By Robert P. Heaney, MD
Bone mineral consists of calcium phosphate. not surprisingly, both calcium and phosphorus must be ingested in sufficient quantity to build bone. Although the importance of calcium intake has received the most attention in recent years, vitamin D and even phosphorus intakes also may be marginal. Hence, supplying only calcium may do little more than uncover other nutritional shortfalls.
The one study that used all three of the key nutrients (calcium, phosphorus, and vitamin D) involved no anti-osteoporosis drugs at all; yet it produced a 43% reduction in fracture risk within 18 months of beginning the nutritional repletion.1 The calcium intake required to maintain bone mass in healthy adults has been reasonably well defined,2 but precisely how much calcium, phosphorus, and vitamin D may be needed to optimize bone mass, with or without bone-active drugs, is not known with certainty.
A little-recognized potential for interference between minerals arises with high-dose calcium-only supplementation. Calcium is known to bind phosphorus in the gut and to block its absorption; this property is used therapeutically to manage phosphorus absorption in patients with end-stage renal disease. Although this effect is generally known, it has not been seriously considered with respect to the use of calcium supplements. B.E.C. Nordin and I examined this issue by analyzing 636 individual calcium and phosphorus balance studies performed mostly in middle-aged and elderly women.3 We observed that, even at levels found in typical diets, calcium does interfere with phosphorus absorption.
Quantitatively, 500 mg of calcium prevented the absorption of about 166 mg of phosphorus.
Typical American and British diets contain more phosphorus than calcium;4 therefore, this calcium-phosphorus interaction has no appreciable effect on food sources of both minerals (i.e., dietary calcium will not block enough dietary phosphorus to make a difference). However, when extra calcium is given as the carbonate or citrate salts (especially when given with meals, as is usual to optimize calcium absorption), substantial interference with absorption of food phosphorus can occur. Additionally, women with restricted meat and dairy intakes usually have low total phosphorus intakes;4 in such individuals, supplementation with 1,500 mg calcium could effectively prevent absorption of most or all dietary phosphorus. As both calcium and phosphorus are necessary to mineralize new bone, high doses of calcium-only supplements could counter the very purpose for which they are being used.
Against this background of potentially destructive interference, it is helpful to examine the issue quantitatively. Although most U.S. diets are relatively phosphorus-rich, about 10% of women older than age 60 ingest less than 490 mg of phosphorus per day (i.e., less than 70% of the RDA), and 15% of women older than age 80 fall below this level.4 These individuals, who are at the greatest risk for phosphorus insufficiency, also are the ones likely to be taking calcium supplements, and likely to be taking anti-osteoporosis drugs.
The bisphosphonates and raloxifene are mainly resorption suppressors and produce a slow reversal of bone loss by virtue of inhibiting bone resorption more than bone formation. After a 3-5% increase in bone density in the first year of treatment, antiresorptive drugs produce a steady-state gain of 0.5-1.0% per year.5 Teriparatide, an injectable fragment of parathyroid hormone (PTH) soon to be on the market, directly stimulates osteoblastic new bone formation by osteoblasts, and is capable of increasing axial bone mass by as much as 10-15% per year.
All clinical trials of antiresorptives have tested the drugs with supplemental calcium, most commonly 500 mg of calcium carbonate per day. In some cases, vitamin D also was given. Will patients treated with antiresorptive agents have enough total mineral to sustain steady-state bone gain?
An increase of 0.5-1.0% bone mass per year, typically produced by antiresorptive drugs, translates to a positive balance of 10-20 mg calcium/d and 4.6-9.3 mg phosphorus/d. Given the ability of the kidneys to reduce phosphorus loss, it is likely that enough phosphorus will be available to meet this modest need, even in the face of typical doses of calcium supplements. However, with teriparatide, the mineral demand is an order of magnitude greater; a bone gain of 10-15% translates to retention of 93-140 mg phosphorus/d.6,7 For women with low food phosphorus intakes who are receiving high-dose calcium-only supplements, this becomes much more problematic.
Two potential solutions to the problem of interference can be suggested. Calcium supplements can be given between meals or at bedtime, so as to minimize interactions of the supplemental calcium with food phosphorus. The other option is to use a calcium-phosphate supplement, instead of a carbonate or citrate product. Between-meal dosing is the less attractive option because absorption is most efficient when calcium is taken with food,8 and elderly individuals often absorb calcium very poorly on an empty stomach. Protecting phosphorus absorption while reducing calcium absorption defeats the purpose of adding calcium. The use of a calcium-phosphate salt, on the other hand, provides both minerals needed for bone mineralization and seems a more natural solution.
Knowing that calcium binds with phosphorus, one might wonder how calcium phosphate could possibly work as a calcium supplement. The answer lies in the quantitative aspects of the binding. In tricalcium phosphate, there is a surplus of about 100 mg phosphorus for each 500 mg calcium, over and above what is bound; and in dicalcium phosphate, the surplus is even greater. So both currently used calcium phosphates contain more phosphorus than their calcium can bind. Moreover, the supplemental calcium, by complexing with phosphate in the supplement itself, is not available to block absorption of food phosphorus. So a calcium phosphate supplement, taken with food, ensures ample phosphorus as well as calcium to support bone building.
There is even more direct evidence that calcium-phosphate sources are efficacious in supporting bone mineralization. The most dramatic of the calcium supplementation trials reported to date used tricalcium phosphate as the calcium source.1 In this randomized, placebo-controlled trial in 3,270 ambulatory elderly French women in nursing homes (1,765 completed), supplementation of tricalcium phosphate 1,200 mg and vitamin D3 800 IU for 18 months reduced hip fracture incidence by 43% among those who completed the trial. All non-vertebral fractures were reduced by 26% in an intention-to-treat analysis.
Moreover, milk, the primary source of minerals for bone building in all young mammals, contains calcium and phosphorus in about the same ratio as dicalcium phosphate. Clearly, therefore, phosphorus-rich calcium sources work at least as well as calcium-only sources. Finally, studies in my laboratory at Creighton University have shown that calcium as a phosphate salt is absorbed nearly as well as the carbonate or citrate salts.9
A final question is whether the total amount of mineral usually given with current anti-osteoporosis therapies is sufficient to allow the available drugs to exert their maximal effect. Data directly addressing this question are sparse. However, an abundance of relevant calcium physiological data suggests that this question tentatively should be answered in the negative.
Net calcium absorption from a 500 mg supplement averages only about 10% (i.e., 50 mg, and half of that typically is spilled into the urine, leaving only 25 mg to offset sweat losses and to support net bone mineralization).3,10,11 Resorptive interference from the bisphosphonates and raloxifene leads to increased PTH secretion, which in turn would result in somewhat better utilization of ingested calcium than the above estimates.1 Never-theless, 25 mg is very close to the minimum amount needed for a bone gain of 1% per year. Given the fact that most antiresorptives have been tested with only 500 mg of supplemental calcium, and the bone gain reported with their use is about the maximum that the available calcium could support, it is plausible that more calcium could have resulted in greater bone gain. Bones are made out of minerals, after all, not hormones or drugs, and the amount of bone that can be made must ultimately be limited by availability of the bulk raw materials.
This limiting feature of inadequate mineral support is brought into bold relief in the case of teriparatide. Using 1,000 mg of supplemental calcium, Neer et al reported teriparatide-induced bone gain at the spine of 9% per year,6 while Arnaud et al, using 50% more calcium (1,500 mg), reported 15% per year,7 or bone gain that was 67% greater. An often-ignored fact is that rats, which respond exuberantly to intermittent PTH, normally are fed diets with calcium and phosphorus densities several times those of the human diet.
For the moment these issues cannot be settled definitively. Trials need to be done to establish: 1) the absolute quantity of supplemental mineral required to support the full potential of today’s anti-osteoporosis drugs; and 2) whether a phosphate salt of calcium better supports bone building than a carbonate or citrate salt. While waiting for answers it would seem that the prudent course would be to ensure a total calcium intake (food plus supplement) of at least 1,500 mg/d, and to use a phosphate salt—at least for those with low dairy and meat intakes and those receiving teriparatide. [Editor’s Note: Calcium phosphate supplements are widely available, most commonly listed as calcium hydroxyapatite or ossein hydroxyapatite compound.] v
Dr. Heaney is John A. Creighton University Professor and Professor of Medicine, Creighton University, Omaha, NE.
1. Chapuy MC, et al. Vitamin D3 and calcium to prevent hip fractures in elderly women. N Engl J Med 1992; 327:1637-1642.
2. Dietary Reference Intakes for Calcium, Magnesium, Phosphorus, Vitamin D, and Fluoride. Food and Nutrition Board, Institute of Medicine. Washington, DC: National Academy Press; 1997.
3. Heaney RP, Nordin BEC. Calcium effects on phosphorus absorption: Implications for the prevention and co-therapy of osteoporosis. J Am Coll Nutr 2002;21: 239-244.
4. Alaimo K, et al. Dietary intake of vitamins, minerals, and fiber of persons 2 months and over in the United States: Third National Health and Nutrition Examination Survey, Phase 1, 1988-91. Advance data from vital and health statistics; no. 258. Hyattsville, MD: National Center for Health Statistics; 1994.
5. Heaney RP, et al. Bisphosphonate effects and the bone remodeling transient. J Bone Miner Res 1997; 12:1143-1151.
6. Neer RM, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med 2001;344:1434-1441.
7. Arnaud CD, et al. Two years of parathyroid hormone 1-34 and estrogen produce dramatic bone density increases in postmenopausal osteoporotic women that dissipate only slightly during a third year of treatment with estrogen alone: Results from a placebo-controlled randomized trial [abstract]. Bone 2001;28:S77.
8. Heaney RP, et al. Meal effects on calcium absorption. Am J Clin Nutr 1989;49:372-376.
9. Heaney RP, et al. Absorbability of calcium sources: The limited role of solubility. Calcif Tissue Int 1990; 46:300-304.
10. Heaney RP, et al. Calcium balance and calcium requirements in middle-aged women. Am J Clin Nutr 1977;30:1603-1611.
11. Heaney RP, et al. Menopausal changes in calcium balance performance. J Lab Clin Med 1978;92:953-963.