Denosumab-induced hypocalcemia in patients with osteoporosis: can you know who will get low?

Osteoporos Int. 2020 Apr;31(4):655-665. doi: 10.1007/s00198-019-05261-7. Epub 2019 Dec 14.


Hypocalcemia was reported at low rates (0.05-1.7%) in denosumab-treated postmenopausal women with osteoporosis. This real-life study shows a 7.4% rate of denosumab-induced hypocalcemia in community-dwelling osteoporotic men and women. Pretreatment serum calcium and creatinine levels are major predictors for this complication. Serum-calcium monitoring may help to identify and prevent severe hypocalcemia.

Purpose: RCTs have reported a 0.05-1.7% rate of hypocalcemia in denosumab-treated postmenopausal women with osteoporosis, but long-term real-life data are lacking. We assessed the rate of hypocalcemia in osteoporotic community-dwelling patients treated with denosumab.

Methods: A retrospective analysis was conducted based on medical records (2010-2018) from a large HMO. An albumin-adjusted serum calcium concentration lower than 8.5 mg/dL was defined as hypocalcemia.

Results: We included 2005 patients (93% women, mean age 76 ± 9 years). Hypocalcemia developed during treatment in 149 patients (7.4%; 1% less than 8 mg/dL): in 66 after 0.5-1 years; 48 after 1-2 years; 35 after > 2 years. On comparison of the hypocalcemic and normocalcemic patients, the strongest predictors of hypocalcemia were pretreatment levels of albumin-adjusted serum calcium (9.1 ± 0.4 vs. 9.4 ± 0.5 mg/dL, respectively; p < 0.05) and creatinine (0.9 ± 0.5 vs. 0.8 ± 0.3 mg/dL, respectively; p < 0.05). The hypocalcemia rate increased in parallel to a decrease in eGFR (p = 0.032 for the difference between eGFR ranges). Baseline calcium level ≤ 9.31 mg/dL predicted hypocalcemia with a sensitivity of 77% and specificity of 56%. A model of (- 2)*calcium + creatinine predicted hypocalcemia (3.7% when lower and 17.1% when higher than - 17.4). Gender, age, 25-hydroxyvitamin-D, parathyroid hormone, alkaline phosphatase, and whether denosumab was given as first or advanced line of osteoporotic therapy had no predictive value.

Conclusion: Real-life rates of denosumab-induced hypocalcemia are higher than previously reported. Hypocalcemia might develop after each dose of denosumab in ongoing treatment. Adequate calcium and vitamin D supplementation are needed. Serum calcium monitoring is advised in high-risk patients for early detection of severe hypocalcemia.

Keywords: Adverse event; Denosumab; Hypocalcemia; Osteoporosis; Safety.

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • Bone Density Conservation Agents* / adverse effects
  • Calcium
  • Denosumab / adverse effects
  • Female
  • Humans
  • Hypocalcemia* / chemically induced
  • Male
  • Osteoporosis* / drug therapy
  • Retrospective Studies


  • Bone Density Conservation Agents
  • Denosumab
  • Calcium