Idiopathic hypercalciuria: Can we prevent stones and protect bones?

WHAT IS THE MECHANISM OF IDIOPATHIC HYPERCALCIURIA?

The pathophysiology of idiopathic hypercalciuria has been difficult to establish.

Increased sensitivity to vitamin D? In the hyperabsorbing population, activated vitamin D levels are often robust, but a few studies of rats with hyperabsorbing, hyperexcreting physiology have shown normal calcitriol levels, suggesting an increased sensitivity to the actions of 1,25-dihydroxyvitamin D.¹⁶

Another study found that hypercalciuric stone-forming rats have more 1,25-dihydroxyvitamin D receptors than do controls.¹⁷

These changes have not been demonstrated in patients with idiopathic hypercalciuria.

High sodium intake has been proposed as the cause of idiopathic hypercalciuria. High sodium intake leads to increased urinary sodium excretion, and the increased tubular sodium load can decrease tubular calcium reabsorption, possibly favoring a reduction in bone mineral density over time.^18–20

In healthy people, urine calcium excretion increases by about 0.6 mmol/day (20–40 mg/day) for each 100-mmol (2,300 mg) increment in daily sodium ingestion.^21,22 But high sodium intake is seldom the principal cause of idiopathic hypercalciuria.

High protein intake, often observed in patients with nephrolithiasis, increases dietary acid load, stimulating release of calcium from bone and inhibiting renal reabsorption of calcium.^23,24 Increasing dietary protein from 0.5 to 2.0 mg/kg/day can double the urinary calcium output.²⁵

In mice, induction of metabolic acidosis, thought to mimic a high-protein diet, inhibits osteoblastic alkaline phosphatase activity while stimulating prostaglandin E2 production.²⁶ This in turn increases osteoblastic expression of receptor activator for nuclear factor kappa b (RANK) ligand, thereby potentially contributing to osteoclastogenesis and osteoclast activity.²⁶

Decreasing dietary protein decreases the recurrence of nephrolithiasis in established stone-formers.²⁷ Still, urine calcium levels are higher in those with idiopathic hypercalciuria than in normal controls at comparable levels of acid excretion, so while protein ingestion could potentially exacerbate the hypercalciuria, it is unlikely to be the sole cause.

Renal calcium leak? The frequent finding of low to low-normal PTH levels in patients with idiopathic hypercalciuria contradicts the potential etiologic mechanism of renal calcium “leak.” In idiopathic hypercalciuria, the PTH response to an oral calcium load is abnormal. If given an oral calcium load, the PTH level should decline if this were due to renal leak, but in the setting of idiopathic hypercalciuria, no clinically meaningful change in PTH occurs. This lack of response of PTH to oral calcium load has been seen in both rat and human studies. Patients also excrete normal to high amounts of urine calcium after prolonged fasting or a low-calcium diet. Low-calcium diets do not induce hyperparathyroidism in these patients, and so the source of the elevated calcium in the urine must be primarily from bone. Increased levels of 1,25-dihydroxyvitamin D in patients with idiopathic hypercalciuria have been noted.^28,29

Whether the cytokine milieu also contributes to the calcitriol levels is unclear, but the high or high-normal plasma level of 1,25-dihydroxyvitamin D may be the reason that the PTH is unperturbed.

IMPACT ON BONE HEALTH

Nephrolithiasis is strongly linked to fracture risk.

The bone mineral density of trabecular bone is more affected by calcium excretion than that of cortical bone.^18,20,30 However, lumbar spine bone mineral density has not been consistently found to be lower in patients with hyperabsorptive hypercalciuria. Rather, bone mineral density is correlated inversely with urine calcium excretion in men and women who form stones, but not in patients without nephrolithiasis.

In children

In children, idiopathic hypercalciuria is well known to be linked to osteopenia. This is an important group to study, as adult idiopathic hypercalciuria often begins in childhood. However, the trajectory of bone loss vs gain in children is fraught with variables such as growth, puberty, and body mass index, making this a difficult group from which to extrapolate conclusions to adults.

In men

There is more information on the relationship between hypercalciuria and osteoporosis in men than in women.

In 1998, Melton et al³¹ published the findings of a 25-year population-based cohort study of 624 patients, 442 (71%) of whom were men, referred for new-onset urolithiasis. The incidence of vertebral fracture was 4 times higher in this group than in patients without stone disease, but there was no difference in the rate of hip, forearm, or nonvertebral fractures. This is consistent with earlier data that report a loss of predominantly cancellous bone associated with urolithiasis.

National Health and Nutrition Examination Survey III data in 2001 focused on a potential relationship between kidney stones and bone mineral density or prevalent spine or wrist fracture.³² More than 14,000 people had hip bone mineral density measurements, of whom 793 (477 men, 316 women) had kidney stones. Men with previous nephrolithiasis had lower femoral neck bone mineral density than those without. Men with kidney stones were also more likely to report prevalent wrist and spine fractures. In women, no difference was noted between those with or without stone disease with respect to femoral neck bone mineral density or fracture incidence.

Cauley et al³³ also evaluated a relationship between kidney stones and bone mineral density in the Osteoporotic Fractures in Men (MrOS) study. Of approximately 6,000 men, 13.2% reported a history of kidney stones. These men had lower spine and total hip bone mineral density than controls who had not had kidney stones, and the difference persisted after adjusting for age, race, weight, and other variables. However, further data from this cohort revealed that so few men with osteoporosis had hypercalciuria that its routine measurement was not recommended.³⁴