1. Before anything else

• Check the calcium is adjusted. 2.17 mmol/L is just under the usual lower limit of about 2.20 and is only mildly low. Repeat it with albumin.
• Add to the baseline bloods: phosphate, magnesium, PTH, ALP and U&E. Low magnesium needs correcting too.
• The MHRA is explicit. Denosumab 60 mg is contraindicated in hypocalcaemia of any severity. eGFR 15-29 is a named risk factor for severe, sometimes fatal, hypocalcaemia (MHRA Drug Safety Update).

2. Vitamin D replacement

• 50,000 units weekly for 6 weeks
• 40,000 units weekly for 7 weeks
• 4,000 units daily for 10 weeks

• Some use a lower loading course for symptomatic deficiency with renal impairment, such as 25,000 units daily for 7 days then weekly for 4 weeks (275,000 units total). An example is Nottingham APC.
• Some generic vitamin D guidelines exclude eGFR below 30 altogether and want specialist advice.
• Plain colecalciferol is still the first-line way to correct a low 25OHD in CKD G4.
• Active vitamin D (alfacalcidol, 0.25-0.5 micrograms daily) is for persistent hypocalcaemia or raised PTH. Start it with renal or bone team input.

• Aim for 1,000 mg/day total, from diet plus supplement. The denosumab SmPC asks for calcium 1,000 mg and vitamin D at least 800 units daily.
• If dietary calcium is below about 700-800 mg, add something like Adcal-D3 one chewable tablet twice daily. This gives roughly 1,200 mg calcium and 800 units D3.
• In CKD, avoid over-supplementing, because of vascular calcification and phosphate balance. Review dose with the renal team if phosphate or PTH is abnormal.
• If calcium is still low after repletion, involve the bone or renal team about alfacalcidol before any denosumab.

• Check adjusted calcium about 1 month after the loading course.
• Recheck 25OHD at about 3 months.

3. When to give denosumab

1. Gate: corrected calcium must be normal.
2. Vitamin D thresholds vary locally.
   • NHS Grampian wants 25OHD at least 50 nmol/L, or at least 6 weeks of replacement before the first injection. It also says eGFR below 30 should be discussed with the Bone Team.
   • Thames Valley allows denosumab at eGFR or CrCl below 30 if calcium is normal and the patient is vitamin D replete (above 50 nmol/L). It also asks for specialist discussion.
3. Practical approach after a hip fracture. Do not delay treatment longer than needed, because early re-fracture risk is high. Start loading and calcium now. Recheck calcium after 4-6 weeks, or sooner if you want to move faster. Give denosumab once calcium is normal and the vitamin D is replete or clearly on track, as agreed with the bone and renal team. Some pathways accept starting once calcium is normal and loading is under way.
4. Renal function. Use Cockcroft-Gault CrCl rather than eGFR if the patient is over 75, or has BMI below 18 or above 40.
5. Choice of drug. Bisphosphonates are generally avoided at this eGFR (zoledronate is contraindicated at CrCl below 35). That makes denosumab the usual choice, but it needs the extra safeguards here. The textbooks agree that CKD plus vitamin D deficiency is the classic setting for denosumab hypocalcaemia, which needs concurrent vitamin D and calcium (Katzung's Basic and Clinical Pharmacology 16e, Denosumab; National Kidney Foundation Primer on Kidney Diseases 8e, Osteoporosis; Harrison's 22e, Hip fractures).

4. After the first dose

• Calcium check: 1-2 weeks after the injection (some pathways say 2-3 weeks) for eGFR below 30. Repeat before each 6-monthly dose.
• Supplements: continue calcium and vitamin D throughout. Confirm the patient is taking them before each injection.
• Symptoms: warn about cramps, tingling and tetany. Hypocalcaemia usually occurs in the first 6 months but can occur at any time.
• Dental review: arrange this beforehand if possible, because of osteonecrosis of the jaw risk.
• Do not stop or delay doses without specialist advice. Stopping causes rebound bone loss and multiple vertebral fractures. If it must stop, plan an alternative.
• Shared care: patients with eGFR below 30 are often excluded from GP shared care (for example Milton Keynes). Confirm who owns the monitoring.

Evidence check

1. Repeat bloods: adjusted calcium (with albumin), phosphate, Mg, PTH, ALP, U&E. Correct Mg if low.
2. Start colecalciferol loading, about 300,000 units total (ROS): 40,000 units weekly for 7 weeks, or 50,000 units weekly for 6 weeks. With eGFR 26, many local policies use a reduced renal course instead, such as 25,000 units daily for 7 days then weekly for 4 weeks. Follow your local policy.
3. Start calcium to reach about 1,000 mg/day total, for example Adcal-D3 one tablet twice daily if dietary intake is poor.
4. After loading, continue maintenance vitamin D 800-2,000 units daily, long term.
5. Ask for a dental check if feasible.
6. Inform the renal or metabolic bone team. Most UK policies want eGFR below 30 discussed before the first dose.

• Repeat adjusted calcium, 25OHD, Mg and U&E.

• Adjusted calcium is normal. It is contraindicated if hypocalcaemia is present at any level.
• Vitamin D is replete (25OHD at least 50 nmol/L), or replacement has run for at least 6 weeks. This threshold varies by trust. Some accept a normal calcium with loading under way, given the post-hip-fracture re-fracture risk.
• Calcium and vitamin D are being taken.
• The bone or renal team has agreed.

• Check adjusted calcium at 1-2 weeks. Do this every time while eGFR is below 30.
• Warn the patient about cramps, tingling and tetany, and to seek help urgently if they occur.
• Continue calcium and vitamin D without a break.

• Repeat denosumab every 6 months. Check calcium, vitamin D and U&E 1-3 weeks before each dose.
• Never delay or stop it without a plan, because of rebound vertebral fractures.
• Arrange a 3-month 25OHD recheck.

• Use CrCl (Cockcroft-Gault) instead of eGFR if the patient is over 75 or has a very low or high BMI.
• Over-supplementing calcium in CKD carries a vascular calcification risk, so involve the renal team in dosing.

• Plain colecalciferol is still the right way to correct a 25OHD of 16.4, even at eGFR 26. Alfacalcidol does not replace nutritional vitamin D and does not fix the deficiency.
• Alfacalcidol bypasses renal 1-alpha-hydroxylation. It raises calcium and suppresses PTH, but it carries a risk of hypercalcaemia and hyperphosphataemia.
• Calcium 2.17 is only mildly low and probably reflects the vitamin D deficiency. It should correct with loading.

• Adjusted calcium stays low after about 4-6 weeks of colecalciferol and calcium.
• PTH is clearly raised despite replete 25OHD, which suggests CKD-MBD or secondary hyperparathyroidism.
• Calcium falls after denosumab despite supplements. Local pathways, for example Thames Valley, refer to the metabolic bone service for alfacalcidol if calcium is still low at 2 weeks.
• The renal team wants it prophylactically for eGFR below 30 before denosumab. Some units do this, but it is not a universal national rule.

• Typical starting dose is 0.25-0.5 micrograms once daily. The dose should be set by the specialist.
• Check calcium, phosphate and PTH within 1-2 weeks of starting, then regularly. Stop or reduce if calcium is high-normal or raised.
• Keep the colecalciferol going alongside it.

• Begin colecalciferol and calcium.
• Repeat calcium and PTH at 4-6 weeks.
• Add alfacalcidol only if calcium has not normalised, PTH is high, or the renal or bone team advises it.
• If you give denosumab with calcium borderline, discuss alfacalcidol cover with the team first.