Elevations in Cortical Porosity Occur Prior to Significant Rise in Serum Parathyroid Hormone in Young Female Mice with Adenine-Induced CKD

Abstract

Chronic kidney disease (CKD) leads to significant bone loss primarily through the development of cortical porosity. In both patients and animal models of CKD, sustained elevations in serum parathyroid hormone (PTH) is associated with cortical porosity. In this study we aimed to track the progression of cortical porosity and increased PTH utilizing the adenine-induced CKD model. Young female mice (8 weeks) were given 0.2% adenine to induce CKD. Tissues were collected from groups of adenine and age-matched control mice after 2, 6, and 10 weeks. Serum blood urea nitrogen was elevated at all time points in adenine mice, but serum PTH was only statistically elevated at the 10-week time point. Cortical porosity was 7-fold higher in 6-week adenine mice compared to age-matched controls and 14-fold higher in 10-week adenine mice vs. controls. Additionally, osteocyte receptor activator of nuclear factor κB ligand (RANKL) was elevated in adenine-fed mice, while annexin V, an early marker of cellular apoptosis, was mildly decreased in osteocytes in adenine-fed mice. Based on these results, we hypothesize high serum PTH signals to osteocytes prolonging their lifespan resulting in sustained RANKL which drives osteoclastic bone resorption in the cortex. In conclusion, our data show time-dependent elevations in serum PTH and cortical porosity in adenine-induced CKD mice and demonstrate changes in osteocyte RANKL and apoptosis which may contribute to the development of cortical pores.

The Effect of Single Versus Group μCT on the Detection of Trabecular and Cortical Disease Phenotypes in Mouse Bones

“…The adenine diet consisted of 0.2% adenine added to a diet of purified casein‐based feed with adjusted calcium and phosphorus (0.9% phosphorus, 0.6% calcium) as previously described. ( 9 ) A set of age‐matched controls ( n = 8) were fed the casein‐based control diet with an altered calcium:phosphorus ratio for the entire 11‐week period. At study end point, all mice were anesthetized via vaporized inhaled isoflurane and euthanized via exsanguination.…”

“…Adenine-induced CKD mice (n=8) were placed on an adenine diet from 16 weeks of age to 22 weeks, and then returned to the control diet with a maintained calcium and phosphorus ratio for another five weeks for a total of 11 weeks since diet initiation. The adenine diet consisted of 0.2% adenine added to a diet of purified casein-based feed with adjusted calcium and phosphorus (0.9% phosphorus, 0.6% calcium) as previously described (9) . A set of age-matched controls (n=8) were fed the caseinbased control diet with altered calcium/phosphorus ratio for the entire 11-week period.…”

“…This technology has been utilized to demonstrate differences in trabecular bone volume in models such as hindlimb-unloading (1,2) , spaceflight (3,4) , ovariectomy (5) , exercise and mechanical loading studies (6) , aging (7) , drug treatment (8) , as well as diseases such as chronic kidney disease (CKD) (9) and osteogenesis imperfecta (OI) (10) . Similarly, µCT has also been used to detect changes in cortical bone morphology including cortical area, cortical thickness, and cortical porosity (7,9,(11)(12)(13) . µCT scans are widely used to calculate bone and tissue mineral density (BMD and TMD) (14) , achieving greater precision and reproducibility than other common analytical tools, such as dual-energy x-ray absorptiometry (DEXA) (15) or peripheral quantitative computed tomography (p-QCT).…”

“…The determination of the microarchitecture of trabecular bone is a key use of μCT. This technology has been used to show the differences in trabecular bone volume in models such as hindlimb-unloading, (1,2) spaceflight, (3,4) ovariectomy, (5) exercise and mechanical-loading studies, (6) aging, (7) and drug treatment, (8) as well as diseases such as chronic kidney disease (CKD) (9) and osteogenesis imperfecta (OI). (10) Similarly, μCT has also been used to detect changes in cortical bone morphology including cortical area, cortical thickness, and cortical porosity.…”

The CKD-MBD Syndrome: Hysteresis in PTH Involvement and PTH Administration for Its Management

“…It has not, however, been shown to alter bone mechanical strength or increase the risk for hip fractures in clinical trials. (34) Interestingly, CKD can cause cortical porosity attributed to time-dependent elevations of PTH (35,36) In patients with early CKD secondary hyperparathyroidism, intermittent PTH administration could be advantageous, because it would change the constantly elevated serum PTH to a more pulsatile pattern. If the dose and frequency of the administered PTH in CKD-MBD cases is lower and with longer intervals compared to those for osteoporosis, then there is the possibility that it might cause less cortical porosity.…”