nach oben

Osteoporosis International

Erschienen in:

14.12.2019 | Original Article

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

verfasst von: G. Tsvetov, O. Amitai, T. Shochat, I. Shimon, A. Akirov, T. Diker-Cohen

Erschienen in: Osteoporosis International | Ausgabe 4/2020

Einloggen, um Zugang zu erhalten

Abstract

Summary

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.

Cummings SR, Martin JS, McClung MR, Siris ES, Eastell R, Reid IR, Delmas P, Zoog HB, Austin M, Wang A, Kutilek S, Adami S, Zanchetta J, Libanati C, Siddhanti S, Christiansen C (2009) FREEDOM trial. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med 361:756–765. https://doi.org/10.1056/NEJMoa0809493 CrossRefPubMed

Baron R, Ferrari S, Russell RGG (2011) Denosumab and bisphosphonates: different mechanisms of action and effects. Bone 48:677–692. https://doi.org/10.1016/j.bone.2010.11.020 CrossRefPubMed

Drugs@FDA: FDA approved drug products. https://www.accessdata.fda.gov/scripts/cder/daf/index.cfm?event=overview.process&applno=125320. Accessed September 23, 2018

Block GA, Bone HG, Fang L, Lee E, Padhi D (2012) A single-dose study of denosumab in patients with various degrees of renal impairment. J Bone Miner Res 27:1471–1479. https://doi.org/10.1002/jbmr.1613 CrossRefPubMedPubMedCentral

Jamal SA, Ljunggren O, Stehman-Breen C, Cummings SR, McClung MR, Goemaere S, Ebeling PR, Franek E, Yang YC, Egbuna OI, Boonen S, Miller PD (2011) Effects of denosumab on fracture and bone mineral density by level of kidney function. J Bone Miner Res 26:1829–1835. https://doi.org/10.1002/jbmr.403 CrossRefPubMed

Body JJ, Bone HG, de Boer RH, Stopeck A, Van Poznak C, Damião R, Fizazi K, Henry DH, Ibrahim T, Lipton A, Saad F, Shore N, Takano T, Shaywitz AJ, Wang H, Bracco OL, Braun A, Kostenuik PJ (2015) Hypocalcaemia in patients with metastatic bone disease treated with denosumab. Eur J Cancer 51:1812–1821. https://doi.org/10.1016/j.ejca.2015.05.016 CrossRefPubMed

Bridgeman MB, Pathak R (2011) Denosumab for the reduction of bone loss in postmenopausal osteoporosis: a review. Clin Ther 33:1547–1559. https://doi.org/10.1016/j.clinthera.2011.10.008 CrossRefPubMed

Dave V, Chiang CY, Booth J, Mount PF (2015) Hypocalcemia post denosumab in patients with chronic kidney disease stage 4-5. Am J Nephrol 41:129–137. https://doi.org/10.1159/000380960 CrossRefPubMed

Chen J, Smerdely P (2017) Hypocalcaemia after denosumab in older people following fracture. Osteoporos Int 28:517–522. https://doi.org/10.1007/s00198-016-3755-8 CrossRefPubMed

10.

Huynh ALH, Baker ST, Stewardson AJ, Johnson DF (2016) Denosumab-associated hypocalcaemia: incidence, severity and patient characteristics in a tertiary hospital setting. Pharmacoepidemiol Drug Saf 25:1274–1278. https://doi.org/10.1002/pds.4045 CrossRefPubMed

11.

Ishikawa K, Nagai T, Sakamoto K, Eguro T, Ito H, Toyoshima Y, Kokaze A, Toyone T, Inagaki K (2016) High bone turnover elevates the risk of denosumab-induced hypocalcemia in women with postmenopausal osteoporosis. Ther Clin Risk Manag 12:1831–1840. https://doi.org/10.2147/TCRM.S123172 CrossRefPubMedPubMedCentral

12.

Okada N, Kawazoe K, Teraoka K, Kujime T, Abe M, Shinohara Y, Minakuchi K (2013) Identification of the risk factors associated with hypocalcemia induced by denosumab. Biol Pharm Bull 36:1622–1626CrossRef

13.

Asano T, Shimizu T, Takahashi D, Ota M, Sato D, Hamano H, Hiratsuka S, Takahata M, Iwasaki N (2019) Potential association with early changes in serum calcium level after starting or switching to denosumab combined with eldecalcitol. J Bone Miner Metab 37:351–357. https://doi.org/10.1007/s00774-018-0928-x CrossRefPubMed

14.

Toulis K, Iliadou P, Mandanas S, Kazila P, Margaritidou E, Georgopoulos K, Pazaitou-Panayiotou K (2016) Calcium homeostasis in women with non-metastatic breast cancer with osteoporosis after a single dose of denosumab: a pilot study. Hormones 15:560–562. https://doi.org/10.14310/horm.2002.1693 CrossRefPubMed

15.

Miyaoka D, Imanishi Y, Ohara M, Hayashi N, Nagata Y, Yamada S, Mori K, Emoto M, Inaba M (2019) Impaired residual renal function predicts denosumab-induced serum calcium decrement as well as increment of bone mineral density in non-severe renal insufficiency. Osteoporos Int 30:241–249. https://doi.org/10.1007/s00198-018-4688-1 CrossRefPubMed

16.

Nakamura Y, Suzuki T, Kamimura M, Murakami K, Ikegami S, Uchiyama S, Kato H (2017) Vitamin D and calcium are required at the time of denosumab administration during osteoporosis treatment. Bone Res 5:17021. https://doi.org/10.1038/boneres.2017.21 CrossRefPubMedPubMedCentral

17.

Clalit Health Services. https://www.btl.gov.il/Publications/survey/Documents/seker_271.pdf

18.

Naranjo CA, Busto U, Sellers EM et al (1981) A method for estimating the probability of adverse drug reactions. Clin Pharacol Ther 30:239–245. https://doi.org/10.1038/clpt.1981.154 CrossRef

19.

Levey AS, Coresh J, Greene T, Stevens LA, Zhang YL, Hendriksen S, Kusek JW, Van Lente F (2006) Chronic kidney disease epidemiology collaboration. Using standardized serum creatinine values in the modificatin of diet in renal disease study equation for estimating glomerual filtration rate. Ann Intern Med 145:247–254. https://doi.org/10.7326/0003-4819-145-4-200608150-00004 CrossRefPubMed

20.

Bone HG, Wagman RB, Brandi ML, Brown JP, Chapurlat R, Cummings SR, Czerwiński E, Fahrleitner-Pammer A, Kendler DL, Lippuner K, Reginster JY, Roux C, Malouf J, Bradley MN, Daizadeh NS, Wang A, Dakin P, Pannacciulli N, Dempster DW, Papapoulos S (2017) 10 years of denosumab treatment in postmenopausal women with osteoporosis: results from the phase 3 randomized FREEDOM trial and open-label extension. Lancet Diabetes Endocrinol 5:513–523. https://doi.org/10.1016/S2213-8587(17)30138-9 CrossRefPubMed

21.

Prolia (denosumab) package insert. https://www.pi.amgen.com/~/media/amgen/repositorysites/pi-amgen-com/prolia/prolia_pi.pdf

22.

Bekker PJ, Holloway DL, Rasmussen AS, Martin SW, Leese PT, Holmes GB, Dunstan CR, DePaoli AM (2004) A single-dose placebo-controlled study of AMG 162, a fully human monoclonal antibody to RANKL, in postmenopausal women. J Bone Miner Res 19:1059–1066. https://doi.org/10.1359/JBMR.040305 CrossRefPubMed

23.

Chen F, Pu F (2016) Safety of denosumab versus zoledronic acid in patients with bone metastases: a meta-analysis of randomized controlled trials. Oncol Res Treat 39:453–459. https://doi.org/10.1159/000447372 CrossRefPubMed

24.

Stopeck AT, Lipton A, Body J-J, Steger GG, Tonkin K, de Boer RH, Lichinitser M, Fujiwara Y, Yardley DA, Viniegra M, Fan M, Jiang Q, Dansey R, Jun S, Braun A (2010) Denosumab compared with zoledronic acid for the treatment of bone metastases in patients with advanced breast cancer: a randomized, double-blind study. J Clin Oncol 28:5132–5139. https://doi.org/10.1200/JCO.2010.29.7101 CrossRefPubMed

25.

Lechner B, DeAngelis C, Jamal N, Emmenegger U, Pulenzas N, Giotis A, Sheehan P, Tsao M, Bedard G, Chow E (2014) The effects of denosumab on calcium profiles in advanced cancer patients with bone metastases. Support Care Cancer 22:1765–1771. https://doi.org/10.1007/s00520-014-2142-2 CrossRefPubMed

26.

Thongprayoon C, Acharya P, Acharya C, Chenbhanich J, Bathini T, Boonpheng B, Sharma K, Wijarnpreecha K, Ungprasert P, Gonzalez Suarez ML, Cheungpasitporn W (2018) Hypocalcemia and bone mineral density changes following denosumab treatment in end-stage renal disease patients: a meta-analysis of observational studies. Osteoporos Int 29:1737–1745. https://doi.org/10.1007/s00198-018-4533-6 CrossRefPubMed

27.

Pharmaceuticals and Medical Devices Agency. Dear Healthcare Professional Letter of Rapid Safety Communication, RANMARK. https://www.pmda.go.jp/files/000153380.pdf

28.

Takeyama M, Sai K, Imatoh T, Segawa K, Hirasawa N, Saito Y (2017) Influence of Japanese regulatory action on denosumab-related hypocalcemia using Japanese adverse drug event report database. Biol Pharm Bull 40:1447–1453. https://doi.org/10.1248/bpb.b17-00266 CrossRefPubMed

29.

Talreja DB (2012) Severe hypocalcemia following a single injection of denosumab in a patient with renal impairment. J Drug Assess 1:30–33. https://doi.org/10.3109/21556660.2012.668504 CrossRefPubMedPubMedCentral

30.

McCormick BB, Davis J, Burns KD (2012) Severe hypocalcemia following denosumab injection in a hemodialysis patient. Am J Kidney Dis 60:626–628. https://doi.org/10.1053/j.ajkd.2012.06.019 CrossRefPubMed

31.

Monge Rafael P, Arias M, Fernández-Fresnedo G (2016) Hipocalcemia severa tras la administración de una dosis de denosumab en un paciente con insuficiencia renal avanzada. Nefrología 36:446–448. https://doi.org/10.1016/j.nefro.2016.02.007 CrossRefPubMed

32.

Takami H, Washio K, Gotoh H (2017) Denosumab for male hemodialysis patients with low bone mineral density: a case-control study. Int J Nephrol 2017:1–5. https://doi.org/10.1155/2017/6218129 CrossRef

33.

Monge Rafael P, Martin de Francisco ÁL, Fernández-Fresnedo G (2018) Denosumab y enfermedad renal crónica avanzada: hipocalcemia severa con riesgo vital. Nefrología 38:97–98. https://doi.org/10.1016/j.nefro.2017.01.004 CrossRefPubMed

34.

Hiramatsu R, Ubara Y, Sawa N, Hoshino J, Hasegawa E, Kawada M, Imafuku A, Sumida K, Mise K, Hayami N, Suwabe T, Takaichi K (2015) Denosumab for low bone mass in hemodialysis patients: a noncontrolled trial. Am J Kidney Dis 66:175–177. https://doi.org/10.1053/j.ajkd.2015.03.012 CrossRefPubMed

35.

Festuccia F, Jafari MT, Moioli A, Fofi C, Barberi S, Amendola S, Sciacchitano S, Punzo G, Menè P (2017) Safety and efficacy of denosumab in osteoporotic hemodialysed patients. J Nephrol 30:271–279. https://doi.org/10.1007/s40620-016-0334-1 CrossRefPubMed

36.

Cernes R, Barnea Z, Biro A, Zandman-Goddard G, Katzir Z (2017) Severe hypocalcemia following a single denosumab injection. Isr Med Assoc J 19:719–721PubMed

37.

Farinola N, Kanjanapan Y (2013) Denosumab-induced hypocalcaemia in high bone turnover states of malignancy and secondary hyperparathyroidism from renal failure. Intern Med J 43:1243–1246. https://doi.org/10.1111/imj.12283 CrossRefPubMed

38.

Chen CL, Chen NC, Hsu CY, Chou KJ, Lee PT, Fang HC, Renn JH (2014) An open-label, prospective pilot clinical study of denosumab for severe hyperparathyroidism in patients with low bone mass undergoing dialysis. J Clin Endocrinol Metab 99:2426–2432. https://doi.org/10.1210/jc.2014-1154 CrossRefPubMed

39.

Martín-Baez IM, Blanco-García R, Alonso-Suárez M, Cossio-Aranibar C, Beato-Coo LV, Fernández-Fleming F (2013) Severe hypocalcaemia post-denosumab. Nefrologia 33:614–615. https://doi.org/10.3265/Nefrologia.pre2013.Apr.11922 CrossRefPubMed

40.

Ishikawa K, Nagai T, Tsuchiya K, Oshita Y, Kuroda T, Ito H, Tani S, Dodo Y, Toyone T, Inagaki K (2018) High bone turnover status as a risk factor in symptomatic hypocalcemia following denosumab treatment in a male patient with osteoporosis. Clin Interv Aging 13:1929–1934. https://doi.org/10.2147/CIA.S180614 CrossRefPubMedPubMedCentral

41.

Kostenuik PJ, Smith SY, Samadfam R, Jolette J, Zhou L, Ominsky MS (2015) Effects of denosumab, alendronate, or denosumab following alendronate on bone turnover, calcium homeostasis, bone mass and bone strength in ovariectomized cynomolgus monkeys. J Bone Miner Res 30:657–669. https://doi.org/10.1002/jbmr.2401 CrossRefPubMed

42.

Body J-J, Niepel D, Tonini G (2017) Hypercalcaemia and hypocalcaemia: finding the balance. Support Care Cancer 25:1639–1649. https://doi.org/10.1007/s00520-016-3543-1 CrossRefPubMedPubMedCentral

43.

Makras P, Polyzos SA, Papatheodorou A, Kokkoris P, Chatzifotiadis D, Anastasilakis AD (2013) Parathyroid hormone changes following denosumab treatment in postmenopausal osteoporosis. Clin Endocrinol 79:499–503. https://doi.org/10.1111/cen.12188 CrossRef

Titel: Denosumab-induced hypocalcemia in patients with osteoporosis: can you know who will get low?
verfasst von: G. Tsvetov
O. Amitai
T. Shochat
I. Shimon
A. Akirov
T. Diker-Cohen
Publikationsdatum: 14.12.2019
Verlag: Springer London
Erschienen in: Osteoporosis International / Ausgabe 4/2020
Print ISSN: 0937-941X
Elektronische ISSN: 1433-2965
DOI: https://doi.org/10.1007/s00198-019-05261-7

Chronic kidney disease–related osteoporosis is associated with incident frailty among patients with diabetic kidney disease: a propensity score–matched cohort study

Original Article

Incidence of distal radius fracture in a general population in southern Sweden in 2016 compared with 2001

Open Access
Original Article

Adherence to fracture liaison service programs in patients over 70: the hidden part of the iceberg

Original Article

Parenthood and risk of hip fracture: a 10-year follow-up prospective study of middle-aged women and men in China

Open Access
Original Article

Bone strength of the proximal femur in healthy subjects with ossification of the posterior longitudinal ligament

Original Article

Low volumetric bone density is a risk factor for early complications after spine fusion surgery

Original Article

Arthropedia

Grundlagenwissen der Arthroskopie und Gelenkchirurgie erweitert durch Fallbeispiele, Videos und Abbildungen. Zur Fortbildung und Wissenserweiterung, verfasst und geprüft von Expertinnen und Experten der Gesellschaft für Arthroskopie und Gelenkchirurgie (AGA).

Jetzt entdecken!

Neu im Fachgebiet Orthopädie und Unfallchirurgie

Nagel und Platte am Humerus funktionell gleich effektiv

17.03.2025
Osteosynthese
Nachrichten

Ob dislozierte proximale Frakturen des Humerus mit drei oder vier Fragmenten in funktioneller Hinsicht besser mit einem Marknagel oder plattenosteosynthetisch versorgt werden sollten, hat ein orthopädisches Team aus Norwegen untersucht.

Plättchenreiches Plasma ohne Wirkung beim Trochanter-Schmerzsyndrom

14.03.2025
Schmerzsyndrome
Nachrichten

Bei Patientinnen mit lateralen Hüftschmerzen aufgrund eines Trochanter-Schmerzsyndroms sind Injektionen mit plättchenreichem Plasma einer randomisierten Studie zufolge wirkungslos.

So oft sind chronische Schmerzen mit Depression und Angststörung verbunden

11.03.2025
Diagnostik in der Schmerzmedizin
Nachrichten

Eine aktuelle Studie aus den USA und Australien legt nahe, dass rund 40% der Patientinnen und Patienten mit chronischen Schmerzen unter Depressionen und Angstzuständen leidet. Allerdings variiert die Prävalenz je nach Schmerzerkrankung.

Diagnostik von Rippenfrakturen: KI schlägt Radiologen

07.03.2025
Rippenfraktur
Nachrichten

Mensch gegen Maschine: Beim Erkennen von Rippenfrakturen in Röntgen- und CT-Aufnahmen entschied sich dieses Duell zugunsten der künstlichen Intelligenz (KI). Die Algorithmen zeigten eine höhere Sensitivität als ihre menschlichen Kollegen.

Update Orthopädie und Unfallchirurgie

Bestellen Sie unseren Fach-Newsletter und bleiben Sie gut informiert.

Newsletter bestellen

Springer Medizin

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