Black cohosh
DOSAGE RANGE Australian RDIs
• Infants 1–3 years: 500 mg/day. 4–8 years: 700 mg/day. • Children 9–11 years: 1000 mg/day. 12–18 years: 1300 mg/day. • Adults <70 years: 1000 mg/day. >70 years: 1300 mg/day. • Pregnancy: 1000–1300 mg/day. • Lactation: 1000–1300 mg/day.
According to clinical studies
• Osteoporosis prophylaxis: 1500 mg/day in combi- nation with vitamin D and accessory nutrients (e.g. zinc, manganese, copper and fluoride) and/ or antiresorptive agents
• Premenstrual syndrome: 1200–1600 mg/day; however, 500 mg calcium carbonate twice daily for 3 months is also effective
• Prevention of preeclampsia: 2000 mg/day. • Increased BMD in children with low intake:
100 mg/day.
• Supplementation during pregnancy to increase mineral accretion in fetus: 2000 mg/day for last trimester.
• Allergic rhinitis: 100 mg/day.
• Hyperacidity: 500–1500 mg/day as required. • Hyperlipidaemia: 400 mg three times daily. • Hypertension: 1000–2000 mg/day.
• Dry eye: 10% w/w calcium carbonate in petrola- tum base applied twice daily.
• Fluorosis in children: 250 mg/day.
• Prevention of colorectal cancer: 1200 mg/day. • Weight loss: 1000–1200 mg/day long term.
ADVERSE REACTIONS
Oral administration of calcium supplements may cause gastrointestinal discomfort, nausea, constipa- tion and flatulence.
Hypercalcaemia
Increased serum calcium may be associated with anorexia, nausea and vomiting, constipation, hypo- tonia, depression and occasionally lethargy and coma. Prolonged hypercalcaemic states, especially if associated with normal or elevated serum phosphate, can precipitate ectopic calcification of blood vessels, connective tissues around joints, gastric mucosa, cornea and renal tissue (Wilson et al 1991).
SIGNIFICANT INTERACTIONS
Calcium carbonate when taken as an antacid alters the absorption and excretion of a wide range of drugs. Please refer to a drug interaction guide for specific concerns. Only those interactions encoun- tered with oral administration of calcium supple- ments will be included in this section.
Antacids, including H2 antagonists and proton
pump inhibitors
Use of drugs that raise gastric pH may reduce calcium absorption, especially that of calcium car- bonate or calcium phosphate as these salts require an acidic environment for solubilisation before
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Recently, concern has emerged regarding a poten- tial increase in cardiovascular events associated with long-term high-dose calcium supplementa- tion. This was largely triggered by the results of a New Zealand RCT investigating the effect of calcium supplements (1000 mg/day elemental calcium as calcium citrate) administered to 1471 postmenopausal women, with an average age 74 years, over 5 years. Concomitant vitamin D sup- plements were not given to participants in this trial (Bolland et al 2008). The primary outcome of this study was bone density; however, the researchers also hypothesised that a secondary effect of the treatment would be a reduction in cardiovascular (CV) events, based on existing observational studies highlighting calcium’s positive effect on blood lipids and blood pressure (Nainggolan 2008). However, secondary analysis of the data revealed that the women taking calcium supplements expe- rienced an increase in CV events rather than the expected decrease in CV event. In the calcium- treated group, there was a statistically significant higher rate of verified myocardial infarction (MI) (P = 0.05), and a non-significant increase in all vascular events (P = 0.08) and stroke (P = 0.21), compared to those taking placebo. While the authors concluded that their study does not unequivocally demonstrate causality, it did suggest that high calcium intakes may have an adverse effect on vascular health (Bolland et al 2008).
The same authors subsequently conducted a meta-analysis of 15 RCT of calcium ≥500 mg vs placebo, concluding that in the absence of vitamin D, calcium supplements were associated with a significant increase in MI (P = 0.035) and non- significant increase in composite end point of MI, stroke or sudden death (P = 0.057) or death (P = 0.18) (Bolland et al 2010). In addition, this research group conducted a re-analysis of data from a sub-group in the Women’s Health Initia- tive Calcium Vitamin D study (WHI CaD) and concluded that calcium, with or without vitamin D, modestly increased risk of CV events, especially for MI (Bolland et al 2011).
While these findings have caused substantial alarm and led to much speculation, the evidence suggesting cardiovascular harm needs to be bal- anced against the body of opposing evidence that reports that calcium does not significantly increase cardiovascular event risk.
Daily supplementation with calcium carbonate 1000 mg plus vitamin D 400 IU for 7 years showed neither an increase nor a decrease in coro- nary or cerebrovascular events in a large-scale study (WHI CaD) involving 36,282 postmeno- pausal women aged 50–79 years (Hsia et al 2007). Another prospective study (EPIC-Heidelberg) that involved almost 24 000 participants with an 11-year follow-up found no significant association between calcium intake and risk of stroke or cardiovascular mortality. Interestingly, a trend towards a decrease in MI risk was observed in those with a moder- ately high dairy calcium intake (mean = 820 mg/
day), especially in women. By contrast, a statistically significant increase in MI was found in the group taking supplemental calcium in the absence of vitamin D; however, this may not be clinically meaningful as it translated to only 20 cases of MI in the calcium users, out of 24,000 participants (Li et al 2012). Results from the NHANES III study (n = 20,024) reported that there was no clear association for CVD death and intake of dietary or supplemental calcium (van Hemelrijk et al 2013). Another large prospective study involving 388,229 men and women aged 50–71 years, with a 12-year follow-up, reported that supplemental calcium intake was not associated with increased CVD or cerebrovascular death in women, although an increase CV risk was observed in men taking supplemental calcium (>1000 mg/day), who were also smokers (Xiao et al 2013).
Further to this, a 5-year study of 1460 older women suggested that supplementation with calcium carbonate (1200 mg/day) may reduce risk of hospitalisation and mortality in patients with pre- existing atherosclerotic CVD (Lewis et al 2011). It has been proposed that high calcium intake may increase risk of vascular calcification, or carotid atherosclerosis, although this effect was not dem- onstrated in recent studies (Lewis et al 2013, Kim et al 2012). In addition, there is some evidence that calcium may have a beneficial role in terms of cardiovascular disease by modestly reducing blood pressure and improving serum lipid profiles (Guessous et al 2011). In addition, a review of studies involving over 70,000 people concluded that mortality was reduced with vitamin D plus calcium (odds ratio, 0.94; 95% CI, 0.88–0.99), but not with vitamin D alone (odds ratio, 0.98; 95% CI, 0.91–1.06) (Rejnmark et al 2012).
While it is difficult at this stage to either confirm or refute the association between calcium supplementation and cardiovascular disease, there are a few factors for consideration:
• No RCTs have been conducted to specifically examine the effects of calcium supplementation on CVD morbidity and mortality; concerns have been raised due to secondary data analysis • Current data does not support an association
between dietary or supplemental calcium intake and an increased risk of stroke, cerebrovascular disease, cardiovascular disease or cardiovascular death
• Increased dietary intake of calcium has not been associated with an increase in risk of myocardial infarction
• Supplemental calcium may possibly be associated with an increased risk of myocardial infarction, but this appears to be limited to calcium given alone, without vitamin D.
• Known benefits of combined calcium and vitamin D therapy for reducing risk of osteoporotic fractures needs to be balanced against unproven risk of MI when making treatment decisions for an individual patient, and research now indicates that calcium and vitamin D reduce mortality in the elderly. Clinical note — Is calcium supplementation a risk for increased vascular events?
Lysine
Additive effects may occur as lysine enhances intes- tinal absorption and reduces renal excretion of calcium — potentially beneficial interaction.
Magnesium
Magnesium decreases calcium absorption as they compete for the same absorption pathway, however it is unclear if this mineral interaction is clinically significant — it is advisable to separate doses by at least 2 hours.
Oestrogen and progesterone
Calcium supplementation in combination with these hormones will have an additive effect on minimising bone resorption in postmenopausal women — potential beneficial interaction, so consider increas- ing intake.
Phosphorus
Excess intake (soft drinks, meat consumption) can increase urinary excretion of calcium — ensure adequate calcium intake and monitor for signs and symptoms of deficiency.
Quinolone antibiotics
Drug bioavailability may be reduced by concurrent administration with calcium supplements, reducing drug efficacy and increasing risk of developing bacterial resistance — quinolones should be taken either 2 hours before or 4–6 hours after calcium.
Tetracyclines
Calcium supplements form complexes with these antibiotics and render 50% or more insoluble, there- fore reducing the efficacy of the drug and absorption of calcium — separate doses by at least 2 hours.
Thiazide diuretics
These diuretics decrease urinary excretion of calcium. Monitor serum calcium and look for signs of hypercalcaemia, such as anorexia, polydipsia, polyuria, constipation and muscle hypertonia when using high-dose calcium supplements. Contributing risk factors are the presence of hyperparathyroidism or concurrent use of vitamin D.
Zinc
Concurrent administration of calcium and zinc may reduce absorption of both minerals, however it is unclear if this is clinically significant. Calcium sup- plementation has been shown in some studies to increase faecal losses of zinc (McKenna et al 1997) — ensure adequate zinc intake and monitor for signs and symptoms of deficiency.
calcium can be absorbed. Aluminium- and magnesium-containing antacids may increase urinary excretion of calcium.
Bisphosphonates
Bisphosphonates (e.g. alendronate) are indicated for the treatment of osteoporosis; however, they com- monly cause hypocalcaemia as an adverse effect, which reduces drug effectiveness in maintaining bone mineral density. Adequate intake of both calcium and vitamin D is essential for those taking bisphosphonates, however the drug must be taken on an empty stomach, at least 30 minutes before calcium supplementation.
Caffeine
Caffeine increases urinary excretion of calcium and may affect calcium absorption — ensure adequate calcium intake and monitor for signs and symptoms of deficiency in those with high caffeine intake.
Calcium channel blockers
Calcium supplements can have an antagonistic effect on the desired action of calcium channel blockers that could precipitate the re-emergence of arrhyth- mias — avoid high-dose supplements unless under professional supervision.
Cardiac glycosides (e.g. digoxin)
Administered concurrently, high-dose calcium may potentiate digoxin toxicity — use this combination with caution unless under medical supervision.
Corticosteroids
Long-term use of corticosteroids, especially oral for- mulations, may lead to reduced intestinal calcium absorption, increased calcium excretion and inhib- tion of osteoblasts, leading to drug-induced osteo- porosis — ensure adequate calcium intake and monitor for signs and symptoms of deficiency. Con- sider supplementation with long-term drug therapy.
Excess dietary fat
This increases urinary excretion of calcium — ensure adequate calcium intake and monitor for signs and symptoms of deficiency.
Excess fibre, including guar gum
May simply delay or decrease absorption of calcium — separate doses by at least 2 hours.
Iron
Concurrent administration of calcium with iron may reduce absorption of both minerals. Separate supplemental or dietary intake of minerals by at least 2 hours.
Levothyroxine
Calcium administered concurrently may reduce drug absorption, while levothyroxine may block absorption of calcium, e.g. calcium carbonate — separate doses by at least 4 hours.
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Are there any safety issues?
In very high doses, calcium supplements can cause some side effects, including constipation, but gener- ally calcium is considered safe and has a wide thera- peutic range. High-dose supplements should not be used by people taking some medications. Caution should also be exercised with high doses in individuals with preexisting cardiovascular disease. (See Significant interactions above for specific information.)
REFERENCES
Abrahamsen B et al. Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe. BMJ 340 (2010).
Ahn J et al. Serum vitamin D concentration and prostate cancer risk: a nested case-control study. J Natl Cancer Inst 100.11 (2008): 796–804. Allen NE et al. Animal foods, protein, calcium and prostate cancer risk:
the European Prospective Investigation into Cancer and Nutrition. Br J Cancer 98.9 (2008): 1574–1581.
Aloia JF et al. Calcium and vitamin D supplementationa in postmenopausal women. Journal of Clinical Endocrinology and Metabolism 98.11 (2013).
Alonso A et al. Low-fat dairy consumption and reduced risk of hypertension: the Seguimiento Universidad de Navarra (SUN) cohort. Am J Clin Nutr 82.5 (2005): 972–979.
Astrup A. The role of calcium in energy balance and obesity: the search for mechanisms. Am J Clin Nutr 88.4 (2008) 873–874.
Atallah AN et al. Calcium supplementation during pregnancy for preventing hypertensive disorders and related problems. Cochrane Database Syst Rev 1 (2002): CD001059.
Bailey CS et al. Excessive calcium ingestion leading to milk-alkali syndrome. Annals of Clinical Biochemistry. 45 (Pt 5) (2008): 527–529. Barba G, Russo P. Dairy foods, dietary calcium and obesity: a short
review of the evidence. Nutrition, Metabolism & Cardiovascular Diseases. 16 (2006): 445–451.
Baron JA et al. Risk of prostate cancer in a randomized clinical trial of calcium supplementation. Cancer Epidemiol Biomarkers Prev 14.3 (2005): 586–589.
Beall DP, Scofield RH. Milk-alkali syndrome associated with calcium carbonate consumption. Report of 7 patients with parathyroid hormone levels and an estimate of prevalence among patients hospitalized with hypercalcemia. Medicine. 74.2 (1995): 89–96.
Beers MH, Berkow R (eds). The Merck Manual of Diagnosis and Therapy, 17th edn. Rahway, NJ: Merck, 2003.
Behringer M et al. Effects of weight-bearing activities on bone mineral content and density in children and adolescents: a meta-analysis. J Bone Miner Res, 29.2 (2014) 467–478.
Belizan JM et al. Long-term effect of calcium supplementation during pregnancy on the blood pressure of offspring: follow up of a randomised controlled trial. BMJ 315.7103 (1997): 281–285. Bell L et al. Cholesterol-lowering effects of calcium carbonate in patients
with mild to moderate hypercholesterolemia. Arch Intern Med 152.12 (1992): 2441–2444.
Bergel E, Barros AJ. Effect of maternal calcium intake during pregnancy on children’s blood pressure: a systematic review of the literature. BMC Pediatr 7 (2007): 15.
Bertone-Johnson ER et al. Calcium and vitamin D intake and risk of incident premenstrual syndrome. Arch Intern Med 165.11 (2005): 1246–1252.
Bischoff-Ferrari HA Which vitamin D oral supplement is best for postmenopausal women? Curr Osteoporos Rep 10.4 (2012): 251–257. Bolland MJ et al. Calcium supplements with or without vitamin D and
risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ 2011 doi 10.1136/bmj.d2040
Bolland MJ et al. Effect of calcium on risk of myocardial infarction and cardiovascular events:meta-analysis. BMJ 341 (2010): c3691. Bolland MJ et al. Vascular events in healthy older women receiving
calcium supplementation: randomised controlled trial. BMJ 336.7638 (2008): 262–266.
Borghi L et al. Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med 346.2 (2002): 77–84. Bowen J, Noakes M, Clifton P. A high dairy protein, high-calcium diet
minimizes bone turnover in overweight adults during weight loss. J Nutr 134 (2004): 568–573.
Bucher HC et al. Effect of calcium supplementation on pregnancy- induced hypertension and preeclampsia. JAMA 275 (1996): 1113–11117.
Practice points/Patient counselling
• Calcium is an essential mineral required for the proper functioning of numerous intracellular and extracellular processes, including muscle con- traction, nerve conduction, beating of the heart, hormone release, blood coagulation, energy pro- duction and maintenance of immune function. • Low-calcium states are associated with several
serious diseases such as colorectal cancer, osteo- porosis types I and II, hypertension, preeclamp- sia and eclampsia.
• Although supplementation is traditionally used to correct or avoid deficiency states, research has also shown a role in the prevention of osteoporosis, preeclampsia and management of numerous disease states and research now indi- cates that calcium and vitamin D reduces mor- tality in the elderly.
• Clinical studies show that calcium supplemen- tation has benefits in symptomatic relief in premenstrual syndrome, reducing the risk of fracture (when combined with vitamin D), reducing the risk of preeclampsia and improv- ing birthweight, weight loss and reducing incidence of some cancers.
• Calcium can interact with numerous drugs and should be used with caution by people with renal disease or hyperparathyroid conditions.
PREGNANCY USE
The safety of calcium supplementation during pregnancy in doses up to 2000 mg elemental calcium per day is well established in clinical trials.
CONTRAINDICATIONS AND PRECAUTIONS