Dietary supplements are a simple, noninvasive measure with potential preventive health benefits. The current analysis supports our hypothesis and suggests that expanding the use of these supplements to 100% of adults aged ≥ 50 years could reduce the annual number of fractures by 544,687 in the EU and 323,566 in the US, resulting in a net cost benefit of over €5.71 billion and $3.31 billion, respectively, in avoided fracture-related hospital costs. Thus, it can be concluded that calcium and vitamin D supplements are highly cost-effective. However, it is important to note that the benefits observed in the overall population may in part be driven by greater reductions in the older populations, in particular in those aged ≥ 65 years, who comprise the majority of the population used to calculate the risk reduction, have higher risks for osteoporosis-related fractures, and may be more detrimentally affected by vitamin D deficiencies. As noted above, the benefits increased with age in these analyses. These findings may assist persons with osteoporosis, their healthcare providers, government and private insurance companies, and employers in making decisions or recommendations that could help minimize current and future fracture risks and related costs.
Fracture reduction and cost savings were predicted for both genders and across all age groups 50 years and older; however, increased use of calcium and vitamin D supplementation by women, particularly older women, has the potential to produce the greatest benefits with regard to fracture reduction and cost savings. One caveat is that our analysis applied a 14% reduction in fracture risk with supplementation across all age groups and both genders. The 14% total fracture reduction was derived from the recent meta-analysis by Weaver and colleagues ; most of the individuals enrolled in the studies included in that meta-analysis were 65 years of age and older, and only 1 study contributed data from women aged 50 years and older (Table 1) . Therefore, future cost-benefit analyses in this area may benefit from additional analyses that control for age and determine the benefits for the different age groups evaluated. Also, the studies included in the Weaver et al. meta-analysis included fewer men, and the authors did not attempt to determine whether RRR varies by age or gender. Although men have a lower baseline risk of fracture , there is evidence in other studies and meta-analyses that they derive a benefit from calcium and vitamin D supplementation similar to women [31, 36]. Further studies are needed to confirm whether persons in their 50s derive the same benefits from calcium and vitamin D supplementation in terms of fracture reduction as older persons; it is possible that by applying the same RRR across all age groups, we have overestimated benefits in this younger age group and also underestimated benefits in the oldest groups. In addition, it should be noted that the original meta-analysis evaluated fracture reduction with calcium and vitamin D supplements in generally healthy adults, whereas our cost analysis is limited to persons with osteoporosis, who represent a high-risk subgroup.
A previous cost analysis predicted that costs of osteoporosis-related fracture in the US would grow from $16.9 billion in 2005 to $25.3 billion in 2025 . Similarly, another previous cost analysis estimated that overall costs of osteoporotic fracture in Europe would increase from approximately €37.4 billion in 2010 to nearly €46.8 billion by 2025 . Using their initial costs as a base and adjusting for price inflation and PPP between US states and EU countries, we estimated that hospital costs related to osteoporotic fractures have already exceeded $28.4 billion in 2016–2017 in the US and €50.1 billion in Europe. Future survey research is required to verify the estimated annual cost of an osteoporosis-attributed bone fracture. Another analysis predicted that adequate dairy intake containing 1000 to 1500 mg/day calcium could provide a 20% reduction in fracture risk and cost savings totaling $3.5 billion per year ; however, a subsequent meta-analysis found no overall association between dairy consumption and hip fracture risk .
It should be noted that the 14% RRR may be a conservative estimate of fracture reduction with calcium and vitamin D supplements. An earlier meta-analysis found vitamin D supplements at doses of 482–770 IU/day with or without calcium supplements were associated with a 20% reduction in all nonvertebral fractures and an 18% reduction in hip fracture . In addition, the meta-analysis we used to derive the RRR included studies of supplements containing 500–1200 mg/day of calcium and 400–800 IU/day of vitamin D . On the other hand, we may have overestimated a benefit of calcium in combination with vitamin D given the most recent meta-analysis by Zhao and colleagues , in which the authors found only a 10% nonsignificant reduction in total fracture risk with these supplements (risk ratio = 0.90; 95% CI, 0.78–1.04). However, 1 of the 8 trials included in that meta-analysis had a follow-up of less than 12 months, which is too short for fracture benefits to be expected; half of the studies had no control intervention; and the focus was on individuals aged ≥ 50 years, which may have lessened the impact that may have been observed in an older population. These limitations may have prevented the authors from documenting a benefit. Further, the most recent meta-analyses by Bolland and colleagues, which concluded there was no benefit of vitamin D on fracture risk, excluded all trials of vitamin D plus calcium [39, 40].
Our analysis was based on costs of supplements containing 1000 mg/day calcium and 600 IU/day vitamin D. Additional analyses to determine the exact impact of calcium and vitamin D supplement dose on the relative risk of fracture and related costs should be considered for future investigation, especially since benefits of vitamin D supplementation have been found to be dose related .
There are a number of challenges inherent to studies of nutritional interventions. For example, control groups are not truly untreated since they still have some level of intake from diet, as well as production of vitamin D from sun exposure, and possible intake of other dietary supplements containing these nutrients. The underlying meta-analysis by Weaver and colleagues  and the current cost analysis were not adjusted for baseline dietary or supplemental calcium and vitamin D intake. Data from the National Health and Nutrition Examination Survey (NHANES) show that usual intake among US adults age 19 years and older is 1061 ± 15 mg calcium from food alone versus 1277 ± 1 mg from food and supplements among supplement users; usual vitamin D intake is 5.17 ± 0.16 μg from food alone versus 17.1 ± 0.3 μg from food and supplements . It can be seen from these NHANES data that supplements often help bring calcium and vitamin D intake closer to recommended levels.
Thereby, we note that the assumption of the current model that each target population shifts from zero to 100% usage of calcium and vitamin D supplements may overestimate the expected cost-benefit, as we do not take into account that each target population already includes some proportion of persons who are regular users of calcium and vitamin D supplements. Such individuals have therefore already realized the potential risk- and cost-reducing benefits of these supplements. A 2017 survey of 2001 US adults (age 18 years and older) by the Council for Responsible Nutrition found that 20% were using calcium supplements and 28% were using vitamin D supplements . Thus, as a rough estimate, assuming that the 20% of calcium supplement users were all also vitamin D supplement users and that a similar proportion of the subgroup of persons aged 50 years and older were regular users, then a conservative estimate would be that at least 80% of persons in this age group have not yet realized the benefits of regular use. This still amounts to an unrealized potential reduction of 258,852 fractures and $2,649,789,001 net cost benefit in the US. Future investigations should include sensitivity analyses using different estimates of risk reduction and taking into account the impact of adherence and personal supplement use on both fracture risk reduction and supplement cost.
This cost model is based on 100% adherence, which represents an ideal scenario not typical of real-world use. Nonetheless, this model provides information as to maximum potential benefit from calcium and vitamin D supplements in the target populations, with the understanding that actual net benefits would be lower with lower rates of supplement uptake or less than 100% adherence among supplement users.
Currently, there is some controversy as to whether meta-analyses of calcium and vitamin D supplements should include all subjects (intent-to-treat population) or only those who were adherent during clinical trials [4, 29, 42]. Data from the Women’s Health Initiative (WHI) studies have been analyzed using multiple approaches: an intent-to-treat approach that evaluated the total population irrespective of adherence, a subgroup analysis that included only those subjects who were not taking personal supplements at baseline, and a per-protocol analysis that included only subjects who were not using supplements at baseline and who then adhered to the assigned supplement . Not surprisingly, since treatments can only work if they are taken, the third approach provided the most compelling support for fracture reduction with calcium and vitamin D supplementation . The meta-analysis used to determine RRR for the current cost analysis included the latter of these three groups from the WHI, and sensitivity analyses conducted using the other WHI analysis populations produced fairly similar results . Data on fracture reduction in the subgroup of adherent participants were lacking in other studies included in the meta-analysis; however, it should be noted that the 14% reduction in fracture was seen even with less than 100% adherence in all of the trials . In fact, reported adherence rates were as low as 55% to 63% in some of the included trials [28, 31]. Thus, the RRR used in this analysis is likely a conservative estimate of the benefit of supplements, given that those in the placebo group still have some baseline exposure to calcium and vitamin D and those in the treated group were not fully adherent.
The RRR for fracture in this analysis was derived from a meta-analysis in healthy community-dwelling and institutionalized adults and applied to a subgroup of such persons with osteoporosis; actual RRR may be higher or lower in this subgroup. In addition, since a majority of fragility fractures occur in persons with bone mineral density in the osteopenic range , additional cost analyses are needed to identify potential cost savings if calcium and vitamin D supplementation was expanded to include those with osteopenia, especially at elevated risk based on Fracture Risk Assessment Tool thresholds (e.g., ≥ 20% 10-year probability for major osteoporotic fracture or ≥ 3% 10-year probability of hip fracture in the US) .
The current analysis measures total benefits and does not necessarily predict fracture risk and savings for individual persons whose potential benefits vary with their specific risk of osteoporosis-related fracture. Individual fracture risk is dependent on a variety of factors such as age, race, gender, body mass index, bone mineral density, previous fracture history, health conditions (e.g., rheumatoid arthritis, hyperthyroidism, chronic liver disease), concurrent medications (e.g., glucocorticoids), and alcohol and tobacco use . Evaluating the effects of calcium and vitamin D supplements on fracture risk would benefit from also evaluating their effects on bone quality. In addition, cost benefits might differ if looked at from either a patient or a payer perspective instead of a societal perspective. In real-world settings, actual costs are borne by a combination of insurers and patients. While insurers probably cover a majority of the hospital-based costs associated with fracture, patients likely bear the out-of-pocket costs of over-the-counter supplements, although in Europe, individual countries (e.g., Switzerland and Germany) reimburse the costs via health insurance claims for patients with established osteoporosis. Theoretically, if the out-of-pocket costs of the supplements were shifted to insurers, the removal of a cost barrier for patients could potentially lead to increased supplement use and associated decreases in fractures that would still result in cost savings for insurers based on the current analysis.
Only direct costs of hospitalization related to fracture were included in this cost-benefit analysis. Thus, the analysis does not take into account impact on other medical expenses (e.g., long-term care) or indirect costs (e.g., absenteeism and loss of productivity) related to fracture, nor does it take into account the impact to society of potential lost tax revenue. Some of those costs can be extensive (e.g., the cost of long-term care for disability from osteoporosis was €10.7 billion in Europe in 2010 ). Therefore, additional cost benefits beyond those measured in this analysis are potentially realized if fractures are reduced through expanded supplementation use.
As global populations continue to age, a considerable increase in osteoporosis prevalence is anticipated . In fact, the number of individuals over the age of 50 years worldwide who are at high risk of osteoporotic fracture is expected to rise by about 30% in Europe and more than 50% in North America from 2010 to 2040 . The current analysis suggests that expanding combined use of calcium and vitamin supplements among adults in this age group has the potential to reduce the risk of fractures and substantially reduce hospital costs for osteoporosis-attributable fractures. Potential cost savings based on 2016–2017 data amount to over €5.71 billion and nearly $3.31 billion per year in Europe and the US, respectively.