PDF )  Rev Osteoporos Metab Miner. 2019; 11 (Supl 1): S13-17

DOI: 10.4321/S1889-836X2019000200003

Martínez-Laguna D1,2,3
1 Primary Care Center Barcelona City. Catalan Health Institute. Barcelona (Spain)
2 Research Group on Prevalent Diseases of the Locomotor System in Primary Care (GREMPAL); University Institute for Research in Primary Health Care Jordi Gol i Gurina (IDIAP Jordi Gol). Autonomous University of Barcelona. Barcelona (Spain)
3 Network Biomedical Research Center – Fragility and Healthy Aging (CIBERFES). Carlos III Health Institute (ISCIII). Madrid (Spain)


The role of calcium and vitamin D in bone metabolism has been known for many years. Calcium is one of the main components of bone and, together with the collagen matrix, it is responsible for facilitating the strength and resistance of the skeleton [1].
The maximum bone mass is acquired by 30 years of age and depends on genetic and environmental factors, including calcium intake. Once the bone mass peak is achieved, it is necessary to maintain a minimum calcium intake to avoid bone loss.
Vitamin D is responsible for maintaining calcium and phosphorus homeostasis, favoring its reabsorption at the renal and intestinal levels. Its deficit is associated with an alteration of bone mineralization, causing rickets in children and osteomalacia in adults.
Osteoporosis is a prevalent chronic process. It poses a public health problem associated with significant morbidity and mortality [2]. With the aging of the population its prevalence is expected to increase [3]. Physical activity and proper nutrition are two measures associated with a reducted risk of osteoporosis [4]. Adequate calcium intake, together with sufficient levels of vitamin D, have proven to be a good option to maintain a healthy bone state [5].

Calcium, vitamin D and muscle function
The interaction between the skeleton and its associated musculature occurs through direct mechanical effect and potential hormonal mechanisms.
In this sense, calcium plays a very important role through the control and neuromuscular regulation of intracellular myosin fibers, responsible for the contraction and relaxation of skeletal muscle [6]. Vitamin D absorbs and regulates calcium in muscle cells [7].
There is limited evidence regarding the use of calcium and vitamin D supplements and the loss of muscle mass and the increase in falls associated with aging. A systematic review suggests a low but significant positive effect of supplementation on muscle strength, but not on muscle mass or power [8]. No differences were observed between the use of vitamin D supplements compared to vitamin D supplements with calcium.
Reduced muscle function is associated with an increased risk of falls and, consequently, an increased risk of osteoporotic fractures. Supplementation with 700-1,000 IU of vitamin D (alone or associated with calcium) is associated with a 19% decrease in the risk of falls [9]. The role of calcium is controversial, although recent data suggest that its addition or not to vitamin D does not affect the risk of falls [10,11].
Thus, although calcium is intimately involved in muscular physiology, the evidence suggests that optimization of vitamin D, instead of calcium supplementation, reduces the risk of falls [12].

Calcium, vitamin D and bone metabolism
Proper nutrition with a sufficient calcium intake is necessary to acquire correct peak bone mass towards the third decade of life. Beyond that era, bone mass begins to decrease progressively, steadily in men and accelerated in postmenopausal women. To curb the slope of bone loss, an adequate supply of calcium and optimal levels of vitamin D should be maintained.
In general, a daily calcium intake of 1,000 mg is considered appropriate in children until adolescence, at which time the calcium provided should be about 1,300 mg/day. Between the ages of 19 and 50, a contribution of 1,000 mg/day is recommended, which should increase to 1,200 mg/day in women after menopause and in men after the seventh decade of life. As for the vitamin D intake, it is recommended that it be between 600-800 IU/day [13].
A recent meta-analysis observed a slight increase in bone mineral density (BMD) in relation to the increase in calcium intake, both through diet (0.6-1.8%) and supplements (0.7-1.8%) [14].
As for vitamin D, it is responsible for the maintenance of calcium homeostasis. Very low levels are associated with the appearance of osteomalacia and high levels can increase bone resorption and deteriorate mineralization, so prudent use in normal clinical practice is recommended [15]. In addition, observed BMD change is related to the basal plasma levels of 25-OH vitamin D and changes in levels over time [16].
Therefore, the European Medicines Agency recommends an adequate supply of calcium (in the diet or through the use of supplements), as well as physical activity and adequate levels of vitamin D to maintain bone health [17].

Calcium and vitamin D in the treatment of osteoporosis
Most drugs approved for the treatment of osteoporosis are authorized in the context of a replenishment of calcium and vitamin D. For the registration process, participants are almost always supplemented with calcium and vitamin D, both in the placebo group as in the group with active drug (Table 1).

The current trend is to analyze the intake of calcium in the diet through dietary surveys. If it is insufficient, supplement if possible through the diet or, otherwise, prescribed supplements [17]. Regarding vitamin D, determining the plasma levels of 25-OH-vitamin D is recommended. If they are below 20 ng/ml, supplement with a dose of 800-1,000 IU/day. Different clinical practice guides, both national [18] and international [19] advocate this practice.
In addition, insufficient levels of vitamin D have been described associated with an inadequate response of osteoporosis drugs. In a study that included 210 women with postmenopausal osteoporosis treated with bisphosphonates (mostly oral; only 38 patients with zoledronate) it was observed that those patients who maintained levels of 25-OH-vitamin D ≥33 ng/ml presented a probability 4, 5 times greater than presenting a favorable response to antiresorptive treatment [20]. Along the same lines, an observational study, carried out with the patients of the SIDIAP database (System of Information for the Development of Research in Primary Care) that initiated an oral bisphosphonate between 2006-2007, observed that the probability of response Inadequate to treatment, assessed as the presence of any fracture during treatment, was 2.7 times more likely in those patients with vitamin D insufficiency [21].
In an analysis of the FOCUS-D clinical trial (Fosavance vs. standard care-use and study of vitamin D) of patients treated with alendronate and vitamin D it was found that plasma levels of vitamin D correlated with changes in BMD, both at lumbar level as well as femoral, in patients treated with alendronate [22].
In a study conducted on 153 women with postmenopausal osteoporosis who were to receive a first dose of zoledronate, it was observed that 25-OH-vitamin D levels were lower in those who had an acute phase reaction, so that those with 25-OH-vitamin D levels <30 ng/ml presented 4.2 times the risk of presenting said reaction [23]. In patients treated with zoledronate, the assessment of plasma levels of creatinine, calcemia and 25-OH-vitamin D is recommended, being necessary to correct them before administration to avoid the occurrence of clinically significant hypocalcemia.
A population-based Taiwanese observational study analyzed the relationship between the use of bisphosphonates and the occurrence of atrial fibrillation, observing an increased risk in patients treated with bisphosphonates, but a potential beneficial effect of vitamin D reducing the occurrence of atrial fibrillation [24].
Regarding denosumab, a study conducted of 41 patients with primary osteoporosis, where 18 received only denosumab and 23 denosumab together with 1,200 mg calcium and 400 IU of vitamin D per day, observed a greater change in BMD in the combined group compared with the group treated exclusively with denosumab [25]. At 12 months, an increase of 6% was observed at lumbar level in the monotherapy group and 8.9% in the combined treatment group, a non-significant difference (p=0.22). At femoral level, an increase of 1.2% and 3.6% was observed at 12 months respectively, a statistically significant difference (p<0.05). Although no patient presented hypocalcemia, the addition of calcium and vitamin D, was not associated with a decrease in calcemia levels, a fact that was observed in the monotherapy group. The authors conclude the need to supplement patients treated with denosumab with calcium and vitamin D.
The VERO clinical trial (The vertebral fracture treatment comparisons in osteoporotic women) has recently been published, where 1,360 women with established postmenopausal osteoporosis were randomized to receive teriparatide or risedronate for two years, together with 500-1,000 mg/day of calcium and 400- 800 IU/day of vitamin D (mainly cholecalciferol). A post-hoc analysis [26] observed that patients treated with teriparatide presented at six months a decrease in the average levels of 25-OH-vitamin D (from 31.9 ng/ml to 24.5 ng/ml), a fact that did not It was observed in patients treated with risedronate (from 31.5 ng/ml to 32.2 ng/ml). The percentage of patients with insufficient levels of vitamin D increased in the teriparatide group, while the risedronate group decreased. There were, however, no significant differences in the anti-fracture effect in relation to 25-OH-vitamin D levels.
Finally, commenting that a cost-effectiveness study concluded that the use of calcium and vitamin D supplements in women and men >60 years with osteoporosis was cost-effective, recommending its use from an economic perspective, even in patients treated with other osteoporosis drugs [27].

Correcting the levels of calcium and vitamin D is recommended, preferably through diet or the use of supplements, in patients with osteoporosis who are going to receive an antiresorptive or osteoforming drug. It is a cost-effective intervention. In addition, the correction of vitamin D levels can be associated with a decrease in the risk of falls, and therefore with a lower risk of osteoporotic fracture.


Conflict of interests: The author declares to have received personal fees from Eli Lilly, Amgen, Ferrer, Rubió and Novartis.



1. Seeman E. Structural basis of growth-related gain and age-related loss of bone strength. Rheumatology (Oxford). 2008;47(Suppl 4):iv2-8.
2. Hernlund E, Svedbom A, Ivergård M, Compston J, Cooper C, Stenmark J, et al. Osteoporosis in the European Union: medical management, epidemiology and economic burden. A report prepared in collaboration with the International Osteoporosis Foundation (IOF) and the European Federation of Pharmaceutical Industry Associations (EFPIA). Arch Osteoporos. 2013;8:136.
3. Cummings SR, Kelsey JL, Nevitt MC, O’Dowd KJ. Epidemiology of osteoporosis and osteoporotic fractures. Epidemiol Rev. 1985;7:178-208.
4. Mendoza N, De Teresa C, Cano A, Godoy D, Hita-Contreras F, Lapotka M, et al. Benefits of physical exercise in postmenopausal women. Maturitas. 2016;93:83-8.
5. Rizzoli R. Nutritional aspects of bone health. Best Pract Res Clin Endocrinol Metab. 2014;28:795-808.
6. Gehlert S, Bloch W, Suhr F. Ca2+-dependent regulations and signaling in skeletal muscle: from electro-mechanical coupling to adaptation. Int J Mol Sci. 2015;16:1066-95.
7. Rizzoli R, Stevenson JC, Bauer JM, van Loon LJC, Walrand S, Kanis JA, et al. The role of dietary protein and vitamin D in maintaining musculoskeletal health in postmenopausal women: a consensus statement from the European Society for Clinical and Economic Aspects of Osteoporosis and Osteoarthritis (ESCEO). Maturitas. 2014;79:122-32.
8. Beaudart C, Buckinx F, Rabenda V, Gillain S, Cavalier E, Slomian J, et al. The effects of vitamin D on skeletal muscle strength, muscle mass, and muscle power: a systematic review and meta-analysis of randomized controlled trials. J. Clin. Endocrinol Metab. 2014; 99:4336-45.
9. Bischoff-Ferrari HA, Dawson-Hughes B, Staehelin HB, Orav JE, Stuck AE, Theiler R, et al. Fall prevention with supplemental and active forms of vitamin D: a meta-analysis of randomised controlled trials. BMJ. 2009;339:b3692.
10. LeBlanc ES, Chou R. Vitamin D and Falls-Fitting new data with current guidelines. JAMA Intern Med. 2015; 175:712-3.
11. Kalyani RR, Stein B, Valiyil R, Manno R, Maynard JW, Crews DC. Vitamin D treatment for the prevention of falls in older adults: systematic review and meta-analysis. J Am Geriatr Soc. 2010; 58:1299-310.
12. Harvey NC, Biver E, Kaufman J-M, Bauer J, Branco J, Brandi ML, et al. The role of calcium supplementation in healthy musculoskeletal ageing. Osteoporos Int. 2017;28:447-62.
13. Institute of Medicine (US) Committee to Review Dietary Reference Intakes for Vitamin D and Calcium. Dietary Reference Intakes for Calcium and Vitamin D. Washington, D.C.: National Academies Press; 2011.
14. Tai V, Leung W, Grey A, Reid IR, Bolland MJ. Calcium intake and bone mineral density: systematic review and meta-analysis. BMJ. 2015;351:h4183.
15. Reid IR, Bolland MJ. Skeletal and nonskeletal effects of vitamin D: is vitamin D a tonic for bone and other tissues? Osteoporos Int. 2014;25:2347-57.
16. Clifton-Bligh PB, Nery ML, Clifton-Bligh RJ, Fulcher GR, Baber R. Changes in bone mineral density related to changes in serum 25-OH vitamin D concentrations over a two-year period in postmenopausal women. Endocrine. 2017;58:587-90.
17. Cano A, Chedraui P, Goulis DG, Lopes P, Mishra G, Mueck A, et al. Calcium in the prevention of postmenopausal osteoporosis: EMAS clinical guide. Maturitas. 2018;107:7-12.
18. González-Macías J, del Pino-Montes J, Olmos JM, Nogués X. Clinical practice guidelines for postmenopausal, glucocorticoid-induced and male osteoporosis. Spanish Society for Research on Bone and Mineral Metabolism (3rd updated version 2014). Rev Clin Esp. 2015;215:515-26.
19. Kanis JA, Cooper C, Rizzoli R, Reginster J-Y. European guidance for the diagnosis and management of osteoporosis in postmenopausal women. Osteoporos Int. 2019;30:3-44.
20. Carmel AS, Shieh A, Bang H, Bockman RS. The 25(OH)D level needed to maintain a favorable bisphosphonate response is ≥33 ng/ml. Osteoporos Int. 2012;23:2479-87.
21. Prieto-Alhambra D, Pagès-Castellà A, Wallace G, Javaid MK, Judge A, Nogués X, et al. Predictors of fracture while on treatment with oral bisphosphonates: a population-based cohort study. J Bone Miner Res. 2014;29:268-74.
22 Roux C, Binkley N, Boonen S, Kiel DP, Ralston SH, Regnister J-Y, et al. Vitamin D status and bone mineral density changes during alendronate treatment in postmenopausal osteoporosis. Calcif Tissue Int. 2014;94:153-7.
23. Crotti C, Watts NB, De Santis M, Ceribelli A, Fabbriciani G, Cavaciocchi F, et al. Acute phase reactions after zoledronic acid infusion: protective role of 25-hydroxyvitamin D and previous oral bisphosphonate therapy. Endocr Pract. 2018;24:405-10.
24. Yang HY, Huang JH, Chiu HW, Lin YK, Hsu CY, Chen YJ. Vitamin D and bisphosphonates therapies for osteoporosis are associated with different risks of atrial fibrillation in women: A nationwide population-based analysis. Medicine (Baltimore). 2018;97:e12947.
25. Nakamura Y, Suzuki T, Kamimura M, Murakami K, Ikegami S, Uchiyama S, et al. Vitamin D and calcium are required at the time of denosumab administration during osteoporosis treatment. Bone Res. 2017;5:17021.
26. Minisola S, Marin F, Kendler DL, Geusens P, Zerbini CAF, Russo LA, et al. Serum 25-hydroxy-vitamin D and the risk of fractures in the teriparatide versus risedronate VERO clinical trial. Arch Osteoporos. 2019;14:10.
27. Hiligsmann M, Ben Sedrine W, Bruyere O, Evers SM, Rabenda V, Reginster J-Y. Cost-effectiveness of vitamin D and calcium supplementation in the treatment of elderly women and men with osteoporosis. Eur J Public Health. 2015; 25:20-5.
28. Black DM, Thompson DE, Bauer DC, Ensrud K, Musliner T, Hochberg MC, et al. Fracture risk reduction with alendronate in women with osteoporosis: the Fracture Intervention Trial. J Clin Endocrinol Metab. 2000;85:4118-24.
29. Harris ST, Watts NB, Genant HK, McKeever CD, Hangartner T, Keller M, et al. Effects of risedronate treatment on vertebral and nonvertebral fractures in women with postmenopausal osteoporosis: a randomized controlled trial. Vertebral Efficacy With Risedronate Therapy (VERT) Study Group. JAMA. 1999;282:1344-52.
30. Delmas PD, Recker RR, Chesnut CH, Skag A, Stakkestad JA, Emkey R, et al. Daily and intermittent oral ibandronate normalize bone turnover and provide significant reduction in vertebral fracture risk: results from the BONE study. Osteoporos Int. 2004; 15:792-8.
31. Black DM, Delmas PD, Eastell R, Reid IR, Boonen S, Cauley JA, et al. Once-yearly zoledronic acid for treatment of postmenopausal osteoporosis. N Engl J Med. 2007;356:1809-22.
32. Ettinger B, Black DM, Mitlak BH, Knickerbocker RK, Nickelsen T, Genant HK, et al. Reduction of vertebral fracture risk in postmenopausal women with osteoporosis treated with raloxifene: results from a 3-year randomized clinical trial. Multiple Outcomes of Raloxifene Evaluation (MORE) Investigators. JAMA. 1999; 282:637-45.
33. Silverman SL, Christiansen C, Genant HK, Vukicevic S, Zanchetta JR, de Villiers TJ, et al. Efficacy of bazedoxifene in reducing new vertebral fracture risk in postmenopausal women with osteoporosis: results from a 3-year, randomized, placebo-, and active-controlled clinical trial. J Bone Miner Res. 2008;23:1923-34.
34. Neer RM, Arnaud CD, Zanchetta JR, Prince R, Gaich GA, Reginster JY, et al. Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis. N Engl J Med. 2001;344:1434-41.
35. Cummings SR, San Martin J, McClung MR, Siris ES, Eastell R, Reid IR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361:756-65.
36. Cosman F, Crittenden DB, Adachi JD, Binkley N, Czerwinski E, Ferrari S, et al. Romosozumab treatment in postmenopausal women with osteoporosis. N Engl J Med. 2016;375:1532-43.