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Calcium and vitamin D supplementation in osteoporosis

Calcium and vitamin D supplementation in osteoporosis
Literature review current through: Sep 2023.
This topic last updated: Aug 09, 2023.

INTRODUCTION — Vitamin D deficiency was originally discovered as the cause of rickets due to lack of exposure to sunshine or vitamin D-rich food. This disease is still endemic in major parts of the world [1]. Vitamin D enhances intestinal absorption of calcium and phosphate. Low concentrations of vitamin D are associated with impaired calcium absorption, a negative calcium balance, and a compensatory rise in parathyroid hormone (PTH), which results in excessive bone resorption.

The optimal calcium and vitamin D supplementation for skeletal health is uncertain. Many community-dwelling adults who are getting adequate calcium and vitamin D from dietary intake (and sun exposure) do not need to take any supplements. However, calcium and vitamin D supplementation is typically suggested as part of the treatment of osteoporosis, particularly for patients who are receiving osteoporosis medications.  

Calcium and vitamin D supplementation for people with osteoporosis will be reviewed here. Detailed information regarding the role of calcium and vitamin D in the regulation of bone cells and vitamin D for extraskeletal health is discussed separately. (See "Normal skeletal development and regulation of bone formation and resorption", section on 'Systemic and local regulators of bone cells' and "Vitamin D and extraskeletal health".)

OPTIMAL INTAKE — The optimal intake of calcium and vitamin D and the optimal serum 25-hydroxyvitamin D (25[OH]D) concentration to maintain skeletal health are not firmly established. A 25(OH)D serum value exceeding 12 to 22 ng/mL (30 to 55 nmol/L) is supported by observational studies [2-5]. The safe upper boundary, and whether serum 25(OH)D levels above 45 to 50 ng/mL (99 to 125 nmol/L) are associated with an increased risk of fracture, falls, or other adverse effect is also uncertain [5]. The controversy surrounding optimal serum 25(OH)D concentration for skeletal health is reviewed in more detail separately. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Defining vitamin D sufficiency'.)

Based upon the meta-analyses discussed below, we suggest 1200 mg of calcium (total of diet and supplement) and 800 international units of vitamin D daily for postmenopausal osteoporosis (table 1) (see 'Skeletal health outcomes' below). Although the optimal intake (diet plus supplement) has not been clearly established in premenopausal osteoporosis (or in males with osteoporosis), 1000 mg of calcium (total of diet and supplement) and 600 international units of vitamin D daily are generally suggested. We recommend not administering yearly high-dose (eg, 500,000 international units) vitamin D.

These recommendations are largely consistent with the Institute of Medicine Dietary Reference Intakes for calcium and vitamin D [6] and guidelines from the Bone Health and Osteoporosis Foundation (formerly the National Osteoporosis Foundation) [7]. The American Geriatrics Society recommends a slightly higher dose of vitamin D supplementation (at least 1000 international units daily), as well as calcium supplements, to older adults (≥65 years) to reduce the risk of fractures and falls [8]. (See 'Skeletal health outcomes' below and "Falls: Prevention in community-dwelling older persons", section on 'Vitamin D supplementation'.)

Certain coexisting medical problems may alter these requirements. (See 'Coexisting medical problems' below.)

Optimal intake can be achieved with a combination of diet plus supplements, although we prefer that as much as possible (at least half) of the calcium come from dietary sources. Calcium appears to be as well absorbed from supplements as from milk [9], and supplements were used in the above trials demonstrating benefit from increased calcium intake. It is likely, therefore, that supplements are not less effective than calcium found naturally in dairy products. However, supplements may have more adverse effects, particularly kidney stones. (See 'Side effects' below.)

It is important for patients to be aware that calcium and vitamin D alone are insufficient to prevent fracture [10,11], although they may be beneficial in some subgroups (older adults, those with low intake at baseline). (See "Overview of the management of osteoporosis in postmenopausal women" and "Treatment of osteoporosis in men".)

DIETARY SOURCES

Calcium — During clinic visits, we estimate dietary calcium intake with the aim of recommending increased dietary calcium (or calcium supplements) to patients with inadequate dietary intake and preventing excessive calcium supplementation in patients with adequate dietary intake. A rough method of estimating dietary calcium intake is to multiply the number of dairy servings consumed per day by 300 mg. One serving is 8 oz (240 mL) of milk or yogurt or 1 oz (29 g) of hard cheese. Cottage cheese and ice cream contain approximately 150 mg of calcium per 4 oz (113 g). Other foods in a well-balanced diet (dark green vegetables, some nuts, breads, and cereals) supply an average of 100 to 200 mg of calcium daily (table 2). Some cereals, soy products, and fruit juices are fortified with up to 1000 mg of calcium.

While it is possible to estimate the amount of calcium in other sources of dietary calcium, such as green vegetables and nuts, calcium absorption from these sources is more variable. In addition, vegetables and nuts have much lower calcium content than dairy products so that much more would need to be consumed to meet daily requirements. Detailed lists of the calcium content of various foods are available from the US Department of Agriculture [12].

Increased intake of dairy products or calcium-rich foods should be encouraged if dietary calcium intake is below recommended levels [13] (see 'Optimal intake' above). If this is not possible and supplements are needed, it is important to note that the intake suggested above reflects the amount of elemental calcium in supplements, not the total calcium content (see 'Calcium' below). In addition, the total intake of calcium (diet plus supplements) should not routinely exceed 2000 mg/day, because of the possibility of adverse effects [14]. (See 'Side effects' below.)

Vitamin D — In the United States, commercially fortified milk is the largest source of dietary vitamin D, containing approximately 100 international units of vitamin D per 8 oz (240 mL) (table 3) [15]. Thus, vitamin D intake can be estimated by multiplying the number of cups of milk consumed per day by 100. Vitamin D is also found in cod liver oil, but some fish oils also contain high doses of vitamin A, and therefore, they are not the best source of vitamin D [16]. Sunlight exposure also increases vitamin D concentrations. However, the use of sunscreen products effectively blocks vitamin D synthesis. In addition, the skin of those older than 70 years of age does not convert vitamin D as efficiently as in younger individuals (see "Overview of vitamin D", section on 'Metabolism'). Thus, vitamin D supplements are necessary for older adults and for people who avoid sunlight. The safe upper limit for vitamin D dosing is unclear. In 2010, the Institute of Medicine defined the Safe Upper Limit for vitamin D as 4000 international units per day [6]. (See 'Side effects' below.)

SUPPLEMENTS — In patients requiring calcium and vitamin D supplementation, a daily multivitamin is both convenient and economical. However, most multivitamins contain only 400 international units of vitamin D, which is insufficient, and not all individuals require or tolerate multivitamins (see "Vitamin intake and disease prevention"). Individuals with osteoporosis can also increase vitamin D and calcium intake by taking plain vitamin D supplements and/or calcium supplements that also contain vitamin D, usually 200 to 500 international units per 500 or 600 mg of calcium. It is important to note that there is not a direct linear relationship between supplemental dosing and level of serum 25-hydroxyvitamin D (25[OH]D). Individuals with low levels at baseline (<10 ng/mL) generally have an increase in 25(OH)D of 1.0 to 1.5 ng/mL for every 100 international units of vitamin D; however, individuals at levels above 20 ng/mL show an attenuated increase in serum 25(OH)D (ie, usually 0.5 ng/mL for every 100 international units). (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Dosing'.)

Calcium — The most widely available calcium supplements are calcium carbonate and calcium citrate (table 4). Calcium carbonate is cheapest and therefore often a good first choice. However, there are some limitations to its use compared with calcium citrate:

Calcium carbonate absorption is better when taken with meals; in comparison, calcium citrate is well absorbed in the fasting state [9,17] and is equally absorbed compared with calcium carbonate taken with a meal [18]. This may be particularly important in patients with achlorhydria. Thus, it seems prudent to take calcium carbonate with meals since it is often hard to know who has achlorhydria.

Calcium carbonate is also poorly absorbed in patients taking proton pump inhibitors (PPIs) or H2 blockers. We usually recommend calcium citrate as a first-line calcium supplement in these patients. (See "Drugs that affect bone metabolism", section on 'Proton pump inhibitors'.)

Many natural calcium carbonate preparations such as oyster shells or bone meal contain some lead, and small amounts are present in refined (antacid) calcium carbonate or calcium citrate [19,20]. The low lead levels in calcium supplements are unlikely to be a health risk, because calcium blocks lead absorption [21].

The intake recommendations given above refer to the amount of elemental calcium (see 'Optimal intake' above). As an example, calcium carbonate is 40 percent elemental calcium, so that 1250 mg of calcium carbonate contains 500 mg of elemental calcium. The dose of elemental calcium is listed on some supplement labels but not others. If the labeling reports the amount per "serving" instead of the amount per tablet, it is important to verify that the patient is taking the correct number of tablets per serving.

Calcium supplementation in excess of 500 mg/day should be given in divided doses. Higher individual doses are associated with a plateau in calcium absorption that may prevent the attainment of positive calcium balance [22].

Side effects — The total intake of calcium (diet plus supplements) should not routinely exceed 2000 mg/day, because of the possibility of adverse effects [6].

Nephrolithiasis — In general, concern that high dietary calcium increases the risk of nephrolithiasis in otherwise healthy patients is unfounded as the incidence of stone formation appears to be reduced in both females and males [23,24]. In randomized, clinical trials, however, calcium supplements have been associated with an increased risk of kidney stones [23]. The Women's Health Initiative (WHI) trial reported an increased risk of kidney stones in postmenopausal women who were supplemented with calcium and vitamin D when compared with placebo [25]. This issue is discussed in detail separately. (See "Kidney stones in adults: Epidemiology and risk factors", section on 'Calcium'.)

Cardiovascular disease — The effect of calcium supplementation on risk of cardiovascular disease (CVD), particularly myocardial infarction (MI), is controversial [26-31]. However, neither calcium supplements (up to 1000 mg daily), increased dietary intake of calcium, nor vitamin D supplements have been shown to increase all-cause [32] or cardiovascular [33] mortality, and in one meta-analysis of trials comparing vitamin D with or without calcium with no treatment or placebo, calcium plus vitamin D was associated with reduced all-cause mortality in older adults (hazard ratio [HR] 0.91, 95% CI 0.84-0.98) [34]. We and others [35] suggest combined calcium and vitamin D supplementation, as reviewed above. The National Osteoporosis Foundation considers supplementation in this dose range safe from a cardiovascular viewpoint [35]. (See 'Optimal intake' above.)

In the WHI trial, there was no effect of calcium and vitamin D supplementation on CVD [26]. In this trial, 36,282 postmenopausal women ages 50 to 69 years were randomly assigned to calcium (1000 mg/day) plus vitamin D (400 international units/day) or placebo (personal supplementation of up to 1000 mg additional calcium and 600 international units vitamin D was also allowed) [25]. CVD was a prespecified secondary outcome [26]. At baseline, mean calcium intake (diet plus supplements) was approximately 1150 mg/day, and 54 percent of participants were taking nonprotocol calcium supplements. After seven years, calcium plus vitamin D supplementation had no significant effect on the incidence of MI (confirmed in 411 and 390 women assigned to calcium/vitamin D and placebo, respectively; HR 1.05, 95% CI 0.91-1.20) or stroke (362 versus 377 strokes; HR 0.95, 95% CI 0.82-1.10).

However, the findings of two meta-analyses evaluating calcium or calcium with or without vitamin D supplementation (eight and nine trials, respectively) raised some concern about an increased risk of MI in patients randomly assigned to calcium versus placebo (166 versus 130 MIs; pooled relative risk [RR] 1.27, 95% CI 1.01-1.59) or calcium with or without vitamin D versus placebo (374 versus 302 MIs; RR 1.24, 95% CI 1.07-1.45) [27,28]. The meta-analyses had several limitations. The trials in the meta-analyses were not designed to explore cardiovascular outcomes, which were not uniformly collected or adjudicated. Patient-level data were not available from all the trials. In one of the meta-analyses, only data from a subgroup of participants in the WHI (those not taking personal calcium supplements at randomization), rather than all participants, were included in the analysis [28]. The baseline dietary calcium intake in the trials ranged from 750 to 1240 mg daily, and the addition of calcium supplements raised total intake over 1500 to 2000 mg daily in many patients, which is higher than recommended.

In contrast, other meta-analyses have not shown an increased risk of cardiovascular events with calcium with or without vitamin D supplementation [29,33,36]. As an example, in a pooled analysis of four trials, calcium supplementation did not significantly increase the risk of CVD events compared with placebo (RR 1.14, 95% CI 0.92-1.41). In these trials, dietary intake of calcium ranged from 800 to 900 mg daily, and the dose of calcium supplements ranged from 600 to 1200 mg daily. In a pooled analysis of two trials (one of which was the WHI and included data from all participants), combined vitamin D and calcium supplementation versus double placebos (RR 1.04, 95% CI 0.92-1.18) and vitamin D alone compared with placebo (RR 0.90, 95% CI 0.77-1.05) also did not significantly increase the risk of CVD, and there was a suggestion of a benefit in CVD reduction with vitamin D alone. As in the meta-analyses described above, none of the trials were designed to assess the effects of calcium or vitamin D on cardiovascular outcomes.

In some [37,38], but not all [39-41], prospective studies, there was an increased risk of cardiovascular problems with calcium supplements. As examples:

One prospective study showed a significant increased risk of MI in users versus nonusers of calcium supplements (HR 1.86, 95% CI 1.17-2.96) [37], and the other showed an increased risk of heart disease death among men, but not women, who used calcium supplements (>1000 mg daily) versus men who did not take supplements (RR 1.19, 95% CI 1.03-1.37) [38]. There were only 20 to 60 events in the calcium group, which reduced the precision of the analyses [37,38].

A very large prospective cohort study from the United Kingdom did not show evidence of an association in females or males between use of calcium and/or vitamin D supplements and hospitalization for MI or ischemic heart disease, or death after an ischemic cardiovascular event [41]. The HR for admission with MI was 0.97 (95% CI 0.79-1.2) for females taking calcium supplementation and 1.16 (95% CI 0.92-1.46) for males. There were many more events in this study compared with prior prospective studies (eg, 929 females and 2456 males were admitted with MI).

In contrast to the concern raised with calcium supplements, prospective cohort studies have shown either no relationship [38,39] or an inverse relationship [37,42] between dietary calcium intake and risk of heart disease death or MI. As an example, in one study (23,980 participants with mean follow-up of 11 years), there was a significant reduction in MI risk in patients with higher versus lower total dietary calcium intake (HR 0.69, 95% CI 0.50-0.94 for the third compared with lowest quartile of total dietary calcium intake) [37]. Thus, it is unclear from the present data whether intake of dietary calcium versus calcium supplements confers different cardiovascular risks. Randomized trials of calcium and vitamin D supplementation with CVD events ascertained as a primary endpoint are required to determine if calcium supplementation is associated with an increased occurrence of these events [43].

Other — Other potential side effects of high calcium intake include dyspepsia and constipation. In addition, calcium supplements interfere with the absorption of iron and thyroid hormone, and therefore, these medications should be taken at different times.

Vitamin D — Vitamin D is generally easier to absorb than calcium, and it may be taken as one dose with or without food. The two commonly available forms of vitamin D supplements are ergocalciferol (vitamin D2) and cholecalciferol (vitamin D3). Some [44,45], but not all [46], studies suggest that vitamin D3 increases serum 25(OH)D more efficiently than does vitamin D2 [44,45]. In addition, vitamin D2 is not accurately measured in all vitamin D assays [47]. For these reasons, we suggest supplementation with vitamin D3, when possible, rather than vitamin D2.

Calcitriol is the most active metabolite of vitamin D. It can frequently cause hypercalcemia and/or hypercalciuria, necessitating close monitoring and adjustment of calcium intake and calcitriol dose. Therefore, calcitriol is not used for vitamin D supplementation in osteoporosis. However, calcitriol or other vitamin D analogs are an important component of therapy for secondary hyperparathyroidism in chronic kidney disease (CKD). (See "Management of secondary hyperparathyroidism in adult dialysis patients" and "Management of secondary hyperparathyroidism in adult nondialysis patients with chronic kidney disease".)

Side effects — The intake at which the dose of vitamin D becomes toxic is not clear. Although there are few long-term safety data, the Institute of Medicine defined the Safe Upper Limit for vitamin D as 4000 international units per day [6]. However, higher doses are sometimes required for the initial treatment of vitamin D deficiency. (See "Overview of vitamin D", section on 'Excess' and "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Dosing'.)

It is important to inquire about additional dietary supplements (some of which contain vitamin D) that patients may be taking before prescribing extra vitamin D [48]. Excessive vitamin D, especially combined with calcium supplementation, may cause hypercalcemia, hypercalciuria, and kidney stones. In addition, chronically high levels of 25(OH)D (exceeding 40 and 50 ng/mL [100 and 125 nmol/L], respectively) have been found in some association studies to be linked to a modest increase in risk of some cancers (eg, pancreatic), mortality, and falls. More studies are needed to define the upper level of serum 25(OH)D that is safe, not only in respect to the risk of kidney stones, but also for falls and chronic diseases. (See "Vitamin D and extraskeletal health", section on 'Cancer' and "Vitamin D and extraskeletal health", section on 'Mortality' and "Vitamin D and extraskeletal health", section on 'Falls'.)

Coexisting medical problems — Many individuals with osteoporosis have underlying medical conditions that predispose to osteoporosis. Recommendations for calcium and vitamin D supplementation may vary with the underlying condition.

Vitamin D deficiency — Vitamin D deficiency may result from inadequate intake combined with lack of sun exposure, malabsorption, or genetic abnormalities in vitamin D metabolism. (See "Causes of vitamin D deficiency and resistance".)

Vitamin D deficiency is often overlooked, unless serum 25(OH)D concentrations are measured. Individuals with vitamin D deficiency generally require higher doses of vitamin D initially, followed by maintenance doses as described above. (See 'Optimal intake' above.).

In patients at very high risk for fracture in whom there is a clinical suspicion that the usual doses of calcium and vitamin D are inadequate (malabsorption, decreasing bone mass), we measure 25(OH)D concentrations to ensure that supplementation is adequate. Commercial assays measure total 25(OH)D, but some labs report vitamin D2 (25[OH]D2) and D3 (25[OH]D3) values separately. The optimal serum concentration refers to the combined total. The optimal serum 25(OH)D concentration for skeletal health is controversial. The Institute of Medicine supports concentrations above 20 ng/mL (50 nmol/L) but not chronically exceeding 50 ng/mL (125 nmol/L) [49]. Candidates for measurement of serum 25(OH)D, optimal serum 25(OH)D concentrations, and treatment of vitamin D deficiency are discussed in more detail elsewhere. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment".)

Commonly used antiresorptive agents, such as bisphosphonates, may be less effective in patients with occult vitamin D deficiency. In addition, hypocalcemia can occur in patients with vitamin D deficiency who are treated with bisphosphonates, particularly when administered intravenously, prior to repletion of vitamin D [50,51]. (See "Bisphosphonate therapy for the treatment of osteoporosis", section on 'Pretreatment evaluation'.)

Primary hyperparathyroidism — Adequate dietary calcium (800 to 1000 mg daily) and vitamin D supplementation (400 to 600 international units daily) is encouraged for patients with primary hyperparathyroidism. Cautious calcium supplementation is safe in individuals with poor dietary intake. Patients with overt vitamin D deficiency may have more clinically significant hyperparathyroidism and may require cautious supplementation with higher doses of vitamin D. (See "Primary hyperparathyroidism: Management", section on 'Preventive measures' and "Primary hyperparathyroidism: Management", section on 'Concomitant vitamin D deficiency'.)

Underlying gastrointestinal disease — Patients with malabsorption or short-bowel syndrome may have higher than normal calcium and vitamin D requirements due to diminished calcium absorption. This problem can occur even with relatively minor disruption of gastrointestinal function, as in patients who have undergone gastrectomy [52-54].

Several factors can contribute to the malabsorption of calcium in these patients:

Reduced gastric acidity and mild generalized malabsorption due to impaired mixing of food with pancreatic secretions and decreased gut transit time

Binding of calcium to fatty acids in patients with steatorrhea [52]

Vitamin D deficiency due to both malabsorption and the tendency to avoid milk [53-55]

Optimal calcium and vitamin D supplementation must be determined empirically and must be adjusted in order to normalize the serum concentrations of calcium, phosphate, alkaline phosphatase, 25(OH)D, and parathyroid hormone (PTH) and 24-hour urinary calcium excretion. (See "Bariatric operations: Late complications with subacute presentations" and "Metabolic bone disease in inflammatory bowel disease" and "Management of celiac disease in adults".)

Proton pump inhibitor therapy — Insoluble calcium, such as calcium carbonate, requires an acid environment for optimal absorption. As a result, drugs that reduce stomach acid secretion (PPIs and H2 blockers) may reduce calcium absorption. We usually recommend calcium citrate as a first-line calcium supplement in these patients. (See "Drugs that affect bone metabolism", section on 'Proton pump inhibitors'.)

Diuretic therapy — Concomitant administration of diuretics can influence calcium balance. Loop diuretics increase calcium excretion, while thiazide diuretics have a hypocalciuric effect that can protect against calcium stones and possible bone loss. The effect of diuretics on optimal dietary calcium intake is not known. (See "Drugs that affect bone metabolism".)

Chronic kidney disease — Similar to individuals with normal renal function, an optimal diet for the prevention of fracture in patients with CKD includes an adequate intake of calories (to avoid malnutrition), calcium, and vitamin D. For patients with CKD but an estimated glomerular filtration rate (eGFR) >30 mL/minute who have no biochemical evidence of related metabolic bone disorder (eg, hyperparathyroidism, hyperphosphatemia), intake of calcium and vitamin D should be the same as for patients without CKD. The effect of calcium and vitamin D supplementation on fracture risk or falls in patients with CKD and eGFR <30 mL/minute has not been adequately studied. Excess calcium supplementation (as opposed to calcium obtained by nutritional means) in patients with eGFR<30 mL/minute may be associated with an increase in greater arterial calcification and CVD. Recommendations regarding calcium and vitamin D supplementation for the management of osteoporosis in patients with eGFR <30 mL/minute are reviewed separately. (See "Osteoporosis in patients with chronic kidney disease: Management", section on 'Calcium and vitamin D'.)

Cystic fibrosis — Patients with advanced cystic fibrosis are usually deficient in vitamin D, and they require more than the usual recommended dose for young adults (eg, more than 400 international units/day). (See "Cystic fibrosis: Clinical manifestations and diagnosis", section on 'Musculoskeletal disorders'.)

Granulomatous diseases — Individuals with granulomatous diseases, such as sarcoidosis, are often treated with glucocorticoids and therefore have an increased risk of osteoporosis. However, they also tend to have hypercalcemia and hypercalciuria due to extrarenal production of calcitriol by activated macrophages and consequent increased intestinal absorption of calcium (see "Hypercalcemia in granulomatous diseases"). In patients with sarcoidosis and osteoporosis, serum and urinary calcium and vitamin D concentrations must be carefully monitored if supplements are required [56,57].

SKELETAL HEALTH OUTCOMES

Calcium and/or vitamin D — Vitamin D enhances intestinal absorption of calcium and phosphate. Low concentrations of vitamin D are associated with impaired calcium absorption, a negative calcium balance, and a compensatory rise in parathyroid hormone (PTH), which results in excessive bone resorption. (See "Normal skeletal development and regulation of bone formation and resorption", section on 'Systemic and local regulators of bone cells'.)

Many studies, including a large, population-based study (National Health and Nutrition Examination Survey [NHANES]-III) that included 13,432 participants, have shown a positive association between serum 25-hydroxyvitamin D (25[OH]D) and bone mineral density [4,58-60]. In several [2,3,5,61-64], but not all [65-68], observational studies, low serum concentrations of 25(OH)D (calcidiol) were associated with a higher risk of hip fracture, particularly among individuals with serum 25(OH)D <12 compared with ≥30 ng/mL (<30 compared with ≥75 nmol/L) [5].

Prospective, randomized, placebo-controlled trials have generally not shown a benefit of calcium and/or vitamin D supplementation for fracture prevention [25,69-74]. The majority of the trials evaluated supplementation in the general population of older adults, who were not specifically selected for vitamin D deficiency or a diagnosis of osteoporosis. Calcium and vitamin D supplementation in individuals who already have adequate calcium intake and normal vitamin D levels is unlikely to be of benefit [75].

Calcium or calcium plus vitamin D Although a number of trials have reported a beneficial effect of calcium or calcium plus vitamin D on bone density in older adults , the data on fracture rates are more variable. Some trials have reported a reduction in fracture [25,76-85], but larger randomized trials have not shown any reduction in fracture risk with calcium plus vitamin D (figure 1) [25,69]. The variability may be due to differences in patient populations (community dwelling versus nursing home) and study design.

Vitamin D – In the Vitamin D and Omega-3 Trial (VITAL) trial, in which 25,871 community dwelling men (≥50 years of age) and women (≥55 years) were randomly assigned to vitamin D (cholecalciferol) 2000 units (50 mcg) daily or placebo, the rate of total fractures (5.9 versus 6 percent, hazard ratio [HR] 0.98, 95% CI 0.89-1.08), nonvertebral fractures (5.6 versus 5.7 percent), and hip fractures (0.44 versus 0.43 percent) was similar in the two groups [74]. The participants were not selected on the basis of vitamin D deficiency, low bone mass, or osteoporosis. The mean 25(OH)D level (in a subset of participants) was 30 ng/mL (75 nmol/L), approximately 10 percent of the total group had a history of a fragility fracture, and approximately 5 percent were taking osteoporosis medications.

In two earlier placebo-controlled trials of high-dose (300,000 to 500,000 international units) vitamin D administered once yearly (without calcium supplementation), vitamin D did not reduce the risk of fracture [86,87]. In one of the trials, the risk of falls and fracture was increased in the vitamin D group (RRs 1.15, 95% CI 1.02-1.30 and 1.26, 95% CI 1.00-1.59 for falls and fracture, respectively) [87]. In the vitamin D group, the median 25(OH)D concentrations after one and three months were approximately 48 and 36 ng/mL (120 and 90 nmol/L), respectively. (See "Vitamin D and extraskeletal health", section on 'Falls'.)

Systematic reviews and meta-analyses have reported variable results [88-92].

Meta-analyses of trials comparing calcium, vitamin D, or both with placebo or no treatment in older adults in the community, nursing home, or hospital inpatient service, reported a beneficial reduction in fracture with calcium [88] and calcium plus vitamin D [88,93,94], but not with vitamin D alone [93-95]. Relative risk (RR) reductions for hip fracture ranged from 0.81 to 0.87 for combined calcium plus vitamin D supplementation [94]. These findings suggest that supplementation with vitamin D does not reduce the risk of fracture unless there is adequate calcium.

In a systematic review of 11 trials comparing vitamin D (300 to 700 international units/day or 100,000 international units monthly), calcium (500 to 1600 mg daily), or both with placebo or control in 51,419 community-dwelling adults ≥50 years of age, vitamin D supplementation reduced the incidence of total fracture (one trial, absolute risk difference [ARD] -2.26 percent, 95% CI -4.53 to 0 percent) but not hip fracture (three trials, ARD -0.01 percent, 95% CI -0.8 to 0.78 percent) [90]. Supplementation with vitamin D and calcium had no effect on incidence of total or hip fracture. The evidence for calcium alone was limited.

The benefit of nutrient supplementation with calcium and vitamin D appears to be greater among institutionalized or hospitalized than community-dwelling individuals.

In a cluster randomized trial evaluating the addition of dairy products (eg, milk, yogurt, or cheese to provide 562 mg/day of calcium and 12/g/day of protein) in over 7000 institutionalized, vitamin D-supplemented, older adults (mean age 86 years), the incidence of total fractures (3.7 versus 5.2 percent in controls, hazard ratio [HR] 0.67, 95% CI 0.48-0.93), hip fractures (1.3 versus 2.4 percent, HR 0.54, 95% CI 0.35-0.83), and falls (57 versus 62 percent, HR 0.89, 95% CI 0.78-0.98) was lower in the dairy product group (mean follow-up 12.6 months) [96]. There was no difference in mortality.

Racial differences — African Americans have lower fracture risks, higher bone density, and lower vitamin D levels than other races. They have skeletal resistance to parathyroid hormone (PTH). In the WHI, Black American women had a higher rate of fracture when the vitamin D level was >20 ng/mL (50 nmol/L), which is the opposite of the risk in White American women, in whom the fracture rate was lower when the vitamin D level was >20 ng/mL [97]. There is very little evidence about effects of vitamin D or calcium supplementation in persons who are not White, but since racial differences in mineral metabolism are substantial, we cannot apply findings from one race to other races. It has been shown that Black American women do increase their circulating levels of vitamin D after oral supplementation to levels similar to White American women, but it is not clear if this is beneficial [98,99]. However, there may be differences in the vitamin D-binding protein levels by race (depending on the assay employed), which complicates interpretation of the total 25(OH)D level and their PTH response. Currently it is unclear whether "free" 25(OH)D levels (either calculated or directly measured) differ by race or ethnicity. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment", section on 'Population differences'.)

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Osteoporosis" and "Society guideline links: Vitamin D deficiency".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

Basics topics (see "Patient education: Calcium and vitamin D for bone health (The Basics)")

Beyond the Basics topics (see "Patient education: Calcium and vitamin D for bone health (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

Optimal intake – The optimal intake of calcium and vitamin D for skeletal health is uncertain. Many community-dwelling adults who are getting adequate calcium and vitamin D from dietary intake (and sun exposure) do not need to take any supplements. However, calcium and vitamin D supplementation is typically suggested as part of the treatment of osteoporosis, particularly for patients who are receiving osteoporosis medications.

In postmenopausal osteoporosis, 1200 mg of calcium daily (total diet plus supplement) and 800 international units of vitamin D daily are advised. In premenopausal osteoporosis or in males with osteoporosis, 1000 mg of calcium (total of diet and supplement) and 600 international units of vitamin D daily are generally suggested. (See 'Optimal intake' above and "Overview of the management of osteoporosis in postmenopausal women" and "Evaluation and treatment of premenopausal osteoporosis" and "Treatment of osteoporosis in men".)

Dietary sources – Optimal intake can be achieved with a combination of diet plus supplements, although we prefer that at least half come from dietary sources. Dairy products have the highest calcium content per serving (table 2). In the United States, commercially fortified milk is the largest source of dietary vitamin D (table 3). (See 'Dietary sources' above.)

Supplements – Increased intake of dairy products or calcium-rich foods should be encouraged if dietary calcium intake is below recommended levels. If this is not possible, we suggest calcium and vitamin D supplementation in patients with osteoporosis and inadequate dietary intake (Grade 2C). (See 'Supplements' above.)

Calcium – The most widely available calcium supplements are calcium carbonate and calcium citrate (table 4). In most individuals, calcium carbonate taken with meals is adequate for supplementation and is inexpensive. However, we recommend calcium citrate in patients taking proton pump inhibitors (PPIs) or H2 blockers or who have achlorhydria (Grade 1B) (see "Drugs that affect bone metabolism", section on 'Proton pump inhibitors'). The intake recommendations given above refer to the amount of elemental calcium in the calcium supplement. (See 'Calcium' above.)

Vitamin D – We suggest cholecalciferol (vitamin D3), when available, rather than ergocalciferol (vitamin D2) for vitamin D supplementation (Grade 2C). (See 'Vitamin D' above.)

Side effects

Safe upper limits – The total intake of calcium (diet plus supplements) should not routinely exceed 2000 mg/day. The Safe Upper Limit for vitamin D is 4000 international units daily, but this is based on limited data. (See 'Side effects' above and 'Side effects' above.)

Nephrolithiasis – Calcium supplements (but not dietary calcium) have been associated with an increased risk of kidney stones. (See 'Nephrolithiasis' above.)

Cardiovascular – There is debate about the cardiovascular risk of calcium supplementation, particularly when the total calcium intake exceeds the recommended amounts or supplements are given in large doses. Until this issue is settled, it would be wise to avoid excess supplementation, to avoid doses over 500 mg at one time, and to encourage dietary intake over tablets. (See 'Cardiovascular disease' above.)

Coexisting medical problems – The dose of calcium and vitamin D may vary in individuals with coexisting medical conditions. As an example, individuals with vitamin D deficiency due to malabsorption or coexistent liver disease require higher initial doses of vitamin D (see 'Coexisting medical problems' above). The evaluation and treatment of vitamin D deficiency are reviewed separately. (See "Vitamin D deficiency in adults: Definition, clinical manifestations, and treatment" and "Causes of vitamin D deficiency and resistance".)

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References

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