Endocrine Feedback Loop - Episode EFL065

"MACS and Vertebral Fractures"

Podcast Date: September 18, 2025
Host: Dr. Chase Hendrickson (Vanderbilt University)
Guests: Dr. Jill Wagner (University of Nebraska Medical Center), Dr. Oksana Hamidi (University of Texas Southwestern)

Episode Overview

This episode takes a deep dive into a forthcoming Journal of Clinical Endocrinology & Metabolism (JCEM) article examining the relationship between mild autonomous cortisol secretion (MACS) and vertebral fractures—specifically, whether adrenalectomy (surgical removal of the adrenal adenoma) reduces fracture risk compared to conservative treatment. The team reviews key background, discusses methodology, analyzes both a retrospective cohort and a randomized trial, and explores the implications for clinical practice.

Key Discussion Points & Insights

1. Clinical Importance of MAX (MACS)

[02:33–04:57]

• Rising Awareness: Detection rates of adrenal incidentalomas (AIs) have increased, especially among adults over 60, with up to 50% resulting in MACS.
• Clinical Risks: MACS is linked to worsened cardiovascular outcomes and growing evidence suggests notable bone health implications, particularly vertebral fractures.

  "MACS or mild autonomous cortisol secretion is associated with a 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." — Dr. Oksana Hamidi, [03:21]

2. Diagnosis of MACS

[04:57–07:39]

• Updated Criteria:
  • Diagnosed via a post-dexamethasone suppression test (DST) cortisol level ≥1.8 μg/dL, absent classic Cushing’s features.
  • Additional tests: low ACTH, low DHEA-S, high 24h urinary free cortisol, elevated late-night salivary cortisol may support diagnosis, but aren’t always required.
  • Contrast with overt Cushing’s: MACS lacks classic symptoms but can still have metabolic and skeletal comorbidities.

  “Patients with MAX do not exhibit these specific signs… despite this they may still experience metabolic complications.” — Dr. Oksana Hamidi, [06:47]

3. Why Focus On Vertebral Fractures?

[07:39–09:32]

• Prevalence: Vertebral fractures are more common in MACS (up to 63%) compared to non-functioning adrenal incidentalomas (28%).
• Risk Assessment: Bone mineral density (BMD) may remain normal even when fracture risk is high, underscoring that bone quality, rather than quantity, is impaired in MACS.
• Clinical Guidance: Early identification of vertebral fractures is vital as they predict future fractures and affect quality of life.

4. The JCEM Article: Two Complementary Studies

[09:32–22:13]

• Study 1: Retrospective cohort from two Italian centers (2008-2013); compared outcomes in MACS patients by whether they had surgery.
  • Limitation: Non-random assignment (possible selection bias).
• Study 2: Prospective randomized clinical trial (2016-2020); enrolled patients 40–75 y/o with unilateral adrenal incidentaloma.
  • Key features: Excluded overt Cushing's, pheochromocytoma, large tumors, and comorbidities affecting bone.
  • Randomized 62 subjects (31 per arm), but high loss to follow-up—especially in the surgery group.
  • Analysis Caveat: Per-protocol rather than intention-to-treat, thus losing some benefits of randomization.

  “...you lose that randomization, and I think we're going to see evidence of that in the results.” — Dr. Chase Hendrickson, [15:44]

Post-Surgical Management

[17:47–20:55]

• Steroid Replacement: All adrenalectomy patients received hydrocortisone post-op, with follow-up testing to wean as tolerated.

  "By using steroids empirically for everyone, we are truly potentially subjecting at least half of the patients to unnecessary glucocorticoid replacements." — Dr. Oksana Hamidi, [19:24]

Imaging & Fracture Assessment

• DEXA & Plain Films: All patients had both, though radiologists were not blinded to group assignment—potential bias noted.
• Bone Medications: High-risk, conservatively managed patients could receive bisphosphonates (few did).

5. Study Results

Study 1 (Retrospective):

[22:13–24:19]

• Baseline: Similar demographics; conservative group had slightly more diabetes and lower BMD in the surgical group.
• Fracture Rates:
  • More new vertebral fractures in the conservative group (11 new cases) compared to the surgical group (3 new cases).
  • Logistic regression: Adrenalectomy conferred a 6.8-fold risk reduction.

  "Despite the higher risk of lead time bias, only three from the surgical group experienced new fractures." — Dr. Jill Wagner, [23:16]

• Bone Density: No significant change in BMD or labs between groups.

Study 2 (Randomized Trial):

[27:10–30:04]

• Baseline: Groups well-matched; both had ~21% baseline vertebral fractures.
• Outcomes after 24 Months:
  • Normalization of cortisol parameters in surgical group.
  • Only 1 surgical patient had a new vertebral fracture vs. 7 in the conservative arm.
  • No appreciable change in BMD in either group.
  • Odds Ratio: Adrenalectomy reduced risk by 4.5-fold after adjusting for age (corrected OR = 0.65).

  “The protective effect remained significant even after adjusting for age, which is a major risk factor for fractures.” — Dr. Oksana Hamidi, [29:28]

Age Adjustment & Confounders:

[30:04–30:51]

• Noted shift in odds ratio upon age adjustment suggests possible baseline imbalances due to loss of randomization.

  “Whenever you have adjustment and see a pretty big shift in an odds ratio or relative risk, you have to wonder... could [confounders] be driving the rest of that?” — Dr. Chase Hendrickson, [30:31]

6. Discussion & Clinical Implications

[31:01–35:35]

• Major Findings:
  • Adrenalectomy reduces vertebral fracture incidence in MACS.
  • BMD is not a good surrogate for bone quality or fracture risk in these patients.
  • Having a baseline fracture increases risk of recurrence regardless of management.
  • No strong dose-response relationship between cortisol suppression test results and actual fracture risk.

The Role of Trabecular Bone Score (TBS)

• TBS may better predict fracture risk than BMD in MACS.

  “TBS is indeed more helpful than bone mineral density in predicting fractures in patients with MAX... it’s more closely linked to fracture risk than BMD.” — Dr. Oksana Hamidi, [33:33]

• Suggests future studies should incorporate TBS and bone turnover markers.

Study Limitations

• Absence of TBS and bone turnover marker assessment.
• Residual confounding possible (e.g., smoking status missing).
• Differences in observation periods could bias results, but likely favor conservative group.
• Evolving diagnostic criteria impacted prevalence and possibly selection.

7. Overall Quality and Future Practice

[37:12–41:49]

• Quality Assessment:

  “I really liked the quality of this study... they approached things with as much normalization as they could... I appreciate that they monitored as many parameters as they did.” — Dr. Jill Wagner, [37:12]

  “This article provides important new evidence... supporting a more proactive surgical approach in selected patients, but also highlighting the need for larger, longer-term randomized trials.” — Dr. Oksana Hamidi, [37:53]

• Practice-Changing?

  • Both experts agree these findings support earlier consideration of adrenalectomy in eligible MACS patients, especially those with vertebral fractures or high osteoporosis risk.
  • BMD alone is insufficient; vertebral imaging and/or TBS should be considered routine.

  “I do think this is going to lower my threshold for encouraging adrenalectomy—especially my patients that are at high risk for osteoporosis…” — Dr. Jill Wagner, [39:39]

  “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.” — Dr. Oksana Hamidi, [41:06]

Notable Quotes & Memorable Moments

• On BMD and fracture risk:

  “The risk of fracture in MAX patients is often disproportionate to the degree of bone mineral density loss... bone quality deterioration plays a major role.” — Dr. Oksana Hamidi, [03:49]

• On perioperative glucocorticoid management:

  “By using steroids empirically for everyone, we are truly potentially subjecting at least half of the patients to unnecessary glucocorticoid replacement.” — Dr. Oksana Hamidi, [19:24]

• On the importance of vertebral fracture screening:

  “This work aligns with prior literature... supports the need for systematic vertebral fracture assessment in this population.” — Dr. Oksana Hamidi, [26:15]

Important Segment Timestamps

| Timestamp | Segment | Content | |------------------|----------------------------------------|--------------------------------------| | 00:00 - 02:33 | Introduction & Episode Theme | MACS overview, study setup | | 03:21 - 04:57 | MACS Pathophysiology | Impact on bone, osteoporosis | | 05:34 - 07:39 | Diagnostic Criteria Review | MACS vs Cushing’s syndrome | | 09:32 - 22:13 | Study Overviews & Methodology | Retrospective vs randomized trial | | 22:13 - 24:19 | Study 1 Results | Fracture rates & implications | | 27:10 - 30:04 | Study 2 Results | Randomized outcomes, odds ratios | | 33:33 - 35:35 | Discussion: TBS & Fracture Prediction | Future directions for assessment | | 37:12 - 41:49 | Quality, Limitations, Clinical Impact | Practice implications, future steps |

Summary

This episode illuminates crucial new evidence that adrenalectomy significantly lowers vertebral fracture risk in MACS patients—even when BMD remains unchanged. The team underscores that bone quality, not just BMD, should inform risk assessment, and advocates for broader implementation of vertebral imaging and consideration of TBS. The findings support a more proactive and nuanced surgical approach for selected MACS patients, especially those at increased risk for osteoporosis and fragility fractures.

Bottom line:
Adrenalectomy reduces vertebral fracture risk in MACS. BMD alone is insufficient as a screening tool—vertebral imaging and expanded assessment should become standard in evaluating MACS patients for surgery.