Frequently Asked Questions

Frequently Asked Question: Does denosumab increase the risk of severe hypocalcemia in chronic
kidney disease (CKD) and dialysis patients, and should it be used in these patient populations?

Summary Response:
 Denosumab (Prolia®) is a medication used to treat osteoporosis, often prescribed by those
without substantial knowledge of use of medications in CKD or dialysis.
 Denosumab has a high risk of severe, protracted, treatment-resistant hypocalcemia in Stage 4
and 5 CKD (including dialysis). There is a new FDA Boxed Warning of this adverse effect.1
 In a recent study, this risk was over 20 times higher vs bisphosphonates (41.1% vs 2%).2
 Usual treatment is lengthy courses of high-dose calcium (po +/- IV) and vitamin D analogues.3
 The FDA now advises that denosumab should only be prescribed by a healthcare provider with
expertise in the diagnoses and management of CKD-MBD for patients with Stage 4 & 5 CKD.1
 Calcium, magnesium, & vitamin D levels should be checked and corrected prior to treatment.4
 Efforts should be made to avoid denosumab use if possible for patients with Stage 4 and 5 CKD
outside of specific scenarios (e.g. hypercalcemic patients).
 If a risk-benefit assessment determines the benefits outweigh risks, patients should be closely
monitored for severe hypocalcemia.

Clinical Presentation:5
 Low serum calcium considered “severe” if below 1.9 mmol/L (normal range 2.2-2.6mmol/L).
o Serum calcium levels need to be corrected for serum albumin.
o Ionized calcium can be used as an alternative (normal range 1.15 to 1.35 mmol/L).
 Signs and Symptoms: Muscle cramps, weakness & spasms (especially carpopedal), shaking,
numbness or tingling of the peri-oral area and/or digits of hands/feet, tetany, voice changes
due to laryngospasm, dysphagia, mood changes (anxiety, lability), confusion, hallucinations,
syncope, QTc prolongation, bradycardia, arrhythmias (ventricular tachycardia, ventricular
fibrillation, AV block, Torsades de Pointes), cardiac arrest, seizures, coma, and death.
 Positive Chvostek and Trousseau signs: https://www.youtube.com/watch?v=kvmwsTU0InQ.

Timing: 6
 Onset usually occurs 1 to 2 weeks post-dose.
 Nadir (i.e. lowest calcium) occurs at 2 to 8 weeks.
 Low calcium is often protracted (multiple months) due to denosumab’s half-life of ~30 days.

Background/Evidence:
 While treating osteoporosis in general populations can be relatively straightforward, it can be
more challenging in those with CKD.7
 Challenges With Treating Osteoporosis in CKD
The underlying pathology of altered bone metabolism differs for those with CKD vs those without.1,8
 Parathyroid hormone (PTH) and vitamin D are the main hormones to maintain calcium levels.
 Patients with CKD are at risk of CKD-related mineral bone disorder (CKD-MBD), which
manifests as abnormalities in calcium, phosphorous, vitamin D, and PTH.
 There is a lack of available testing (i.e. bone biopsy) to diagnose the underlying pathology (not
done for this indication in Ontario per conversations with local Hematologists).
Medications often used to treat osteoporosis in non-CKD populations have a more complex risk-
benefit assessment in CKD patients, since many are renally excreted, have increased rates of side
effects, and lack data for efficacy & safety.1
 E.g. osteoporosis treatment usually includes starting vitamin D but even this simple
intervention frequently results in hyperphosphatemia in CKD patients.9
There is an overall lack of evidence and guidance regarding how to best treat osteoporosis in CKD.10,11
 Most osteoporosis guidelines fail to give direction on treatment for patients with CKD.10
 Bisphosphonates are historically the first-line treatment for osteoporosis, but are renally
excreted and not recommended per their product monographs if creatinine clearance is less
than 30 or 35mL/min.12,13,15 IV bisphosphonates (zoledronic acid, pamidronate) also have a
risk of nephrotoxicity14 which is not seen with denosumab.

Denosumab:
 Denosumab is a monoclonal antibody which binds to the RANK ligand. It is not renally excreted,
does not require dose-adjustment for CKD, and has been shown to prevent fractures in CKD
patients down to GFRs of 15mL/min.16
 It reduces osteoclast formation, activity, and survival resulting in improved bone density via
reduced bone resorption. However, this reduced resorption also decreases calcium mobilization
from the bone to the bloodstream, resulting in hypocalcemia.16
 Denosumab-induced hypocalcemia is usually asymptomatic or mild, occurring in ~5 to 10% of
patients.17 Severe hypocalcemia occurs in ~1 to 2% of general populations.18
 However, certain populations are at higher risk of developing severe hypocalcemia:

Risk Factors for Development of Severe Hypocalcemia from Denosumab4,24,27

Disease  CKD, especially those with CKD-MBD (e.g. secondary hyperparathyroidism):
States & o Secondary hyperparathyroidism seen with CKD places a greater dependence
Labs on PTH-mediated bone resorption to maintain serum calcium levels.17,19,28
o i.e. CKD patients depend on high bone turnover to maintain serum calcium,
and denosumab significantly reduces bone turnover.
 Vitamin D deficiency:
o 1-alpha-hydroxylase, the enzyme required to activate vitamin D, has reduced
activity in CKD, resulting in reduced GI absorption of calcium.19,24
 Dialysis: due to removal of calcium during dialysis.
 Low and high magnesium33,34
 Metastatic bone cancer
 Hypoparathyroidism, especially hungry bone syndrome post-parathyroidectomy
 Critical illness/sepsis
Meds  Lack of prophylactic calcium and vitamin D supplementation
  Drugs which increase calcium loss, or potentiate the effects of denosumab:
o Loop diuretics, calcimimetics (e.g. cinacalcet), glucocorticoids, calcitonin,
barbiturates, bisphosphonates, foscarnet, ketoconazole.
 Drugs that can lower magnesium: e.g. cisplatin, PPIs.

 Many case reports of denosumab-induced severe hypocalcemia in CKD patients have been
published.20,21,22,23,24,29,32
 A recent article in JAMA2 looked at the risk of severe hypocalcemia in older female patients on
dialysis given either bisphosphonates or denosumab. This study found the incidence of severe
hypocalcemia with denosumab was over 20 times higher with denosumab vs bisphosphonates
(41.1% vs 2.0%), which is reasonably consistent with previous meta-analyses.6

Prevention:
 Calcium, magnesium, vitamin D, and PTH should be checked and corrected prior to giving each
dose of denosumab.1
o Pre-treatment calcium and vitamin D supplementation can reduce the risk of
developing hypocalcemia by 40%.31
 Assess for medications that can lower calcium or magnesium (see Risk Factors above).
 Check calcium levels regularly.
o Educating patients on the importance of regular bloodwork is important.
o This helps to identify declining calcium levels so intervention (e.g. supplementation) can
be initiated before hypocalcemia occurs.24
Management:30
 Note: due to a lack of data on optimal management, treatment is largely based on historical
practice and clinical experience.35,36 Severity of symptoms and acute changes guide therapy.
 Please see guidelines on acute hypocalcemia and Appendix 1 below for specific details.36,37,40,41,42

 Calcium should be increased to within the normal range as soon as possible and maintained.
 Hold or stop medications that can cause hypocalcemia and/or hypomagnesemia if possible.
 Correct any hypomagnesemia concomitantly with other interventions.
 Calcium supplementation +/- vitamin D analogs are the mainstays of treatment.
 For inpatients, high-dose IV & oral calcium is likely to be required.
o IV calcium gluconate should be given for corrected calcium <1.9 mmol/L, symptomatic
hypocalcemia (from muscle spasms to arrhythmias), or if QTc is prolonged.
o Note that since oral calcium is a phosphate-binder, phosphate should also be checked
regularly and supplementation given if indicated.40
 In dialysis patients, it should be ensured they are on the highest concentration of calcium
solution in their dialysate that is available. IV calcium can be given at dialysis as needed.

Below are some brief examples of denosumab-induced hypocalcemia treatment, chosen to illustrate
various points:

1) Example #1 is the high doses of supplemental calcium required for treatment from a case
report, see the below graph.19
o In the first 24 hrs, calcium 16g IV + 2.5g po (plus magnesium 8g IV + 0.4g po) was given.
o The dose of calcium required by Day 4 was 6.25mg po QID (total elemental calcium 10g).
o Calcium 10g daily was required on hospital discharge.
 2) Example #2 is the high doses of vitamin D analogues (e.g. calcitriol) that can be required, as well
as the protracted duration of hypocalcemia23:
 For this case patient, calcitriol 32 mcg po daily was required at hospital discharge.
 The usual starting dose of calcitriol for secondary hyperparathyroidism is 0.25 mcg po q2d.38
 It took over 1 month of IV calcium & calcitriol supplementation to even reach normal range,
and required ~80 days of IV calcium.

3) Example #3 also illustrates the high doses of supplementation required, as well as the
protracted nature of denosumab-induced hypocalcemia after hospital discharge:39

Monitoring:30
 If used for patients with eGFR less than 30mL/min, baseline labs before each dose should
include serum calcium, albumin, vitamin D, PTH, magnesium, phosphate, and eGFR.
 These labs (excluding vitamin D and PTH) should be checked within 10 to 14 days after
denosumab, then weekly for at least 4 weeks1 (up to 10 weeks)24 then monthly thereafter.
 Vigilant monitoring for signs & symptoms of low calcium by the patient and healthcare workers.

Conclusions:
 Denosumab should generally be avoided if possible for patients with Stage 4 and 5 CKD.
 If used, vigilant monitoring of signs/symptoms of hypocalcemia and labs is required.
References:
1) FDA Boxed warning: https://www.fda.gov/drugs/drug-safety-and-availability/fda-adds-boxed-warning-
increased-risk-severe-hypocalcemia-patients-advanced-chronic-kidney-disease.
2) Bird ST, et al. Severe Hypocalcemia With Denosumab Among Older Female Dialysis-Dependent Patients.
JAMA. 2024 Jan 19:e2328239. doi: 10.1001/jama.2023.28239. Epub ahead of print. PMID: 38241060.
3) Kim, D. (2022). Hypocalcemia After the Administration of Denosumab in a Patient With Osteoporotic Fracture
and Vitamin D Deficiency. Journal Of Endocrinology And Metabolism, 12(3), 111-115.
4) Spångeus A, Rydetun J, Woisetschläger M. Prevalence of denosumab-induced hypocalcemia: a retrospective
observational study of patients routinely monitored with ionized calcium post-injection. Osteoporos Int. 2024
Jan;35(1):173-180. Epub 2023 Sep 26. PMID: 37750930; PMCID: PMC10786736.
5) Duval M, et al. Is severe hypocalcemia immediately life-threatening? Endocr Connect. 2018 Aug
31;7(10):1067–74. doi: 10.1530/EC-18-0267. Epub ahead of print. PMID: 30311756; PMCID: PMC6198192.
6) Thongprayoon C, et al. Hypocalcemia and bone mineral density changes following denosumab treatment in
end-stage renal disease patients: a meta-analysis of observational studies. Osteoporos Int. 2018;29(8):1737-
1745.
7) Sadowski CA, Lyder C, Yuksel N. Bisphosphonates for Osteoporosis in Patients with Renal Insufficiency:
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low? Osteoporos Int. 2020;31(4):655-665.
18) Kim, et al. A simple-to-use score for identifying individuals at high risk of denosumab-associated hypocalcemia
in postmenopausal osteoporosis: a real-world cohort study. Calcif Tissue Int. 2020;107(6):567-575.
19) Laskowski LK, et al. A RANKL Wrinkle: Denosumab-Induced Hypocalcemia. J Med Toxicol. 2016 Sep;12(3):305-
8. Epub 2016 Mar 17. PMID: 26987988; PMCID: PMC4996783.
20) Ungprasert P, et al. Life-threatening hypocalcemia associated with denosumab in a patient with moderate
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BMJ Case Rep. 2018 May 30;2018:bcr2017224068. PMID: 29848528; PMCID: PMC5990053.
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Appendix 1:37

Note: while this management algorithm is specific to patients without CKD-MBD, the algorithm is still
reasonable as an example for the purposes of this topic.

IV: intravenous; D5W: 5% dextrose; NS: normal saline.

* Ionized calcium remains the gold standard for assessing calcium status, particularly if the diagnosis of hypocalcemia is in
doubt due to hypoalbuminemia, atypical or absent symptoms, or a minimally reduced serum calcium concentration. If a
laboratory known to measure ionized calcium reliably is not available, the total calcium should be corrected for any
abnormalities in serum albumin, using a calcium correction formula.
¶ In patients with milder degrees of hypocalcemia or chronic hypocalcemia (due to hypoparathyroidism) who become unable
to take or absorb oral supplements, as may occur after complex surgical procedures requiring prolonged recuperation, IV
calcium may be needed to prevent acute hypocalcemia.
Δ Initially, IV calcium (1 or 2 g of calcium gluconate, equivalent to 90 or 180 mg elemental calcium, in 50 mL of D5W or NS) can
be infused over 10 to 20 minutes. May repeat after 10 to 60 minutes if needed to resolve symptoms. Equivalent dose, SI units:
2.25 to 4.5 mmol calcium in 50 mL D5W or NS infused over 10 to 20 minutes.

 This should be followed by a slow infusion of calcium in patients with persistent hypocalcemia (eg, hypoparathyroidism,

pancreatitis) – An IV solution containing 1 mg/mL of elemental calcium is prepared by adding 11 g of calcium gluconate

(equivalent to 1000 mg elemental calcium) to normal saline or D5W to provide a final volume of 1000 mL.

 This solution is administered at an initial infusion rate of 50 mL/hour (equivalent to 50 mg elemental/hour).

 Equivalent dose, SI units – Add 24.75 mmol calcium to NS or D5W to provide a final volume of 1000 mL (final concentration

of 0.025 mmol/mL) initiated at 50 mL per hour.

Refer to UpToDate content on treatment of hypocalcemia.
◊ Patients receiving digoxin should be monitored closely for acute digitalis toxicity, which can develop with calcium infusion.
§ Initially, 1 to 4 g of elemental calcium given as calcium carbonate or calcium citrate daily, in divided doses. Refer to UpToDate
content on treatment of hypocalcemia.
¥ In addition to calcium, patients with vitamin D deficiency or hypoparathyroidism require vitamin D supplementation, which
often permits a lower dose of calcium supplementation. Refer to UpToDate content on hypoparathyroidism and vitamin D
deficiency.
‡ In patients with hypoparathyroidism, monitoring of urinary and serum calcium and serum phosphate is required weekly
initially, until a stable serum calcium concentration (at the low end of the normal range) is reached. Thereafter, monitoring at 3-
to 6-month intervals is sufficient. Refer to UpToDate content on hypoparathyroidism.