Veverimer to decrease net acid excretion and bone resorption in adults with osteopenia: a dose-finding randomized controlled trial - PROJECT SUMMARY Starting in mid-life, bone resorption rises and exceeds bone formation – a process that leads to progressive loss of bone mass, destruction of bone architecture, and ultimately an increased risk of fracture later in life. Acid- producing diets, such as the modern Western diet, have been implicated as contributors to increased bone resorption in mid-life and older adults. Younger adults are able to excrete the acid produced from the diet in their urine but in mid-life and thereafter, the kidney loses the capacity to quantitatively excrete the daily acid load due to age-related declines in both glomerular filtration rate and the tubular capacity to excrete acid. Through the release of bone alkali as an acid buffer, bone helps preserve systemic neutrality, but at the expense of greater bone resorption, bone loss, and an increased fracture risk. Adults with osteopenia who consume acid-producing diets are at particularly high risk of progressing to osteoporosis. Evidence from our group and others indicates that neutralizing excess acid with alkali therapy, such as potassium or sodium bicarbonate, reverses these adverse bone effects. However, alkali treatment poses several challenges: it requires frequent and inconvenient dosing schedules, gastrointestinal discomfort, and a substantial load of sodium or potassium which can aggravate hypertension or risk hyperkalemia. Veverimer, a non-absorbable polymer that binds hydrochloric acid in the intestine and excretes it in stool, offers a novel alternative to reversing the adverse effect of excess dietary acid on bone. To date, veverimer in doses up to 9 g/d has mainly been tested in adults with advanced chronic kidney disease and with metabolic acidosis. In those trials, veverimer corrected metabolic acidosis by 4 weeks of treatment but bone outcomes have never been assessed. Veverimer was well tolerated without altering potassium or sodium metabolism. We propose a Phase 1 randomized controlled trial in adults 50 years and older with osteopenia who consume acid-producing diets (based on a 24-hr urinary net acid excretion [NAE] level of ≥15 mmol/d). Lower doses of veverimer were selected as our osteopenic adults will have minimal impairments in kidney function. Participants will be randomized to treatment for 12 weeks with placebo or veverimer in a dose of 3 g/d or 6 g/d to meet the following aims: Aim 1: Identify the extent to which each dose of veverimer (vs. placebo) reduces 24-hr urinary NAE. Aim 2: Describe the safety of veverimer as indicated by changes in serum HCO3-. Aim 3: Assess the variability in change in bone resorption (serum C-telopeptide level). Aim 4: Assess the variability in change in bone formation (serum procollagen type I N-terminal propeptide ) in response to the different doses of veverimer. This information is needed to estimate the sample size of a future trial. Identifying the dose of veverimer that safely lowers NAE to the optimal level is an essential first step in the process of assessing whether veverimer is a promising approach to reducing bone loss attributable to acid-producing diets. This Phase 1 dose-finding study will provide the information needed to design a clinical trial to determine the effect of veverimer on bone resorption, bone mass, and ultimately fracture risk in adults at risk for osteoporosis.
