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Theoretically bisphosphonates could accelerate or retard vascular calcification. In subjects with low GFR, the position is further confounded by a combination of uncertain pharmacokinetics (GI absorption is poor and inconsistent at all levels of renal function and the effect of low GFR generally is to increase bioavailability) and a highly variable skeletal substrate with extremes of turnover that increase unpredictably further. Although bisphosphonates reduce bone formation by 70–90% in subjects with normal GFR and reduce the ability of bone to buffer exogenous calcium fluxes, in bisphosphonate treated postmenopausal women accelerated vascular calcification has not been documented. The kidneys assist with this buffering, but the capacity to modulate calcium excretion declines as GFR falls, increasing the risk of hypercalcaemia in the event of high calcium influx. In the ESRD patient, decreased buffering capacity substantially increases the risk of transient hypercalcaemia, especially in the setting of dialysis, and as such may promote vascular calcification which is highly prevalent in the CKD population. Low bone turnover may thus be less of a vascular problem in patients with preserved renal function and a bigger problem when the GFR is low. In patients with stage 4 and 5 CKD, adynamic bone disease associates with the severity and progression of arterial calcification, including coronary artery calcification, and further suppression of bone turnover by a bisphosphonate might exacerbate an already high predisposition to vascular calcification. No convincing signal of harm has emerged from clinical studies thus far. For example 51 individuals with CKD stage 3–4 treated with either alendronate 70 mg per week or placebo for 18 months showed no difference in the rate of vascular calcifications. Conversely an observational study of women with stage 3–4 CKD with pre-existing cardiovascular disease found an increased risk of mortality with a hazard ratio of 1.22 (1.04–1.42) in those given bisphosphonates. Direct suppression of vascular calcification by bisphosphonates is probably confined to etidronate – treatment of soft tissue calcification was a recognized indication for this drug and etidronate markedly reduced progression of vascular calcification in CKD patients. Bisphosphonates are analogues of pyrophosphate, a potent calcification inhibitor in bone and soft tissue. Thus the efficacy of etidronate as treatment for soft tissue calcification brought with it a problematic tendency to cause osteomalacia. In contrast, conventional doses of nitrogen-containing bisphosphonates fail to yield circulating concentrations sufficient to exert direct anti-calcifying effects, at least in patients with good renal function and studies using alendronate and ibandronate have yielded inconsistent vascular outcomes. • The decreased bone buffering capacity of the kidney in advanced renal disease may lead to medial vascular calcification • Bisphosphonates reduce bone turnover, and with this, reduce calcium flux • The reduction in vascular calcification shown by etidronate has not been replicated by later generation bisphosphonates [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is commonly associated with mineral and bone metabolism disorders, but these are less frequently studied in non-dialysis CKD patients than in dialysis patients. We examined and described international variation in mineral and bone disease (MBD) markers and their treatment and target levels in Stage 3–5 CKD patients. Prospective cohort study of 7658 adult patients with eGFR <60 mL/min/1.73 m2, excluding dialysis or transplant patients, participating in the Chronic Kidney Disease Outcomes and Practice Patterns Study (CKDopps) in Brazil, France, Germany, and the US. CKD-MBD laboratory markers included serum levels of phosphorus (P), calcium (Ca), intact parathyroid hormone (iPTH), and 25-hydroxyvitamin D (25-D). MBD treatment data included phosphate binders and vitamin D (nutritional and active). Nephrologist survey data were collected on target MBD marker levels. Over two-thirds of the patients had MBD markers measured at time intervals in line with practice guidelines. P and iPTH increased and Ca decreased gradually from eGFR 60–20 mL/min/1.73m2 and more sharply for eGFR<20. 25-D showed no relation to eGFR. Nephrologist survey data indicated marked variation in upper target P and iPTH levels. Among patients with P > 5.5 mg/dL, phosphate binder use was 14% to 43% across the four countries. Among patients with PTH >300 pg/mL, use of active (calcitriol and related analogs) vitamin D was 12%–51%, and use of any (active or nutritional) vitamin D was 60%–87%. Although monitoring of CKD-MBD laboratory markers by nephrologists in CKDopps countries is consistent with guidelines, target levels vary notably and prescription of medications to treat abnormalities in these laboratory markers is generally low in these cross-sectional analyses. While there are opportunities to increase treatment of hyperphosphatemia, hyperparathyroidism, and vitamin D deficiency in advanced CKD, the effect on longer-term complications of these conditions requires study. • Serum phosphorous and iPTH increase as chronic kidney disease progresses. • Use of phosphate binders and vitamin D varies by country. • Nephrologist surveys indicate variation in upper target phosphorous, iPTH levels. • Serum 25OH vitamin D shows an association with iPTH levels. • Vitamin D use varied by iPTH, but not by serum 25OH vitamin D level. [ABSTRACT FROM AUTHOR]