ORIGINAL ARTICLE Skeletal consequences of familial hypocalciuric hypercalcaemia vs. primary hyperparathyroidism Signe Engkjær Christensen*, Peter H. Nissen†, Peter Vestergaard*, Lene Heickendorff†, Lars Rejnmark*, Kim Brixen‡ and Leif Mosekilde* *Department of Endocrinology and Metabolism C, †Department of Clinical Biochemistry, Aarhus University Hospital, Aarhus and ‡Department of Endocrinology, Odense University Hospital, Odense, Denmark Summary Objectives Bone metabolism is only superficially described in familiar hypocalciuric hypercalcaemia (FHH). We describe and compare biochemical and osteodensitometric variables in FHH and primary hyperparathyroidism (PHPT) and assess whether they can improve the diagnostic discrimination between the groups. Design Cross-sectional. Patients Sixty-six FHH patients with known calcium-sensing receptor (CASR) gene mutations and 147 PHPT patients. Measurements We determined calcium, creatinine, phosphate, magnesium, parathyroid hormone (PTH), 25OHD, 1,25(OH) 2 D and alkaline phosphatase (AP) in plasma, NTx/creatinine ratio in urine and calculated the calcium/creatinine clearance ratio (CCCR). We performed dual energy X-ray absorptiometry at the lumbar spine, hip, forearm and whole body. Results When compared with normal controls, the FHH patients had increased levels of PTH and AP with normal U-NTx and regio- nal Z-scores. Increased phenotypic expression of CASR mutations in terms of hypercalcaemia was associated with higher lumbar spine bone mineral density, but not with bone markers. FHH were younger and leaner than the PHPT patients. They had comparable plasma Ca 2+ and 25OHD, but lower levels of PTH, 1,25(OH) 2 D, AP and U-NTx. They had higher Z-scores in the hip and in the forearm. We achieved the best discrimination between groups by multiplying CCCR with AP, 1,25(OH) 2 D and PTH, but the dif- ference between the area under the curves by receiver operating characteristic analysis remained insignificant. Conclusion Familiar hypocalciuric hypercalcaemia is associated with increased PTH and AP compared to normal controls, but not with bone loss irrespective of the severity of the CASR mutations. A multiplicative model including CCCR, AP, 1,25(OH) 2 D and PTH insignificantly improved the power of the CCCR to differentiate between FHH and PHPT. However, we still recommend CASR gene analysis in patients with a CCCR <0Æ020. (Received 4 July 2008; returned for revision 12 August 2008; finally revised 31 December 2008; accepted 6 January 2009) Introduction Familial hypocalciuric hypercalcaemia (FHH, OMIM#145980) is an autosomal dominant condition caused by heterozygous in- activating mutations in the gene encoding the calcium-sensing receptor (CASR). 1,2 At least 64 inactivating mutations have pre- viously been described in the CASR gene. 3 In the present popu- lation of FHH patients, we have recently described 22 inactivating mutations, of which 19 are novel. 4 Patients with FHH and PHPT are characterized by elevated plasma calcium, normal or elevated plasma parathyroid hormone (PTH), and typically normal renal function. In PHPT, bone min- eral density (BMD, g/cm 2 ) is usually reduced in the hip and the forearm. The spine, which is rich in trabecular bone, is less affected. 5–7 Bone markers are typically increased 5,8,9 as a result of enhanced bone turnover leading to an expanded remodelling space and younger and less mineralised bone structural units. 9 PHPT also carries an increased risk of fractures 9,10 because of structural changes in trabecular bone and reduced cortical thickness. 7–9,11 In addition, low plasma levels of 25-hydroxy-vitamin D (25OHD) may contribute to low BMD and increased fracture risk. 5,12 Unlike PHPT, bone metabolism has not previously been investigated in detail in FHH patients, but existing results point towards normal bone mass. 13–15 We hypothesized that the increase in circulating PTH observed in some of the FHH patients could increase plasma 1,25(OH) 2 D and bone markers and decrease BMD to the same extent as in PHPT. The primary aim of the present study was to compare bio- chemical and osteodensitometric characteristics in FHH with normal reference levels. Secondly, we compared 1,25(OH) 2 D, bone turnover markers and BMD measurements between FHH and PHPT patients. Thirdly, we aimed at appraising whether the inclu- sion of other biochemical variables could improve the diagnostic Correspondence: Signe Engkjær Christensen, Department of Endocrinology and Metabolism C, Aarhus University Hospital, Aarhus Sygehus, Tage-Hansens Gade 2, DK 8000 A ˚ rhus C, Denmark. Tel.: +45 4037 0321; Fax: +45 8949 7659; E-mail: doktor_signe@hotmail.com Clinical Endocrinology (2009) 71, 798–807 doi: 10.1111/j.1365-2265.2009.03557.x 798 Ó 2009 Blackwell Publishing Ltd