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- [00:01]
A
This is Endocrine Feedback Loop. I am your host Chase Hendrickson and welcome you to this Journal Club podcast series brought to you by the Endocrine Society. Thanks for joining us as we explore an important article recently published in one of the Society's clinical journals. Hello and welcome back to the Intricun Feedback Loop podcast. For our 65th episode today we go to the JCEM to look at a report of two different studies that investigate the relationship between max, mild autonomous cortisol secretion and vertebral fractures. MAX has been of increasing interest endocrinologists over the past few years with a greater recognition of its health impact and new guidelines on its assessment and treatment. As this topic continues to evolve, we thought that this paper has a high likelihood of impact our clinical care and so is well worth discussion. As mentioned, the paper has two different studies within it, both an observational study and a clinical trial, so we will compare those methodologies. As a part of this episode, I host the Endocrine Feedback Loop and work at the Vanderbilt University Medical center as a general endocrinologist and medical director. Back today is Our regular contributor is Jill Wagner, who comes today from the University of Nebraska Medical Center. She too works as a general endocrinologist and is an expert educator in the field of endocrinology. With us today in our virtual recording studio as our guest expert is Oksana Hamidi from the University of Texas Southwestern. Her work focuses on adrenal disorders, including the pathophysiology and management of max. She is well published in this field along with giving frequent talks and leading clinical trials, all of which testify to her expertise in this burgeoning area. So, as usual, the perfect pair of endocrinologists joins me to discuss this article today. As is also always the case, everything we discuss is our opinions only and not those of our respective of institutions or the Endocrine Society. For this episode of the podcast we look at Adrenalectomy Reduces the Risk of Vertebral Fractures in Patients with Mild Autonomous Cortisol Secretion, which is a forthcoming article in the Journal of Clinical Endocrinology and Metabolism. Valentina Morelli and Vittoria Favero shared the role of first author for this manuscript, which comes to us from multiple institutions in Italy. I will now turn things over to Jill who will highlight the key points that those authors make in their introduction and we'll get Oksana to give us some key background information.
- [02:33]
B
Jill well, thank you Chase and I appreciate you having me back for another round. Let's get started and bring up what I think is going to be a very interesting discussion with this article. Awareness and guideline updates have spawned higher diagnoses of mild autonomous cortisol secretion in recent years, with adrenal incidentalomas being detected in up to 7% of patients over the age of 60 and up to 50% of those resulting in Max. We are just seeing this more and more. Max has been linked to worsened cardiovascular outcomes, with some studies suggesting a link to bone fragility as well. Oksana, could you give us a brief overview of how MAX itself impacts bone?
- [03:22]
C
All right, I'm happy to talk about this topic. So, as we know, MAX or mild autonomous cortisol secretion is associated with a significant significantly increased risk for osteoporosis and fragility fractures. But specifically we see more vertebral fractures. This is despite absence of any overt Cushingoid symptoms or Cushing's syndrome. Pathophysiology involves chronic low grade cortisol excess and this cortisol excess impairs bone formation and also impairs bone quality. Primarily this happens to through reduced osteoblast activity. Also we see altered osteocyte function. This is also reflected in lower sclerostin levels as well as changes in bone turnover markers. So what's interesting is that the fracture risk in MAX patients is often disproportionate to the degree of bone mineral density loss, which is measured by daxa. And this indicates that the bone quality deterioration plays a major role. We know that from large cohort studies, postmenopausal women with MAX have a markedly higher prevalence and incidence of vertebral fractures and this would be compared to those with non functioning adrenal incidentalomas. We see this odds ratio for fracture exceeds actually 2 in some analyses. The risk is also elevated in men, but this is less pronounced. And as we know, and we'll discuss this more, management of MAX related bone disease is still evolving.
- [04:58]
B
Thank you. It also seems that the diagnosis of MAX itself has changed with revised criteria just over the last few years. And now based on a Cortisol level of 1.8 or above following a dexamethasone suppression test. Specifically in the absence of overt hypercortisolism. However, there are more features of this that are coming to light. Oksana, could you help us review and kind of remind us what the European Endocrine Society and Study of Adrenal Tumors, their diagnostic criteria and kind of what they mean by this overt hypercortisolism so.
- [05:34]
C
The diagnostic criteria for MAX focus on identifying patients who have adrenal incidentaloma and have biochemical evidence of cortisol access. Also, these patients tend to lack classic clinical features of Cushing's syndrome, so the cornerstone for diagnosis is to conduct a 1mg overnight dexamethasone suppression test and according to the eSenset, Max is defined by a post dexamethasone suppression test, serum cortisol level greater than 1.8 microgram per deciliter or 50 nanomole per liter. But again without overt clinical features of Cushing's syndrome, we oftentimes perform additional biochemical tasks such as we see low ACTH level, low DHEA sulfate and occasionally we can see elevated 24 hour urine free cortisol, high late night salivary cortisol levels that help support the diagnosis, but these are not required for max. If clinical features are absent, overt hypercortisolism reverse to clinically appear in cortisol access. So typically we see this patient with Cushing's syndrome. It's characterized by distinct physical and biochemical features. So for instance, the classic signs and symptoms of Cushing Syndrome include moon phases, buffalo pump, central obesity. We can also observe a purple stria, easy bruising, muscle weakness and patients tend to have metabolic complications like hypertension, glucose intolerance, osteoporosis as well as psychiatric symptoms such as depression or anxiety. Now in contrast, patients with MAX do not exhibit these specific signs and despite this they may still experience metabolic complications. So we see higher prevalence of hypertension, diabetes, dyslipidemia as well as bone health issues including osteoporosis and fragility fractures.
- [07:40]
B
Thank you for summarizing all of that. Recent data suggest that there's a link between MAX and vertebral fractures, but specifically no intervention studies using the current criteria exist. And the purpose of this study? To evaluate the incidence of vertebral fractures in patients with adrenal incidentyloma with MAX after surgical versus conservative treatment. So Oksana, why specifically look at vertebral fractures for this outcome? Why not look at all fractures?
- [08:10]
C
Evaluating vertebral fractures as the outcome of interest is extremely clinically meaningful. It's actually also increasingly recommended and here are the reasons for this. First, studies show that patients with MAX have a significantly higher prevalence of vertebral fractures and this is up to 63% compared to compared to 28% in patients who have non functioning adrenal incidentaloma. Secondly, fractures can occur despite normal BMD bone mineral density. And many patients with MAX experience fracture even when their bone marrow density appears normal on DEXA scans. This suggests that bone quality, not just quantity, is compromised. The third is while ESE NSAID guidelines acknowledge that there is an association between MAX and osteoporosis, this is currently still under investigation. Yet they encourage vertebral fracture screening in MAX patients. The last point is that vertebral fractures are strong predictors for future fractures. This is also independent of bmd. Vertebral fractures can also increase the risk for disability and reduce quality of life. Identifying them early can guide more aggressive or targeted interventions.
- [09:32]
A
We will now jump into the methodology and as mentioned earlier, you get a two for one on this one. So the authors here combine two different studies in this paper and they've labeled them Study 1 and Study 2 to help us keep track of them. And Study 1 is a retrospective cohort study, and then Study 2 is a clinical trial. So we'll talk about those methodologies, contrast them just a little bit here before we dive into the specifics of these two studies. As a reminder, retrospective cohort studies, the way those work is you have at least two different groups, and it's two here. And those groups are defined based on an exposure. It can be a little bit hard to think about it in intervention studies like this, or meaning where the exposure is an intervention. And here it's going to be a surgical intervention that we're going to be talking about. So that's the exposure. So all of these individuals have MAX meet criteria for that. And then they're split into groups based on whether they had a surgery or did not have a surgery. They're then followed over time. That's the key aspect of a cohort study. And one, I think, really important thing to keep in mind with, with this is with all cohort studies, is that assignment to be in the exposed group or the unexposed group, that's not a random assignment. So there's something driving that. And it may be clinicians who are determining that it may be patients. And this is just a part of usual clinical care. These things are appropriate. It is challenging, though, when we turn these into studies and we try to investigate differences, because we often don't know what's driving that decision to have a surgery or to not have a surgery or whatever else the exposure might be. So we're going to have to keep that in mind. The benefit of a clinical trial, so that's the second study here, is that it helps with a lot of these issues and in particular, when it is a randomized clinical trial, then that decision of whether you're going to be exposed or not exposed, that is not based on somebody making a decision. It's based on a random allocation that helps. In particular with confounders, it's not that it gets rid of confounders that could be driving the outcome. The idea is if you've done your randomization correctly, it's. It balances them out. And so in a way of speaking, they're going to cancel each other out. Now, one key caveat to that is that assumes that after you've done your randomization, that you're able to maintain all of those subjects, or at least most of those subjects in both of those groups, and then that you analyze them as they were randomized. That's that intention to treat analysis. We're going to have to think about that carefully here. Another thing that I think we also want to keep in mind as we look at these studies is often, we assume with clinical trials is that they're placebo control, that that's often a fe, particularly with medications, that is very difficult to do. As I'm sure you can imagine with surgical studies, it's not impossible. There are clinical trials that sham surgeries are used. But again, as you can probably imagine, that is not an easy thing to pull off. And so whenever you don't have that, that sets up yourself for some other biases that you have to keep in mind. So we're going to think about those as well. Okay, now long enough, we're going to dive into these studies in particular. So study one, again, that's that retrospective cohort study. This came from two different centers in Italy and looked at dates from January 2008 through June 2013. And initially, so Jill walked us through, there are evolving criteria. So initially this cohort was formed based on older criteria for whether they would recommend surgery in patients with adrenal incidentalomas. So to give you an overview of those. So if you had a deck suppression test, the cortisol level that was greater than five, that was a reason to intervene surgically. There was also another criteria where it could be one of the as two out of three things. So if your cortisol after deck suppression was greater than 3, had an ACTH less than 10, or urine free cortisol that was greater than 70, again, any two of those three that met criteria. So in this original cohort, there were 605 patients with adrenal incidentalomas, and then 55 of them met criteria and had surgery recommended. The authors went back and looked at this cohort and then applied these newer criteria to that. And with that, most of those patients still met criteria. It was 53, so two of them didn't. But 53 met criteria. And when they looked at what happened to those individuals, 31 of them underwent surgery and 22 opted for conservative treatment. Here, this is where we've got to think about that. It's a selection bias. In particular, we don't have a great understanding of why most of those patients decided to undergo surgery, but a significant number elected for conservative treatment. And you do have to worry that, well, whatever was driving that decision, maybe that's going to be what drives the outcome of interest, which to skip ahead and you can already guess, is going to be vertebral fractures. We're going to keep that in mind. Now, the authors recognize this. They do a good job of describing the inherent issues, the limitations of observational studies, and that's why they wanted to couple their investigation with a clinical trial. So this is study two. This was a randomized clinical trial, and the dates from that were September of 2016 through February 2020. The inclusion criteria for this is that you had to have a unilateral adrenal incidentaloma that was greater than a centimeter in diameter and the CT scan to be consistent with it being adenoma. And they were looking at individuals ages 40 to 75. There were several important exclusion criteria. So, as Oksana mentioned, we don't think about max if somebody has obvious Cushing's syndrome. So having signs or symptoms of hypercortisolism was an exclusion criteria here. If you had a large tumor, so if your adrenal insuloma was greater than 5, or if the imaging characteristics were not suggestive of an adenoma, that was an exclusion criteria. If you had biochemical evidence of either a pheo or primary aldo, that was also exclusion criteria. If you were missing data, and then also they listed if you had interfering drugs or medical conditions well known to affect bone health, all of those were removed from the study here. So with that, after they excluded all those individuals, they were left with 71 eligible subjects. 62 of them agreed to participate in that. So at that point, they did their randomization. So 62 individuals randomized. They got two equal groups of 31 in each.
- [15:44]
B
Each.
- [15:45]
A
Now, this is a key step here, is that the patients who actually completed this protocol, and you'll see it involves surgery and then follow up afterwards. Of the 31 who were randomized to undergo surgery. Only 21 actually underwent surgery and completed this entire protocol. Far more. 28 in the conservatively managed group completed this protocol. So there's a couple things that we really have to keep in mind here. So I don't think that this would fit the description of an intention to treat analysis. So several of these individuals were lost to follow up or elected to not undergo surgery, and they weren't included in this analysis. So I think this would be a better way of describing it would be a per protocol analysis which has strengths when you're really trying to understand the impact of your intervention. The problem is, is that you lose that randomization, and I think we're going to see evidence of that in the results. So the randomization was a big strength of the clinical trial. But then when you analyze it this way, you start sacrificing that a little bit, that there may be reasons to do that and it may be justified. Just have to realize that that's a major downside to making that decision. Another one here is that the loss to follow up is fairly unequal. You lost 10 individuals in the group randomized to undergo surgery and only three from the group that were managed conservatively. So we have to at least ask the question of why That's a lot more obvious. In studies that are looking at a medication, for example, you worry about the side effect of the medicine was that making people drop out. So not obviously the case here, but still raises a bunch of questions that I'm sure we know the answer to. Okay, so that's the patients, the subject and how they ended up in each group. As far as the surgical intervention, I'm going to try, but a really high level here. So this was an adrenalectomy, and then afterwards hydrocortisone was started on all patients post op. So Oksana wanted to get your input on this. I know it can be a bit of a wild west of what you do after surgery. For folks who have max, what are your thoughts on what the authors did here? Would that be fairly standard or is that one of many different ways it could be choosing. Give us your thoughts on that.
- [17:48]
C
Chase, the quick answer to your question is the standard. So I would say no, but there's really no standard. So I just wanted to give you an idea what the recommendations are based on. Guidelines. European Society of Endocrinology ese NSAID guidelines recommend routine perioperative glucocorticoid treatment at surgical stress doses for all patients undergoing adrenalectomy format. And this approach prioritizes safety by preventing adrenal crisis due to potential hypothalamic pituitary adrenal suppression. In contrast, American association of Endocrine Surgeons suggest a more selective approach. So they propose to use post operative day one morning basal cortisol. So that's around 8am they also suggest colcentropin stimulation test to determine the need for glucocorticoid replacement. Glucocorticoid therapy should initiated only if adrenal insufficiency is confirmed based on these tests and then discontinued once HPA X is recovered. And that's been documented. So now I wanted to briefly share our experience and also clinical experience from multiple US centers. So what we saw is that the prevalence of adrenal insufficiency following unilateral adrenalectomy for max is about 55%. So and that's also what's seen in previously published data as well. What we see is that younger patients or those who have a higher biochemical severity are at increased risk for adrenal insufficiency. So when we are looking at this particular study that indeed many of them had pretty high biochemical severity based on their dexamethasone suppression tests, even urine free cortisol. So I would say that yes, this particular group of patients in both studies actually is at increased risk for adrenal sufficiency. However, by using steroids empirically for everyone, we are truly potentially subjecting at least half of the patients to unnecessary glucocorticoid replacements. Moreover, in the study they use this extensive taper process that took about a year and looking at the median time to recovery from adrenal insufficiency. In previously reported studies that median time to Recovery is about 3.9 months. So just under 4 months months and longer duration of adrenal sufficiency again is associated with higher biochemical and clinical severity. These findings highlight the importance for testing cortisol levels after adrenalectomy of fourx to guide glucocorticoid therapy to help avoid unnecessary treatment. But depending on feasibility of this approach in centers who for example are not able to perform these post operative protocols, then indeed periglucorticoid therapy would be indicated for all patients until biochemical evaluation can.
- [20:56]
A
Be done for these patients after surgery again all were started on hydrocortisone. They underwent a stimulation test two months later and then as needed had repeat labs every six months until there was clear demonstration of recovery of the HPA axis. Finally, give a really high level summary of the bone monitoring and treatment. All individuals underwent a DEXA scan and plainfill films and then those were reviewed by unblinded radiologists. A comment on here. It was really good, obviously that all individuals underwent this imaging. So it wasn't just people who they suspected might have a vertebral fracture, but everybody had not only adexa but also plain films. It would have been ideal if the radiologist had been clearly blinded, so they did not know what had happened with these individuals. And the authors mentioned this as well. Hopefully not a major, major issue, but something we need to keep in mind. And then finally, for those individuals who were conservatively managed and had a high fracture risk, they were offered oral bisphosphonate therapy. Only turned out to be a handful of individuals, but was a bit of a difference there in in that group. Okay, so that is our overview of the methodology. I'm now going to turn things back over to Jill and she's going to go through both of these studies and I'll let her take it away for.
- [22:14]
B
Study 1, this retrospective observational study. The baseline data between the adrenalectomy group and the conservative management groups was similar, though there were two small differences. There was a slightly higher rate of type 2 diabetes in the conservative management group, while bone mineral density of the lumbar spine was lower at baseline in the surgical group. Each group had a similar number of individuals with with baseline fractures, though this represented actually a higher percentage in the conservative group compared to the surgical group where 45% of people registered to the surgical group had baseline fractures, whereas 63% in the conservative group had baseline fractures. There was no significant change in bone mineral density or lab parameters in either group throughout the study. There was an increased incidence of vertebral fractures in the conservative management group compared to the surgical management group. Eleven new fractured occurred in the conservative group. Only five of the eleven had pre existing vertebral fractures at baseline. Surgical management outcomes were assessed a full 24 months after steroid replacement had ceased, which was a median duration of 12 months months. Despite the higher risk of lead time bias, only three from the surgical group experienced new fractures. All of these fractures in the adrenalectomy group had a baseline fracture. Logistic regression analysis demonstrated that adrenalectomy was associated with a 6.8 fold risk reduction of developing an incident vertebral fracture fracture. No other associations showed significance. Afzana, could I ask you to comment on thoughts of these fractures occurring but bone mineral density not changing and not being associated with incident fractures?
- [24:20]
C
The Absence of a low BMD at baseline despite high prevalence of vertebral fracture is not surprising in patients with nax. It's widely accepted that BMD evaluation is not entirely reliable for predicting the fracture risk in, for instance glucocorticoid induced osteoporosis since bone quality, which is not captured by BMD assessment, plays an important role. So the prevalence of morphometric vertebral fractures in a general population so these are not patients with Max, but patients over the age of 50 varies by age and sex, generally increasing the age and it's known to be higher in women, so that's about 10 to 20%. In a Western population this prevalence is up to 30%. So how does this extrapolate to patients with max? Patients with max have an increasingly higher prevalence and incidence of vertebral fractures compared to those who have non functioning adrenal incidentalomas and we know from a prior retrospective cross sectional study of about 474 patients with adrenal incidentaloma. They noted that prevalence of vertebral fractures was about 24% in non functioning tumors tumors and then 34% in patients with max with significant difference between non functioning and max. Also in a multicenter Italian cohort, the cross sectional analysis found a vertebral fracture prevalence of about 63% in patients with Max versus 23% in non Max patients with Max, conferring an odds ratio of about about 5.2 for prevalent vertebral fractures. This is independent of age, sex, lumbar spine, BMD, BMI and type 2 diabetes. From the longitudinal arm we saw that a higher incidence of new vertebral fractures in Max, which is 36% compared to non Max patients which was about 10% with a relative risk of 4.6%. This is again independent of confounding. These findings reinforce that fracture risk in MAX is not fully explained by bmd, implicating that impaired bone quality is a key factor here and the results are consistent across both sexes and are robust to adjustment for traditional risk factors. So this work aligns with prior literature showing increased skeletal fragility MAX and also supports the need for systematic vertebral fracture assessment in this population.
- [27:11]
B
Moving on to study two this proctive randomized protocol. In this study again no difference in characteristics of age, sex, bmi, baseline labs or bone mineral density existed. Both groups had 21% of its subjects with a baseline vertebral fracture fracture following the full 24 months after intervention depth suppression test, ACTH, urine free cortisol levels normalized in the surgical group, and in the conservative group, these levels stayed steady. Also in the surgical treatment group, there was an increase in calcium and phosphate levels throughout the study that was not mirrored in the conservative management group. At 24 months, one patient of the 63 in the adrenalectomy group had an incident vertebral fracture. This one patient also had one at baseline. Of the conservative group, seven patients experienced vertebral fractures, with four of those having had a vertebral fracture at baseline. After the full 24 months, bone mineral density again was unchanged in both corners groups. Adrenalectomy showed to reduce the risk of vertebral fracture by 4.5 fold even after adjusting for age. However, the odds ratio was a little bit interesting. When the collective odds ratio was considered, we received an odds ratio of 0.22, which increased to 0.65 after adjusting for age. What do we think about this big difference between age corrected and uncorrected odds ratios?
- [28:58]
C
So I have some thoughts on this. Unadjusted odds ratio was, as you mentioned, 0.22. So this odds ratio suggests a very strong predictive effect of adrenalectomy. And patients who had surgery were at 78% less likely to experience vertebral fractures compared to those who are managed conservatively. Now, when the odds rat ratio was adjusted for age, it changed from 0.22 up to 0.65. So what we saw with this, that the protective effect is still present, but it's less dramatic. So now the surgery is associated with a 35% reduction in fracture risk. Patients with MAX who had adrenalectomy were 4.5 times less likely to develop vertebral fractures compared to those who were were managed conservatively. And importantly, this protective effect remained significant even after adjusting for age, which is a major risk factor for fractures.
- [30:04]
A
The one thing that I would add is a possible implication of that odds ratio shifting. So Oksana is absolutely right. It's still statistically significant even after that. But again, with the age, it was randomized. And so at least initially, those should have been pretty balanced. Now we lost some of the effects, the benefits of that randomization. And I think we're seeing seeing that here because after you adjust for something that should have been accounted for already, you have a relatively big shift in that odds ratio from 0.22 to 0.65. So in my mind, it at least raises the question of, well, okay, so that extra 35% that we still got there, how much of that is being accounted for? Other things that are not balanced between those two groups because we lost that beneficial effect of the randomization? You don't know. It's an unanswered question, but I think it's at least one that we have to ask and wonder about that. Whenever you have adjustment and see a pretty big shift in an odds ratio or relative risk, you have to wonder, well, what about unmeasured confounders that exist? Could they be driving the rest of that? Again, we don't want to know. Just. Just questions to ask there. So now we're going to move on to the discussion and I'm going to start by quoting the authors with a couple of their main findings. So first of all, they say we found that subjects who underwent the removal of the adrenal adenoma causing MAX had an important vertebral fracture risk reduction while conservatively treated patients main contained a high rate of vertebral fracture incidence. And then a second one is bone mineral density did not significantly change in both surgically and conservatively treated patients. The authors then go on to compare what they found to the medical literature. Oxana's actually told us about some of that already, but they point out that their findings were in line with observational studies. But this is the first interventional study to show a benefit using the current criteria. A few additional findings that the authors point out. They mentioned that the fracture risk persists even after surgery, so even though it goes down, it does not go away after an adrenalectomy. And they also mentioned that for conservatively managed patients that the risk factors for a fracture were not identified other than possibly a baseline fracture indicating a higher risk, I will mention just as an aside that I thought it was interesting that the cortisol levels following dexamethasone suppression test did not predict whether you were going to have a fracture or not. Particularly in observational studies, you like to see a dose response relationship. It makes you more encouraged that whatever you're seeing is going to be a real thing here. So if this had been a had a dose response relationship, you'd expected that higher cortisol levels after dexamethasone would have given you a higher fracture risk. So it may not be as simple here as that, but it might have been supportive if we had seen that. Okay. Finally, the authors add a speculation which I think is interesting, worth us thinking about. So for the reasons that Oxana is actually already highlighted for us in the pathophysiology of bone loss from glucocorticoids. The authors point out that something else besides just bone mineral density might be helpful in assessing that risk, and they say specifically something like a trabecular bone score might be more helpful at predicting fracture risk and max. So, Oksana, interested in your thoughts? The authors are very clear. That's just speculation. They don't have data suggesting this, but I thought that would be worth us thinking about a little bit more. What is your impression on that? And might that be something worth pursuing in other studies in the future?
- [33:33]
C
Yes, indeed. So, trabecular bone score, or TBS for short. We know that it independently predicts vertebral fracture risk and adds incremental value to bone mineral density. What we see is low TBS is associated with significantly higher odds of vertebral fractures even after adjusting for bone mineral density and other risk factors. So TBS is indeed more helpful than bone mineral density in predicting fractures in patients with max. And in MAX and related conditions, TBS declines in proportion to cortisol access and it's more closely linked to fracture risk than bmd. Another interesting point is that TBS also improves more rapidly than BMD after remission of hypercortisolism, which would suggest that it's a more sensitive marker for for bone quality changes. Another thing to add is that TBS is more sensitive to deterioration of microarchitecture of the bone, which is a key driver to skeletal fragility in max. In contrast, BMD may remain normal or only mildly reduced in many affected patients who nonetheless experience fragility fractures. So this discordance highlights the limitation of relying solely on on bone mineral density for fracture risk assessment in max. While BMD still remains useful for osteoporosis diagnosis and for risk stratification, trabecular bone score should be considered as a complementary tool for patients with max, especially when BMD is not markedly reduced. But clinical suspicion for skeletal fragility is high. Prospective data specifically in MAX are limited, but current evidence supports that TBS could add information to the risk of fragility fractures regardless of bone mineral density.
- [35:35]
A
The authors then go on to list the limitations of their study. They do mention that lack of trabecular bone score and also bone turnover markers didn't have either of those. They mentioned confounding Residual confounding could be an issue. In study one, they gave the example of tobacco use was not information that they had available. They also point out something that we've alluded to before is that there are differences in observation periods, so the surgery patients were followed for an additional 12 months while on glucocorticoid replacement, though if that had had an impact, it would have reduced the difference between the groups and we still saw a difference there, so didn't have an obvious major impact. And then finally they point out that back in study one they did have a fairly low prevalence of max and that was potentially due to differences in criteria for max. All right, so the author's conclusion. I'm going to start with what I would describe as their summary and I'll quote them where they say subjects undergoing the removal of the adren adenoma causing MAX have an important vertebral fracture risk reduction, while conservatively treated subjects maintain a high rate of vertebral fracture incidence. And then they go on to give what I would say is a recommendation as quote, physicians should take into consideration the risk of vertebral fracture in patients who do not undergo surgery. As we wrap up ourselves here, I want us to start by thinking about the quality of this report overall. Jill, let's start with you. As you were working through this article and thinking through all the different aspects of the study, what has been your impression of just the quality of the study as it's reported by the authors here?
- [37:13]
B
You know, I really liked the quality of this study. I think that they took two different angles from things. They approached things with as much normalization as they could with a very obvious intervention that is hard to sometimes standardize across the other group. In general, I think that they used to a good randomization. I think that they did what they could and I appreciate that they monitored as many parameters as they did where we could truly see that the things that changed was purely the incidence and fractures when many things along both of these populations stayed steady.
- [37:49]
A
Oksana, same question for you. Just your thoughts on the quality of this report.
- [37:54]
C
In my opinion, this article indeed provides important new evidence showing that adrenalectomy reduces the risk of vertebral fractures in patients with max. There are certain issues with the study, including selection bias as we discussed, but that it does have important clinical implications, meaning that bone health assessment in MAX should include evaluation of bone quality and vertebral fracture screening, not just bone mineral density. These findings, as we mentioned, are consistent with earlier observational studies and meta analyses showing increased vertebral fracture risk in MAX and benefit of adrenalectomy for bone health. However, prior studies were limited by their retrospective design, small sample size, or lack of randomization. This current study is strengthened by its prospective randomized component by directly addressing a Key evidence, evidence gap highlighted in recent reviews. So I would conclude that this study provides the strongest evidence that we have to date that adrenalectomy reduces vertebral fracture risk in max, supporting a more proactive surgical approach in selected patients, but also highlighting the need for larger, longer term randomized trials to confirm these findings and clarify patients selection.
- [39:22]
A
We've hinted at changes in our practice and whether we think that should be happening, but we'll, we'll be more explicit about that. Jill, let's start again with you. Do you see your practice changing? Would you advocate that other endocrinologists change their practice regarding MAX based on this information?
- [39:40]
B
You know, I do think this is going to lower my threshold for encouraging adrenaline mastectomy in especially my patients that are at high risk for osteoporosis in the first place. I find that a lot of the people that I am diagnosing with this are people that have a new onset fracture at potentially a younger age. So that is actually the initial prompt to have me screen people for bushings in the first place. And I'm detecting more MAX in that specific scenario. And I think in time it may be be that incidental. Especially vertebral fractures in the setting of MAX becomes its own surgical pathway where the incidence of both of those together we know would be protective if we send them for adrenalectomy. I think that this is the first study that opens a clean pathway in that direction. And I think I'm going to be more open to using this comorbidity of vertebral fracture as encouragement to support surgery for these patients in an effort to prevent further vertebral fracture side effects. Right.
- [40:49]
A
Oksana, we're going to finish up with you. You've given us your views already. It sounds like you are have been impressed with this data and think that it should change. So unpack that for us just a little bit. Do you think this should change our practice patterns? And if so, how do you think it's going to move our practice practice forward?
- [41:06]
C
I do think that this is practice changing in terms of realizing that we are not identifying or stratifying patients with MAX properly by just looking at their bone mineral density by daxa. So indeed, we have to expand our tools to either spinal X rays or trabecular bone scores to characterize those patients a little bit more carefully and then discuss the role for adrenalectomy in those particular patients. So just like we are screening patients for hypertension, diabetes, obesity that are known comorbidities in this patient population. We also need to do a better job evaluating their bone health.
- [41:49]
A
And with that, I would like to thank Jill Wagner and Oksana Hamidi for joining me for this month's edition of Endocrine Feedback Loop. I hope that you all learned as much as I did and that you will join us again again next month. And now you're in the loop. This has been Endocrine Feedback Loop. Endocrine Feedback Loop is brought to you by the Endocrine Society with Production Oversight by Brandy Brown and Andrew Harmon. If you want to like and subscribe, you can find us on Apple, Spotify, or wherever you get your podcast. We'd love to hear your feedback on this episode of the podcast itself. Please email email us@podcastren.org Endocrine Feedback Loop is a free service of the Endocrine Society. To learn more or to become a member, visit the society's website at www.endocrine.org.