight, postural sway
• Gait
• Mobility, muscle strength

Risk factors for falls:

• Intrinsic: visual impairment, vestibular dysfunction, peripheral neuropathy (diabetic), muscle weakness / sarcopenia, cognitive impairment, postural hypotension, previous falls
• Extrinsic (environmental): poor lighting, loose rugs, wet floors, lack of handrails, inappropriate footwear
• Medications that ↑ fall risk: hypnotics, diuretics ^[1], antihypertensives (postural hypotension), opioids, antipsychotics, antidepressants (SSRIs), anticonvulsants

Primary Osteoporosis (most common):

• Type I (Postmenopausal): Women within 15–20 years of menopause; primarily trabecular bone loss; driven by oestrogen deficiency
• Type II (Senile/Age-related): Both sexes, age > 70; involves both cortical and trabecular bone; driven by age-related decline in osteoblast function + secondary hyperparathyroidism (from vitamin D deficiency and renal impairment)

Secondary Osteoporosis: Due to an identifiable underlying cause (see table above)

By age 60, approximately half of women will have low bone mass or osteoporosis ^[4]

Clinically silent until the occurrence of fracture ^[2]

This is the key clinical paradox: osteoporosis itself produces no symptoms. It is a "silent disease" — patients feel well until they fracture. The clinical features discussed below are all consequences of fractures or findings on examination/investigation.

X-ray features: decreased bone density, cortical thinning, loss of trabeculae ^[7]

From the GC lecture slide ^[1]:

Initial evaluation of osteoporosis — 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
  • Increased risk of osteoporosis: glucocorticoid, PPI, anticonvulsants, thiazolidinediones
  • Increased risk of fall: hypnotics, diuretics

Physical examination approach ^[4]:

• Height and weight — document serial height measurements; BMI < 19 or weight < 45 kg increases risk
• Dental exam — loss of teeth and need for dentures (early sign of mandibular osteoporosis)
• Observe posture and estimate degree of kyphosis
• Examine for tenderness along the spine (percussion tenderness = possible acute fracture)
• Signs of secondary osteoporosis:
  • Signs of endocrine disease (e.g., Cushingoid features, thyroid eye signs)
  • Signs of myeloma (anaemia, bone tenderness, hypercalcaemia)
  • Signs of hypogonadism
• Fall assessment (critical in elderly):
  • Agility, hearing, eyesight, postural sway
  • Gait — observe for shuffling, wide base, Trendelenburg
  • Mobility, muscle strength — grip strength, chair stand test ("timed up and go")

• Available online (https://frax.shef.ac.uk) — country-specific algorithms (including Hong Kong)
• Uses clinical risk factors ± femoral neck BMD
• Estimates:
  • 10-year probability of major osteoporotic fracture (hip, spine, forearm, proximal humerus)
  • 10-year probability of hip fracture specifically

Age, sex, BMI, previous fragility fracture, parental history of hip fracture, current smoking, glucocorticoid use, rheumatoid arthritis, secondary osteoporosis, alcohol ≥ 3 units/day, femoral neck BMD (optional)

FRAX applies only to postmenopausal women or men ≥ 50 years who have NOT been treated. It does NOT apply to premenopausal women or younger adults ^[2]

Other limitations:

• Does not account for dose of glucocorticoids (just yes/no)
• Does not account for number of prior fractures
• Does not account for fall risk (a major limitation)
• Underestimates risk in patients with very high number of vertebral fractures

From the GC lecture slide ^[1]:

How is osteoporosis diagnosed?

Diagnostic Category	Definition
Normal	BMD within 1 SD of the young adult mean (T-score ≥ −1.0)
Osteopenia	BMD > 1 SD below the young adult mean, but < 2.5 SD below this value (T-score < −1.0 and > −2.5)
Osteoporosis	BMD ≥ 2.5 SD below the young adult mean (T-score ≤ −2.5)
Severe (established) osteoporosis	BMD ≥ 2.5 SD below the young adult mean (T-score ≤ −2.5) in the presence of ≥ 1 fragility fractures

Why −2.5 SD? This threshold was chosen because the prevalence of osteoporosis defined by T-score ≤ −2.5 roughly matches the lifetime fracture risk in postmenopausal women (~30%). It's a statistical cut-off, not a biological on/off switch — fracture risk is a continuum.

DXA is the only means for diagnostic classification of osteoporosis based on the WHO definition ^[2]

Clinical definition: 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][2]

This means: if a 70-year-old woman falls from standing and fractures her hip, she has osteoporosis clinically — even before you get a DXA. This clinical definition is important because:

• Many patients are diagnosed after their first fracture
• In resource-limited settings, DXA may not be available
• It guides immediate treatment decisions

Why T-score for postmenopausal women? Because even though bone loss is "expected" with ageing, it still increases fracture risk. Comparing to age-matched peers would falsely reassure elderly patients.

Why Z-score for younger patients? In premenopausal women or young men, you expect normal bone density. If the Z-score is ≤ −2.0, it means their BMD is worse than expected for their age → a secondary cause is driving the bone loss and must be investigated ^[6].

For every reduction of 1 SD in BMD, the fracture risk increases by 1.5 to 2 times overall ^[2]

More specifically:

• 1 SD ↓ BMD (by DXA at spine/hip/forearm) = 2× ↑ risk of hip fracture ^[4]

This gradient of risk makes BMD a continuous prognostic variable, not just a binary diagnostic tool.

DXA (sometimes written "DEXA") is the gold standard for diagnosing osteoporosis ^[1][2].

How it works: DXA fires two X-ray beams at different energy levels through bone. Bone absorbs more of one energy than the other depending on its mineral content. By comparing absorption of the two beams, the machine calculates areal BMD (g/cm²) — the amount of mineral per unit area of bone scanned.

Central DXA at the hip and spine — these are the locations where fractures have the greatest impact on life, and BMD measurements at these regions of interest are the best predictors of fracture risk for the corresponding sites ^[2]

Sites measured:

• Lumbar spine (L1–L4, anteroposterior view) — predominantly trabecular bone; best for monitoring treatment response (earliest changes seen here)
• Proximal femur — includes femoral neck and total hip; best predictor of hip fracture risk
• Distal 1/3 radius — used when spine/hip cannot be measured (e.g., bilateral hip replacement, severe degenerative spine disease, hyperparathyroidism, very obese patients) ^[9][12]

Interpretation: Report the lowest T-score from any of the measured sites for diagnosis.

Who should be screened with DXA?

• All women ≥ 65 years and men ≥ 70 years (universal screening)
• Postmenopausal women < 65 and men 50–69 with risk factors
• Anyone with a fragility fracture
• Anyone on long-term glucocorticoids (≥ 5 mg prednisolone for ≥ 3 months)
• Anyone with diseases known to cause secondary osteoporosis
• Monitoring response to treatment (repeat DXA at 1–2 year intervals)

FRAX is a prognostic tool for assessing 10-year probability of major osteoporotic fracture and hip fracture ^[2]

• Uses clinical risk factors ± femoral neck BMD
• Country-specific algorithms (including Hong Kong)
• Outputs: 10-year probability of (a) major osteoporotic fracture (hip, spine, forearm, proximal humerus) and (b) hip fracture

Applies only to postmenopausal women or men ≥ 50 years who have NOT been treated. Does NOT apply to premenopausal women or younger adults ^[2]

Limitations:

• Does not account for dose of glucocorticoids (just yes/no)
• Does not account for number or recency of prior fractures
• Does not include fall risk
• May underestimate in patients with very high fracture burden

Clinical utility: Used to guide treatment decisions in patients with osteopenia (T-score −1.0 to −2.5) — if the FRAX score exceeds a country-specific threshold, treatment is recommended even without a T-score ≤ −2.5.

X-ray is NOT a screening tool for osteoporosis (needs ~30–40% bone loss to be visible) but is essential for:

• Detecting fractures — vertebral compression fractures, hip fractures, Colles' fractures
• Excluding other causes of bone pain — metastases, myeloma lytic lesions, Paget's disease, infection

XR spine: thinning of cortex, codfish sign (biconcave vertebra), compression fracture ^[6]

X-ray features of osteoporosis:

• VFA by DXA: A lateral spine image obtained during the DXA scan to detect prevalent vertebral fractures
• Advantages: lower radiation dose than standard lateral spine X-ray; done at the same visit as BMD measurement
• Limitations: lower image resolution than conventional X-ray; may miss upper thoracic fractures
• Indicated when vertebral fracture is suspected but conventional radiography has not been done

Vertebral spine assessment (X-ray or Vertebral Fracture Assessment by DXA) is recommended in evaluation of primary hyperparathyroidism and suspected osteoporosis ^[12]

In selected patients: bone turnover markers, serum protein electrophoresis, serum and/or urinary cortisol, prolactin, anti-tissue transglutaminase antibodies ^[1]

The key discriminators are ALP (normal in osteoporosis, elevated in almost everything else), calcium (distinguishes hyperPTH and myeloma), and PTH (separates primary from secondary hyperPTH from non-PTH causes).

• Acute back pain in elderly → rule out vertebral compression fracture
• After a fall → detect fracture (hip, wrist, humerus, pelvis)
• Suspected malignancy or Paget's → characterise the lesion

• MRI spine: If neurological deficit (cord compression), if need to distinguish acute vs. chronic fracture (marrow oedema on STIR/T2), or if metastatic disease suspected
• Bone scan: Metastatic survey (but NOT for myeloma), Paget's disease assessment
• CT: When MRI contraindicated; skeletal survey for myeloma (whole-body low-dose CT now preferred over conventional skeletal survey)

ALP is normal in osteoporosis ^[1]

This is the single most useful biochemical distinction:

• Normal ALP → osteoporosis (or myeloma, which also has normal ALP)
• Elevated ALP → osteomalacia, Paget's, hyperPTH, or metastatic bone disease (blastic type)

Why is ALP normal in osteoporosis? Because ALP is an osteoblast marker. In osteoporosis, the problem is that resorption exceeds formation, but osteoblasts are not hyperactive — they're either normal or suppressed. In osteomalacia and Paget's, osteoblasts are working overtime (laying down osteoid in osteomalacia; disorganised remodelling in Paget's), so ALP rises.

Always use albumin-corrected calcium when interpreting serum calcium:

Corrected Ca²⁺ = Total Ca²⁺ + 0.02 × (40 − albumin in g/L) ^[14]

Why? About 50% of serum calcium is bound to albumin. If albumin is low (e.g., nephrotic syndrome, chronic liver disease, malnutrition), total calcium will appear falsely low even though the biologically active ionised calcium fraction is normal. The correction adjusts for this.

Calcium and vitamin D rich diet ± supplements (to prevent secondary hyperparathyroidism) ^[6]

Calcium sources: milk, yogurt, salmon, broccoli, orange. Vitamin D sources: fortified milk, egg, fish ^[6]

Practical points:

• Dietary calcium is preferred over supplements where possible — calcium supplements in high doses ( > 500 mg at once) may increase cardiovascular risk (controversial but prudent to advise dietary sources first)
• If supplements are needed, give calcium carbonate with meals (needs gastric acid for absorption) or calcium citrate (can be taken without food — better option for patients on PPIs, as PPI use can decrease calcium absorption ^[4])
• Always replenish vitamin D before starting antiresorptive therapy — starting a bisphosphonate or denosumab in a vitamin D–deficient patient can precipitate symptomatic hypocalcaemia

Vitamin D supplement in older people with confirmed 25-hydroxycholecalciferol deficiency ( < 50 nmol/L) who are housebound or experiencing falls or with osteopenia ^[16]

Regular weight-bearing exercise ^[4][6]

• Mechanism: Mechanical loading on bone stimulates osteoblast activity (Wolff's law — bone remodels in response to the forces placed on it). Impact and gravitational forces stimulate mechanosensory osteocytes embedded in bone matrix → they signal osteoblasts via sclerostin downregulation → more bone formation.
• Examples: Walking, jogging, dancing, stair climbing, resistance/strength training
• NOT: Swimming and cycling (non-weight-bearing — good for cardiovascular fitness but do not load bone)
• Additional benefits: improves muscle strength, balance, and coordination → reduces fall risk

Fall prevention and rehabilitation ^[6]

This is often under-emphasised but is arguably as important as pharmacotherapy in the elderly. Components include:

• Medication review: stop or reduce hypnotics, diuretics, and other drugs that increase fall risk ^[1]
• Vision assessment and correction: refer for ophthalmology/optometry review
• Home safety evaluation: remove loose rugs, improve lighting, install handrails and grab bars, non-slip mats
• Physiotherapy: balance training, gait retraining, Tai Chi (evidence-based for fall reduction), muscle strengthening
• Assistive devices: walking aids (stick → tripod → walking frame → rollator) as appropriate
• Postural hypotension management: review antihypertensives, advise slow position changes
• Footwear: low heels, high surface contact area ^[15]

Treatment of osteoporosis reduces hip fractures in single interventions in the falls prevention literature ^[15]

Quit smoking and alcohol ^[6] Sunlight exposure — especially important in institutionalised patients ^[4]

• Smoking: directly toxic to osteoblasts, anti-oestrogenic, reduces intestinal calcium absorption
• Alcohol: > 3 units/day directly suppresses osteoblast function AND increases fall risk

Always treat the underlying condition if secondary osteoporosis is identified:

• Cushing's syndrome → control hypercortisolism
• Hyperthyroidism → normalise thyroid function
• Hypogonadism → hormone replacement
• Coeliac disease → gluten-free diet
• Primary hyperparathyroidism → parathyroidectomy if indicated
• CKD-MBD → phosphate binders, vitamin D analogues, PTH control ^[8]

Name breakdown: "bis" = two, "phosphonate" = phosphate group. Bisphosphonates have two phosphonate groups that bind avidly to hydroxyapatite on the bone surface.

Bisphosphonates attach to bone surface and inhibit osteoclast-mediated bone resorption ^[17]

Mechanism of action (detailed):

1. Bisphosphonates are incorporated into bone matrix by binding to hydroxyapatite at sites of active resorption
2. When osteoclasts resorb the bone, they ingest the bisphosphonate
3. Nitrogen-containing bisphosphonates (alendronate, risedronate, zoledronate) inhibit farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway within osteoclasts
4. This blocks prenylation of small GTPases (Ras, Rho, Rac) → osteoclast cytoskeletal disruption, loss of ruffled border, inability to form resorption pits → osteoclast apoptosis
5. Net result: reduced bone resorption → preservation and gradual increase in BMD

Pharmacokinetics: bound to bone (40–60%); remainder excreted unchanged through kidney (both glomerular filtration and active tubular secretion) ^[17]

This renal excretion is critical — bisphosphonates are contraindicated in severe renal impairment (eGFR < 30–35 mL/min).

Commonly used bisphosphonates:

Instructions for oral bisphosphonates (extremely important for efficacy and safety):

• Take on an empty stomach, first thing in the morning
• Swallow with a full glass of plain water (not mineral water, juice, or tea)
• Remain upright (sitting or standing) for ≥ 30 minutes after taking
• Do not eat, drink, or take other medications for ≥ 30 minutes after
• Why? Oral bisphosphonates have extremely poor bioavailability (~1%) — food, calcium, and other minerals chelate them and prevent absorption. The upright posture prevents oesophageal irritation/ulceration.

Side effects:

Bisphosphonates for osteoporosis — side effects: GI upset (most common), jaw osteonecrosis, atypical femoral fractures ^[7]

Contraindications to oral bisphosphonates:

• Oesophageal disorders (stricture, achalasia, inability to remain upright)
• Hypocalcaemia (must correct first)
• eGFR < 30–35 mL/min
• Pregnancy/breastfeeding
• Known hypersensitivity

Contraindications to IV bisphosphonates:

• eGFR < 35 mL/min ^[9]
• Hypocalcaemia (correct first)

Name breakdown: "de" = against, "nos" = ? (brand derivation), "umab" = fully human monoclonal antibody.

Denosumab is a monoclonal antibody against RANKL. RANKL causes increased formation, function and survival of osteoclasts → inhibiting RANKL leads to less osteoclasts → less bone resorption, calcium levels fall ^[9]

Mechanism: Denosumab binds to RANKL (Receptor Activator of Nuclear Factor κB Ligand) and prevents it from binding to RANK on osteoclast precursors. This is essentially a pharmacological mimic of osteoprotegerin (OPG) — the body's natural RANKL decoy receptor.

Dosing: 60 mg subcutaneous injection every 6 months

Advantages over bisphosphonates:

• Not excreted through kidneys — can be given to CKD patients (this is a major advantage when bisphosphonates are contraindicated due to renal impairment) ^[9]
• No GI side effects
• Simple dosing (twice yearly injection)
• Consistently superior BMD gains at most sites

Side effects:

• Hypocalcaemia (must ensure adequate calcium and vitamin D supplementation; higher risk in CKD)
• ONJ and atypical femoral fractures (similar to bisphosphonates, but lower incidence)
• Infections (slightly increased risk of cellulitis, skin infections — RANKL/RANK pathway has roles in immune function)

Critical issue — Rebound effect on discontinuation:

Anti-resorptive treatment after discontinuation of at least two doses of denosumab (rebound increased bone turnover markers, BMD loss, and increased risk of vertebral fracture following denosumab discontinuation) ^[16]

This is a key exam point: unlike bisphosphonates (which remain stored in bone for years after stopping), denosumab is a circulating antibody that is cleared within ~6 months. When you stop denosumab:

• RANKL is suddenly unopposed → massive surge in osteoclastogenesis
• Rapid BMD loss (can lose all the gains from years of therapy within 12–18 months)
• Rebound vertebral fractures — multiple vertebral compression fractures can occur
• Must transition to a bisphosphonate (e.g., zoledronate or alendronate) before or at the time of denosumab discontinuation to prevent rebound

Name breakdown: "ral" = brand prefix, "oxifene" = oestrogen-receptor modulator.

Mechanism: Raloxifene is a SERM that acts as an oestrogen agonist on bone (mimics oestrogen's bone-protective effects → ↓ osteoclast activity) but as an oestrogen antagonist on breast and uterine tissue (anti-oestrogenic → no increased breast or endometrial cancer risk, actually reduces breast cancer risk).

Indications:

• Postmenopausal osteoporosis in women at moderate fracture risk
• Particularly useful if the patient also has elevated breast cancer risk (dual benefit)

Efficacy: Reduces vertebral fracture risk by ~30–40%, but no proven reduction in hip fracture — so it is a second-line agent for most patients.

Side effects / Contraindications:

• Increased risk of venous thromboembolism (VTE) — DVT, PE (oestrogen agonist effect on coagulation)
• Hot flushes (anti-oestrogenic effect centrally)
• Leg cramps
• Contraindicated: active or past VTE, immobilisation, pregnancy

Name breakdown: "teri" = brand, "paratide" = parathyroid peptide.

Mechanism: Teriparatide is a recombinant fragment of PTH (amino acids 1–34). This seems paradoxical — doesn't PTH cause bone resorption? The key is the pattern of exposure:

• Chronic continuous PTH elevation (as in hyperparathyroidism) → predominantly bone resorption
• Intermittent pulsatile PTH exposure (as with once-daily injection) → predominantly bone formation

The intermittent pulse of PTH stimulates osteoblasts more than osteoclasts → increased osteoblast proliferation, differentiation, and survival → new bone formation (especially trabecular bone). It literally builds new bone, unlike antiresorptives which only slow bone loss.

Dosing: 20 μg subcutaneous injection once daily (self-administered)

Duration: Maximum 2 years — there is a theoretical concern about osteosarcoma based on animal studies (rats given high-dose continuous PTH developed osteosarcoma). This risk has not been confirmed in humans, but the time limit remains.

Anti-resorptive treatment after discontinuation of teriparatide/abaloparatide treatment for osteoporosis ^[16]

Critical point: After completing the 2-year course, the BMD gains will be lost unless you consolidate with an antiresorptive agent (bisphosphonate or denosumab). This is called the "anabolic-first, then antiresorptive" sequential strategy.

Indications:

• Very high fracture risk: multiple vertebral fractures, very low T-score ( < −3.0 to −3.5), fracture on existing antiresorptive therapy
• Glucocorticoid-induced osteoporosis (severe cases)
• Patients who have failed or cannot tolerate bisphosphonates/denosumab

Contraindications:

• Open epiphyses (children/adolescents)
• Pre-existing hypercalcaemia
• Severe renal impairment (PTH fragments accumulate)
• Unexplained ↑ ALP
• Prior radiation therapy to the skeleton
• Bone metastases or skeletal malignancy
• Paget's disease
• Pregnancy/breastfeeding

Side effects:

• Transient hypercalcaemia
• Nausea, dizziness, leg cramps
• Injection site reactions
• Theoretical osteosarcoma risk (from animal data)

Name breakdown: "romo" = brand, "sozumab" = sclerostin-targeting monoclonal antibody ("so" = sclerostin, "zu" = humanised, "mab" = monoclonal antibody).

Mechanism: Sclerostin is a protein produced by osteocytes that inhibits the Wnt signalling pathway in osteoblasts → suppresses bone formation. Romosozumab binds and neutralises sclerostin → dual effect:

1. ↑ Bone formation (Wnt pathway disinhibited → osteoblast activation)
2. ↓ Bone resorption (through downstream effects on RANKL/OPG balance)

This unique dual mechanism produces the most rapid BMD gains of any osteoporosis therapy.

Dosing: 210 mg subcutaneous monthly for 12 months (limited duration)

Key clinical consideration: Must be followed by antiresorptive therapy to consolidate gains.

Contraindications / Cautions:

• Cardiovascular risk: Clinical trials showed a signal of increased MI and stroke → contraindicated in patients with recent MI/stroke (within 1 year) or high cardiovascular risk
• Hypocalcaemia (correct first)
• Hypersensitivity

Side effects:

• Injection site reactions
• Arthralgia
• Headache
• ONJ and atypical femoral fractures (rare, as with all antiresorptives)
• Cardiovascular events (the main concern)

Mechanism: Oestrogen directly protects bone by ↓ RANKL, ↑ OPG, ↓ osteoblast apoptosis, ↑ osteoclast apoptosis (as detailed in Part 1).

Current role in osteoporosis: HRT is effective for fracture prevention but is no longer recommended as first-line osteoporosis therapy due to the increased risk of:

• Breast cancer (with combined oestrogen + progesterone HRT beyond 5 years)
• Venous thromboembolism
• Stroke
• Cardiovascular events (in older postmenopausal women starting HRT late)

When to consider: Women with menopausal symptoms (vasomotor, urogenital) who are within 10 years of menopause or under age 60 and who also need osteoporosis prevention. In this window, the benefit–risk ratio is more favourable.

Mechanism: Calcitonin (from salmon = "sal-calcitonin") directly inhibits osteoclast activity by binding to calcitonin receptors on osteoclasts → ↓ resorption. Also has analgesic properties for vertebral fracture pain.

Calcitonin: relatively weak agent but works rapidly within hours. Not first-line; given subcutaneously every 12 hours. Tachyphylaxis is a limitation ^[9]

Current role: Rarely used for osteoporosis treatment due to weak antiresorptive effect and tachyphylaxis. Main indication now is short-term pain management in acute vertebral compression fractures (nasal spray).

Concerns: Long-term use associated with a possible slight increase in cancer risk → regulatory agencies have restricted its use to short courses.

• Any patient on ≥ 5 mg prednisolone for ≥ 3 months should receive calcium + vitamin D + bisphosphonate from the start
• Alendronate or risedronate (oral) or zoledronate (IV) are first-line
• Teriparatide is preferred in severe GIOP (it counteracts the primary mechanism — glucocorticoids mainly suppress osteoblasts, and teriparatide stimulates them)

• Same pharmacological agents are used (alendronate, risedronate, zoledronate, denosumab, teriparatide all have evidence in men)
• Always check testosterone — hypogonadism is a common and treatable cause
• Consider testosterone replacement if hypogonadal (but testosterone alone is usually insufficient; combine with osteoporosis-specific therapy)

• Bisphosphonates contraindicated if eGFR < 30–35 mL/min
• Denosumab can be used (not renally excreted) ^[9] — but monitor calcium closely (high risk of hypocalcaemia in CKD)
• CKD stage 4–5: bone disease is often renal osteodystrophy/CKD-MBD rather than simple osteoporosis → consult nephrology; may need phosphate binders, calcitriol, cinacalcet rather than standard osteoporosis drugs ^[8]

Bone mineral density should be assessed at time of diagnosis of PBC and at 2-yearly intervals thereafter. Vitamin D and calcium supplementation. Bisphosphonate therapy if evidence of osteoporosis — alendronate ^[18]

• Pioglitazone (thiazolidinedione) — diverts mesenchymal stem cells from osteoblast to adipocyte lineage → ↓ bone formation ^[19]
• Canagliflozin (SGLT2i) — may cause low bone mass, increased fracture risk ^[19]
• These two drugs share the side effect of increasing fracture risk and should be avoided in patients with osteoporosis ^[19]

Vertebral fractures are the most common osteoporotic fracture, yet the majority (~2/3) are clinically silent or present insidiously. Their complications are cumulative:

Vertebroplasty — a palliative procedure for patients with collapsed vertebral bodies due to osteoporosis — can be considered for pain relief ^[20]

Hip fractures are the most serious complication of osteoporosis. They carry enormous mortality and morbidity.

Though less devastating than hip fracture, Colles' fractures have their own complications:

• Proximal humerus: difficulty with overhead activities; rotator cuff dysfunction; axillary nerve injury
• Rib fractures: pain with breathing → splinting → atelectasis → pneumonia
• Pelvic (sacral insufficiency) fractures: severe pain, difficulty with mobility, may mimic cauda equina syndrome or visceral pathology

Bisphosphonates for osteoporosis: side effects — GI upset (most common), jaw osteonecrosis, atypical femoral fractures ^[7]

Question 29 from 2023 Fourth Summative MCQ: A 75-year-old woman who had a history of multiple fragility fractures decided to start teriparatide for her osteoporosis. Which of the following is a known side effect of teriparatide? Answer: B. Dizziness ^[21]

When osteoporosis is secondary to glucocorticoid use (e.g., in GCA, RA, dermatological conditions), the steroid itself creates a cycle of complications:

Increased infections and osteoporosis with steroids. Recommend fracture prevention and GI prophylaxis. ^[22]

In the context of GCA treatment: corticosteroid side effects to consider include osteoporosis, DM, hepatitis, increased CV risk — hence the need for bisphosphonates or more potent agents for bone protection ^[10]