Vitamin D and calcium are required at the time of denosumab administration during osteoporosis treatment

Abstract

To evaluate the differences in outcomes of treatment with denosumab alone or denosumab combined with vitamin D and calcium supplementation in patients with primary osteoporosis. Patients were split into a denosumab monotherapy group (18 cases) or a denosumab plus vitamin D supplementation group (combination group; 23 cases). We measured serum bone alkaline phosphatase (BAP), tartrate-resistant acid phosphatase (TRACP)-5b and urinary N-terminal telopeptide of type-I collagen (NTX) at baseline, 1 week, as well as at 1 month and 2, 4, 8 and 12 months. We also measured bone mineral density (BMD) of L1–4 lumbar vertebrae (L)-BMD and bilateral hips (H)-BMD at baseline and at 4, 8 and 12 months. There was no significant difference in patient background. TRACP-5b and urinary NTX were significantly suppressed in both groups from 1 week to 12 months (except at 12 months for NTX). In the combination group, TRACP-5b was significantly decreased compared with the denosumab monotherapy group at 2 and 4 months (P<0.05). BAP was significantly suppressed in both groups at 2–12 months. L-BMD significantly increased at 8 and 12 months (8.9%) in the combination group and at 4, 8 and 12 months (6.0%) in the denosumab monotherapy group, compared with those before treatment. H-BMD was significantly increased in the combination group (3.6%) compared with the denosumab group (1.2%) at 12 months (P<0.05). Compared with denosumab monotherapy, combination therapy of denosumab with vitamin D and calcium stopped the decrease in calcium caused by denosumab, inhibited bone metabolism to a greater extent, and increased BMD (especially at the hips).

Osteoporosis: Vitamin D and calcium augment drug treatment

Vitamin D and calcium supplements help make an osteoporosis drug called denosumab safer and more effective. Researchers in Japan led by Yukio Nakamura of Shinshu University School of Medicine ran a year-long clinical trial in which 18 patients with primary osteoporosis received denosumab alone while another 23 patients received denosumab plus vitamin D tablets and calcium. Denosumab helps treat osteoporosis by blocking the RANKL protein involved in promoting the formation of bone-resorbing cells. Since RANKL also regulates calcium levels, one side effect of denosumab treatment is the risk of low blood calcium. The researchers found that the combination therapy worked better than denosumab alone at inhibiting bone resorption and increasing bone mineral density (especially in the hips). The combination also helped keep blood calcium levels in a healthier range.

References

[1] McClung MR, Lewiecki EM, Cohen SB et al. Denosumab in postmenopausal women with low bone mineral density. N Engl J Med, 2006, 354: 821-831

[2] Silva I, Branco JC. Denosumab: recent update in postmenopausal osteoporosis. Acta Reumatol Port, 2012, 37: 302-313

[3] Sugimoto T, Matsumoto T, Hosoi T et al. Three-year denosumab treatment in postmenopausal Japanese women and men with osteoporosis: results from a 1-year open-label extension of the Denosumab Fracture Intervention Randomized Placebo Controlled Trial (DIRECT). Osteoporos Int, 2015, 26: 765-774

[4] Kamimura M, Nakamura Y, Ikegami S et al. Significant improvement of bone mineral density and bone turnover markers by denosumab therapy in bisphosphonate-unresponsive patients. Osteoporos Int, 2017, 28: 559-566

[5] DeLuca HF. Overview of general physiologic features and functions of vitamin D. Am J Clin Nutr, 2004, 80 6 Suppl 1689S-1696SS

[6] Bouillon R, Okamura WH, Norman AW. Structure-function relationships in the vitamin D endocrine system. Endocr Rev, 1995, 16: 200-257

[7] Shiraki M, Fukuchi M, Kiriyama T et al. Alfacalcidol reduces accelerated bone turnover in elderly women with osteoporosis. J Bone Miner Metab, 2004, 22: 352-359

[8] Nakamura T, Matsumoto T, Sugimoto T et al. Clinical Trials Express: fracture risk reduction with denosumab in Japanese postmenopausal women and men with osteoporosis: denosumab fracture intervention randomized placebo controlled trial (DIRECT). J Clin Endocrinol Metab, 2014, 99: 2599-2607

[9] Diab DL, Watts NB. Denosumab in osteoporosis. Expert Opin Drug Saf, 2014, 13: 247-253

[10] Okada N, Kawazoe K, Teraoka K et al. Identification of the risk factors associated with hypocalcemia induced by denosumab. Biol Pharm Bull, 2013, 36: 1622-1626

[11] Body JJ, Bone HG, de Boer RH et al. Hypocalcaemia in patients with metastatic bone disease treated with denosumab. Eur J Cancer, 2015, 51: 1812-1821

[12] Soen S. New diagnostic criteria and guidelines on osteoporosis. Diagnostic criteria for primary osteoporosis: year 2012 revision. (Article in Japanese). Clin Calcium, 2014, 24: 323-329

[13] Uchiyama S, Ikegami S, Kamimura M et al. The skeletal muscle cross sectional area in long-term bisphosphonate users is smaller than that of bone mineral density-matched controls with increased serum pentosidine concentrations. Bone, 2015, 75: 84-87

[14] Ikegami S, Kamimura M, Uchiyama S et al. Clinical implications of hip flexion in the measurement of spinal bone mineral density. J Clin Densitom, 2016, 19: 270-276

[15] Nakamura Y, Ikegami S, Takanashi Y et al. Value changes in bone turnover markers and bone mineral density using ibandronate in Japanese postmenopausal osteoporotic patients. J Nutr Disorders Ther, 2016, 6: 188

[16] Shiraki M, Kushida K, Fukunaga M et al. A double-masked multicenter comparative study between alendronate and alfacalcidol in Japanese patients with osteoporosis. The Alendronate Phase III Osteoporosis Treatment Research Group. Osteoporos Int, 1999, 10: 183-192

[17] Ebina K, Kashii M, Hirao M et al. Comparison of the effects of denosumab between a native vitamin D combination and an active vitamin D combination in patients with postmenopausal osteoporosis. J Bone Miner Metab, 2016, 35: 571-580

[18] Olmos JM, Hernández JL, Llorca J et al. Effects of 25-hydroxyvitamin D3 therapy on bone turnover markers and PTH levels in postmenopausal osteoporotic women treated with alendronate. J Clin Endocrinol Metab, 2012, 97: 4491-4497

[19] Silva BC, Bilezikian JP. Parathyroid hormone: anabolic and catabolic actions on the skeleton. Curr Opin Pharmacol, 2015, 22: 41-50

[20] Leslie WD, Majumdar SR, Morin SN et al. Change in bone mineral density is an indicator of treatment-related antifracture effect in routine clinical practice: A Registry-Based Cohort Study. Ann Intern Med, 2016, 165: 465-472

[21] Antoniucci DM, Vittinghoff E, Palermo L et al. Vitamin D insufficiency does not affect response of bone mineral density to alendronate. Osteoporos Int, 2009, 20: 1259-1266

[22] Bourke S, Bolland MJ, Grey A et al. The impact of dietary calcium intake and vitamin D status on the effects of zoledronate. Osteoporos Int, 2013, 24: 349-354

[23] Heckman GA, Papaioannou A, Sebaldt RJ et al. Effect of vitamin D on bone mineral density of elderly patients with osteoporosis responding poorly to bisphosphonates. BMC Musculoskelet Disord, 2002, 3: 6

[24] Peris P, Martínez-Ferrer A, Monegal A et al. 25 hydroxyvitamin D serum levels influence adequate response to bisphosphonate treatment in postmenopausal osteoporosis. Bone, 2012, 51: 54-58

[25] Roux C, Binkley N, Boonen S et al. Vitamin D status and bone mineral density changes during alendronate treatment in postmenopausal osteoporosis. Calcif Tissue Int, 2014, 94: 153-157