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What data are available to support the use of bisphosphonates in calciphylaxis?

Background

Calciphylaxis, also known as calcific uremic arteriolopathy, is a rare but life-threatening cutaneous vascular disease.1,2 Calciphylaxis typically affects patients with end-stage renal disease (ESRD); in the US population, the estimated incidence among hemodialysis patients is 35 cases per 10,000 patients.1 However, calciphylaxis can also affect patients with acute kidney injury, milder forms of chronic kidney disease (CKD), or prior kidney transplant. In rare cases, calciphylaxis has been reported in patients with normal kidney function (this is often termed “nonuremic calciphylaxis”).

In calciphylaxis, the calcification of blood vessels in the dermis and subcutaneous adipose tissue leads to microvascular occlusion and painful, ischemic lesions on the skin.1 These lesions tend to occur on areas of the body with more adipose tissue, such as the abdomen and thighs. Although the pathogenesis of calciphylaxis is still uncertain, the blood vessel calcification seen in this disease is likely the result of an imbalance between calcification promoting factors and calcification inhibiting factors. Decreased levels of calcification inhibiting factors have been observed in patients with calciphylaxis. Calcification and narrowing of microvessels results in chronic, low-grade ischemia. When endothelial injury and microthrombosis occurs in calcified vessels, it results in further occlusion and eventual infarction. Risk factors for calciphylaxis include dialysis dependence for >2 years, obesity, diabetes mellitus, and female sex. Prognosis for this disease is poor, particularly in patients with ESRD. The 1-year mortality rate for calciphylaxis in patients without ESRD is 25 to 45%; this rate rises to 45 to 80% in patients with ESRD.

Overview of Treatment Options

No therapies are approved to treat calciphylaxis, but several off-label therapies have been proposed; data for these therapies primarily come from observational studies and case reports.1,2 In 2015, an expert panel of nephrologists, cardiologists, and biochemists published a consensus statement on the diagnosis and treatment of dialysis-associated calciphylaxis.3 In general, the panel recommends a multimodal treatment strategy. Treatment options proposed by this group include increased dialysis intensity to enhance calcium and phosphate removal, reduced calcium intake, vitamin K supplementation, and avoidance of vitamin K antagonist therapy. It is thought that vitamin K may help protect against vascular calcification, or even reverse the process of calcification; a small clinical trial of vitamin K supplementation in calciphylaxis was recently completed, but results of this trial are not yet available.3,4 Other proposed treatments include sodium thiosulfate (STS), bisphosphonates, parathyroidectomy, or cinacalcet; however, no treatment could be definitively agreed upon as a first-line therapy due to lack of prospective controlled studies.3 A clinical trial of STS in calciphylaxis is currently underway.5

In addition to the above, adjunct therapies are typically required to address the symptoms of calciphylaxis and prevent or treat complications.1,5 Pain management is a key factor in improving quality of life for patients with calciphylaxis; a combination of opioid analgesics, gabapentin, ketamine, and/or spinal anesthetic agents may be necessary to achieve adequate pain relief. Wound care measures are also important to prevent infection, promote healing, and remove any necrotic tissue. Prophylactic antibiotics are not indicated, but antibiotic treatment may be necessary if infection develops.

Rationale for Bisphosphonates

Bisphosphonates inhibit osteoclast action and prevent bone resorption; these drugs are frequently used in osteoporosis and other disease states to preserve bone mineral density.6 The mechanism of action for bisphosphonates in calciphylaxis is not well understood. Bisphosphonates are pyrophosphate analogues; pyrophosphate is a potent inhibitor of calcium hydroxyapatite formation.5 Bisphosphonates have also been noted to produce anti-inflammatory effects, which may help decrease the calcification of vascular smooth muscle.

The majority of experts on the 2015 consensus panel were not in favor of recommending bisphosphonates as a first-line treatment option for dialysis-associated calciphylaxis.3 The authors of the consensus statement note that the published evidence for bisphosphonates is scarce, and that bisphosphonates have the potential to worsen adynamic bone disease, particularly in patients with stage 4 or 5 CKD. Therefore, bisphosphonates should only be considered in cases where adynamic bone disease has been ruled out or determined to be highly unlikely.

Literature Review

A number of case reports and case series have been published describing the use of bisphosphonates in calciphylaxis (Table 1).7-23 Intravenous pamidronate was a commonly-used bisphosphonate in case reports, but etidronate and other bisphosphonates were also used with positive results. Pamidronate was typically used at a dose of 30 mg, but dosing frequency varied substantially.

One case series compared a prospective cohort of 11 bisphosphonate-treated patients with a historical cohort of 12 patients treated with conventional therapies (wound debridement, antibiotics, and/or increased dialysis time with low calcium in the dialysate); in this case series, all patients who were treated with bisphosphonates (in addition to supportive therapy) recovered successfully without sequelae, while 7 patients in the conventional therapy cohort required amputation and 2 patients in the conventional therapy cohort died due to septic complications.13 However, it is possible that these outcome differences may have been due to other factors, such as change in the quality of supportive care interventions over time; patients in the historical cohort were all treated prior to 2002. There were no studies comparing bisphosphonate therapy to STS. In 1 report, 2 patients who did not respond to or tolerate STS therapy had successful outcomes with bisphosphonate therapy plus negative pressure wound therapy.12 However, another report described a patient who did not experience a complete response with initial bisphosphonate therapy; full recovery was only achieved after initiation of treatment with STS.8 In 2 reports, bisphosphonate therapy was added to STS therapy, and the combination was able to successfully resolve skin lesions that were refractory to STS alone.10,15

Bisphosphonate therapy was useful for the majority of reported case patients; however, bisphosphonates were typically used as part of a multimodal approach, and bisphosphonate treatment was not effective in all patients.7-23 Publication bias may have favored the publication of cases with positive results. The number of case reports describing bisphosphonate therapy for calciphylaxis remains small, and larger prospective studies are needed to confirm efficacy.

Table 1. Summary of reports describing bisphosphonate use in calciphylaxis.7-23
CitationPatient(s)Intervention(s)Outcome
Rzepecki 20197

Case report		25-year-old female with systemic lupus erythematosus, lupus nephritis, and nonuremic calciphylaxis

Presented with numerous indurated papules and thin plaques on the trunk and upper extremities, as well as retiform purpuric and necrotic indurated plaques on the buttocks and proximal inner thighs		STS IV (dose not specified), plasmapheresis, IV bisphosphonates (agent/dose not specified), discontinuation of systemic corticosteroidsSignificant, rapid progression of retiform purpura and necrotic ulcerations; patient died within 5 weeks of initial presentation.
Massimetti 20198

Case report		70-year-old female with calciphylaxis after renal transplantation and restoration of renal function

Presented with extensive erythema, livedo reticularis, and painful subcutaneous nodules in both legs; skin ulcer developed on right leg a few weeks later		Initial therapy:

Pamidronate 30 mg IV weekly for 5 weeks plus cinacalcet 30 mg PO daily and surgical debridement with vacuum-assisted closure therapy

Warfarin therapy was continued		Pamidronate only partially reduced the pain and extent of ulcer. Cinacalcet was discontinued due to AEs.

Approximately 6 months after initial presentation, STS was initiated at 12.5g twice weekly (later increased to thrice weekly). Ulcer healed completely after 4 months of STS therapy.
Truong 20199

Case report		75-year-old female with nonuremic calciphylaxis

Presented with painful, discolored lesions on right leg that later became necrotic		Pyoderma gangrenosum initially suspected, but oral corticosteroid treatment did not improve lesions

Warfarin was switched to rivaroxaban and opioids were given for pain

When wounds did not improve after discontinuation of warfarin, pamidronate 30 mg IV every 2 weeks was initiated, along with compression wrapping of the wound		After a total of 4 pamidronate infusions and 6 months of treatment, the patient’s wounds healed completely without recurrence.
Fernandez Canabate 201810

Case report		68-year-old female with calciphylaxis and ESRD (on hemodialysis)

Presented with painful nodular lesion on left thigh		Initial therapy:

STS 12.5 g after dialysis plus discontinuation of acenocoumarol and paricalcitol. Patient was already receiving cinacalcet for secondary hyperparathyroidism.

After 10 weeks of initial therapy, pamidronate 30 mg IV weekly was added due to evolution of disease. Cinacalcet was replaced by etelcalcetide due to GI effects.		Pamidronate was stopped after 14 weeks of treatment, and STS was stopped the following week. Patient experienced resolution of painful lesions and size reduction of nodules.
Hooman 201511

Case report		21-month-old female with calciphylaxis and ESRD due to diffuse mesengeal sclerosis

Presented with fever, cough, and superficial erythematous lesion on the left wrist; lesion progressed to a hard, tender nodule, and a blister appeared on the right wrist, eventually progressing to skin necrosis		Initial therapy:

Debridement of necrotic tissue on the right wrist, increased peritoneal dialysis dwell volume, wound care, and antibiotics; calcium supplements were discontinued and sevelamer was initiated

Lesions progressed or did not improve, so pamidronate was initiated at 0.5 mg/kg IV; this was given daily for 6 days, then every other day; after the 8th dose, frequency of infusion was decreased to once weekly		Lesions had fully recovered 45 days after initiating pamidronate.
Lorriaux 201512

Case series		2 adult females with nonuremic calciphylaxis

Patient 1 (aged 55 years) presented with painful purple plaques on the lower abdomen and indurated nodules on her upper thighs

Patient 2 (aged 69 years) presented with several painful necrotic ulcers around the lap belt, surrounded by purple indurated retiform plaques		Patient 1:

Initial therapy with wound care measures and STS 25 g IV 3 times weekly

STS was stopped due to GI intolerance after 1 month (no improvement in wounds was observed)

Negative pressure wound therapy plus pamidronate 30 mg IV every 2 weeks was subsequently initiated

Patient 2:

Initial therapy with STS, but STS was poorly tolerated and produced no response after 2 months of therapy (existing lesions worsened, and new lesions appeared)

Negative pressure wound therapy plus pamidronate 30 mg IV every 2 weeks was subsequently initiated		Patient 1: After 8 pamidronate infusions, good response was observed with a decrease in pain.

Patient 2: Marked improvement in wounds was observed after 3 months; complete healing was achieved after 6 months.
Torregrosa 201513

Case series with retrospective and prospective cohorts		Group 1 (n=12): received treatment for calciphylaxis prior to 2002

Group 2 (n=11): received treatment for calciphylaxis after 2002		Group 1 received conventional treatments: wound debridement (n=12), antibiotics (n=12), increased hemodialysis time (n=6), parathyroidectomy (n=3)

Group 2 received bisphosphonate treatment in addition to supportive therapy; bisphosphonate therapy was alendronate 70 mg PO weekly for 6 months (n=1), risedronate 35 mg PO weekly for 6 months (n=4), or ibandronate 6 mg IV x1, then 3 mg IV 2 weeks later, then 150 mg PO monthly until lesions were resolved (n=7)		In Group 1, 3 patients recovered, 7 required limb amputation, and 2 died of septic complications.

In Group 2, progression of skin lesions decreased after 2 to 4 weeks of treatment in all patients; all patients survived without recurrence. Patients who received IV therapy had faster, more effective resolution of wounds.
Torregrosa 201214

Prospective case series		8 patients diagnosed with calciphylaxis between 2002 and 2010

5 patients were on hemodialysis, 3 had functioning kidney grafts

Presented with purple ulcerous necrotic lesions and livedo reticularis on the inner thighs (n=6) and/or tibial area (n=3)		Patients received alendronate 70 mg PO weekly (n=1), risedronate 35 mg PO weekly (n=4), or ibandronate 6 mg IV x1, then 3 mg IV after 15 days, then 150 mg PO monthly for 6 months (n=3)

Bisphosphonate treatment continued until all lesions were completely healed (at least 6 months)

Dicoumarin therapy was continued in patients on dicoumarin therapy (n=6)		Skin lesions began to heal and decrease in size after 2 to 4 weeks of treatment in all patients; pain began to decrease after 2 to 5 days. Patients who received IV therapy had faster resolution of wounds. All patients survived without recurrence (follow-up period of 1 to 9 years).
Malabu 201115

Case report		46-year-old female with calciphylaxis and normal kidney function

Presented with painful erythematous hard nodules that progressed to ulcerated lesions over her calves and thighs; wounds complicated by MRSA infection		Initial therapy:

STS 25 g every other day, antibiotics, surgical debridement and skin grafting, hyperbaric oxygen sessions

Wounds persisted after 6 months of therapy, so pamidronate 30 mg IV monthly was initiated		Ulcers resolved completely within 5 months of starting pamidronate.
Yoshikawa 201116

Case report		57-year-old male with POEMS syndrome and calciphylaxis

Presented with ulcers on lower extremities in areas with reticular purple-colored erythema; some ulcers were necrotic. Ulcers later expanded to the trunk and upper extremities		Initial therapy:

Wound debridement and hyperbaric oxygen therapy

No improvement was seen, so etidronate disodium 200 mg daily was initiated (route unspecified)		After 1 month of etidronate, ulcers had decreased to less than half of the original size; patient died suddenly 3 months later due to cardiorespiratory failure.
Almafragi 200917

Case report		54-year-old female with calciphylaxis and normal kidney function

Presented with livedo reticularis on the left shin and painful, progressive necrotic ulceration of both legs		Initial therapy:

Antibiotics, local wound care, IV bisphosphonate (drug/dose not specified)		IV bisphosphonates were reported to produce “limited results.” Patient was discharged from the hospital with daily wound care only; lesions were almost closed at 1 year.
Schliep 200818

Case report		72-year-old male with calciphylaxis and normal kidney function

Presented with painful skin necrosis on right lower leg		Initial therapy:

Surgical debridement and wound care plus pamidronate 30 mg IV (6 infusions over a period of 2 months; first 2 infusions were given at an interval of 5 days, and subsequent infusions were given every 2 weeks)		First 2 pamidronate infusions produced significant pain relief; ulcers decreased in size. At 4 months, a 5 mm ulcer remained; this subsequently healed with local wound therapy.
da Costa 200819

Case report		64-year-old male with calciphylaxis on dialysis

Presented with painful plaques on the left pretibial area and foot that progressed to necrosis		Initial therapy:

Antibiotics, surgical debridement and wound dressings, sevelamer 1600 mg 3 times daily, and pamidronate 30 mg IV in 3 alternate dialysis sessions

Pamidronate 30 mg IV was administered every 15 days for an additional 3 months		After hospital discharge, the patient developed new lesions on the other leg that responded to similar treatment measures; most lesions had healed by 6 months post-admission. At 2 years post-admission, the patient remained asymptomatic.
Hanafusa 200720

Case report		53-year-old male with calciphylaxis and CKD (on dialysis)

Presented with necrotic ulcers on lower legs		Initial therapy:

Surgical debridement and wound care, increased dialysis time, increased dose of sevelamer, initiation of etidronate 200 mg PO daily for 14 days		Leg ulcers immediately began to decrease in size, and all wounds had healed completely at the time of hospital discharge (approximately 3 months after initial presentation).
Musso 200621

Case report		57-year-old female with calciphylaxis and CKD (on dialysis)

Presented with painful, nonulcerated subcutaneous lesion in the left groin area		Initial therapy:

Ibandronate 2 mg IV after dialysis once a month		After 2 months of treatment, inflammation around the lesion had disappeared, leaving only a hard subcutaneous plaque.
Shiraishi 200622

Case report		59-year-old female with calciphylaxis and CKD (on dialysis)

Presented with painful erythema on legs, which subsequent progressed to ulcerated lesions with necrosis despite local wound care		Initial therapy:

Antibiotics, wound care, surgical debridement

Ulcers increased in size and local infection persisted, so etidronate 200 mg PO daily was given for 14 days

Sevelamer was initiated on day 11 of etidronate therapy		Improvement in skin ulcers was noted within a few days of starting etidronate therapy; ulcer size had decreased significantly after 10 days of etidronate. Patient survived and was discharged when ulcers had almost completely healed.
Monney 200423

Case report		59-year-old female with calciphylaxis and CKD

Presented with painful erythematous lesions on the legs and 3 necrotic ulcers on the calves		Initial therapy:

Daily hemodialysis for 10 days then 4 hours of dialysis 3 times weekly, antibiotics, opioid pain medications, and local wound care

Condition continued to worsen, so pamidronate 30 mg IV was initiated (5 doses were given on days 23, 25, 29, 30, and 48 of hospitalization)		Within 48 hours of the first pamidronate dose, pain in the legs had resolved, allowing for discontinuation of opioids; ulcers healed within 1 month, and the patient was discharged 5 weeks after initiating pamidronate.  Pain in the legs recurred at 6 weeks post-discharge, but pain was resolved with a single dose of pamidronate 30 mg IV. No subsequent recurrences were reported.
Abbreviations: AE=adverse event; CKD=chronic kidney disease; GI=gastrointestinal; IV=intravenous; MRSA=methicillin-resistant Staphylococcus aureus; PO=oral; POEMS=polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes; STS=sodium thiosulfate.

Conclusion

The evidence for bisphosphonate therapy in calciphylaxis is limited to case reports and small case series. Although positive outcomes have been observed in some patients who received bisphosphonates as part of a multimodal intervention, evidence from prospective trials is needed to determine the place in therapy for bisphosphonates, as well as optimal dosing and treatment duration. In general, there is a lack of high-quality evidence for proposed calciphylaxis treatments, although clinical trials for other therapies (such as STS) are currently underway. Bisphosphonates are not indicated for routine use in calciphylaxis, but they may be considered for select patients, including those who cannot receive STS and those who do not respond to STS therapy.

References

  1. Nigwekar SU, Thadhani R, Brandenburg VM. Calciphylaxis. N Engl J Med. 2018;378(18):1704-1714.
  2. Garcia-Lozano JA, Ocampo-Candiani J, Martinez-Cabriales SA, Garza-Rodriguez V. An update on calciphylaxis. Am J Clin Dermatol. 2018;19(4):599-608.
  3. Brandenburg VM, Evenepoel P, Floege J, et al. Lack of evidence does not justify neglect: how can we address unmet medical needs in calciphylaxis? Nephrol Dial Transplant. 2016;31(8):1211-1219.
  4. Evaluation of vitamin K supplementation for calcific uremic arteriolopathy (VitK-CUA). clinicaltrials.gov website. https://clinicaltrials.gov/ct2/show/NCT02278692. Accessed December 13, 2019.
  5. Seethapathy H, Brandenburg VM, Sinha S, El-Azhary RA, Nigwekar SU. Review: update on the management of calciphylaxis. QJM. 2019;112(1):29-34.
  6. Dayanand P, Sandhyavenu H, Dayanand S, Martinez J, Rangaswami J. Role of bisphosphonates in vascular calcification and bone metabolism: a clinical summary. Curr Cardiol Rev. 2018;14(3):192-199.
  7. Rzepecki AK, Park M, Amin B, Dunec A, McLellan BN, Balagula Y. A unique clinical and histologic presentation of catastrophic systemic calciphylaxis in a nonuremic patient with systemic lupus erythematosus. JAAD Case Rep. 2019;5(3):245-248.
  8. Massimetti C, Bellasi A, Modoni A, Gomes V, Feriozzi S. Multifaceted approach to a rare clinical case of calciphylaxis in a renal transplant recipient. G Ital Nefrol. 2019;36(5).
  9. Truong DH, Riedhammer MM, Zinszer K. Non-uraemic calciphylaxis successfully treated with pamidronate infusion. Int Wound J. 2019;16(1):250-255.
  10. Fernandez Canabate S, Alvarez CL, Ortega Valin L, Estifan Ksabji J. Sodium thiosulfate and pamidronate for treatment of calciphylaxis: case report. Colomb Med (Cali). 2018;49(4):288-291.
  11. Hooman N, Naghshi-Zadiyan R, Mehrazma M, Jahangiri F. Successful treatment of calciphylaxis with pamidronate. Iran J Kidney Dis. 2015;9(1):67-70.
  12. Lorriaux A, Chaby G, Dhaille F, et al. Nonuraemic calciphylaxis: response to treatment with pamidronate and negative pressure therapy. Clin Exp Dermatol. 2015;40(1):52-55.
  13. Torregrosa JV, Sanchez-Escuredo A, Barros X, Blasco M, Campistol JM. Clinical management of calcific uremic arteriolopathy before and after therapeutic inclusion of bisphosphonates. Clin Nephrol. 2015;83(4):231-234.
  14. Torregrosa JV, Duran CE, Barros X, et al. Successful treatment of calcific uraemic arteriolopathy with bisphosphonates. Nefrologia. 2012;32(3):329-334.
  15. Malabu UH, Roberts LJ, Sangla KS. Calciphylaxis in a morbidly obese woman with rheumatoid arthritis presenting with severe weight loss and vitamin D deficiency. Endocr Pract. 2011;17(4):e104-108.
  16. Yoshikawa M, Uhara H, Arakura F, et al. Calciphylaxis in POEMS syndrome: A case treated with etidronate. Acta Derm Venereol. 2011;91(1):98-99.
  17. Almafragi A, Vandorpe J, Dujardin K. Calciphylaxis in a cardiac patient without renal disease. Acta Cardiol. 2009;64(1):91-93.
  18. Schliep S, Schuler G, Kiesewetter F. Successful treatment of calciphylaxis with pamidronate. Eur J Dermatol. 2008;18(5):554-556.
  19. da Costa JB, da Costa AG, Gomes MM. Pamidronate as a treatment option in calciphylaxis. J Eur Acad Dermatol Venereol. 2008;22(9):1128-1130.
  20. Hanafusa T, Yamaguchi Y, Tani M, Umegaki N, Nishimura Y, Katayama I. Intractable wounds caused by calcific uremic arteriolopathy treated with bisphosphonates. J Am Acad Dermatol. 2007;57(6):1021-1025.
  21. Musso CG, Enz PA, Guelman R, et al. Non-ulcerating calcific uremic arteriolopathy skin lesion treated successfully with intravenous ibandronate. Perit Dial Int. 2006;26(6):717-718.
  22. Shiraishi N, Kitamura K, Miyoshi T, et al. Successful treatment of a patient with severe calcific uremic arteriolopathy (calciphylaxis) by etidronate disodium. Am J Kidney Dis. 2006;48(1):151-154.
  23. Monney P, Nguyen QV, Perroud H, Descombes E. Rapid improvement of calciphylaxis after intravenous pamidronate therapy in a patient with chronic renal failure. Nephrol Dial Transplant. 2004;19(8):2130-2132.

Prepared by:
Laura Koppen, PharmD, BCPS
Clinical Assistant Professor, Drug Information Specialist
University of Illinois at Chicago College of Pharmacy

January 2020

The information presented is current as of December 6, 2019. This information is intended as an educational piece and should not be used as the sole source for clinical decision-making.

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