Skeletal consequences of familial hypocalciuric hypercalcaemia vs. primary hyperparathyroidism

Clin Endocrinol (Oxf). 2009 Dec;71(6):798-807. doi: 10.1111/j.1365-2265.2009.03557.x. Epub 2009 Feb 25.


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 regional 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 difference 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 <0.020.

MeSH terms

  • Alkaline Phosphatase / blood
  • Calcium / blood
  • Creatinine / blood
  • Cross-Sectional Studies
  • Humans
  • Hypercalcemia / blood
  • Hypercalcemia / congenital
  • Hypercalcemia / genetics
  • Hypercalcemia / physiopathology
  • Hyperparathyroidism, Primary / blood*
  • Hyperparathyroidism, Primary / genetics*
  • Hyperparathyroidism, Primary / physiopathology
  • Magnesium / blood
  • Mutation
  • Parathyroid Hormone / blood
  • Phosphates / blood
  • Receptors, Calcium-Sensing / genetics
  • Vitamin D / blood


  • Parathyroid Hormone
  • Phosphates
  • Receptors, Calcium-Sensing
  • Vitamin D
  • Creatinine
  • Alkaline Phosphatase
  • Magnesium
  • Calcium

Supplementary concepts

  • Hypocalciuric hypercalcemia, familial, type 1