Successful treatment of calciphylaxis with pamidronate

ARTICLE

Auteur(s) : Stefan Schliep, Gerold Schuler, Franklin Kiesewetter

Department of dermatology and venerology, Universitätsklinikum Erlangen, Hartmannstr. 14, 91052 Erlangen, Germany

accepté le 29 Avril 2008

Calciphylaxis is a rare syndrome characterized by painful ecchymosis and irregularly shaped skin necrosis. In the case of associated renal insufficiency it is also called calcific uraemic arteriolopathy. Most of the lesions are localized on the legs, but involvement of most parts of the integument and even visceral disease has been reported [1]. The histological examination reveals microcalcifications of small to medium-sized blood vessels, panniculitis and endothelial proliferation and fibrosis [2]. The pathogenesis of calciphylaxis is poorly understood, but a number of associated diseases and trigger factors are known [1]. The most common underlying conditions are chronic renal insufficiency and secondary hyperparathyroidism leading to an elevated calcium phosphorus product. However, in some patients, no underlying pathological condition can be found, a condition referred to as primary or idiopathic calciphylaxis [1]. Patients with calciphylaxis often develop severe complications, e.g. sepsis, and have overall a poor prognosis. In a recent study, a 1-year survival rate of only 45.8% was calculated [3]. Bisphosphonates inhibit osteoclasts by various mechanisms and are the major drugs in the treatment of resorptive bone disease such as osteoporosis, Morbus Paget, multiple myeloma and tumor-induced hypercalcemia [4]. The bisphosphonates pamidronate [5, 6] and etidronate [7, 8] were recently applied in the therapy of calciphylaxis in patients with renal insufficiency with impressive clinical responses. In an animal model, bisphosphonates prevented arterial calcification both associated with and in the absence of renal impairment [9, 10].

We report for the first time a case of calciphylaxis without concomitant renal insufficiency successfully treated with pamidronate.

Case report

The patient presented in a reduced general condition and complained about dyspnea on exertion and occasional vertigo. On the right lower leg we saw multiple irregularly shaped necroses with erythematous edges (figure 1), measuring up to 15 cm. Blood pressure was 110/70 mm Hg, heart rate 64 bpm, temperature 36.7 °C. Pupils were equal, round and reactive to light and accommodation; cardiac auscultation revealed absolute arrhythmia, breathing sounds were normal, the abdomen was soft, non-tender, normal bowel sounds. The peripheral pulses were palpable, no paresthesias or pareses were present.

The patient had suffered from atrial fibrillations, hypertension and depression for about 10 years. In addition, congestive heart failure was known. His medication included Enalapril, Phenprocoumon, Allopurinol, Quetiapin, Mirtazapin, Lorazepam, Venlafaxin and Magnesium. Phenprocoumon had not been started within the last six months. The patient was a non-smoker.

Blood tests on admission showed the following values (normal range in brackets): the complete blood cell count was normal except for a hemoglobin of 12.7 g/dL [13-17] and a hematocrit of 41.4% [42-52]. Serum creatinin was 1.23 mg/dL [0.5-1.2], urea 36 mg/dL [17-43], Calcium 2.3 mmol/L [2.1-2.7], phosphate 1.07 mmol/L [0.84-1.45], CRP 14 mg/L [<5], alkaline phosphatase 125 U/L [56-119], total protein 61.8 g/L [66-83], PTT 38.9 seconds [26-38], INR 2.00. The levels of glucose, uric acid, magnesium, LDH, ALAT, ASAT, Bilirubin, triglycerides, cholesterine, TSH, T3, T4, ferritin, IgG, IgM, IgA, C3, C4 and a protein electrophoresis were all within the normal range.

Further testing included a hepatitis serology, ANCA and anti-phospholipid-anibody screening, and cryoglobulins, all of which were negative. Creatinine clearance in a 24h urine specimen was 70 mL/min [49-79]. The parathyroid hormone was slightly increased with 89.7 pg/ml [10-50], calcitonin 13.2 pg/mL [< 11.5], 25-OH-vitamin D3 32.5 ng/mL [20-120]. A chest x-ray showed an aortic sclerosis and elongation. The abdominal ultrasound was unremarkable except for a fatty liver and a cyst in the right kidney. Plain radiographs of the legs showed symmetric extensive calcification of the A. femoralis communis, A. superficialis and their outlets. An angiographic examination (DSA) of the legs showed bilateral calcifications and several stenoses of the A. tibialis anterior, A. fibularis und A. tibialis posterior.

Skin biopsies revealed an extensive calcification of small and middle-sized blood vessels accompanied by pannicilitis (figure 2) and the diagnosis of calciphylaxis was established.

The local treatment included a surgical debridement and subsequent wound dressing with calcium alginate.

We performed a therapy with i.v. pamidronate with the aim of lowering the calcium level. The patient received 6 infusions with 30 mg pamidronate each (a total of 180 mg) over a period of two months. The first two infusions were given at an interval of 5 days, and were followed by a dramatic relief of the local pain. After the first infusion with pamidronate, reduced values of calcium (1.9 mmol/L) and phosphate (0.69 mmol/L) were observed. Subsequent infusions were given at intervals of two weeks. The ulcers steadily decreased in size. Furthermore, an improvement of the patient’s general condition was noted. Calcium and phosphate levels were normal throughout in the remaining course. A control measurement of parathyroid hormone assessed after completion of therapy revealed a stable value of 88.7 pg/mL [10-50].

After 4 months, an ulceration measuring 5 mm remained, followed by complete healing under local care. In a repeated skin biospy, the arterial calcification had vanished (figure 2).

Discussion

Bisphosphonates have a strong affinity to hydroxyapatite and efficiently bind to bone surfaces. Taken up by osteoclasts during bone resorption, they are able to affect the activity and differentiation of these cells by interfering with various cellular pathways [4].

Price et al. [9, 10] have shown that bisphosphonates represent strong inhibitors of experimental arterial calcification in rats. In uraemic rats arterial calcification was prevented by doses of ibandronate, which inhibits bone resorption [9]. In further experiments, calcification was triggered by treatment with warfarin alone and warfarin in combination with vitamin D3. Again, ibandronate and also alendronate were able to completely inhibit arterial calcification [10]. Importantly, the values of calcium and phosphorus did not change significantly in these experiments. The effect therefore cannot simply be explained by lowering the calcium phosphorus product. A close connection between bone turnover and arterial calcification was proposed. Although this relationship is not understood to date, there is substantial experimental and clinical data supporting this theory [11]. In the literature there are cases of calciphylaxis successfully treated with bisphosphonates associated with long-standing chronic renal insufficiency [5-8]. In one case, the therapy with bisphosphonate (etidronate) came along with a normalization of the calcium phosphorus product [7]. According to the above-mentioned, bisphosphonates represent promising candidates for the treatment of calciphylaxis and other diseases associated with calcification [11].

In our case, the parathyroid hormone level was slightly elevated, creatinine and calcitonin were borderline high. All other parameters regarding the calcium phosphorus metabolism were normal. Therefore, we assume that these minimal disturbances were not responsible for the rapid calcification process in this patient.

Coumarins are known to inhibit the generation of physiological calcification inhibitors like matrix Gla protein [12]. As phenprocoumon was not recently started and was not discontinued, it is rather unlikely that it initiated the calciphylaxis in this patient. Nevertheless, the intake of phenprocoumon might have contributed to the development of calciphylaxis.

Investigations and laboratory values revealed no hint for a neoplastic or autoimmune disease as triggers of calciphylaxis. Beside the calciphylaxis the patient also had prominent calcifications of large-sized blood vessels in the radiographs of the legs. This indicates an overlap of the calcification of small, medium and large-sized vessels, which was also present in other comparable cases [5, 6, 8]. Arteriosclerosis itself does usually not show calcification of small blood vessels associated with panniculitis.

As it was not possible in this patient to find a cause for secondary calciphylaxis, we classified this case as idiopathic calciphylaxis. Additionally to a debridement and wound care, we decided to perform a therapy with bisphosphonates. We saw an impressive clinical response with marked pain relief and complete healing of the necrotic ulcers. The patient’s general condition also improved. Except for a transient reduction of calcium and phosphate, no side effect of pamidronate was observed. A skin biopsy performed after the completion of therapy showed blood vessels without signs of calcification.

In conclusion, this case suggests that bisphosphonates are indeed successful treatment options in calciphylaxis patients, independent of renal funtion or disturbances of the calcium phosphorous metabolism. This positive effect might be due to the influence on bone turnover, resulting in reduced arterial calcification by an unknown mechanism. Especially, pamidronate may have a favorable effect. More clinical investigations are needed to assess the effect of different bisphosphonates in calciphylaxis of any origin.

Acknowledgements

References

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