Antiresorptive drugs: bisphosphonates and denosumab

At a glance

• Bone is remodelled by osteoclasts (resorb, driven by RANKL from osteoblasts and osteocytes) and osteoblasts (form). Osteoporosis is resorption outpacing formation.
• Bisphosphonates concentrate in bone and kill osteoclasts. Denosumab blocks RANKL so osteoclasts aren't formed or activated.
• The pharmacokinetics differ completely: bisphosphonates persist in the skeleton for years; denosumab wears off in months.
• Paper 1 tests the molecular mechanisms, the dosing rules that follow from absorption, the denosumab rebound, and rare adverse effects.
• Treatment thresholds and PBS criteria: osteoporosis. After a hip fracture: fragility fractures.

Bisphosphonates

Chemistry and mechanism

Bisphosphonates are analogues of pyrophosphate with a P-C-P backbone that resists hydrolysis. They bind hydroxyapatite, most avidly where bone is exposed and actively remodelling, and are taken up by osteoclasts as they resorb.

Group	Drugs	Mechanism
Nitrogen-containing	Alendronate, risedronate, zoledronic acid (most potent), ibandronate, pamidronate	Inhibit farnesyl pyrophosphate synthase; GTPases aren't prenylated; ruffled border lost; apoptosis
Non-nitrogen	Etidronate, clodronate	Metabolised to toxic, non-hydrolysable ATP analogues

Pharmacokinetics that shape practice

• Oral bioavailability under 1%. Food, coffee, orange juice, calcium and iron cut it further. Hence: fasting, plain water, wait 30 minutes (alendronate, standard risedronate). The exception is enteric-coated risedronate 35 mg weekly (Actonel EC), which is taken straight after breakfast.
• About half the absorbed dose binds bone; the rest is excreted unchanged in urine within hours. Avoid alendronate and risedronate below CrCl about 30 to 35 mL/min, and zoledronic acid below 35 mL/min (infuse over at least 15 minutes, hydrated).
• Bound drug is released slowly as bone remodels, with a terminal half-life of more than 10 years. Effect persists after stopping, which is the basis for drug holidays.

Worked example: absorption. Alendronate 70 mg weekly at 0.6% bioavailability puts about 0.4 mg into the circulation. Coffee or orange juice cuts absorption by about 60%, to about 0.17 mg. Taken with breakfast, or up to 2 hours after it, absorption is negligible, and even dosing 30 to 60 minutes before breakfast (rather than 2 hours) cuts it by about 40% (US Fosamax label). The skeleton gets almost nothing, and the patient is labelled a non-responder.

Drug-specific points

• Oesophagitis and ulcers with oral drugs, especially if not upright. Avoid with oesophageal stricture, achalasia or inability to sit upright.
• Acute phase reaction after the first zoledronic acid infusion in about 30%: fever, myalgia, flu-like illness for 1 to 3 days. Blocking farnesyl pyrophosphate synthase builds up isopentenyl pyrophosphate, which activates gamma-delta T cells. Pretreat with paracetamol.
• Hypocalcaemia, mainly after IV drugs with vitamin D deficiency. Check 25-OH vitamin D (aim for at least 50 nmol/L) and calcium first.
• HORIZON-PFT: zoledronic acid 5 mg yearly cut vertebral fractures by 70% and hip fractures by 41%. HORIZON-RFT, given after hip fracture, reduced mortality by 28%.

Drug holidays

RACGP/Healthy Bones Australia 2024 says to reconsider continuing after 5 to 10 years in good responders (T-score above -2.5, no recent fracture), and to continue if the T-score stays at -2.5 or below or fractures occur. The ASBMR rule of thumb is a break after 5 years of oral or 3 years of IV therapy if risk is no longer high. FLEX and the HORIZON extension showed little loss of vertebral protection over the next few years. Reassess at 1 to 3 years with BMD and clinical risk.

Denosumab

• A fully human IgG2 monoclonal antibody against RANKL. It mimics osteoprotegerin, the natural decoy receptor.
• 60 mg SC every 6 months for osteoporosis; 120 mg monthly (Xgeva) for bone metastases and bisphosphonate-refractory hypercalcaemia of malignancy (not PBS-subsidised for that).
• Cleared by the reticuloendothelial system, not the kidney. No renal dose adjustment, but the risk of severe hypocalcaemia is highest with eGFR below 30 or on dialysis, where high-turnover bone takes up calcium fast (see CKD-MBD drugs).
• FREEDOM: vertebral fractures 68% lower, hip 40%, non-vertebral 20%. BMD keeps rising for 10 years in the extension, unlike bisphosphonates, which plateau.

Worked NNT (FREEDOM): new vertebral fracture 7.2% on placebo versus 2.3% on denosumab over 3 years. ARR 4.9%, NNT about 21 for 3 years.

Why stopping is dangerous

Denosumab suppresses osteoclast formation but osteoclast precursors accumulate. When levels fall, about 7 months after the last dose, the precursors mature together and RANKL activity surges. Resorption markers rise above baseline, BMD gained over years is lost within 1 to 2 years, and some people have multiple spontaneous vertebral fractures.

• Give doses on time (no more than 4 weeks late).
• If stopping, follow with a bisphosphonate for at least 12 months (RACGP/Healthy Bones Australia 2024), typically zoledronic acid about 6 months after the last injection. Check CTX at 3 and 6 months and repeat zoledronic acid if it rises. After long treatment (more than 2 to 3 years) one infusion is often not enough.
• Oral bisphosphonate is an option after short courses.

Shared rare adverse effects

	Osteonecrosis of the jaw	Atypical femoral fracture
Mechanism	Suppressed remodelling of jaw bone, infection, reduced angiogenesis	Suppressed repair of microcracks in the lateral femoral cortex
Risk	1 in 10,000 to 100,000 per year at osteoporosis doses; 1 to 2% at oncology doses	Rises with more than 3 to 5 years of use; higher in Asian women and with glucocorticoids
Clue	Exposed bone after dental extraction	Thigh or groin pain for weeks, then a transverse low-energy fracture
Action	Dental review before oncology dosing	Image both femurs; stop the antiresorptive; consider teriparatide

Black and colleagues (2020) estimated that over 3 years of bisphosphonate use in white women, 149 hip fractures were prevented for every 2 atypical femoral fractures caused.

Monitoring

Fasting morning CTX (resorption) falls by more than 30% within 3 to 6 months of oral bisphosphonate if the patient is absorbing and adherent. P1NP (formation) falls later. A flat CTX points to poor technique or adherence, or a secondary cause such as hyperparathyroidism or myeloma.

How it's tested

• Fever and aches the day after a first zoledronic acid infusion.
• Vertebral fractures 10 months after the last denosumab dose.
• Thigh pain after 7 years of alendronate.
• Choosing denosumab with eGFR 25 and what to check first.
• A patient whose CTX doesn't fall on alendronate.

Pitfalls

• Stopping denosumab without a bisphosphonate is the error; a denosumab "holiday" doesn't exist.
• Bisphosphonates are avoided at low CrCl because unbound drug is renally excreted and can injure the tubule (zoledronic acid infused too fast causes AKI). Denosumab has no such limit, but brings hypocalcaemia.
• Correct vitamin D before IV zoledronic acid or denosumab.
• The acute phase reaction is not an allergy and is less likely with the second infusion.
• Atypical femoral fractures are rare compared with the fractures prevented, which is why duration is reviewed rather than treatment avoided.