AUA Update Series

Lesson 6 Volume 29

2010

Lifestyle Changes, Nutritional Supplements and General Preventive Medicine Recommendations That Can Simultaneously Improve Heart and Urological HealthWhat do I Tell Patients? Part III: Calcium and Vitamin D
Learning Objective: At the conclusion of this continuing medical education activity, the participant will be able to provide simple, practical, realistic and evidence-based general dietary supplement advice as well as calcium and vitamin D supplement recommendations that should consistently and simultaneously promote overall and urological health.

Mark A. Moyad, M.D., M.P.H.

Disclosures: Abbott: Consultant/Lecturer; Guthy-Renker: Consultant/Inventor; NBTY Inc., Embria Health Sciences, Farr-Labs: Consultant Jenkins/Pokempner Director of Complementary & Alternative Medicine

Department of Urology University of Michigan Medical Center Ann Arbor, Michigan

This self-study continuing medical education activity is designed to provide urologists, Board candidates and/or residents affordable and convenient access to the most recent developments and techniques in urology. The American Urological Association (AUA) is accredited by the Accreditation Council for Continuing Medical Education (ACCME) to provide continuing medical education for physicians. The AUA takes responsibility for the content, quality and scientific integrity of this CME activity. Credit Designation Statement: The American Urological Association designates this educational activity for a maximum of 1.0 AMA PRA Category 1 Credit. Each physician should only claim credit commensurate with the extent of their participation in the activity.

AUA Disclosure Policy: As a provider accredited by the ACCME, the AUA must insure balance, independence, objectivity and scientific rigor in all its activities. All faculty participating in an educational activity provided by the AUA are required to disclose to the provider any relevant financial relationships with any commercial interest. The AUA must determine if the facultys relationships may influence the educational content with regard to exposition or conclusion and resolve any conflicts of interest prior to the commencement of the educational activity. The intent of this disclosure is not to prevent faculty with relevant financial relationships from serving as faculty, but rather to provide members of the audience with information on which they can make their own judgments.

Unlabled/Unapproved Uses: It is the policy of the AUA to require the disclosure of all references to unlabeled or unapproved uses of drugs or devices prior to the presentation of educational content. Please consult the prescribing information for full disclosure of approved uses. Evidence-Based Content: As a provider of continuing medical education accredited by the ACCME, it is the policy of the AUA to review and certify that the content contained in this CME activity is valid, fair, balanced, scientifically rigorous and free of commercial bias. Disclaimer: The opinions and recommendations expressed by faculty, authors and other experts whose input is included in this program are their own and do not necessarily represent the viewpoint of the AUA. Publication date: February 2010 Expiration date: February 2013

2010 American Urological Association, Education and Research Inc., Linthicum, MD

KEY WORDS: calcium, vitamin D, diet, complementary therapies,

preventive medicine,prostatic neoplasms INTRODUCTION A total of $34 billion a year is spent on alternative medicine in the United States,1 representing a growth of more than 25% in the last decade according to a recent 2009 survey of 23,000 American adults by the Centers for Disease Control and the National Institutes of Health. Alternative therapies account for 11% of the total amount Americans spend on health care. It is popular among all age groups because 38% of adults and 12% of children have used such therapies in the last year. The bulk ($22 billion) of the expense on alternative medicine or complementary and alternative medicine is directed toward self-care or treatments such as homeopathic medications and dietary supplements that are bought without necessarily physician approval or guidance. Thus, there is little need to convince the reader of the popularity of complementary and alternative medicine but is there any evidence that it should be used by patients with prostate cancer? The 2 dietary supplements, calcium and vitamin D, for prostate cancer prevention, treatment and amelioration of side effects are reviewed because they are arguably the only ones that should have general consensus in urology for their use in most patients. The 4 themes that I would like to proffer for the reader are 1) treat your dietary supplements like aspirin, 2) less is more, 3) when making a dietary supplement recommendation remember to inquire about whether it is heart healthy and 4) if you were wrong in your dietary supplement recommendation then it should still have been right for the patient. Although obviously not a dietary supplement, aspirin serves as the ideal paradigm of why dietary supplements need to be treated carefully with no patient taking them without first qualifying for their use after a strong review of the risk-to-benefit ratio with the physician.2-4 Aspirin is natural because it is derived from willow bark. It is inexpensive and easy to obtain OTC, and seems to be touted to provide numerous benefits. However, aspirin can cause significant morbidity and mortality in the wrong patient, especially one who takes it before surgery. In my opinion aspirin has been one of the most misconstrued OTC products because it is so easy for patients to obtain. Yet what is intriguing is perhaps the fact that one of the largest and most recent meta-analyses published on aspirin for primary (not secondary) prevention concluded that the net benefit was nebulous in healthy individuals.5 A total of 6 primary prevention trials and 95,000 individuals were included in the study using intent-to-treat analyses.5 Aspirin reduced the risk of serious cardiovascular events by 12%, primarily from a reduction in non-fatal myocardial infarction. The net (risk vs benefit) impact on stroke and death from cardiovascular causes was not significant. Aspirin significantly (p <0.001) increased the risk of gastrointestinal ulcers and extra-cranial bleeds. The authors concluded that aspirin is of uncertain value in primary prevention of cardiovascular disease. This type of careful review and analysis should be somewhat similar to how the doctor and patient ponder the use or non-use of a dietary supplement. Numerous dietary supplements have

potential blood thinning capabilities for example if used before surgery, and the impact on platelets and other parameters are at times more qualitative than quantitative, making it difficult for any laboratory test to detect this abnormality before the procedure.6 Therefore, ideally 2 to 3 weeks before surgery, radiation or any other conventional therapy most dietary supplements (not calcium and vitamin D) should be discontinued in my opinion until the patient recovers from the procedure or the majority of the radiation has dissipated (brachytherapy or external beam). Other indirect concerns support this cautious preprocedure behavior. Few patients or health care professionals may realize that in one of the largest randomized trials of a dietary supplement compared to placebo for patients with cancer the use of high dose antioxidant supplements during and after the procedure reduced the adverse effects of treatment at the expense of efficacy.7, 8 This outcome resulted in a significant increase in all cause mortality and higher recurrence rates in the dietary supplement group. Theme 2, less is more, does not necessarily imply that one should not use a dietary supplement, but rather that lower priced dietary supplements in my opinion have quality control and safety that are generally identical to the most expensive dietary supplements, for example fish oil,9 and lower dosages are generally safest.4 The literature is now replete with examples of more must be better but this philosophy needs to change because unlike pharmaceutical medications, many popular ingredients are added back to the diet and in higher amounts in supplements the moment they become popular. This simply means that what is a so-called deficiency in medicine can quickly become an excess, thus eliminating any opportunity to really determine what the health impact of the compound would have been originally in the at risk patients. In other words the market corrects the deficiency before research has an opportunity to determine the impact of the original deficiency which limits the ability to truly test a hypothesis. This is one of the many reasons I believe the SELECT trial, the largest cancer and prostate cancer prevention trial ever conducted,10 was compromised before it had a real chance to answer the actual question of whether selenium and/or vitamin E reduces the risk of prostate cancer. The popularity and marketability of selenium and vitamin E before and during the trial in my opinion dramatically increased the mean baseline blood level of selenium by approximately 20 points for example in this trial compared to previous trials but who could have anticipated this dramatic commercial influence? Another theme of this Update revolves around the expected safety of prescription drugs compared to dietary supplements. If a prescription product is not heart healthy, the chances that it will remain on the market or continue selling without a label warning seem minimal regardless of the efficacy for a non-cardiovascular condition. This was the case for example with hormone replacement therapy for postmenopausal women, selective cyclooxygenase-2 inhibitors for arthritis and tegaserod for irritable bowel syndrome.11 However, this policy does not appear to apply to dietary supplements, which leaves the burden up to the clinician and patient to determine whether a dietary supplement is indeed safe from a

ABBREVIATIONS: ADT (androgen deprivation therapy), BMD (bone mineral density), OTC (over-the-counter), PSA (prostate specific antigen), PTH (parathyroid hormone), UVB (ultraviolet B)
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cardiovascular standpoint. For this reason in my opinion any dietary supplement that is tested against prostate cancer or recommended for patients should be at minimum heart healthy at the recommended dosages. Parts I (Recommendations 1 to 5) and II (Recommendations 6 to 10) of this AUA Update series emphasized the importance and relevance of this approach from a dietary standpoint12, 13 but the same policy needs reinforcement from a dietary supplement perspective. For example, individual vitamin E dietary supplements have and continue to be a concern because of the potential for cardiovascular and overall toxicity14-16 despite any positive impact on cancer. This is precisely what was a recent concern of one of the largest prevention trials (Physicians Health Study II) in prostate cancer research, which demonstrated a significantly higher number of hemorrhagic strokes.17 It is for this reason that individual high dose vitamin E supplements should not be recommended for any urological condition. With regard to theme 4, can a supplement that did not provide direct improvement for the patient still be right for the patient, the answer is yes and this is tantamount to first do no harm but try to provide at least some ancillary benefit. For example, this is precisely the reason why a discussion of calcium and vitamin D supplementation makes realistic and logical sense. The recommended daily allowance does not cause any documented toxicity and, if it does not reduce prostate cancer risk or progression for example, there is at least the knowledge that it will provide bone health and potential improvement in this patient population.18 This is a sound clinical recommendation due to the now well-known deficiency of this mineral and vitamin throughout the world. In addition, vitamin D tends to encompass some element of all 4 themes in this lesson because the recommended dose needs to be respected as higher intakes can cause hypercalcemia and hypercalciurua, less is more, it is heart healthy and it provides ancillary benefits.4 Recommendation 11: Calcium (1200 to 1500 mg a day) and vitamin D (1000 IU vitamin D3 and/or blood testing to achieve an optimum level of 36 to 40 ng/ml or 90 to 100 nmol/l) intake from diet and dietary supplements should be discussed, especially with men on androgen deprivation for prostate cancer, and perhaps with all men with prostate cancer and older urological patients because of the higher risk of bone loss and fractures. The importance of daily elemental calcium intake for women seems to have received adequate attention. However, whether men are also consuming adequate levels of calcium, regardless of prostate cancer status, has not been adequately researched. A recent cross-sectional study of 372 men with prostate cancer and without bone metastases was conducted.19 Approximately 72% of the patients were receiving ADT and 28% had undergone a radical prostatectomy but were not getting ADT. Daily calcium intake and bone mineral density were assessed using a questionnaire and dual-energy x-ray absorptiometry at the lumbar spine and hip. An abnormal daily calcium intake (less than 1000 mg a day) was found in 93% of the men regardless of treatment status. Osteoporosis was identified in approximately 50% of the men (55% receiving ADT and 35% after surgery). The average daily calcium intake was significantly (p <0.001) lower and approximately 610 mg in those men with osteoporosis compared to 683 mg in those without this condition.

In a multivariate analysis daily calcium intake was an independent risk factor for osteoporosis along with patient age, ADT and length of time on ADT. This finding would suggest that a lack of adequate calcium intake is a notable issue in patients with prostate cancer but this research is in agreement with what I have witnessed over the years in men with and without prostate cancer. Of every 10 men 9 are potentially not following bone health recommendations, including men on ADT, and research has documented that these men are at risk for significant BMD reductions that increase with the duration of treatment.20 In a recent study from North America only 18% of patients on ADT actually received calcium and vitamin D recommendations when ADT was initiated.21 Men with and without prostate cancer should receive adequate calcium and vitamin D supplementation counseling (approximately 1200 to 1500 mg a day of calcium and at least 1000 IU vitamin D3 from diet and dietary supplements), and potentially vitamin D testing.22, 23 There has been some general concern that a higher risk of prostate cancer progression can occur with higher calcium intakes. This has not only been preliminarily found for calcium from dietary sources but calcium supplements as well.24, 25 The problem with this theory is that it tends to exist without a general reminder to clinicians about the other health benefits of the recommended doses of calcium for patients because these negative past studies have suggested a concern primarily for individuals with higher than recommended intakes (>2000 mg a day). Additionally, before discussing the ancillary benefits of calcium, are there any data from randomized trials that suggest a concern for patients with prostate cancer? Researchers directing one of the largest calcium supplement trials to reduce colon polyps published their findings on prostate cancer risk.26 The original clinical trial began in 1988 and randomly assigned 672 men to receive 1200 mg a day of calcium carbonate or placebo for 4 years. No patient had a history of prostate cancer in the study. For the male participants in this study mean age was 62 years, PSA was 1.8 ng/ml, time of calcium supplementation was 44 months (range 3.5 to 4 years) and follow-up was 10 years. A total of 24 prostate cancers were diagnosed during the 4-year treatment phase and 46 cases were diagnosed during the 6-year followup after the trial. Average Gleason score was approximately 6, and 11 tumors were diagnosed as non-localized. The risk of prostate cancer was reduced approximately 2 years after the calcium supplement study commenced and also significantly persisted approximately 2 years after the treatment ended. The authors concluded: In this randomized controlled clinical trial, there was no increase in prostate cancer risk associated with calcium supplementation and some suggestion of a protective effect. Interestingly, to my knowledge, the only other randomized trial to assess calcium supplementation was the Prostate Cancer Prevention Trial which revealed a significant reduction in PSA velocity in men taking calcium supplements, and no other dietary supplement was found to possess this potential activity.27 Obviously more research is needed but many men need to take calcium supplements for bone health, and they should not be discouraged to do so until there is some solid evidence suggesting that the risk of taking calcium actually exceeds the benefits. However, this does not seem to be the case based on preliminary evidence and especially when following the recommended daily allowance or the less is more theory. What about ancillary benefits of calcium supplementation for men? Two notable randomized trials have been published which
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included 1346 patients with previous colon polyps.28, 29 Daily doses of elementary calcium were 1200 mg in 1 trial28 and 2000 mg in the other trial.29 A moderate and significant 26% reduction in the risk of recurrent colon polyps was found when the results of both trials were combined.30 Calcium carbonate dietary supplements were used in both trials, and further analysis of the first trial demonstrated an enhanced reduction in aggressive histological polyps compared to well differentiated forms in the calcium supplement group.31 Another notable finding was a greater reduction in polyps in individuals with higher blood levels of vitamin D.32 A large randomized trial has confirmed that normalizing calcium intake helps reduce recurrent nephrolithiasis.33 Table 1 provides a partial listing of diverse food sources of calcium and Appendix 1 provides a quick review of the commercially available calcium supplements.4, 22, 34, 35 This table and the appendix should become standard handouts for any patient with prostate cancer concerned about bone loss. Please inform patients that the calcium supplements that are the least expensive, such as calcium carbonate, are at least equivalent in bioavailability and clinical efficacy compared to the most expensive calcium supplements.4, 36 This fact should improve patient compliance, which is a primary issue when taking any form of effective preventive medication.37 There may be a correlation between lower rates of a variety of chronic diseases and early mortality, and vitamin D supplementation.38 In a large meta-analysis of vitamin D 18 independent randomized controlled trials with 57,311 participants were identified in which a significant 7% reduction in total mortality was noted.39 In my opinion vitamin D represents the only dietary supplement in medicine with adequate evidence that it may impact all cause mortality. Minimally the impact of vitamin D on calcium absorption, and improving bone mineral density with and without calcium supplementation is impressive enough from the Table 1. Approximate calcium content of some low saturated fat/healthy foods Dietary Item Collards Orange juice (fortified) Sardines Oatmeal (instant) Yogurt Milk Figs (dried) Cheese Spinach Almonds Brewers yeast Soybeans Watercress Beans (other) Nuts (other) Kale Brussel sprouts Orange Raisins Brown rice Carrots
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Calcium Amount (mg/serving) 360 350 325 325 300 300 270 270 244 235 210 175 150 50-100 50-100 95 55 55 50 50 35

largest meta-analysis of 29 randomized trials with 63,897 patients to garner attention.40 Calcium doses of 1200 mg a day and higher, and vitamin D doses of 800 IU or more had a significantly greater treatment effect as well as greater compliance rates which resulted in a significantly greater fracture reduction. Dietary supplementation of vitamin D is not difficult and should be discussed with most patients, again with a focus on compliance and the low cost of this intervention. An objective overall review is still necessary for the clinician to gain confidence in recommending this supplement, which functions similar to a hormone and not a vitamin.41 It has become difficult to identify a population of individuals with sufficient blood levels of vitamin D. Why are so many individuals vitamin D deficient? The various factors, acting alone or synergistically, that can cause vitamin D deficiency are listed in Appendix 2.18, 42,43 For example aging can reduce vitamin D levels because the mechanisms needed to synthesize its structure from cholesterol become less efficient (hydroxylation in the liver and kidney) and skin thickness reduction occurs, which results in lower levels of the precursor of vitamin D synthesis (7-dehydrocholesterol) in the epidermis.44, 45 I often explain to patients that in addition to the obvious external signs of aging, such as wrinkles, gray hair, loss of hair etc, human beings also age internally, and inadequate vitamin D synthesis is just 1 example of the internal aging process. Adipose tissue and increased cholesterol have also been associated with lower vitamin D status.18, 42, 43, 46, 47 Reliable dietary sources that contain consistently higher levels of vitamin D are also an issue.18, 42, 43 The highest concentration of vitamin D is found in some of the heart healthiest fish, and so patients receive a dual benefit by consuming fish high in omega3 compounds and vitamin D such as salmon. Fortification of some foods and beverages has not been a solution to the vitamin D deficiency rates, and recent studies suggest that the regular daily intake of vitamin D by older individuals may increase blood levels greater than weekly or monthly oral intakes of equivalent doses.48 However, keep in mind that the ongoing excitement and enthusiasm for vitamin D in my opinion will translate into overcompensation of vitamin D added to food and beverage products in the next few years. Again this is another reason to encourage moderate and evidence-based intakes of this vitamin (less is more) as the hype exceeds the clinical benefits and expectations. Sunscreen and windowpane glass have the ability to block UVB light, and it is this form of light that stimulates vitamin D synthesis in skin tissue.49 Thus, wearing sunscreen and sun protective clothing, and avoiding sunlight can reduce blood levels of vitamin D. However, no clinician should encourage sun exposure to increase vitamin D status while simultaneously increasing melanoma risk. Vitamin D supplementation is simplistic, cost-effective, generally safe and perhaps the best method along with fish consumption to increase blood levels of vitamin D, regardless of the ethnicity of the patient.50 Patients and clinicians often suggest that individuals residing in areas with more sun exposure experience higher blood levels of vitamin D. Theoretically this makes sense but it has not been substantiated as recent research has demonstrated low blood levels of vitamin D in people residing in Florida and southern Arizona.51, 52 Perhaps regular sun avoidance via clothing, wide brimmed hats, aging and obesity are independently or synergistically involved in lowering vitamin D levels in some of these geographic areas.

The only foods that naturally contain vitamin D are seafood, mushrooms and egg yolks. A partial list of foods and their natural vitamin D content is given in table 2.53, 54 Wild salmon contains as much as 3 times the amount of vitamin D compared to farmed salmon.54 Patients inquiring about the differences and similarities between farmed and wild fish should be given an objective overview. Although both types of fish are equally high in omega-3 fatty acids, which are heart healthy, and both tend to have a low level of mercury and other environmental contaminants,55 a preliminary difference lies in the inherent vitamin D content of these fish. Regardless, both types of fish are healthy to consume, and the demand and cost for fish globally cannot be sustained without farmed fish becoming another viable option. What about the differences in vitamin D dietary supplements? The 2 types of vitamin D supplements available for OTC purchase are vitamin D2 and vitamin D3, although vitamin D3 (not vitamin D2) is the type that most experts believe should be recommended in clinical practice.42, 56 Vitamin D2 is known as ergocalciferol and vitamin D3 is known as cholecalciferol. Most individuals should eventually transition to D3. There are a multitude of reasons for advocating the use of vitamin D3 compared to vitamin D2 dietary supplements,4, 42, 56 including 1) vitamin D3 is as costeffective as vitamin D2; 2) vitamin D3 has been used more often in clinical trials with appropriate end points such as fractures, bone mineral density measured changes, and serum bone and urine marker changes; 3) vitamin D3 is more efficacious at increasing

Table 2. Foods that naturally contain vitamin D Food Oysters Salmon (wild) Cod liver oil Catfish Bluefish Mackerel Trout (farmed) Salmon (farmed) Sardines (canned in oil) Halibut Tuna (bluefin) Tuna (canned in water) Shrimp Milk (reference, not natural source)* Cod Mushrooms (Shitake) Mushrooms (Chanterelle) Sole/flounder Bass (freshwater) Swordfish Clams Egg (whole) Serving Size 3 3 1 3 3 3 3 3 3 3 3 3 3 1 3 2 2 3 3 3 3 1 oz oz teaspoon oz oz oz oz oz oz oz oz oz oz cup oz oz oz oz oz oz oz Vitamin D (IU) 545 1000 450 425 415 395 375 275 230 170 170 135 120 100 80 55 50 50 35 35 30 25

* Whole, low fat or non-fat/skim is supposed to be fortified with 100 IU of vitamin D per cup but past studies have not yet definitively proven the reliability of the fortification process, and many studies have suggested that many dairy products are under fortified with vitamin D despite claims in the label.

and maintaining the vitamin D blood test because D2 has less binding capacity at the vitamin D receptor and a more limited halflife; 4) UVB light from the sun causes vitamin D3 synthesis and so it is the most natural form; 5) human beings do not synthesize vitamin D2; and 6) wild fish contains vitamin D3. All of these factors should theoretically increase compliance rates. Vitamin D2 is a plant or a fungus/yeast derived product that is synthetically produced from radiating a compound (ergosterol) from the mold ergot.42, 56 Vitamin D3 is produced commercially and synthetically in a somewhat similar method to human intrinsic synthesis. Wool sources of 7-dehydrocholesterol are used (from cholesterol) and irradiated to produce active vitamin D3. Vegetarians and especially vegans may choose not to take vitamin D3 supplements because they are derived from an animal source, and understandably they should be directed to take vitamin D2. Multivitamins have either vitamin D2 or D3 but many companies are now using primarily vitamin D3. Cod liver oil supplements contain vitamin D3. Rickets, a defect in bone growth in infancy and childhood, was first identified in 1650.57 It was not until 1922 that medical research demonstrated that a compound in cod liver oil prevented and cured rickets. Vitamin D2 was also created and added to milk in the United States and Europe in the 1930s which essentially eliminated rickets or osteomalacia. Currently, fortification with vitamin D2 or D3 has continued to keep rickets an anomaly in North America. The minimum amount of vitamin D needed to prevent rickets is 100 IU (2.5 mcg) a day in infants with little to no sun exposure.In the 1970s the vitamin D blood test (known as the 25-OH vitamin D test) emerged clinically to detect vitamin D deficiency (<20 ng/ ml) and insufficiency (<30 ng/ml).58 The total amount of vitamin D in the body that was extracted from all sources (diet, dietary supplements and the sun) was reflected in this blood test. Low concentrations of 25-OH vitamin D caused secondary hyperparathyroidism, which results in greater calcium bone deficits when PTH is abnormally high (PTH >65 pg/ml). Ideally the vitamin D blood test should be offered from fall through winter of the year when blood levels are the most reduced. Spring through summer can give the patient and clinician a false sense of vitamin D security but still may provide some value in the high risk patient. Fasting is not necessary to obtain a vitamin D level but obtaining other blood tests at the same time (lipids, PSA) seems more logical to reduce the time burden on the patient. Most health insurances cover vitamin D testing but some do not. Prices vary from $10 to $20 to as much as $500 out of pocket, and so the cost from the local laboratory should be obtained before telling the patient that a vitamin D level is required.59 Medicare covers the cost of the test but has proposed recently to limit its use only to those at highest risk of deficiency. However, the concern over this restriction is that without the blood test, deficiency and insufficiency are difficult to establish. For example, how does or would a clinician establish dyslipidemia without a lipid analysis? Vitamin D is no different in this regard. A perfect example of the greater need for using vitamin D blood testing and supplementation is the men on ADT for prostate cancer or the men and women on corticosteroids.60-62 Some men and women will be prescribed a bisphosphonate or another drug without hesitation if needed. However, how many of these men and women given these medications had the opportunity to maintain BMD for 6 months through lifestyle changes (weight lifting), supplement
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intake of calcium and vitamin D, and vitamin D and dual-energy xray absorptiometry monitoring before being offered the prescription medication? Health care professionals offer cholesterol lowering medications if diet and exercise do not work, which makes sense in the area of cardiovascular prevention. However, this should be true for all areas of preventive medicine, including proper bone health in my opinion. Therefore when diet, exercise and blood tests are not enough to maintain BMD, then bisphosphonates and other osteoporosis prevention medications are the ideal option, in addition to diet, exercise, and calcium and vitamin D supplementation. Many past and recent clinical trials of bisphosphonates for men experiencing bone loss tended to follow this protocol to some degree, and patients should be reminded of this important observation so that the research mirrors current clinical recommendations.63-65 In a recent retrospective review of 396 patients a significant (p=0.017) reduced risk of new onset diabetes mellitus was noted in men taking vitamin D supplements during ADT.66 This finding is preliminary but profound because a variety of primary prevention studies have suggested that vitamin D may reduce the risk of insulin resistance and autoimmune diseases such as diabetes and multiple sclerosis.67-70 During the last few decades the normal blood level of vitamin D or 25-OH vitamin D was based on the amount required to keep PTH from becoming abnormally high.42 However, PTH can change due to renal function, exercise level, time of day and diet. There has been no consensus on the optimal level of vitamin D intake to reduce PTH, which is why laboratories report a wide normal range of vitamin D (from 20 to 40 ng/ml to 50 to 100 nmol). This is tantamount to a normal total cholesterol level between 200 to 300 mg/dl in my opinion. What is the optimum blood level of vitamin D? Numerous vitamin D experts published a consensus review of a large number of past clinical studies to arrive at an appropriate clinical answer to this question.71 A variety of health changes and clinical end points were evaluated including bone health, fracture prevention, muscle strength, prevention of falls, dental health and colorectal cancer. Other evidence for vitamin D that is not as robust but was considered is prevention of multiple sclerosis, insulin problems (diabetes), other cancers, arthritis, hypertension and tuberculosis. Researchers also analyzed other variables apart from keeping PTH normal, reviewed studies of multiple ethnic groups and followed adverse event rates. A consistent clinical numerical answer for vitamin D blood level for preventive health was 90 to 100 nmol/l (or 36 to 40 ng/ml). Why not extend the ideal laboratory values of normalcy well beyond 36 to 40 ng/ml? If no acute toxicity (hypercalcemia/ hypercalciuria) is associated with blood levels of 70 or 80 ng/ml and higher (or only 500 nmol/l), or more than 20,000 IU of vitamin D per day causes adverse events,72 then why not recommend higher blood levels? Higher must be better? More must be better? This simply cannot be the case and a history lesson is needed. Medical nutritional research is replete with examples of when more was not necessarily better. Such examples include beta-carotene supplementation increasing the risk of lung cancer in smokers from 2 different randomized trials,73, 74 high dose selenium increasing the risk of type II diabetes mellitus in healthy individuals in another randomized trial,75 and high dose folic acid supplements increasing the risk of colon polyp recurrence and prostate cancer in one of the most recent chemoprevention trials.76 All of these clinical trials were placebo controlled, and had the opposite intended
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results and consequences but, nevertheless, they offered a lesson on why more is not necessarily better. Supraphysiological levels, or beyond what is recommended in this Update, are simply not supported by the medical literature. Overall cancer incidence and mortality do not seem to be impacted by a higher vitamin D level but more research is needed.77 Thus, prostate cancer outcome studies have not yet identified considerable prevention or direct treatment benefits to achieving higher/supraphysiological vitamin D levels.78 In fact, there is even a suggestion from 3 epidemiological studies that long-term significant increases in vitamin D could be detrimental, and increase the risk of prostate cancer and more aggressive disease.79-81 Perhaps chronic high dose supplementation should be the concern, so the focus on the lack of acute adverse effects is a myopic perspective. Again, there is no universally accepted measure of normal or adequate levels of 25-OH vitamin D,82-84 but the aforementioned 36 to 40 ng/ml level (90 to 100 nmol/l) has the most clinical consensus with respect to acute and chronic efficacy and safety.71 What is the dosage of vitamin D needed to achieve 36 to 40 ng/ ml (90 to 100 nmol/l)? Historically, 400 IU (10 ug) of vitamin D was recommended for improved health because it closely approximated the amount of vitamin D in a teaspoonful of cod liver oil.85 In 1997 the Institute of Medicine recommended daily doses of vitamin D of 200 IU for children and young adults, 400 IU for those 51 to 70 years old and 600 IU for those older than 70 years.86 These recommendations are not only being challenged and altered,87 but 800 to 1000 IU is the dose that is known to increase the probability of achieving a vitamin D level of 36 to 40 ng/ml.88, 89 Some countries refer to vitamin D amounts in micrograms and the conversion is shown in table 3. Health care professionals need to keep in mind that in general 100 IU (2.5 mcg) of vitamin D3 daily can increase the vitamin D blood test only 1 ng/ml or just 2.5 nmol/l after 2 to 3 months regardless of age.90,91 Vitamin D2 is less predictable and produces approximately half the response rate compared to vitamin D3 in the elderly,90 which again is another reason to encourage vitamin D3 intake. A review of this critical point is necessary for the clinician initiating vitamin D testing with patients. How much vitamin D3 is needed for a normal level vitamin D blood test is detailed in table 4. For example, if the vitamin D blood test result was 30 ng/ml (75 nmol/l) and the clinician wanted to achieve 40 ng/ml (100 nmol/l), a total of 1000 IU (25 mcg) of vitamin D daily for several months, not a few days or weeks, would be recommended to achieve a normal blood level. Upon reaching the goal, most individuals need to supplement with approximately 800 to 1000 IU daily to maintain this level. Again, this is a generality from clinical research and only working closely with a clinician over time can provide the most accurate answer. However, issues of insurance and health care access lead to the thought that 1000

Table 3. Conversion of vitamin D levels from IU to micrograms 100 200 400 600 800 1000 IU IU IU IU IU IU = = = = = = 2.5 mcg 5 mcg 10 mcg 15 mcg 20 mcg 25 mcg

IU is ample currently for most individuals who cannot have the blood test performed. In some past and recent studies high dose vitamin D supplementation has been used to rapidly correct deficiencies, for example a 100,000 IU pill every 4 months and other permutations of high and low doses.92-95 This dosing may be more sensible for individuals in institutionalized or long-term and community care facilities due to compliance and access issues. What has also been learned from this alternative dosing schedule for at risk populations is that perhaps vitamin D is impacting fracture rates or improving bone health via a reduction in the number of falls leading to fracture by improving muscle strength and coordination because vitamin D receptors also exist in skeletal muscle.96 Vitamin D has been shown to improve muscle strength and reduce body sway that may lead to traumatic falls.97, 98 Certainly, there are numerous studies to support this alternative theory of fracture prevention.99 CONCLUSION This lesson focused on the 2 dietary supplements, calcium and vitamin D. It is difficult to remember receiving any education in medical school or from a urology conference on these supplements despite their profound role in urology, and the daunting amount of information on calcium and vitamin D that is available. Perhaps this is reflected in the lack of patient education in this area of urological oncology compared to what is perceived to be more relevant pharmacological intervention. Perhaps it is reflected in the fact that a combination of nutritional counseling, adequate (not minimal) calcium and vitamin D supplementation, vitamin D blood testing and monitoring, and weight lifting for 6 months to 1 year is not considered standard preventive therapy for men on ADT before pharmacological therapy. Or that no randomized trial in

Table 4. Daily doses of vitamin D required for normal vitamin D test result 100 IU (2.5 mcg)/day increases vitamin D blood levels 1 ng/ml (2.5 nmol/l) 200 IU (5 mcg)/day increases vitamin D blood levels 2 ng/ml (5 nmol/l) 400 IU (10 mcg)/day increases vitamin D blood levels 4 ng/ml (10 nmol/l) 800 IU (20 mcg)/day increases vitamin D blood levels 8 ng/ml (20 nmol/l) 1000 IU (25 mcg)/day increases vitamin D blood levels 10 ng/ml (25 nmol/l) urology to the best of my knowledge has ever used this multiple series of preventive measures in a placebo or intervention group of pharmacological therapy for bone loss, which is perplexing. There are small studies of patients on ADT to suggest that just one or more of these aggressive preventive measures may prevent or at least dramatically minimize bone and muscle loss, regardless of the duration of ADT.100 Clinicians should not wait for more phase III data so to speak because the interventions from this lesson are logical, practical, research-based, safe, cost-effective and only implemented currently in a minority of patients. Again, the most interesting observation is that these interventions result in a potential win-win-win situation for the patient because they may reduce bone loss and/or improve another area of health already prevalent in this population. If the patient requires pharmacological intervention these lifestyle and supplement additions work synergistically with the medication. Now, the only issue left to ponder is why no pens, notepads, bags, cups or television commercials advertising or touting this lesson in urological oncology currently exist?

APPENDIX 1: SIMILARITIES AND DIFFERENCES BETWEEN SOME COMMERCIALLY AVAILABLE CALCIUM SUPPLEMENTS Calcium Supplement (elemental amount, higher percentage=less pills needed for efficacy) Calcium carbonate (contains 40% elemental calcium) Calcium citrate or calcium citrate malate (contains 21% elemental calcium) Brand Name Example (all products come with a generic option) Caltrate, OsCal, Rolaids, TUMS, Viactiv (chewable calcium product, 20 calories each) Citracal Absorption Requirements/Commentary

Should be taken with food for better absorption, used in the colon polyp prevention trial, may cause constipation Can be taken with or without food (probably the preferred form for those with a history or risk of oxalate kidney stones because of the adequate citrate content), need to take more pills due to the lower elemental calcium amount per pill Can be taken with or without food, needs more clinical trials in men and women

Calcium phosphate (contains 39% elemental calcium)

Posture-D

Calcium supplements should be taken in divided doses because the human body generally absorbs 500 mg of elemental calcium at a time. Check for the amount of elemental calcium in each tablet because this is the type of calcium that is absorbed and actually counted for the required calcium intake for women and men. Some of these supplements may also contain vitamin D, which minimally increases tablet size, but vitamin D does not have to be in the calcium supplement to enhance absorption as long as vitamin D is being derived from another source (supplement, diet) on a regular basis.
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APPENDIX 2: PRIMARY FACTOR(S) THAT CAN POTENTIALLY DETERMINE VITAMIN D BLOOD LEVEL FROM A TO Z Factors Aging Commentary Older individuals just make less vitamin D due to less epidermal tissue, 7dehydrocholesterol in the skin decreases with time so it is more difficult to make vitamin D3 (for example, individuals older than 65 years have a 4-fold reduction in the capacity of the skin to produce vitamin D3), liver and kidney function is not as efficient, the gastrointestinal ability to absorb vitamin D from food or supplements is reduced Obese individuals tend to have lower vitamin D concentrations because this vitamin gets absorbed by adipose tissue and is not easily released in the blood stream or the volume of blood is so large that it dilutes the detecting ability of this nutritional test Preliminary research suggests that lowering cholesterol may increase vitamin D levels The more vitamin D one gets from dietary sources the higher the blood level, fish and other seafood are the best naturally producing dietary sources followed by mushrooms and egg yolks, which are substantially lower sources. In the U.S. and Canada milk, soy milk, bread products, cereals, protein bars, and other foods and beverages are fortified with vitamin D; in Europe margarine is one of the more common fortified sources of vitamin D; independent surveys have found that many of these products do not contain the amount of vitamin D on the label (usually less); as vitamin D gains popularity expect an overcompensation of fortification by some companies in their food and beverage products Recent research indicates that taking a daily vitamin D3 pill has a higher probability of keeping a normal blood level of vitamin D compared to a once a week or once a month dosage of equivalent formulations The more your occupation or activities involves being outdoors, especially in the spring and summer, the greater the chance you will have higher vitamin D levels Darker skinned individuals have more melanin (increased skin pigmentation) which blocks the impact of UVB radiation and reduces production of vitamin D, AfricanAmericans have a higher risk of vitamin D deficiency The higher the SPF of your sunscreen or clothing, the more it blocks the ability of UVB light from the sun to increase vitamin D level, individuals completely covered by clothing for a variety of purposes (including religious) have lower vitamin D levels Multivitamins generally contain 400 IU (10 mcg) per capsule, vitamin D individual tablets can now be purchased and are cost-effective, some of the pills and liquids contain vitamin D2 and not the preferred vitamin D3 form, vitamin D3 has a more profound effect on increasing vitamin D blood levels. Tanning beds can increase vitamin D levels at the risk of also increasing melanoma and so should be discouraged as a viable source of vitamin D UVB radiation from the sun is the primary source of vitamin D for most people, geographic location (where you live) has an impact on how much sun and vitamin D you produce (more sun or closer to the equator=more vitamin D), vitamin D production in skin rarely occurs in the winter above and below latitudes of approximately 40 degrees north and south (Boston, MA is 42 degrees and Edmonton, Canada is 53 degrees) 4. Moyad MA: No Bogus Science Health Advice. Ann Arbor, Michigan: Ann Arbor Media Group 2009. 5. Antithrombotic Trialists (ATT) Collaboration: Aspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomized trials. Lancet 2009; 373: 1849. 6. Ang-Lee MK, Moss J and Yuan CS: Herbal medicines and perioperative care. JAMA 2001; 286: 208. 7. Bairati I, Meyer F, Gelinas M et al: Randomized trial of antioxidant vitamins to prevent acute adverse events of radiation therapy in head and neck cancer patients. J Clin Oncol 2005; 23: 5805. 8. Meyer F, Bairati I, Jobin E et al: Acute adverse effects of radiation therapy and local recurrence in relation to dietary and plasma beta

Belly fat/abdominal obesity/visceral tissue

Cholesterol lowering medications (statins) Dietary vitamin D intake: Natural or non-fortified sources Fortified vitamin D sources

Frequency of vitamin D intake

Outside sunlight exposure Skin pigmentation

Sunscreen/sun protective clothing and other measures Supplemental vitamin D and form of vitamin D3 vs D2

Ultraviolet exposure from tanning beds UVB light radiation (wavelength = 290-315 nm) exposure based on residence

REFERENCES 1. Nahin RL, Barnes PM, Stussman BJ et al: Costs of complementary and alternative medicine (CAM) and frequency of visits to CAM practitioners: United States, 2007. Natl Health Stat Report 2009; 18: 1. 2. Moyad MA: An introduction to aspirin, NSAIDs, and COX-2 inhibitors for the primary prevention of cardiovascular events and cancer and their potential preventive role in bladder cancer carcinogenesis: part I. Semin Urol Oncol 2001; 19: 294. 3. Moyad MA: An introduction to aspirin, NSAIDs, and COX-2 inhibitors for the primary prevention of cardiovascular events and cancer and their potential preventive role in bladder cancer carcinogenesis: part II. Semin Urol Oncol 2001; 19: 306.
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27. Kristal AR, Chi C, Tangen CM et al: Associations of demographic and lifestyle characteristics with prostate-specific antigen (PSA) concentration and rate of PSA increase. Cancer 2006; 106: 320. 28. Baron JA, Beach M, Mandel JS et al: Calcium supplements for the prevention of colorectal adenomas. Calcium Polyp Prevention Study Group. N Engl J Med 1999; 340: 101. 29. Bonithon-Kopp C, Kronborg O, Giacosa A et al: Calcium and fibre supplementation in prevention of colorectal adenoma recurrence: a randomized intervention trial. European Cancer Prevention Organization Study Group. Lancet 2005; 356: 1300. 30. Weingarten MA, Zalmanovici A and Yaphe J: Dietary calcium supplementation for preventing colorectal cancer and adenomatous polyps. Cochrane Database Syst Rev 2005; CD003548. 31. Wallace K, Baron JA, Cole BF et al: Effect of calcium supplementation on the risk of large bowel polyps. J Natl Cancer Inst 2004; 96: 921. 32. Grau MV, Baron JA, Sandler RS et al: Vitamin D, calcium supplementation, and colorectal adenomas: results of a randomized trial. J Natl Cancer Inst 2003; 95: 1765. 33. Borghi L, Schianchi T, Meschi T et al: Comparison of two diets for the prevention of recurrent stones in idiopathic hypercalciuria. N Engl J Med 2002; 346: 77. 34. USDA Dietary Guidelines for Americans. Food Sources of Calcium. Available at http://www.health.gov/DIETARYGUIDELINES/dga2005/document/html/AppedixB.htm. Accessed February 15, 2009. 35. Moyad MA: Osteoporosispart II. Dietary and/or supplemental calcium and vitamin D for overall general health. Urol Nurs 2003; 22: 405. 36. Martini L and Wood RJ: Relative bioavailability of calcium-rich dietary sources in the elderly. Am J Clin Nutr 2002; 76: 1345. 37. Ansell BJ: Not getting to goal: the clinical costs of noncompliance. J Manag Care Pharm 2008; 14: 9. 38. Khazai N, Judd SE and Tangpricha V: Calcium and vitamin D: skeletal and extraskeletal health. Curr Rheumatol Rep 2008; 10: 110. 39. Autier P and Gandini S: Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med 2007; 167: 1730. 40. Tang BMP, Eslick GD, Nowson C et al: Use of calcium or calcium in combination with vitamin D supplementation to prevent fractures and bone loss in people aged 50 years and older: a meta-analysis. Lancet 2007; 370: 657. 41. Coen G: Vitamin D: an old prohormone with an emergent role in chronic kidney disease. J Nephrol 2008; 21: 313. 42. Wolpowitz D and Gilchrest BA: The vitamin D questions: how much do you need and how should you get it? J Am Acad Dermatol 2006; 54: 301. 43. Giovannucci E, Liu Y, Rimm EB et al: Prospective study of predictors of vitamin D status and cancer incidence and mortality in men. J Natl Cancer Inst 2006; 98: 451. 44. Bell NH: Vitamin D metabolism, aging, and bone loss. J Clin Endocrinol Metab 1995; 80: 1051. 45. Need AG, Morris HA, Horowitz M et al: Effects of skin thickness, age, body fat, and sunlight on serum 25-hydroxyvitamin D. Am J Clin Nutr 1993; 58: 882. 46. Aasheim ET, Hofso D, Hjelmesaeth J et al: Vitamin status in morbidly obese patients: a cross-sectional study. Am J Clin Nutr 2008; 87: 362.
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47. Perez-Castrillon JL, Abad L, Vega G et al: Effect of atorvastatin on bone mineral density in patients with acute coronary syndrome. Eur Rev Med Pharmacol Sci 2008; 12: 83. 48. Chel V, Wijnhoven HA, Smit JH et al: Efficacy of different doses and time intervals of oral vitamin D supplementation with or without calcium in elderly nursing home residents. Osteoporos Int 2008; 19: 663. 49. Holick MF: Environmental factors that influence the cutaneous production of vitamin D. Am J Clin Nutr 1995; 61: 638S. 50. van der Meer IM, Boeke AJ, Lips P et al: Fatty fish and supplements are the greatest modifiable contributors to the serum 25-hydroxyvitamin D concentration in a multiethnic population. Clin Endocrinol (Oxf) 2008; 68: 466. 51. Levis S, Gomez A, Jimenez C et al: Vitamin D deficiency and seasonal variation in an adult South Florida population. J Clin Endocrinol Metab 2005; 90: 1557. 52. Jacobs ET, Alberts DS, Foote JA et al: Vitamin D insufficiency in southern Arizona. Am J Clin Nutr 2008; 87: 608. 53. National Institutes of Health (NIH), Office of Dietary Supplements, Dietary Supplement Fact Sheet: Vitamin D. Available at http:// ods.od.nih.gov/factsheets/vitamind.asp. Accessed July 30, 2008. 54. Chen TC, Chimeh F, Lu Z et al: Factors that influence the cutaneous synthesis and dietary sources of vitamin D. Arch Biochem Biophys 2007; 460: 213. 55. Mozaffarian D and Rimm EB: Fish intake, contaminants, and human health: evaluating the risks and benefits. JAMA 2006; 296: 1885. 56. Houghton LA and Vieth R: The case against ergocalciferol (vitamin D2) as a vitamin supplement. Am J Clin Nutr 2006; 84: 694. 57. Welch TR, Bergstrom WH and Tsang RC: Vitamin D-deficient rickets: the reemergence of a once-conquered disease. J Pediatr 2000; 137: 143. 58. Zerwekh JE: Blood markers of vitamin D status. Am J Clin Nutr 2008; 87: 1087S. 59. Flores P: Medicare proposes restrictions on vitamin D testing. Available at http://www.healthcentral.com/osteoporosis/c/76444/ 62610/restrictions. Accessed August 30, 2009. 60. Lattouf JB and Saad F: Preservation of bone health in prostate cancer. Curr Opin Support Palliat Care 2007; 1: 192. 61. Tuck SP and Datta HK: Osteoporosis in the aging male: treatment options. Clin Interv Aging 2007; 2: 521. 62. Moyad MA: Promoting general health during androgen deprivation therapy (ADT): a rapid 10-step review for your patients. Urol Oncol 2005; 23: 56. 63. Orwoll E, Ettinger M, Weiss S et al: Alendronate for the treatment of osteoporosis in men. N Engl J Med 2000; 343: 604. 64. Ryan CW, Huo D, Bylow K et al: Suppression of bone density loss and bone turnover in patients with hormone-sensitive prostate cancer and receiving zoledronic acid. BJU Int 2007; 100: 70. 65. Ryan CW, Huo D, Demers LM et al: Zoledronic acid initiated during the first year of androgen deprivation therapy increases bone mineral density in patients with prostate cancer. J Urol 2006; 176: 972. 66. Derweesh IH, DiBlasio CJ, Kincade MC et al: Risk of new-onset diabetes mellitus and worsening glycaemic variables for established diabetes in men undergoing androgen-deprivation therapy for prostate cancer. BJU Int 2007; 100: 1060. 67. Teegarden D and Donkin SS: Vitamin D: emerging new roles in insulin sensitivity. Nutr Res Rev 2009; 22: 82. 68. Harris SS: Vitamin D in type 1 diabetes prevention. J Nutr 2005; 135: 323.
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69. Hypponen E, Laara E, Reunanen A et al: Intake of vitamin D and risk of type 1 diabetes: a birth-cohort study. Lancet 2001; 358: 1500. 70. Munger KL, Levin LI, Hollis BW et al: Serum 25-hydroxyvitamin D levels and risk of multiple sclerosis. JAMA 2006; 296: 2832. 71. Bischoff-Ferrari HA, Giovannucci E, Willett WC et al: Estimation of optimal serum concentrations of 25-hydroxyvitamin D for multiple health outcomes. Am J Clin Nutr 2006; 84: 18. 72. Heaney RP: Vitamin D: criteria for safety and efficacy. Nutr Rev 2008; 66: S178. 73. Omenn GS, Goodman GE, Thornquist MD et al: Risk factors for lung cancer and for intervention effects in CARET, the BetaCarotene and Retinol Efficacy Trial. J Natl Cancer Inst 1996; 88: 1550. 74. Albanes D, Heinonen OP, Taylor PR et al: Alpha-tocopherol and beta-carotene supplements and lung cancer incidence in the alphatocopherol, beta-carotene cancer prevention study: effects of baseline characteristics and study compliance. J Natl Cancer Inst 1996; 88: 1560. 75. Stranges S, Marshall JR, Natarajan R et al: Effects of long-term selenium supplementation on the incidence of type 2 diabetes: a randomized trial. Ann Intern Med 2007; 147: 217. 76. Cole BF, Baron JA, Sandler RS et al: Folic acid for the prevention of colorectal adenomas: a randomized clinical trial. JAMA 2007; 297: 2351. 77. Freedman DM, Looker AC, Chang S-C et al: Prospective study of serum vitamin D and cancer mortality in the United States. J Natl Cancer Inst 2007; 99: 1594. 78. Mucci LA and Spiegelman D: Vitamin D and prostate cancer riska less sunny outlook? J Natl Cancer Inst 2008; 100: 759. 79. Tuohimaa P, Tenkanen L, Ahonen M et al: Both high and low levels of blood vitamin D are associated with a higher prostate cancer risk: a longitudinal, nested case-control study in the Nordic countries. Int J Cancer 2004; 108: 104. 80. Ahn J, Peters U, Albanes D et al: Serum vitamin D concentration and prostate cancer risk: a nested case-control study. J Natl Cancer Inst 2008; 100: 796. 81. Travis RC, Crowe FL, Allen NE et al: Serum vitamin D and risk of prostate cancer in a case-control analysis nested within the European Prospective Investigation into Cancer and Nutrition (EPIC). Am J Epidemiol 2009; 169: 1223. 82. Vieth R: Vitamin D supplementation, 25-hydroxyvitamin D concentrations, and safety. Am J Clin Nutr 1999; 69: 842. 83. Weaver CM and Fleet JC: Vitamin D requirements: current and future. Am J Clin Nutr 2004; 80: 1735S. 84. Hollis BW: Circulating 25-hydroxyvitamin D levels indicative of vitamin D sufficiency: implications for establishing a new effective dietary intake recommendation for vitamin D. J Nutr 2005; 135: 317. 85. Rajakumar K and Thomas SB: Reemerging nutritional rickets: a historical perspective. Arch Pediatr Adolesc Med 2005; 159: 335. 86. Institute of Medicine, Food and Nutrition Board, Standing Committee on the Scientific Evaluation of Dietary Reference Intakes: Vitamin D. In: Dietary Reference Intakes for Calcium, Phosphorus, Magnesium, Vitamin D, and Fluoride. Washington, D.C.: National Academy Press 1997; pp 250-287. 87. Wagner CL, Greer FR, and the Section on Breastfeeding and Committee on Nutrition: Prevention of rickets and vitamin D deficiency in infants, children, and adolescents. Pediatrics 2008; 122: 1142.

88. Tangpricha V, Pearce EN, Chen TC et al: Vitamin D insufficiency among free-living healthy young adults. Am J Med 2002; 112: 659. 89. Barger-Lux MJ, Heaney RP, Dowell S et al: Vitamin D and its major metabolites: serum levels after graded oral dosing in healthy men. Osteoporos Int 1998; 8: 222. 90. Harris SS, Dawson-Hughes B and Perrone GA: Plasma 25-hydroxyvitamin D responses of younger and older men to three weeks of supplementation with 1800 IU/day of vitamin D. J Am Coll Nutr 1999; 18: 470. 91. Harris SS and Dawson-Hughes B: Plasma vitamin D and 25OHD responses of young and old men to supplementation with vitamin D3. J Am Coll Nutr 2002; 21: 357. 92. Trivedi DP, Doll R and Khaw KT: Effect of four monthly oral vitamin D3 (cholecalciferol) supplementation on fractures and mortality in men and women living in the community: randomised double blind controlled trial. BMJ 2003; 326: 469. 93. Lyons RA, Johansen A, Brophy S et al: Preventing fractures among older people living in institutional care: a pragmatic randomised double blind placebo controlled trial of vitamin D supplementation. Osteoporos Int 2007; 18: 811.

94. Flicker L, MacInnis RJ, Stein MS et al: Should older people in residential care receive vitamin D to prevent falls? Results of a randomized trial. J Am Geriatr Soc 2005; 53: 1881. 95. Broe KE, Chen TC, Weinberg J et al: A higher dose of vitamin D reduces the risk of falls in nursing home residents: a randomized, multiple-dose study. J Am Geriatr Soc 2007; 55: 234. 96. Vieth R: Why the optimal requirement for vitamin D3 is probably much higher than what is officially recommended for adults. J Steroid Biochem Mol Biol 2004; 89: 575. 97. Pfeifer M, Begerow B and Minne HW: Vitamin D and muscle function. Osteoporos Int 2002; 13: 187. 98. Glerup H, Mikkelsen K, Poulsen L et al: Hypovitaminosis D myopathy without biochemical signs of osteomalacic bone involvement. Calcif Tissue Int 2000; 66: 419. 99. Bischoff-Ferrari HA, Dawson-Hughes B, Willett WC et al: Effect of vitamin D on falls: a meta-analysis. JAMA 2004; 291: 1999. 100. Galvao DA, Nosaka K, Taaffe DR et al: Resistance training and reduction of treatment side effects in prostate cancer patients. Med Sci Sports Exerc 2006; 38: 2045.

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Study Questions Volume 29 Lesson 6

1. Regardless of ethnicity and disease status, the best way to increase vitamin D blood levels in an individual is a. Lose weight b. Reduce cholesterol c. Consume fish d. Dietary supplements e. Sunlight 2. Which dietary supplement has consistent clinical evidence that it may reduce or favorably impact all cause mortality? a. None b. Calcium c. Multivitamin d. Vitamin D e. Vitamin E 3. How many days/weeks ideally should most dietary supplements be discontinued before surgery or radiation therapy to prevent a bleeding or adverse event? a. No days, dietary supplements now have quality control measures b. 1 to 3 Days c. 5 to 7 Days d. 1 to 2 Weeks e. 2 to 3 Weeks 4. Which form of calcium is superior to another in terms of supplementation and clinical end points (bioavailability, fracture prevention)? a. Calcium carbonate b. Calcium citrate c. Calcium phospahate d. Calcium citrate and phosphate e. All 3 are equivalent 5. In 2 to 3 months a total of 500 IU (12.5 mcg) per day of vitamin D3 from a dietary supplement or prescription increases vitamin D blood levels approximately a. 1 ng/ml (2.5 nmol/l) b. 2 ng/ml (5.0 nmol/l) c. 3 ng/ml (7.5 nmol/l) d. 4 ng/ml (10 nmol/l) e. 5 ng/ml (12.5 nmol/l)

Take this test online at http://www.auanet.org/eforms/cme/