Comprehensive Associations between Acidosis and the Skeleton in Patients with Kidney Disease

Abstract

Significance statement: Renal osteodystrophy (ROD) contributes substantially to morbidity in CKD, including increased fracture risk. Metabolic acidosis (MA) contributes to the development of ROD, but an up-to-date skeletal phenotype in CKD-associated acidosis has not been described. We comprehensively studied associations between acidosis and bone in patients with CKD using advanced methods to image the skeleton and analyze bone-tissue, along with biochemical testing. Cross-sectionally, acidosis was associated with higher markers of bone remodeling and female-specific impairments in cortical and trabecular bone quality. Prospectively, acidosis was associated with cortical expansion and trabecular microarchitectural deterioration. At the bone-tissue level, acidosis was associated with deficits in bone mineral content. Future work investigating acidosis correction on bone quality is warranted.

Background: Renal osteodystrophy is a state of impaired bone quality and strength. Metabolic acidosis (MA) is associated with alterations in bone quality including remodeling, microarchitecture, and mineralization. No studies in patients with CKD have provided a comprehensive multimodal skeletal phenotype of MA. We aim to describe the structure and makeup of bone in patients with MA in the setting of CKD using biochemistry, noninvasive imaging, and histomorphometry.

Methods: The retrospective cross-sectional analyses included 180 patients with CKD. MA was defined as bicarbonate ≤22 mEq/L. We evaluated circulating bone turnover markers and skeletal imaging with dual energy x-ray absorptiometry and high-resolution peripheral computed tomography. A subset of 54 participants had follow-up. We assessed associations between baseline and change in bicarbonate with change in bone outcomes. Histomorphometry, microCT, and quantitative backscatter electron microscopy assessed bone biopsy outcomes in 22 participants.

Results: The mean age was 68±10 years, 54% of participants were male, and 55% were White. At baseline, acidotic subjects had higher markers of bone turnover, lower areal bone mineral density at the radius by dual energy x-ray absorptiometry, and lower cortical and trabecular volumetric bone mineral density and impaired trabecular microarchitecture. Over time, acidosis was associated with opposing cortical and trabecular effects: cortical expansion but trabecular deterioration. Bone-tissue analyses showed reduced tissue mineral density with increased heterogeneity of calcium distribution in acidotic participants.

Conclusions: MA is associated with multiple impairments in bone quality. Future work should examine whether correction of acidosis improves bone quality and strength in patients with CKD.

Graphical abstract

Figure 1

Representative images from high-resolution peripheral computed tomography from a 71-year-old man with acidosis and with eGFR 26 ml/min and PTH 72 pg/ml (A) and an 86-year-old man without acidosis and with an eGFR 32 ml/min and PTH 92 pg/ml (B). PTH, parathyroid hormone.

Figure 2

Box plots showing BMDD measurements in trabecular (A–E) and cortical (F–J) bone for acidotic and nonacidotic participants including (A, F) CaMean which is the weighted mean Ca-concentration of the bone area; (B, G) CaPeak which is the histogram peak position (indicating the most frequently measured calcium concentration); (C, H) CaWidth which is the full width at half maximum of the distribution (describing the variation in mineralization density); (D, I) CaLow which is the percentage of low mineralized bone (i.e., bone areas having a calcium content of <5th percentile of our reference BMDD); and (E, J) CaHigh which is the percentage of highly mineralized bone areas (i.e., bone areas having a calcium content of >95th percentile of our reference BMDD). The center line represents the median, with the box outlining the interquartile range and whiskers showing minimum and maximum. The overlying gray boxes show the trabecular reference ranges for an adult population without CKD published previously. There are no reference data for cortical bone. BMDD, bone mineralization density distribution. * p < 0.05