Endocrine Abstracts

Aims: We have previously shown that orchidectomy (ORX) in adult mice induces hypercalciuria and upregulation of renal Ca²⁺ and PO₄³⁻ transporters, but also bone loss already after 2 weeks. Pretreatment with risedronate inhibited bone resorption and hypercalciuria but confirmed the upregulation of renal Ca²⁺ and PO₄³⁻ transporters, suggesting bone-independent renal effects of androgens. We hypothesize that androgens regulate renal Ca²⁺ and PO₄³⁻ homeostasis, independent of the dietary Ca²⁺ content as well.

Methods: We performed ORX on 18-week-old male mice (vs SHAM) and pretreated all animals with risedronate. Mice were fed either a normal Ca²⁺ diet (NCD, 1%) or a low Ca²⁺ diet (LCD, 0.02%), while PO₄³⁻ was unchanged (0.6%). At 1 and 2 weeks post-ORX, 24 hr urine (metabolic cages) and serum was collected. After sacrifice (2 w post-ORX), kidneys were taken for qPCR of Ca²⁺ and PO₄³⁻ transporters, trabecular bone was analyzed by microCT (L5 vertebra), and femoral bone was analyzed for Ca²⁺ content by ashing.

Results: Serum Ca²⁺ and PO₄³⁻, and urinary Ca²⁺ excretion were similar under both diets, but PO₄³⁻ excretion was significantly increased in both the SHAM and ORX groups (239 and 268%, P< 0.0001) under LCD diet. Under LCD, increased serum levels of 1,25-dihydroxyvitamin D and PTH were observed. While risedronate efficiently blocked ORX-induced bone loss under the NCD, microCT analysis revealed that bone resorption was not fully blocked under the LCD, with a decrease in bone volume density of 14% compared to the NCD fed SHAM mice (P < 0.05). Also the femur Ca²⁺ content was significantly reduced in the LCD group (7.2 vs 8.8 mg in the NCD fed SHAM mice, P< 0.0001). Under the NCD, an increase of renal Ca²⁺ and PO₄³⁻ transporter expression after ORX was confirmed. In the LCD group a small but significant additional increase of renal Ca²⁺ transporter expression was observed, with a 1.7-fold increase for TRPV5, a 2.1-fold increase for CaBP9K and a 1.5-fold increase for PMCA (vs respectively a 1.6-, 1.5- and 1.3-fold increase for the NCD). Expression of PO₄³⁻ transporters (NaPi-2c, PiT1, PiT2) was similar in both diet groups.

Conclusions: Low dietary Ca²⁺ results in secondary hyperparathyroidism with LCD-induced bone loss despite treatment with bisphosphonates, and an additional increase in renal Ca²⁺ transporters. These findings underline the importance of adequate dietary Ca²⁺ intake along with anti-resorptive drugs in circumstances of bone loss post-androgen deprivation.