Effects of Denosumab and Alendronate on Bone Health and Vascular Function in Hemodialysis Patients: A Randomized, Controlled Trial

Abstract

Mineral and bone disorders including osteoporosis are common in dialysis patients and contribute to increased morbimortality. However, whether denosumab and alendronate are effective and safe treatments in hemodialysis patients is not known. Thus, we conducted a prospective, three-center study of 48 hemodialysis patients who were diagnosed as having osteoporosis and had not received anti-osteoporotic agents previously. Participants were randomized to either denosumab or intravenous alendronate, and all subjects received elemental calcium and calcitriol during the initial 2 weeks. The primary endpoint was the percent change in lumbar spine bone mineral density (LSBMD) at 12 months of treatment. The secondary endpoints included the following: change in BMD at other sites; change of serum bone turnover markers (BTM), coronary artery calcium score (CACS), ankle-brachial pressure index (ABI), brachial-ankle pulse wave velocity (baPWV), flow mediated dilation (FMD), and intima-media thickness at the carotid artery (CA-IMT); change from day 0 to day 14 in serum levels of Ca and P; time course of serum calcium (Ca), phosphorus (P), and intact parathyroid hormone (i-PTH); new fractures; and adverse events. Initial supplementation with elemental calcium and calcitriol markedly ameliorated the decrease of serum corrected calcium (cCa) levels induced by denosumab during the first 2 weeks, whereas serum cCa levels in the alendronate group were increased. Denosumab and alendronate markedly decreased serum levels of BTM and increased LSBMD at 12 months compared with baseline. However, no significant differences were found in the changes in LSBMD between the two groups. The serum cCa, P, and i-PTH levels in the two groups were maintained within the appropriate range. In contrast to the anti-osteoporotic effects, no significant differences after 12 months of treatment were found in the CACS, CA-IMT, ABI, baPWV, and FMD compared with pretreatment in both groups. Denosumab and alendronate treatment improved LSBMD, reduced BTM, and appeared to be safe in hemodialysis patients with osteoporosis. Ca ¼ calcium; P ¼ phosphate; ALP ¼ alkaline phosphatase; PTH ¼ parathyroid hormone; TRACP-5b ¼ tartrate-resistant acid phosphatase 5b; t-PINP ¼ total-type I collagen N-terminal propeptide; BAP ¼ bone-specific ALP; Hs-CRP ¼ high-sensitivity C-reactive protein; CACS ¼ coronary artery calcium score; CA-IMT ¼ intima-media thickness at the carotid artery; ABI ¼ ankle brachial pressure index; baPWV ¼ brachial-ankle pulse wave velocity; FMD ¼ flow mediated dilation.Data are presented as mean AE SD (range from 25th to75th percentile) or n (%). Journal of Bone and Mineral ResearchEFFECTS OF ANTI-OSTEOPOROTIC AGENTS IN HEMODIALYSIS PATIENTS 5 ISERI ET AL.

Elimination of intravenous alendronate by hemodialysis: A kinetic study

“…Fifty percent of intravenous alendronate was removed by hemodialysis, which is nearly equal to elimination of alendronate in patients with normal renal function. In addition to our previous study showing safety of intravenous alendronate on osteoporosis in hemodialysis patients, 4 the present study suggested that the elimination by hemodialysis would decrease the risk of excessive accumulation in bone. Manuscript received January 2019; revised June 2019; accepted June 2019.…”

“…Six outpatients who had been undergoing maintenance hemodialysis therapy three times a week (3.5–4 h/session) over 3 months at our hospital were recruited. The inclusion criteria were: outpatients receiving hemodialysis in a stable condition; age > 20 years; on maintenance hemodialysis for more than 3 months; and diagnosed with osteoporosis, using the Japanese Society for Bone and Mineral Research criteria, and already treated with intravenous alendronate prior to the study. Exclusion criteria were: severe liver disease; severe heart disease; active infections; and bad oral condition.…”

“…The inclusion criteria were: outpatients receiving hemodialysis in a stable condition; age > 20 years; on maintenance hemodialysis for more than 3 months; and diagnosed with osteoporosis, using the Japanese Society for Bone and Mineral Research criteria, and already treated with intravenous alendronate prior to the study. Exclusion criteria were: severe liver disease; severe heart disease; active infections; and bad oral condition. All subjects used the same dialyzer (APS‐15SA® (polysulfone membrane); Asahi‐kasei, Tokyo, Japan), and the blood flow rate (Qb) and dialysate flow rate (Qd) were fixed at 200 mL/min and 500 mL/min, respectively.…”

“…If the elimination of alendronate by hemodialysis is low, the accumulated alendronate in bone after injection in HD patients would be greater than that in patients with normal renal functions. Although our previous study showed that administration of intravenous alendronate appeared to be safe on the basis of safety analysis during 1‐year follow‐up, the pharmacokinetics of intravenous alendronate in patients on hemodialysis was not clear.…”

“…As regarding renal failure patients, there is much less information about the use of alendronate. However, our recent study, showing improved lumber spine bone mineral density (LSBMD) and suppression of serum bone turnover markers (BTM) with clinically safe, indicated that intravenous alendronate might be a useful option for osteoporosis treatment in hemodialysis patients . It has also been reported that oral alendronate therapy significantly decreased serum osteocalcin levels at 1 month compared to placebo in 31 hemodialysis patients …”