Pycnogenol by Bronson Laboratories

EFFECTIVE

• Dyspepsia. Oral calcium carbonate is approved by the US Food and Drug Administration (FDA) as an antacid. Details: Taking calcium carbonate orally as an antacid is effective for treating dyspepsia (1843). Calcium carbonate has FDA approval as an antacid.
• Hyperkalemia. Intravenous calcium gluconate is approved by the US Food and Drug Administration (FDA) for preventing hyperkalemia-induced cardiac abnormalities. Details: Administering calcium gluconate intravenously can reverse electrocardiographic changes and arrhythmias induced by hyperkalemia (12946). Intravenous calcium gluconate is FDA-approved for preventing hyperkalemia-induced cardiac abnormalities.
• Hypocalcemia. Oral calcium treats and prevents hypocalcemia. Intravenous calcium is used to treat severe hypocalcemia. Details: Taking calcium orally is effective for treating and preventing hypocalcemia. Intravenous calcium gluconate, acetate, gluceptate, or chloride is effective for severe hypocalcemia or hypocalcemic tetany (12928).
• Kidney failure. Oral calcium carbonate or calcium acetate is used as a phosphate binder during kidney failure. Details: Taking calcium carbonate or calcium acetate orally is effective as a phosphate binder. Calcium acetate (PhosLo) appears to control hyperphosphatemia better than sevelamer (Renagel) (12943,12944,38990). Calcium citrate is not recommended for this purpose because it increases aluminum absorption and does not bind phosphate as efficiently as calcium acetate or calcium carbonate (21631). Some clinical research also shows that taking calcium orally reduces blood pressure in patients with kidney failure (975).

LIKELY EFFECTIVE

• Corticosteroid-induced osteoporosis. Oral calcium in combination with vitamin D prevents bone density loss that occurs during long-term treatment with corticosteroids. Details: Taking calcium in combination with vitamin D as adjunctive therapy seems to be effective for reducing bone mineral density loss in people using corticosteroids long-term (982,1046,1830,1831,1832,4462,4463,4464,4465,4466)(4467,12945,38493). One specific product used in clinical research is Oscal (Marion Merrel Dow Inc.), which contains elemental calcium 500 mg per tablet plus vitamin D 125 IU per tablet (982). Another product used is Oscal 250 + D (SmithKline Beecham Healthcare), which contains elemental calcium 250 mg and vitamin D 125 IU per tablet (1046).
• Hyperparathyroidism. Oral calcium reduces parathyroid hormone levels in patients with secondary hyperparathyroidism due to kidney failure. Details: Taking calcium orally reduces parathyroid hormone levels in patients with kidney failure and secondary hyperparathyroidism (1827,1828,1829,39174,39425). In elderly women, the combination of calcium and vitamin D reverses secondary hyperparathyroidism and reduces hip fracture risk (8818). Also, population research suggests increased calcium intake from the diet and supplements reduces the risk of primary hyperparathyroidism in women. Supplemental intakes of at least 500 mg/day and dietary intakes of approximately 1100 mg/day are considered to be protective (91353).
• Osteoporosis. Adequate calcium intake, from the diet and/or supplements, is recommended for the prevention and treatment of osteoporosis. Details: The Bone Health and Osteoporosis Foundation (BHOF) recommends ensuring adequate calcium intake in line with the recommended dietary allowance (RDA) by age, along with adequate vitamin D intake, for the prevention and treatment of osteoporosis in adults over 50 years of age. Supplementation can be used to augment dietary intake when adequate dietary intake is not feasible (109425). In the US and Canada, foods containing at least 200 mg calcium with less phosphorous content than calcium can be labelled with a health claim regarding the relationship between adequate calcium intake and a reduced risk for osteoporosis (11940,102148). However, calcium supplementation is not recommended specifically for the primary prevention of osteoporosis. The US Preventive Task Force (USPSTF) states that the current evidence is insufficient to assess the balance of benefits and harms of vitamin D and calcium supplementation, alone or in combination, for the primary prevention of fractures in community dwelling adults without osteoporosis (95695). Also, calcium supplements do not seem to be effective for preventing loss of bone mineral density (BMD) during lactation (988), in patients who have had bone marrow transplantation (1817), or in patients who have had renal transplantation (4823,38736,38871). Maximal bone growth occurs in the teenage years, and then BMD in females remains relatively constant until age 30-40. After age 40, bone loss typically occurs at rates of 0.5% to 1% per year. In males, this occurs several decades later. Bone loss is more pronounced if dietary calcium intake is below the RDA, which is the case for many Americans (2571,2578). One meta-analysis of randomized controlled trials in healthy children 7-14 years old shows that fortifying food with calcium 250-1000 mg daily for up to 24 months modestly improves femoral neck BMD, but not hip or spine BMD. However, the included trials did not supplement vitamin D (107232). During the 5 years immediately after menopause, calcium supplementation has very little effect on bone loss (2569,2570,2575,2576). The rapid loss of estrogen causes a high bone resorption rate, which increases serum calcium levels and therefore decreases intestinal absorption of calcium (2570). After this period, the typical rate of bone loss is 2% per year (2572,2576). Taking calcium 1000-1600 mg daily as carbonate, citrate, lactate gluconate, or citrate malate salt decreases this rate by 0.25% to 1% annually (977,979,981,2569,2571,2572,2575,2576,2578,6850)(38978,38980,39064). The greatest reductions (1% or more) are seen in the first 1-2 years of supplementation when bone remodeling foci can be filled (2569,2576). After this period, the differences in rate of loss between supplemented and non-supplemented females are closer to 0.25% per year (2569,2577). A meta-analysis of clinical evidence suggests that there is no additional benefit after 4 years (38980). Small clinical studies have found that continuous calcium supplementation at an average daily dose of 1050 mg, started after menopause and continued for 1.5-4 years, may reduce fracture rates by 26% when compared with no calcium supplementation. The largest of these studies was conducted in nursing home residents who also received daily vitamin D; the benefits of calcium, specifically, are unclear (39386). Some research also suggests that calcium and vitamin D improves primary prevention of osteoporotic fractures in some older individuals with osteoporosis, particularly the elderly and those who are no longer community dwelling (12930,38875,38849,39026,109471). However, not all research is positive. One large clinical trial in elderly adults with a low-trauma fracture show that taking calcium 1000 mg daily with or without vitamin D 800 IU daily for 2-7 years does not reduce the risk of a second fracture when compared with placebo (13073). Another clinical study shows that taking calcium 1000 mg daily plus vitamin D 800 IU daily does not prevent a second fracture in elderly patients, or prevent a first fracture in elderly patients with other risk factors such as low body weight (less than 58 kg, 127.6 pounds), smoking, family history of hip fracture, or fair or poor self-reported health (12929). Also, some exploratory research suggests that supplements may need to be continued indefinitely; in adults over 68 years of age, any effects of 2 years of calcium supplements on BMD appear to be lost within 2 years after discontinuing supplements (6853). Calcium has additive effects when used with other agents such as vitamin D, estrogens, or calcitonin. Whereas calcium alone generally reduces or prevents loss of BMD, combination with other agents can produce small increases in BMD ranging from 0.3% to 3.3% depending on the combination and dosages used (978,980,1836,2570,2571,2572,2576). However, one meta-analysis in healthy adults shows that fortifying foods with calcium 250-1000 mg daily, in conjunction with vitamin D supplementation, for up to 24 months does not improve BMD when compared with control (107232). The full potential of osteoporosis treatments cannot be realized without adequate calcium intake (2569,2570,2571,2572). Advise patients taking agents such as estrogens, calcitonin, bisphosphonates, or raloxifene (Evista) to ensure that their daily calcium intake meets the RDA. Use supplements if necessary. The usefulness of calcium in preventing osteoporosis in males is not as well-studied. Some observational research has found that calcium 870 mg daily is not associated with changes in BMD and bone loss in males (97201). However, clinical evidence suggests that taking calcium 1000 mg daily for 2 years might improve trabecular or cortical bone mass by 2% to 4% (980,8827,8873). Dietary supplementation with calcium and vitamin D seems to moderately reduce bone loss measured in the femoral neck, spine, and total body, and seems to reduce the incidence of nonvertebral fractures in older patients with osteopenia or low BMD (980).
• Premenstrual syndrome (PMS). Adequate calcium intake seems to prevent symptoms of PMS. Details: There seems to be a link between low dietary calcium intake and symptoms of PMS (2004,6847,39007). Taking calcium 1000-1336 mg daily seems to significantly reduce depressed mood, water retention, and pain, especially if daily calcium intake is inadequate (1822,1823,1824,2004,95821). Calcium carbonate 1200 mg daily seems to decrease PMS symptom scores by about 18% when compared with placebo (1822). Increasing dietary calcium intake is also associated with a decreased risk of developing PMS. Consuming an average of 1283 mg of calcium per day from foods is associated with about a 30% lower risk of developing PMS compared with consuming an average of 529 mg daily (13094); however, taking calcium supplements does not appear to be associated with the risk of developing PMS.

POSSIBLY EFFECTIVE

• Colorectal cancer. Oral calcium seems to be beneficial for preventing colorectal cancer, especially in those with adequate vitamin D levels and normal body mass index (BMI). Details: Population studies have found that increased intake of dietary or supplemental calcium is associated with a reduced risk of colorectal cancer and colorectal adenomas (1047,8820,12120,38951,98898,98899). Clinical trials and meta-analyses of clinical research also show that taking calcium supplements 1.2-2 grams daily for up to 4 years can reduce the risk of colorectal adenoma recurrence by up to 29% (970,12118,12950,15267,34596,38718,39042,95817). However, not all research has been positive. Some meta-analyses of clinical research or observational studies suggest that taking calcium does not reduce the risk of familial adenomatous polyposis or colorectal cancer (34596,39042,39349). Other contradictory research suggests that postmenopausal females who take calcium 1000 mg daily plus vitamin D 400 IU daily do not have a reduced risk of developing colorectal cancer (14290); however, this finding may not be reliable due to the high baseline intake of calcium in study participants. The reason for these conflicting findings is not entirely clear. Vitamin D might be an important factor. People with lower than average vitamin D levels do not seem to get any benefit from calcium supplements (12118). Also, one meta-analysis of previous trials suggests that taking calcium 1200 mg daily reduces the risk of colorectal adenomas in people with a normal BMI, but not in those who are overweight or obese (99715). Despite this conflicting evidence, the US Food and Drug Administration (FDA) approved a qualified health claim in 2005 stating that calcium supplements may reduce the risk of colorectal cancer and colorectal adenomas. However, the FDA has determined that there is little scientific evidence to support this claim (102366).
• Fetal bone mineralization. If calcium intakes are low during pregnancy, oral calcium seems to be beneficial for increasing fetal bone density. Details: With low dietary calcium intake (less than 562 mg elemental calcium daily) during pregnancy, calcium supplementation increases fetal bone mineralization and density. However, calcium supplementation does not offer any additional benefit if calcium intakes are adequate (3263,3264).
• Hypertension. Oral calcium seems to reduce blood pressure by a small amount. However, it is unclear if this reduction is clinically significant. Details: Many clinical trials and observational studies show that intake of calcium supplements or dietary calcium modestly reduces blood pressure in patients with or without hypertension, usually around 1-2 mmHg. Calcium seems to be more effective for certain subpopulations of patients, such as salt-sensitive people and patients with low baseline dietary calcium intake (945,972,974,976,984,1818,1819,1820,1821,6852)(13138,14406,38803,39063,39094,39221). Also, a meta-analysis of clinical research shows that calcium intake during pregnancy reduces systolic blood pressure in offspring by 1-2 mmHg (38852). However, a large-scale clinical trial in postmenopausal females shows that taking vitamin D (cholecalciferol) 400 IU daily in combination with elemental calcium 1000 mg daily does not lower blood pressure or reduce the risk of developing hypertension (16714). Additionally, a meta-analysis of 8 clinical trials shows that taking calcium in combination with vitamin D for up to 7 years has no effect on blood pressure (98861). The validity of this finding is limited by the poor methodological quality of the included studies. Some observational research suggests that calcium can reduce the risk for hypertension. Population research in females aged 45 years and older suggests that higher intake of calcium from both diet and supplement sources is linked to a lower risk of developing hypertension when compared to lower calcium intake (14265). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim stating that calcium supplements may reduce the risk of hypertension. However, the FDA has concluded that this claim is based on supporting, rather than conclusive, evidence (102367).
• Osteomalacia. Oral calcium seems to reverse osteomalacia caused by very low calcium intakes. Details: Osteomalacia is commonly caused by vitamin D deficiency; however, very low calcium intake can also lead to osteomalacia in children and adults. Calcium supplementation can reverse osteomalacia caused by calcium deficiency. Along with appropriate vitamin D supplementation, individuals at risk of osteomalacia need sufficient calcium intake (94819).
• Pre-eclampsia. Oral calcium seems to reduce the risk of pre-eclampsia in high risk pregnancies, especially if calcium intakes are low. Details: Although there is some conflicting evidence (971,38756), most clinical research shows that taking calcium orally 1-2 grams daily reduces pregnancy-related hypertension and pre-eclampsia (973,1833,8828,39043,39319,39426,96480). Calcium appears to reduce the risk of pre-eclampsia by about 50% when compared with placebo. One meta-analysis of 19 controlled trials involving over 29,000 pregnancies found that for every 19 females treated with calcium, one episode of pre-eclampsia would be avoided (96480). Calcium appears to have the greatest effect in individuals at high-risk of pre-eclampsia or with low calcium levels, and when taken at greater than or equal to 20 weeks of gestation (15029,38497,96480,99714). In 2005, the US Food and Drug Administration (FDA) approved a qualified health claim regarding the use of calcium supplements to reduce the risk of pregnancy-induced hypertension and pre-eclampsia. However, due to the limited and conflicting research available at that time, the FDA stated that this outcome was highly unlikely. Since then, large, high-quality clinical research has supported this finding. In fact, in 2016 the World Health Organization (WHO) released a recommendation to prescribe oral calcium supplementation 1.5-2 grams daily during pregnancies at high risk of pre-eclampsia if dietary calcium intakes are low, in order to prevent pre-eclampsia (97347).
• Rickets. Oral calcium seems to reverse rickets caused by very low calcium intakes. Details: Rickets is commonly caused be vitamin D deficiency; however, very low calcium intake can also lead to rickets. Calcium supplementation can reverse rickets caused by calcium deficiency (94819). A small clinical study in children with nutritional rickets shows that taking calcium 500-2000 mg daily for 24 weeks improves radiographically measured rickets caused by calcium deficiency. Rickets seems to improve more rapidly with calcium 1000 mg compared to calcium 500 mg. However, increasing the calcium dose to 2000 mg daily is not more beneficial than calcium 1000 mg daily (98904).
• Tooth retention. Oral calcium with vitamin D seems to help with tooth retention in the elderly population. Details: A clinical trial in the elderly population shows that taking calcium citrate malate 500 mg daily along with vitamin D3 (cholecalciferol) 700 IU daily orally for 3 years reduces the risk of tooth loss by about 52% when compared with placebo (8816).

POSSIBLY INEFFECTIVE

• Breast cancer. Oral calcium does not seem to be beneficial for breast cancer prevention. Details: Although some population research disagrees (15631,39041,95811,107237), most research shows that increased calcium intake is not associated with a reduced risk of breast cancer (15631,16715,98895,107236,107237). Subgroup analyses of population research suggest that calcium intake may reduce the risk of breast cancer in postmenopausal, but not pre-menopausal, adults (15631,107237). Another subgroup analysis in a large meta-analysis of population research also suggests that dietary intake may reduce estrogen receptor(ER)-negative breast cancer, but not ER-positive breast cancer (107236). However, most other research has not evaluated the effects of calcium supplementation or intake on breast cancer subtypes. The best evidence to date, from a large scale clinical trial (Women's Health Initiative), shows that taking vitamin D (cholecalciferol) 400 IU daily plus calcium 1000 mg daily for 7 years after menopause does not reduce the risk of developing invasive breast cancer at the end of the study and 5 years after the end of the intervention (16715,98895).
• Fractures. Although oral calcium prevents fractures in osteoporosis, most evidence shows that calcium does NOT prevent factures in people who do not have osteoporosis. See Osteoporosis discussion for more information on the use of calcium for this purpose. Details: The most recent and robust meta-analysis of clinical research shows that calcium supplementation with or without vitamin D is NOT associated with reduced fractures in older adults without osteoporosis (95822). A large-scale study in postmenopausal females aged 50-79 years suggests calcium 1000 mg plus vitamin D 400 IU daily for 7 years only modestly improves bone mineral density (BMD) and does not significantly reduce fracture risk. This lack of effect may have been due to low adherence to the treatment regimen. In those who were 80% adherent, the combination of calcium plus vitamin D reduced the risk of hip fracture by about 29% (14282). Also, some clinical research shows that taking calcium carbonate 1000 mg and vitamin D 400 IU for 5 years does not attenuate loss of height after menopause when compared with placebo (95810). Additional meta-analyses of clinical and observational evidence suggest that calcium supplementation is not associated with a reduced risk of vertebral or nonvertebral fractures, such as hip fractures (38589,38888,98895). Some other research has suggested that calcium in combination with vitamin D reduces fracture risk in older patients without osteoporosis (980,1836,8818,12930,12933,12952,38849,102145,107235); however, this research is confounded by a number of variables, including the presence of hormonal therapy and differing levels of fracture risk at baseline (1836,8818,95822). Conflicting findings on this topic might also be due to genetic differences in patient populations. A population analysis of the Women's Health Initiative study found that, in older females with the lowest genetic susceptibility to low bone mineral density (BMD), taking calcium with vitamin D is associated with a reduction in fracture risk. However, in females with a higher genetic susceptibility to low BMD, there is no association between supplementation and fracture risk. This might be because individuals with a lower susceptibility to low BMD are also more responsive to calcium and vitamin D supplementation (97357). As of April 2018, the U.S. Preventative Services Task Force (USPSTF) concludes that there is insufficient evidence to determine whether supplementing with vitamin D >400 IU daily along with calcium >1000 mg daily is safe and effective for preventing fractures in community dwelling adults without vitamin D deficiency, osteoporosis, or a history of fracture. USPSTF recommends against supplementing with calcium 1000 mg daily or less along with vitamin D 400 IU daily or less for preventing primary fractures in community-dwelling postmenopausal females (95695).
• Obesity. Oral calcium does not seem to improve weight loss. Details: Observational research has found that adults and children with low calcium intake are more likely to gain weight, have a higher body mass index (BMI), and be overweight or obese when compared to people with high calcium intake (12124,12125,12126,12127,14265). Additional observational research has found that increasing calcium intake is associated with weight loss in females; the results in males have been conflicting (12127,15602,15603). Despite these findings from observational research and a few small clinical studies (12128,15397,14438,98905), most clinical research has found that increased calcium intake does not increase weight loss (12052,13138,15396,15399,38985,39004,97356). The most recent meta-analysis of 20 clinical studies shows that daily dietary and supplemental calcium intake that meets the dietary reference intake (DRI) of 1000 mg or more daily does not increase weight loss in overweight individuals or patients with obesity when compared with intake below the DRI (95813). An older meta-analysis of 13 clinical trials also shows that increased dietary and supplemental calcium intake does not increase weight loss (15605).
• Overall mortality. Oral calcium does not seem to reduce overall mortality. Details: While some population research has found that calcium taken in combination with vitamin D in older females is associated with a lower risk of death (97353), most evidence shows that calcium, with or without vitamin D, has no effect on all-cause mortality (93533,97308).

INEFFECTIVE

• Cardiovascular disease (CVD). Oral calcium does not reduce the risk of developing CVD and may actually increase risk in some patients. Details: Clinical research shows that calcium does not decrease CVD risk. Several separate meta-analyses of clinical and population research involving over 50,000 patients show that taking calcium 600-1200 mg daily for up to 7 years does not reduce the risk of CVD-related outcomes, including stroke and myocardial infarction, cardiovascular death, or overall mortality (39018,91350,92994,93533,97308,98902,107231,107233). No association was found between total dietary or supplemental calcium intake with or without vitamin D and the risk of CVD or mortality (91350,93533,97308). In fact, some population and clinical research has found that when calcium is used alone or with vitamin D, there is an INCREASED risk of CVD and coronary heart disease (38077,107233). However, other clinical research disagrees (93533). One meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years increases the risk of CVD and coronary heart disease by 1.1-1.2 times when compared with control. However, the majority of the included research evaluated postmenopausal females and it is unclear if this finding is applicable to other populations (107233).
• Chemotherapy-induced peripheral neuropathy. Intravenous calcium does not prevent nerve pain in patients given oxaliplatin. Oral calcium has not been evaluated for this purpose. Details: While pooled analyses of cohort studies and randomized controlled trials suggest that calcium and magnesium infusion decreases the incidence of oxaliplatin-induced neurotoxicity, a meta-analysis of only randomized controlled trials shows that the infusion has no effect in preventing neurotoxicity (90028,90029,90031). Additionally, clinical trials show that administering calcium gluconate 1 gram with magnesium sulfate 1 gram intravenously immediately before, or before and after, the administration of a single oxaliplatin cycle (90005), or over the entire 6-cycle course of oxaliplatin, does not improve symptoms of neurotoxicity when compared with placebo (96474).
• Myocardial infarction (MI). Oral calcium does not prevent MI. When taken in the absence of vitamin D, oral calcium may increase the risk of MI. Details: Population research has found that increased dietary intake of calcium is associated with a decreased risk of MI (91350). However, a 2010 meta-analysis of clinical research shows that taking calcium at a dose of at least 500 mg daily is associated with an approximate 30% INCREASE in the risk of MI in patients over the age of 40. According to this analysis, one additional case of MI will occur for every 69 patients that take calcium for 5 years (17482). A more recent meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years increases the risk of MI by 1.2 times when compared with control. However, the majority of the included research studied postmenopausal females and it is unclear if this finding is applicable to other populations (107233) In contrast, other meta-analyses of clinical research have shown that taking calcium for up to 7 years is NOT associated with an increased risk of MI, including a meta-analysis that only included postmenopausal females (93533,107231). Reasons for these discrepancies are not entirely clear. It may relate to whether calcium is taken as monotherapy or in combination with vitamin D. When taken with vitamin D, which is commonly recommended, calcium supplementation does not appear to be associated with an increased risk of MI in postmenopausal females (93533). Also, the association between calcium supplementation and MI risk may be influenced by the amount of calcium consumed as part of the diet. Supplementation with calcium may be associated with an increased risk of MI in people with dietary calcium intake above 805 mg daily, but not in those with dietary calcium intake below 805 mg daily (17482)

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Alcohol use disorder. It is unclear if oral calcium is beneficial for alcohol use disorder. Details: Preliminary clinical research shows that taking calcium carbonate 800 mg and vitamin D 200 IU orally daily for 14 days modestly reduces alcohol craving scores and withdrawal scores when compared with placebo in adults with alcohol dependence that are undergoing withdrawal. Taking calcium carbonate did not reduce the need for diazepam; however, the study may have been inadequately powered to detect a difference between groups (107234).
• Atherosclerosis. It is unclear if oral calcium is beneficial for atherosclerosis. Details: A population study has found that taking calcium 1.2 grams daily for 3 years has no effect on carotid intima thickness or carotid atherosclerosis incidence. A total calcium intake (dietary and supplemental) of at least 1794 mg daily in older females may be associated with a decreased risk of carotid atherosclerosis when compared with a total calcium intake below 1010 mg daily (97351).
• Autism spectrum disorder. It is unclear if oral calcium during pregnancy is beneficial for reducing the odds of autism spectrum disorder in the offspring. Details: A small observational study found that calcium supplementation during pregnancy is associated with a 52% reduced odds of an autism spectrum disorder in the offspring (98900).
• Cancer. Oral calcium alone does not seem to prevent cancer. It is unclear if oral calcium with vitamin D is beneficial for preventing cancer. Details: Taking calcium alone does not seem to significantly reduce the risk of cancer (12118,15629). The role of calcium in cancer prevention when taken along with vitamin D is controversial, as conflicting results exist. One clinical trial shows that healthy postmenopausal females who take supplemental calcium 1400-1500 mg daily plus vitamin D3 (cholecalciferol) 1100 IU daily have a 60% lower relative risk for developing cancer of any type. Approximately 25 postmenopausal females would need to take this combination for 4 years to prevent one occurrence of cancer (15629). However, a more recent clinical study shows that healthy postmenopausal females who take supplemental calcium 1500 mg daily plus vitamin D3 (cholecalciferol) 2000 IU daily do not have a reduced risk of cancer at 4 years (93943). Reasons for the disparate results are not entirely clear. The discrepancies do not appear to be related to baseline vitamin D levels or different study populations. It is possible that, given the 10-year time lapse between the two publications, the discrepancies result from differences in cancer detection capability. Also, since cancer risk was a secondary outcome measure in the earlier study and a primary outcome measure in the more recent study, it is possible that the discrepancies result from differences in statistical methodologies. The effect of vitamin D and calcium on cancer risk in males and younger patients is not known. There is also interest in using calcium for reducing the risk of hematological malignancies. An analysis of the Women's Health Initiative study shows that taking calcium 1000 mg daily in combination with vitamin D3 400 IU for up to 10 years is associated with a 20% reduction in the risk of hematologic malignancies when compared with placebo. However, no effect on hematologic malignancy related mortality was seen (97354).
• Depression. It is unclear if oral calcium is beneficial for depression prevention. Details: Population research has found no association between a higher dietary intake of calcium and the risk of depression when compared with a lower dietary intake of calcium (96480).
• Diabetes. It is unclear if oral calcium is beneficial for type 2 diabetes prevention. Details: Some population research has found that a higher intake of calcium from diet or supplements, alone or in combination with vitamin D, is associated with a lower risk of developing type 2 diabetes when compared with lower calcium intake (14265,16713,96473). However, population research is often limited by confounding variables. For example, one analysis found that any beneficial effect might be influenced by concomitant magnesium intake (96473). Furthermore, other population research has found that serum calcium levels higher than 9.6 mg/dL are associated with greater risk of developing diabetes in Chinese adults with osteoporosis. This study is limited because it was not determined whether increased serum calcium was due to increased calcium intake or another factor such as parathyroid function (95815).
• Dysmenorrhea. It is unclear if oral calcium is beneficial for reducing pain associated with dysmenorrhea. Details: Clinical research shows that taking calcium carbonate 1000 mg with vitamin D 5000 IU daily for three menstrual cycles does not reduce pain when compared with placebo in patients with primary dysmenorrhea (95821). However, calcium carbonate 1000 mg taken alone seems to reduce pain when compared with placebo.
• Endometrial cancer. It is unclear if oral calcium is beneficial for endometrial cancer prevention. Details: A meta-analysis of population research suggests that calcium supplements may reduce the risk of endometrial cancer, but dietary calcium does not seem to have any effect (38893).
• Fall prevention. It is unclear if oral calcium with vitamin D is beneficial for preventing falls. Details: Research suggests that calcium in combination with vitamin D, but not calcium alone, might prevent falls by decreasing body sway and normalizing systolic blood pressure (6362,11939,39038). Some experts think the combination of calcium and vitamin D may be important (11916). Preliminary clinical research in adults residing in a health care facility shows that taking vitamin D supplements while increasing dietary calcium and protein for 2 years reduces falls by 11% when compared with standard diets. Intervention diets were supplemented with milk, yogurt, and cheese to provide calcium 1142 mg and protein 69 grams daily (107235). There might also be different effects in females compared to males. In one study, females aged 65 years or older who took vitamin D 700 IU plus calcium citrate 500 mg daily over a 3-year period had a 46% lower risk of falling. However, this combination did not decrease falls in males (14291).
• Fluorosis. Oral calcium has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: Taking calcium orally, in combination with ascorbic acid (vitamin C) and vitamin D, seems to be effective for reducing excessive fluoride levels in children and improving symptoms of fluorosis in children aged 6-12 years (990).
• Heart failure. It is unclear if oral calcium in combination with vitamin D is beneficial for preventing heart failure. Details: Based on a secondary analysis of a large-scale clinical trial (Women's Health Initiative), taking calcium 1000 mg with vitamin D 400 IU daily does not reduce the risk of heart failure in the overall population or in individuals at high risk. However, in a subgroup of postmenopausal females without risk factors for heart failure, calcium and vitamin D supplementation might reduce the risk of developing heart failure by about 37% (97307).
• Hypercholesterolemia. It is unclear if oral calcium is beneficial for hypercholesterolemia. Details: Some evidence shows that taking calcium carbonate 400 mg three times daily reduces low-density lipoprotein (LDL) cholesterol levels by 4% and increases high-density lipoprotein (HDL) cholesterol levels by 4% after 6 weeks of treatment when used in combination with a low-fat diet (American Heart Association Step 1) (2557). In contrast, a study in females with dyslipidemia shows that taking calcium 800 mg daily for 2 years might INCREASE total cholesterol levels by about 12 mg/dL when compared with placebo. This same study showed an association between calcium supplementation and an increase in total cholesterol levels and carotid intimal thickness in postmenopausal females, but not premenopausal females (97350). A recent meta-analysis of randomized controlled trials which included both healthy patients and patients with dyslipidemia shows that taking calcium 500-2000 mg daily and vitamin D 200-7142 IU daily modestly improves HDL cholesterol and triglyceride levels, but not LDL cholesterol levels, when compared with placebo. Subgroup analyses suggest that calcium and vitamin D supplementation is more effective in patients with dyslipidemia at baseline. It is unclear if this effect is due to calcium, vitamin D, or the combination (107227). However, other research shows that taking a specific supplement containing calcium 600 mg plus vitamin D 200 IU (Caltrate 600 D, Wyeth Consumer Healthcare Inc.) twice daily in combination with calorie restriction does not reduce total or LDL cholesterol levels when compared with placebo (15601).
• Lead toxicity. It is unclear if oral calcium is beneficial for reducing blood levels of lead. Details: Lead is mobilized along with calcium from bone during pregnancy and lactation, resulting in increased serum concentrations of lead. One clinical study suggests that calcium supplementation does not significantly decrease these elevated lead concentrations (1586). However, another clinical study suggests that taking calcium reduces blood lead levels by 11% when compared with placebo, with greatest effects observed in those with high baseline levels of lead (38957).
• Lyme disease. Although there is interest in using oral calcium for Lyme disease, there is insufficient reliable information about the clinical effects of calcium for this condition.
• Metabolic syndrome. It is unclear if oral calcium alone or with vitamin D is beneficial for metabolic syndrome prevention. Details: Population research has found that a higher intake of calcium from diet and supplements alone, or in combination with vitamin D, is associated with a lower risk of developing metabolic syndrome when compared with lower calcium intake (14265,16713).
• Nephrotic syndrome. It is unclear if oral calcium with vitamin D is beneficial for preventing nephrotic syndrome. Details: Clinical research shows that taking calcium 500-1000 mg daily for 3 months in combination with vitamin D3 60,000 IU daily or weekly for 4 weeks has no effect on bone mineral density or the risk of relapse in children with steroid-sensitive nephrotic syndrome (97355).
• Nonmelanoma skin cancer. It is unclear if oral calcium is beneficial for preventing keratinocyte carcinomas. Details: In middle aged and older adults recently diagnosed with a colorectal adenoma, clinical research shows that taking calcium 1200 mg daily as calcium carbonate for 3-5 years does not reduce the incidence of keratinocyte cancer when compared with placebo over a median of 8 years. A sub-group analysis shows that taking calcium alone or with vitamin D3 1000 IU daily reduced the risk of invasive cutaneous squamous cell carcinoma by a moderate amount, but had no effect on the risk of basal cell carcinoma (104622).
• Oral mucositis. When used in combination with fluoride treatments, a calcium phosphate mouth rinse seems to prevent and reduce mucositis-related pain in patients undergoing hematopoietic stem cell transplantation (HSCT). Details: A small clinical study in patients undergoing HSCT shows that using a particular mouth rinse (Caphosol, EUSA Pharma) containing calcium phosphate, in combination with fluoride treatments, reduces days of mucositis, the duration of pain, and the dose and days of morphine used when compared with placebo and fluoride treatment (38611).
• Ovarian cancer. It is unclear if oral calcium is beneficial for ovarian cancer prevention. Details: An older meta-analysis of 12 cohort studies found that dietary calcium intake is not associated with a reduced risk of ovarian cancer (38792). However, a more recent pooled analysis of 15 cohort and case-control studies has found that the highest intake of dietary or dairy calcium is associated with a 20% lower risk of ovarian cancer when compared to the lowest intake (97349).
• Postpartum depression. It is unclear if oral calcium is beneficial for reducing postpartum depression risk. Details: Preliminary clinical research shows that taking calcium 2 grams daily beginning at 11-21 weeks gestation reduces depression at 12 weeks postpartum when compared with placebo. However, no benefit is seen at 6 weeks postpartum (39447).
• Pregnancy-related leg cramps. It is unclear if oral calcium is beneficial for preventing leg cramps during pregnancy. Details: A small clinical study shows that taking calcium 1 gram twice daily (as a mixture of salts) for 2 weeks can reduce pregnancy-related leg cramps during the second half of pregnancy when compared with no treatment (2567).
• Prostate cancer. It is unclear if oral calcium is beneficial for prostate cancer prevention. Details: Some clinical research shows that taking calcium 1200 mg daily might decrease the risk of developing prostate cancer (14133). However, some epidemiological research suggests that consuming very high doses of calcium, over 2000 mg daily, might actually increase the risk of developing prostate cancer (14134). Some epidemiological research also suggests that doses greater than 1500 mg daily increase the risk of poorly differentiated, clinically advanced, and fatal prostate cancer (14132). Consumption of dairy products has also been weakly linked to a modest increase in risk of prostate cancer (98894). However, contradictory research suggests that there is no association between dietary intake of calcium and overall risk of prostate cancer (14131,14132,104630).
• Stroke. It is unclear if oral calcium is beneficial for stroke prevention. Details: Some population research has found that increasing dietary calcium intake is associated with a decreased risk of ischemic stroke (4822,38678). However, other population research has found that increasing dietary calcium intake is not associated with a decreased risk of stroke (91350). One meta-analysis of high-quality randomized controlled trials shows that taking calcium for 2-7 years does not affect the risk of stroke when compared with control. However, the majority of the included research evaluated postmenopausal females, and it is unclear if this finding is applicable to other populations (107233).
• Vertigo. Oral calcium with vitamin D might reduce positional vertigo; the effect of calcium when used alone is unclear. Details: A large clinical study in adults with recurrent benign paroxysmal positional vertigo shows that taking calcium 500 mg and vitamin D 400 IU twice daily for one year reduces annual recurrence of vertigo by 27% when compared with no treatment. The number needed to treat to prevent vertigo was 3.7 (103681). It is unclear if this benefit is due to vitamin D, calcium, or the combination. More evidence is needed to rate calcium for these uses.

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POSSIBLY EFFECTIVE

• Asthma. Oral maritime pine bark extract, taken as an adjunct to conventional asthma medications, may improve symptoms and reduce rescue inhaler use in patients with asthma. Details: Three small clinical studies in children and adults with asthma of varying severity show that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 1 mg/lb body weight or 100 mg daily in addition to conventional asthma medications increases peak expiratory flow, decreases asthma symptoms, and decreases the need for rescue medications when compared with conventional therapy alone (13120,50863,50926). Maritime pine bark extract has not been studied as monotherapy for asthma and should not be used in place of conventional medicine for this purpose.
• Chronic venous insufficiency (CVI). Oral maritime pine bark extract may improve leg pain and heaviness and reduce edema in patients with CVI. Details: Several clinical studies in patients with CVI show that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) reduces edema, the rate of ankle swelling, and symptoms of leg pain and heaviness when used for 3-12 weeks. The most commonly used dose is 100-120 mg three times daily (2451,2462,2493,7693,50892). However, lower doses of 50 mg three times daily (16906,50892,50900,50915) or 45-100 mg once daily also seem to be effective (2435,97401). When compared with the use of below-knee compression stockings worn throughout the day, maritime pine bark reduces induration and the rate of ankle swelling when compared to baseline in patients with CVI. While both treatments reduce venous edema and pain when compared with baseline, a more pronounced reduction is seen in patients taking the maritime pine bark extract (97401). Other clinical research in adults who have had CVI for more than 3 years shows that taking the same extract, 50 mg three times daily for 8 weeks, in addition to wearing compression stockings, improves microcirculation and subjective symptom scores when compared with compression stockings alone (103616). However, compliance with the use of compression stockings in this study was poor.
• Osteoarthritis. Small clinical studies suggest that oral maritime pine bark extract may modestly improve symptoms and reduce the need for analgesics in patients with knee osteoarthritis. Details: Two small clinical studies in patients with knee osteoarthritis shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 100-150 mg daily for 3 months reduces overall osteoarthritis symptoms, pain, and the use of anti-inflammatory medication when compared with placebo (50903,50905). Topical maritime pine bark has also been evaluated. Observational research in patients with knee osteoarthritis found that applying standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 220 mg, as two patches daily, for three weeks is associated with reduced pain and reduced need for rescue analgesics when compared with control (100356).

POSSIBLY INEFFECTIVE

• Hyperlipidemia. Oral maritime pine bark extract may not improve lipid levels in patients with hyperlipidemia. Details: Although individual clinical trials have shown mixed results (7693,91965,97408), a meta-analysis of 4 small clinical trials in patients with hyperlipidemia shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 100-150 mg daily for 4-24 weeks does not reduce total cholesterol, low-density lipoprotein (LDL) cholesterol, or triglyceride levels when compared with a control (100357).

INSUFFICIENT RELIABLE EVIDENCE to RATE

• Age-related cognitive decline. It is unclear if oral maritime pine bark extract is beneficial in elderly patients with age-related cognitive decline. Details: One observational registry study in healthy elderly patients ages 55-70 years has found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 100 mg daily for 12 months is associated with improved cognitive function, mental performance, and attention when compared with matched controls (97405). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study. Also, a small clinical study in healthy elderly patients 60-85 years of age shows that taking the same extract, 150 mg daily for 3 months, improves spatial working memory, but not numeric working memory, episodic memory, attention, or psychomotor performance, when compared with placebo (50906).
• Aging skin. Although there has been interest in using oral and topical maritime pine for aging skin, there is insufficient reliable information about the clinical effects of maritime pine for this purpose.
• Allergic rhinitis (hay fever). It is unclear if oral maritime pine bark extract is beneficial in people with allergic rhinitis. Details: A small clinical study in patients with birch allergies shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50 mg twice daily, starting at least 5 weeks before allergy season, decreases nasal symptoms associated with birch allergies when compared with placebo (17300).
• Androgenic alopecia. It is unclear if oral maritime pine bark is beneficial for androgenic alopecia. Details: A small clinical study in postmenopausal patients conducted in China shows that taking maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily for 6 months improves hair density when compared to baseline (112713). However, the interpretation of these findings is limited by the lack of a statistical comparison to the placebo group.
• Antidepressant-induced sexual dysfunction. It is unclear if oral maritime pine bark is beneficial for improving sexual function in adults taking escitalopram. Details: A small, open-label clinical study shows that taking standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50 mg daily for 4 months with escitalopram 10-20 mg daily seems to improve sexual dysfunction when compared with escitalopram alone (100361).
• Atherosclerosis. Oral maritime pine bark extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A non-randomized clinical trial in adults with atherosclerosis shows that taking a specific maritime pine bark product (Pycnogenol, Horphag Research) 150 mg and gotu kola 225 mg, in two divided doses daily for 3 months, reduces plaque height and length and increases plaque echogenicity and stability when compared to control (97030). However, these benefits may be at least partially due to gotu kola. Another non-randomized clinical study in adults with atherosclerotic plaques and no other cardiovascular risk factors shows that taking Pycnogenol 100 mg and gotu kola extract 100 mg daily for up to 4 years reduces plaque progression and increases plaque echogenicity to a greater extent than Pycnogenol alone or no treatment at all. Taking Pycnogenol with gotu kola is also associated with a reduced rate of clinical vascular events, including angina, myocardial infarction, minor transient ischemic attacks (TIAs), and minor strokes, when compared with taking Pycnogenol alone or receiving no treatment at all (97029).
• Athletic performance. It is unclear if oral maritime pine bark extract is beneficial for improving exercise capacity in recreationally trained adults; the available evidence is conflicting. Details: One small clinical study shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 200 mg orally daily for 30 days improves exercise capacity during a treadmill test in recreational athletes aged 20-35 years (2554). Additionally, an observational registry study found that taking this same maritime pine bark extract 100 mg orally daily for 8 weeks along with training improves performance in the Army Physical Fitness Test, including reducing two-mile treadmill time by about 45-60 seconds and increasing the number of push-ups and sit-ups by about 5-7 when compared to control training alone. Taking this maritime pine bark extract during training also appears to improve total triathlon time by about 6 minutes when compared with training alone (91966). However, the validity of this finding is limited by the unblinded, non-randomized nature of the study. Additionally, a small study in college-age males who exercise regularly shows that taking the same maritime pine bark extract 800 mg daily, starting 14 days prior to a cycle ergometer test and continuing for 2 days after, does not improve maximum oxygen consumption or power generated in the test when compared with placebo (103617). Maritime pine extract has also been studied in combination with other ingredients. A small clinical study in non-professional athletes shows that taking a combination product (PycnoRacer, Kobayashi Pharmaceutical Company) containing maritime pine extract 15 mg, L-leucine 0.6 grams, L-arginine 0.3 grams, L-isoleucine 0.3 grams, and L-valine 0.3 grams four times daily for 3 weeks during training improves running distance by about 19%, compared with 9% in athletes drinking water plus Gatorade. Maritime pine park also improved maximal oxygen consumption and reduced subjective scores of muscle pain and cramps when compared with water and Gatorade (103613). It is unclear if these benefits are due to maritime pine, other ingredients, or the combination.
• Attention deficit-hyperactivity disorder (ADHD). It is unclear if oral maritime pine bark extract is beneficial in children or adults with ADHD. Details: A small clinical study in adults with ADHD shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) does not seem to improve ADHD symptoms when compared with placebo (9984). However, a small clinical study in children with ADHD shows that taking this standardized maritime pine bark extract 1 mg/kg daily for one month appears to improve attention and hyperactivity scores when compared with placebo (50891).
• Behcet syndrome. It is unclear if oral maritime pine bark extract is beneficial in patients with Behcet syndrome. Details: A small clinical study in patients with Behcet syndrome shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily for 3 weeks reduces skin ulcer size and improves self-reported symptoms of burning and pain when compared to baseline (100358). The validity of these findings is limited by the lack of a comparator group.
• Benign prostatic hyperplasia (BPH). It is unclear if oral maritime pine bark extract is beneficial in patients with BPH. Details: A small observational registry study in patients with BPH found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily for 8 weeks is associated with modest improvement of symptoms such as bladder emptying, urgency, flow, straining, and nocturia (100359). This study was limited by small size, reporting inaccuracies, and its unblinded, non-randomized design.
• Cognitive function. Small clinical studies suggest that oral maritime pine bark extract might improve cognitive function in healthy adults. Details: A small observational registry study in healthy adults aged 30-55 years found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily for 12 weeks is associated with slightly improved memory and cognition when compared with matched controls (97410). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study. A small clinical study in healthy college students also shows that taking the same extract 100 mg daily for 2 months seems to reduce failed tests by 4.5% and improve average test scores by about 8% when compared with control (50928).
• Cognitive impairment. It is unclear if oral maritime pine bark extract improves cognitive function in patients with mild cognitive impairment. Details: An observational registry study in adults with mild cognitive impairment found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily for 8 weeks improves global cognitive function when compared to no supplementation. All patients in this study also received standard management of mild cognitive impairment, which included lifestyle modifications such as improved sleep, physical exercise, reduced sugar and salt intake, lowering cardiovascular risk factors, and avoiding use of stimulants or depressants (97406). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study.
• Common cold. It is unclear if oral maritime pine bark extract is beneficial in the treatment of the common cold. Details: An observational registry study in otherwise healthy adults with a cold found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50 mg twice daily, along with best management for colds, is associated with about one less day of a perceived cold when compared to "best management" alone. This standardized maritime pine bark extract is also linked to reduced use of over-the-counter products to manage symptoms in cases of colds lasting longer than 4 days (91962). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study.
• Dental plaque. It is unclear if chewing gum containing maritime pine bark extract can reduce dental plaque. Details: A small clinical study shows that chewing a minimum of six pieces of gum containing a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 5 mg daily for 14 days reduces gingival bleeding by 55% and prevents an increase in gingival plaque when compared with a control sugar-free gum (50857).
• Diabetes. Small clinical studies suggest that oral maritime pine bark extract may modestly improve glycemic control in patients with type 2 diabetes. Details: Three small clinical studies in patients with type 2 diabetes show that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50-200 mg daily for 3-12 weeks modestly decreases blood glucose and glycated hemoglobin (HbA1C) levels when compared with placebo (15521,15522,50908). Another small clinical trial in patients with type 2 diabetes and microalbuminuria shows that taking a different standardized maritime pine bark extract (Oligopin, DRT Group) 100 mg daily for 8 weeks reduces HbA1c by around 1%, but does not reduce fasting blood glucose, when compared with placebo (105781).
• Diabetic foot ulcers. It is unclear if oral or topical maritime pine bark extract is beneficial for diabetic foot ulcers. Details: A small clinical study in patients with diabetic foot ulcers shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily orally as well as applying the extract topically 100 mg daily heals ulcers in 89% of subjects compared with 61% of control subjects. Using oral or topical maritime pine bark extract alone seems to result in complete ulcer healing in about 85% of subjects (50896).
• Diabetic microangiopathy. It is unclear if oral maritime pine bark extract is beneficial in patients with diabetic microangiopathy. Details: A small, unblinded clinical study in patients with diabetic microangiopathy, symptoms of neuropathy, and edema in the absence of severe cardiovascular disease shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50 mg three times daily for 4 weeks improves microcirculation (measured by laser Doppler flowmetry) and symptoms when compared with no treatment (15523).
• Diabetic retinopathy. It is unclear if oral maritime pine bark extract is beneficial in patients with diabetic retinopathy. Details: A small, unblinded clinical study in patients with retinopathy due to various causes, including diabetes, atherosclerosis, or central venous thrombosis, shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50 mg three times daily for 2 months may slow or prevent further deterioration of retinal function when compared with no treatment (2536).
• Dry mouth. It is unclear if oral maritime pine bark extract is beneficial in patients with dry mouth. Details: Two small observational studies in otherwise healthy adults or patients with diabetes suggest that adding a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) for 2 weeks along with standard saliva supplements is associated with improvement in patient-reported mouth dryness, salivary flow, and the number of small mucosal breaks when compared with saliva supplements alone. One study dosed maritime pine bark extract 150 mg orally daily and the other used a spray formulation dosed 10 mg six times daily (103612,112714). However, the validity of these findings is limited by the unblinded, non-randomized nature of the studies.
• Dysmenorrhea. It is unclear if oral maritime pine bark extract is beneficial in patients with dysmenorrhea. Details: Two small clinical studies in patients with dysmenorrhea show that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 30-60 daily for up to 3 menstrual cycles reduces pain when compared to baseline (15424,50904). The validity of this finding is limited by the lack of a comparator group.
• Erectile dysfunction (ED). Small clinical studies suggest that oral maritime pine bark extract, taken alone or in combination with L-arginine, may modestly improve sexual function in patients with ED. Details: Several small clinical studies in adults with ED show that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) at a dose of 120 mg daily for 3 months, either alone (12012) or in combination with L-arginine (10416,32149,50924), might improve sexual function when compared with placebo or baseline measurements. It seems to take up to 3 months of treatment for significant improvement. Similarly, a meta-analysis of 2 small clinical studies in males with mild to moderate ED shows that taking maritime pine 80 mg with L- arginine daily for 1-6 months improves International Index of Erectile Dysfunction scores by 9 points when compared with control (112715). It is unclear if this effect is from maritime pine, L-arginine, or the combination.
• Exercise-induced muscle soreness. Oral maritime pine bark extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in non-professional athletes shows that taking a combination product (PycnoRacer, Kobayashi Pharmaceutical Company) containing maritime pine extract 15 mg, L-leucine 0.6 grams, L-arginine 0.3 grams, L-isoleucine 0.3 grams, and L-valine 0.3 grams four times daily for 3 weeks during training improves subjective scores for muscle pain and cramps when compared with water plus Gatorade (103613). It is unclear if these benefits are due to maritime pine, other ingredients, or the combination.
• Glaucoma. Oral maritime pine has only been evaluated in combination with other ingredients; its effects when used alone is unclear. Details: One small, unblinded clinical trial in Japanese patients with open-angle glaucoma shows that taking a specific product (Sante Glagenox, Saten Pharmaceutical Co. Ltd.) containing maritime pine extract 40 mg and bilberry fruit extract 90 mg daily for 4 weeks reduces intraocular pressure by 8.7% when compared to baseline (104192). The validity of this finding is limited by the lack of a comparator group.
• Heart failure. Oral maritime pine bark extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small observational study in patients with mild to moderate heart failure has found that taking a specific combination product (PycnoQ10, Natural Health Science Inc.) containing a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) and coenzyme Q10 for 12 weeks is associated with improved exercise capacity and heart function (44178). It is unclear if these findings are due to maritime pine, coenzyme Q10, or the combination.
• Hemorrhoids. It is unclear if oral or topical maritime pine bark extract is beneficial in patients with hemorrhoids. Details: A small clinical study in patients with acute hemorrhoidal episodes shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150-300 mg daily orally, alone or in combination with a cream containing 0.5% standardized maritime pine bark extract (Pycnogenol, Horphag Research) for 7 days, improves both quality of life and hemorrhoidal symptoms when compared with placebo tablets/cream (50912). Additionally, an observational registry study in postpartum adults with internal or external hemorrhoids found that taking this same extract of maritime pine bark 150 mg daily for 6 months, in conjunction with standard hemorrhoid care, is associated with improved symptoms, including thrombosis, pain, swelling, and bleeding, when compared to standard care alone (97416). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study.
• Hypertension. It is unclear if oral maritime pine bark reduces blood pressure; the available research is conflicting. Details: A very small clinical study in patients with mild hypertension (systolic 140-159 mm Hg; diastolic 90-99 mm Hg) shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 200 mg daily for 8 weeks may modestly reduce systolic, but not diastolic, blood pressure when compared with placebo (10214). Another very small study in hypertensive patients treated with ramipril, taking this same standardized maritime pine bark extract 50 mg three times daily for 6 months, appears to further reduce diastolic, but not systolic, blood pressure (50913). Conflicting results have been reported with other maritime pine products. A small clinical study in adults with untreated, mild hypertension shows that taking a different standardized extract of maritime pine (Oligopin, DRT Group), 75 mg twice daily for 5 weeks, does not lower systolic or diastolic blood pressure when compared with placebo (97407). Also, a small clinical study in obese patients with prehypertension or hypertension shows that taking a different maritime pine bark extract (Toyo-FVG, Toyo Bio-Pharma) 200 mg daily for 12 weeks does not lower systolic or diastolic blood pressure when compared with placebo (50919). Results of meta-analyses are also contradictory. An analysis of 7 clinical trials using maritime pine bark extract 90-200 mg daily for 2-24 weeks shows no significant effect overall on systolic or diastolic blood pressure, mean arterial pressure, or pulse pressure (103609). However, an analysis of 12 trials using doses of 60-200 mg daily for 4-24 weeks shows a mean reduction of about 3 mmHg in systolic blood pressure, and about 2 mmHg in diastolic blood pressure. There was high heterogeneity between the studies, and the effect on diastolic blood pressure was only seen with a treatment duration of at least 12 weeks (103610).
• Idiopathic interstitial pneumonia. Oral maritime pine bark extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small observational registry study in males less than 65 years old with idiopathic interstitial pneumonia has found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50 mg three times daily in combination with gotu kola (Centellicum; Horphag Research) 225 mg three times daily for 8 months is associated with a modest improvement in Karnofsky Performance Scale scores and a reduction in fatigue when compared with pirfenidone (108862). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study.
• Irritable bowel syndrome (IBS). It is unclear if oral maritime pine bark extract is beneficial in patients with IBS. Details: An observational registry study in adults with idiopathic IBS found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily for 4 weeks, in conjunction with standard treatment, is associated with reduced abdominal pain, cramps, and the use of medical care and rescue medications when compared to standard treatment alone. In both groups, standard treatment included specific nutritional recommendations and Buscopan Compositum, hyoscine-N-butylbromide, or acetaminophen for pain relief (97402). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study.
• Jet lag. It is unclear if oral maritime pine bark extract can prevent or treat jet leg. Details: An observational registry study found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily for up to 10 days, starting 3 days before a plane flight, is associated with reduced signs and symptoms of jet lag when compared to control (97437). Additionally, a small clinical study shows that taking this extract 50 mg three times daily for 7 days, starting 2 days before a plane flight, reduces jet lag symptoms and the average duration of symptoms by a little over 1 day when compared with placebo (97412).
• Leg cramps. It is unclear if oral maritime pine bark extract is beneficial for leg cramps. Details: A small clinical study in patients experiencing at least 4 episodes of leg cramps per week associated with athletic activity, venous insufficiency, or an unknown cause shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 200 mg daily for 4 weeks may decrease the incidence of leg cramps when compared to baseline (15524). The validity of this finding is limited by the lack of a comparator group.
• Male infertility. Although there has been interest in using oral maritime pine for male infertility, there is insufficient reliable information about the clinical effects of maritime pine for this purpose.
• Melasma. It is unclear if oral maritime pine bark extract is beneficial for melasma. Details: A small clinical study in females with melasma shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 75 mg twice daily for 60 days, along with topical application of sunscreen during the day and a triple cream containing hydroquinone, tretinoin, and fluocinolone at night, improves scores related to melasma severity and aesthetics, but not quality of life, when compared with placebo plus sunscreen and triple cream (105782).
• Meniere disease. It is unclear if oral maritime pine bark extract is beneficial in patients with Meniere disease. Details: Observational registry research in patients with Meniere disease found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily along with standard treatment is associated with a greater reduction in the severity of tinnitus and the number of work-days lost when compared with standard treatment alone. After 6 months of treatment, about 87% of patients taking maritime pine bark were asymptomatic, compared to about 35% of patients receiving standard treatment alone (97413). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study.
• Menopausal symptoms. Small clinical studies suggest that oral maritime pine bark extract might improve some menopausal symptoms. Details: Several small clinical studies in patients with menopausal symptoms shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 60-200 mg daily for 2-6 months modestly reduces perimenopausal symptoms, including tiredness, headache, depression and anxiety, sleep disturbances, vaginal dryness, hot flashes, and loss of memory, when compared with placebo or control (14899,50927,50945).
• Metabolic syndrome. It is unclear if oral maritime pine bark extract is beneficial in patients with metabolic syndrome. Details: A small clinical study in patients with metabolic syndrome shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50 mg three times daily for 6 months lowers triglyceride levels by 46 mg/dL, increases high-density lipoprotein (HDL) cholesterol levels by about 10 mg/dL, reduces fasting plasma glucose by 18 mg/dL, and lowers systolic and diastolic blood pressure by 7 mmHg and 5 mmHg, respectively, when compared to baseline. The validity of these findings is limited by the lack of statistical comparison to a control group. Taking the maritime pine bark extract was also associated with a reduction in the percentage of patients presenting with five risk factors of metabolic syndrome (91960).
• Oral mucositis. It is unclear if topical maritime pine bark extract is beneficial in children with chemotherapy-related oral mucositis. Details: A small clinical study in children 6-15 years of age with chemotherapy-related oral mucositis shows that application of a solution containing a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 1 mg/kg in three divided doses daily for one week promotes complete healing in 58% of patients and improved healing in 38% of patients. This improvement was significantly greater than treatment with glycerine solution and similar to treatment with vitamin E solution (91964).
• Osteopenia. It is unclear if maritime pine bark extract is beneficial in patients with osteopenia. Details: A small clinical study in postmenopausal adults with osteopenia shows that taking a standardized extract of maritime pine bark (Oligopin, DRT Group) 150 mg daily for 12 weeks improves markers of bone turnover when compared with placebo (105783). It is unknown if maritime pine bark extract improves bone mineral density or reduces the risk of fractures in patients with osteopenia.
• Parkinson disease. It is unclear if oral maritime pine bark extract is beneficial in patients with Parkinson disease. Details: Two small observational studies in adults with mild to moderate Parkinson disease suggest that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily for 4 or 8 weeks in conjunction with carbidopa/levodopa therapy is associated with a reduction in scores for tremor, bradykinesia, and rigidity when compared with carbidopa/levodopa therapy alone. Maritime pine is also associated with an increase in the Karnofsky Performance Status Scale score from approximately 75 (cares for self, unable to carry on normal activity or do active work) to approximately 85 (normal activity with effort, some signs or symptoms of disease), compared with little to no change from a score of around 75 in the control group (103614,112716).
• Pregnancy-related pain. It is unclear if oral maritime pine bark extract is beneficial for reducing pain during the third trimester of pregnancy. Details: A small clinical study in patients in the third trimester of pregnancy shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 30 mg daily modestly reduces lower back pain, hip joint pain, pelvic pain, and pain due to varicose veins or calf cramps when compared with a control group (15423).
• Psoriasis. It is unclear if oral maritime pine bark extract is beneficial in patients with psoriasis. Details: An observational registry study in adults with moderate to severe plaque psoriasis found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily for 12 weeks along with standard treatment is associated with improved quality of life, increased water and moisture content of the skin, reduced plaque severity and total affected body area, and reduced use of corticosteroids when compared with standard treatment alone (97417). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study.
• Raynaud syndrome. It is unclear if oral maritime pine bark extract is beneficial in patients with Raynaud syndrome. Details: A small clinical study in females with mild, primary Raynaud syndrome shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50 mg twice daily for 4 weeks decreases coldness, burning pain, paresthesias, skin color changes, and low temperature areas of the hands when compared with lifestyle changes alone. The lowest finger temperature increased by 30% in those taking this product, compared with 13% in those implementing lifestyle changes alone (103615).
• Restless legs syndrome (RLS). It is unclear if oral maritime pine is beneficial for RLS. Details: A small observational study in adults with RLS suggests that taking maritime pine bark extract (Pycnogenol, Horphag Research) 150 mg daily along with standard management (i.e., regular sleep, exercise, vitamin C, B vitamins, proper footwear, and instruction on diet and posture) improves self-reported symptoms associated with RLS when compared to baseline. Maritime pine bark may also be associated with less analgesic use compared with standard management alone (112717). However, the interpretation of these findings, other than analgesic use, is limited by lack of a statistical comparison to the other study group.
• Sarcopenia. It is unclear if oral maritime pine bark extract is beneficial in patients with sarcopenia. Details: Observational registry research in adults over 70 years of age with signs of muscle loss has found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily along with strength training for 2 months improves hand grip strength, walking distance, total weight lifted, number of steps climbed, and general fitness scores when compared with strength training alone (97404). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study.
• Sexual dysfunction. Oral maritime pine bark extract has only been evaluated in combination with other ingredients; its effect when used alone is unclear. Details: A small clinical study in females with sexual dysfunction shows that taking a specific combination tablet (Lady Prelox, Horphag Research) containing a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 20 mg, L-arginine 200 mg, L-citrulline 200 mg, and a standardized rose hip extract (Rosvita) orally 50 mg daily for 8 weeks, in combination with a management program consisting of lifestyle, diet, exercise, and stress control changes, improves overall sexual function when compared with the management program alone (91963). Taking the same product in a dose of 2 tablets twice daily for 8 weeks, in addition to the lifestyle management program, improves vaginal dryness in pre- and post-menopausal patients when compared with lifestyle management alone (103611). The effect of maritime pine alone on sexual dysfunction is unclear.
• Sjogren syndrome. It is unclear if oral maritime pine bark extract is beneficial in patients with Sjogren syndrome. Details: A very small observational study in patients with Sjogren syndrome found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily in addition to standard therapy is associated with a reduction in dry eye, dry mouth, and the need for corticosteroids when compared with standard therapy alone (100360).
• Systemic lupus erythematosus (SLE). It is unclear if oral maritime pine bark extract is beneficial in patients with SLE. Details: A very small clinical study in adults with SLE shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 120 mg daily for 30 days, followed by 60 mg daily for 30 days, modestly reduces symptoms of SLE in some patients when compared with control (50851).
• Traumatic brain injury (TBI). It is unclear if oral maritime pine bark extract is beneficial in patients with TBI. Details: A clinical study in patients admitted to the intensive care unit with TBI shows that administering a standardized maritime pine bark extract (Oligopin, DRT Group) 50 mg three times daily with enteral nutrition for 10 days improves scores on the sequential organ failure assessment (SOFA) and APACHE II [Acute Physiology and Chronic Health Evaluation II], as well as nutritional status, when compared with placebo. At day 28, survival rate was 86% in the treatment group, compared to 71% in the placebo group; however, this difference was not statistically significant (108861).
• Urinary tract infections (UTIs). It is unclear if oral maritime pine bark extract is beneficial in patients with recurrent UTIs or interstitial cystitis. Details: An observational registry study in adults aged 30-40 years with a recent history of recurrent UTIs has found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily for 2 months is associated with a normal urinalysis in 92% of patients, compared with 68% of those who received no supplementation (108860). Another observational registry study in patients with recurrent UTIs or interstitial cystitis has found that taking this same dose for 2 months is associated with a normal urinalysis in 100% of patients, compared with 35% of patients who took oral cranberry extract 400 mg daily and 36% of those who received no treatment (108859). However, the validity of these findings is limited by the unblinded, non-randomized nature of these studies.
• Varicose veins. It is unclear if oral maritime pine bark extract is beneficial in patients with varicose veins. Details: Observational registry research in postpartum adults has found that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50 mg daily for 6 months, in addition to using below-knee compression stockings, is associated with reduced edema, leg cramps, total number of varicose veins, and number of visible spider vein clusters when compared with compression stockings alone (97403). However, the validity of these findings is limited by the unblinded, non-randomized nature of the study.
• Venous thromboembolism (VTE). While some conflicting evidence exists, low-quality clinical research suggests that oral maritime pine bark extract might prevent superficial thrombosis during flights and reduce the incidence of post-thrombotic syndrome (PTS) in patients with a history of deep vein thrombosis (DVT). Details: Observational registry research has found that a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 150 mg daily for 10 days is not associated with reduced occurrence of DVT, a type of VTE, when compared with compression stockings or control (97437). However, an older clinical study in patients at moderate or high risk for thrombotic events shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 200 mg 2-3 hours before a flight seems to reduce superficial thrombosis, but not DVT risk, when compared with placebo (50874). Some observational research also has also found that taking standardized maritime pine bark extract (Pycnogenol, Horphag Research) is associated with reduced post-thrombotic syndrome (PTS) and recurrent DVT (100355). Also, some clinical research shows that taking standardized extract of maritime pine bark (Pycnogenol, Horphag Research) daily for one year, while wearing or not wearing compression stockings, reduces the incidence of PTS in patients with a single prior episode of DVT (50925). Maritime bark has also been studied in combination with other natural products. There is some evidence that taking a specific combination product (Flite Tabs, Aidan Products) before a flight and then again 6 hours later might decrease the risk of DVT during long-haul plane flights in high-risk patients. The product combines a blend of 150 mg of standardized extract of maritime pine bark (Pycnogenol, Horphag Research) plus nattokinase (12075).
• Wrinkled skin. It is unclear if oral maritime pine bark extract can reduce wrinkles or improve skin health in people with significant sun exposure. Details: A small crossover study in Chinese adults working outdoors shows that taking a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 50 mg twice daily for 12 weeks improves skin hydration and reduces transepidermal water loss and skin darkening when compared with placebo (105784). More evidence is needed to rate maritime pine for these uses.

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LIKELY SAFE ...when used orally or intravenously and appropriately. Calcium is safe when used in appropriate doses (7555,12928,12946,95817). However, excessive doses should be avoided. The Institute of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: Age 0-6 months, 1000 mg; 6-12 months, 1500 mg; 1-8 years, 2500 mg; 9-18 years, 3000 mg; 19-50 years, 2500 mg; 51+ years, 2000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stone, hypercalciuria, hypercalcemia, and milk-alkali syndrome. There has also been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these studies, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Many of these trials also only included postmenopausal females. Other analyses report conflicting results, and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Advise patients not to consume more than the recommended daily intake of 1000-1200 mg per day and to consider total calcium intake from both dietary and supplemental sources (17484). Also, advise patients taking calcium supplements to take calcium along with vitamin D (93533).

POSSIBLY UNSAFE ...when used orally in excessive doses. The National Academy of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: 19-50 years, 2500 mg; 51 years and older, 2000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stones, hypercalciuria, hypercalcemia, and milk-alkali syndrome. There has also been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these studies, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Many of these trials also only included postmenopausal females. Other analyses report conflicting results, and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Advise patients to not consume more than the recommended daily intake of 1000-1200 mg per day and to consider total calcium intake from both dietary and supplemental sources (17484). Also, advise patients taking calcium supplements to take calcium along with vitamin D (93533).

CHILDREN: LIKELY SAFE
when used orally and appropriately. Calcium is safe when used in appropriate doses (17506).

CHILDREN: POSSIBLY UNSAFE
when used orally in excessive doses. The Institute of Medicine sets the daily tolerable upper intake level (UL) for calcium according to age as follows: 0-6 months, 1000 mg; 6-12 months, 1500 mg; 1-8 years, 2500 mg; 9-18 years, 3000 mg (17506). Doses over these levels can increase the risk of side effects such as kidney stones, hypercalciuria, hypercalcemia, and milk-alkali syndrome.

PREGNANCY AND LACTATION: LIKELY SAFE
when used orally and appropriately (945,1586,3263,3264,17506). The World Health Organization (WHO) recommends prescribing oral calcium supplementation 1.5-2 grams daily during pregnancy to those with low dietary calcium intake to prevent pre-eclampsia (97347).

PREGNANCY AND LACTATION: POSSIBLY UNSAFE
when used orally in excessive doses. The Institute of Medicine sets the same daily tolerable upper intake level (UL) for calcium according to age independent of pregnancy status: 9-18 years, 3000 mg; 19-50 years, 2500 mg (17506). Doses over these amounts might increase the risk of neonatal hypocalcemia-induced seizures possibly caused by transient neonatal hypoparathyroidism in the setting of excessive calcium supplementation during pregnancy, especially during the third trimester. Neonatal hypocalcemia is a risk factor for neonatal seizures (97345).

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POSSIBLY SAFE ...when used orally and appropriately. A standardized extract of maritime pine bark (Pycnogenol, Horphag Research) has been safely used in doses of 50-450 mg daily for up to one year (2435,2451,2462,2554,2556,7693,10214,10416,12012,14899) (15424,15521,15522,15523,15524,100359,105782). The same extract has also been used with apparent safety in a dose of 800 mg daily for 16 days (103617). A different standardized extract of maritime pine bark (Oligopin, DRT Group) has been used with apparent safety in doses of up to 150 mg daily for up to 12 weeks (105781,105783). ...when applied topically as a cream or powder. A standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 0.5% cream has been used for up to 7 days (50912). Powder from a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) 100 mg has been applied to the skin daily for up to 6 weeks (50887,50896).

CHILDREN: POSSIBLY SAFE
when used orally and appropriately, short-term. A standardized extract of maritime pine bark (Pycnogenol, Horphag Research), administered in a dose of 1 mg/lb body weight daily, has been safely used in a clinical study of children aged 6-18 years for up to 3 months (13120).

PREGNANCY: POSSIBLY SAFE
when used orally during the third trimester of pregnancy. In one small clinical study, a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) has been used at a dose of 30 mg daily with apparent safety during the third trimester of pregnancy (15423). However, more evidence is needed; use cautiously or avoid using.

LACTATION:
There is insufficient reliable information available regarding the safety of maritime pine when used during lactation; avoid using.

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ALUMINUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Calcium citrate might increase aluminum absorption and toxicity. Other types of calcium do not increase aluminum absorption.  Details Calcium citrate can increase the absorption of aluminum when taken with aluminum hydroxide. The increase in aluminum levels may become toxic, particularly in individuals with kidney disease (21631). However, the effect of calcium citrate on aluminum absorption is due to the citrate anion rather than calcium cation. Calcium acetate does not appear to increase aluminum absorption (93006).

BISPHOSPHONATES Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Calcium reduces the absorption of bisphosphonates.  Details Advise patients to take bisphosphonates at least 30 minutes before calcium, but preferably at a different time of day. Calcium supplements decrease absorption of bisphosphonates (12937).

CALCIPOTRIENE (Dovonex) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Taking calcipotriene with calcium might increase the risk for hypercalcemia.  Details Calcipotriene is a vitamin D analog used topically for psoriasis. It can be absorbed in sufficient amounts to cause systemic effects, including hypercalcemia (12938). Theoretically, combining calcipotriene with calcium supplements might increase the risk of hypercalcemia.

CALCIUM CHANNEL BLOCKERS Interaction Rating = Minor Be watchful with this combination. Severity = Moderate •  Occurrence = Unlikely •  Level of Evidence = D Intravenous calcium may decrease the effects of calcium channel blockers; oral calcium is unlikely to have this effect.  Details Intravenous calcium is used to decrease the effects of calcium channel blockers in the management of overdose. Intravenous calcium gluconate has been used before intravenous verapamil (Isoptin) to prevent or reduce the hypotensive effects without affecting the antiarrhythmic effects (6124). But there is no evidence that dietary or supplemental calcium when taken orally interacts with calcium channel blockers (12939,12947).

CEFTRIAXONE (Rocephin) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = D Co-administration of intravenous calcium and ceftriaxone can result in precipitation of a ceftriaxone-calcium salt in the lungs and kidneys.  Details Avoid administering intravenous calcium in any form, such as parenteral nutrition or Lactated Ringers, within 48 hours of intravenous ceftriaxone. Case reports in neonates show that administering intravenous ceftriaxone and calcium can result in precipitation of a ceftriaxone-calcium salt in the lungs and kidneys. In several cases, neonates have died as a result of this interaction (15794,21632). So far there are no reports in adults; however, there is still concern that this interaction might occur in adults.

DIGOXIN (Lanoxin) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Using intravenous calcium with digoxin might increase the risk of fatal cardiac arrhythmias.  Details Hypercalcemia increases the risk of fatal cardiac arrhythmias with digoxin (12940). However, one retrospective analysis of clinical data suggests that intravenous calcium does not increase the risk of dysrhythmias or mortality in patients receiving digoxin (38960).

DILTIAZEM (Cardizem, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, calcium may reduce the therapeutic effects of diltiazem.  Details Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically, calcium might increase this risk of hypercalcemia and reduce the effectiveness of diltiazem.

DOLUTEGRAVIR (Tivicay) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce levels of dolutegravir.  Details Advise patients to take dolutegravir either 2 hours before or 6 hours after taking calcium supplements. Pharmacokinetic research suggests that taking calcium carbonate 1200 mg concomitantly with dolutegravir 50 mg reduces plasma levels of dolutegravir by almost 40%. Calcium appears to decrease levels of dolutegravir through chelation (93578).

ELVITEGRAVIR (Vitekta) Interaction Rating = Major Do not take this combination. Severity = High •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce levels of elvitegravir.  Details Advise patients to take elvitegravir either 2 hours before or 2 hours after taking calcium supplements. Pharmacokinetic research suggests that taking calcium along with elvitegravir can reduce blood levels of elvitegravir through chelation (94166).

LEVOTHYROXINE (Synthroid, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce the absorption and effectiveness of levothyroxine.  Details Advise patients to take levothyroxine and calcium supplements at least 4 hours apart. Calcium reduces levothyroxine absorption, probably by forming insoluble complexes (5082). Calcium carbonate supplements reduce effectiveness of levothyroxine in patients with hypothyroidism (5081,5082,6137).

LITHIUM Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, concomitant use of calcium and lithium may increase this risk of hypercalcemia.  Details Clinical research suggests that long-term use of lithium may cause hypercalcemia in 10% to 60% of patients (38953). Theoretically, concomitant use of lithium and calcium supplements may further increase this risk.

QUINOLONE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = B Calcium seems to reduce the absorption of quinolone antibiotics.  Details Advise patients to take oral quinolones at least 2 hours before or 4-6 hours after calcium supplements or calcium-fortified foods. Taking calcium at the same time as oral quinolones can reduce quinolone absorption. Calcium binds to quinolones in the gut (4412,10339,21638,38570).

RALTEGRAVIR (Isentress) Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = B Calcium may reduce levels of raltegravir.  Details Pharmacokinetic research shows that taking a single dose of calcium carbonate 3000 mg along with raltegravir 400 mg twice daily modestly decreases the mean area under the curve of raltegravir, but the decrease does not necessitate a dose adjustment of raltegravir (94164). However, a case of elevated HIV-1 RNA levels and documented resistance to raltegravir has been reported for a patient taking calcium carbonate 1 gram three times daily plus vitamin D3 (cholecalciferol) 400 IU three times daily in combination with raltegravir 400 mg twice daily for 11 months. It is thought that calcium reduced raltegravir levels by chelation, leading to treatment failure (94165).

SOTALOL (Betapace) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Calcium seems to reduce the absorption of sotalol.  Details Advise patients to separate doses by at least 2 hours before or 4-6 hours after calcium. Calcium appears to reduce the absorption of sotalol, probably by forming insoluble complexes (10018).

TETRACYCLINE ANTIBIOTICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Calcium seems to reduce the absorption of tetracycline antibiotics.  Details Advise patients to take oral tetracyclines at least 2 hours before, or 4-6 hours after calcium supplements. Taking calcium at the same time as oral tetracyclines can reduce tetracycline absorption. Calcium binds to tetracyclines in the gut (1843).

THIAZIDE DIURETICS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = C Taking calcium along with thiazides might increase the risk of hypercalcemia and renal failure.  Details Thiazides reduce calcium excretion by the kidneys (1902). Using thiazides along with moderately large amounts of calcium carbonate increases the risk of milk-alkali syndrome (hypercalcemia, metabolic alkalosis, renal failure). Patients may need to have their serum calcium levels and/or parathyroid function monitored regularly.

VERAPAMIL (Calan, others) Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Probable •  Level of Evidence = D Theoretically, calcium may reduce the therapeutic effects of verapamil.  Details Hypercalcemia can reduce the effectiveness of verapamil in atrial fibrillation (10574). Theoretically, use of calcium supplements may increase this risk of hypercalcemia and reduce the effectiveness of verapamil.

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ANTICOAGULANT/ANTIPLATELET DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = D Theoretically, maritime pine bark extract might increase the risk of bleeding when used with antiplatelet or anticoagulant drugs.  Details Clinical research suggests that maritime pine bark extract inhibits platelet aggregation (3283,50844,50942). However, the clinical significance of this effect is unclear.

ANTIDIABETES DRUGS Interaction Rating = Moderate Be cautious with this combination. Severity = Moderate •  Occurrence = Possible •  Level of Evidence = B Theoretically, maritime pine bark extract might increase the risk of hypoglycemia when used with antidiabetes drugs.  Details One clinical study shows that maritime pine bark extract decreases blood sugar in patients with diabetes being treated with antidiabetes agents (15522). Monitor blood glucose levels closely. Dose adjustments might be necessary.

IMMUNOSUPPRESSANTS Interaction Rating = Moderate Be cautious with this combination. Severity = High •  Occurrence = Possible •  Level of Evidence = D Theoretically, maritime pine bark extract might decrease the effectiveness of immunosuppressant therapy.  Details In vitro and animal research suggests that maritime pine bark extract has immunostimulant activity (2435,2636). This effect has not been reported in humans.

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General ...Orally and intravenously, calcium is well-tolerated when used appropriately.
Most Common Adverse Effects:
Orally: Belching, constipation, diarrhea, flatulence, and stomach upset.
Serious Adverse Effects (Rare):
Orally: Case reports have raised concerns about calciphylaxis and kidney stones.

Cardiovascular ...There has been concern that calcium intake may be associated with an increased risk of cardiovascular disease (CVD) and coronary heart disease (CHD), including myocardial infarction (MI). Some clinical research suggests that calcium intake, often in amounts over the recommended daily intake level of 1000-1300 mg daily for adults, is associated with an increased risk of CVD, CHD, and MI (16118,17482,91350,107233). However, these results, particularly meta-analyses, have been criticized for excluding trials in which calcium was administered with vitamin D (94137). Many of these trials also only included postmenopausal females. Other analyses report conflicting results, and have not shown that calcium intake affects the risk of CVD, CHD, or MI (92994,93533,97308,107231). Reasons for these discrepancies are not entirely clear. It may relate to whether calcium is taken as monotherapy or in combination with vitamin D. When taken with vitamin D, which is commonly recommended, calcium supplementation does not appear to be associated with an increased risk of CVD, CHD, or MI (93533,107231). Also, the association between calcium supplementation and CVD, CHD, or MI risk may be influenced by the amount of calcium consumed as part of the diet. Supplementation with calcium may be associated with an increased risk of MI in people with dietary calcium intake above 805 mg daily, but not in those with dietary calcium intake below 805 mg daily (17482). To minimize the possible risk of CVD, CHD, or MI, advise patients not to consume more than the recommended daily intake of 1000-1200 mg and to consider total calcium intake from both dietary and supplemental sources (17484). While dietary intake of calcium is preferred over supplemental intake, advise patients who require calcium supplements to take calcium along with vitamin D, as this combination does not appear to be associated with an increased risk of MI (93533).
Rarely, calcium intake can increase the risk of calciphylaxis, which usually occurs in patients with kidney failure. Calciphylaxis is the deposition of calcium phosphate in arterioles, which causes skin ulcers and skin necrosis. In a case report, a 64-year-old female with a history of neck fracture, sepsis, and ischemic colitis presented with painful leg ulcers due to calciphylaxis. She discontinued calcium and vitamin D supplementation and was treated with sodium thiosulfate and supportive care (95816).

Gastrointestinal ...Orally, calcium can cause belching, flatulence, nausea, gastrointestinal discomfort, and diarrhea (1824,1843,12950,38803). Although constipation is frequently cited as an adverse effect of calcium, there is no scientific substantiation of this side effect (1824,1843,1844,1845,12950,38978). Calcium carbonate has been reported to cause acid rebound, but this is controversial (12935,12936).

Oncologic ...There is some concern that very high doses of calcium might increase the risk of prostate cancer. Some epidemiological evidence suggests that consuming over 2000 mg/day of dietary calcium might increase the risk for prostate cancer (4825,12949). Additional research suggests that calcium intake over 1500 mg/day might increase the risk of advanced prostate cancer and prostate cancer mortality (14132). Consumption of dairy products has also been weakly linked to a small increase in prostate cancer risk (98894). However, contradictory research suggests no association between dietary intake of calcium and overall prostate cancer risk (14131,14132,104630). More evidence is needed to determine the effect of calcium, if any, on prostate cancer risk.

Renal ...Kidney stones have been reported in individuals taking calcium carbonate 1500 mg daily in combination with vitamin D 2000 IU daily for 4 years (93943).

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General ...Orally and topically, maritime pine bark extract seems to be well tolerated.
Most Common Adverse Effects:
Orally: Gastrointestinal complaints, dizziness, and vertigo.

Cardiovascular ...A single case of chest pain has been reported for a patient treated with a standardized extract of maritime pine bark (Pycnogenol, Horphag Research). However, the patient had a history of myocardial infarction (50905). Another patient taking the same maritime pine bark extract experienced acute decompensation of heart failure. The patient previously has stable coronary artery disease (50929). It is not clear if either of these adverse effects were directly related to maritime pine bark extract.

Gastrointestinal ...Orally, a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) may cause gastrointestinal problems (15521,15522,17300,50891,50942). Also, mouth ulcer and bad breath have been reported in a single trial (15521).

Neurologic/CNS ...Orally, a standardized extract of maritime pine bark (Pycnogenol, Horphag Research) may cause dizziness and severe vertigo (15521,15522,17300,50904,50933). Also, headache has been reported in a single trial (15521).

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