You are viewing the site in preview mode

Skip to main content
Download PDF

Vitamin D and calcium supplementation in women undergoing pharmacological management for postmenopausal osteoporosis: a level I of evidence systematic review

European Journal of Medical Research volume 30, Article number: 170 (2025) Cite this article

Abstract

The present systematic review investigates whether different doses of vitamin D and calcium supplementation in women with postmenopausal osteoporosis undergoing antiresorptive therapy have an association with BMD (spine, hip, femur neck), serum markers of osteoporosis (bone-ALP, NTX, CTX), the rate of pathological vertebral and non-vertebral fractures, adverse events, and mortality. This systematic review was conducted according to the PRISMA 2020 guidelines. PubMed, Google Scholar, Embase, and Scopus databases were accessed in September 2024. All randomised clinical trials (RCTs) comparing two or more treatments for postmenopausal osteoporosis supplemented with vitamin D and/or calcium were accessed. Only studies that indicated daily vitamin D and/or calcium supplementation doses were accessed. Data from 37 RCTs (43,397 patients) were retrieved. Patients received a mean of 833.6 ± 224.0 mg and 92.8 ± 228.7 UI of calcium and vitamin D supplementation, respectively. The mean length of the follow-up was 25.8 ± 13.3 months. The mean age of the patients was 66.4 ± 5.6 years, and the mean BMI was 25.2 ± 1.6 kg/m2. There was evidence of a statistically significant negative association between daily vitamin D supplementation and gastrointestinal adverse events (r = − 0.5; P = 0.02) and mortality (r = − 0.7; P = 0.03). No additional statistically significant associations were evidenced. In postmenopausal women who undergo antiresorptive treatment for osteoporosis, vitamin D was associated with a lower frequency of gastrointestinal adverse events and mortality. Calcium supplementation did not evidence an association with any of the endpoints of interest.

Level of evidence Level I, systematic review of RCTs.

Introduction

Osteoporosis is a metabolic bone disease characterised by loss of bone mineral density (BMD) and bone mass and deterioration of bone microarchitecture, increasing the risk of fracture [1,2,3]. The prevalence of osteoporosis is very high, and the social and economic impact associated with osteoporosis-related fractures is particularly significant [4, 5]. The rate of bone loss increases with advancing age, especially in the first few menopausal years, constituting a major concern for women warranting the term postmenopausal osteoporosis (PMO) [6,7,8,9]. Since calcium and vitamin D play a synergistic role in preventing BMD loss and maintaining bone homeostasis [10,11,12], deficiency of these elements, especially in the elderly, is likely associated with alterations in bone remodelling and poor skeletal muscle health [13,14,15]. A diet rich in calcium and vitamin D appears to have a favourable impact on BMD. Since vitamin D status is critical for calcium absorption, the combined intake of these micronutrients could prevent hip fractures in postmenopausal women [3, 16, 17]. Pharmacological management of osteoporosis includes bisphosphonates, highly effective antiresorptive agents, as first-line therapy [18,19,20]. However, their effects vary among patients with a risk of treatment failure and adverse events [21, 22]. Given the chronic nature of osteoporosis, long-term treatment is necessary. Therefore, it becomes essential to identify therapeutic approaches that can complement drug therapy effectively and well-tolerated. Calcium and vitamin D supplements have been proposed as an anti-osteoporotic therapy recommended for their potential to reduce fracture rates in both institutionalised elderly and community-dwelling patients [23,24,25]. In PMO, combining vitamin D supplementation and bisphosphonates increases the efficacy of anti-osteoporotic treatment [26]. Vitamin D appears to play a role in enhancing the bisphosphonate tail effect on BMD after discontinuation of drug therapy [27]. However, although most randomised clinical trials (RCTs) have evaluated the efficacy and safety of antiresorptive drugs in patients receiving calcium and vitamin D supplementation, international guidelines now recommend individualising the use of these micronutrients according to risk factors for their insufficiency [28, 29]. Meta-analyses of RCTs reported only a weak effect on the occurrence of fractures and have drawn attention to possible side effects of calcium supplements previously ignored [30]. The role of calcium and vitamin D supplementation in the management of osteoporosis remains controversial, and data on the efficacy and safety effects in women with PMO undergoing antiresorptive treatment are lacking [31, 32].

The present systematic review investigates whether different doses of vitamin D and calcium supplementation in postmenopausal women undergoing antiresorptive therapy for osteoporosis are associated with BMD (spine, hip, femur, neck), serum markers of osteoporosis (bone-ALP, NTX, CTX), the rate of pathological fractures (vertebral and non-vertebral), adverse events, and mortality.

Method

Search strategy

This systematic review was conducted according to the PRISMA 2020 guidelines [33]. The PICOT algorithm was preliminarily established:

  • P (Population): postmenopausal osteoporosis;

  • I (Intervention): antiresorptive treatments;

  • C (Comparison): vitamin D and calcium supplementation;

  • O (Outcomes): BMD, serum markers, pathological fractures, adverse events, mortality;

  • T (Type of study): RCT.

Data source and extraction

Two authors (G.C. and M.M.) independently performed the literature search in September 2024. The following databases were accessed: PubMed, Google Scholar, Embase, and Scopus. The following keywords were used in combination: osteoporosis, vitamin D, calcium, treatment, management, drug, pharmacology, pharmacological, medicament, mineral, density, bone, BMD, postmenopausal, spine, pathological, fragility, fractures, hip, vertebral, disability, adverse events. The same authors independently performed the initial screening. The full text was accessed if the title and abstract matched the topic of interest. A cross reference of the bibliographies was also performed.

Eligibility criteria

All randomised controlled trials (RCTs) comparing two or more treatments for postmenopausal osteoporosis supplemented with vitamin D and/or calcium were accessed. Only studies that stated daily vitamin D and/or calcium supplementation doses were accessed. According to the authors’ language capabilities, English, French, German, Italian, Portuguese and Spanish articles were eligible. Only RCTs level I evidence, according to the Oxford Centre of Evidence-Based Medicine [34], were considered. Articles including patients with glucocorticoid-induced osteoporosis were excluded. Studies conducted on patients with tumours and/or bone metastases and studies reporting data on patients with iatrogenic-induced menopausal and those on paediatric and/or adolescent patients were not included. Studies regarding selected patients undergoing immunosuppressive therapies or organ transplantation were not considered. Studies reporting data on combined therapy with multiple anti-osteoporotic or experimental drugs were also not included. Only articles reporting quantitative data under the outcomes of interest were eligible.

Outcomes of interest

Two authors (F.M. and G.C.) independently examined the resulting articles for inclusion criteria. Study generalities (author, year, journal, length of the follow-up) and baseline demographic information were collected: the number of patients and relative mean age, mean bone mass index (BMI), mean BMD (spine, hip, femur neck), antiresorptive therapy. The outcome of interest was whether different doses of vitamin D and calcium supplementation have an association with BMD (spine, hip, femur neck), serum markers of osteoporosis (bone-ALP, NTX, CTX, PINP), the rate of pathological fractures (vertebral and non-vertebral), adverse events, and mortality.

Methodology quality assessment

The risk of bias summary tool of the Review Manager Software (The Nordic Cochrane Collaboration, Copenhagen) was used to assess the methodological quality of the article included in the present systematic review. The following risks of bias were evaluated: selection, detection, attrition, and other sources of bias.

Statistical analysis

The statistical analysis was performed by the main author (F.M.). The STATA Software/MP version 16 (StataCorporation, College Station, Texas, USA) was used for the statistical analyses. For descriptive statistics, the arithmetic mean and standard deviation were evaluated. The baseline comparability was assessed using the unpaired t-test, with P values > 0.1 considered satisfactory. A multivariate analysis diagnostic was used to analyse the association between the doses of vitamin D and calcium supplementation and the variables of BMD (spine, hip, and femur neck), serum markers of osteoporosis (bone-ALP, NTX, CTX), the rate of pathological fractures, adverse events, and death. Within studies, data concerning control groups or treatment arms which did not meet the inclusion criteria were not included in the statistical analyses. The Pearson product-moment correlation coefficient (r) was used. The linear regressions were evaluated according to the Cauchy–Schwarz inequality: + 1 (positive linear correlation) and − 1 (negative linear correlation). Values of 0.1 <|r|< 0.3, 0.3 <|r|< 0.5, and |r|> 0.5 were considered to have weak, moderate, and strong correlations, respectively. Overall significance was evaluated through the χ2 test. Values of P < 0.05 were considered statistically significant.

Results

Search result

A total of 6953 articles were identified from the four searched databases. Of them, 2962 studies were excluded as duplicates. An additional 3936 studies were excluded for the following reasons: not matching the topic (N = 1918), not reporting the exact amount of daily vitamin D and/or calcium (N = 1705), poor level of evidence (N = 149), referring to glucocorticoid-induced osteoporosis (N = 95), including patients with combined therapy with multiple anti-osteoporotic or experimental drugs (N = 21) language limitation (N = 19), including patients undergoing immunosuppressive therapies or organs transplantation (N = 13), including paediatric and/or adolescent patients with iatrogenic-induced menopausal (N = 9), including patients with tumours and/or bone metastases (N = 7). A further 18 articles were not eligible as they did not report quantitative data on the outcomes of interest. Finally, 37 RCTs were included in the present study (Fig. 1).

Fig. 1
figure 1

Flowchart of the literature search

Full size image

Methodological quality assessment

The risk of bias summary evidenced the strengths of the present study. First, the choice to include only RCTs reflected the low risk of selection bias. In addition, most patients and assessors were blinded, which resulted in a moderate–low risk of detection and performance bias. The high quality of the included studies also showed a low risk of attrition and reporting bias. In conclusion, the methodological assessment reported an overall low bias risk, leading to a very good methodological assessment (Fig. 2).

Fig. 2
figure 2

Methodological quality assessment

Full size image

Patient demographics

Data from 43,397 patients were retrieved. Patients received a mean of 833.6 ± 224.0 mg and 92.8 ± 228.7 UI of calcium and vitamin D supplementation, respectively. The mean length of the follow-up was 25.8 ± 13.3 months. The mean age of the patients was 66.4 ± 5.6 years, and the mean BMI was 25.2 ± 1.6 kg/m2. Study characteristics and patient data at baseline are shown in detail in Table 1.

Table 1 Study characteristics and patient data at baseline of the included studies
Full size table

Outcomes of interest

There was evidence of a statistically significant negative association between daily vitamin D supplementation and gastrointestinal adverse events (r = − 0.5; P = 0.02) and mortality (r = − 0.7; P = 0.03). No additional statistically significant associations were evidenced (Table 2).

Table 2 Results of the multivariate analyses
Full size table

Discussion

According to the published level I of evidence articles, in postmenopausal women who undergo antiresorptive treatment for osteoporosis, vitamin D was associated with a lower frequency of gastrointestinal adverse events and mortality. Calcium supplementation did not evidence an association with any of the endpoints of interest.

Poor vitamin D status, identified by low serum levels of 25-hydroxyvitamin D (25(OH)D), has been associated with poor skeletal muscle health. Therefore, vitamin D, like calcium, has long been identified as a key element in preventing and treating bone loss and bone diseases such as osteoporosis [72]. A diet rich in calcium and vitamin D appears to have a favourable impact on BMD. Since vitamin D status is critical for calcium absorption, combining these micronutrients could prevent hip fractures in postmenopausal women [16]. However, the data available to date are conflicting, partly because of the heterogeneity of the studies regarding sample size and length of follow-up. In addition, one of the most debated issues concerns the variability of vitamin D dosages used. Some studies may not have revealed a significant effect, having probably used inadequate doses not commensurate with patients' needs. On the other hand, excess vitamin D might have less than positive effects, leading to reduced BMD and increased risk of fractures [16].

The present study found a statistically significant negative association between daily vitamin D supplementation and mortality. This is an important finding because the strong association between osteoporosis and fracture risk, especially in older adults, consequently increases patients’ morbidity and mortality [73]. Some observational studies have shown a possible association between low vitamin D status and increased mortality [74, 75]. However, this association may be nonlinear and appears lost at serum 25(OH)D concentrations above 87.5 nmol/L [76]. Vitamin D might significantly improve the survival of elderly subjects living in institutional care. Notably, this finding was independent of the baseline vitamin D status [77]. In postmenopausal women with osteoporosis, vitamin D supplements could be associated with decreased mortality [78]. However, several randomised controlled trials (RCTs) have reported only a trend toward reduced mortality without reaching statistical significance [78, 79]. The influencing factors are undoubtedly multiple, including the variable age of study participants and supplement dosage, so the relationship linking them to total mortality rates remains to be clarified. Given the strong interaction between calcium and vitamin D, a major concern is whether the beneficial effects on improved skeletal health attributed to vitamin D may result from concomitant calcium supplementation [80]. LaCroix et al. [81] performed a thorough analysis to evaluate the effects of combined supplementation of vitamin D and calcium in 36,282 postmenopausal women aged 51–82 years already enrolled in the “Women's Health Initiative (WHI) trial of CaD”, which had shown non-significant reductions in all-cause mortality [79]. Calcium/vitamin D supplementation reduced the risk of all-cause, cardiovascular, and cancer death in women younger than 70. In contrast, in older women, this combined treatment was only associated with a reduction in cancer mortality [81]. It is essential to monitor treatment adherence, as age did not influence the effects on mortality. Still, calcium and vitamin D supplements reduced all-cause mortality rates in women who adhered to this treatment. In this large RCT, as in other studies, the effects of vitamin D could not be distinguished from those of calcium, and notably, fixed dosages of 1000 mg of calcium carbonate and 400 IU of vitamin D3 were used. Based on this evidence, the results of WHI CaD appear to be inconclusive [81], and whether vitamin D given as monotherapy or combined with calcium may be able to reduce all-cause mortality remains an open question.

The present study demonstrates that, in contrast to findings related to vitamin D, the use of calcium supplements was not associated with either mortality or the other endpoints evaluated. Indeed, beneficial effects were found in mixed populations, including women with postmenopausal osteoporosis, subjects receiving combined vitamin D and calcium supplementation and those treated with vitamin D only [82,83,84,85]. A recent meta-analysis suggested that vitamin D supplementation between 700 and 800 IU/d (but not at lower doses) should reduce the risk of hip and non-vertebral fractures by about 25% in subjects aged 60. However, the authors did not define the role (if any) of concomitant calcium supplementation [83].

Another question is the safety profile of supplementation. The present systematic review found no association between calcium supplementation and side effects. In contrast, the use of vitamin D was associated with a lower frequency of gastrointestinal toxicity. The risk of kidney stones is common in patients taking calcium and vitamin D supplements simultaneously, while gastrointestinal side effects have been reported in patients taking calcium [83]. While vitamin D supplementation may reduce cardiovascular risk, calcium supplementation may increase it [86]. Calcium-related gastrointestinal toxicity, which is very common, is associated with an unfavourable risk–benefit profile that often leads to poor long-term therapeutic adherence. As a result, some authors suggest that calcium supplementation should not be recommended [87].

This study has some limitations. Variability in the mean follow-up (6 to 48 months) was evident. A shorter follow-up might reduce the efficacy of the present research in identifying the rate of pathologic fractures and their association with vitamin D and calcium doses. Another limitation is that in all included studies, vitamin D was taken together with calcium, so it is not possible to assess clearly whether the association between vitamin D supplementation and reduced mortality rate would have been found in the absence of calcium supplementation. On the other hand, because calcium and vitamin D play a synergistic role in preventing BMD loss and maintaining homeostasis and bone health, most osteoporotic patients use these supplements concomitantly.

Conclusion

In postmenopausal women receiving antiresorptive treatment for osteoporosis, vitamin D was associated with a lower frequency of gastrointestinal adverse events and mortality. Calcium supplementation showed no association with any of the endpoints of interest. Since calcium absorption depends on vitamin D status and given the favourable benefit/risk profile associated with vitamin D supplementation, vitamin D as monotherapy or calcium co-administration appears superior to calcium supplements alone.

Availability of data and materials

No datasets were generated or analysed during the current study.

References

  1. Rachner TD, Khosla S, Hofbauer LC. Osteoporosis: now and the future. Lancet. 2011;377(9773):1276–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Gargano G, Asparago G, Spiezia F, et al. Small interfering RNAs in the management of human osteoporosis. Br Med Bull. 2023;148(1):58–69.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Migliorini F, Vecchio G, Weber CD, et al. Management of transient bone osteoporosis: a systematic review. Br Med Bull. 2023;147(1):79–89.

    Article  PubMed  PubMed Central  Google Scholar 

  4. Migliorini F, Cocconi F, Vecchio G, et al. Pharmacological agents for bone fracture healing: talking points from recent clinical trials. Expert Opin Investig Drugs. 2023;32(9):855–65.

    Article  CAS  PubMed  Google Scholar 

  5. Migliorini F, Maffulli N, Trivellas M, et al. Total hip arthroplasty compared to bipolar and unipolar hemiarthroplasty for displaced hip fractures in the elderly: a Bayesian network meta-analysis. Eur J Trauma Emerg Surg. 2022;48(4):2655–66.

    Article  PubMed  PubMed Central  Google Scholar 

  6. Eastell R, O’Neill TW, Hofbauer LC, et al. Postmenopausal osteoporosis. Nat Rev Dis Prim. 2016;2:16069.

    Article  PubMed  Google Scholar 

  7. Kanis JA, Norton N, Harvey NC, et al. SCOPE 2021: a new scorecard for osteoporosis in Europe. Arch Osteoporos. 2021;16(1):82.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Salari N, Ghasemi H, Mohammadi L, et al. The global prevalence of osteoporosis in the world: a comprehensive systematic review and meta-analysis. J Orthop Surg Res. 2021;16(1):609.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Curtis EM, Moon RJ, Harvey NC, et al. The impact of fragility fracture and approaches to osteoporosis risk assessment worldwide. Bone. 2017;104:29–38.

    Article  PubMed  PubMed Central  Google Scholar 

  10. Heaney RP. Vitamin D and calcium interactions: functional outcomes. Am J Clin Nutr. 2008;88(2):541S-544S.

    Article  CAS  PubMed  Google Scholar 

  11. Migliorini F, Maffulli N, Spiezia F, et al. Biomarkers as therapy monitoring for postmenopausal osteoporosis: a systematic review. J Orthop Surg Res. 2021;16(1):318.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Migliorini F, Colarossi G, Baroncini A, et al. Pharmacological management of postmenopausal osteoporosis: a level I evidence based—expert opinion. Expert Rev Clin Pharmacol. 2021;14(1):105–19.

    Article  CAS  PubMed  Google Scholar 

  13. Ensrud KE, Duong T, Cauley JA, et al. Low fractional calcium absorption increases the risk for hip fracture in women with low calcium intake. Study of Osteoporotic Fractures Research Group. Ann Intern Med. 2000;132(5):345–53.

    Article  CAS  PubMed  Google Scholar 

  14. Migliorini F, Maffulli N, Colarossi G, et al. Effect of drugs on bone mineral density in postmenopausal osteoporosis: a Bayesian network meta-analysis. J Orthop Surg Res. 2021;16(1):533.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Migliorini F, Maffulli N, Spiezia F, et al. Potential of biomarkers during pharmacological therapy setting for postmenopausal osteoporosis: a systematic review. J Orthop Surg Res. 2021;16(1):351.

    Article  PubMed  PubMed Central  Google Scholar 

  16. Liu C, Kuang X, Li K, et al. Effects of combined calcium and vitamin D supplementation on osteoporosis in postmenopausal women: a systematic review and meta-analysis of randomized controlled trials. Food Funct. 2020;11(12):10817–27.

    Article  CAS  PubMed  Google Scholar 

  17. Migliorini F, Colarossi G, Eschweiler J, et al. Antiresorptive treatments for corticosteroid-induced osteoporosis: a Bayesian network meta-analysis. Br Med Bull. 2022;143(1):46–56.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Chen JS, Sambrook PN. Antiresorptive therapies for osteoporosis: a clinical overview. Nat Rev Endocrinol. 2011;8(2):81–91.

    Article  PubMed  Google Scholar 

  19. Zhang C, Li Q, Ye Z, et al. Mechanism of Circ_HECW2 regulating osteoblast apoptosis in osteoporosis by attenuating the maturation of miR-1224-5p. J Orthop Surg Res. 2024;19(1):40.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Luo Y, Xiang Y, Lu B, et al. Correction: Association between dietary selenium intake and the prevalence of osteoporosis and its role in the treatment of glucocorticoid-induced osteoporosis. J Orthop Surg Res. 2024;19(1):36.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Conti V, Russomanno G, Corbi G, et al. A polymorphism at the translation start site of the vitamin D receptor gene is associated with the response to anti-osteoporotic therapy in postmenopausal women from southern Italy. Int J Mol Sci. 2015;16(3):5452–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Eastell R, Szulc P. Use of bone turnover markers in postmenopausal osteoporosis. Lancet Diabetes Endocrinol. 2017;5(11):908–23.

    Article  PubMed  Google Scholar 

  23. Weaver CM, Alexander DD, Boushey CJ, et al. Calcium plus vitamin D supplementation and risk of fractures: an updated meta-analysis from the national osteoporosis foundation. Osteoporos Int. 2016;27(1):367–76.

    Article  CAS  PubMed  Google Scholar 

  24. An R, Luo Q, Li L, et al. The effects of resveratrol in animal models of primary osteoporosis: a systematic review and meta-analysis. J Orthop Surg Res. 2024;19(1):137.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Jiang C, Zhu S, Zhan W, et al. Comparative analysis of bone turnover markers in bone marrow and peripheral blood: implications for osteoporosis. J Orthop Surg Res. 2024;19(1):163.

    Article  PubMed  PubMed Central  Google Scholar 

  26. Jing W, Dai Y, Zhu J, et al. Clinical efficacy and safety evaluation of calcitriol combined with bisphosphonates in the therapy of postmenopausal osteoporosis: based on a retrospective cohort study. Biomed Res Int. 2022;2022:2711938.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Catalano A, Bellone F, Santoro D, et al. Vitamin D boosts alendronate tail effect on bone mineral density in postmenopausal women with osteoporosis. Nutrients. 2021;13(6):1878.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Morin SN, Feldman S, Funnell L, et al. Clinical practice guideline for management of osteoporosis and fracture prevention in Canada: 2023 update. CMAJ. 2023;195(39):E1333–48.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Qaseem A, Hicks LA, Etxeandia-Ikobaltzeta I, et al. Pharmacologic treatment of primary osteoporosis or low bone mass to prevent fractures in adults: a living clinical guideline from the American college of physicians. Ann Intern Med. 2023;176(2):224–38.

    Article  PubMed  PubMed Central  Google Scholar 

  30. Bolland MJ, Grey A, Reid IR. Should we prescribe calcium or vitamin D supplements to treat or prevent osteoporosis? Climacteric. 2015;18(Suppl 2):22–31.

    Article  PubMed  Google Scholar 

  31. Farrah Z, Jawad AS. Optimising the management of osteoporosis. Clin Med. 2020;20(5):e196–201.

    Article  Google Scholar 

  32. Tu KN, Lie JD, Wan CKV, et al. Osteoporosis: a review of treatment options. P T. 2018;43(2):92–104.

    PubMed  PubMed Central  Google Scholar 

  33. Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ. 2021;372: n71.

    Article  PubMed  PubMed Central  Google Scholar 

  34. Howick JCI, Glasziou P, Greenhalgh T, Heneghan C, Liberati A, Moschetti I, Phillips B, Thornton H, Goddard O, Hodgkinson M. The Oxford CEBM levels of evidence. Oxford: Oxford Centre for Evidence-Based Medicine; 2011. Accessed Jan 2024.

    Google Scholar 

  35. Anastasilakis AD, Polyzos SA, Gkiomisi A, et al. Denosumab versus zoledronic acid in patients previously treated with zoledronic acid. Osteoporos Int. 2015;26(10):2521–7.

    Article  CAS  PubMed  Google Scholar 

  36. Atmaca A, Gedik O. Effects of alendronate and risedronate on bone mineral density and bone turnover markers in late postmenopausal women with osteoporosis. Adv Ther. 2006;23(6):842–53.

    Article  CAS  PubMed  Google Scholar 

  37. Bai H, Jing D, Guo A, et al. Randomized controlled trial of zoledronic acid for treatment of osteoporosis in women. J Int Med Res. 2013;41(3):697–704.

    Article  CAS  PubMed  Google Scholar 

  38. Body JJ, Gaich GA, Scheele WH, et al. A randomized double-blind trial to compare the efficacy of teriparatide [recombinant human parathyroid hormone (1–34)] with alendronate in postmenopausal women with osteoporosis. J Clin Endocrinol Metab. 2002;87(10):4528–35.

    Article  CAS  PubMed  Google Scholar 

  39. Bone HG, Downs RW Jr, Tucci JR, et al. Dose–response relationships for alendronate treatment in osteoporotic elderly women. Alendronate elderly osteoporosis study centers. J Clin Endocrinol Metab. 1997;82(1):265–74.

    CAS  PubMed  Google Scholar 

  40. Brumsen C, Papapoulos SE, Lips P, et al. Daily oral pamidronate in women and men with osteoporosis: a 3-year randomized placebo-controlled clinical trial with a 2-year open extension. J Bone Miner Res. 2002;17(6):1057–64.

    Article  CAS  PubMed  Google Scholar 

  41. Chesnut CH 3rd, Skag A, Christiansen C, et al. Effects of oral ibandronate administered daily or intermittently on fracture risk in postmenopausal osteoporosis. J Bone Miner Res. 2004;19(8):1241–9.

    Article  CAS  PubMed  Google Scholar 

  42. Chung YS, Lim SK, Chung HY, et al. Comparison of monthly ibandronate versus weekly risedronate in preference, convenience, and bone turnover markers in Korean postmenopausal osteoporotic women. Calcif Tissue Int. 2009;85(5):389–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  43. Clemmesen B, Ravn P, Zegels B, et al. A 2-year phase II study with 1-year of follow-up of risedronate (NE-58095) in postmenopausal osteoporosis. Osteoporos Int. 1997;7(5):488–95.

    Article  CAS  PubMed  Google Scholar 

  44. Cummings SR, Black DM, Thompson DE, et al. Effect of alendronate on risk of fracture in women with low bone density but without vertebral fractures: results from the Fracture Intervention Trial. JAMA. 1998;280(24):2077–82.

    Article  CAS  PubMed  Google Scholar 

  45. Cummings SR, San Martin J, McClung MR, et al. Denosumab for prevention of fractures in postmenopausal women with osteoporosis. N Engl J Med. 2009;361(8):756–65.

    Article  CAS  PubMed  Google Scholar 

  46. Delmas PD, Ensrud KE, Adachi JD, et al. Efficacy of raloxifene on vertebral fracture risk reduction in postmenopausal women with osteoporosis: four-year results from a randomized clinical trial. J Clin Endocrinol Metab. 2002;87(8):3609–17.

    Article  CAS  PubMed  Google Scholar 

  47. Ettinger B, Black DM, Mitlak BH, 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(7):637–45.

    Article  CAS  PubMed  Google Scholar 

  48. Fogelman I, Ribot C, Smith R, et al. Risedronate reverses bone loss in postmenopausal women with low bone mass: results from a multinational, double-blind, placebo-controlled trial. BMD-MN Study Group. J Clin Endocrinol Metab. 2000;85(5):1895–900.

    CAS  PubMed  Google Scholar 

  49. Gonnelli S, Caffarelli C, Tanzilli L, et al. Effects of intravenous zoledronate and ibandronate on carotid intima-media thickness, lipids and FGF-23 in postmenopausal osteoporotic women. Bone. 2014;61:27–32.

    Article  CAS  PubMed  Google Scholar 

  50. Greenspan SL, Perera S, Ferchak MA, et al. Efficacy and safety of single-dose zoledronic acid for osteoporosis in frail elderly women: a randomized clinical trial. JAMA Intern Med. 2015;175(6):913–21.

    Article  PubMed  PubMed Central  Google Scholar 

  51. Grey A, Bolland MJ, Wattie D, et al. The antiresorptive effects of a single dose of zoledronate persist for two years: a randomized, placebo-controlled trial in osteopenic postmenopausal women. J Clin Endocrinol Metab. 2009;94(2):538–44.

    Article  CAS  PubMed  Google Scholar 

  52. Grey A, Bolland M, Wong S, et al. Low-dose zoledronate in osteopenic postmenopausal women: a randomized controlled trial. J Clin Endocrinol Metab. 2012;97(1):286–92.

    Article  CAS  PubMed  Google Scholar 

  53. Guanabens N, Monegal A, Cerda D, et al. Randomized trial comparing monthly ibandronate and weekly alendronate for osteoporosis in patients with primary biliary cirrhosis. Hepatology. 2013;58(6):2070–8.

    Article  CAS  PubMed  Google Scholar 

  54. Harris ST, Watts NB, Jackson RD, et al. Four-year study of intermittent cyclic etidronate treatment of postmenopausal osteoporosis: three years of blinded therapy followed by one year of open therapy. Am J Med. 1993;95(6):557–67.

    Article  CAS  PubMed  Google Scholar 

  55. Harris ST, Watts NB, Genant HK, 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(14):1344–52.

    Article  CAS  PubMed  Google Scholar 

  56. Iwamoto J, Takeda T, Ichimura S. Effect of menatetrenone on bone mineral density and incidence of vertebral fractures in postmenopausal women with osteoporosis: a comparison with the effect of etidronate. J Orthop Sci. 2001;6(6):487–92.

    Article  CAS  PubMed  Google Scholar 

  57. Liberman UA, Weiss SR, Broll J, et al. Effect of oral alendronate on bone mineral density and the incidence of fractures in postmenopausal osteoporosis. The Alendronate Phase III Osteoporosis Treatment Study Group. N Engl J Med. 1995;333(22):1437–43.

    Article  CAS  PubMed  Google Scholar 

  58. Lufkin EG, Whitaker MD, Nickelsen T, et al. Treatment of established postmenopausal osteoporosis with raloxifene: a randomized trial. J Bone Miner Res. 1998;13(11):1747–54.

    Article  CAS  PubMed  Google Scholar 

  59. McClung MR, Grauer A, Boonen S, et al. Romosozumab in postmenopausal women with low bone mineral density. N Engl J Med. 2014;370(5):412–20.

    Article  CAS  PubMed  Google Scholar 

  60. McClung MR, Brown JP, Diez-Perez A, et al. Effects of 24 months of treatment with romosozumab followed by 12 months of denosumab or placebo in postmenopausal women with low bone mineral density: a randomized, double-blind, phase 2, parallel group study. J Bone Miner Res. 2018;33(8):1397–406.

    Article  CAS  PubMed  Google Scholar 

  61. Meunier PJ, Roux C, Seeman E, et al. The effects of strontium ranelate on the risk of vertebral fracture in women with postmenopausal osteoporosis. N Engl J Med. 2004;350(5):459–68.

    Article  CAS  PubMed  Google Scholar 

  62. Meunier PJ, Roux C, Ortolani S, et al. Effects of long-term strontium ranelate treatment on vertebral fracture risk in postmenopausal women with osteoporosis. Osteoporos Int. 2009;20(10):1663–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Miller PD, Pannacciulli N, Brown JP, et al. Denosumab or zoledronic acid in postmenopausal women with osteoporosis previously treated with oral bisphosphonates. J Clin Endocrinol Metab. 2016;101(8):3163–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Mortensen L, Charles P, Bekker PJ, et al. Risedronate increases bone mass in an early postmenopausal population: two years of treatment plus one year of follow-up. J Clin Endocrinol Metab. 1998;83(2):396–402.

    CAS  PubMed  Google Scholar 

  65. Neer RM, Arnaud CD, Zanchetta JR, 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(19):1434–41.

    Article  CAS  PubMed  Google Scholar 

  66. Paggiosi MA, Peel N, McCloskey E, et al. Comparison of the effects of three oral bisphosphonate therapies on the peripheral skeleton in postmenopausal osteoporosis: the TRIO study. Osteoporos Int. 2014;25(12):2729–41.

    Article  CAS  PubMed  Google Scholar 

  67. Peretz A, Siderova V, Body JJ, et al. Response to alendronate in osteoporotic women previously treated with pamidronate. Maturitas. 2003;44(2):111–5.

    Article  CAS  PubMed  Google Scholar 

  68. Recknor C, Czerwinski E, Bone HG, et al. Denosumab compared with ibandronate in postmenopausal women previously treated with bisphosphonate therapy: a randomized open-label trial. Obstet Gynecol. 2013;121(6):1291–9.

    Article  CAS  PubMed  Google Scholar 

  69. Reginster J, Minne HW, Sorensen OH, et al. Randomized trial of the effects of risedronate on vertebral fractures in women with established postmenopausal osteoporosis. Vertebral efficacy with risedronate therapy (VERT) study group. Osteoporos Int. 2000;11(1):83–91.

    Article  CAS  PubMed  Google Scholar 

  70. Sanad Z, Ellakwa H, Desouky B. Comparison of alendronate and raloxifene in postmenopausal women with osteoporosis. Climacteric. 2011;14(3):369–77.

    Article  CAS  PubMed  Google Scholar 

  71. Tucci JR, Tonino RP, Emkey RD, et al. Effect of three years of oral alendronate treatment in postmenopausal women with osteoporosis. Am J Med. 1996;101(5):488–501.

    Article  CAS  PubMed  Google Scholar 

  72. Sunyecz JA. The use of calcium and vitamin D in the management of osteoporosis. Ther Clin Risk Manag. 2008;4(4):827–36.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Brauer CA, Coca-Perraillon M, Cutler DM, et al. Incidence and mortality of hip fractures in the United States. JAMA. 2009;302(14):1573–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  74. Melamed ML, Michos ED, Post W, et al. 25-hydroxyvitamin D levels and the risk of mortality in the general population. Arch Intern Med. 2008;168(15):1629–37.

    Article  PubMed  PubMed Central  Google Scholar 

  75. Johansson H, Oden A, Kanis J, et al. Low serum vitamin D is associated with increased mortality in elderly men: MrOS Sweden. Osteoporos Int. 2012;23(3):991–9.

    Article  CAS  PubMed  Google Scholar 

  76. Zittermann A, Iodice S, Pilz S, et al. Vitamin D deficiency and mortality risk in the general population: a meta-analysis of prospective cohort studies. Am J Clin Nutr. 2012;95(1):91–100.

    Article  CAS  PubMed  Google Scholar 

  77. Bjelakovic G, Gluud LL, Nikolova D, et al. Vitamin D supplementation for prevention of mortality in adults. Cochrane Database Syst Rev. 2011;6(7):CD007470.

    Google Scholar 

  78. Autier P, Gandini S. Vitamin D supplementation and total mortality: a meta-analysis of randomized controlled trials. Arch Intern Med. 2007;167(16):1730–7.

    Article  CAS  PubMed  Google Scholar 

  79. Jackson RD, LaCroix AZ, Gass M, et al. Calcium plus vitamin D supplementation and the risk of fractures. N Engl J Med. 2006;354(7):669–83.

    Article  CAS  PubMed  Google Scholar 

  80. Boonen S, Lips P, Bouillon R, et al. 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. 2007;92(4):1415–23.

    Article  CAS  PubMed  Google Scholar 

  81. LaCroix AZ, Kotchen J, Anderson G, et al. Calcium plus vitamin D supplementation and mortality in postmenopausal women: the Women’s Health Initiative calcium-vitamin D randomized controlled trial. J Gerontol A Biol Sci Med Sci. 2009;64(5):559–67.

    Article  PubMed  Google Scholar 

  82. Jackson C, Gaugris S, Sen SS, et al. The effect of cholecalciferol (vitamin D3) on the risk of fall and fracture: a meta-analysis. QJM. 2007;100(4):185–92.

    Article  CAS  PubMed  Google Scholar 

  83. Bischoff-Ferrari HA, Willett WC, Wong JB, et al. Fracture prevention with vitamin D supplementation: a meta-analysis of randomized controlled trials. JAMA. 2005;293(18):2257–64.

    Article  CAS  PubMed  Google Scholar 

  84. Latham NK, Anderson CS, Reid IR. Effects of vitamin D supplementation on strength, physical performance, and falls in older persons: a systematic review. J Am Geriatr Soc. 2003;51(9):1219–26.

    Article  PubMed  Google Scholar 

  85. 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(9588):657–66.

    Article  CAS  PubMed  Google Scholar 

  86. Wang L, Manson JE, Song Y, et al. Systematic review: Vitamin D and calcium supplementation in prevention of cardiovascular events. Ann Intern Med. 2010;152(5):315–23.

    Article  PubMed  Google Scholar 

  87. Chiodini I, Bolland MJ. Calcium supplementation in osteoporosis: useful or harmful? Eur J Endocrinol. 2018;178(4):D13–25.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

None.

Registration and protocol

The present review was not registered.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Author information

Authors and Affiliations

  1. Department of Orthopaedic, Trauma, and Reconstructive Surgery, RWTH University Hospital, RWTH University Medical Centre, Pauwelsstraße 30, 52074, Aachen, Germany

    Filippo Migliorini

  2. Department of Orthopedics and Trauma Surgery, Academic Hospital of Bolzano (SABES-ASDAA), 39100, Bolzano, Italy

    Filippo Migliorini & Michael Memminger

  3. Department of Life Sciences, Health, and Health Professions, Link Campus University, Via del Casale Di San Pio V, 00165, Rome, Italy

    Filippo Migliorini

  4. Department of Medicine and Psychology, University La Sapienza, Rome, Italy

    Nicola Maffulli

  5. School of Pharmacy and Bioengineering, Keele University Faculty of Medicine, ST4 7QB, Stoke On Trent, England

    Nicola Maffulli

  6. Barts and the London School of Medicine and Dentistry, Centre for Sports and Exercise Medicine, Queen Mary University of London, Mile End Hospital, E1 4DG, London, England

    Nicola Maffulli

  7. Department of Medicine, Academic Hospital of Würselen, Würselen, Aachen, Germany

    Giorgia Colarossi

  8. Clinical Pharmacology and Pharmacogenetics Unit, University Hospital “San Giovanni Di Dio E Ruggi d’Aragona”, 84131, Salerno, Italy

    Amelia Filippelli & Valeria Conti

Authors
  1. Filippo Migliorini
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Nicola Maffulli
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Giorgia Colarossi
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Amelia Filippelli
    View author publications

    You can also search for this author inPubMed Google Scholar

  5. Michael Memminger
    View author publications

    You can also search for this author inPubMed Google Scholar

  6. Valeria Conti
    View author publications

    You can also search for this author inPubMed Google Scholar

Contributions

FM: conception and design, statistical analysis, drafting (original and revision); NM: supervision, drafting (revision); VC: drafting (original); GC: literature search, study selection and data extraction, risk of bias assessment; MKM: literature search, study selection and data extraction, risk of bias assessment; AF: supervision, drafting (revision). All authors have agreed to the final version to be published and agree to be accountable for all aspects of the work.

Corresponding author

Correspondence to Filippo Migliorini.

Ethics declarations

Ethical approval and consent to participate

This study complies with ethical standards.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Migliorini, F., Maffulli, N., Colarossi, G. et al. Vitamin D and calcium supplementation in women undergoing pharmacological management for postmenopausal osteoporosis: a level I of evidence systematic review. Eur J Med Res 30, 170 (2025). https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40001-025-02412-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • DOI: https://doiorg.publicaciones.saludcastillayleon.es/10.1186/s40001-025-02412-x

Keywords

European Journal of Medical Research

ISSN: 2047-783X

Contact us