Novel homozygous inactivating mutation of the calcium-sensing receptor gene (CASR) in neonatal severe hyperparathyroidism-lack of effect of cinacalcet.

BACKGROUND: NSHPT is a life-threatening disorder caused by homozygous inactivating calcium-sensing receptor (CASR) mutations. In some cases, the CaSR allosteric activator, cinacalcet, may reduce serum PTH and calcium levels, but surgery is the treatment of choice. OBJECTIVE: To describe a case of NSHPT unresponsive to cinacalcet. PATIENT AND RESULTS: A 23-day-old girl was admitted with hypercalcemia, hypotonia, bell-shaped chest and respiratory distress. The parents were first-degree cousins once removed. Serum Ca was 4.75 mmol/l (N: 2.10-2.62), P: 0.83 mmol/l (1.55-2.64), PTH: 1096 pg/ml (9-52) and urinary Ca/Cr ratio: 0.5mg/mg. First, calcitonin was given (10 IU/kg × 4/day), and then 2 days later, pamidronate (0.5mg/kg) for 2 days. Doses of cinacalcet were given daily from day 28 of life starting at 30 mg/m2 and increasing to 90 mg/m2 on day 43. On day 33, 6 days after pamidronate, serum Ca levels had fallen to 2.5 mmol/l but, thereafter, rose to 5 mmol/l despite the cinacalcet. Total parathyroidectomy was performed at day 45. Hungry bone disease after surgery required daily Ca replacement and calcitriol for 18 days. At 3 months, the girl was mildly hypercalcemic, with no supplementation, and at 6 months, she developed hypocalcemia and has since been maintained on Ca and calcitriol. By CASR mutation analysis, the infant was homozygous and both parents heterozygous for a deletion-frameshift mutation. CONCLUSION: The predicted nonfunctional CaSR is consistent with lack of response to cinacalcet, but total parathyroidectomy was successful. An empiric trial of the drug and/or prompt mutation testing should help minimize the period of unnecessary pharmacotherapy.

Common genetic variants of the vitamin D binding protein (DBP) predict differences in response of serum 25-hydroxyvitamin D [25(OH)D] to vitamin D supplementation.

BACKGROUND: To determine the effect of vitamin D binding protein (DBP) genotypes on 25-hydroxyvitamin D [25(OH)D] changes with vitamin D supplements, we studied 98 adults receiving 600 or 4000 IU/d vitamin D(3) for one year. METHODS: The DBP functional variant, T436K, was genotyped by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). RESULTS: Mean 25(OH)D increases were 97% for TT (n=48), 151% for TK (n=31) and 307% (n=6) for KK genotypes (p=.004). CONCLUSIONS: As with baseline 25(OH)D, T436K genotype predicts 25(OH)D changes after long-term vitamin D supplementation.

Phase II trial evaluating the palliative benefit of second-line zoledronic acid in breast cancer patients with either a skeletal-related event or progressive bone metastases despite first-line bisphosphonate therapy.

PURPOSE: This study evaluated whether additional palliative benefits could be derived from the second-line use of the more potent bisphosphonate zoledronic acid in metastatic breast cancer patients with either progressive bone metastases or skeletal-related events (SRE), despite first-line therapy with either pamidronate or clodronate. PATIENTS AND METHODS: This prospective study evaluated the impact of second-line zoledronic acid on pain, quality of life, and markers of bone turnover (for example, urinary N-telopeptide [NTX]). Patients received monthly zoledronic acid (4 mg) for 3 months. Study evaluations were made weekly during the first month and again at week 8. No changes in chemotherapy or endocrine therapy were allowed in the month before or after commencing study treatment. RESULTS: Thirty-one women completed this study. By week 8, patients had experienced significant improvements in pain control (P < .001). There was a downward trend in urinary NTX levels over the same time period (P = .008). Overall, there was a trend towards a positive correlation between improvement in pain control and reduction in week one urinary NTX relative to baseline (Spearman's rho r = 0.27; P = .15). CONCLUSION: This is the first study to demonstrate that patients with either progressive bone metastases or SREs while on clodronate or pamidronate can have relevant palliative benefits with a switch to the more potent bisphosphonate zoledronic acid. This is reflected by significant improvements in pain control and bone turnover markers. If confirmed in randomized trials, these findings have major implications to the use of bisphosphonates in both the metastatic and adjuvant settings.