Evaluation of 41calcium as a new approach to assess changes in bone metabolism: effect of a bisphosphonate intervention in postmenopausal women with low bone mass.
A new technique was evaluated to identify changes in bone metabolism directly at high sensitivity through isotopic labeling of bone Ca. Six women with low BMD were labeled with 41Ca up to 700 days and treated for 6 mo with risedronate. Effect of treatment on bone could be identified using 41Ca after 4-8 wk in each individual.


BACKGROUND
Isotopic labeling of bone using 41Ca, a long-living radiotracer, has been proposed as an alternative approach for measuring changes in bone metabolism to overcome current limitations of available techniques. After isotopic labeling of bone, changes in urinary 41Ca excretion reflect changes in bone Ca balance. The aim of this study was to validate this new technique against established measures. Changes in bone Ca balance were induced by giving a bisphosphonate.


METHODS
Six postmenopausal women with diagnosed osteopenia/osteoporosis received a single oral dose of 100 nCi 41Ca for skeleton labeling. Urinary 41Ca/40Ca isotope ratios were monitored by accelerator mass spectrometry up to 700 days after the labeling process. Subjects received 35 mg risedronate per week for 6 mo. Effect of treatment was monitored using the 41Ca signal in urine and parallel measurements of BMD by DXA and biochemical markers of bone metabolism in urine and blood.


RESULTS
Positive response to treatment was confirmed by BMD measurements, which increased for spine by +3.0% (p = 0.01) but not for hip. Bone formation markers decreased by -36% for bone alkaline phosphatase (BALP; p = 0.002) and -59% for procollagen type I propeptides (PINP; p = 0.001). Urinary deoxypyridinoline (DPD) and pyridinoline (PYD) were reduced by -21% (p = 0.019) and -23% (p = 0.009), respectively, whereas serum and urinary carboxy-terminal teleopeptides (CTXs) were reduced by -60% (p = 0.001) and -57.0% (p = 0.001), respectively. Changes in urinary 41Ca excretion paralleled findings for conventional techniques. The urinary 41Ca/40Ca isotope ratio was shifted by -47 +/- 10% by the intervention. Population pharmacokinetic analysis (NONMEM) of the 41Ca data using a linear three-compartment model showed that bisphosphonate treatment reduced Ca transfer rates between the slowly exchanging compartment (bone) and the intermediate fast exchanging compartment by 56% (95% CI: 45-58%).


CONCLUSIONS
Isotopic labeling of bone using 41Ca can facilitate human trials in bone research by shortening of intervention periods, lowering subject numbers, and having easier conduct of cross-over studies compared with conventional techniques.
Denk
Eberhard
E
Human Nutrition Laboratory, Institute of Food Science and Nutrition, ETH-Zurich, Zurich, Switzerland.
Hillegonds
Darren
D
Hurrell
Richard F
RF
Vogel
John
J
Fattinger
Karin
K
Häuselmann
Hans J
HJ
Kraenzlin
Marius
M
Walczyk
Thomas
T
D000368:Aged; D015415:Biomarkers; D015519:Bone Density / Q000187:drug effects*; D001851:Bone Diseases, Metabolic / Q000188:drug therapy; D002132:Calcium Radioisotopes / Q000652:urine; D004164:Diphosphonates / Q000494:pharmacology* / Q000627:therapeutic use; D012968:Etidronic Acid / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use; D005260:Female; D006801:Humans; D007700:Kinetics; D015663:Osteoporosis, Postmenopausal / Q000188:drug therapy; D017698:Postmenopause / Q000378:metabolism* / Q000652:urine*; D000068296:Risedronic Acid; D012680:Sensitivity and Specificity
D015415:Biomarkers; D002132:Calcium Radioisotopes; D004164:Diphosphonates; D000068296:Risedronic Acid; D012968:Etidronic Acid