Tackling the Myths and Realities of Calcium Supplementation in CKD: An Expert Interview With Sophie A. Jamal, MD, PhD
Anne Le, PharmD, RPh
Medscape Nephrology. 2008; ©2008 Medscape
In patients with chronic kidney disease (CKD), disturbances of mineral metabolism are associated with significant morbidity and mortality. Unfortunately, recent evidence shows that treatment with calcium-based phosphate binders contributes to increasing coronary artery and aorta calcification compared with non-calcium-containing binders. It has also been shown that hyperphosphatemia and excess exogenous calcium administration can accelerate vascular calcification. Therefore, calcium-based phosphate binders should be avoided in many, if not most of CKD patients undergoing dialysis. Anne G. Le, PharmD, RPh, Editorial Director of Medscape Nephrology, spoke with Sophie A. Jamal, MD, PhD, Assistant Professor/Clinician Scientist at the University of Toronto and Clinical & Research Director of the Osteoporosis Program at Women's College Hospital in Toronto, about the use of calcium supplementation in CKD, the impact of high phosphorus levels, the prevalence of hypocalcemia, and the management of calcification.
Medscape: Can you tell us if there is any scientific evidence that shows that calcium has a direct impact on osteoporosis in the general population and in patients with chronic kidney disease [CKD]?
Sophie A. Jamal, MD, PhD: There are 2 parts to this question: the first concerns the relationship between calcium supplementation and osteoporosis in the general population. When we think about calcium supplementation and osteoporosis prevention in the general population, there are 2 groups to consider: young men and women acquiring peak bone mass, older men and postmenopausal women. Calcium plays an important role in enhancing the acquisition of peak bone mass. Most studies of calcium for osteoporosis prevention have included vitamin D supplementation and it is very difficult to tease out whether it is the calcium or vitamin D that influences fracture risk. There has been a meta-analysis that examined the effects of modest amounts of vitamin D 400 IU a day with calcium supplementation, and that data demonstrate that in women 45 years or older, calcium supplementation over about 2 years or so modestly prevents decreases in bone mineral density. That systematic review also demonstrated a trend for fewer spinal fractures among calcium-supplemented patients; however, that didn't reach statistical significance. Indeed, there are no data that definitively demonstrate that calcium alone reduces fracture incidence. Probably a reasonable approach in healthy postmenopausal women and men would be to ensure an adequate but not excessive calcium intake.
Regarding patients with chronic kidney disease and osteoporosis, there are no data that demonstrate that giving calcium in the form of either a calcium binder or a calcium supplement, either in dietary or dairy, reduces the risk of osteoporotic fracture.
Medscape: Is there any evidence that calcium has a direct impact on arterial calcification in the CKD population?
Dr. Jamal: Yes, there have been 2 observational studies in patients with stage 5 CKD that demonstrated a positive association between calcium supplementation, calcium phosphate cross-product, and arterial calcification measured with EBCT [electron beam computed tomography] or with ultrasound.[2,3] There has also been a randomized control trial that compared calcium-based binders vs non-calcium-based binders regarding a progression in vascular calcification. The trial demonstrated that patients who were randomized to the non-calcium binder, in this case, the sevelamer, did not have a progression of arterial calcification, compared to patients who were randomized to the calcium-based binder.
Medscape: For the majority of patients with CKD stages 3-4, could you tell us if there is a medical need to give calcium beyond what is found in the diet, and what about for patients with CKD stage 5?
Dr. Jamal: Generally speaking, regardless of whether you have kidney disease or not, most men and women are not particularly good at obtaining calcium from their diet. It has been estimated that we take in 1-2 dairy servings a day -- which is equivalent to about 300-600 mg of calcium, so there is likely a need to supplement with calcium. The real crux of the matter, both at stages 3-4, as well as at stage 5, is the dose of the supplement. In patients with stage 5 kidney disease, there may be a mild calcium deficit so it may be reasonable to supplement those patients with a little bit more calcium than in patients with stages 3 and 4 kidney disease. However, it should be stressed that there are no data that identify the optimum amount of calcium supplementation. I think that decisions concerning calcium supplementation need to be done on an individual basis.
Medscape: From a physiologic standpoint, what happens when patients with CKD are given calcium therapy and where does that excess calcium go?
Dr. Jamal: That is a good question but unfortunately, there is no clear answer. In otherwise healthy men and women, a large proportion of calcium is taken up by the bone during remodeling. The concern about giving calcium to patients with CKD is that the calcium therapy will not be taken up by the bone. In contrast, a large number of patients with CKD have unpaired bone remodeling (low turnover or adynamic bone) and as such calcium therapy will not be taken up by the bone and theoretically may deposit in other tissues -- such as the blood vessels or skin.
Medscape: Can you tell us if there is a role for calcium in the management of mineral and bone disorder associated with CKD?
Dr. Jamal: I think the role of calcium depends on the cause of the bone mineral disorder. Patients with CKD have a variety of different causes of bone mineral disorder, some of which respond appropriately to calcium and some of which don't. So, for example, if someone has hyperparathyroid bone disease due to end-stage CKD, calcium supplementation is not necessarily going to be an appropriate treatment for them. If someone had osteomalacia and there was a vitamin D deficiency, then vitamin D replacement with calcium may be helpful. Thus, the physician who is treating these patients needs to consider the underlying cause of the bone disease or the CKD mineral disorder before recommending calcium. Unfortunately, we will not have a general prescription that will apply to all patients with CKD mineral bone disorder.
Medscape: Can you describe what the correlation is between elevated serum phosphorus and calcification?
Dr. Jamal: Elevated serum phosphorus may result in an elevated calcium/phosphate cross-product. Regarding calcification, the issue is that the calcium will precipitate out and that could lead to calcification in the skin, in internal organs, and in blood vessels.
Medscape: Do you think more could be done to educate healthcare professionals about the importance of treating elevated serum phosphorus to goal in CKD stages 3 and 4?
Dr. Jamal: Absolutely. Physicians need to be educated about the fact that abnormalities in mineral metabolism start very early in chronic kidney disease. Indeed, they occur prior to starting dialysis and physicians should be testing for abnormalities in mineral metabolism in stages 3 and 4 kidney disease. Regarding treatment of elevated serum phosphorous, we need to reconsider what level of serum phosphorous we should be aiming to achieve and how we should meet this goal. To apply a prescription of lowering the phosphorus by a certain amount with a particular product may not be the best approach. Indeed, an individualized treatment approach based on factors such as the state of renal disease and the underlying bone mineral disorder may be better.
Medscape: Do you think using a non-calcium sub-element binder like sevelamer provides added cardiovascular benefit by attenuating the degree of calcification in patients with CKD, and if so, does this apply to all stages of CKD?
Dr. Jamal: It is important when discussing cardiovascular benefit to distinguish between arterial calcification and clinical vascular endpoints. Prospective randomized control trials demonstrate that sevelamer does prevent the progression of arterial calcification. Thus, theoretically, if we can prevent the progression of arterial calcification, we may be able to prevent vascular mortality and morbidity. The underlying assumption here is that vascular calcification leads to an increase in vascular morbidity and mortality. Unfortunately this hypothesis has not been proven. We know that giving treatment with a non-calcium-based binder prevents progression of arterial calcification, but what we don't know is whether preventing that progression of arterial calcification decreases cardiovascular morbidity and mortality and while this makes physiologic sense, given the lack of data, we need to be very cautious in drawing these types of conclusions. Clearly, we need further studies in this area.
Medscape: Why do you think that calcium binders are seen as a preferred first line treatment in CKD stages 3 and 4, when in fact prevalence of hypocalcemia in these patients is as low as 5% in stage 3 patients, and only 20% in stage 4 patients?
Dr. Jamal: The majority of physicians give a calcium binder to lower phosphorous, not to correct hypocalcemia; however, it is important to remember that a calcium binder is still calcium, which may increase serum calcium.
Medscape: Does calcium supplementation put patients with kidney disease at an increased risk for adverse cardiovascular events associated with calcium overload?
Dr. Jamal: That is the crucial clinical question. Unfortunately, we don't know the answer as of yet. We know that elevated serum calcium and elevated calcium phosphate cross products lead to increased arterial calcification and increased mortality. We also know that giving a non-calcium-based binder will decrease arterial calcification, decrease serum calcium levels and theoretically will decrease calcium phosphate cross products. What we don't know is whether there is a direct link between arterial calcification, calcium phosphate cross products, and cardiovascular morbidity and mortality.
Medscape: For a long time now, it was thought that lipids are the only factor that will increase one's cardiac risk. Now is it safe to assume that we should add calcium to that list?
Dr. Jamal: Absolutely. Whether calcium in and of itself is a direct risk factor, needs further study. Patients with CKD are at an increased risk of cardiovascular disease and there are a multitude of factors that will increase that risk, some of which are related to the renal failure and those include things like anemia, hyperhomocystinuria, and perhaps -- arterial calcification.
Medscape: You touched on this a little bit before, but is there a widely held misconception in the medical community that patients with CKD stages 3-4 suffer from hypocalcemia and if so, how would you advise healthcare professionals to approach the issue of calcium supplementation in these patients?
Dr. Jamal: Some of this misconception comes from the fact that patients who have CKD do have an elevation in parathyroid hormone or PTH. Initially, it was hypothesized that this increase in PTH was due to low levels of serum calcium (which stimulates PTH secretion). However, further understanding of renal pathophysiology, particularly in early stages of CKD, has led most to agree that it is the elevated serum phosphorous that results in increased PTH and not decreased serum calcium. Hypocalcemia is very uncommon, particularly in early stages of CKD. Late in renal disease, there may be hypocalcemia related to 125 vitamin D deficiency, but this is also rare. Again, the best way to sort of deal with issues such as hypocalcemia is to treat the primary cause, so in the case of early kidney disease, a reasonable approach would be to try to lower levels of serum phosphorous, and later on it would be to replace vitamin D, as well as try to lower levels of serum phosphorus.
1. Shea B, Wells G, Cranney A, et al; for the Osteoporosis Methodology Group and the Osteoporosis Research Advisory Group. Meta-analysis of calcium supplementation for the prevention of postmenopausal osteoporosis. Endocr Rev. 2002;23:552-559. Abstract
2. Goodman WG, Goldin J, Kuizon BD, et al. Coronary-artery calcification in young adults with end-stage renal disease who are undergoing dialysis. N Engl J Med. 2000;342:1478-1483. Abstract
3. Mazhar AR, Johnson RJ, Gillen D, et al. Risk factors and mortality associated with calciphylaxis in end-stage renal disease. Kidney Int. 2001;60:324-332. Abstract
4. Ahmed S, O'Neill KD, Hood AF, Evan AP, Moe SM. Calciphylaxis is associated with hyperphosphatemia and increased osteopontin expression by vascular smooth muscle cells. Am J Kidney Dis. 2001;37:1267-1276. Abstract
Interviewer: Anne Le, PharmD, RPh, Editorial Director, Nephrology, Medscape, LLC, New York, NY
Interviewee: Sophie A. Jamal, MD, PhD, Assistant Professor/Clinician Scientist, Department of Medicine, University of Toronto, Toronto, Ontario, Canada; Clinical & Research Director, Osteoporosis Program, Women's College Hospital, Toronto, Ontario, Canada
Disclosure for Interviewer: Anne Le, PharmD, RPh, has disclosed no relevant financial relationships.
Disclosure for Interviewee: Sophie A. Jamal, MD, PhD, has disclosed no relevant financial relationships.