Good afternoon. It's my pleasure to be with you again in this Meet the Experts session on the ongoing controversy in calcium and vitamin D in bone health. I'd like to start with physiologic consideration, describe data in high-risk individuals with regards to fracture, fall, then discuss calcium D in the context of osteoporosis drug trials and adverse events, switching gear to guidelines on calcium D in high-risk and low-risk populations, and then a conclusion. We all know the critical role that parathyroid plays in keeping calcium homeostasis normal. And therefore, low vitamin D, low calcium level will decrease calcium absorption, cause secondary hyperparathyroidism and bone loss, possibly increasing the risk of fracture. This may also decrease bone formation through osteoblast suppression. Conversely, vitamin D supplementation has been shown to decrease BTH level, suppress bone resorption, reverse bone loss, and possibly reduce fracture. This slides on rickets in children that was shared with us from Tom Carpenter at Yale shows the very sensitive relationship between vitamin D and calcium. They work in tandem and can compensate for each other. Therefore, if calcium intake is replete in this area, it can compensate for low vitamin D levels here, and you have normal homeostasis. Similarly, if calcium level is low, high vitamin D intake or exposure can compensate to keep normal homeostasis. Below these critical levels of calcium and vitamin D, there is development of rickets in children, osteomalacia, and secondary hyperparathyroidism in adults. So keep in mind vitamin D level alone are not independent predictors of bone loss. It really has to do with how much calcium that individual is taking, how is the absorption proceeding, estrogen status, so on and so forth. And this probably explains why subgroup analysis by vitamin D levels do not always show what we expect to see. This post hoc analysis from an observational cohort in elderly individuals, approximately 450, mean age 72, two-thirds women, one-third men, mean vitamin D level 14, BMI as it is in our region of 29, shows that in the two subgroups with vitamin D levels above 20, vitamin D levels below 20, but normal PTH level, there is absolutely no bone loss at the total hip. Interestingly, the group with low vitamin D level below 20 and secondary hyperparathyroidism had substantial bone loss over three years of 8% at the total hip. Please note that secondary hyperparathyroidism would cause bone loss specifically at cortical sites and the hip is one of them. Similarly, along those same physiologic consideration, vitamin D supplementation in community older individuals with vitamin D of 22 was shown to attenuate bone loss at the hip by 0.5% in the VIDA study and similar findings in the WHI study for other additional trials have shown the same effect on hip BMT. Significant, modest, but consistently present. Now this slide illustrates the relationship between physiologic function and nutritional status for any nutrients, vitamin D included. And this is a clearly bell-shaped curve. With levels that are marginal or deficient, there is quick decrease in physiologic function. Conversely, with toxic or marginally high level, there is also decrease in physiologic function. And therefore, we ideally should like to operate on a sweet spot. But if you conduct trials where the baseline nutrient level is almost sufficient, then you do not expect to see further increments in physiologic function and thus the explanation for many of the null modern mega-trials we have seen. Let's discuss calcium and vitamin D on fracture. I'd like to start with showing the latest two systematic reviews, umbrella reviews actually on this topic. The first one is a rigorous umbrella review of systematic review and meta-analysis. The other one is a narrative review by the SQ group, both published in the same year. I'll concentrate on our study starting with vitamin D alone versus no supplementation. There was absolutely no effect on hip fracture reduction. And you can see the effect size estimates all overlap one. Similar findings for any fractures. Conversely, when we look at calcium with vitamin D supplementation versus no supplementation, on the left-hand panel for hip fracture and on the right-hand panel for any fracture, the studies, the systematic reviews are listed in color codes. And to summarize, eight out of 12 meta-analyses described here show a decrease in hip fracture by anywhere from 15 to 40%. Only subset of these trials measured baseline vitamin D. In a similar trend, seven out of the 11 meta-analyses showed a decrease in any fracture. The effect size estimate was 6 to 26%. These were mostly secondary fracture prevention. Let's dig further into subgroup analyses. So these have described pooled relative risk. They then describe analyses sometimes in institutionalized versus community dwelling individual. We implemented AMSTAR quality assessment to these meta-analyses. And the definition of the fracture, of course, varied between these two meta-analyses. The first point to be made is that there was a clear hip fracture reduction in the institutionalized individual compared to control. The effect size estimate was anywhere from 15 to 24%. This was highly driven by the CHAPRI trials that we all recall were in older individual with baseline vitamin D levels below 20, mild secondary hyperparathyroidism. In the same meta-analyses that combined institutionalized with community dwelling, the effect size estimate remained significant in these groups. However, the magnitude of the decrease became different. The Cochrane by Avenel is probably the highest quality assessment tool, which is what we used in our Lebanese guidelines as the evidence. Now let's look at mega-trials. These all administered calcium and vitamin D or vitamin D alone to various extent. What we can see here is the mean age was above 60. The baseline level was quite replete, a very important point. But importantly, there was a null effect on whatever outcome in terms of fracture they were interested in. So more is not better when we start with a replete level. These are also relatively younger elderly individuals. Now what about falls? The data is more muddy. Now we just finished completing a systematic review and meta-analyses umbrella review on five databases for the last 12 years using mSTAR again of Western women. The challenges were to describe the endpoint, shall we look at falls, fuller, or incidence of fall. The analysis was often combining data from these meta-analyses from community dwelling and institutionalized individual. And the analysis often came combining data from various combinations of intervention, so could not do subgroup analyses, vitamin D alone versus D and calcium. Let's start with fullers. This actually shows effect size estimate expressed as relative risk or odds ratio in community, individual, institutionalized, combined. These are the authors here. And the color codes simply reveal the diversity of the combination of vitamin D with calcium versus calcium versus placebo versus no supplementation. It was a very heterogeneous population. With all these reservations, community dwelling individuals showed a decrease in falls in only two out of eight meta-analyses. Institutionalized alone did not show any risk reduction. And when you combine those, you see an effect in three out of almost 10 meta-analyses. So not very impressive. The quality of these studies were critically low to low except for Boland, which was moderate quality evidence, and that only showed an effect in the combined because you increased power and number. What was the reason for discrepancy? Well, there was a variable overlap in the included trials between the analyses, different search periods and eligibility criteria, wide range of vitamin D anywhere from 8 to 28 at entry when specified, variability in doses, frequency preparation and duration, and variability in the methods used. Let's look at fall alone. The number of meta-analyses that looked at falls versus fullers was lower. And what we can see here is significant decrements of almost 25% in the institutionalized. When combined with community, it's more modest, but three out of four were significant. The quality was critically low to low. What about megatrials and falls? I'm showing the same format, the same megatrials, meaning trials above 2,000 individuals. The baseline level were replete for the most part, and there was a null effect on fall, as we can see. And actually, too much was bad, as we would have expected from the bell-shaped curve I have shared with you in the JAMA paper. Well, what do we have as far as calcium and vitamin D supplementation in the context of the pivotal osteoporosis drug trial? This is a table we had summarized in an invited review in JBMR almost 10 years ago, updated for the debate with Steve Cummings two years ago at the Endocrine Society. But if you look at the elandrinate trial, the risidrinate trial, teriparatide, solidronic acid, dinosumab, abalo, and romo, all of them used calcium anywhere from 500 to almost 1,500 milligrams per day, and almost all of them used vitamin D anywhere from 500 all the way to 1,200. So all of them used calcium vitamin D, with the exception of Lieberman, where the vitamin D dose was not stated. So these drug trials in the placebo and in the treatment arm received calcium and vitamin D. And this is a very important consideration, because we have to remember that with antiresorptive drugs, vitamin D deficiency is clearly a risk factor for the development of hypocalcemia, both with the solidronic acid and dinosumab, and low calcium intake is a risk factor for hypocalcemia in renal failure patients getting dinosumab. Finally, with anabolic therapies such as romo, this could lead to a rapid increase in bone formation, and therefore a substantial efflux of calcium to bone, which may result in possible hypocalcemia and adverse events. Well, what about adverse events with calcium vitamin D supplementation? This is always a concern. I want to underscore that rather than looking at individual trials, we decided to look at meta-analyses, and I list them here. I think let's concentrate on the Avenel, which has the best quality. The relative risk of hypocalcemia was not significant in a follow-up of two to three years. Calculi or renal insufficiency, slight increased risk, follow-up three to seven years. And this was also shown in Kahwati, which was critically low quality. But importantly, these are trials conducted in Western population, and these Western population use calcium supplementation as a baseline much more frequently than we do in our population. So I think this is something to be kept in mind. Our mean calcium intake in various subgroups when we looked at it in Lebanon was anywhere between 400 and 600 per day. GI diseases, constipation, bloating, et cetera, a small risk of 1.05 over a follow-up of two to seven years. So relatively small risks. Switching gear to guidelines. I'll try to give a brief overview. This by itself is a talk. There are over 50 guidelines that have been nicely summarized in a paper a couple of years ago in Nutrients, but let's look at the relevant one. And I want to classify guidelines by risk. So this is 2010 to 2024, starting with the original Endocrine Society guidelines in JCNM 2011. It was for the prevention and treatment of vitamin D deficiency. So this was high-risk group to start with. Their recommendations were, as listed there, anywhere between 1,500 and 2,000 for all ages. Similarly for the ACE, Osteoporosis Prevention guidelines. So when you're looking at osteoporosis prevention, you're looking already at high-risk group, and it was 800 to 2,000. Please note the desirable level here and the end point similarly between the two. Full and fracture reduction were the consideration. Now I'd like to look at the European CTI, which I was part of. Again, older institutionalized, giving some vitamin D, albeit the dose is lower. Finally, in green are the regional guidelines, starting with the UAE guidelines in 2016, 1,000 to 2,000 in 18 to 64. I apologize for the typo. And more than 65 is 2,000 per day. Finally, I'll show you more details on the grade-based Lebanese guidelines. It is actually in press. We stratified risk, and we gave a wide range to accommodate that stratification. For the high-risk, we only considered fracture, not falls, because of the data I showed you. Now moving on to low-risk, this is the Institute of Medicine, a public health approach. Lower doses, lower desirable level. The same thing is seen for the European with a higher dose. And finally, grade-based guidelines, we did not define a desirable level, but we defined a range of doses depending on the risk stratification. Now let's talk about the Endocrine Society guidelines that had generated a lot of noise when they were launched at the endocrine meeting last June. With the first important remark, in contrast to the EndoSociety 2011 guidelines that broadly address evaluation treatment and prevention of vitamin D deficiency, with an emphasis on the care of patients who are at risk, the goal of the 2024 guidelines is to establish guidelines for the use of vitamin D to lower the risk of disease in individuals without established indications for vitamin D treatment or testing. So automatically, this puts us in the low-risk group. And let's talk about these guidelines. So first of all, I'd like to say what they meant by empiric vitamin D supplementation, because this is a breakdown by ages and by specific risks. Empiric vitamin D supplementation means doses above the IOM DRI, i.e. above 600 to 800. No empiric vitamin D supplementation means that the DRI is the recommended intake by default. So if we go to 1 to 18, they recommend empiric vitamin D supplementation, meaning over and above the DRI, depending on the society, to prevent nutritional rickets and because of the potential risk of lowering respiratory tract infection. I'm not sure this is true. Today, Andrea Martineau, who's the authority on that, gave us a talk, mostly concentrating of adults, showing precious little data on the risk of respiratory tract infection risk reduction based on the most recent analyses, although there were signals for that earlier on. Now, importantly, in the otherwise healthy population, 19 all the way to 74, no empiric vitamin D supplementation, follow the Institute of Medicine recommended daily allowance of 600 below, 70 and 800 above. Now, where they recommend, again, vitamin D empiric supplementation, older because of a lower risk of mortality, pregnant women because of the potential to lower the risk of preeclampsia, intrauterine mortality, preterm birth, small for gestational age, and neonatal mortality, and prediabetes because of the potential to lower the risk of progression to diabetes. Tasso Pitas was the co-chair with Mary Demay, and you know that Tasso has been leading a lot of the trial, the D2D mega trial, and all of the data on this high-risk group. I'd like to underscore that in the aging hormone statements of the endocrine society, again, I have underscored accumulating evidence for a lower risk of mortality with vitamin D supplementation in older population. What about the vitamin D guidelines? I think this is relevant to our region. These were launched in 2022. They are almost ready to be released in Osteoporosis International, but they're nicely summarized in a document online by the WHO. So, first of all, the first question is, should we screen adults for vitamin D? And the panel suggests no screening for vitamin D deficiency. This recommendation applies to both community-dwelling and institutionalized individual. It is low-evidence, low-certainty conditional recommendations. But we do say that we could test as opposed to screen in high-risk subgroups. These are individuals at risk for low vitamin D levels, individuals with osteoporosis, and individuals on drugs that affect vitamin D metabolism. What about community-dwelling recommendation? The panel suggests, so it's a conditional recommendation, moderate certainty evidence, no supplementation with calcium D over supplementation in community-dwelling individuals. Again, the exceptions are high-risk individuals, as outlined before, with a cautionary effect on the side effects for stone and gastrointestinal effect. What about institutionalized adults? Then we suggest supplementation with calcium D over no supplementation, and again, underscore the high-risk population in the institutionalized, similarly to the community-dwelling, and the same cautionary measures for adverse events. Now, what is the optimal dose? We decided to keep a wide range because the profile, the risk profile of the various groups we have underscored varies, but we said in institutionalized and community-dwelling individuals for whom there was a decision to supplement with high risk, with calcium vitamin D, meaning high-risk populations as defined before, then we say 600 to 2,000. And we leave a range because the risk profile would differ, the requirement would differ. This actually is just to underscore that today there is still diversions in what is defined as desirable level of vitamin D. By the endocrine society, you know, optimal is above 30. By IOM, optimal is above 20. Mayo Clinic is 25 to 80. And for ACE, optimal is 30 to 50. To conclude, very low calcium or low vitamin D results in breakouts in children, osteomalacia in adults, and results in secondary hyperparathyroidism. But calcium and vitamin D together are important. Vitamin D screening is not recommended in low-risk population. Testing, on the other hand, in high-risk populations is. In high-risk population, calcium D, but not vitamin D or calcium alone, reduce fractures. I think the subgroup clearly to benefit the most, as shown in our umbrella review and in the Cochrane-Avenel, a systematic review meta-analysis, are older individual and institutionalized. Calcium D supplementation must be implemented in the setting of osteoporosis drug therapy. This is how the pivotal trials were constructed. Data on falls is less clear. The doses for high risk should be probably more than the DRI, but we leave it up to the national societies and organization. For us, it was 600 to 2,000. And in the low-risk where disease prevention matters, the Endocrine Society new guidelines shows in low-risk the DRI 600 until 70 and 800 after that. Most societies in the low-risk, as I've shown you in the table, is low doses. I think the Middle East is slightly different due to the low levels, the lifestyle, and the range varies and accommodates higher doses below what we think will cause toxicity. I'd like to thank you very much for your attention and open the floor for discussions and questions. Thank you.

calcium

vitamin D

bone health

supplementation

fracture risk

osteoporosis