Alonzo E, Bellorin-Font E, Machado C, Carlini R, Paz-Martinez
V, Weisinger JR
A controlled, long-term study on the effect of alendronate in
idiopathic hypercalcuria
Am Soc Nephrol
J Am Soc Nephrol (abstract)
(Sep) 7:2697 1996
The etiology of idiopathic hypercalciuria with stone formation
remains difficult to elucidate. Hypercalciuria which persists after
low calcium diet even in many patients classified as having
"absorptive" hypercalciuria, is taken as clear evidence that bone
makes an important contribution to the urinary calcium excretion.
Further, the frequent finding of diminished low bone density in stone
formers is consistent with this idea, and has important therapeutic
implications. A thorough review is provided by Dr. Weisinger's recent
Nephrology Forum in KI 49:1507 (96). His group has also been among
several to investigate the important potential role of interleukin 1,
produced by circulating monocytes, and capable of stimulating bone
resorption. Other cytokines, like IL-6 and tumor necrosis factor may
also be important.
In this study, alendronate, an anti-resorptive aminobisphosphonate,
was used for one year at a dose of 10mg/day in 18 idiopathic
hypercalciuric patients, and 8 normocalciuric stone formers. Urine
calcium excretion decreased significantly after one month; at one year
UCa had decreased from 277 to 195 mg/g creatinine. Urinary
hydroxyproline decreased, while there was no effect on serum calcium,
GFR or UNa. Lumbar spine bone mineral density increased at one year
from 1.162 to 1.197 g/cm2. IL-1-alpha mRNA transcription by
unstimulated blood monocytes decreased significantly as well. There
was also reduction in monocyte production of IL-1. Normocalciuric
subjects showed no changes in UCa or bone density.
Comment: This is very important work. The pathophysiologic
significance is that a reduction in urinary calcium was accompanied by
an increase in bone mineral, providing further suggestive evidence
that bone contributes to hypercalciuria. This remains to be proved
however; the effects of alendronate have not been completely
elucidated. Also very interesting is the previously demonstrated
effect of alendronate on monocyte cytokine production.
This leaves unresolved the question of the initiating event in
idiopathic hypercalciuria. What are the relative contributions of
local cytokine production in bone, and circulating cytokine release?
The latter may correlate with hypercalciuria and inversely with bone
density, but most cytokines are thought to have paracrine or autocrine
function. Half-lives in the circulation are too brief to be
meaningful. The effect of alendronate, also, could be on bone
resorption directly (via osteoclasts), or inhibition of cytokines
locally or at a distance. The therapeutic implication is of course the
potential for bisphosphonates to be used in the management of stone
disease. The dose used here is a relatively low one, and has been well
tolerated in the treatment of osteoporosis.
(David S. Goldfarb, M.D., NYU School of Medicine)
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Am Soc Nephrol
Nephrolithiasis :
Renal Stones: Treatment