How long do you wait before reassessing a 24 hour urine calcium level in patients with recurrent nephrolithiasis, hypercalciuria, and osteoporosis who are initiated on bisphosphonate therapy?

Thank you for your excellent question. This is a relatively common concern, and yet I am aware of very little hard data. Opinions will differ; here is mine:

In this scenario, it is my practice to have the patient visit with our Stone Clinic dietitian regarding dietary recommendations for calcium, sodium, oxalate and fluid consumption. I provide the patient with a return container for a 24-hour urine supersaturation and ask them to return it in 1-2 months, or when they feel their new diet is at a new steady state. One caveat is that general dietitians seem overwhelmed dealing with obesity, diabetes, hyperlipidemia and hypertension. Their expertise regarding dietary manipulation of mineral metabolism maybe limited; hence the specialized Stone Clinic dietitian, if you can find one.

The next reasonable question is how do I interpret the data? First, I would like to see the 24-hour urine calcium below the stone-forming threshold. This is a vague number because there are multiple factors in addition to hypercalciuria that determine urinary supersaturation. However, at Mayo Clinic, we would like to see 24-hour urine calcium below 200 mg. Note this is probably different than the "normal" value provided by your laboratory. That is because normal typically refers to the 95 percentile, but more than 5% of the population will make kidney stones in their lifetime. Hence the more restrictive definition.

As noted above, since there are multiple factors that determine urine supersaturation, I look even harder at the urine supersaturation with the idea of modifying all risk factors to get that number into the undersaturated zone.

Unfortunately, the reality is that neither urine calcium nor urinary supersaturation determination on a single specimen are predictive of the "bottom line": Is the patient's stone disease metabolically active? Note that metabolic activity refers to new stone formation and existing stone growth. The stone passage number or rate, almost always used as the main metric for most metabolic stone studies, may include stones that formed prior to the dietary /medication changes or stones that have stopped growing since the dietary changes, making the conclusion of those studies suspect. Instead, I "eyeball" noncontrast CT studies before and at least six months after dietary/medication changes to assess an increase in stone number or size. Quantitative CT scanning, usually measured in mm3 or Agatston units can also be used but, again, cannot account for interim stone passages.

The osteoporosis aspect in the Mayo system is managed by our endocrinology colleagues in metabolic bone clinic, and I hope to see some responses from their perspective.

Stephen B. Erickson, MD

I agree with Dr. @Dr. First Last; there is very little literature on this topic.

I think, to answer this question, we need to understand if bisphosphate therapy alters UrCa levels, and if so, when is their peak and steady-state effect given their long half-lives? Dr. Curhan's group did look at this retrospectively (retrospective observational study, and they do note several limitations) in the Nurse Health data (Prochaska et al., PMID 28576907) and there was no change in UrCa with bisphosphate therapy, but the risk of stones did decrease. It is not clear why.

However, anecdotally when my CKD 4/5 and even ESRD patients are given bisphosphonates or denosumab, I do see the iPTH levels change (indicating some change in bone mineral deposition and calcium metabolism) within 3-6 months and sometimes earlier, so I think it is reasonable to wait for at least 3-6 months to see if the bisphosphate will change the urine biochemical profile if it will change it at all. But I agree, more important than the urine studies is to see if the patient has a metabolically active disease (i.e., new stone formation or growth).

In patients with hypercalciuria and osteoporosis, along with bisphosphonates, I also include hydrochlorothiazide daily and encourage good fluid intake with a moderate sodium diet.

In 4 to 8 weeks, I recheck the 24-hour urine calcium and target a 24-hour urine calcium of less than 200 mg. I instruct the patient not to stop the HCTZ during the urine collection, as I have had other providers who may be taking care of the patient telling them to stop the HCTZ for the urine collection.