Drugs Used in Osteoporosis

Osteoporosis pharmacology is a perennial NEET PG favourite from Pharmacology and Medicine, blending mechanism-of-action MCQs with adverse-effect recognition and the "which drug after a fragility fracture" clinical vignette. Master the antiresorptive-versus-anabolic divide, the signature toxicities (ONJ, atypical femur fracture), and the few high-yield cut-offs and you have most marks in the bag.

Definition & the core therapeutic divide

Osteoporosis is a systemic skeletal disease of low bone mass and micro-architectural deterioration leading to increased fragility and fracture risk. WHO densitometric definition: T-score ≤ −2.5 (osteoporosis), −1.0 to −2.5 (osteopenia), ≥ −1.0 (normal). Bone is in constant turnover — osteoclasts resorb, osteoblasts form. Drugs act on one of two arms.

Class	Mechanism arm	Example drugs	Net effect on BMD
Antiresorptive	↓ Osteoclast activity/survival	Bisphosphonates, denosumab, raloxifene, oestrogen, calcitonin	Stabilise/modestly raise BMD
Anabolic (osteoanabolic)	↑ Osteoblast bone formation	Teriparatide, abaloparatide, romosozumab	Robust BMD gain, new bone
Dual / mixed	↑ Formation + ↓ resorption	Romosozumab (sclerostin inhibitor)	Largest short-term gain
Supplements	Substrate/permissive	Calcium, vitamin D	Permissive, adjunctive

High-yield: The single most-tested concept is the antiresorptive vs anabolic classification. Teriparatide, abaloparatide and romosozumab are the only true anabolics; everything else commonly listed is antiresorptive.

Bisphosphonates — the first-line workhorses

Bisphosphonates are stable pyrophosphate analogues (a non-hydrolysable P–C–P backbone) that bind avidly to hydroxyapatite at sites of active remodelling. When osteoclasts resorb the mineral, they ingest the drug and undergo apoptosis.

Two pharmacological generations:

• Non-nitrogen-containing (etidronate, clodronate, tiludronate): metabolised to a toxic non-hydrolysable ATP analogue that triggers osteoclast apoptosis. Largely historical.
• Nitrogen-containing / aminobisphosphonates (alendronate, risedronate, ibandronate, zoledronic acid, pamidronate): inhibit farnesyl pyrophosphate synthase (FPPS) in the mevalonate pathway. This blocks prenylation of small GTPases (Ras, Rho, Rac), disrupting the osteoclast cytoskeleton/ruffled border → apoptosis. These are far more potent.

High-yield: Nitrogen-containing bisphosphonates inhibit farnesyl pyrophosphate synthase (mevalonate pathway). This exact enzyme is a repeat one-liner.

Pharmacokinetics worth remembering:

• Oral bioavailability is dismal (<1%) and abolished by food, calcium, coffee.
• Dosing rule: take on an empty stomach with a full glass of plain water, remain upright (sitting/standing) for at least 30 minutes (60 min for ibandronate) — prevents pill oesophagitis.
• Long skeletal half-life (years) — drug remains buried in bone, the basis for a "drug holiday."
• Renally excreted unchanged → avoid if eGFR < 30–35 mL/min.

Bisphosphonate	Typical route/frequency	Niche
Alendronate	Oral weekly	First-line PMO osteoporosis
Risedronate	Oral weekly/monthly	Better GI tolerance
Ibandronate	Oral monthly / IV q3-monthly	Vertebral fracture data
Zoledronic acid	IV once yearly	Adherence problems, post-hip-fracture
Pamidronate / zoledronic acid	IV	Hypercalcaemia of malignancy, Paget, bone mets

Adverse effects (heavily tested):

1. Pill oesophagitis / GI upset — oral agents.
2. Acute-phase reaction — flu-like fever/myalgia within 24–72 h of the first IV zoledronic/pamidronate dose; self-limiting, paracetamol helps.
3. Hypocalcaemia — correct vitamin D deficiency before starting (especially IV).
4. Osteonecrosis of the jaw (ONJ) — exposed necrotic jaw bone; risk highest with IV high-dose oncology regimens + dental extraction. Dental clearance before therapy.
5. Atypical femoral fractures (AFF) — subtrochanteric/diaphyseal, transverse, often bilateral, preceded by prodromal thigh pain; linked to long (>5 yr) use → rationale for drug holiday.
6. Atrial fibrillation and ocular inflammation (scleritis/uveitis) — less commonly examined.

High-yield: ONJ + atypical (subtrochanteric, transverse, bilateral) femoral fracture are the bisphosphonate "signature" toxicities. Prodromal thigh pain in a long-term bisphosphonate user = think AFF and image the femur.

High-yield: Always check and replete vitamin D and correct hypocalcaemia before IV zoledronic acid — otherwise severe symptomatic hypocalcaemia.

Denosumab — RANK-L inhibitor

A fully human monoclonal antibody against RANK-L (receptor activator of NF-κB ligand). Osteoblasts/stromal cells express RANK-L, which binds RANK on osteoclast precursors to drive their differentiation and survival. Osteoprotegerin (OPG) is the natural decoy receptor for RANK-L. Denosumab mimics OPG → potent suppression of osteoclastogenesis.

• Dose: 60 mg subcutaneously every 6 months (osteoporosis); 120 mg monthly for bone metastases/giant cell tumour of bone.
• Not renally cleared → usable in renal impairment (a key advantage over bisphosphonates).
• Adverse effects: hypocalcaemia (check vit D first), ONJ, atypical femur fractures, cellulitis/skin infection.

High-yield: Effect is NOT retained in bone — denosumab does not bind hydroxyapatite. Stopping it causes a rebound increase in bone turnover with multiple vertebral fractures. Never simply discontinue; transition to a bisphosphonate. (Contrast with bisphosphonates, where a holiday is safe.)

RANK–RANKL–OPG axis flow: Osteoblast RANK-L → binds RANK on osteoclast precursor → osteoclast maturation/survival → bone resorption. OPG (and denosumab) intercept RANK-L → resorption ↓.

Teriparatide & abaloparatide — anabolic PTH analogues

Teriparatide = recombinant PTH(1-34); abaloparatide is a PTHrP(1-34) analogue. The paradox: continuous high PTH (e.g., hyperparathyroidism) causes net bone resorption, but intermittent once-daily injection preferentially stimulates osteoblasts → net bone formation. This is the classic "intermittent vs continuous" MCQ.

• Route: daily subcutaneous injection.
• Strongly reduces vertebral and non-vertebral fractures; preferred in severe osteoporosis / very high fracture risk / multiple vertebral fractures / glucocorticoid-induced osteoporosis.
• Course limited to 2 years (lifetime) because of an osteosarcoma signal seen in rats.
• After stopping, must follow with an antiresorptive (bisphosphonate/denosumab) to lock in gains.

Contraindications / cautions (osteosarcoma-risk states): Paget disease, prior skeletal irradiation, open epiphyses (children/young adults), unexplained raised alkaline phosphatase, bone metastases, hypercalcaemia.

High-yield: Teriparatide is given intermittently (daily SC) to be anabolic; continuous PTH is catabolic. Maximum 24 months; contraindicated where osteosarcoma risk is raised (Paget, prior radiation, open epiphyses).

Romosozumab — sclerostin inhibitor (dual action)

Monoclonal antibody against sclerostin, a Wnt-pathway inhibitor secreted by osteocytes. Blocking sclerostin disinhibits Wnt signalling → ↑ bone formation and simultaneously ↓ resorption — a dual effect giving rapid BMD gains.

• Monthly SC for 12 months, then follow with an antiresorptive.
• Black-box cardiovascular warning — avoid within 1 year of MI/stroke.

Raloxifene — SERM

A selective oestrogen receptor modulator: agonist on bone (antiresorptive, ↑ BMD, reduces vertebral fractures) and breast/uterus antagonist (so reduces ER-positive breast cancer risk, no endometrial stimulation).

• Best niche: postmenopausal woman who also needs breast cancer risk reduction, or who cannot take bisphosphonates.
• Limited efficacy at the hip / non-vertebral sites.
• Adverse: hot flushes, leg cramps, and crucially venous thromboembolism (DVT/PE) — same class risk as tamoxifen.

High-yield: Raloxifene = bone/lipid agonist, breast/endometrium antagonist; main toxicity is VTE, and it reduces ER+ breast cancer risk. Reduces vertebral but not hip fractures.

Oestrogen / HRT & calcitonin (secondary agents)

• Oestrogen (HRT): antiresorptive, prevents bone loss, but no longer first-line for osteoporosis alone because of breast cancer, VTE and cardiovascular risks (WHI data). Useful for vasomotor symptoms.
• Calcitonin (salmon): weak antiresorptive; nasal spray. Notable for an analgesic effect on acute vertebral compression fracture pain. Concern over long-term malignancy risk limits use.

Calcium & vitamin D — the permissive backbone

Every regimen sits on adequate calcium (≈1000–1200 mg/day) and vitamin D (800–1000 IU/day; target 25-OH-D > 30 ng/mL).

• Vitamin D → hepatic 25-hydroxylation → renal 1-α-hydroxylase → calcitriol (1,25-(OH)₂-D), the active form promoting intestinal calcium absorption.
• Calcitriol/alfacalcidol preferred in renal failure (kidney cannot 1-α-hydroxylate).
• Calcium carbonate (needs acid, take with food) vs calcium citrate (acid-independent, better with PPIs/achlorhydria).

High-yield: Correcting vitamin D and calcium is mandatory before any potent antiresorptive (especially IV zoledronate or denosumab) to avoid severe hypocalcaemia.

Drug selection after a fragility fracture — the exam vignette

Stepwise approach:

1. Confirm fragility fracture / T-score ≤ −2.5 / high FRAX risk.
2. Correct calcium & vitamin D.
3. First-line = oral bisphosphonate (alendronate/risedronate) for most.
4. IV zoledronic acid if oral intolerance, poor adherence, or after hip fracture (mortality benefit shown).
5. Renal impairment (eGFR <30) → denosumab (avoid bisphosphonates).
6. Very severe / multiple vertebral fractures / glucocorticoid-induced → anabolic first (teriparatide or romosozumab), then antiresorptive.
7. Postmenopausal woman needing breast-cancer chemoprophylaxis → raloxifene.

High-yield: After a hip fracture, IV zoledronic acid is the evidence-backed choice (reduces refracture and mortality). In CKD/low eGFR, choose denosumab over bisphosphonates.

Glucocorticoid-induced osteoporosis (GIOP)

Most common cause of secondary/drug-induced osteoporosis. Steroids ↓ osteoblast function and ↑ osteoclast activity/RANK-L, plus ↓ intestinal calcium absorption. Bone loss is fastest in the first months. Treat with bisphosphonates (first-line); teriparatide is particularly effective and often preferred in high-dose chronic steroid users.

Complications & monitoring

• Monitor serum calcium before/after potent antiresorptives.
• Dental evaluation before bisphosphonate/denosumab to mitigate ONJ.
• Reassess BMD by DXA every 1–2 years; bone turnover markers (CTX, P1NP) optionally track response.
• Consider bisphosphonate drug holiday after 3–5 years in lower-risk patients (because drug persists in bone) — does not apply to denosumab.

Key differentials / look-alike comparisons

Feature	Bisphosphonate	Denosumab	Teriparatide	Raloxifene
Class	Antiresorptive	Antiresorptive	Anabolic	SERM (antiresorptive)
Target	FPP synthase	RANK-L	PTH receptor (intermittent)	Oestrogen receptor
Route	Oral/IV	SC q6 months	Daily SC	Oral
Retained in bone	Yes (holiday OK)	No (rebound on stopping)	No	No
Signature harm	ONJ, AFF, oesophagitis	Hypocalcaemia, rebound #, ONJ	Osteosarcoma signal (rat)	VTE
Renal use	Avoid <30	Safe	Caution	OK

Mnemonics:

• "BRD-A" for the big four: Bisphosphonate, RANK-L (denosumab), Donor PTH (teriparatide anabolic), Antibody sclerostin (romosozumab).
• ONJ + AFF = Bisphosphonate "Jaw and Femur."
• Raloxifene: "Bone friend, Vein foe" (good for bone, causes VTE).

Recently asked / exam angle

• MOA of nitrogen-containing bisphosphonates → farnesyl pyrophosphate synthase inhibition (recurrent single-best-answer).
• Mechanism of denosumab → RANK-L monoclonal antibody; and why stopping causes rebound vertebral fractures.
• Why teriparatide must be given intermittently to be anabolic; its 2-year cap and osteosarcoma contraindications.
• Adverse-effect matching: ONJ / atypical femoral fracture → bisphosphonate; VTE → raloxifene; acute-phase reaction → first IV zoledronate.
• Drug of choice in CKD (denosumab) and after hip fracture (IV zoledronic acid).
• Romosozumab = anti-sclerostin with a cardiovascular black-box warning — newer favourite.
• Calcitonin's analgesic role in acute vertebral fracture.

Rapid revision

1. Nitrogen bisphosphonates inhibit farnesyl pyrophosphate synthase → osteoclast apoptosis.
2. Take oral bisphosphonate empty stomach, full water, stay upright 30 min (avoid pill oesophagitis).
3. Zoledronic acid = once-yearly IV; first dose → flu-like acute-phase reaction.
4. Bisphosphonate signature toxicities: osteonecrosis of jaw + atypical (subtrochanteric, transverse, bilateral) femoral fracture; prodromal thigh pain → image femur.
5. Denosumab = anti-RANK-L mAb, SC every 6 months, safe in renal failure, never abruptly stop (rebound fractures).
6. Teriparatide = PTH(1-34), intermittent daily SC is anabolic; max 2 years; avoid in Paget/prior radiation/open epiphyses.
7. Romosozumab = anti-sclerostin, dual action, cardiovascular black-box.
8. Raloxifene = SERM: bone agonist, breast/endometrium antagonist; main risk VTE; reduces vertebral (not hip) fractures.
9. OPG is the natural RANK-L decoy; denosumab mimics it.
10. Correct calcium + vitamin D before IV zoledronate or denosumab to prevent hypocalcaemia.
11. Hip fracture → IV zoledronic acid (cuts refracture + mortality); CKD eGFR <30 → denosumab.
12. Calcium ~1000–1200 mg/day + vitamin D 800–1000 IU/day are the permissive backbone; calcitriol in renal failure.