Genetics of hypercalciuria-related osteoporosis

Summary
Osteoporosis and genetics of chronic high urinary calcium excretion. Searching for a genetic cause of chronic high urinary calcium excretion leading to recurrent renal stone formation and osteoporosis.

Background
Osteoporosis is a debilitating disease leading to increased risk of fracture and subsequent complications, including chronic pain and increased morbidity. Environmental and genetic factors are relevant for this complex disease. Chronic high urinary calcium excretion, called hypercalciuria, is found in up to 38% of osteoporosis patients. It is associated with renal stone (kidney stone) formation and has a strong genetic background. In addition, more than 50% of patients with recurrent renal calcium stones exhibit hypercalciuria and reduced bone mass. Hypercalciuria can be caused by a variety of mechanisms; the most common types of linically significant hypercalciuria are:

• absorptive hypercalciuria, resulting from hyper-absorption of calcium in the small intestine
• resorptive hypercalciuria, resulting from bone resorption and
• renal leak, due to kidney defects and causing excessive calcium excretion.

We hypothesize that a substantial number of patients with recurrent calcium enal stones have a genetic defect accounting for a renal leak of calcium, hich causes chronic negative bone balance and osteoporosis.

Aim
The goal of the study is to identify new genetic determinants that are relevant in musculo-skeletal health. We will recruit hypercalciuric osteoporotic renal stone formers in Switzerland to participate in outpatient fasting and calcium-loading testing in order to differentiate the type of hypercalciuria in these patients. For the genetic analyses, identically characterised hypercalciuria patients in Dallas, Texas, USA, will supplement the Swiss group of patients.

Significance
Defining the molecular mechanisms of hypercalciuria and the genetic defects that cause negative calcium balance and osteoporosis will provide an evidence base for the design of behavioural and pharmacological strategies to prevent osteoporosis and renal stones. Hypercalciuric patients with known reduced bone mass and patients with untreated hypercalciuria should have periodic bone density measurements. For calcium renal stone formers at risk for osteoporosis, tailored preventive measures to reduce the risk of a bone mass decrease may ultimately be derived from the present investigation.

Investigators
Dr. Olivier Bonny and Dr. Ute Eisenberger

Sponsor
Swiss National Foundation, NRP 53 (Musculoskeletal Health - Chronic Pain), Project no. 104538