Procollagen C Proteinase case of NPHT treated with pamidronate, described by Waller et al,7 showed a similar fall in PTH but a rebound 2 months later. In this case, however, only 1 dose of pamidronate was given. Our patient stayed on bisphosphonates for.3 years, and we did not notice any secondary effects. In particular, growth improved, and long bone radiographs were normal apart from the bisphosphonate induced transverse sclerotic lines, but there were no changes suggestive of osteopetrosis. Because adverse effects from long term treatment with bisphosphonates are largely unknown, we decided to stop the bisphosphonates treatment and initiate cinacalcet therapy.11 The half life of bisphosphonates in the skeleton is long because it is incorporated in the bone and released during bone remodeling. It has been demonstrated that the effect of bisphosphonates on bone density can be sustained for 2662 months after discontinuation in children.12 In our case, cinacalcet was started shortly after bisphosphonates P-glycoprotein discontinuation, and the initial results observed on hypercalcemia may be, in part, due to the remaining effects of the bisphosphonates therapy.
Cinacalcet was started at 30mgper day and increased to 3.5mg/kg per day while DPP-4 monitoring the impact on PTH and calcium level becausenostandardtherapywasavailable for this condition. Under therapy with cinacalcet, we observed normalization of PTH and phosphate and near normalization of calcium, suggesting a positive effect of the calcimimetic on the mutant CaSR in the parathyroid gland. In the kidney, the activation of CaSR leads to an increase in calcium excretion directly through a diminished paracellular passive reabsorption in the thick ascending loop of Henle and indirectly through a diminution of PTH. In our patient, calciuria did not increase after the initiation of treatment and stayed low compared with the value of serum calcium. In the bone, CaSR is present in the osteoblasts and the growth plate. Both in vitro and in vivo data indicate a role of CaSR in osteoblast and osteoclast recruitment, differentiation, and survival. In mice experiments, tissue specific deletion of CaSR in osteoblasts resulted in profound bone defects, whereas Diosmetin CaSR deletion in chondrocytes resulted in delayed growth plate development.13,14 Calcimimetics exert an indirect effect on bone via modulation of PTH.
Direct effects of calcimimetic targeting bone CaSR is difficult to predict. In our patient, we did not observe any adverse effect on bone metabolism of the treatment. On the contrary, bone turnover markers stayed in the normal range for age and gender, and growth followed the same percentile. A bone age assessment, according to Greulich and Pyle, was performed both while receiving bisphosphonates and later cinacalcet. It showed a delay of 1 year between chronological age and bone age, which was not modified by the introduction of cinacalcet. On follow up, 6 years after the bisphosphonates were discontinued, calcium and PTH are stable under cinacalcet alone. When cinacalcet was introduced, the patient felt much better without any adverse secondary effect at 6 years follow up. In 2010, calcium increased to 2.8 mmol/L and PTH to 5.5 pmol/L, and we decided to increase the cinacalcet further to 90 mg each day with a good response.