Markers of inflammation after zoledronic acid redosing.

The symptoms of acute phase response (APR) following the first infusion of zoledronic acid (ZA) are attenuated after re-administration. We investigated the reasons for this attenuation, focusing on the changes in several hormones, bone markers and markers of inflammation occurring after the second ZA injection in patients who had experienced a severe APR after their first ZA infusion. Twenty-two postmenopausal women with osteoporosis and severe symptoms of APR following the first ZA infusion were included in the study (group A1). A year later, the same women (possibly with a residual activity of ZA) were subjected to ZA re-administration (group A2). Urine NTx (uNTx), white blood cells, parathyroid hormone, serum calcium, phosphorus and several serum markers of inflammation were measured before (0) and at 1 and 2 days following the first as well as the second infusion. In group A1, the APR was associated with a significant increase in serum C-reactive protein (CRP), high-sensitive interleukin 6 (hsIL-6), high-sensitive tumor necrosis factor alpha (hsTNF-α) and cortisol within 24 h after the infusion. The majority of the patients in group A2 did not experience an APR and serum calcium, phosphorus, CRP, hsIL-6, hsTNF-α, and cortisol remained essentially unchanged throughout the study. In group A2, on day 0, the uNTx were significantly lower than in group A1. In group A1 the uNTx decreased by 69 and 78% from baseline on days 1 and 2, whereas in group A2, they decreased by 48 and 53% (p < 0.01), respectively. A positive correlation was found between the degree of uNTx decline from the baseline levels (Δ-uNTx) and hsTNF-α and between Δ-uNTx and CRP. The Δ-uNTx, reflecting the osteoclast-mediated bone resorption, may play some role in the APR appearance, although it must be excluded if the relationships of the changes between uNTx and hsTNF-α/CRP are coincidental effects and not causal.

Cytokines and insulin resistance after zoledronic acid-induced acute phase response.

Zoledronic acid is known to induce a transient acute phase response (APR). The aim of the study was to investigate whether an APR caused by zoledronic acid administration can induce insulin resistance in post-menopausal osteoporotic women and the potential involvement of different inflammatory markers, cytokines and adipokines to this response. Insulin resistance was calculated by the homeostasis model assessment (HOMA-IR). APR symptoms appeared in 30 post-menopausal osteoporotic women within 24 h and attenuated on day 3 after zoledronic acid infusion. Twenty-eight age- and body mass index-matched, patients without an APR following zoledronic acid administration, served as a control group. In patients with APR, concurrently with a significant increase in serum high sensitive C-reactive protein (hsCRP), interleukin-6 (hsIL-6), tumour necrosis factor-alpha (hsTNF-α) and cortisol levels on days one and two, serum insulin was also significantly elevated, resulting in an increased HOMA-IR. Leptin and resistin significantly increased on day two in contrast to adiponectin which declined, though not statistically significant. The alterations in HOMA-IR were mainly associated to the increase of hsCRP and leptin. In conclusion, zoledronic acid induces an acute, short term insulin resistance, due to an APR, by altering the levels of various adipokines and cytokines.

Transient changes in thyroid functions tests after zoledronic acid infusion.

Zoledronic acid (ZA) induces an acute phase response in association with elevation of serum cytokines, which possibly alter the 3 types of iodothyronine deiodinase activity. We therefore studied the possible alteration in thyroid function tests by ZA. We investigated the acute changes in serum thyroid hormones, TSH, cortisol, white blood cells, CRP, interleukin-6 (IL-6) and tumor necrosis factor (TNF-α), before (0) and 1, 2 and 3 days after iv infusion of 5 mg ZA in 24 asymptomatic postmenopausal women with osteoporosis (ZA group) in comparison with a placebo group. In the majority of patients the ZA infusion was associated with acute phase response and fever within 24h after infusion which became attenuated on day three. Concurrently with increase in serum cortisol, CRP, IL-6 and TNF-α, on day 1 and 2, total serum T3 (TT3), free T3 (fT3), total T4 (TT4) and fT4 decreased with a nadir on day 2 in association with an increase in the fT4/fT3 ratio and reverse T3 (rT3) levels. All thyroid function changes returned to the baseline levels on day 3, with cytokines still at higher levels, although lower than those on day 2. Serum TSH remained essentially unchanged throughout the study. The changes in thyroid hormones were at least in part explained by the increased TNF-α, but not by IL-6. ZA induces short term changes in thyroid hormones, characteristic of nonthyroidal illness syndrome (NTIS), in association with an increase in TNF-α and IL-6.

Vitamin D deficiency in the elderly in Athens, Greece.

Vitamin D deficiency characterized by low 25-hydroxyvitamin D [25(OH)D] levels has been found to be prevalent among the elderly in many regions of the world. To investigate the vitamin status in elderly community-living persons in Athens, we measured 25(OH)D and parathyroid hormone (PTH) in elderly persons and young blood donors during the winter and summer. The changes in these parameters in a subgroup of the elderly were studied longitudinally. The blood donors had mean 25(OH)D levels similar in winter and summer and twice as high in winter compared to the elderly. At the end of the winter, about 20% of the elderly had severe vitamin D deficiency, with 25(OH)D below 25 nmol/l, and only 6.5% could be judged as vitamin D sufficient with values above 80 nmol/l. The situation improved during summer, although 64.8% of the elderly continued to have levels below 80 nmol/l. Mean plasma PTH in the elderly in summer was not different from that of blood donors; however, it was doubled during the winter. Regression of PTH on 25(OH)D demonstrated that PTH starts to rise when 25(OH)D falls below approximately 80 nmol/l. We conclude that severe vitamin deficiency associated with secondary hyperparathyroidism is not uncommon in the elderly in Athens during the winter; it subsides during summer, although only one-third of the elderly population attain vitamin D sufficiency during summer. We found that a threshold value of 25(OH)D exists at approximately 80 nmol/l, below which secondary hyperparathyroidism ensues, as described previously.