PharmacologyTier 1Medical Sciences concept

Osteoporosis drug mechanisms (teriparatide, denosumab/RANKL, bisphosphonates, SERMs)

Core concept

Every agent acts on the RANKL / RANK / OPG axis or on osteoblast Wnt signalling
- Osteoblast RANKL -> osteoclast precursor RANK -> differentiation, activation, survival
- OPG is the decoy receptor for RANKL

Antiresorptive

Bisphosphonates - bind hydroxyapatite at resorption sites, taken up by osteoclasts
- N-containing (alendronate, risedronate, zoledronic acid) inhibit farnesyl pyrophosphate synthase in the mevalonate pathway
- dec prenylation of GTPases -> loss of ruffled border -> osteoclast apoptosis
- Skeletal half-life measured in years -> residual effect after stopping
Denosumab - human mAb to RANKL; a pharmacological OPG mimic
- dec osteoclast formation, function and survival
- Not incorporated into bone -> effect fully reversible
SERMs (raloxifene) - ER agonist in bone, antagonist in breast

Anabolic

Teriparatide PTH(1-34) - intermittent daily dosing is anabolic; continuous PTH is catabolic
- Osteoblast PTH1R -> inc RUNX2, dec sclerostin -> inc bone formation
Romosozumab - mAb to sclerostin -> Wnt disinhibition
- Dual action - inc formation and dec resorption

Agent	Target	Route / duration	Key caution
Alendronate	FPPS	70 mg weekly PO	Oesophagitis; F ~1%
Zoledronic acid	FPPS	5 mg IV yearly	Acute phase reaction, dec Ca; eGFR >35
Denosumab	RANKL	60 mg SC 6-monthly	Rebound vertebral fractures on cessation
Raloxifene	ER	60 mg daily PO	inc VTE, hot flushes; dec breast cancer
Teriparatide	PTH1R	20 mcg SC daily, max 24 months	dec in prior skeletal radiotherapy
Romosozumab	Sclerostin	210 mg SC monthly, 12 months only	MI/stroke warning - avoid if CVD in past 12 months

Oral bisphosphonate bioavailability ~1%, abolished by food, calcium, coffee
- Empty stomach, plain water, upright 30 min
Correct vitamin D and calcium before any antiresorptive - hypocalcaemia risk, worst with denosumab in CKD
Denosumab must never simply be stopped - rapid rebound resorption, multiple vertebral fractures within 3-18 months
- Follow with zoledronic acid or oral bisphosphonate; do not delay the 6-monthly dose beyond ~7 months
Sequence matters - anabolic first, then antiresorptive
- Romosozumab -> alendronate/denosumab beats the reverse (ARCH, FRAME)
- Teriparatide after a bisphosphonate blunts the BMD gain

Very high risk (recent vertebral fracture, multiple fractures, T-score < -3.0) -> start anabolic, then lock in with an antiresorptive
Build bone then lock it in
Osteonecrosis of the jaw and atypical femoral fracture - both classes, risk rises with duration; dental clearance before IV bisphosphonate or denosumab
- Prodromal thigh/groin pain -> image both femora
Bisphosphonate drug holiday after 5 years oral / 3 years IV in moderate risk; no equivalent holiday exists for denosumab
Glucocorticoid-induced osteoporosis - treat early, fractures occur at higher BMD than in postmenopausal disease
Teriparatide is a good choice where the fracture is already established and healing is needed

Bone remodelling - RANK/RANKL/OPG pathway regulation
Glucocorticoid-induced osteoporosis; endocrine risk factors for fragility fracture
Vitamin D metabolism; calcium-sensing receptor
Selective estrogen receptor modulators - tamoxifen vs raloxifene
Denosumab in malignancy - hypercalcaemia, skeletal-related events

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