*4.1. Bisphosphonates*

Bisphosphonates, also known as pyrophosphate analogs, are antiresorptive drugs that are administered to treat diseases with high-turnover bone resorption, like osteoporosis, Paget's disease, and multiple myeloma. In CKD–MBD, they are applied to treat the dysregulated bone metabolism [8]. Bisphosphonates inhibit osteoclast activity. There are two groups of bisphosphonates, with different nitrogen content. Non-nitrogen-containing bisphosphonates (e.g., etidronate) cause osteoclast apoptosis, while nitrogen-containing equivalents (e.g., alendronate; pamidronate) inhibit osteoclast activity. Nitrogen-containing bisphosphonates show 10–10,000 times increased potency in inhibiting bone resorption [45]. Bisphosphonate-associated nephrotoxicity has been reported [46,47]. Especially, intravenously applied bisphosphonates can cause acute kidney injury [47–49]. Therefore, doses and treatment period has to be adjusted in patients with pre-existing CKD [46]. Other known side effects are focal segmental glomerulosclerosis, hypocalcemia, and pathological fractures like bisphosphonate-related osteonecrosis of the jaw [46,50]. Still, bisphosphonates are in generally well tolerated, and severe side effects are rare [50–52]. The mechanisms of action and pharmacokinetics of bisphosphonates have recently been reviewed [53].

Etidronate reduced aortic calcification in five-sixths nephrectomy-induced CKD rats (Table 2), as well as in HD and CKD patients [54,55]. Alendronate did not alter aortic calcification in CKD stages 3 and 4 [56]. These results sugges<sup>t</sup> that the nitrogen content of bisphosphonates may affect the potency of bisphosphonates to alter CV calcification. A systematic review summarized 20 performed trials and illustrated contrasting results of the existing bisphosphonate studies [55]. In CKD patients, coronary artery calcification (CAC) and aortic calcification were increased after 12–24 months of bisphosphonate treatment. In a non-CKD cohort of postmenopausal osteoporotic women, intima–media thickening was reduced under bisphosphonate therapy [55]. Evidence remains unclear regarding the effect on arterial stiffness and atherosclerotic plaques in humans. In a retrospective study, female CKD patients had a 22% reduced risk for all-cause mortality when treated with bisphosphonates. However, there was no benefit regarding CV mortality [57]. In different cohorts, beneficial effects were found on arterial calcification, but not on arterial stiffness. CV events were not improved by bisphosphonate therapy [58]. Due to the small amount of studies performed in CKD patients, evidence for a beneficial effect of bisphosphonates on vascular calcification in CKD–MBD is still unclear.

A novel strategy to alter osteoclast activity is the use of a neutralizing antibody against receptor activator of NFκB-ligand (RANKL), called denosumab, which inhibits bone resorption and reduces fracture risk [59]. RANKL is crucial for proper osteoclast function [60] and was shown to promote vascular calcification in vitro and in vivo [61,62]. In contrast to bisphosphonates, denosumab is not eliminated by the kidney [63] and appeared to be safe in HD patients. Nevertheless, a recent study revealed a denosumab-associated increased risk of renal function decline in male patients, patients with renal insufficiency, and patients with acute kidney injury [63]. In HD patients, neither alendronate nor denosumab treatment improved vascular function and CAC score [63].

Clinically and in animal models, there is an association between osteoporosis and CV calcification—the so called osteoporosis–vascular calcification paradox [64,65]. However, current evidence suggests that improving bone mineral density does not alter CV calcification.


**Table 2.** Novel therapeutic strategies that attenuate CV calcification in non-transgenic animal CKD models.

S.c: subcutaneous; i.p.: intraperitoneal; i.v.: intravenous; Ref: Reference.
