Acute Phase Reactions After Zoledronic Acid Infusion

Protective Role of 25-hydroxyvitamin D and Previous Oral Bisphosphonate Therapy

Chiara Crotti, MD; Nelson B. Watts, MD; Maria De Santis, MD, PhD; Angela Ceribelli, MD, PhD; Gianluigi Fabbriciani, MD; Francesca Cavaciocchi, PhD; Bianca Marasini, MD; Carlo Selmi, MD, PhD; Marco Massarotti, MD


Endocr Pract. 2018;24(5):405-410. 

In This Article


Table 1 describes the characteristics of the study population. Of the 153 patients, 68 had been previously treated with oral BPs. Of the 85 naïve patients, 3 received teriparatide and 3 received strontium ranelate.

APR occurred in 68/153 (44.4%) patients. Symptoms were fever plus arthromyalgia (muscle and/or joint pain) in 57.4%, fever alone in 33.8%, arthromyalgia alone in 7.4%, and fever plus diarrhea in 1.5%. The type of symptoms was similar for patients with prior BP treatment compared with those not previously exposed to BP (Table 2).

The observed 25(OH)D levels were significantly lower in APR+ patients compared with patients without APR (APR-) (26.3 ± 12.7 vs. 37.0 ± 13.5 ng/mL, respectively; P<.0001). Moreover, 65% (44/68) of APR+ patients had 25(OH)D levels <30 ng/mL versus 31% (26/85) of APR- subjects (P<.0001, Figure 1). The OR for APR was 4.2 (95% CI 2.1, 8.2) for 25(OH)D <30 ng/mL. On the ROC curve, 25(OH)D <30 ng/mL had a sensitivity of 70% and a specificity of 62%.

Figure 1.

25(OH)D insufficiency and the risk of develop APR after zolderonic acid infusion. APR = acute phase reaction; 25(OH)D = 25-hydroxyvitamin D.

The highest 25(OH)D in a patient with APR was 58 ng/mL; none of the 5 patients with 25(OH)D >58 ng/mL experienced APR. The lowest 25(OH)D among patients who did not experience APR was 12 ng/mL; APR occurred in all 12 patients with 25(OH)D <12 ng/mL (range 4–11 ng/mL).

Among the prior oral BP group, 25(OH)D levels were significantly lower in the APR+ group (29.0 ± 14.4 ng/mL) compared with the APR- patients (37.8 ± 11.6 ng/mL, P = .02; Figure 2). However, 25(OH)D inadequacy by itself was not significantly associated with APR in the prior oral BP group. In fact, 52.2% (12/23) of APR+ patients who received prior oral BP had inadequate 25(OH)D versus 26.7% (12/45) of APR- subjects who received prior oral BP (OR for developing APR in patients with inadequate 25(OH)D was 3.0 (95% CI 1.1, 8.5, P = .037). This may be due to the higher levels of 25(OH)D in patients who received oral BPs compared with BP-naïve patients (34.8 ± 13.2 vs. 30.1 ± 14.5 ng/mL, P = .03; Figure 3) and/or to the small sample size.

Figure 2.

25-OH D levels in APR+ and APR- patients among patients previously treated with oral BPs (mean and SD). APR = acute phase reaction; BP = amino-bisphosphonate; 25(OH)D = 25-hydroxyvitamin D.

Figure 3.

25-OH D levels in patients previously treated with oral BPs and in BP-naïve patients (mean and SD). APR = acute phase reaction; BP = amino-bisphosphonate; 25(OH)D = 25-hydroxyvitamin D.

Prior oral BP therapy was reported less frequently in the APR+ group compared to the APR- group (23/68 [33.8%] vs. 45/85 [52.9%]; OR 0.5 [95% CI 0.2, 0.9]; P = .02). On logistic regression, previous oral BP treatment was weakly associated with APR after adding 25(OH)D levels as a variable (OR 0.5 [95% CI 0.3, 1.1]; P = .08) but remained significant after excluding subjects with 25(OH)D levels <12 and >58 ng/mL (19/56 [33.9% APR+] vs. 42/80 [52.5% APR-]; OR 0.46 [95% CI 0.23, 0.94]; P = .032).

Of the 18 (11.8%) patients using statins, 11 had APR and 7 did not (P = .14). No association was found between APR occurrence and type or duration of previous oral BP treatment or the time-interval between oral BP cessation and ZOL infusion. All patients had been on vitamin D supplementation for at least 3 months at the time of ZOL infusion; we found no association between cholecalciferol daily dose and APR occurrence.

Finally, no association was found between the occurrence of APR and diabetes, smoking, immunosuppressant use (possibly due to small numbers), age, or levels of serum PTH or calcium (Table 1).