Preclinical studies in osteoblast-specific conditional knockout mice demonstrated critical roles of CASRs in bone growth, mineralization, and osteoblast differentiation suggesting a role for CASRs in bone formation. To test whether CASR and PTHR activation might produce greater anabolism, we treated adult male mice with daily injections of PTH (1-34) + calcimimetic NPS R-568 for 28 days. Mice treated with PTH (1-34) and calcimimetic had greater responses in bone volume/tissue volume (BV/TV) at the distal femur and at L5 and greater increases in cortical thickness (Ct.Th) at the tibio-fibular junction by microCT vs PTH (1-34) alone.

To test the hypothesis that concomitant activation of PTHRs and CASRs could produce greater effects on bone mass, we randomized 40 men with low bone mineral density (BMD) to either teriparatide (20 mcg/day) + cinacalcet (30 mg/day) (Combination) or teriparatide + placebo (Monotherapy) for 48 weeks. BMD was assessed by DXA at baseline (BL) vs 48 weeks and bone turnover by changes in the serum C-telopeptide (CTX) and N-terminal pro-peptide of type 1 collagen (P1NP) at BL vs timepoints over 48 weeks. Endpoints were differences in lumbar spine (LS) BMD (at 48 weeks) (primary) and differences in femoral neck (FN) BMD (at 48 weeks) and change in P1NP (at 12 weeks) (both secondary) – compared to BL. LS, FN, and total hip (TH) BMD rose by +6.1%, +2.4%, and +1.5%, respectively (Combination), while changes in LS, FN, and TH BMD were +5.8%, -0.5% and +0.4%, respectively, (Monotherapy). Only TH BMD changes were significantly greater with Combination treatment (p=0.047). CTX was significantly higher with Combination vs Monotherapy over 48 weeks (p< 0.03). Treatments were overall well-tolerated; 39/40 participants completed endpoint assessments. Greater TH BMD increases suggest that concomitant activation of PTHRs and CASRs counteracted usually negligible effects of teriparatide alone on cortical-rich bone like the TH.