Controversal question: Is systematic supplementation with calcium/vitamin D necessary to treat postmenopausal osteoporosis?



1. S. Y. Chia, Singapore
2. A. Gur, Turkey
3. P. Lakatos, Hungary
4. O. M. Lesnyak, Russian Federation
5. R. S. Mason, Australia
6. J. L. A. Morales-Torres, Mexico
7. R. Nuti, Italy
8. R. Sánchez-Borrego, Spain
9. M. E. Simões, Portugal
10. T. J. de Villiers, South Africa
11. S. S. Yeap, Malaysia


1. S. Y. Chia, Singapore



CHIA Su-Ynn,, MBBS, MRCP (UK),
FAMS (Endocrinology)
Consultant Endocrinologist & Physician
Alumnus, The Cleveland Clinic (USA)
The Endocrine Clinic
#17-16 Mount Elizabeth Medical
Centre S228510, SINGAPORE
(e-mail: drchia@the-endo-clinic.com)



Calcium and vitamin D are important for skeletal homeostasis, and postmenopausal women have a higher risk of both calcium and vitamin D deficiencies. Many large population-based studies, including the National Health And Nutrition Examination Survey III (NHANES III; n=13 432), have shown a positive association between serum25-hydroxyvitamin D [25(OH)D] levels and bone mineral density (BMD), with BMD increasing monotonically with higher 25(OH)D levels up to at least 32 ng/mL (80 nmol/L).1,2 Serum 25(OH)D levels in institutionalized individuals and the very elderly (>70 years) have also been found to correlate with muscular strength and postural balance, both important factors for fall risk. Most (including NHANES III),3 but not all, observational studies have found that lower serum 25(OH)D levels are associated with a higher risk of hip, vertebral, and non-vertebral fractures in postmenopausal women. These studies seem to suggest that serum 25(OH)D levels exceeding 19 to 24 ng/mL (47.5 to 60 nmol/L) are necessary to maintain skeletal health in older individuals.3

Randomized placebo-controlled trials have generally reported a beneficial effect of calcium or calcium plus vitamin D supplementation on bone density in postmenopausal women.4 However, data on fracture prevention have been more conflicting. The two largest trials, WHI (Women’s Health Initiative; n=36 282) and RECORD (Randomised Evaluation of Calcium OR vitamin D; n=5292), showed no significant reduction in fracture risk (primary and secondary prevention) with calcium (1000 mg/day) and vitamin D (400-800 IU/day) supplementation.4,5 Meta-analyses have also yielded variable conclusions depending on the trials included. The largest and probably most comprehensive meta-analysis6 found that overall there was a statistically significant reduction in the incidence of hip fracture with calcium/vitamin D supplementation (relative risk [RR], 0.84; 95% confidence interval [CI], 0.73-0.96), particularly in institutional residents but not in community dwellers. Overall, there was no statistically significant reduction in the incidence of new non vertebral fractures, although this was significant in institutional residents (RR, 0.85; 95% CI, 0.74-0.98). No risk reduction was found for clinical vertebral fractures regardless of residential status.

Several factors may be responsible for the conflicting results. These may include differing patient populations (community dwelling or institutionalized, aged below or above 70-75 years), adherence to therapy, doses of calcium and vitamin D used, baseline vitamin D levels, and target vitamin D levels achieved after treatment. Current data seem to suggest that calcium and vitamin D supplementation probably has the most fracture risk reduction in institutionalized residents and in those who are very elderly and who are compliant with therapy. The optimal daily dose of calcium for women with postmenopausal osteoporosis appears to be 1000-1500 mg/day, with no additional benefit being seen above 1500-2000 mg/day. Vitamin D doses of at least 700-800 IU/day appear to be associated with significant reductions of almost 20% in both hip and non-vertebral fractures, whereas no risk reduction was seen in trials and cohorts using 400 IU/day. Fracture risk reduction appears to be optimal with achieved serum 25(OH)D levels of between 75-110 nmol/L (30-44 ng/mL). This may require between 1800 to 4000 IU of vitamin D per day in individuals with low baseline 25(OH)D level. It has been recommended that the upper safety limits for vitamin D supplementation be revised upwards from 2000 IU/day to 10 000 IU/day, with minimal risk of hypercalcemia.

In conclusion, calcium and vitamin D supplementation remains an important part of therapy for postmenopausal osteoporosis, with optimum efficacy for fracture risk reduction in older women who are compliant with therapy, institutionalized residents, and those with low baseline 25(OH)D levels. Ideal calcium intake should be between 1000-1500 mg/day, while vitamin D doses should be at least 800 IU/day and tailored to achieve 25(OH)D levels between 75-110 nmol/L (30- 44 ng/mL).

References
1. Bischoff-Ferrari HA, Dietrich T, Orav EJ, et al. Positive association between 25- hydroxy vitamin D levels and bone mineral density: a population-based study of younger and older adults. Am J Med. 2004;116:634-639.
2. Kuchuk NO, van Schoor NM, Pluijm SM, et al. Vitamin D status, parathyroid function, bone turnover, and BMD in postmenopausal women with osteoporosis: global perspective. J Bone Miner Res. 2009;24:693-701.
3. Gerdhem P, Ringsberg KA, Obrant KJ, et al. Association between 25-hydroxy vitamin D levels, physical activity, muscle strength and fractures in the prospective population-based OPRA Study of Elderly Women. Osteoporos Int. 2005;16: 1425-1431.
4. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354:669-683.
5. Grant AM, Avenell A, Campbell MK, et al. Oral vitamin D3 and calcium for secondary prevention of low-trauma fractures in elderly people (Randomised Evaluation of Calcium Or vitamin D, RECORD): a randomised placebo-controlled trial. Lancet. 2005;365:1621-1628.
6. Avenell A, Gillespie WJ, Gillespie LD, O’Connell D. Vitamin D and vitamin D analogues for preventing fractures associated with involutional and post-menopausal osteoporosis. Cochrane Database Syst Rev. 2007;2:1-161.



2. A. Gur, Turkey



Ali GUR, MD
Gaziantep University Medical School
Department of Physical Medicine
and Rehabilitation
Gaziantep, TURKEY
(e-mail: aligur1970@gmail.com)



Osteoporosis-related fractures are associated with significant morbidity and mortality. The importance of this disease as a worldwide public health problem is evident. Since reduction of fracture risk is the main goal in treating patients with osteoporosis, a complete strategy against this devastating disease should always include trying to reduce the risk of falls. Prerequisites for any therapeutic strategy to prevent osteoporosis and fractures are sufficient calcium and vitamin D intake, physical activity, and fall prevention. Vitamin D supplements today play a key therapeutic role. The efficacy of specific drugs for osteoporosis has been shown only when such supplements are given concurrently. Guidelines therefore recommend adequate calcium and vitamin D intake in addition to antiresorptive medications for the prevention of osteoporotic fractures.

Vitamin D deficiency and insufficiency afflict approximately one billion individuals worldwide. Vitamin D has a proven impact on bone mineral density and bone quality.1 It is important to determine the optimal intake of calcium and vitamin D to minimize the risk of falls and fractures. In older men and women, higher 25-hydroxyvitamin D [25(OH)D] levels have been associated with better muscle performance and balance, and vitamin D supplementation has reduced body sway—a measure of balance—and improved grip strength. Desirable levels of 30 ng/ml have been shown to reduce the risk of falls and fractures.2 The function of vitamin D is not limited to maintaining normal bone mineralization, but involves different organs and tissues containing specific receptors.3 Maintaining sufficient levels of 25(OH)D (>30 ng/ml) helps prevent several pathologies and maintain good general health.4 Routine screening of 25(OH)D levels is not recommended for those at normal risk, but is advisable for higher-risk older adults.

Calcium and vitamin D are recommended as a baseline supplemental therapy to sustain bone health, rather than to treat osteoporosis. Evidence suggests that vitamin D/calcium supplementation may have favorable effects on bone mineral density and even reduce the risk of fracture,5 although some recent randomized controlled trials have shown no evidence of a reduced fracture risk with vitamin D/calcium supplementation. In a recent meta-analysis in men and women aged 50 years or older, a combination of calcium and vitamin D was shown to significantly reduce the risk of non-vertebral fracture, and to reduce bone loss at the hip and at the spine.6 In this study, treatment effects were greatest with daily doses of calcium ≥1200 mg and of vitamin D ≥800 IU. Additional benefits of vitamin D/calcium supplementation in postmenopausal women are a notable reduction in the incidence of falls, which may be attributed to effects on muscle strength and balance.

The American Society for Bone and Mineral Research has issued a statement recommending the use of combined vitamin D and calcium supplementation instead of calcium-only supplementation, and a preference for increased dietary uptake of calcium over calcium supplements.

In conclusion, adequate intake of vitamin D and calcium is recommended as an inexpensive baseline therapy for the prevention and treatment of postmenopausal osteoporosis, and is included in most clinical trials evaluating newer therapeutic osteoporosis agents.


References
1. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Prevention of nonvertebral fractures with oral vitamin D and dose dependency: a meta-analysis of randomized controlled trials. Arch Intern Med. 2009;169:551-561.
2. Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ. 2009;339:b3692.
3. Hollick MF. Vitamin D deficiency. N Engl J Med. 2007;357:266-281.
4. Freedman BI,Wagenknecht LE, Hairston KG, et al. Vitamin D, adiposity, and calcified atherosclerotic plaque in African-Americans. J Clin Endocrinol Metab. 2010; 95:1076-1083.
5. Jackson RD, La Croix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354:669-683.
6. Tang BM, 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;370:657-666.



3. P. Lakatos, Hungary



Peter LAKATOS, MD, PhD, DSc
Professor of Medicine
1st Department of Medicine
Semmelweis University
Budapest, HUNGARY
(e-mail: lakpet@bel1.sote.hu)



One of the major components of the skeleton is calcium. Calcium absorption and its proper incorporation into bone tissue are stimulated by vitamin D. Based on these simple facts, calcium and vitamin D supplementation appears to be a logical step in the treatment of osteoporosis. Especially if we consider that a large proportion of the population worldwide has low calcium intake as well as vitamin D deficiency/insufficiency.

In the case of calcium, the necessary intake for maintenance of calcium balance was previously determined and is 1000- 1500 mg/day, depending on the physiological condition (during growth, in the elderly, menopause, pregnancy, etc). Reduced calcium intake may lead to a negative calcium balance and deterioration of bone mass. Thus, supplementation in patients with osteoporosis should be beneficial. However, five large-scale, randomized, controlled trials have questioned the benefits of calcium in reducing fracture risk.1 Calcium users have also been suspected of being at increased risk for renal stones and gastrointestinal problems. Nevertheless, these studies had important limitations, including selection bias, high baseline calcium intake, and low adherence to treatment regimens. Moreover, in some of the studies, vitamin D was not included in the treatment protocol or was not used at levels sufficient to optimize calcium absorption. In trials with the most treatment-adherent participants, significant reduction in osteoporotic fracture risk with calcium supplement use was found.1

High calcium intake (>2000 mg daily) may, however, result in an increased number of fractures.2 To increase the turmoil further, some evidence has been published showing an association between calcium supplementation of more than 500 mg/day and increased risk of cardiovascular disease.3,4 However, a number of criticisms can be brought against these studies, thus the data need validation in prospective, randomized, placebo-controlled trials.4,5 Vitamin D has been in existence for about 500 million years, which suggests that the primary target of this compound is not the skeleton. During the last two decades, a number of other functions for vitamin D have been reported, including antitumor, immune-modulatory, endocrine, and neural effects. With the change in our lifestyles, ie, not staying long enough in the sunshine, vitamin D deficiency/insufficiency has become extremely widespread. 6 According to recent reports, 50%-70% of the elderly populations of developed countries suffer from this condition. Vitamin D supplementation alone or in combination with calcium results in a consistent bone-protective effect. Daily administration of 800-1000 IU vitamin D in those with osteoporosis inevitably reduces fracture rate. However, very high doses of vitamin D once per year may have adverse effects. The extra skeletal effects of vitamin D are in addition to the beneficial effect on bone, but these are still under investigation.

Anti-osteoporotic drugs cannot exert their therapeutic effects unless proper calcium and vitamin D supply is present. When patients with osteoporosis are treated with a bisphosphonate, they should receive a vitamin D and calcium supplement to avoid secondary hyperparathyroidism caused by markedly decreased calcium efflux from bone. Analysis of all the available data suggest that in postmenopausal osteoporotic patients receiving therapy, we should obtain and maintain a serum 25(OH)D level of between 30-50 ng/mL and a calcium intake of 1200 mg/day, by supplementation if needed.


References
1. Spangler M, Phillips BB, Ross MB, Moores KG. Calcium supplementation in postmenopausal women to reduce the risk of osteoporotic fractures. Am J Health Syst Pharm. 2011;68:309-318.
2. Klompmaker TR. Lifetime high calcium intake increases osteoporotic fracture risk in old age. Med Hypotheses. 2005;65:552-558.
3. Bolland MJ, Grey A, Avenell A, Gamble GD, Reid IR. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ. 2011;342:d2040.
4. Miller PD. Vitamin D, calcium, and cardiovascular mortality: a perspective from a plenary lecture given at the annual meeting of the American Association of Clinical Endocrinologists. Endocr Pract. 2011;17:798-806.
5. Meier C, Kränzlin M. Calcium supplementation, osteoporosis and cardiovascular disease. Swiss Med Wkly. 2011;141:w13260.
6. van Schoor NM, Lips P. Worldwide vitamin D status. Best Pract Res Clin Endocrinol Metab. 2011;25:671-680.



4. O. M. Lesnyak, Russian Federation



Olga M. LESNYAK, MD
Professor, Doctor of Medical Science
Head, Family Medicine Department
Ural State Medical Academy
Department of Rheumatology
Sverdlovsk Regional Hospital #1
185, Volgogradskaya Street
Yekaterinburg 620102
RUSSIAN FEDERATION
(e-mail: lesnyak@sky.ru)



Vitamin D and calcium play key roles in bone physiology. Inadequate serum 25-hydroxyvitamin D [25(OH)D] concentrations have been shown to be very common in postmenopausal osteoporosis. Vitamin D deficiency leads to decreased intestinal calcium absorption, which, in turn, results in secondary hyperparathyroidism, increased bone turnover, and accelerated bone loss, and can eventually increase fracture risk. In addition, declining serum levels of vitamin D in elderly people are associated with muscle weakness and sarcopenia, resulting in reduced physical performance and higher propensity to falls. Vitamin D thus affects fracture risk through its effects on both bone metabolism and falls. As such, vitamin D supplementation may provide additional benefits given on top of other anti-osteoporotic therapy, because the latter does not influence muscle strength and balance and therefore does not reduce the risk of falls. Moreover, it has been shown that adequate vitamin D supplementation is necessary for optimal response to antiresorptives.1 As a result, there is no doubt that vitamin D/calcium supplementation is necessary in all cases of postmenopausal osteoporosis. However, the available data on the antifracture efficacy of vitamin D, as well as its dosage, are still controversial. Vitamin D supplementation has been inconsistently shown to reduce the risk of non-vertebral fractures, particularly hip fractures. By contrast, it does not seem to influence the risk of vertebral fracture, and cannot be used in the treatment of osteoporosis alone without other approved antiresorptive or anabolic agents.

In recent years, several meta-analyses have been performed to study the effect of vitamin D on fracture risk and falls. The majority have found that the degree of reduction in falls and fracture risk was dose dependent and higher in those who received higher doses of vitamin D. Supplementation of at least 700 IU of vitamin D, preferably cholecalciferol, was required to achieve risk reduction. At doses of <400 IU/day, no significant benefit was found for reduction of falls and fracture rate. Bischoff-Ferrari et al2 suggest a daily dose of vitamin D providing a 25(OH)D concentration of ≥75 nmol/L (in the range 1800-4000 IU), although other guidelines are more conservative. The International Osteoporosis Foundation Working Group3 proposes 2000 IU daily for people at risk of vitamin D deficiency, while Osteoporosis Canada recommends 800- 2000 IU daily for osteoporosis patients over 50 years old, emphasizing that in some cases, the dosage of vitamin D can be even higher.4 The absence of a clear consensus stems from the fact that the efficacy and safety of doses >800 IU for fracture and 1000 IU for falls have not been evaluated in randomized controlled trials. We should be cautious in interpreting the results of studies showing the usefulness of large loading doses of vitamin D in patients with severe vitamin D deficiency. Such an approach might be effective in achievement of rapid repletion and normalization of vitamin D status; however, it was reported that an annual oral intake of 500 000 IU of Vitamin D3 resulted in an increased risk of falls and fractures.5

In my view, at present, daily doses of vitamin D should not exceed 2000 IU. Doses should be determined based on the initial 25(OH)D level, body size, age, presence of obesity, and sun exposure limitation, etc. The International Osteoporosis Foundation Working Group recommends estimating the required dose of cholecalciferol based on the measured 25(OH)D level: each 100 IU of added vitamin D will increase serum 25(OH)D by about 2.5 nmol/L.3 In addition, it is reasonable to perform a retest about 3 months after starting supplementation in order to confirm that the target concentration has been reached. We need further robust data from randomized controlled trials using high-dose vitamin D supplementation.


References
1. Adami S, Giannini S, Bianchi G, et al. Vitamin D status and response to treatment in post-menopausal osteoporosis. Osteoporos Int. 2009;20:239-244.
2. Bischoff-Ferrari HA, Shao A, Dawson-Hughes B, et al. Benefit-risk assessment of vitamin D supplementation. Osteoporos Int. 2010;21:1121-1132.
3. Dawson-Hughes B, Mithal A, Bonjour JP, et al. IOF position statement: vitamin D recommendations for older adults. Osteoporos Int. 2010;21:1151-1154.
4. Hanley DA, Cranney A, Jones G, et al. Vitamin D in adult health and disease: a review and guideline statement from Osteoporosis Canada. CMAJ. 2010;182: E610-E618.
5. Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women: a randomized controlled trial. JAMA. 2010;303:1815-1822.



5. R. S. Mason, Australia



Rebecca S. MASON, MBBS, PhD
Physiology and Bosch Institute
for Medical Research
Sydney Medical School
Physiology, F13
University of Sydney NSW, 2006
Sydney, AUSTRALIA
(e-mail: rebecca.mason@sydney.edu.au)



The point of treating osteoporosis is to reduce fractures. From basic physiology, ionized calcium must be maintained within a relatively narrow range for optimal sensitivity to depolarization of excitable tissues, nerve, and muscle. Calcium is also an essential component of bone mineral. Calcium is not plentiful in food, however, and ingested calcium is inefficiently absorbed. There is an obligatory daily loss of 150-200 mg calcium in urine, higher in postmenopausal women. If blood calcium is to be maintained, the lost calcium will have to come from absorption of ingested calcium, or from bone. Generally, neutral calcium balance requires ingestion of around 1000-1200 mg calcium, with the higher amounts required for postmenopausal women.1 Vitamin D, or at least its hormonal form, 1,25-dihydroxyvitamin D [1,25(OH)2D] is also required for active gut calcium absorption.

If either ingested calcium is inadequate, or 25-hydroxyvitamin D [25(OH)D] levels are low, more parathyroid hormone is secreted and bone turnover increases. High bone turnover is itself a risk factor for fracture. Continued resorption of bone, particularly in older individuals, whose capacity to replace bone is limited, will reduce bone density and impair bone architecture. There is some evidence that low calcium intake, mal-absorption, and/or raised parathyroid hormone levels also accelerate the degradation of vitamin D.2 Recently, local 1,25(OH)2D production in osteoblasts has been reported, with somewhat different physiological outcomes described when 1,25(OH)2D is produced within bone cells compared with exogenous addition.3 This provides another theoretical basis for ensuring adequate circulating concentrations of substrate to optimize bone function. With moderate consistency, cross-sectional studies in older individuals show that bone density generally increases with 25(OH)D up to around 50 nmol/L.4 There is also evidence, at least in older individuals, that optimal lower extremity muscle function increases with 25(OH)Dup to around 50 nmol/L,4 which could contribute to fewer falls and fewer fractures. From this physiology, it is reasonable to propose that adequate calcium intake and vitamin D levels sufficient to suppress parathyroid hormone levels ought to be a minimum base in postmenopausal women. A third pillar, adequate weight-bearing exercise, would also be physiologically ideal.

Trials of supplemental vitamin D and calcium have produced mixed results. But calcium and vitamin D are not like ordinary pharmacological agents, and are normally present in the body. So any increases above “optimal” levels may not show a benefit. Benefits are more likely to be seen if the study population is substantially deficient in vitamin D and/or has low calcium intake at baseline. Often forgotten is that even 1000 IU vitamin D per day is only likely to raise 25(OH)D by 10-20 nmol/L, so smaller doses of 400 IU/day may not achieve much. Compliance issues are well recognized. Several meta-analyses have mostly concluded that despite a relatively large number of trials showing no benefit, there is a moderate consensus that supplementation with vitamin D, mostly with calcium, modestly decreases fractures, provided the caveats are kept in mind. While there are theoretical reasons, outlined above, as to why the combination of vitamin D and calcium might be more effective than vitamin D alone, it should be noted that the vast majority of the individual study participants were enrolled in trials of vitamin D with calcium, rather than vitamin D alone.

Given the myriad of other problems in postmenopausal women, it is hardly surprising that additional pharmacological intervention might be needed to more robustly decrease fracture risk. There is limited evidence that the effectiveness of agents such as bisphosphonates and selective estrogen receptor modulators is reduced if calcium and vitamin D levels are less than optimal.5,6 Accordingly, it is reasonable to propose that calcium and vitamin D repletion might form a reasonable baseline on which to add further pharmacological interventions.

Acknowledgements: Funding for research studies has been provided by the National Health and Medical Research Council of Australia; the Australian Research Council; Servier, France; Nestle, Australia. Speaker fees and honoraria from Bayer Health Care, Servier, Australia, Key Pharmaceuticals, Mushroom Growers Association of Australia.



References
1. Nordin BE. Calcium and osteoporosis. Nutrition. 1997;13:664-686.
2. Davies M, Heys SE, Selby PL, Berry JL, Mawer EB. Increased catabolism of 25- hydroxyvitamin D in patients with partial gastrectomy and elevated 1,25-dihydroxyvitamin D levels. Implications for metabolic bone disease. J Clin Endocrinol Metab. 1997;82:209-212.
3. Atkins GJ, Anderson PH, Findlay DM, et al. Metabolism of vitamin D3 in human osteoblasts: evidence for autocrine and paracrine activities of 1 alpha,25-dihydroxyvitamin D3. Bone. 2007;40:1517-1528.
4. Lips P, Bouillon R, van Schoor NM, et al. Reducing fracture risk with calcium and vitamin D. Clin Endocrinol. 2010;73:277-285.
5. Adami S, Giannini S, Bianchi G, et al. Vitamin D status and response to treatment in post-menopausal osteoporosis. Osteoporos Int. 2009;20:239-244.
6. Ishijima M, Sakamoto Y, Yamanaka M, et al. Minimal required vitamin D level for optimal increase in bone mineral density with alendronate treatment in postmenopausal women. Calcif Tissue Int. 2009;85:398-404.



6. J. L. A. Morales-Torres, Mexico



Jorge L. A. MORALES-TORRES, MD
Professor of Rheumatology
Clínica de Osteoporosis
Hospital Aranda de la Parra
Hidalgo 329-704
León 37000, GTO
MEXICO
(e-mail: jorgitomorales@prodigy.net.mx)



There is a very high prevalence of calcium, protein, and vitamin D insufficiency in the elderly. Calcium and vitamin D supplementation reverses secondary hyperparathyroidism, has beneficial effects on bone density, and additionally, improves body sway and lower extremity strength, reducing the risk of falls.1-3 Conflicting results—both positive and negative—regarding the effect of supplementation on fracture risk raise questions as to the rationale behind its indication. Some of the discrepancies reported in the existing literature may arise from the fact that subjects entering clinical trials with these agents show great differences in baseline calcium intake and vitamin D status, different doses during the trials, and limited compliance, resulting in controversial conclusions.1-3 Meta-analysis of many of these trials reports a modest reduction of fracture risk in compliant patients.4

Practically all of the evidence-based guidelines on prevention and treatment of osteoporosis support the need to supplement calcium and vitamin D in women with a deficiency or at risk of having a deficiency, and in all of those who receive antiresorptive or anabolic therapy. Supplementation is widely accepted as a preventive therapy in women at risk, particularly in those with dietary insufficiencies, but should not be recommended as a single therapy for women with fragility fractures or women who fulfill criteria for osteoporosis, or those who have an elevated 10-year absolute fracture risk as defined by FRAX. In those patients, currently-approved antiresorptive and bone forming agents have been shown to significantly decrease the risk of both vertebral and non-vertebral fractures when compared with patients receiving placebo plus calcium and vitamin D in randomized controlled clinical trials.1-3

Maintaining adequate intake of calcium and vitamin D through diet modification and/or supplementation should be considered part of the standard care of patients with postmenopausal osteoporosis. Dairy products constitute the main nutritional source of calcium in the Western diet. Most guidelines state the need to reach a daily intake of 1200-1500 mg of calcium in postmenopausal women. Rarely will patients include such an intake in their regular diet, and therefore estimation of consumption (with simple questionnaires on sources of calcium in the usual diet) may help in practically defining the dose to add in the form of supplements for each patient. Calcium carbonate and citrate are the most commonly used forms, with some advantages for the latter in terms of digestive tolerance.1-3

Based on the relationship between serum 25-hydroxyvitamin D [25(OH)D], bone mineral density, bone turnover, lower extremity function, and falls, it has been suggested that 50 nmol/L is the appropriate serum 25(OH)D concentration threshold to define vitamin D insufficiency. The aim of supplementation should therefore generally be to increase 25(OH)D levels to within the 50-75 nmol/L range. The estimated average vitamin D requirements for older adults to reach an “optimal” serum 25(OH)D concentration of 75 nmol/L (30 ng/ml) is 20-25 μg/day (800 to 1000 IU/day of vitamin D3 or cholecalciferol).1-6

Although gastro intestinal upset with most calcium forms is not uncommon, serious toxicity is rare. Concerns about the relationship between calcium supplementation and kidney stones, atherosclerosis, and colorectal cancer have been reasonably ruled out by several studies. Recommended doses of vitamin D also show a very low incidence of side effects.

In conclusion, every woman with postmenopausal osteoporosis should receive supplementation with calcium and vitamin D simultaneously alongside adequate pharmacological therapy, and should be properly followed to ensure compliance.


References
1. Kanis JA, Burlet N, Cooper C, et al. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. 2008; 19:399-428.
2. Body JJ, Bergmann P, Boonen S, et al. Evidence-based guidelines for the pharmacological treatment of postmenopausal osteoporosis: a consensus document by the Belgian Bone Club. Osteoporos Int. 2010;21:1657-1680.
3. NIH Consensus Development Panel on Osteoporosis Prevention, Diagnosis, and Therapy. Osteoporosis prevention, diagnosis, and therapy. JAMA. 2001;285: 785-795.
4. Tang BM, Eslick GD, Nowson C, Smith C, Bensoussan A. 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: 657-666.
5. Mithal A, Wahl DA, Bonjour JP, et al; IOF Committee of Scientific Advisors (CSA) Nutrition Working Group. Global vitamin D status and determinants of hypovitaminosis D. Osteoporos Int. 2009;20:1807-1820.
6. Dawson-Hughes B, Mithal A, Bonjour JP, et al. IOF position statement: vitamin D recommendations for older adults. Osteoporos Int. 2010;21:1151-1154.



7. R. Nuti, Italy



Ranuccio NUTI, MD
Full Professor of Internal Medicine
University of Siena
Dipartimento di Medicina Interna
e Specialistica
UO Medicina Interna I
Policlinico Santa Maria delle Scotte
Viale Bracci, 2
53100 Siena, ITALY
(e-mail: nutir@unisi.it)



Calcium plays a fundamental role in promoting bone health, as well as in blood coagulation, muscle contraction, and regulation of nerve excitability. 1200 mg/ day of calcium for men and women aged over 50 years has been proposed by the US National Academy of Sciences as an adequate intake, whereas 1000 mg/day is considered sufficient for younger adults.1 European recommendations indicate lower doses: 800 mg/day for women aged 50-65 years. Many studies report that healthy adults have calcium intakes below both these benchmarks. Vitamin D is essential for maintaining calcium homeostasis, mainly through regulation of intestinal calcium absorption. Circulating 25-hydroxyvitamin D [25(OH)D] concentration indicative of a deficiency state is typically defined as ≤25 nmol/L. In the presence of inadequate vitamin D levels, calcium absorption is reduced and there is a homeostatic increase in parathyroid hormone levels with a consequent stimulation of bone resorption and accelerated bone loss.2 In elderly people, vitamin D deficiency is common because of decreased exposure to sunshine and reduced capacity of the skin to synthesize vitamin D. Muscular strength is also regulated by vitamin D: vitamin D levels lower than 25- 30 nmol/L in older individuals are associated with muscular weakness, decreased physical performance, and increased propensity to falls. Moreover, falls are considered one of the main risk factors for pathological fractures.3

Many randomized controlled trials have been performed over the past two decades investigating the efficacy of calcium plus vitamin D in the prevention of fractures, with conflicting results. The daily oral dose of calcium used in the trials has ranged from 500 mg to 1200 mg, and from 400 IU to 800 IU for vitamin D. In terms of fracture risk reduction or decrease in fall incidence, in general, more positive results have been observed using vitamin D 800 IU/day. The percentage reduction in parathyroid hormone levels does not seem to correlate with antifracture efficacy.2 A recent meta-analysis performed on 12 randomized controlled trials reported that in 8 of the 12 trials, together with the correction of secondary hyperparathyroidism, there was a relative risk of 0.86 for non-vertebral fractures and 0.91 for hip fractures, underlining the relationship between efficacy and the optimal dose of 800 IU/day of vitamin D.3 As regards calcium intake, calcium supplementation is particularly important when baseline calcium intake is low. In our experience, mean calcium intake in elderly people may sometimes be less than 600 mg/day.4 New estimates from the National Health And Nutrition Examination Survey (NHANES) show that American adults are characterized by an age-related decline in calcium intake, partly explained by a concurrent decline in energy intake, while supplemental calcium use is highest in older age groups.5 Besides the need for vitamin D, another crucial problem with calcium supplementation is compliance and persistence: adherence with medication in osteoporosis is frequently less than optimal and this may modify the treatment effect. In our opinion, the use of calcium-dense foods could be encouraged to maintain adequate calcium intake across the lifespan. Considering that low calcium intake and poor vitamin D status play a significant role in increasing osteoporotic fracture risk, we believe that calcium and vitamin D must be considered determinant components in the prevention of bone loss and falls, and in the treatment of osteoporosis together with antiresorptive or bone-forming agents.

Finally, there is a growing issue as regards calcium supplementation and the risk of cardiovascular events. A recent reanalysis of the Women’s Health Initiative CaD study suggests that calcium supplements taken with or without vitamin D modestly increase the risk of cardiovascular events, especially myocardial infarction.6 The question remains under discussion.


References
1. Heaney RP. The importance of calcium intake for lifelong skeletal health. Calcif Tissue Int. 2002;70:70-73.
2. Lips P, Bouillon R, van Schoor N, et al. Reducing fracture risk with calcium and vitamin D. Clin Endocrinol. 2010;73:277-285.
3. Nuti R, Martini G, Valenti R, et al. Vitamin D status and bone turnover in women with acute hip fracture. Clin Orthop Relat Res. 2004:208-213.
4. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Prevention of non-vertebral fractures with oral vitamin D and dose dependency. A meta-analysis of randomized controlled trials. Arch Inter Med. 2009;169:551-561.
5. Mangano K, Walsh S, Insogna K, Kenny A, Kerstetter J. Calcium intake in the United States from dietary and supplemental sources across adult age groups: new estimates from the National Health and Nutrition Examination Survey 2003- 2006. J Am Diet Assoc. 2011;111:687-695.
6. Bolland M, Grey A, Avenell A, Gamble G, Reid I. Calcium supplements with or without vitamin D and risk of cardiovascular events: reanalysis of the Women’s Health Initiative limited access dataset and meta-analysis. BMJ. 2011;342: d2040.



8. R. Sánchez-Borrego, Spain



Rafael SÁNCHEZ-BORREGO, MD, PhD
President, Spanish Menopause Society
Clinica Diatros
Avda. Aragon, 103-405, esc. B-2°-3°
08013 Barcelona, SPAIN
(e-mail: rschez.borrego@diatros.com)



The rationale for calcium and vitamin D supplementation in the prevention and treatment of osteoporosis is that low dietary calcium intake and/or vitamin D deficiency or insufficiency may contribute to bone loss.1 Additionally, supplementation is generally recommended as an adjunct to other osteoporosis therapies (antiresorptive and anabolic agents, and strontium ranelate).

Nevertheless, it is still unclear whether the addition of calcium/ vitamin D supplements leads to an incremental benefit in patients taking these bone-active drugs. It is also unclear as to what extent osteoporosis treatment maintains its efficacy in patients with an inappropriate intake of calcium or with vitamin D deficiency. Patients receiving treatment for osteoporosis in a routine clinical setting are often older and frailer than those recruited in clinical trials. Thus, individuals placed on pharmacological treatment for osteoporosis are likely to be at the highest risk of vitamin D deficiency.2 This high proportion of patients on pharmacological treatment for osteoporosis with vitamin D deficiency may sound somewhat surprising, since all guidelines recommend that any pharmacological intervention should include calcium and vitamin D supplements. Implementation of these guidelines, however, is hampered by a number of factors.

Recently, there have been concerns in the literature about potential risks (ie, excess cardiovascular events) with calcium supplementation and high normal serum calcium levels. Additionally, concerns have been expressed that higher treatment doses of vitamin D than those conventionally used may induce vitamin D toxicity.

The Institute of Medicine has issued guidance on vitamin D and calcium intake. Their consensus report found strong support for the use of vitamin D for bone health, but not for other conditions. Vitamin D is involved in calcium homeostasis, and calcium-associated toxicities at high concentrations include kidney and tissue damage.3 Resolving whether the benefits outweigh the risks will determine the appropriateness of supplemental nondietary calcium in fracture prevention.

The most obvious reason to supplement a patient’s anti-osteoporosis medication with calcium and vitamin D is that all clinical trials having demonstrated antifracture efficacy have been performed by adding—in both groups (placebo and treated)—a combination of calcium and vitamin D.

Additionally, it has been demonstrated that differences in vitamin D status may affect the anticatabolic response to antiosteoporotic treatment,4 and that optimal vitamin D repletion appears to be a prerequisite for maximizing the response to antiresorbers in terms of both bone mineral density changes and antifracture efficacy. Greater benefits can even be achieved when blood vitamin D levels are higher than those recently recommended by the Institute of Medicine to maintain bone health.5

In conclusion, it is evident that calcium and vitamin D supplementation should be a prerequisite for maximizing the response to anti-osteoporosis drugs in terms of both bone mineral density changes and antifracture efficacy. However, the treatment adherence to these calcium and/or vitamin D formulations is modest as a result of poor tolerability.6 The consequence of this is that many patients receive neither calcium nor vitamin D. Given this issue,more effortmay be usefully applied to encourage persistence with treatment.


References
1. Pérez-López FR, Chedraui P, Fernández-Alonso AM. Vitamin D and aging: beyond calcium and bone metabolism. Maturitas. 2011;69:27-36.
2. Adami S, Giannini S, Bianchi G, et al. Vitamin D status and response to treatment in post-menopausal osteoporosis. Osteoporos Int. 2009;20:239-244.
3. Institute of Medicine. Dietary reference intakes for calcium and vitamin D:Washington, DC. December 15, 2010. Available at: www.iom.edu/Reports/2010/ Dietary-Reference-Intakes-for-Calcium-and-Vitamin-D.aspx. Accessed December 18th, 2011.
4. Mastaglia SR, Pellegrini GG, Mandalunis PM, Gonzales Chaves MM, Friedman SM, Zeni SN. Vitamin D insufficiency reduces the protective effect of bisphosphonate on ovariectomy-induced bone loss in rats. Bone. 2006;39:837-844.
5. Shieh A, Carmel A, Bockman R. Vitamin D insufficiency is associated with decreased bisphosphonate response. Presented at The Endocrine Society’s 93rd Annual Meeting & Expo; June 4-7, 2011; Boston, MA. Abstract #P1-228.
6. Quesada JM, Blanch J, Díaz-Curiel M, Díez-Pérez A. Calcium citrate and vitamin D in the treatment of osteoporosis. Clin Drug Investig. 2011;31:285-298.



9. M. E. Simões, Portugal



Maria Eugénia SIMÕES, MD
Portuguese Rheumatology Institute
Osteoporosis and Other Metabolic Bone
Diseases Portuguese Society (SPODOM)
Rua da Beneficência, n°7 r/c
1050-034 Lisbon, PORTUGAL
(e-mail: eugenia.simoes@netcabo.pt)



Calcium is the most important mineral in bone, and the skeleton comprises its biggest store; when serum levels of calcium decline, parathyroid hormone is released and osteoclastic activity increases, mobilizing calcium from bone to blood in an attempt to maintain calcium homeostasis. Thus, it is easy to see that adequate calcium intake and metabolism is needed to maintain healthy bones. It has never been proven, however, that calcium alone is enough to prevent osteoporotic fractures—despite the demonstration that calcium supplements can reduce bone resorption markers and produce slight increases in bone mineral density.

Vitamin D is of growing interest to the medical community, as an increasing volume of data is becoming available on its functions related to protecting bones, preventing falls, maintaining and improving equilibrium, and reducing mortality rates, as well as its antineoplastic functions and immune properties. Its efficacy as an isolated treatment against fractures has not been demonstrated, however, other than in institutionalized elderly patients also taking calcium supplements.1

All available anti-osteoporotic treatments have only shown their efficacy in clinical trials in association with calcium and vitamin D; additionally, the placebo in the comparison groups was not really placebo, but rather it was calcium and vitamin D. But are the available anti-osteoporotic drugs still effective in the absence of supplementation with calcium and vitamin D? There are few data to answer this question, but in a randomized controlled trial of 2 years’ duration in about 700 postmenopausal women treated with either 400 UI of vitamin D and alendronate, alendronate plus calcium, alendronate alone, or calcium alone, the authors failed to demonstrate any differences in bone mineral density increases in the group taking alendronate plus calcium compared with those taking alendronate alone. However, there was a significant difference in the excretion of urinary N-terminal telopeptide (NTX), suggesting an optimization of antiresorptive action.2 It has been shown in pharmacological studies that the efficacy of strontium ranelate is not dependent on supplementation with calcium and vitamin D.3-5 In phase 3 clinical studies, all patients (strontium ranelate–treated patients and placebo groups) were given supplements with calcium and vitamin D according to their needs, as required for the treatment of postmenopausal osteoporosis in current medical practice.

Questions have been raised about the cardiovascular safety of calcium supplements. A recent meta-analysis of 26 clinical trials with about 20 000 participants showed that the use of calcium supplements alone was associated with a modest increase in the risk of myocardial infarction (about 30%), but not with an increased risk of stroke or mortality.6 Analysing the data more carefully, one can see that this risk is bigger in patients with the biggest intake of calcium; the dangerous cutoff seems to be 1300 mg of calcium a day (combining dietary and supplemental intake). Moreover, the majority of the trials were conducted with considerable amounts of calcium given in supplements, some of them with about 1.5 g/day. We also do not know the cardiovascular effects of the combination of calcium and vitamin D, although some data (for instance, the Women’s Health Initiative population) suggest that vitamin D can be protective.

In conclusion, this really is a controversial point, and the question posed deserves two different answers: (i) Yes, for systematic supplementation with vitamin D to treat postmenopausal osteoporosis; and (ii) No, for systematic supplementation with calcium to treat postmenopausal osteoporosis. Particularly, no for calcium alone (without vitamin D), and no if dietary calcium intake is sufficient (avoid a total calcium intake greater than 1300 mg/day).


References
1. DIPART Group. Patient level pooled analysis of 68 500 from seven major vitamin D fracture trials in US and Europe. BMJ. 2010;340:b5443.
2. Bonnick S, Broy S, Kaiser F, et al. Treatment of alendronate plus calcium, alendronate alone, or calcium alone for postmenopausal low bone mineral density. Cur Med Res Opin. 2007;23:1341-1349.
3. Hurtel AS, Mentaverri R, Caudrillier A, et al. The calcium-sensing receptor is involved in strontium ranelate-induced osteoclast apoptosis: new insights into the associated signalling pathways. J Biol Chem. 2009;284:575-584.
4. Caverzasio J. Strontium ranelate promotes osteoblastic cell replication through at least two different mechanisms. Bone. 2008;42:1131-1136.
5. Bonnelye E, Chabadel A, Saltel F, Jurdic P. Dual effect of strontium ranelate: stimulation of osteoblast differentiation and inhibition of osteoclast formation and resorption in vitro. Bone. 2008;42:129-138.
6. Bolland M, Avenell A, Baron J. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events: meta-analysis. BMJ. 2010;341:c3691.



10. T. J. de Villiers, South Africa



Tobie J. DE VILLIERS, FRCOG,
FCOG (SA), M. Med (O&G)
Mediclinic Panorama and
University of Stellenbosch
Cape Town, SOUTH AFRICA
(e-mail: Tobie@iafrica.com)



Systemic supplementation of calcium and vitamin D in the treatment and prevention of postmenopausal osteoporosis has, until recently, been a knee-jerk reaction based on physiological considerations and the belief that this practice was safe. This was in spite of the fact that the results of fracture prevention studies of calcium supplementation were inconsistent and complicated by population differences, differences in calcium and vitamin D baseline status, differences in doses, and poor compliance.

In a recent meta-analysis, it was reported that calcium supplements are associated with an increased risk of myocardial infarction that is greater than the expected reduction in fracture risk. The authors warned that as calcium supplements are widely used, these modest increases in risk of cardiovascular disease might translate into a large burden of disease in the population. More prospective studies are needed to quantify the risk.

Since food sources of calcium produce similar benefits for bone density as do supplements, and dietary calcium intake does not seem to be related to adverse cardiovascular effects, calcium intake from nutritional sources needs to be encouraged. According to the latest 2010 guidelines of the Institute of Medicine (IOM), postmenopausal women need a dietary reference intake (DRI) of 1200 mg of elemental calcium. The best dietary source of calcium is dairy products because of their favorable elemental calcium content, their ability to be absorbed, and their cost effectiveness. Doses of supplemental calcium should be restricted to cover the shortfall between dietary intake and the DRI of 1200 mg. This should equate in most instances to not more than 500 mg of daily elemental calcium.

The role of vitamin Din bone homeostasis has been reassessed in the past few years. As many as 60% of older patients may have inadequate levels of vitamin D, caused by the age-related inability of the skin and kidney to produce the active form of vitamin D, and a general trend of less sunlight exposure. Dietary supplementation is a practical option, as the normal diet contains very little vitamin D. It is possible to directly determine vitamin D status by measuring the blood level of 25- hydroxyvitamin D [25(OH)D]. The latest recommendation of the IOM is a DRI of 600 IU (previously 400 IU) of vitamin D for women aged 51-70 years and 800 IU after age 70 years. The target 25(OH)D level was set at 50 nmol/L (20 ng/ml). Expert opinion and the International Osteoporosis Foundation disagree with these values, and recommend a DRI of 800-1000 IU of vitamin D in order to achieve a target serum 25(OH)D level of 75 nmol/L (30 ng/ml). Vitamin D supplementation has been shown to independently lower the risk of falling in elderly patients.

In conclusion, routine supplementation of calcium and vitamin D cannot be supported in the treatment of osteoporosis. It should rather be replaced by a case-specific approach according to the principles discussed.



11. S. S. Yeap, Malaysia



Swan Sim YEAP, MD
Consultant Rheumatologist
Sime Darby Medical Centre Subang Jaya
Selangor, MALAYSIA
(e-mail: yeapss@myjaring.net)



Osteoporosis is a disorder of bone metabolism characterized by micro architectural deterioration, low bone mass, and an increased risk of fractures. Bone is made up of one third organic material such as collagen and two-thirds inorganic material consisting of carbonated hydroxyapatite; ie, calcium and phosphate salts—Ca10(PO4)6(OH)2. As 99% of the body’s calcium stores are in bone and teeth, it makes intuitive sense that calcium plays an important role in bone diseases. Vitamin D is also critical in calcium homeostasis; too little vitamin D leads to increased parathyroid hormone secretion, which increases intestinal calcium absorption but also increases bone resorption tomobilize bone calcium stores, thus reducing bone mineral density (BMD).

In the clinical setting, in population groups above the age of 50 years, calcium and/or vitamin D on their own have been shown to have beneficial effects on BMD and the risk of fractures. Daily intake of calcium at a dose of 1200 mg elemental calcium reduced the risk of fractures.1 Calcium or calcium and vitamin D supplementation has been shown to reduce BMD loss, and is associated with a reduced risk of osteoporotic fractures.2 Vitamin D supplementation has been shown to reduce the risk of falling at doses of 700-1000 IU daily,3 which thus reduces one of the risk factors for fracture. Aside from this, vitamin D supplementation has also been shown to reduce the risk of vertebral and non-vertebral fractures4 at doses above 400 IU daily. Thus, maintaining an adequate calcium/ vitamin D intake is recommended as part of the standard of care in all osteoporosis guidelines, with a suggested intake of 1000-1200 mg elemental calcium and 800-1000 IU vitamin D daily.5

However, not all studies have been uniformly positive. A meta-analysis showed that calcium intake was not related to hip fracture risk.6 Other studies showed that calcium and vitamin D supplementation was no better than placebo in improving BMD7 or preventing fractures.8 An important factor for calcium/ vitamin D efficacy may hinge on the degree of compliance with the supplements; when only compliant subjects were considered in the otherwise negative studies, there was an improvement in BMD9 and a reduction in hip fracture.8 More worryingly, there have been recent concerns that taking these supplements can actually cause harm. One study showed that an annual oral administration of high-dose vitamin D paradoxically resulted in an increased risk of falls and fractures.9 In addition, there has been some concern about the adverse side effects of high-dose calcium supplementation, especially with regard to an increased risk of myocardial infarction.10

Last, but not least, in trials of osteoporosis treatments with either bisphosphonates, strontium, or parathyroid hormone, supplementary calcium and vitamin D were given in both the placebo and treatment arms. Thus, all the data that is available on the efficacy of osteoporosis treatments is data that included calcium and vitamin D supplements, and it is not known if the efficacy of these drugs would be reduced without adequate calcium/vitamin D intake.

Therefore to conclude, the answer is yes, systematic supplementation with calcium/vitamin D is necessary in the treatment of postmenopausal osteoporosis. However, in view of the possible adverse effects, it is suggested that they are not used alone, but taken together with the pharmacological treatment options for osteoporosis.


References
1. Bischoff-Ferrari HA, Rees JR, Grau MV, Barry E, Gui J, Baron JA. Effect of calcium supplementation on fracture risk: a double-blind randomized controlled trial. Am J Clin Nutr. 2008;87:1945-1951.
2. Tang BMP, Eslick GD, Nowson C, Smith C, Bensoussan A. 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; 370:657-666.
3. Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomized controlled trials. BMJ. 2009;339:b3692.
4. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Prevention of nonvertebral fractures with oral vitamin D and dose dependency. A meta-analysis of randomized controlled trials. Arch Intern Med. 2009;169:551-561.
5. Body JJ, Bergmann P, Boonen S, et al. Evidence-based guidelines for the pharmacological treatment of postmenopausal osteoporosis: a consensus document by the Belgian Bone Club. Osteoporos Int. 2010;21:1657-1680.
6. Bischoff-Ferrari HA, Dawson-Hughes B, Baron JA, et al. Calcium intake and hip fracture risk in men and women: a meta-analysis of prospective cohort studies and randomized controlled trials. Am J Clin Nutr. 2007;86:1780-1790.
7. Kärkkäinen M, Tuppurainen M, Salovaara K, et al. Effect of calcium and vitamin D supplementation on bone mineral density in women aged 65-71 years: a 3-year randomized population-based trial (OSTPRE-FPS). Osteoporos Int. 2010;21:2047-2055.
8. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354:669-683.
9. Sanders KM, Stuart AL, Williamson EJ, et al. Annual high-dose oral vitamin D and falls and fractures in older women. A randomized controlled trial. JAMA. 2010;303:1815-1822.
10. Bolland MJ, Avenell A, Baron JA, et al. Effect of calcium supplements on risk of myocardial infarction and cardiovascular events:meta-analysis. BMJ. 2010;341: c3691.