Podcast Summary: Endocrine Feedback Loop – Episode 068

Title: Hypocalcemia in CKD after Denosumab
Release Date: December 18, 2025
Host: Dr. Chase Hendrickson
Contributors: Dr. Amal Shibley Rahal, Dr. Kristin Clemens

Episode Overview

This episode focuses on the risk of hypocalcemia in patients with chronic kidney disease (CKD) receiving denosumab for osteoporosis, based on a recent paper from the Journal of Clinical Endocrinology and Metabolism. The hosts discuss the study's findings on how hypocalcemia risk varies between initial and subsequent doses of denosumab, the implications for clinical practice, and the unique challenges of osteoporosis management in patients with CKD.

Key Discussion Points & Insights

1. Background: Osteoporosis & CKD Complexity

• Denosumab Use:
  • Potent antiresorptive agent, often favored for osteoporosis in CKD.
  • Remains effective across a spectrum of renal function, including patients requiring dialysis.

    “Denosumab is a potent antiresorptive agent that is often preferentially used in patients with chronic kidney disease and osteoporosis.” (Amal, 02:54)

• Treatment Complexity in CKD:
  • Patients may have other bone diseases (osteomalacia, osteitis fibrosa cystica, adynamic bone disease) complicating management.
  • Many osteoporosis drugs (bisphosphonates) are contraindicated in advanced renal impairment.
  • Hyperparathyroidism and other vascular risks may preclude certain agents (e.g., teriparatide, romosozumab).

    "Fragility fracture prevention is extremely important in patients with chronic kidney disease, but it is complex." (Kristin, 03:40)

2. Biology of Hypocalcemia with Denosumab in CKD

• Mechanisms:
  • CKD impairs vitamin D activation and thus GI calcium absorption.
  • CKD patients become more reliant on bone-derived calcium, mediated by osteoclasts.
  • Denosumab inhibits bone resorption, thus decreasing available calcium, provoking hypocalcemia.

    “Patients with advanced chronic kidney disease have impaired gastrointestinal calcium absorption...they are more dependent on osteoclast mediated calcium mobilization from the bone.” (Amal, 04:36) “When we give patients a dose of denosumab, it potently inhibits the osteoclast… you can get a precipitous decline in calcium levels.” (Kristin, 05:36)

3. Study Design Highlights

• Retrospective cohort using Mass General Brigham data (Jan 2016 – Feb 2024).
• Inclusion:
  • Adults who received at least two (secondary cohort) or three (primary cohort) consecutive 60mg doses of denosumab for osteoporosis.
  • Baseline and post-dosing lab data required, increasing risk of selection and detection bias.
• Outcomes:
  • Primary: Serum calcium change after denosumab doses.
  • Secondary: Incidence of hypocalcemia.

    "These individuals had to have received at least two doses to be included in this study..." (Chase, 09:57)

4. Key Results

• Major “N” Drop:
  • 10,398 eligible patients identified, but only 159 in the primary and 325 in the secondary analytic cohort, highlighting major selection constraints.

    "What is very striking is that they initially identified about 10,000 subjects...and ended up with a couple of cohorts that consisted of only a few hundred patients." (Amal, 14:16)

• Cohort Breakdown:
  • ~15% of primary cohort had GFR <30 mL/min/1.73m² (advanced CKD).
  • Mean age: ~73 years; 87% women.
• Serum Calcium Changes:
  • First dose:
    • GFR >60: average drop of 0.34 mg/dL
    • GFR 30-59: drop of 0.52 mg/dL
    • GFR <30: drop of 1.12 mg/dL

    “The drop in calcium for the GFR group below 30 was significantly higher compared to the...other two GFR groups.” (Amal, 17:30)

  • Second/Third doses (GFR <30):
    • Drop lessened to 0.72–0.6 mg/dL; no significant difference between subsequent doses.
  • Timing:
    • Nadir calcium reached at 6-7 weeks (GFR <30), 9 weeks (GFR >60).
• Incidence of Hypocalcemia (within 4 weeks):
  • After first dose:
    • GFR >60: 4.1%
    • GFR 30-59: 7.6%
    • GFR <30: 21.3%
  • After second dose (GFR <30): 14.9% (not statistically significant decline)

    “The lower your GFR, the higher the likelihood that they developed hypocalcemia.” (Amal, 21:30)

5. Interpretation & Limitations

• Selection Bias:
  • High-risk patients with severe hypocalcemia after first dose may be excluded (since ≥2 doses required), skewing results.

    “Are we actually missing the sicker patients or the more severe cases too?” (Amal, 17:30)

• Detection Bias:
  • Patients at perceived higher risk may have been monitored more aggressively.
• Cohort Not Fully Generalizable:
  • Underrepresentation of advanced CKD; focused on academic settings.

    "These clinicians did keep higher risk patients with them...People don't necessarily always continue on denosumab..." (Kristin, 17:00)

• Unmeasured Confounders:
  • Cannot account for calcium/vitamin D supplementation.
  • Did not include fracture/BMD data; only looked at one health system.

    “Calcium intake could not be quantified here.” (Chase, 28:36)

6. Physiologic Mechanism and Clinical Reasoning

• Why less hypocalcemia with subsequent doses?
  • First dose most strongly suppresses bone resorption; subsequent compensation possible with PTH rise and improved prophylaxis (e.g., increased supplementation after initial hypocalcemia noted).

    “From a physiologic standpoint, it makes sense.” (Kristin, 27:47) “I also wonder if...patients were supplemented more appropriately (after first episode of hypocalcemia).” (Kristin, 27:47)

7. Conclusions & Recommendations

• Main Takeaways:
  • Initial denosumab dose in advanced CKD patients is associated with greatest risk of hypocalcemia.
  • Less risk with subsequent doses, but interpretation limited due to cohort selection.

    “Serum calcium decreases less following subsequent doses than following the initial dose...in advanced CKD.” (Chase quoting authors, 28:36)

• Clinical Recommendations:
  • Improve patient counseling.
  • Engage in multidisciplinary (especially nephrology) collaboration.
  • Proactively increase calcium supplementation around initial administration.

    “I also appreciated that the authors mentioned needing...other baseline blood work...important to kidney bone disease management, need to be optimized prior to providing the denosumab injection.” (Kristin, 33:46)

8. Implications for Clinical Practice

• Careful patient selection and risk assessment for denosumab in advanced CKD.
• Aggressive monitoring and prophylactic calcium supplementation remains critical, especially after the first dose.
• Study results reassure providers treating less severe CKD but do not change the cautious approach in advanced disease.

  “I am very aggressive about monitoring (in advanced CKD) and quite aggressive about prophylactically increasing their calcium supplementation...it reaffirms what I do.” (Amal, 32:42) “I really liked that the authors did pick that up...I don't prescribe the medication unless I have an engaged nephrologist, engaged patient or caregiver.” (Kristin, 33:46)

Notable Quotes & Memorable Moments

• On patient selection bias:

  "I just worry that...if we've got such a small subset...we're really basing that on such a small subset. Not that it's invalid, but it's the biggest question that I had about this study." (Chase, 15:48)

• On clinical applicability:

  "I think it's reasonably reassuring for people with less severe degrees of CKD that their calcium does not seem to drop by that much...I find myself less reassured when it comes to those with a GFR less than 30." (Amal, 30:27)

• On clinical practice impact:

  "I don't see anything in this study that will make me change that practice...it reaffirms what I do." (Amal, 32:42) "I also share the same sentiment as Amal. One to make sure that denosumab is the right fit for the right patient...making sure you've got a strong multidisciplinary team." (Kristin, 33:46)

Timestamps of Key Segments

• Background & CKD challenges: 03:40
• Mechanism of hypocalcemia in CKD: 05:36
• Study design explanation: 07:07
• Discussion of cohort selection/bias: 14:16, 15:48, 17:00
• Primary results (serum calcium changes): 17:30
• Incidence of hypocalcemia: 21:30
• Discussion on generalizability and limitations: 24:32, 25:57, 28:36
• Physiologic discussion (less hypocalcemia after first dose): 27:47
• Clinical practice recommendations: 32:42, 33:46

Overall Tone

The episode is expert-driven, evidence-based, and clinically pragmatic. The discussion is collegial, reflective, and at times cautious, reflecting the real-world uncertainties and complexities of osteoporosis management in the context of CKD.

This episode is a must-listen for clinicians navigating bone health in individuals with complex renal disease, providing both practical insights and a measured discussion of the evidence's strengths and limitations.