Osteoporos Int (2014) 25:2499–2500 DOI 10.1007/s00198-014-2841-z
LETTER
Vitamin D: is evidence of absence, absence of evidence? S. Minisola & J. Pepe & C. Cipriani & A. Scillitani & S. Piemonte
Received: 25 July 2014 / Accepted: 4 August 2014 / Published online: 13 August 2014 # International Osteoporosis Foundation and National Osteoporosis Foundation 2014
Vitamin D nutritional status, as assessed by serum 25hydroxyvitamin D [25-(OH)D] levels, has long been considered to be of greatest importance in maintaining skeletal health in both physiological [1, 2] and pathological conditions [3, 4]. This concept stems from the observations that both ultraviolet irradiation and administration of cod fish liver are able to cure defective mineralization seen in children with rickets or in adults with osteomalacia [5, 6]. In their review of the journal, Reid and Bolland [7] reconsider the actions of vitamin D based on a recently published paper [8]. They conclude that vitamin D is not a tonic for bone, and therefore, we need only small amounts of vitamin D to maintain bone health. This is not as simple as what their conclusion implies and may have obvious implications for defining thresholds for optimal vitamin D status and consequently modalities of vitamin D supplementation [9, 10]. Recent papers attempt to distinguish the skeletal effect of vitamin D during a normal calcium balance and when the intestinal calcium absorption is impaired [11]. In the first situation, the role of the final metabolite, 1,25(OH)2D, is to enhance intestinal calcium transport to get enough calcium. The influx of calcium from the intestine into the circulation is then beneficial to bone health. In the second, 1,25OH2D levels increase disproportionately leading to 1,25OH2D-mediated bone resorption and possibly also suppress bone matrix mineralization [8]. A similar condition could be expected by administering excessive vitamin D [owing to an excessive production of 1,25(OH)2D]. These data, together with S. Minisola (*) : J. Pepe : C. Cipriani : S. Piemonte Department of Internal Medicine and Medical Disciplines, “Sapienza” Rome University, Rome, Italy e-mail: [email protected] A. Scillitani Unit of Endocrinology, “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Italy
experimental animal models showing that osteomalacia of vitamin D receptor (VDR) knockout mouse is rescued by selective expression of VDR is the enterocyte [12], emphasize the relative importance of VDR in the intestine (and of the absorption of calcium and phosphate) compared to the VDR receptors in bone. However, there are some other points in the review that deserve clarification. First, it is difficult to understand the physiological role of VDR if it is not critical to the maintenance of bone health. Severe rickets and osteomalacia are cured by doses of vitamin D, that also increase 1,25(OH)2D levels to the point that theoretically can negatively affect the skeleton. Second, concerning the correlation between calcifediol and PTH put forward by the authors as an explanation for a detrimental effect of low vitamin D levels unless there is a concomitant PTH increase. However, some of the confounding in correlations might be ascribed to the fact that we are not measuring free fraction of 25-OHD [13]; alternatively, magnesium deficiency could influence this relationship [14]. Third, Reid and Bolland conclude that some meta-analyses show no effect of vitamin D alone on fractures, but the most important effect of vitamin D is to increase calcium (and phosphate) absorption, as they acknowledge when emphasizing the role of VDR in the intestine. It is therefore logical that in order for vitamin D to fully exert its effect, some calcium should be found in the intestine. Boonen et al. [15] and Murad et al. [16] addressed very well this concept. Fourth, concerning the point about optimal threshold, we believe that the histological data, reported by Priemel et al. [17] should also be taken into consideration. Indeed, they showed that some parameters of mineralization were compromised in 25-OHD, ranging from 20–30 ng/mL, suggesting that the issue of optimal threshold is yet to be determined. Finally, caution should be exercised regarding the nonskeletal effects of vitamin D. We should at least await the results of
2500
ongoing trials specifically aimed at evaluating the effect of vitamin D on neoplastic and cardiovascular end points [18]. We do agree with the final conclusion that inferences cannot be drawn from studies of associations. However, it is also true that the absence of evidence at present does not necessarily mean evidence of absence in the future.
Osteoporos Int (2014) 25:2499–2500
9.
10.
Conflicts of interest None. 11.
References 1. Rao DS (1999) Perspective on assessment of vitamin D nutrition. J Clin Densitom 2:457–464 2. Romagnoli E, Pepe J, Piemonte S, Cipriani C, Minisola S (2013) Management of endocrine disease: value and limitations of assessing vitamin D nutritional status and advised levels of vitamin D supplementation. Eur J Endocrinol 169:R59–R69 3. Carnevale V, Manfredi G, Romagnoli E, De Geronimo S, Paglia F, Pepe J, Scillitani A, D'Erasmo E, Minisola S (2004) Vitamin D status in female patients with primary hyperparathyroidism: does it play a role in skeletal damage? Clin Endocrinol (Oxf) 60:81–86 4. Shah VN, Shah CS, Bhadada SK, Rao DS (2014) Effect of 25 (OH) D replacements in patients with primary hyperparathyroidism (PHPT) and coexistent vitamin D deficiency on serum 25(OH) D, calcium and PTH levels: a meta-analysis and review of literature. Clin Endocrinol (Oxf) 80:797–803 5. Parfitt AM, Gallagher JC, Heaney RP, Johnston CC, Neer R, Whedon GD (1982) Vitamin D and bone health in the elderly. Am J Clin Nutr 36(5 Suppl):1014–1031 6. Basha B, Rao DS, Han ZH, Parfitt AM (2000) Osteomalacia due to vitamin D depletion: a neglected consequence of intestinal malabsorption. Am J Med 108:296–300 7. Reid IR, Bolland MJ (2014) Skeletal and nonskeletal effects of vitamin D: is vitamin D a tonic for bone and other tissues? Osteoporos Int [Epub ahead of print] 8. Lieben L, Masuyama R, Torrekens S, Van Looveren R, Schrooten J, Baatsen P, Lafage-Proust MH, Dresselaers T, Feng JQ, Bonewald LF, Meyer MB, Pike JW, Bouillon R, Carmeliet G (2012) Normocalcemia is maintained in mice under conditions of calcium
12.
13. 14.
15.
16.
17.
18.
malabsorption by vitamin D-induced inhibition of bone mineralization. J Clin Invest 122:1803–1815 Gallagher JC, Sai A, Templin T 2nd, Smith L (2012) Dose response to vitamin D supplementation in postmenopausal women: a randomized trial. Ann Intern Med 156(9):672 Cipriani C, Romagnoli E, Pepe J, Russo S, Carlucci L, Piemonte S, Nieddu L, McMahon DJ, Singh R, Minisola S (2013) Long-term bioavailability after a single oral or intramuscular administration of 600,000 IU of ergocalciferol or cholecalciferol: implications for treatment and prophylaxis. J Clin Endocrinol Metab 98:2709–2715 Lieben L, Carmeliet G (2013) The delicate balance between vitamin D, calcium and bone homeostasis: lessons learned from intestinaland osteocyte-specific VDR null mice. J Steroid Biochem Mol Biol 136:102–106 Xue Y, Fleet JC (2009) Intestinal vitamin D receptor is required for normal calcium and bone metabolism in mice. Gastroenterology 36: 1317–1327 Carter GD, Phinney KW (2014) Assessing vitamin D status: time for a rethink? Clin Chem 60:809–811 Sahota O, Mundey MK, San P, Godber IM, Hosking DJ (2006) Vitamin D insufficiency and the blunted PTH response in established osteoporosis: the role of magnesium deficiency. Osteoporos Int 17: 1825–1826 Boonen S, Lips P, Bouillon R, Bischoff-Ferrari HA, Vanderschueren D, Haentjens P (2007) Need for additional calcium to reduce the risk of hip fracture with vitamin d supplementation: evidence from a comparative metaanalysis of randomized controlled trials. J Clin Endocrinol Metab 92:1415–1423 Murad MH, Drake MT, Mullan RJ, Mauck KF, Stuart LM, Lane MA, Abu Elnour NO, Erwin PJ, Hazem A, Puhan MA, Li T, Montori VM (2012) Clinical review. Comparative effectiveness of drug treatments to prevent fragility fractures: a systematic review and network metaanalysis. J Clin Endocrinol Metab 97:1871–1880 Priemel M, von Domarus C, Klatte TO, Kessler S, Schlie J, Meier S, Proksch N, Pastor F, Netter C, Streichert T, Püschel K, Amling M (2010) Bone mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients. J Bone Miner Res 25:305–312 Manson JE, Bassuk SS, Lee IM, Cook NR, Albert MA, Gordon D, Zaharris E, Macfadyen JG, Danielson E, Lin J, Zhang SM, Buring JE (2012) The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials 33:159–171
LETTER
Vitamin D: is evidence of absence, absence of evidence? S. Minisola & J. Pepe & C. Cipriani & A. Scillitani & S. Piemonte
Received: 25 July 2014 / Accepted: 4 August 2014 / Published online: 13 August 2014 # International Osteoporosis Foundation and National Osteoporosis Foundation 2014
Vitamin D nutritional status, as assessed by serum 25hydroxyvitamin D [25-(OH)D] levels, has long been considered to be of greatest importance in maintaining skeletal health in both physiological [1, 2] and pathological conditions [3, 4]. This concept stems from the observations that both ultraviolet irradiation and administration of cod fish liver are able to cure defective mineralization seen in children with rickets or in adults with osteomalacia [5, 6]. In their review of the journal, Reid and Bolland [7] reconsider the actions of vitamin D based on a recently published paper [8]. They conclude that vitamin D is not a tonic for bone, and therefore, we need only small amounts of vitamin D to maintain bone health. This is not as simple as what their conclusion implies and may have obvious implications for defining thresholds for optimal vitamin D status and consequently modalities of vitamin D supplementation [9, 10]. Recent papers attempt to distinguish the skeletal effect of vitamin D during a normal calcium balance and when the intestinal calcium absorption is impaired [11]. In the first situation, the role of the final metabolite, 1,25(OH)2D, is to enhance intestinal calcium transport to get enough calcium. The influx of calcium from the intestine into the circulation is then beneficial to bone health. In the second, 1,25OH2D levels increase disproportionately leading to 1,25OH2D-mediated bone resorption and possibly also suppress bone matrix mineralization [8]. A similar condition could be expected by administering excessive vitamin D [owing to an excessive production of 1,25(OH)2D]. These data, together with S. Minisola (*) : J. Pepe : C. Cipriani : S. Piemonte Department of Internal Medicine and Medical Disciplines, “Sapienza” Rome University, Rome, Italy e-mail: [email protected] A. Scillitani Unit of Endocrinology, “Casa Sollievo della Sofferenza” Hospital, San Giovanni Rotondo, Italy
experimental animal models showing that osteomalacia of vitamin D receptor (VDR) knockout mouse is rescued by selective expression of VDR is the enterocyte [12], emphasize the relative importance of VDR in the intestine (and of the absorption of calcium and phosphate) compared to the VDR receptors in bone. However, there are some other points in the review that deserve clarification. First, it is difficult to understand the physiological role of VDR if it is not critical to the maintenance of bone health. Severe rickets and osteomalacia are cured by doses of vitamin D, that also increase 1,25(OH)2D levels to the point that theoretically can negatively affect the skeleton. Second, concerning the correlation between calcifediol and PTH put forward by the authors as an explanation for a detrimental effect of low vitamin D levels unless there is a concomitant PTH increase. However, some of the confounding in correlations might be ascribed to the fact that we are not measuring free fraction of 25-OHD [13]; alternatively, magnesium deficiency could influence this relationship [14]. Third, Reid and Bolland conclude that some meta-analyses show no effect of vitamin D alone on fractures, but the most important effect of vitamin D is to increase calcium (and phosphate) absorption, as they acknowledge when emphasizing the role of VDR in the intestine. It is therefore logical that in order for vitamin D to fully exert its effect, some calcium should be found in the intestine. Boonen et al. [15] and Murad et al. [16] addressed very well this concept. Fourth, concerning the point about optimal threshold, we believe that the histological data, reported by Priemel et al. [17] should also be taken into consideration. Indeed, they showed that some parameters of mineralization were compromised in 25-OHD, ranging from 20–30 ng/mL, suggesting that the issue of optimal threshold is yet to be determined. Finally, caution should be exercised regarding the nonskeletal effects of vitamin D. We should at least await the results of
2500
ongoing trials specifically aimed at evaluating the effect of vitamin D on neoplastic and cardiovascular end points [18]. We do agree with the final conclusion that inferences cannot be drawn from studies of associations. However, it is also true that the absence of evidence at present does not necessarily mean evidence of absence in the future.
Osteoporos Int (2014) 25:2499–2500
9.
10.
Conflicts of interest None. 11.
References 1. Rao DS (1999) Perspective on assessment of vitamin D nutrition. J Clin Densitom 2:457–464 2. Romagnoli E, Pepe J, Piemonte S, Cipriani C, Minisola S (2013) Management of endocrine disease: value and limitations of assessing vitamin D nutritional status and advised levels of vitamin D supplementation. Eur J Endocrinol 169:R59–R69 3. Carnevale V, Manfredi G, Romagnoli E, De Geronimo S, Paglia F, Pepe J, Scillitani A, D'Erasmo E, Minisola S (2004) Vitamin D status in female patients with primary hyperparathyroidism: does it play a role in skeletal damage? Clin Endocrinol (Oxf) 60:81–86 4. Shah VN, Shah CS, Bhadada SK, Rao DS (2014) Effect of 25 (OH) D replacements in patients with primary hyperparathyroidism (PHPT) and coexistent vitamin D deficiency on serum 25(OH) D, calcium and PTH levels: a meta-analysis and review of literature. Clin Endocrinol (Oxf) 80:797–803 5. Parfitt AM, Gallagher JC, Heaney RP, Johnston CC, Neer R, Whedon GD (1982) Vitamin D and bone health in the elderly. Am J Clin Nutr 36(5 Suppl):1014–1031 6. Basha B, Rao DS, Han ZH, Parfitt AM (2000) Osteomalacia due to vitamin D depletion: a neglected consequence of intestinal malabsorption. Am J Med 108:296–300 7. Reid IR, Bolland MJ (2014) Skeletal and nonskeletal effects of vitamin D: is vitamin D a tonic for bone and other tissues? Osteoporos Int [Epub ahead of print] 8. Lieben L, Masuyama R, Torrekens S, Van Looveren R, Schrooten J, Baatsen P, Lafage-Proust MH, Dresselaers T, Feng JQ, Bonewald LF, Meyer MB, Pike JW, Bouillon R, Carmeliet G (2012) Normocalcemia is maintained in mice under conditions of calcium
12.
13. 14.
15.
16.
17.
18.
malabsorption by vitamin D-induced inhibition of bone mineralization. J Clin Invest 122:1803–1815 Gallagher JC, Sai A, Templin T 2nd, Smith L (2012) Dose response to vitamin D supplementation in postmenopausal women: a randomized trial. Ann Intern Med 156(9):672 Cipriani C, Romagnoli E, Pepe J, Russo S, Carlucci L, Piemonte S, Nieddu L, McMahon DJ, Singh R, Minisola S (2013) Long-term bioavailability after a single oral or intramuscular administration of 600,000 IU of ergocalciferol or cholecalciferol: implications for treatment and prophylaxis. J Clin Endocrinol Metab 98:2709–2715 Lieben L, Carmeliet G (2013) The delicate balance between vitamin D, calcium and bone homeostasis: lessons learned from intestinaland osteocyte-specific VDR null mice. J Steroid Biochem Mol Biol 136:102–106 Xue Y, Fleet JC (2009) Intestinal vitamin D receptor is required for normal calcium and bone metabolism in mice. Gastroenterology 36: 1317–1327 Carter GD, Phinney KW (2014) Assessing vitamin D status: time for a rethink? Clin Chem 60:809–811 Sahota O, Mundey MK, San P, Godber IM, Hosking DJ (2006) Vitamin D insufficiency and the blunted PTH response in established osteoporosis: the role of magnesium deficiency. Osteoporos Int 17: 1825–1826 Boonen S, Lips P, Bouillon R, Bischoff-Ferrari HA, Vanderschueren D, Haentjens P (2007) Need for additional calcium to reduce the risk of hip fracture with vitamin d supplementation: evidence from a comparative metaanalysis of randomized controlled trials. J Clin Endocrinol Metab 92:1415–1423 Murad MH, Drake MT, Mullan RJ, Mauck KF, Stuart LM, Lane MA, Abu Elnour NO, Erwin PJ, Hazem A, Puhan MA, Li T, Montori VM (2012) Clinical review. Comparative effectiveness of drug treatments to prevent fragility fractures: a systematic review and network metaanalysis. J Clin Endocrinol Metab 97:1871–1880 Priemel M, von Domarus C, Klatte TO, Kessler S, Schlie J, Meier S, Proksch N, Pastor F, Netter C, Streichert T, Püschel K, Amling M (2010) Bone mineralization defects and vitamin D deficiency: histomorphometric analysis of iliac crest bone biopsies and circulating 25-hydroxyvitamin D in 675 patients. J Bone Miner Res 25:305–312 Manson JE, Bassuk SS, Lee IM, Cook NR, Albert MA, Gordon D, Zaharris E, Macfadyen JG, Danielson E, Lin J, Zhang SM, Buring JE (2012) The VITamin D and OmegA-3 TriaL (VITAL): rationale and design of a large randomized controlled trial of vitamin D and marine omega-3 fatty acid supplements for the primary prevention of cancer and cardiovascular disease. Contemp Clin Trials 33:159–171
