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The Use of Alendronate to Enhance Transcranial Transmission of Focused Ultrasound for Successful Ablations in Brain

T0 review · 5 major / 5 minor · reviewed 2026-08-07 · deepseek-v4-flash

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Pith's one-line read Alendronate increases skull ultrasound permeability and turned five failed brain ablations into successful repeat procedures

desk verdict A well-meaning five-patient case series that overreaches its causal claim; the temperature data are worth a look, but the CT normalization is internally inconsistent. read the letter →

arxiv 2505.24349 v1 pith:XXAMCCXV submitted 2025-05-30 physics.med-ph physics.data-an

G. Sakharova , A. Krokhmal , R. Galimova , A. Khatmullina , D. Nabiullina , I. Buzaev , D. Avzaletdinova , D. Chupova
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V. Khokhlova
This is my paper
classification physics.med-phphysics.data-an
keywords MR-guidedfocusedultrasoundalendronateskulldensityratiotranscranialtrabecularbonedensificationCThistogramanalysisablationmovementdisorders
verification ladder T0 review T1 audit T2 compute T3 formal

The pith

A machine-rendered reading of the paper's core claim, the machinery that carries it, and where it could break.

The reading

This paper tries to establish that the osteoporosis drug alendronate can be used as a preparatory treatment to make the skull more transparent to focused ultrasound, converting failed MR-guided focused ultrasound (MRgFUS) brain ablations into successful ones. In five patients whose first ablation failed because of insufficient heating or pain from skull heating, 6–12 months of alendronate raised the skull density ratio (SDR, a CT-based measure of ultrasound permeability) in four patients and increased peak focal temperatures in all five; the repeat procedure was successful in every case. The paper also proposes CT density histograms as a supplementary way to see that low-density, porous regions of skull bone have become denser and more uniform, which it interprets as the mechanism behind better ultrasound transmission. If true, this gives clinicians a reversible, drug-based way to widen the pool of patients eligible for MRgFUS rather than excluding those with low SDR.

What carries the argument

The central object is the skull density ratio (SDR), the ratio of minimum to maximum skull density along the ultrasound beam paths from transducer to focus, computed from CT and used to decide MRgFUS eligibility. The paper's new instrument is a calibrated CT density histogram of the skull region exposed to ultrasound: post-treatment scans are scaled so that voxels above 1500 HU align with the baseline scan, on the assumption that alendronate does not densify the densest cortical bone, and then the shift of low-density voxels toward higher HU is read as trabecular densification and reduced acoustic mismatch. That histogram shift, together with the SDR change, is what carries the argument that alendronate improves ultrasound transmission.

What would settle it

Re-analyse the pre- and post-treatment CT images after calibrating both scans to an electron-density phantom using identical reconstruction settings, and compare the SDR and histogram shifts without the 1500 HU anchor; if the density shift and the temperature rise disappear or shrink to non-significance, the causal claim that alendronate improved transmission is not supported. A prospective arm with untreated patients scanned on the same scanner after the same 6–12 month wait would further test whether the repeat success is due to the drug rather than to natural variation or added operator experience.

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Extended reading notes

Core claim

The paper's central claim is causal: in five patients with movement disorders whose initial MRgFUS thalamotomy was unsuccessful, a 6–12 month course of alendronate (with vitamin D and calcium) improved the density distribution of the skull, and this improvement is what allowed a repeat ablation to reach the 55 °C target and succeed in all five cases. The quantitative evidence is the SDR increasing from $0.378\pm0.037$ to $0.424\pm0.045$ in four of five patients, the per-sonication average maximum focal temperature rising from $53.6\pm4.0$ °C to $55.7\pm4.1$ °C ($p=0.018$), and the per-patient maximum temperature rising from $57.0\pm2.4$ °C to $60.2\pm1.8$ °C ($p=0.031$). The paper reads the CT histogram shift toward higher Hounsfield units as densification of trabecular bone and reduced porosity, and registered 3D CT images show local density increases, defect filling, and void reduction in the sonicated skull region.

Load-bearing premise

The load-bearing premise is that the before-and-after CT scans are quantitatively comparable even though several patients were scanned with different scanners, kernels, tube currents, and kVp, and that the densest cortical bone above 1500 HU is unchanged by the drug so that histograms can be anchored to it.

Editorial extensions

If this is right

  • After 6–12 months of alendronate, a patient whose first MRgFUS ablation failed can reach the 55 °C ablation temperature and complete a successful repeat procedure.
  • SDR is not the whole story: one patient's SDR fell after treatment yet the repeat ablation still succeeded, suggesting density distribution matters as much as the ratio.
  • CT density histograms, and visual inspection of registered CT scans, can support the decision to retry MRgFUS in borderline or previously failed cases.
  • The approach could expand MRgFUS eligibility to patients with low SDR who would otherwise be turned away.
  • No medication-related adverse effects were reported in the five patients, supporting the feasibility of this preparatory regimen.

Reading between the lines

Editorial extensions of the paper, not claims the author makes directly.

  • If the causal link survives scanner-controlled replication, a standardized pre-treatment protocol with alendronate could be offered to low-SDR candidates before deciding they are ineligible for MRgFUS.
  • The 1500 HU normalization anchor is in tension with the paper's own finding of cortical thickening; recalibrating against an electron-density phantom might reveal even larger or different treatment effects.
  • Patient E's success despite a lower SDR suggests that a volumetric density-distribution metric, not just SDR, should be tested retrospectively against existing outcome data as a predictor of repeat-procedure success.
  • A prospective registry with untreated controls and matched scan protocols would separate the drug's effect from natural bone changes and from the surgical team's increased experience on repeat attempts.
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Editorial analysis

A structured set of objections, weighed in public.

Desk editor's note, referee report, and a circularity audit.

Referee Report

5 major / 5 minor

Summary. The paper reports a retrospective, uncontrolled case series of five patients who had an unsuccessful first transcranial MR-guided focused ultrasound (MRgFUS) ablation and then received 6–12 months of alendronate with calcium and vitamin D before a second MRgFUS attempt. The authors report that the second procedure was successful in all five patients, that per-sonication and per-patient maximum focal temperatures increased, that the skull density ratio (SDR) increased in four of five patients, and that CT histogram analysis showed an apparent shift from lower to higher Hounsfield unit values, which they interpret as trabecular bone densification and reduced skull porosity. They conclude that alendronate enhanced skull ultrasound permeability and thereby enabled successful repeat MRgFUS, and they propose CT density histograms as a supplementary planning metric.

Significance. If the causal claim were supported, this would be a clinically valuable finding: a common cause of MRgFUS failure (low skull transmission) would become a modifiable condition, expanding eligibility for this non-invasive treatment. The manuscript is honest in presenting raw patient-level data, including temperature values, SDR changes, CT acquisition parameters, and explicit imaging limitations. It also engages with the existing literature on bisphosphonate effects on bone. However, the study is a small retrospective case series with no control arm, and the load-bearing mechanistic evidence rests on CT comparisons that are internally inconsistent and partly confounded by acquisition changes. As a hypothesis-generating report, the observations are worth further investigation; as a demonstration of efficacy, the current analysis is not sufficient.

major comments (5)
  1. [Sec. 2.3 and Table 3] The main statistical comparison treats repeated sonications from the same patient as independent observations: the Wilcoxon rank-sum test on N=38 versus N=34 maximum temperatures pools sonications without accounting for patient-level clustering. This inflates the effective sample size and can produce spuriously small p-values. The per-patient paired analysis (N=5, p=0.031) is more appropriate but has very low power and is based on a single selected maximum per procedure, which may reflect differences in the number of sonications, power levels, and target points rather than skull permeability alone. Please report a mixed-effects or per-patient summary analysis, and explicitly state how many hypotheses were tested.
  2. [Sec. 6 and Sec. 2.2] The conclusion that alendronate therapy 'enhanced skull bone density distribution and thus ultrasound permeability' is not supported by the retrospective uncontrolled design. With five patients, no comparator, no randomization, and no blinding, the observed temperature increases and clinical success could be due to operator learning, different target selection, altered sonication parameters, regression to the mean, or natural disease fluctuation. The paper should be reframed as a hypothesis-generating case series, and all causal wording in the abstract, Discussion, and Conclusions should be tempered accordingly.
  3. [Sec. 2.5, Sec. 4.3, and Discussion] There is an internal contradiction in the histogram normalization. Section 2.5 states that each post-treatment CT was scaled so that the regions above 1500 HU align with baseline, justified by the assumption that alendronate does not significantly change the densest cortical bone. However, Section 4.3 reports that the amplitude of the ~1500 HU peak increased in four of five patients, interpreted as cortical thickening, and the Discussion explicitly acknowledges that substantial cortical changes, as in Patient E, may complicate this normalization. If the anchor region itself changes biologically, the scaling factor absorbs part of the treatment effect, so the pre/post histogram comparison is no longer a valid measure of density modification. This affects the central mechanistic evidence for trabecular densification.
  4. [Sec. 2.4 and Table 2] For patients B and C, the pre- and post-treatment CT scans were acquired with different tube currents and kVp settings (Table 2), and the paper itself notes that SDR values depend on scanner and acquisition parameters. The histogram normalization in Sec. 2.5 is the only bridge across these protocol differences, but as argued above that bridge is not reliable. The reported SDR increases in four of five patients may therefore reflect acquisition changes rather than alendronate effects, and the same concern applies to the porosity maps derived from the calibrated CT data. The paper should either restrict the CT-based claims to patients with identical acquisition settings or provide phantom-based calibration evidence.
  5. [Sec. 4.2 and Table 3] Patient E's SDR decreased from 0.39 to 0.37 after alendronate therapy, yet the repeat procedure achieved the target temperature and was clinically successful. This observation undercuts the proposed mechanism that alendronate improves skull transmission primarily through a measurable increase in SDR. The authors invoke density distribution changes as an alternative explanation, but no direct acoustic measurement links the CT histogram changes to improved ultrasound transmission. The temperature rises in Table 3 remain raw observations; without a valid CT-based mechanism they cannot be causally attributed to alendronate.
minor comments (5)
  1. [Table 2] The layout of Table 2 is difficult to read because the pre- and post-treatment entries for each patient are presented in a single row without clear column separation. Please reformat the table with explicit pre/post columns.
  2. [Sec. 3.4 and Table 3] The baseline SDR for Patient D is given as 0.36 in Sec. 3.4 but as 0.37 in Table 3. This inconsistency affects the reported mean SDR in Sec. 4.2 and should be corrected.
  3. [Sec. 4.1] The text contains the typo 'MRregFUS' in the phrase 'MRregFUS treatment trials' and should read 'MRgFUS'.
  4. [Discussion] There is a duplicated phrase 'treatment effects treatment effects' in the first paragraph of the Discussion.
  5. [Across manuscript] The abbreviation 'V AS' for the visual analog scale appears with inconsistent spacing; please standardize it.

Circularity Check

1 steps flagged · score 6.0 of 10

CT histogram normalization makes the 'unchanged' 1500 HU peak a by-construction result, partially forcing the trabecular-densification evidence; the temperature endpoints remain independent observations.

  1. fitted input called prediction [Sec. 2.5 (Image Registration and Analysis) and Sec. 4.3 (Histograms Changes); see also Discussion, last paragraph before Conclusions]
    "each post-treatment CT scan was normalised to the pre-treatment scan by multiplying the HU values by a scaling factor so that the histogram regions above 1500 HU were aligned, and the HU value for water (0 HU) did not change. ... we assumed that ... the densest skull regions above 1500 HU would not undergo further significant densification. ... The second peak, located around 1500 HU and presumably representing the cortical bone mass, remains unchanged across all cases. However, in four out of five cases, the peak amplitude is higher, which can be interpreted as ..."

    The HU scaling factor is fitted to make the post-treatment histogram above 1500 HU coincide with the baseline. Reporting that the ~1500 HU cortical peak 'remains unchanged across all cases' is therefore true by construction, not an independent measurement. If alendronate did change the densest cortical bone, the scaling factor would absorb that change and redistribute it as apparent shifts at lower HU, so the calibrated histograms used to infer trabecular densification are not independent of the anchor assumption.

full rationale

The paper's most direct clinical endpoints—successful repeat ablations and higher measured focal temperatures (average per-sonication maximum from 53.6±4.0 °C to 55.7±4.1 °C, p=0.018; per-patient maximum from 57.0±2.4 °C to 60.2±1.8 °C, p=0.031)—are plain MR-thermometry observations and are not circular. The SDR values are also independently measured rather than derived from the model, although their validity is weakened by the scanner-protocol mismatches documented in Table 2; that is a confounding and reproducibility problem, not a circularity. The one by-construction element is the CT histogram calibration in Sec. 2.5: the normalization factor is fitted under the assumption that voxels above 1500 HU are unchanged, and Sec. 4.3 then reads the constancy of that high-density region as a result while also interpreting amplitude increases around 1500 HU as cortical thickening. The Discussion's own admission that substantial cortical changes, as in Patient E, complicate the normalization confirms that the anchor is not robust. So the histogram-based trabecular-densification evidence is partially forced by the fitting procedure. I found no load-bearing self-citation chain: references [17] and [21] support registration and aberration-correction methodology but are not invoked as an external uniqueness principle or to forbid alternative interpretations. Overall, score 6 reflects partial circularity in the mechanistic CT-histogram evidence while the raw temperature and clinical-success endpoints remain independent.

Assumptions & free parameters 3 free parameters · 6 assumptions · 0 invented entities

The causal claim rests on several unvalidated premises: comparability of CT scans acquired with different protocols for patients A, B, and C (Table 2), a histogram calibration anchored on the assumption that cortical bone above 1500 HU does not change under alendronate (Sec. 2.5), and statistical independence of repeated sonications from the same patient (Sec. 4.1). The paper sets three hand-chosen thresholds (200 HU mask, 300/1200/1500 HU tissue anchors) and a per-scan scaling factor for histogram normalization; all affect the reported density changes. No new physical entities are introduced; the histogram metric is an analytical tool, not an entity. The 55°C ablation threshold and the HU-to-density conversion are taken from cited literature.

free parameters (3)
  • Histogram normalization scaling factor (per post-treatment scan) = not reported numerically
    Chosen in Sec. 2.5 so that voxels above 1500 HU align with the baseline scan and water stays at 0 HU. This factor directly shapes the histogram results in Sec. 4.3 and is not validated against an independent calibration phantom.
  • Skull mask threshold = 200 HU
    Hand-set in Sec. 2.5 to define which voxels count as skull tissue. All density statistics, including mean HU changes, depend on this cutoff.
  • Histogram tissue anchors = 300 HU (trabecular), 1200 HU (cortical), 1500 HU (cortical unchanged)
    Hand-chosen bounds in Sec. 2.5 used to assign histogram peaks to tissue types and to justify the normalization anchor. The 1500 HU anchor is the same assumption later contradicted by the reported cortical thickening.
assumptions (6)
  • ad hoc to paper Cortical bone above 1500 HU is unaffected by alendronate, so post-treatment histograms can be scaled to align with baseline above 1500 HU.
    Invoked in Sec. 2.5 to calibrate histograms; contradicted by the paper's own cortical-thickening result in Sec. 4.3 and Sec. 5.
  • domain assumption CT Hounsfield units are linearly related to physical bone density via the Schneider calibration [9].
    Used in Sec. 2.5 to convert HU to density maps; the calibration is taken from cited literature and not re-validated for the scanners and kernels used here.
  • domain assumption Individual sonications from the same patient are independent samples for statistical testing.
    Implicit in the Wilcoxon rank-sum test over N=38 versus N=34 sonications in Sec. 4.1. Sonications cluster within patients and share target, power, and patient anatomy, so independence is likely violated.
  • domain assumption The only clinically relevant change between the first and second procedure is the drug-induced skull change; operator learning, target selection, and concurrent vitamin D and calcium do not explain the outcome.
    Implicit in the causal conclusion. The uncontrolled retrospective design in Sec. 2.1 does not rule out these confounders.
  • domain assumption Attaining 55°C focal temperature corresponds to a successful ablation.
    Used in Sec. 4.1 as the success criterion, following the cited threshold in [6].
  • domain assumption Pre- and post-treatment CT scans are comparable despite scanner and protocol differences for patients A, B, and C.
    Underlies all SDR and histogram comparisons. Protocol differences are documented in Table 2 and partially acknowledged in Sec. 5, but the analysis does not quantify the resulting bias.

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Cite this review

Pith. "Pith review of The Use of Alendronate to Enhance Transcranial Transmission of Focused Ultrasound for Successful Ablations in Brain." pith.science (2026). https://pith.science/paper/XXAMCCXV

@misc{pith2026250524349,
  author       = {Pith},
  title        = {Pith review of: The Use of Alendronate to Enhance Transcranial Transmission of Focused Ultrasound for Successful Ablations in Brain},
  year         = {2026},
  howpublished = {\url{https://pith.science/paper/XXAMCCXV}},
  note         = {Machine review of arXiv:2505.24349}
}
abstract

Objective: The aim of this study was to evaluate the efficacy of alendronate therapy in improving bone density distribution in skull bones and corresponding ultrasound permeability in patients who had previously experienced unsuccessful transcranial MR-guided focused ultrasound (MRgFUS) ablation. The ability of alendronate treatment to modify skull bone characteristics and enhance the success rate of repeat MRgFUS procedures was assessed. Methods: Five patients with initially unsuccessful MRgFUS ablations underwent a 6-12 month regimen of alendronate to improve bone density. Repeat MRgFUS procedures were performed, and changes in skull density ratio (SDR) and peak focal temperatures were evaluated statistically using CT and MR imaging. Histograms of skull bone density were introduced and analysed as an additional metric. Results: After therapy, SDR increased in four out of five patients (from 0.378$\pm$0.037 to 0.424$\pm$0.045, p>0.05). All repeated procedures were successful. The maximum focal temperature, averaged over sonications, increased from 53.6$\pm$4.0{\deg}C to 55.7$\pm$4.1{\deg}C (p=0.018), while the maximum temperature per patient rose from 57.0$\pm$2.4{\deg}C to 60.2$\pm$1.8{\deg}C (p=0.031). Histograms of CT scans showed a reduction in low-density voxels, indicating trabecular bone densification. 3D CT scan registration revealed local density changes, defect filling, and void reduction. Conclusions: Alendronate therapy enhanced skull bone density distribution and thus ultrasound permeability, which has facilitated successful repeat MRgFUS. By visually analysing CT changes, healthcare professionals can better inform their decision-making regarding repeat surgeries. This method broadens the pool of patients with low SDR eligible for MRgFUS treatment and underscores the potential benefits of alendronate in improving treatment outcomes.

Figures

Figures reproduced from arXiv: 2505.24349 by the authors.

Figure 1
Figure 1. Process of CT image registration before and after alendronate treatment. (a) Initial skull masks with low [PITH_FULL_IMAGE:figures/full_fig_p005_1.png] view at source ↗
Figure 2
Figure 2. (a) The temperature during the MRgFUS sonication with the maximum heating for each patient, (b) [PITH_FULL_IMAGE:figures/full_fig_p008_2.png] view at source ↗
Figure 3
Figure 3. Change in SDR during the alendronate therapy. [PITH_FULL_IMAGE:figures/full_fig_p008_3.png] view at source ↗
Figures from the paper (2 more)
Figure 4
Figure 4. Figure 4: Density distributions within the compared skull sections before and after alendronate treatment (columns 1 [PITH_FULL_IMAGE:figures/full_fig_p009_4.png]
Figure 5
Figure 5. Figure 5: Skull density before treatment and areas of densification on skulls; skulls are labelled (A – E) according to the [PITH_FULL_IMAGE:figures/full_fig_p010_5.png]

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Pith tools

Reviewed August 7, 2026 · model on record in the stance chip above.