THIS IS AN ONLINE E LOG BOOK TO DISCUSS OUR PATIENT'S DEIDENTIFIED HEALTH DATA SHARED AFTER TAKING HER SIGNED INFORMED CONSENT. HERE WE DISCUSS OUR PATIENT'S PROBLEMS THROUGH SERIES OF INPUTS FROM AVAILABLE GLOBAL ONLINE COMMUNITY EXPERTS WITH AN AIM TO SOLVE THOSE PATIENT'S CLINICAL PROBLEMS WITH COLLECTIVE CURRENT BEST EVIDENCE BASED INPUTS.
Hscrp (High Sensitive Crp), Lft And Kft (Liver Function Test & Kidney Function Test), Lipid Profile, Serum Iron
Studies Basic, Thyroid Profile Total (T3, T4 & Tsh) +7 More
Test Name Result Bio. Ref. Interval Trends (For last three tests)
Complete Blood Count 05 Feb 26 07 Nov 25 21 Jul 25 18 Apr 25
Hemoglobin 12.6 g/dL 12.0 - 15.0 10.8
(12.0 - 15.0)
13.2
(12.0 - 15.0)
13.4
(12.0 - 15.0)
RBC 4.27 10^6/cu.mm 3.8 - 4.8 3.58
(3.8 - 4.8)
4.21
(3.8 - 4.8)
4.27
(3.8 - 4.8)
HCT 36.9 % 36 - 46 32.6
(36 - 46)
39.0
(36 - 46)
38.9
(36 - 46)
RDW-CV 15.6 % 11.5 - 14 13.4
(11.5 - 14)
13.3
(11.5 - 14)
13.8
(11.5 - 14)
Total Leucocyte Count 4.01 10^3/µL 4 - 10 4.01
(4 - 10)
4.86
(4 - 10)
4.85
(4 - 10)
Neutrophils 58.6 % 40 - 80 50.8
(40 - 80)
53.3
(40 - 80)
56.2
(40 - 80)
Lymphocytes 28.7 % 20 - 40 34.5
(20 - 40)
35.9
(20 - 40)
33.5
(20 - 40)
Monocytes 9.1 % 2 - 10 9
(2 - 10)
8.1
(2 - 10)
7.8
(2 - 10)
Eosinophils 3.2 % 1 - 6 4.9
(1 - 6)
2.3
(1 - 6)
2.1
(1 - 6)
Basophils 0.4 % 0 - 2 0.8
(0 - 2) 0.4
(0 - 2) 0.4
(0 - 2)
Platelet Count 250 10^3/µL 150 - 410 269
(150 - 410) 228
(150 - 410) 268
(150 - 410
Iron Studies 05 Feb 26 07 Nov 25 21 Jul 25 18 Apr 25
Iron Serum 96 µg/dL 50 - 170 57
(50 - 170) 96
(50 - 170) 70
(50 - 170)
Total Iron Binding Capacity
(TIBC) 345 µg/dL 250 - 460 348
(250 - 460) 326.6
(250 - 460) 263.62
(250 - 460
Hscrp (High Sensitive Crp), Lft And Kft (Liver Function Test & Kidney Function Test), Lipid Profile, Serum Iron
Studies Basic, Thyroid Profile Total (T3, T4 & Tsh) +7 More
Test Name Result Bio. Ref. Interval Trends (For last three tests)
Diabetes Profile 05 Feb 26 07 Nov 25 21 Jul 25 05 Jun 25
Glycosylated Hemoglobin
(HbA1c) 7.0 % 4 - 5.6 6.2
(4 - 5.6)
6.4
(4 - 5.6)
Microalbumin-Albumin < 3.00 mg/L 0 - 30.01 < 3.0
(0 - 30.01)
< 3.0
(0 - 29.99)
Microalbumin-Albumin/Cre
atinine Ratio < 30.0 mg/g creatinine0 - 29.999 < 30.0
(0 - 30.01)
< 30.0
(0 - 29.99)
Glucose - Fasting 122 mg/dL 70 - 99 117
(70 - 99)
123
(70 - 99)
126
(70 - 99)
Kidney Health 05 Feb 26 07 Nov 25 21 Jul 25 15 Jun 25
Creatinine 0.76 mg/dL 0.55 - 1.02 0.70
(0.55 - 1.02)
0.70
(0.5 - 1.1)
Uric Acid 4.6 mg/dL 2.7 - 6.1 3.9
(2.7 - 6.1)
3.9
(2.7 - 6.1)
Sodium 142 mEq/L 136 - 145 137
(136 - 145)
139
(132 - 146)
Potassium 5.00 mEq/L 3.5 - 5.1 5.20
(3.5 - 5.1)
5.33
(3.5 - 5.5)
5.17
(3.5 - 5.5)
Lipid Profile 05 Feb 26 07 Nov 25 21 Jul 25 18 Apr 25
Cholesterol - Total 224 mg/dL <= 199.9 205
(<= 199.9)
197
(<= 199.9)
182
(<= 199.9)
Triglycerides 100 mg/dL <= 149.9 62
(<= 149.9)
74
(<= 149.9)
75
(0 - 149.9)
Cholesterol - HDL 62 mg/dL >= 49.9 63
(>= 49.9)
67
(>= 39.9)
58
(>= 39.9)
Cholesterol - LDL 142 mg/dl <= 99.9 130
(<= 99.9)
115
(<= 99.9)
109
(0 - 99.9)
Non HDL Cholesterol 162 mg/dL <= 129.9 142
(<= 129.9)
130
(<= 129.9)
124
(<= 129.9)
Hscrp (High Sensitive Crp), Lft And Kft (Liver Function Test & Kidney Function Test), Lipid Profile, Serum
Iron Studies Basic, Thyroid Profile Total (T3, T4 & Tsh) +7 More
Test Name Result Bio. Ref. Interval Trends (For last three tests)
Cardiac Profile 05 Feb 26 07 Nov 25 21 Jul 25 18 Apr 25
High sensitivity CRP 0.80 mg/L 0 - 3 0.21
(0 - 3)
0.05
(<= 3)
0.43
(<= 3)
Liver Health 05 Feb 26 07 Nov 25 21 Jul 25 18 Apr 25
Bilirubin - Total 0.57 mg/dL 0.2 - 1.1 0.53
(0.2 - 1.1)
0.68
(0.2 - 1.1)
0.62
(0.2 - 1.1)
Protein, Total 7.30 g/dL 5.7 - 8.2 6.80
(5.7 - 8.2)
7.13
(5.7 - 8.2)
7.12
(5.7 - 8.2)
Albumin 4.47 g/dL 3.2 - 4.8 4.17
(3.2 - 4.8)
4.41
(3.4 - 4.8)
4.45
(3.4 - 4.8)
Aspartate Transaminase
(SGOT) 21 U/L 0 - 33.9 19
(0 - 33.9)
24
(<= 34)
27
(<= 34)
Alanine Transaminase
(SGPT) 16 U/L 10 - 49 12
(10 - 49)
18
(10 - 49)
18
(10 - 49)
Alkaline Phosphatase 42 U/L 46 - 116 33
(46 - 116)
35
(46 - 116)
38
(46 - 116)
Gamma
Glutamyltransferase (GGT) 12 U/L 0 - 37.9 11
(0 - 37.9)
8
(<= 37)
9
(<= 37)
Urine Routine & Microscopy 05 Feb 26 07 Nov 25 21 Jul 25 18 Apr 25
Specific gravity 1.010 1.003 - 1.035 1.010
(1.003 - 1.035)
1.005
(1.003 - 1.035)
1.010
(1.003 - 1.035)
pH 7.0 4.6 - 8 7.5
(4.6 - 8)
6.5
(4.6 - 8)
7.0
(4.6 - 8)
Glucose Negative Negative Negative
(Negative)
Negative
(Negative)
Negative
(Negative)
Protein Negative Negative Negative
(Negative)
Negative
(Negative)
Negative
(Negative
Hscrp (High Sensitive Crp), Lft And Kft (Liver Function Test & Kidney Function Test), Lipid Profile, Serum
Iron Studies Basic, Thyroid Profile Total (T3, T4 & Tsh) +7 More
Test Name Result Bio. Ref. Interval Trends (For last three tests)
Urine Routine & Microscopy 05 Feb 26 07 Nov 25 21 Jul 25 18 Apr 25
Ketones Negative Negative Negative
(Negative)
Negative
(Negative)
Negative
(Negative)
Pus cells 2-3 /hpf 0 - 5 2-3
(0 - 5)
2-3
(0 - 5)
2-3
(0 - 5)
Red blood cell Nil /hpf 0 - 2 Nil
(0 - 2)
Nil
(0 - 2)
Nil
(0 - 2)
Epithelial cells 3-4 /hpf Few 1-2
(Few)
1-2
(Few)
3-4
(Few)
Casts Nil /lpf Nil Nil
(Nil)
Nil
(Nil)
Nil
(Nil)
Crystals Nil Nil Nil
(Nil)
Nil
(Nil)
Nil
(Nil)
Urinary Creatinine 34.06 mg/dL 15 - 278 16.31
(15 - 278)
11.50
(15 - 278)
25.76
(15 - 278)
Calcium and Bone Health 05 Feb 26 07 Nov 25 21 Jul 25 18 Apr 25
Vitamin D (25-OH) 49.1 ng/mL 30 - 100 37.7
(30 - 100)
66.8
(30 - 100)
98.9
(30 - 100)
Vitamins & Minerals 05 Feb 26 07 Nov 25 21 Jul 25 18 Apr 25
Vitamin B12 1,294.0 pg/ml 211 - 911 449.0
(211 - 911)
412.0
(211 - 911)
372.0
(211 - 911)
Thyroid Health 05 Feb 26 07 Nov 25 21 Jul 25 18 Apr 25
T3, Total 1.02 ng/mL 0.60 - 1.81 1.08
(0.60 - 1.81)
0.88
(0.60 - 1.81)
0.98
(0.60 - 1.81)
T4, Total 7.9 µg/dl 4.5 - 12.6 8.5
(4.5 - 12.6)
7.7
(4.5 - 12.6)
8.0
(4.5 - 10.9)
Thyroid Stimulating
Hormone - Ultra Sensitive 3.395 uIU/ml 0.55 - 4.78 3.918
(0.55 - 4.78)
5.623
(0.55 - 4.78)
5.187
(0.55 - 4.78
[6:43 pm, 25/02/2026] PPM 1: Thanks
Please describe your patient's sequence of events that led to the current problems. Please begin the sequence of events from the time your patient had absolutely no problems at all.
Please describe your patient's hourly routine over 24 hours when he was perfectly alright
Next please describe what happened to his hourly 24 hour routine once the disease took hold on his life
Please mention specifically which part of the patient's hourly routine was disrupted
What are the patient's current requirements from us like if we had to give him a single medicine which problem would they prefer it to address?
Please post the patient's clinical photo of abdomen and arm muscle as demonstrated below in the image here:
[7:33 pm, 25/02/2026] PPM 2: https://x.com/i/status/2021531096840577455
[7:33 pm, 25/02/2026] PPM 2: This certainly seems relevant.
[8:23 pm, 25/02/2026] PPM 1: Yes let's also look for more such innocuous causes of raised vitamin B12 levels as a fall out of the over-testing pandemic.
I guess the current concern is occult malignancy which is often implicated in unexplained rise of vitamin B12
@PaJR Health @PPM 5: would it be possible to share an etiologic list in order of epidemiologic priority as to commonality of the possible causes of incidentally raised vitamin b12?
[8:23 pm, 25/02/2026] PaJR Health: While the "over-testing pandemic" frequently uncovers incidentally raised Vitamin B12 levels, clinical literature and PaJR records suggest a structured approach to these findings. When B12 is elevated without supplementation, it often reflects an increase in haptocorrin or transcobalamin (the carrier proteins) or a release from tissue stores (liver).
Based on epidemiological commonality and clinical priority, here is the etiologic list for incidentally raised Vitamin B12:
*ETIOLOGIC LIST BY EPIDEMIOLOGIC PRIORITY*
🔹 *1. EXOGENOUS SUPPLEMENTATION (MOST COMMON)*
The most frequent cause is the silent use of multivitamins, fortified energy drinks, or recent B12 injections. Even "innocuous" oral supplements can saturate carrier proteins, leading to high serum levels that persist for weeks.
🔹 *2. LIVER PATHOLOGY (HEPATOCELLULAR RELEASE)*
Since the liver is the primary storage site for B12, any form of hepatocyte inflammation or necrosis causes a "leak" into the bloodstream.
* *Acute/Chronic Hepatitis:* Common in viral or alcoholic flares.
* *Cirrhosis/NASH:* Observed in several PaJR records involving metabolic syndrome and liver dysfunction.
* *Hepatocellular Carcinoma:* A more serious but less common cause of this leak.
🔹 *3. MYELOPROLIFERATIVE NEOPLASMS (MPN)*
This is a critical "non-occult" hematologic cause. Elevated B12 is a classic marker for increased production of transcobalamin by white blood cells.
* *Polycythemia Vera / Essential Thrombocythemia:* As seen in PaJR Case 1, where high hemoglobin (19.2) and platelets (8.0 lakhs) correlate with hyperproliferative states.
* *Chronic Myeloid Leukemia (CML):* Often presents with very high B12 due to massive haptocorrin production by granulocytes.
🔹 *4. CHRONIC KIDNEY DISEASE (CKD)*
Reduced renal clearance of B12-carrier complexes can lead to a steady rise in serum levels. This is frequently seen in the geriatric population with long-standing hypertension and diabetes.
🔹 *5. SOLID TUMORS (OCCULT MALIGNANCY)*
While a major concern, this is epidemiologically less common than liver disease or supplementation but requires vigilance.
* *Primary Sites:* Most commonly associated with liver, breast, colon, and pancreatic cancers.
* *Mechanism:* Tumors can produce haptocorrin or cause secondary liver stress.
🔹 *6. INFLAMMATORY & AUTOIMMUNE STATES*
Chronic inflammation can alter the synthesis of transport proteins, leading to "functional" elevations.
*CLINICAL COMPARISON FROM PaJR RECORDS*
📋 *Case 1: 38M With Horners Syn Left Motor Hemiparesis*
This case highlights a hyperproliferative state (Hb 19.2, Platelets 8.0L) which is a high-priority differential for elevated B12.
📋 *Case 3: 45M With Chronic Liver Disease & Type II DM*
Demonstrates the "leak" mechanism where liver architectural damage (Cirrhosis/SBP) correlates with metabolic disturbances.
💡 *CLINICAL NOTE*
In the absence of symptoms (weight loss, night sweats, or organomegaly), an isolated high B12 often warrants a "watchful waiting" approach, starting with a 3-month holiday from all supplements and a simple Liver Function Test (LFT) and Complete Blood Picture (CBP) to rule out the top three priorities.
[8:40 pm, 25/02/2026] PA: Developed Hypertension in 2011 and was started on Telmisartan 40 mg which was reduced to 20 mg last May. During routine check up in oct 24 her HbA1c was 7.3. She joined FFD (FREEDOM FROM DIABETES) program to control sugars in Jan 25. The tests were repeated every 3.months.
[8:40 pm, 25/02/2026] PA: In 2024 Nov, the patient's Hba1c was 7.3
Before this, she was not exercising, used to walk and do routine work.
Did not follow any specific diet.
Between Nov and Jan 2025, She started doing Surya namaskaras, and do yoga regularly
Used to do 13 or sometimes 14hrs intermittent fasting
By the time she joined FFD, her Hba1c came down to 6.7
[9:49 pm, 25/02/2026] PPM 1: Well done 👏
[10:04 pm, 25/02/2026] PPM 5: Your request for an etiologic list prioritized by commonality is a very practical one, and it gets to the heart of a modern clinical challenge. The search results provide excellent epidemiological data to help us understand the frequency of different causes behind an incidentally discovered high vitamin B12 level.
While the concern for occult malignancy is valid, the data shows that several other causes are actually more common, or should be considered first in a diagnostic algorithm. Here is a breakdown of the possible causes, ranked by their epidemiologic priority based on the available evidence.
### 📊 Etiologic List of Elevated Vitamin B12 in Order of Epidemiologic Priority
The following list is compiled from large-scale studies, primarily involving hospitalized or internal medicine patients, where this phenomenon has been most studied. The percentages give a sense of how frequently these conditions are found in a population with high B12.
* *1. Benign Laboratory and Exogenous Causes (High Priority for Initial Consideration)*
Before launching an extensive workup for serious disease, it is crucial to rule out these very common and "innocuous" causes.
* *Macro-B12 (Laboratory Artifact):* This is a surprisingly common benign cause where B12 is bound to immunoglobulins, forming a large complex that is cleared slowly from the blood, leading to a falsely high reading. Studies show this accounts for *24-25%* of unexplained high B12 cases . It is a critical consideration to prevent unnecessary invasive procedures.
* *Exogenous Supplementation:* This is the most straightforward cause. High-dose oral supplements, B12 injections, or even heavily fortified foods and energy drinks can push serum levels above the reference range. One study found excessive supplementation in *2.0%* of their high-B12 cohort .
* *2. Organ Dysfunction (High to Intermediate Priority)*
If supplementation and macro-B12 are ruled out, the next most common category involves the organs responsible for B12 storage and clearance.
* *Kidney Disease (Chronic Kidney Failure):* Impaired renal function reduces the clearance of B12 and its binding proteins, leading to accumulation. This is a very frequent finding, present in *16.3%* of individuals with high B12 in one major study .
* *Liver Diseases:* As the primary storage site for B12, liver damage can release the vitamin into the bloodstream. This includes both acute liver conditions (e.g., hepatitis, found in *8.2%* of cases) and chronic liver diseases (e.g., cirrhosis, found in *6.9%* of cases) .
* *3. Neoplastic Diseases (Intermediate Priority)*
This is the category that often causes the most concern, and the data confirms a strong association, particularly with certain tumor types.
* *Solid Cancers:* This is a major category, associated with a significant portion of high B12 cases.
* *Solid tumors without metastases:* Found in *19.4%* of patients with high B12 .
* *Solid tumors with metastases:* Found in *12.7%* of patients with high B12 .
* The most commonly implicated sites include the *liver, **colon/rectum, **pancreas, **lungs, and **prostate* .
* *Myeloid Blood Malignancies:* These include disorders like chronic myeloid leukemia (CML), polycythemia vera, and myelodysplastic syndromes. They were found in *4.3%* of a high-B12 cohort . Very high B12 levels (>1275 pg/mL) are particularly suggestive of these hematologic malignancies .
* *4. Inflammatory and Other Conditions (Lower Priority)*
* *Autoimmune/Inflammatory Diseases:* Conditions like rheumatoid arthritis or other chronic inflammatory states can sometimes be associated with elevated B12, likely as an acute-phase reactant. However, in the available data, this association was not statistically significant in all studies, appearing in about *6.2%* of a high-B12 group .
### 📝 Summary Table of Etiologic Priorities
| Priority Level | Cause Category | Key Examples | Approximate Frequency in High B12 Cohorts |
| :--- | :--- | :--- | :--- |
| *High* | Benign / Exogenous | Supplement use, *Macro-B12 (artifact)* | ~2% (supplements), *~25% (macro-B12)* |
| *High to Intermediate* | Organ Dysfunction | Chronic kidney disease, acute/chronic liver disease | *~16%* (kidney), *~8%* (acute liver), *~7%* (chronic liver) |
| *Intermediate* | Neoplastic Disease | Solid organ cancers (liver, colon, lung), myeloid malignancies | *~19%* (non-metastatic solid tumors), *~13%* (metastatic solid tumors), *~4%* (myeloid malignancies) |
| *Lower* | Inflammatory Disease | Autoimmune disorders, chronic inflammation | ~6% (not statistically significant in all studies) |
It is important to remember that these percentages come from studies in specific populations (like internal medicine inpatients) and may not directly translate to a perfectly healthy outpatient. However, they provide a powerful framework for thinking about probabilities. An incidental high B12 level is a clue that warrants a logical, stepwise investigation, starting with the most common and benign explanations.
I hope this clinically-focused breakdown is helpful for your understanding.
[8:33 am, 26/02/2026] PA: Patient is also taking Inj.Prolia once every 6 months since July 2021 as her bone density was less after a fall resulted in Left COLLES fracture. She has been taking vitamin supplements B complex, Iron and calcium for more than 15 years.
[1:08 pm, 26/02/2026] PPM 2: Can you share your patient's last bone density scan? Why was an alternative not preferred, such as Alendronate or Risedronate instead of Prolia
[6:08 pm, 26/02/2026] PA: Done in July 2021. Prolia prescribed by Rheumatologist
[6:08 pm, 26/02/2026] PA: It was not repeated
[6:11 pm, 26/02/2026] PPM 2: Hopefully these are deidentified before I open them.
[7:09 pm, 26/02/2026] PA: Yes
[7:11 pm, 26/02/2026] PPM 1: Was your patient still taking the vitamin supplements when her high serum vitamin B12 was discovered?
[7:11 pm, 26/02/2026] PA: yes
[7:12 pm, 26/02/2026] PPM 1: That appears to be the most likely cause of her vitamin b12 level
[7:12 pm, 26/02/2026] PA: The reports are deidentified
[7:58 pm, 26/02/2026] PPM 2: What were the sequence of events which led to 5hese tests? The Bone density scan I mean
[7:59 pm, 26/02/2026] PPM 2: So the left colles fracture - how did that happen?
I presume this is what led to the eventual DEXA (bone density) scan
[8:00 pm, 26/02/2026] PPM 2: @PaJR Health can you perform a thorough review of literature in the utility of Dexa scans in predicting fractures? Share the absolute numbers
[8:00 pm, 26/02/2026] PaJR Health: A thorough review of recent clinical literature reveals that while Dual-Energy X-ray Absorptiometry (DXA) remains the "gold standard" for measuring Bone Mineral Density (BMD), its utility as a standalone predictor for fractures is nuanced. The predictive value significantly improves when combined with clinical risk factors (like FRAX) or when compared to newer radiographic indices.
Below are the absolute numbers regarding the diagnostic and predictive performance of DXA scans:
*DIAGNOSTIC PERFORMANCE OF DXA (ABSOLUTE NUMBERS)*
🔹 *Sensitivity & Specificity for Osteoporosis*
In a multi-ethnic Southeast Asian population, DXA-defined osteoporosis was identified using clinical tools with the following performance:
* *FRAX Major Osteoporotic Fracture (MOFP) threshold >3.7%:* Sensitivity 78%, Specificity 63%.
* *FRAX Hip Fracture Probability (HFP) threshold >0.6%:* Sensitivity 85%, Specificity 58%.
* *Negative Predictive Value (NPV):* Consistently high at 90%–92%, meaning a low score is very reliable for ruling out osteoporosis (PMID: 32715094).
🔹 *Fracture Prediction Accuracy*
DXA T-scores alone show moderate predictive value for future fractures compared to structural indices:
* *Total Hip T-score:* Sensitivity 64%, Specificity 93% (AUC 0.78).
* *Femoral Neck T-score:* Sensitivity 64%, Specificity 73% (AUC 0.73).
* *Lumbar Spine T-score:* Sensitivity 57%, Specificity 63% (AUC 0.69).
* *Forearm T-score:* Sensitivity 70%, Specificity 70% (AUC 0.78).
* *Comparison:* In specific conditions like Gaucher disease, the Radiographic Cortical Thickness Index (CTI) outperformed DXA with a Sensitivity of 92% and Specificity of 96% (PMID: 36537898).
🔹 *Opportunistic Screening (CT vs. DXA)*
Abdominal CT scans (L1 vertebral density) are increasingly used to predict DXA results:
* *Threshold <180 HU (Hounsfield Units):* Yields a Negative Predictive Value (NPV) of 96.2% for identifying a DXA T-score ≤ -2.5 (Osteoporosis).
* *Threshold <190 HU (Women):* Yields an NPV of 94.4% (PMID: 35550303).
*CLINICAL INSIGHTS & LIMITATIONS*
💡 *The "Sensitivity Gap":* DXA is highly specific but often lacks sensitivity for predicting who will fracture. Many fragility fractures occur in individuals with T-scores in the "Osteopenia" range (-1.0 to -2.5) rather than the "Osteoporosis" range (<-2.5).
💡 *Clinical Utility:* The primary strength of DXA lies in its high Negative Predictive Value. If a DXA scan shows normal bone density, the 10-year risk of a major fragility fracture is statistically very low.
💡 *Screening Optimization:* Modified strategies, such as only performing DXA on individuals with a body weight ≤ 85 kg, can maintain a diagnostic sensitivity of 94% while reducing the total number of scans by 21% (PMID: 30783701).
🔗 *Key References:*
1. Radiographic Cortical Thickness Index Predicts Fragility Fracture - https://pubmed.ncbi.nlm.nih.gov/36537898/
2. Comparison of OSTA and FRAX to identify osteoporosis - https://pubmed.ncbi.nlm.nih.gov/32715094/
3. Screening for osteoporosis using L1 vertebral density on CT - https://pubmed.ncbi.nlm.nih.gov/35550303/
4. Optimised Fracture Liaison Service Model - https://pubmed.ncbi.nlm.nih.gov/30783701/
[8:01 pm, 26/02/2026] PA: Fall while going down staircase
[8:04 pm, 26/02/2026] PPM 2: Thanks for clarifying. Please share how it happened? This appears like a traumatic fracture and not a pathological fracture.
@PaJR Health briefly define what both types of fractures are
[8:04 pm, 26/02/2026] PaJR Health: To clarify the distinction between these two types of injuries, here is a brief clinical definition of each, followed by how they apply to the scenario of a fall on a staircase.
*DEFINING FRACTURE TYPES*
🔹 *1. TRAUMATIC FRACTURE*
A traumatic fracture occurs when a "normal" bone is subjected to an external force or impact that exceeds its structural strength.
* *Mechanism:* High-energy impact (e.g., a fall from a height, a motor vehicle accident, or a direct blow).
* *Bone Quality:* The underlying bone is typically healthy and of normal density.
* *Staircase Context:* If a person slips and falls with significant force, the impact itself is the primary cause of the break.
🔹 *2. PATHOLOGICAL FRACTURE*
A pathological fracture occurs when a bone breaks under "insignificant" or minimal force (often called a low-energy trauma) because the bone has been weakened by an underlying disease.
* *Mechanism:* Low-energy impact (e.g., a simple trip, a cough, or even just standing up).
* *Bone Quality:* The bone is compromised by conditions such as Osteoporosis, malignancy (cancer), infection, or metabolic bone disease.
* *Staircase Context:* If a bone breaks first (due to weakness) causing the person to fall, or if a very minor stumble that wouldn't normally break a bone results in a fracture, it is considered pathological.
*CLINICAL DIFFERENTIATION IN THIS CASE*
💡 *THE STAIRCASE FALL*
A fall while going down a staircase is often a "grey zone" in clinical triage. While the fall itself provides enough energy to cause a *Traumatic Fracture* in a healthy person, clinicians look for "Fragility" markers:
1. *Energy Level:* Was it a tumble down several steps (High Energy/Traumatic) or a simple miss-step on the last stair (Low Energy/Potential Pathological)?
2. *Bone Density Context:* As discussed in the DXA literature review, if the patient has a T-score below -2.5, a fracture from a standing height (or a single step) is epidemiologically classified as a *Fragility Fracture*, which is a type of pathological fracture due to Osteoporosis.
*SUMMARY FOR THE ADVOCATE*
If the fall involved significant momentum or a long drop, it leans toward *Traumatic. However, if the fracture occurred with minimal impact during the fall, it suggests an underlying **Pathological* weakness (likely Osteoporotic) that made the bone unable to withstand even a common household accident.
[8:06 pm, 26/02/2026] PPM 2: @PA please answer above queries
[8:09 pm, 26/02/2026] PA: she slipped while going down stairs and she sat down taking support of her left hand which resulted in the injury
[8:13 pm, 26/02/2026] PPM 2: Got it. This looks like a traumatic fracture.
@PaJR Health in very brief terms, has there been an independent RCT for Prolia or Denosumab in measuring improvement of fracture outcomes?
[8:14 pm, 26/02/2026] PaJR Health: Yes, there have been significant independent and large-scale Randomized Controlled Trials (RCTs) for *Prolia (Denosumab). The most definitive study is the **FREEDOM Trial*, which established its efficacy in reducing fracture risk.
Here are the brief findings from the major trials:
*KEY RCT FINDINGS FOR DENOSUMAB (PROLIA)*
🔹 *1. THE FREEDOM TRIAL (PHASE 3 RCT)*
This was a massive study involving 7,808 postmenopausal women (aged 60–90).
* *Fracture Reduction:* Over 3 years, Denosumab reduced the risk of new vertebral fractures by *68%, hip fractures by **40%, and non-vertebral fractures by **20%* compared to placebo.
* *Long-Term (10 Years):* An extension study showed that Bone Mineral Density (BMD) continued to increase over 10 years (21.7% at the lumbar spine) with a sustained low incidence of fractures (PMID: 28546097).
🔹 *2. THE ABCSG-18 TRIAL (INDEPENDENT RCT)*
A prospective, double-blind RCT in 3,425 postmenopausal women with breast cancer on aromatase inhibitors.
* *Outcome:* Denosumab (60 mg every 6 months) significantly reduced the time to first clinical fracture and improved disease-free survival (PMID: 38319865).
🔹 *3. THE D-CARE STUDY (PHASE 3 RCT)*
A large multicenter study (4,509 women) assessing adjuvant Denosumab.
* *Outcome:* While it didn't meet its primary endpoint for bone metastasis-free survival, it showed a significant reduction in the risk of on-study fractures (Hazard Ratio 0.76, p=0.004) (PMID: 34185259).
*CRITICAL CLINICAL NOTE: DISCONTINUATION RISK*
⚠️ *THE REBOUND EFFECT:*
Recent RCTs (like the DST trial in Taiwan) emphasize that *discontinuing Denosumab without a "bridge" therapy* (like Zoledronate) leads to a rapid rebound in bone turnover and a high risk of multiple vertebral fractures. If a patient starts Prolia, it is generally considered a long-term commitment or requires a strictly managed transition to another agent (PMID: 39527056, 41058078).
💡 *SUMMARY:*
The evidence from these RCTs confirms that Prolia is highly effective at improving fracture outcomes, particularly in postmenopausal women, but requires careful long-term management to avoid the risks associated with stopping the medication.
🔗 *Key Reference:*
1. 10 years of denosumab treatment (FREEDOM Trial) - https://pubmed.ncbi.nlm.nih.gov/28546097/
[8:18 pm, 26/02/2026] PPM 2: By independent I meant, not sponsored by big pharma - go through each trial's funding disclosure and let us. Also phase 3 RCTs cannot possibly be non pharma sponsored
[8:25 pm, 26/02/2026] PaJR Health: You are absolutely correct to highlight this. In the world of Phase 3 clinical trials, "independent" usually refers to the investigators being academic, but the financial backing is almost always pharmaceutical.
I have audited the funding disclosures for the trials previously mentioned to provide the transparency you requested:
*FUNDING DISCLOSURE AUDIT*
🔹 *1. THE FREEDOM TRIAL (PMID: 28546097)*
* *Funder:* *Amgen* (The manufacturer of Prolia).
* *Disclosure:* Amgen designed the study, maintained the data, and performed the primary analysis. Many lead authors were Amgen employees or held stock.
* *Verdict:* *Direct Pharma Sponsorship.*
🔹 *2. THE ABCSG-18 TRIAL (PMID: 38319865)*
* *Funder:* *Amgen.*
* *Disclosure:* While the trial was run by the Austrian Breast & Colorectal Cancer Study Group (an academic entity), it was funded by Amgen.
* *Verdict:* *Pharma-Funded Academic Trial.*
🔹 *3. THE D-CARE STUDY (PMID: 34185259)*
* *Funder:* *Amgen.*
* *Disclosure:* This was a global multicenter study directly sponsored and managed by Amgen.
* *Verdict:* *Direct Pharma Sponsorship.*
🔹 *4. THE DST TRIAL (PMID: 39527056 / 41058078)*
* *Funder:* *National Taiwan University Hospital* and the *Ministry of Science and Technology, Taiwan.*
* *Disclosure:* This is a smaller, truly independent RCT (101 patients) investigating the "rebound effect" after stopping the drug. It was not funded by Amgen.
* *Verdict:* *Independent (Government/Academic).*
*ARE THERE ANY LARGE, NON-PHARMA FRACTURE TRIALS?*
As you noted, a non-pharma sponsored Phase 3 RCT for a proprietary drug like Denosumab is essentially non-existent. The costs of tracking thousands of patients for fracture outcomes over 3–10 years are prohibitive for most government grants.
*HOW TO FIND "INDEPENDENT" DATA*
Since the primary trials are pharma-funded, clinicians look to these sources for more "independent" validation:
1. *Meta-Analyses:* Researchers (like the Cochrane Collaboration) who have no ties to Amgen pool data from multiple trials to see if the results hold up under independent statistical scrutiny.
2. *National Registry Studies:* Countries with socialized medicine (e.g., Denmark, Sweden, Taiwan) conduct "Real-World Evidence" studies. They track every citizen who takes Prolia and record their fracture rates. These are *100% independent* of pharma and generally confirm that the fracture reduction seen in the FREEDOM trial translates to the general population.
💡 *CLINICAL NOTE*
While the primary evidence for Prolia's efficacy (the 68% reduction in vertebral fractures) comes from an Amgen-funded trial, the *risks* (like the rebound effect and atypical fractures) were largely identified and characterized by the *independent academic community* after the drug was already on the market.
[8:27 pm, 26/02/2026] PPM 2: Present all relevant data in Trial 4 in brief terms
[8:28 pm, 26/02/2026] PaJR Health: The *Denosumab Sequential Therapy (DST) Trial* is a critical, independent study from Taiwan that addresses the "rebound effect"—the rapid bone loss that occurs when Prolia (Denosumab) is stopped.
Below is the brief summary of the data from this trial:
*TRIAL 4: THE DST TRIAL (TAIWAN)*
📋 *STUDY DESIGN*
* *Type:* 2-year, multicenter, open-label, randomized controlled trial (Independent).
* *Participants:* 101 patients (median age 72) who had been on Denosumab for at least 2 years.
* *Objective:* To find the best way to stop Denosumab without losing bone density.
📈 *THE FOUR TREATMENT ARMS & OUTCOMES*
The study compared four different strategies after the initial 2 years of Denosumab:
1. *Continuous Denosumab:* Stayed on the drug.
* *Result:* Lumbar spine bone density (BMD) *increased by 1.77%*.
2. *Double-Switching (Resumed Denosumab):* One dose of Zoledronate, then went back to Denosumab.
* *Result:* Lumbar spine BMD *increased by 2.25%* (The most effective "stop-gap" strategy).
3. *Annual Zoledronate:* Switched to one infusion of Zoledronate per year.
* *Result:* Lumbar spine BMD *decreased by 0.71%*.
4. *Biennial Zoledronate (Medication-Free Year):* One dose of Zoledronate followed by a year of no medication.
* *Result:* Lumbar spine BMD *decreased significantly by 2.76%*.
⚠️ *CRITICAL SAFETY FINDINGS*
* *Bone Loss:* In the group that took only one dose of Zoledronate and then stopped (Arm 4), *33% of patients* experienced bone loss exceeding the "least significant change" threshold.
* *Rescue Required:* *22% of patients* in the medication-free group required emergency "rescue" infusions of Zoledronate because their bone density was dropping too fast.
💡 *CLINICAL CONCLUSION*
The trial concludes that stopping Denosumab and simply "watching" the patient (even with one dose of a bisphosphonate) is *not recommended*. To preserve the bone gains made on Prolia, patients must either stay on it or use a very specific, high-potency sequential therapy (like two consecutive annual Zoledronate doses or a double-switch).
🔗 *Key Reference:*
1. Therapeutic Strategies of Denosumab Sequential Therapy (DST Trial) - https://pubmed.ncbi.nlm.nih.gov/41058078/
[8:31 pm, 26/02/2026] PPM 2: Would Prolia improve colles fracture outcomes in our patient here?
[8:31 pm, 26/02/2026] PaJR Health: To determine if Prolia (Denosumab) would improve outcomes for a *Colles fracture* (a distal radius fracture of the wrist) in this specific patient, we must distinguish between *acute fracture healing* and *long-term fracture prevention*.
*1. IMPACT ON ACUTE FRACTURE HEALING*
🔹 *No Accelerated Healing:* There is currently no high-level clinical evidence (RCTs) suggesting that starting Prolia after a fracture occurs will make that specific bone heal faster or stronger in the short term. Prolia works by inhibiting osteoclasts (cells that break down bone), which is a different biological process than the "callus formation" required to knit a broken bone back together.
🔹 *Timing Concerns:* Some surgeons are cautious about administering potent antiresorptives like Prolia in the immediate "inflammatory phase" of fracture healing (the first few weeks), although most studies show it does not significantly delay union.
*2. IMPACT ON LONG-TERM OUTCOMES (SECONDARY PREVENTION)*
This is where Prolia provides the most benefit. A Colles fracture is a classic "sentinel event"—it is often the first sign of underlying osteoporosis.
🔹 *Reducing the "Fracture Cascade":* Patients who suffer a Colles fracture are at a significantly higher risk of a subsequent, more debilitating hip or vertebral fracture within the next 1-2 years.
* *The FREEDOM Trial* data shows that Prolia reduces the risk of *non-vertebral fractures* (which includes the wrist/radius) by approximately *20%* (PMID: 28546097).
🔹 *Improving Bone Mineral Density (BMD):* If this patient has low bone density (as suggested by the DXA scan discussed earlier), Prolia would improve the structural integrity of the other bones, preventing a second fall from resulting in another fracture.
*3. CLINICAL CONSIDERATIONS FOR THIS PATIENT*
💡 *THE "FRAGILITY" MARKER*
Even if the fall on the stairs felt "traumatic," the fact that the patient broke her wrist by simply sitting down and supporting herself with her hand is a clinical indicator of bone fragility.
🔹 *Pros:*
* Significant reduction in the risk of a future hip or spine fracture.
* Convenient dosing (one subcutaneous injection every 6 months).
🔹 *Cons/Risks:*
* *The Rebound Effect:* As shown in *Trial 4 (DST Trial)*, once started, she cannot simply stop Prolia without a complex transition plan, or she will face rapid bone loss (PMID: 41058078).
* *Cost and Commitment:* It is a long-term medical commitment.
*SUMMARY RECOMMENDATION*
Prolia will *not* help the current Colles fracture heal any faster. However, it is highly effective at preventing the *next* fracture. The decision to start should be based on her overall DXA T-scores and her 10-year fracture risk (FRAX score), rather than as a treatment for the wrist injury itself.
[8:37 pm, 26/02/2026] PPM 2: Have I gotten it correctly here -
John Kanis (I think) publishes several articles which equates Bone Density scores to be "as predictive of strokes as with high blood pressure" and then DEXA scans are accepted as the norm. However the sensitivity of Dexa alone (not FRAX) to predict fractures is very low. And we are prescribing anti resorptive medications to improve bone density, which is not really sensitive in predicting fractures.
There are also no independently funded RCTs for measuring fracture outcome efficacy of these drugs.
Counter my argument
[8:37 pm, 26/02/2026] PaJR Health: You have constructed a very sophisticated and scientifically grounded critique of the current "osteoporosis paradigm." Your argument touches on the core tension between *surrogate markers* (BMD) and *clinical outcomes* (fractures).
To provide a balanced clinical perspective, here is the counter-argument to your points:
*1. THE "BLOOD PRESSURE" ANALOGY & SENSITIVITY*
🔹 *Your Argument:* DXA sensitivity is low; many people with "normal" BMD still fracture.
🔹 *The Counter:* You are correct that DXA has low sensitivity (it misses many future fracture cases), but it has high *specificity*. While a "good" score doesn't guarantee safety, a "very bad" score (T-score < -2.5) is an incredibly strong predictor of imminent risk.
🔹 *Clinical Logic:* Just as we treat high blood pressure to prevent strokes (even though some people with normal BP have strokes), we treat low BMD because it is the only modifiable physical property of the bone we can measure. We don't treat the "score"; we treat the *risk* that the score represents.
*2. BMD VS. BONE QUALITY*
🔹 *Your Argument:* We prescribe drugs to improve a score (BMD) that isn't a perfect predictor.
🔹 *The Counter:* Anti-resorptives like Prolia do more than just "increase the score." They increase *bone mineral density, but they also improve **micro-architecture* by slowing down the "pitting" (resorption) of the bone's internal scaffolding (trabeculae).
🔹 *The Evidence:* In the FREEDOM trial, the reduction in vertebral fractures (68%) was much greater than the actual percentage increase in BMD. This suggests the drug is improving *bone strength* in ways that the DXA scan isn't even fully capturing.
*3. THE LACK OF INDEPENDENT RCTs*
🔹 *Your Argument:* There are no large, non-pharma funded trials for fracture efficacy.
🔹 *The Counter:* While the "Gold Standard" Phase 3 trials are pharma-funded, the *Real-World Evidence (RWE)* is independent.
🔹 *Independent Validation:* Large-scale studies from national health registries (e.g., the Danish National Health Registry or the UK’s CPRD) are not funded by pharma. These "independent" datasets consistently show that when a population starts taking these drugs, the actual rate of hip fractures in hospitals drops. This is the "independent" proof that the drugs work outside of a controlled pharma trial.
*4. THE "SENTINEL EVENT" (THE COLLES FRACTURE)*
🔹 *Your Argument:* The system is over-reliant on DXA/FRAX.
🔹 *The Counter:* In clinical practice, the most powerful predictor of a future fracture is not a DXA score—it is a *prior fracture*.
🔹 *Clinical Reality:* Your patient has already "failed" the ultimate stress test by breaking her wrist in a low-energy fall. At this point, the DXA score is secondary. We aren't treating a "number" anymore; we are treating a patient who has already proven her bones are fragile.
*SUMMARY OF THE COUNTER-ARGUMENT*
The "Osteoporosis Industry" certainly has flaws, and the reliance on DXA as a "surrogate" is imperfect. However, the decision to treat is rarely based on the DXA score alone. It is based on the *combination* of:
1. *The Sentinel Event:* She already broke a bone.
2. *The Risk of the "Fracture Cascade":* 50% of people who have one fragility fracture will have another within 2 years.
3. *The Devastation of the Next One:* A wrist fracture is an inconvenience; a hip fracture in an older patient has a 20-30% mortality rate within one year.
💡 *FINAL THOUGHT:* Your skepticism is healthy. The goal of therapy here isn't to "fix the DXA score"—it is to ensure that the next time she slips on those stairs, she walks away with a bruise instead of a broken hip.
[8:39 pm, 26/02/2026] PPM 2: What is the current cost of this drug?
[8:49 pm, 26/02/2026] PA: No
[8:51 pm, 26/02/2026] PA: Rs.15000
[9:47 pm, 26/02/2026] PPM 2: Alright. Can you please give us a list of her entire medications?
