Extraosseous Calcification in Kidney Disease: Strategies for Management 

Maintaining a neutral calcium balance, correcting hyperphosphatemia and controlling comorbidities

By Korey Bartolomeo, DO; Xin Yee Tan, MD; and Richard Fatica, MD

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Editor’s note: This is part two of a two-part series on extraosseous calcification in kidney disease. Part one of the series focuses on pathogenesis, presentation and diagnosis. The original article, including a full list of references, was published in the Cleveland Clinic Journal of Medicine and can be accessed here.

Managing extraosseous calcification in kidney disease

Most of the research has focused on therapies directed at vascular calcification, given its clinical implications with cardiovascular disease in end-stage kidney disease.

Dietary phosphate restriction, phosphate binders

Given the central role of elevated phosphate and FGF-23 in the pathogenesis of extraosseous calcification, controlling serum phosphate levels, first through dietary phosphate restriction and then with intestinal phosphate binders, is a logical and low-cost management choice in preventing vascular calcification.

The most commonly used phosphate intestinal binders are calcium-based (e.g., calcium carbonate, calcium acetate) and are used extensively in patients with chronic and end-stage kidney disease for many indications. However, earlier studies demonstrated a relationship between higher calcium intake and higher rates of vascular calcification,33 and subsequent studies called attention to this association, leading to recommendations for using non–calcium-based intestinal phosphate binders to restore normal phosphate levels while limiting calcium intake to maintain normal serum calcium.34,35

A number of randomized trials over the last 20 years have attempted to settle the debate on calcium-based vs non–calcium-based phosphate binders and cardiovascular disease, many of them using vascular calcification as a surrogate end point.

The IMPROVE-CKD trial36 (Impact of Phosphate Reduction on Vascular End-points in Chronic Kidney Disease) tested lanthanum use in patients with advanced chronic kidney disease (eGFR < 30 mL/min/1.73 m2) and evaluated changes in aortic calcification and arterial stiffness. It did not find statistically significant differences with lanthanum compared with placebo. Of note, the trial was limited by recruitment, including patients with normal phosphate levels and excluding those with end-stage kidney disease.36

The Treat-to-Goal study37 in patients with end-stage kidney disease on hemodialysis found less coronary artery and aortic calcification and a lower incidence of hypercalcemia in those randomized to sevelamer compared with calcium acetate. These results may correlate with improved all-cause survival rates in patients newly started on hemodialysis, despite lower rates of normophosphatemia when sevelamer is used.15,38 Subsequent studies comparing lanthanum carbonate with calcium carbonate in patients newly starting on hemodialysis did not find statistically significant differences in calcification scores in heart valves.39

The LANDMARK trial 40 (Outcome Study of Lanthanum Carbonate Compared With Calcium Carbonate on Cardiovascular Mortality and Morbidity in Patients With Chronic Kidney Disease on Hemodialysis), published in 2021, looked at patients with end-stage kidney disease in Japan who had risk factors for vascular calcification who were randomized to receive lanthanum or calcium carbonate. It did not find any statistically significant differences in rates of all-cause mortality or cardiovascular events between the two groups, though the event rates were low. Further, compared with the United States, Japan has lower dietary calcium intake, higher use of arteriovenous fistulas for dialysis access, and different cardiovascular screening practices, which could limit wide applicability of the results.40

In sum, data conflict regarding whether non–calcium-based intestinal phosphate binders are superior to calcium-based binders in preventing vascular calcification and cardiovascular events.

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Bone antiresorptive agents

Pyrophosphates (bisphosphonates), the most commonly used class of drugs for preventing bone resorption, inhibit the activity of osteoclasts, and some of these drugs also induce apoptosis. Bisphosphonates are either retained in the bone or cleared by the kidney.

Robust data exist for using this drug class in bone disorders in patients in the early stages of chronic kidney disease (eGFR > 35 mL/min/1.73 m2), but data are significantly limited in those with stage 4 or 5 chronic kidney disease or end-stage kidney disease, and there are theoretical safety concerns.41 Bisphosphonates are less frequently prescribed in these latter populations, possibly due to concerns about toxicity, as these drugs are excreted by the kidney.42 Reports of worsening kidney disease or kidney injury exist for most drugs in the bisphosphonate class, but larger observational trials have found oral bisphosphonates to be reasonably safe in advanced chronic kidney disease, though bisphosphonate users had a 14% higher risk of progression of chronic kidney disease.43

Zoledronic acid, a potent intravenous formulation, should be avoided if the eGFR is less than 30 mL/min/1.73 m2, in view of stronger associations with direct tubular injury, acute kidney injury, and worsened eGFR.44,45 Pamidronate is generally the preferred intravenous formulation for patients with advanced chronic kidney disease, usually given at a lower dose or infused over a longer time. Rarely, collapsing focal segmental glomerulosclerosis can occur.44,45

Bisphosphonates have been shown to reduce both overall vascular calcification and all-cause mortality in certain groups (eg, patients with osteoporosis or cancer), but not the rate of cardiovascular events.46 Etidronate, a first-generation bisphosphonate now discontinued due to high rates of osteomalacia, was used to treat soft tissue calcifications.47–49 Etidronate also reduced vascular calcification in rat models of chronic kidney disease, while human studies showed reduced coronary artery calcification in patients with advanced chronic kidney disease and end-stage kidney disease.49–51 Newer bisphosphonates have limited data on their effects on vascular calcification in end-stage kidney disease, with one study of alendronate showing no improvement in coronary artery calcification score.52

Denosumab, a RANK ligand inhibitor (RANK stands for receptor activator of nuclear factor kappa B) that prevents osteoclast maturation, has not been studied in soft tissue calcification. Small pilot studies have looked at denosumab’s effects on vascular calcification in humans and have suggested it may slow coronary artery calcification, but this has been challenged in other studies.52,53 More studies are needed to determine the clinical significance of these findings. We are not aware of any studies that have looked at denosumab in soft tissue calcification or calciphylaxis.

Teriparatide is a synthetic formulation of PTH. The only evidence for using it to treat tumoral calcinosis comes from case reports, and no major studies have looked at using it in end-stage kidney disease to prevent vascular calcification.54


Calcimimetics are drugs that bind allosterically to the calcium-sensing receptor on parathyroid cells to suppress PTH release for a given serum calcium level.

Cinacalcet, the most common drug in this class, has been studied extensively in secondary hyperparathyroidism in 2 trials, the EVOLVE55 (Evaluation of Cinacalcet Hydrochloride Therapy to Lower Cardiovascular Events) and ADVANCE56 (A Randomized Study to Evaluate the Effects of Cinacalcet plus Low-Dose Vitamin D on Vascular Calcification in Subjects With Chronic Kidney Disease Receiving Heemodialysis). It did not show improvement in aortic calcification or reduction in cardiovascular outcomes or all-cause mortality despite improvements in serum PTH levels.55,56 In contrast, a more recent meta-analysis of cinacalcet use in end-stage kidney disease did find a benefit in terms of lower rates of all-cause mortality and cardiovascular mortality.57 Other calcimimetics have been studied only in animal models, and thus their clinical effect in humans is undetermined.

Sodium thiosulfate

Sodium thiosulfate is an older medication with antioxidant properties that has been used off-label for years in calcium disorders including vascular calcification and calciphylaxis. It was recently systematically reviewed in treating calciphylaxis, with conflicting results.58,59 More recently, a randomized clinical trial60 showed reduction of iliac artery calcification and arterial stiffness with sodium thiosulfate compared with placebo in calciphylaxis. Ongoing prospective and randomized trials will hopefully provide clarity of the benefit of sodium thiosulfate in vascular calcification and calciphylaxis. In a small case series, the drug has shown improvement in symptom burden in soft tissue calcification of the shoulder and hip, with partial size regression.61

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Vitamin K

Vitamin K is an essential cofactor for carboxylation of numerous proteins, including some that inhibit vascular calcification, such as matrix G1a protein.62 Evidence that lack of vitamin K may be involved in vascular calcification includes a high prevalence of vitamin K deficiency in this population and improvement in carboxylation surrogate markers with supplementation.63,64

Warfarin, a vitamin K antagonist, accelerates medial arterial calcification, particularly in end-stage kidney disease.65 Furthermore, warfarin has been identified observationally as a risk factor for calciphylaxis, and low levels of carboxylation of matrix G1a protein are associated with calciphylaxis in end-stage kidney disease.66 The suspected mechanism by which warfarin may contribute to calciphylaxis is by inhibiting vitamin K-dependent carboxylation of matrix G1a protein, a mineral-binding extracellular matrix protein that prevents calcium deposition in arteries.

Several phase 3 trials are being conducted to determine the benefit of vitamin K supplementation in vascular calcification and calciphylaxis, though a recent trial in patients with stage 4 chronic kidney disease67 did not show improvement in vascular stiffness with vitamin K supplementation. There are no current studies looking at tumoral calcinosis and vitamin K supplementation.

Novel therapies, nonmedical management

SNF472, a myoinositol hexaphosphate that inhibits hydroxyapatite growth, has shown promise in early clinical trials in reduction of coronary artery calcium volume, while tissue-nonspecific alkaline phosphatase inhibitors are in earlier stages of development.68,69

Magnesium and vitamin D supplementation in chronic and end-stage kidney disease has had varying degrees of success in preventing vascular calcification, though more studies are needed to confirm its clinical utility.70,71 With particular relevance to soft tissue calcification, surgical debridement and hyperbaric oxygen therapies hold significant promise as adjunctive therapies to the aforementioned medical therapies.72–74


Dr. Fatica has disclosed working as an advisor or review panel participant for Natera Inc and REATA Pharmaceuticals. The other authors report no relevant financial relationships which, in the context of their contributions, could be perceived as a potential conflict of interest.


  1. Goodman WG, Goldin J, Kuizon BD, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med 2000; 342(20):1478–1483. doi:10.1056/NEJM200005183422003CrossRefPubMedGoogle Scholar
  2. Jamal SA, Vandermeer B, Raggi P, et al. Effect of calcium-based versus non-calcium-based phosphate binders on mortality in patients with chronic kidney disease: an updated systematic review and meta-analysis. Lancet 2013; 382(9900):1268–1277. doi:10.1016/S0140-6736(13)60897-1CrossRefPubMedGoogle Scholar
  3. Ruospo M, Palmer SC, Natale P, et al. Phosphate binders for preventing and treating chronic kidney disease-mineral and bone disorder (CKD-MBD). Cochrane Database Syst Rev 2018; 8(8):CD006023. doi:10.1002/14651858.CD006023.pub3CrossRefPubMedGoogle Scholar
  4. Toussaint ND, Pedagogos E, Lioufas NM, et al. A randomized trial on the effect of phosphate reduction on vascular end points in CKD (IMPROVE-CKD). J Am Soc Nephrol 2020; 31(11):2653–2666. doi:10.1681/ASN.2020040411Abstract/FREE Full TextGoogle Scholar
  5. Chertow GM, Burke SK, Raggi P. Sevelamer attenuates the progression of coronary and aortic calcification in hemodialysis patients. Kidney Int 2002; 62(1):245–252. doi:10.1046/j.1523-1755.2002.00434.
  6. Qunibi WY, Nolan CR. Treatment of hyperphosphatemia in patients with chronic kidney disease on maintenance hemodialysis: results of the CARE study. Kidney Int Suppl 2004; (90):S33–S38. doi:10.1111/j.1523-1755.2004.09006.
  7. Watanabe K, Fujii H, Kono K, Goto S, Nishi S. Comparison of the effects of lanthanum carbonate and calcium carbonate on the progression of cardiac valvular calcification after initiation of hemodialysis. BMC Cardiovasc Disord 2020; 20(1):39. doi:10.1186/s12872-020-01343-1
  8. Ogata H, Fukagawa M, Hirakata H, et al. Effect of treating hyperphosphatemia with lanthanum carbonate vs calcium carbonate on cardiovascular events in patients with chronic kidney disease undergoing hemodialysis: the LANDMARK randomized clinical trial. JAMA 2021; 325(19):1946–1954. doi:10.1001/jama.2021.4807
  9. Toussaint ND, Elder GJ, Kerr PG. Bisphosphonates in chronic kidney disease; balancing potential benefits and adverse effects on bone and soft tissue. Clin J Am Soc Nephrol 2009; 4(1):221–233. doi:10.2215/CJN.02550508Abstract/FREE Full TextGoogle Scholar
  10. Titan SM, Laureati P, Sang Y, et al. Bisphosphonate utilization across the spectrum of eGFR. Arch Osteoporos 2020; 15(1):69. doi:10.1007/s11657-020-0702-2CrossRefGoogle Scholar
  11. Robinson DE, Ali MS, Pallares N, et al. Safety of oral bisphosphonates in moderate-to-severe chronic kidney disease: a binational cohort analysis. J Bone Miner Res 2021: 36(5):820–832. doi:10.1002/jbmr.4235CrossRefGoogle Scholar
  12. de Roij van Zuijdewijn C, van Dorp W, Florquin S, Roelofs J, Verburgh K. Bisphosphonate nephropathy: a case series and review of the literature. Br J Clin Pharmacol 2021; 87(9):3485–3491. doi:10.1111/bcp.14780CrossRefGoogle Scholar
  13. Perazella MA, Markowitz GS. Bisphosphonate nephrotoxicity. Kidney Int 2008; 74(11):1385–1393. doi:10.1038/ki.2008.356CrossRefPubMedGoogle Scholar
  14. Kranenburg G, Bartstra JW, Weijmans M, et al. Bisphosphonates for cardiovascular risk reduction: a systematic review and meta-analysis. Atherosclerosis 2016; 252:106–115. doi:10.1016/j.atherosclerosis.2016.06.039CrossRefPubMedGoogle Scholar
  15. Russell RG, Smith R, Bishop MC, Price DA. Treatment of myositis ossificans progressiva with a diphosphonate. Lancet 1972; 1(7740): 10–11. doi:10.1016/s0140-6736(72)90004-9CrossRefPubMedGoogle Scholar
  16. Fleisch HA, Russell RG, Bisaz S, Mühlbauer RC, Williams. The inhibitory effect of phosphonates on the formation of calcium phosphate crystals in vitro and on aortic and kidney calcification in vivo. Eur J Clin Invest 1970; 1(1):12–18. doi:10.1111/j.1365-2362.1970.tb00591.xCrossRefPubMedGoogle Scholar
  17. Hildebrand S, Cunningham J. Is there a role for bisphosphonates in vascular calcification in chronic kidney disease? Bone 2021: 142:115751. doi:10.1016/j.bone.2020.115751CrossRefGoogle Scholar
  18. Nitta K, Akiba T, Suzuki K, et al. Effects of cyclic intermittent etidronate therapy on coronary artery calcification in patients receiving long-term hemodialysis. Am J Kid Dis 2004; 44(4):680–688. pmid:15384019CrossRefPubMedGoogle Scholar
  19. Hashiba H, Aizawa S, Tamura K, Kogo H. Inhibition of the progression of aortic calcification by etidronate treatment in hemodialysis patients: long-term effects. Ther Apher Dial 2006; 10(1):59–64. doi:10.1111/j.1744-9987.2006.00345.xCrossRefPubMedGoogle Scholar
  20. Iseri K, Watanabe M, Yoshikawa H, et al. Effects of denosumab and alendronate on bone health and vascular function in hemodialysis patients: a randomized, controlled trial. J Bone Miner Res 2019; 34(6):1014–1024. doi:10.1002/jbmr.3676CrossRefGoogle Scholar
  21. Chen C-L, Chen N-C, Wu F-Z, Wu M-T. Impact of denosumab on cardiovascular calcification in patients with secondary hyperparathyroidism undergoing dialysis: a pilot study. Osteoporos Int 2020; 31(8):1507–1516. doi:10.1007/s00198-020-05391-3CrossRefGoogle Scholar
  22. Sin H-K, Wong P-N, Lo K-Y, et al. Treatment of severe tumoral calcinosis with teriparatide in a dialysis patient after total parathyroidectomy. Case Rep Nephrol 2021; 2021:6695906–6695906. doi:10.1155/2021/6695906CrossRefGoogle Scholar
  23. EVOLVE Trial Investigators; Chertow GM, Block GA, Correa-Rotter R, et al., Effect of cinacalcet on cardiovascular disease in patients undergoing dialysis. N Engl J Med 2012; 367(26):2482–2494. doi:10.1056/NEJMoa1205624CrossRefPubMedGoogle Scholar
  24. Raggi P, Chertow GM, Torres PU, et al. The ADVANCE study: a randomized study to evaluate the effects of cinacalcet plus low-dose vitamin D on vascular calcification in patients on hemodialysis. Nephrol Dial Transplant 2011; 26(4):1327–1339. doi:10.1093/ndt/gfq725CrossRefPubMedGoogle Scholar
  25. Zu Y, Lu X, Song J, Yu L, Wang S. Cinacalcet treatment significantly improves all-cause and cardiovascular survival in dialysis patients: results from a meta-analysis. Kidney Blood Press Res 2019; 44(6):1327–1338. doi:10.1159/000504139CrossRefGoogle Scholar
  26. Peng T, Zhuo L, Wang Y, et al. Systematic review of sodium thio-sulfate in treating calciphylaxis in chronic kidney disease patients. Nephrology (Carlton) 2018; 23(7):669–675. doi:10.1111/nep.13081CrossRefGoogle Scholar
  27. Udomkarnjananun S, Kongnatthasate K, Praditpornsilpa K, Eiam-Ong S, Jaber BL, Susantitaphong P. Treatment of calciphylaxis in CKD: a systematic review and meta-analysis. Kidney Int Rep 2019; 4(2):231–244. doi:10.1016/j.ekir.2018.10.002CrossRefGoogle Scholar
  28. Djuric P, Dimkovic N, Schlieper G, et al. Sodium thiosulphate and progression of vascular calcification in end-stage renal disease patients: a double-blind, randomized, placebo-controlled study. Nephrol Dial Transplant 2020; 35(1):162–169. doi:10.1093/ndt/gfz204CrossRefPubMedGoogle Scholar
  29. Malbos S, Urena-Torres P, Cohen-Solal M, et al. Sodium thiosulphate treatment of uraemic tumoral calcinosis. Rheumatology (Oxford) 2014; 53(3):547–551. doi:10.1093/rheumatology/ket388CrossRefPubMedGoogle Scholar
  30. Shioi A, Morioka T, Shoji T, Emoto M. The inhibitory roles of vitamin K in progression of vascular calcification. Nutrients 2020; 12(2):583. doi:10.3390/nu12020583CrossRefGoogle Scholar
  31. Vlasschaert C, Goss CJ, Pilkey NG, McKeown S, Holden RM. Vitamin K supplementation for the prevention of cardiovascular disease: where is the evidence? A systematic review of controlled trials. Nutrients 2020; 12(10): 2909. doi:10.3390/nu12102909CrossRefGoogle Scholar
  32. Fusaro M, D’Alessandro C, Noale M, et al. Low vitamin K1 intake in haemodialysis patients. Clin Nutr 2017; 36(2):601–607. doi:10.1016/j.clnu.2016.04.024CrossRefGoogle Scholar
  33. Alappan HR, Kaur G, Manzoor S, Navarrete J, O’Neill WC. Warfarin accelerates medial arterial calcification in humans. Arterioscler Thromb Vasc Biol 2020; 40(5):1413–1419. doi:10.1161/ATVBAHA.119.313879CrossRefGoogle Scholar
  34. Nigwekar SU, Bloch DB, Nazarian RM, et al. Vitamin K-dependent carboxylation of matrix Gla protein influences the risk of calciphylaxis. J Am Soc Nephrol 2017; 28(6):1717–1722. doi:10.1681/ASN.2016060651Abstract/FREE Full TextGoogle Scholar
  35. Witham MD, Lees JS, White M, et al. Vitamin K supplementation to improve vascular stiffness in CKD: the K4Kidneys randomized controlled trial. J Am Soc Nephrol 2020; 31(10):2434–2445. doi:10.1681/ASN.2020020225Abstract/FREE Full TextGoogle Scholar
  36. Savinov AY, Salehi M, Yadav MC, Radichev I, Milán JL, Savinova OVl. Transgenic overexpression of tissue-nonspecific alkaline phosphatase (TNAP) in vascular endothelium results in generalized arterial calcification. J Am Heart Assoc 2015; 4(12):e002499. doi:10.1161/JAHA.115.002499Abstract/FREE Full TextGoogle Scholar
  37. Raggi P, Bellasi A, Bushinsky D, et al. Slowing progression of cardiovascular calcification with SNF472 in patients on hemodialysis: results of a randomized phase 2b study. Circulation 2020; 141(9):728–739. doi:10.1161/CIRCULATIONAHA.119.044195CrossRefPubMedGoogle Scholar
  38. Alshahawey M, Borolossy R, El Wakeel L, Elsaid T, Sabri NA. The impact of cholecalciferol on markers of vascular calcification in hemodialysis patients: a randomized placebo controlled study. Nutr Metab Cardiovasc Dis 2021; 31(2):626–633. doi:10.1016/j.numecd.2020.09.014CrossRefGoogle Scholar
  39. Sakaguchi Y, Hamano T, Obi Y, et al. A randomized trial of magnesium oxide and oral carbon adsorbent for coronary artery calcification in predialysis CKD. J Am Soc Nephrol 2019 30(6):1073–1085. doi:10.1681/ASN.2018111150Abstract/FREE Full TextGoogle Scholar
  40. Charaghvandi DA, Teguh DN, van Hulst RA. Hyperbaric oxygen therapy in patients suffering from wounds in calciphylaxis: a narrative review. Undersea Hyperb Med 2020; 47(1):111–123. doi:10.22462/01.03.2020.12CrossRefGoogle Scholar
  41. Lai L-A, Hsiao M-Y, Wu C-H, Wang T-G, Özçakar L. Big gain, no pain: tumoral calcinosis. Am J Med 2018. 131(1):45–47. doi:10.1016/j.amjmed.2017.09.003CrossRefGoogle Scholar
  42. Gabel CK, Nguyen ED, Chakrala T, et al. Assessment of outcomes of calciphylaxis. J Am Acad Dermatol 2020; 85(4):1057–1064. doi:10.1016/j.jaad.2020.10.067CrossRefGoogle Scholar