Bone STRENGTH improved by 2800 IU of Vitamin D (not bone density) – RCT Oct 2018

Bone Microstructure in Response to Vitamin D3 Supplementation: A Randomized Placebo-Controlled Trial

Calcified Tissue International, pp 1–11 https://doi.org/10.1007/s00223-018-0481-6
Lise Sofie Bislev, Lene Langagergaard Rødbro Lars Rolighed Tanja Sikjaer Lars Rejnmark

PDF is available free at Sci-Hub  10.1007/s00223-018-0481-6

Vitamin D supplementation is often used in the prevention and treatment of osteoporosis, but the role of vitamin D has lately been questioned. We aimed to investigate the effect of 3 months of daily vitamin D3 supplementation (70 µg [2800 IU] vs. placebo) initiated in winter months on bone health. This study is a double-blinded placebo-controlled randomized trial. Bone health was assessed by bone turnover markers, DXA, HRpQCT, and QCT scans. The participants were 81 healthy postmenopausal women with low 25(OH)D (< 50 nmol/l) and high PTH levels (> 6.9 pmol/l) at screening. Vitamin D3 supplementation significantly increased levels of 25(OH)D and 1,25(OH)2D by 59 nmol/l and 19 pmol/l, respectively, whereas PTH was reduced by 0.7 pmol/l (all p < 0.0001).
Compared with placebo, vitamin D3 did not affect bone turnover markers, aBMD by DXA or trabecular bone score.
Vitamin D3 increased trabecular vBMD (QCT scans) in the trochanter region (0.4 vs. − 0.7 g/cm3) and the femoral neck (2.1 vs. − 1.8 g/cm3) pall < 0.05. HRpQCT scans of the distal tibia showed reduced trabecular number (− 0.03 vs. 0.05 mm−1) and increased trabecular thickness (0.001 vs. − 0.005 mm), as well as an improved estimated bone strength as assessed by failure load (0.1 vs. − 0.1 kN), and stiffness (2.3 vs. − 3.1 kN/mm pall ≤ 0.01).
Changes in 25(OH)D correlated significantly with changes in

• trabecular thickness,
• stiffness, and
• failure load.

Three months of vitamin D3 supplementation improved bone strength and trabecular thickness in tibia, vBMD in the trochanter and femoral neck, but did not affect aBMD.

References (many of which are in VitaminDWiki)

• 1. Cashman KD, Dowling KG (2016) Vitamin D deficiency in Europe: pandemic? Am J Clin Nutr 103:1033–1044. https://doi.org/10.3945/ajcn.115.120873.Am
• 2. Reid IR, Bolland MJ, Grey A (2014) Effects of vitamin D supplements on bone mineral density: a systematic review and meta-Analysis. Lancet 383:146–155. https://doi.org/10.1016/S0140-6736(13)61647-5
• 3. Avenell A, Mak J, O’Connell D (2014) Vitamin D and vitamin D analogues for preventing fractures in post-menopausal women and older men (Review). Cochrane Database Syst Rev. https://doi.org/10.1002/14651858.CD000227.pub4
• 4. Lips P (2001) Vitamin D deficiency and secondary hyperparathyroidism in the elderly: consequences for bone loss and therapeutic implications. Endocr Rev 22:477–501
• 5. Sahota O, Mundey MK, San P et al (2004) The relationship between vitamin D and parathyroid hormone: calcium homeostasis, bone turnover, and bone mineral density in postmenopausal women with established osteoporosis. Bone 35:312–319. https://doi.org/10.1016/j.bone.2004.02.003
• 6. Sambrook PN, Chen JS, March LM et al (2004) Serum parathyroid hormone predicts time to fall independent of vitamin D status in a frail elderly population. J Clin Endocrinol Metab 89:1572–1576. https://doi.org/10.1210/jc.2003-031782
• 7. Rahme M, Sharara SL, Baddoura R et al (2017) Impact of calcium and two doses of vitamin D on bone metabolism in the elderly: a randomized controlled trial. J Bone Miner Res 32:1486–1495. https://doi.org/10.1002/jbmr.3122
• 8. Arabi A, Baddoura R, El-Rassi R, El-Hajj Fuleihan G (2012) PTH level but not 25 (OH) vitamin D level predicts bone loss rates in the elderly. Osteoporos Int 23:971–980. https://doi.org/10.1007/s00198-011-1659-1
• 9. Giusti A, Barone A, Pioli G et al (2010) Heterogeneity in serum 25-hydroxy-vitamin D response to cholecalciferol in elderly women with secondary hyperparathyroidism and vitamin D deficiency. J Am Geriatr Soc 58:1489–1495. https://doi.org/10.1111/j.1532-5415.2010.02970.x
• 10. Rejnmark L, Vestergaard P, Brot C, Mosekilde L (2008) Parathyroid response to vitamin D insufficiency: relations to bone, body composition and to lifestyle characteristics. Clin Endocrinol 69:29–35. https://doi.org/10.1111/j.1365-2265.2008.03186.x
• 11. Rapuri PB, Kinyamu HK, Gallagher JC, Haynatzka V (2002) Seasonal changes in calciotropic hormones, bone markers, and bone mineral density in elderly women. J Clin Endocrinol Metab 87:2024–2032. https://doi.org/10.1210/jcem.87.5.8475 doi
• 12. MacNeil JA, Boyd SK (2008) Bone strength at the distal radius can be estimated from high-resolution peripheral quantitative computed tomography and the finite element method. Bone 42:1203–1213. https://doi.org/10.1016/j.bone.2008.01.017
• 13. Cheung AM, Frame H, Ho M et al (2016) Bone strength and management of postmenopausal fracture risk with antiresorptive therapies: considerations for women’s health practice. Int J Womens Health 8:537–547. https://doi.org/10.2147/IJWH.S112621
• 14. Heaney RP, Davies KM, Chen TC et al (2003) Human serum 25-hydroxycholecalciferol response to extended oral dosing with cholecalciferol. Am J Clin Nutr 77:204–210. https://doi.org/10.1093/ajcn/77.1.204
• 15. Nelson ML, Blum JM, Hollis BW et al (2009) Supplements of 20 g/d cholecalciferol optimized serum 25-hydroxyvitamin D concentrations in 80% of premenopausal women in winter. J Nutr 139:540–546. https://doi.org/10.3945/jn.108.096180
• 16. Bislev L, Rødbro L, Bech J et al (2018) Effects of treatment with an angiotensin 2 receptor blocker and/or vitamin D3 on parathyroid hormone and aldosterone: a randomized, placebo-controlled trial. Clin Endocrinol. https://doi.org/10.1111/cen.13734
• 17. Amstrup AK, Sikjaer T, Mosekilde L, Rejnmark L (2015) The effect of melatonin treatment on postural stability, muscle strength, and quality of life and sleep in postmenopausal women: a randomized controlled trial. Nutr J 14:1–8. https://doi.org/10.1186/s12937-015-0093-1
• 18. Hermann AP, Thomsen J, Vestergaard P, Mosekilde LCP (1999) Assessment of calcium intake. A quick method comparerd to a 7 days food diary. Calcif Tissue Int 82
• 19. Højskov CS, Heickendorff L, Møller HJ (2010) High-throughput liquid-liquid extraction and LCMSMS assay for determination of circulating 25(OH) vitamin D3 and D2 in the routine clinical laboratory. Clin Chim Acta 411:114–116. https://doi.org/10.1016/j.cca.2009.10.010
• 20. Maunsell Z, Wright DJ, Rainbow SJ (2005) Routine isotope-dilution liquid chromatography-tandem mass spectrometry assay for simultaneous measurement of the 25-hydroxy metabolites of vitamins D2 and D3. Clin Chem 51:1683–1690. https://doi.org/10.1373/clinchem.2005.052936
• 21. Khoo BCC, Brown K, Cann C et al (2009) Comparison of QCT-derived and DXA-derived areal bone mineral density and T scores. Osteoporos Int 20:1539–1545. https://doi.org/10.1007/s00198-008-0820-y
• 22. Laib A, Hauselmann HJ, Ruegsegger P (1998) In vivo high resolution 3D-QCT of the human forearm. Technol Health Care 6:329–337
• 23. Burghardt AJ, Link TM, Majumdar S (2011) High-resolution computed tomography for clinical imaging of bone microarchitecture. Clin Orthop Relat Res 469:2179–2193. https://doi.org/10.1007/s11999-010-1766-x
• 24. Sode M, Burghardt AJ, Pialat JB et al (2011) Quantitative characterization of subject motion in HR-pQCT images of the distal radius and tibia. Bone 48:1291–1297. https://doi.org/10.1016/j.bone.2011.03.755
• 25. Roønn SH, Harsloøf T, Pedersen SB, Langdahl BL (2016) Vitamin K2 (menaquinone-7) prevents age-related deterioration of trabecular bone microarchitecture at the tibia in postmenopausal women. Eur J Endocrinol 175:541–549. https://doi.org/10.1530/EJE-16-0498
• 26. Bislev LS, Langagergaard Rødbro L, Bech JN et al (2018) The effect of vitamin D3 supplementation on markers of cardiovascular health in hyperparathyroid, vitamin D insufficient women: a randomized placebo-controlled trial. Endocrine. https://doi.org/10.1007/s12020-018-1659-4
• 27. Lima GL, Paupitz JA, Aikawa NE et al (2017) A randomized double-blind placebo-controlled trial of vitamin D supplementation in juvenile-onset systemic lupus erythematosus: positive effect on trabecular microarchitecture using HR-pQCT. Osteoporos Int. https://doi.org/10.1007/s00198-017-4316-5
• 28. Boyd SK, Burt LA, Sevick LK, Hanley DA (2015) The relationship between serum 25(OH)D and bone density and microarchitecture as measured by HR-pQCT. Osteoporos Int 26:2375–2380. https://doi.org/10.1007/s00198-015-3110-5
• 29. Cheung TF, Cheuk KY, Yu FWP et al (2016) Prevalence of vitamin D insufficiency among adolescents and its correlation with bone parameters using high-resolution peripheral quantitative computed tomography. Osteoporos Int 27:2477–2488. https://doi.org/10.1007/s00198-016-3552-4
• 30. Zanchetta MB, Longobardi V, Costa F et al (2017) Impaired bone microarchitecture improves after one year on gluten-free diet: a prospective longitudinal HRpQCT study in women with celiac disease. J Bone Miner Res 32:135–142. https://doi.org/10.1002/jbmr.2922
• 31. Touvier M, Deschasaux M, Montourcy M et al (2014) Interpretation of plasma PTH concentrations according to 25OHD status, gender, age, weight status, and calcium intake: importance of the reference values. J Clin Endocrinol Metab 99:1196–1203. https://doi.org/10.1210/jc.2013-3349
• 32. Souberbielle JC, Cormier C, Kindermans C et al (2001) Vitamin D status and redefining serum parathyroid hormone reference range in the elderly. J Clin Endocrinol Metab 86:3086–3090. https://doi.org/10.1210/jcem.86.7.7689
• 33. Schlemmer A, Hassager C (1999) Acute fasting diminishes the circadian rhythm of biochemical markers of bone resorption. Eur J Endocrinol 140:332–337. https://doi.org/10.1530/eje.0.1400332
• 34. Fuller H, Fuller R, Pereira RMR (2015) High resolution peripheral quantitative computed tomography for the assessment of morphological and mechanical bone parameters. Rev Bras Reumatol Engl Ed 55:352–362. https://doi.org/10.1016/j.rbre.2014.07.010
• 35. Bouxsein ML, Delmas PD (2008) Considerations for development of surrogate endpoints for antifracture efficacy of new treatments in osteoporosis: a perspective. J Bone Miner Res 23:1155–1167. https://doi.org/10.1359/jbmr.080301
• 36. Bolland MJ, Grey A, Gamble GD, Reid IR (2014) The effect of vitamin D supplementation on skeletal, vascular, or cancer outcomes: a trial sequential meta-analysis. Lancet Diabet Endocrinol 2:307–320. https://doi.org/10.1016/S2213-8587(13)70212-2
• 37. Lai JKC, Lucas RM, Clements MS et al (2010) Hip fracture risk in relation to vitamin D supplementation and serum 25-hydroxyvitamin D levels: a systematic review and meta-analysis of randomised controlled trials and observational studies. BMC Public Health 10:331. https://doi.org/10.1186/1471-2458-10-331
• 38. Abrahamsen B, Masud T, Avenell A et al (2010) Patient level pooled analysis of 68 500 patients from seven major vitamin D fracture trials in US and Europe. BMJ 340:139. https://doi.org/10.1136/bmj.b5463
• 39. Chung M, Lee J, Terasawa T et al (2011) Vitamin D with or without calcium supplementation for prevention of cancer and fractures: an updated meta-analysis for the US preventive services task force. Ann Intern Med 155:827–838
• 40. Murad MH, Drake MT, Mullan RJ et al (2012) Comparative effectiveness of drug treatments to prevent fragility fractures: a systematic review and network meta-analysis. J Clin Endocrinol Metab 97:1871–1880. https://doi.org/10.1210/jc.2011-3060
• 41. Bischoff-Ferrari HA, Willet WC, Wong JB et al (2009) Prevention of nonvertebral fractures with oral vitamin D and dose dependence: a meta-analysis of randomized controlled trials. Arch Intern Med 169:551–561
• 42. Bischoff-Ferrari HA, Willett WC, Wong JB et al (2005) Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials heike. JAMA 293:2257–2264
• 43. Reid IR, Horne AM, Mihov B et al (2017) Effect of monthly high-dose vitamin D on bone density in community-dwelling older adults substudy of a randomized controlled trial. J Intern Med 282:452–460. https://doi.org/10.1111/joim.12651
• 44. Macdonald HM, Reid IR, Gamble GD et al (2018) 25-hydroxyvitamin D threshold for the effects of vitamin D supplements on bone density: secondary analysis of a randomized controlled trial. J Bone Miner Res 33:1464–1469. https://doi.org/10.1002/jbmr.3442
• 45. Joo NS, Dawson-Hughes B, Kim YS et al (2013) Impact of calcium and vitamin D insufficiencies on serum parathyroid hormone and bone mineral density: analysis of the fourth and fifth Korea National Health and Nutrition Examination Survey (KNHANES IV-3, 2009 and KNHANES V-1, 2010). J Bone Miner Res 28:764–770. https://doi.org/10.1002/jbmr.1790
• 46. Steingrimsdottir L (2011) Relationship between serum parathyroid hormone levels vitamin D sufficiency, and calcium intake. JAMA 294:2336–2341