The effects of combined calcium and vitamin D supplementation on bone mineral density and fracture risk in postmenopausal women with osteoporosis: a systematic review and meta-analysis of randomized controlled trials

Abstract

Purpose

This systematic review and meta-analysis assesses the efficacy of combined calcium and vitamin D supplementation on bone mineral density (BMD) and fracture risk among postmenopausal women with osteoporosis.

Methods

We conducted a comprehensive search across multiple medical databases including PubMed, Embase, Cochrane Library, and Web of Science, collecting randomized controlled trials (RCTs) published from database inception to present. Data extraction and analysis were performed to calculate standardized mean differences (SMDs) or risk ratios (RRs) with 95% confidence intervals (CIs), which were then presented in forest plots.

Results

Eleven RCTs with 43,869 participants were included. Combined supplementation modestly improved BMD at the pelvis (SMD = 0.20, 95% CI: 0.05–0.35, p = 0.01) without significant changes in BMD at the lumbar spine, femoral neck, or total hip. The overall fracture risk was not significantly reduced (RR = 0.98, 95% CI: 0.89–1.07, p = 0.68). Subgroup analyses revealed improvements in serum 25‑hydroxyvitamin D levels (25OHD), especially in participants with baseline deficiencies (Z = 10.48, p < 0.001). No dose-response effect was noted for supplementation duration. Fracture outcomes from three large trials (> 42 000 participants) yielded a neutral effect on any clinical fracture (pooled RR = 0.95; 95% CI 0.85–1.07; Z = 1.08, P = 0.28; I² = 0%). Sensitivity analyses affirmed the findings’ stability, with no evident publication bias.

Conclusion

Combined calcium and vitamin D supplementation may improve pelvic BMD and correct serum 25OHD deficiencies in postmenopausal women with osteoporosis, but does not reduce clinical fracture risk in postmenopausal women with osteoporosis. Larger, highdose RCTs with rigorous adherence monitoring and adjudicated fracture endpoints are warranted.

Clinical trial number

Not applicable.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12891-025-09089-7.

Introduction

Osteoporosis, characterized by diminished bone density and an escalated risk of fractures, represents a significant public health challenge, particularly among postmenopausal women. This condition leads to substantial morbidity, decreased quality of life, and elevated mortality rates [1]. The cessation of menstruation brings about a series of physiological changes, notably a significant drop in estrogen levels, which accelerates the rate of bone loss and renders postmenopausal women particularly vulnerable to osteoporosis [2]. In response, current management strategies have been multifaceted, encompassing lifestyle modifications, pharmacotherapy, and nutritional supplementation, aiming to curb the progression of bone loss [3].

Among these strategies, the supplementation of calcium and vitamin D has garnered considerable attention for its potential to maintain bone mineral density (BMD) and reduce the risk of fractures. Additionally, vitamin D supplementation alone has been associated with a reduction in bone turnover markers, suggesting its role in bone metabolism beyond just aiding calcium absorption [4]. Despite these promising outcomes, the debate regarding the optimal effectiveness of calcium and vitamin D supplementation in bolstering BMD and mitigating fracture risk persists. An updated meta‑analysis commissioned by the American National Osteoporosis Foundation reported that calcium plus vitamin D supplementation produced a 15% reduction in total fractures and a 30% reduction in hip fractures across mixed adult populations [5]. In contrast, a large JAMA meta‑analysis of 33 randomized trials in community‑dwelling older adults (> 50 years) found no significant reduction in hip, vertebral, nonvertebral, or total fractures with calcium, vitamin D, or their combination versus placebo/no treatment [6]. Evidence focused specifically on postmenopausal women has been limited and methodologically heterogeneous. Liu et al. pooled randomized controlled trials (RCTs) and observed improvements in several BMD sites and a nominal reduction in hip fractures; yet the review mixed standard supplements with fortified dairy products and multi‑component nutrition‑exercise interventions, and its search ended in February 2020 [7]. Reis et al. (2023) conducted a systematic review of vitamin D supplementation (alone or calcium‑associated) in postmenopausal women especially without osteoporosis and found improvements in 25‑hydroxyvitamin D status and bone remodeling markers [8].

Therefore, we conducted a systematic review and meta‑analysis of RCTs evaluating combined calcium plus vitamin D supplementation versus placebo or usual care in postmenopausal women. This study aims to offer a comprehensive evaluation of the impact of combined calcium and vitamin D supplementation on bone mineral density and fracture risk within this vulnerable demographic. By synthesizing the evidence from RCTs, this study seeks to provide contemporary insights into the efficacy of this prevalent intervention. The imperative for this analysis stems from the ongoing need to develop and refine evidence-based guidelines and recommendations for the nutritional management of osteoporosis among postmenopausal women. Through a rigorous examination of the existing literature, this review endeavors to elucidate the extent to which combined supplementation can serve as an effective strategy in the prevention and management of osteoporosis, thereby contributing to the enhancement of health outcomes for postmenopausal women.

Methods

Literature search and selection

We conducted a comprehensive literature search using multiple medical databases, including PubMed, Embase, Cochrane Library, and Web of Science. The search aimed to identify RCTs examining the effects of combined calcium and vitamin D supplementation on bone mineral density and fracture risk in postmenopausal women. The search was conducted up to November 29, 2023, ensuring the inclusion of the most recent and relevant studies. Search terms included combinations of “vitamin D,” “calcium,” “osteoporosis,” “postmenopausal women,” and “randomized controlled trial.” The detailed search strategy, including the specific keywords and MeSH terms used, is provided in Supplementary Table S1.

Eligibility criteria

Studies were included based on the following criteria: (a) RCTs evaluating the effects of combined calcium and vitamin D supplementation on bone mineral density in postmenopausal women; (b) studies that included postmenopausal women as participants. Studies were excluded if they did not meet these criteria or if they were non-English publications. Two authors independently conducted the study selection, with discrepancies resolved by a third author.

Data extraction and analysis

Relevant data were extracted from the selected studies, including sample size, intervention details, outcomes measured (e.g., changes in bone mineral density, fracture incidence), and duration of follow-up. The primary outcomes of interest were changes in bone mineral density and fracture risk. Meta-analytic techniques were employed to compute pooled estimates of effect sizes, presented as standardized mean differences (SMDs) or risk ratios (RRs) with 95% confidence intervals (CIs).

Quality assessment and publication bias

The methodological quality of the included studies was rigorously assessed using the Cochrane Collaboration’s risk of bias tool. This assessment focused on several critical domains: random sequence generation, allocation concealment, blinding of participants and personnel, completeness of outcome data, selective reporting, and other biases. This quality evaluation aimed to ensure the credibility and reliability of the evidence synthesized from the included studies. Publication bias was assessed through visual inspection of funnel plots and quantitatively using Egger’s regression test. These analyses were designed to detect any asymmetry in the studies that could suggest potential publication bias.

Sensitivity analysis and subgroup analysis

Sensitivity analyses were conducted to assess the robustness of the findings, examining the impact of study quality on the overall results. Subgroup analysis was performed to explore the effects of supplementation duration on 25‑hydroxyvitamin D levels (25OHD).

Results

A total of 2503 documents were retrieved in PubMed, Web of Science, Embase and Cochrane Library. After screening, a total of 11 relevant documents were included, as shown in Fig. 1 for details [9–19].

Fig. 1.

Reference screening flow chart

Study characteristics

A total of 43,869 research subjects were included in 11 studies from 2005 to 2022, including 21,618 in the intervention group and 22,251 in the control group. The duration of intervention for patients spanned a wide range, with longer intervention lasting more than 10 years and shorter intervention lasting only 6 weeks. Of the studies with data, baseline serum 25OHD concentrations were severely deficient (< 25 nmolL − 1) in both groups of patients except one study. The control group of 2 studies had deficient baseline serum 25OHD concentrations (< 50 nmolL − 1), while the intervention group had normal baseline serum 25OHD concentrations (> 50 nmolL − 1). The baseline serum 25OHD concentrations of patients in both groups of another 2 studies were normal, and the remaining studies did not report baseline serum 25OHD concentrations. Patients in the intervention group of 3 studies did not use common calcium supplements and vitamin D supplements, but used dairy alternatives, including milk, yogurt, and cheese. Detailed characteristics are shown in Table 1.

Table 1.

Characteristics of included references

Author	Year	Country	No.(intervention/control)	Age (years); Mean (SD) (intervention; control)	The mean baseline 25OHD concentrations (nmolL−1); Mean (SD) (intervention; control)	Duration (years)	VD (IU)	CA (mg)	Intervention
Porthouse et al.	2005	UK	1321/1993	77.0 (5.10); 76.7 (5.02)	NR	2.8	800	1000	Normal
Jackson et al.	2006	Columbus	18,176/18,106	62.4 (7.0); 62.4 (6.9)	NR	2	400	1000	Normal
Moschonis et al.	2006	Greece	39/36	60.5 (0.71); 61.4 (0.85)	NR	1	300	1200	Milk/yogurt
Bolton-smith et al.	2007	UK	50/56	69.4 (6.4); 67.8 (6.0)	22.8 (6.1); 25.0 (6.2)	2	400	1000	Normal
Moschonis et al.	2010	Greece	35/31	59.0 (4.4); 60.7 (5.0)	NR	2.5	900	400	Milk/yogurt
Salovaara et al.	2010	Finland	1586/1609	67.4 (1.9); 67.3 (1.8)	50.0 (18.7) (n = 279); 49.1 (17.7) (n = 295)	> 10	800	1000	Normal
Kärkkäinen et al.	2010	Finland	287/306	67.4 (2.0); 67.4 (1.9)	50.1 (18.8); 49.2 (17.7)	> 10	800	1000	Normal
Moschonis et al.	2011	Greece	26/39	62.4 (5.3); 62.5 (6.5)	NR	1	400	800	Normal
Bonjour et al.	2012	France	36/35	56.1 (3.9); 57.1 (3.9)	58.8 (20.8) 57.3 (16.8)	0.12	100	400	Skimmed-milk/cheese/vitamin D
Aloia et al.	2013	USA	46/31	58.6 (6.7); 57.6 (7.1)	69 (17); 64 (16)	0.5	4000	1200	Normal
García-Gomariz et al.	2022	Spain	16/9	64.9 (7.1); 60.3 (6.9)	NR	2	400	600	Normal

VD the dose of vitamin D, CA the dose of calcium, VD and CA are the daily intakes of the intervention group

Quality of studies

The risk of bias of the included studies was shown in Fig. 2. All studies were blinded with random sequence generation and had a low risk of bias. Six studies had a low risk of bias in allocation concealment, and the remaining studies had an unclear risk of bias. In terms of blinding of participants and staff, 4 studies had a low risk of bias, 2 studies had an unclear risk, and 5 studies had a high risk. The outcome assessment risk of bias was low in 9 studies and unclear in the remaining studies. Due to incomplete outcome data, 9 studies had a low risk of bias and the remainder had an unclear risk of bias. The risk of bias in selective reporting was unclear in only 1 study, and the risk of bias in the remaining studies was low. Other biases were low in 4 studies and unclear in the remaining studies.

Fig. 2.

Literature quality evaluation

Effects of combined calcium and vitamin D intervention on BMD in postmenopausal women

Four studies analyzed the effect of combined calcium and vitamin D intervention on systemic BMD in postmenopausal women. Although the results showed that the BMD of patients in the intervention group was improved compared with the control group, the effect of combined medication on BMD in postmenopausal women was not significant (Z = 1.80, P = 0.07). Heterogeneity analysis showed that the study results were moderately heterogeneous (I² = 59%) (Fig. 3A, Figure S1 A). Two studies reported the effect of combined calcium and vitamin D intervention on arm BMD in menopausal women. The results showed that there was no significant difference between the intervention and the control (Z = 0.93, P = 0.35), and the heterogeneity was high (I² = 78%) (Fig. 3B, Figure S1 B). Two studies reported the effect of combined calcium and vitamin D intervention on tibial BMD in menopausal women. The results showed that there was no significant difference between the intervention and the control (Z = 0.19, P = 0.85), but the heterogeneity was very low (I² = 0%) (Fig. 3C, Figure S1 C), which indicates that the difference between the results of the two studies is small. For lumbar spine L2-L4 BMD, two studies reported this part, but the difference between groups was not significant (Z = 0.83, P = 0.41) and the heterogeneity was low (I² = 0%) (Fig. 3D, Figure S1 D). It was worth noting that in the analysis of pelvic BMD, a meta-analysis of data from the intervention and control groups of the two studies showed that the combined intervention of calcium and vitamin D significantly enhanced pelvic BMD in women after terminal illness (Z = 2.13, P = 0.03), and heterogeneity analysis showed high consistency between study results (I² = 0%) (Fig. 3E, Figure S1 E). In addition, two studies reported the effects of combined calcium and vitamin D intervention on biochemical markers of bone resorption in postmenopausal women, such as serum C‑terminal telopeptide of type I collagen (CTX), Calcium‑to‑creatinine ratio (Ca/Cr), and TRAP 5b. Aloia et al. [17] showed that serum CTX levels remained more stable in the intervention group compared with the control group. There were no significant differences in changes in serum Ca/Cr and TRAP 5b between the two groups. In addition, García-Gomariz and colleagues [19] believe that moderate exercise when combined with calcium and vitamin D can better improve bone density in postmenopausal women.

Fig. 3.

Effect of combined calcium and vitamin D intervention on bone density in postmenopausal women. A Whole body BMD; (B) Arm BMD; (C) Tibia BMD; (D) Lumbar spine L2-L4 BMD; (E) pelvic BMD

Effects of combined calcium and vitamin D intervention on 25OHD in postmenopausal women

Three articles recorded the changes in 25OHD levels in patients after combined treatment with calcium and vitamins. The results showed that compared with the control group, the 25OHD levels in patients after combined treatment were significantly increased (Z = 10.48, P < 0.001). Heterogeneity was moderate (I² = 62%) (Fig. 4A, Figure S1 F). In addition, we found that in a group of patients with severe deficiencies in serum 25OHD concentrations at baseline, serum 25OHD concentrations in control patients did not return to normal levels after the end of the trial. In the other two control groups, the serum 25OHD concentration returned to normal levels in patients with baseline deficient serum 25OHD concentrations. We conducted a subgroup analysis based on the patient’s supplementation duration, and the results showed that the supplementation duration was not a factor affecting the patient’s serum 25OHD concentration (P = 0.72), and the heterogeneity between studies was low (I² = 0%) (Fig. 4B, Figure S1 G).

Fig. 4.

Effect of combined calcium and vitamin D intervention on 25OHD in postmenopausal women. A 25OHD; (B) Subgroup analysis of the impact of intervention time on 25OHD

Effect of combined calcium and vitamin D on incidence of fractures in postmenopausal women

Fracture outcomes were reported in three RCTs encompassing 42,000 + postmenopausal women. In the Women’s Health Initiative (WHI) trial, supplementation with 1000 mg elemental calcium plus 400 IU vitamin D₃ daily for a mean 7.0 years produced hazard ratios (HRs) of 0.88 (95% CI 0.72–1.08) for hip fracture and 0.96 (0.91–1.02) for total clinical fractures, indicating no statistically significant reduction versus placebo [14]. In the primary‑care trial of women aged ≥ 70 years with ≥ 1 hip‑fracture risk factor, daily 1000 mg calcium plus 800 IU vitamin D3 did not reduce all clinical fractures (adjusted odds ratio [OR] 1.01; 95% CI 0.71–1.43); the OR for hip fracture was 0.75 (0.31–1.78), also non‑significant [15]. Similarly, in the 3‑year The Osteoporosis Risk Factor and Prevention Fracture Prevention Study (OSTPRE‑FPS) population study of 65‑ to 71‑year‑old women, daily 1000 mg calcium plus 800 IU vitamin D3 yielded an adjusted HR of 0.83 (95% CI 0.61–1.12) for any fracture, which was not statistically significant compared with controls [9]. Pooled analysis across these three trials showed that the combination of calcium and vitamin D did not reduce the incidence of total fractures in postmenopausal women (Z = 1.08, P = 0.28). Heterogeneity analysis showed high agreement between study results (I² = 0%) (Fig. 5, Figure S1 H).

Fig. 5.

Effect of combined calcium and vitamin D intervention on fractures in postmenopausal women

Sensitivity analysis and publication bias

Our qualitative assessment did not indicate significant publication bias. The results across studies were consistent, with no evidence suggesting a systematic overrepresentation or underrepresentation of study findings. However, given the limited number of studies, the potential for undetected publication bias cannot be entirely excluded.

Discussion

The synthesis of evidence from 11 randomized controlled trials, encompassing a total of 43,869 participants, underscores the nuanced effects of combined calcium and vitamin D supplementation on BMD and fracture risk among postmenopausal women with osteoporosis. Our analysis reveals that while some contexts show improvement in BMD, the overall impact on fracture risk and BMD across various anatomical sites remains inconclusive. This finding aligns with existing literature, advocating for personalized supplementation approaches based on individual risk profiles and baseline nutritional status [7, 20].

The observed variability in response to supplementation, particularly regarding changes in BMD at different skeletal sites and the absence of a significant reduction in fracture incidence, underscores the intricate nature of managing osteoporosis in postmenopausal women. Studies demonstrate that while calcium and vitamin D supplementation positively affects the skeletal system in postmenopausal women, the variations in BMD changes across different skeletal sites often do not correspond with a marked decrease in fracture incidence. For instance, supplementation has shown to significantly increase total body BMD but not consistently across all skeletal regions, such as the lumbar spine and femoral neck, with the effects being more pronounced in individuals adhering closely to the supplementation regimen [10]. This variability might be attributed to differences in baseline serum 25OHD concentrations among participants, supplementation dosages, duration of intervention, and the inclusion of dietary sources of calcium and vitamin D in some of the intervention groups [21]. Notably, the significant improvement in pelvic BMD with combined calcium and vitamin D supplementation, as opposed to other skeletal sites, suggests a site-specific response that warrants further investigation. A study in 2016 found that consumption of dairy products fortified with calcium and vitamin D3 induced more favorable changes in pelvis, total spine, and total body BMD in postmenopausal women compared to calcium supplementation alone, highlighting the potential site-specific benefits of these nutrients on bone health [12].

Our analysis revealed a moderate heterogeneity among studies, suggesting that factors beyond calcium and vitamin D supplementation, such as physical activity and overall nutrition, play a crucial role in optimizing bone health. Gaffney-Stomberg et al. [22] highlighted that calcium and vitamin D supplementation during periods of activity like military training maintained parathyroid hormone levels and improved bone density, indicating the synergistic effects of nutrition and physical exertion on bone integrity. Furthermore, the increase in serum 25-(OH)D levels following supplementation indicates the efficacy of combined calcium and vitamin D in correcting vitamin D deficiency, a common issue in postmenopausal women. Gallagher et al. demonstrated a curvilinear dose response of serum 25-(OH)D to vitamin D(3) supplementation, suggesting that doses as low as 600 IU/d could effectively increase serum 25-(OH)D levels above 50 nmol/L in the majority of postmenopausal women [23]. Additionally, Schnatz et al. (2014) found that supplemental calcium/vitamin D significantly increased 25OHD concentrations and was associated with improved lipid profiles in postmenopausal women, further supporting the health benefits of these nutrients beyond bone health [24]. However, the lack of correlation between supplementation duration and serum 25OHD levels suggests that factors other than duration, possibly including absorption rates and baseline deficiency levels, influence the efficacy of supplementation [25].

Although calcium and vitamin D supplementation can improve biochemical markers and increase BMD at specific skeletal sites, our findings suggest that this combination does not significantly reduce fracture risk in postmenopausal women with osteoporosis. Our analysis focused on high-risk women with diagnosed osteoporosis, who often have more severe bone loss and structural deterioration. In this group, nutritional supplementation alone may be insufficient to achieve meaningful fracture prevention. Earlier studies support this view. Strause et al. [26] found that calcium supplementation slightly improved lumbar spine BMD in healthy postmenopausal women, but fracture outcomes were not reported, suggesting limited protective effects. Similarly, Henriksen et al. [27] showed that adding calcitonin to calcium and vitamin D in osteoporotic women increased BMD but did not significantly reduce fracture incidence. These results further support the limited clinical benefit of nutritional interventions alone. Another contributing factor may be the vitamin D dosage used. Some trials included in our analysis, such as the WHI study, used a relatively low dose of 400 IU per day, which may not be sufficient to maintain optimal serum 25-hydroxyvitamin D levels. Research has shown that the protective effect of vitamin D on bone health is dose-dependent. Only doses of 800 to 2000 IU per day have been associated with reduced risk of falls and hip fractures, especially in individuals with baseline deficiency [28]. Moreover, responses to supplementation vary widely among individuals. Even at the same dose, serum 25(OH)D levels may differ due to factors such as absorption efficiency, body mass index, gastrointestinal health, and genetic variation in the vitamin D receptor [29]. In summary, while calcium and vitamin D supplementation may serve as supportive care, standard-dose supplementation alone is likely insufficient to reduce fracture risk in high-risk postmenopausal women with osteoporosis. This highlights the need for individualized dosing strategies and combination with pharmacological therapies.

Our study is not without limitations. The moderate heterogeneity observed in our meta-analysis calls for cautious interpretation of the results. Additionally, the inclusion criteria limited our analysis to studies published in English, possibly omitting relevant data from non-English publications. Future research should aim to include more diverse populations and explore the effects of different supplementation formulations and doses.

Conclusion

In conclusion, our systematic review and meta-analysis highlight the potential benefits of combined calcium and vitamin D supplementation in improving pelvic BMD and correcting serum 25OHD deficiencies in postmenopausal women with osteoporosis. However, it does not confer measurable protection against clinical fractures in postmenopausal women with densitometric osteoporosis, which reflects sub-optimal vitamin D dosing, variable adherence, and advanced skeletal micro‑architectural loss in this high‑risk population. Accordingly, calcium + vitamin D should be viewed as essential nutritional support that optimizes the skeletal milieu and facilitates pharmacologic therapy, rather than as a stand‑alone anti‑fracture intervention. Future trials employing higher vitamin D doses, rigorous adherence monitoring, and adjudicated fracture endpoints are needed to determine whether targeted supplementation strategies can translate the observed bone‑density gains into clinically meaningful fracture reductions.

Abbreviations

BMD

bone mineral density

RCTs

randomized controlled trials

SMDs

standardized mean differences

RRs

risk ratios

CIs

confidence intervals

25OHD

25‑hydroxyvitamin D levels

CTX

C‑terminal telopeptide of type I collagen

Ca/Cr

calcium‑to‑creatinine ratio

WHI

women’s health initiative

OR

Odds ratio

HRs

hazard ratios

OSTPRE‑FPS

osteoporosis risk factor and prevention fracture prevention study

Authors’ contributions

BC designed the study, wrote the first draft of the article, collected the data, performed the data analysis and prepared the figures. HZ contributed to the revision of the manuscript. All authors read and approved of the final manuscript.

Funding

Not applicable.

Data availability

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Declarations

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.