Causes of cold or photopenic defects on bone scans

What are the causes of cold or photopenic defects on bone scans?

Cold defects or photopenic defects on bone scans represent areas of decreased radiotracer uptake compared to surrounding normal bone tissue. These defects occur when there is impaired delivery of technetium-99m-labeled bone scanning agents to specific areas or when there is reduced osteoblastic activity. Understanding their causes is crucial for accurate interpretation and appropriate clinical management.

Primary Mechanisms of Cold Defects

The fundamental mechanisms underlying cold defects on bone scans include:

• Vascular compromise leading to decreased blood flow and reduced tracer delivery^[1][2][3]
• Disrupted bone metabolism with suppressed osteoblastic activity^[4][5]
• Compression of microcirculation by pathological processes^[2][6]
• Direct bone tissue death without subsequent repair mechanisms^[3][7]

• There are numerous benign and malignant causes for photopenic regions on a bone scan.
• Bones with avascular necrosis or infarction in the early stage have photopenia.
• Lytic osseous tumors or metastases can be cold because there is an absence of osteoblastic activity.

Major Causes of Cold Defects on Bone Scintigraphy

1. Attenuation artifact due to prosthesis, pacemaker, jewelry, lead shield, barium contrast, etc.
2. Malignant bone tumors
3. Metastatic disease (particularly when lytic such as from thyroid or renal cell carcinomas)
4. Avascular necrosis or bone infarction
5. Disuse atrophy
6. Unicameral bone cyst
7. External radiation therapy
8. Early osteomyelitis

Malignant Causes

Primary and Metastatic Tumors

Lytic metastases are among the most common causes of photopenic defects, particularly from:

• Breast cancer metastases, which can appear as photopenic lesions with peripheral rim uptake^[8][9]
• Multiple myeloma causing extensive lytic destruction^[10][11]
• Renal cell carcinoma and thyroid carcinomas known for purely lytic lesions^[10]

Primary bone tumors may also present as cold defects:

• Malignant fibrous histiocytoma, especially when arising in bone infarcts^[12][13][14]
• Osteosarcomas in certain stages, particularly with central necrosis^[15]
• Neuroblastoma causing multiple cold defects throughout the skeleton^[16]

Hematological Malignancies

• Leukemia, particularly acute lymphoblastic leukemia, can cause multiple cold defects due to bone marrow replacement^[17][1]
• Myelofibrosis resulting in altered bone marrow function and decreased tracer uptake^[1]

Infection

Osteomyelitis

Cold osteomyelitis represents an uncommon but clinically significant presentation:

• Subperiosteal abscesses from underlying osteomyelitis disrupt periosteal blood supply^[6][2]
• More commonly seen in pediatric patients due to thicker, more easily elevated periosteum^[6]
• Associated with more severe infections requiring aggressive treatment^[2][6]
• Can be caused by various organisms including Group A beta-hemolytic Streptococcus^[6]

The mechanism involves compression or disruption of periosteal vessels by the abscess, leading to bone ischemia and reduced tracer delivery.^[2][6]

Vascular and Ischemic Causes

Avascular Necrosis (Osteonecrosis)

Avascular necrosis is a leading cause of cold defects, with characteristic temporal evolution:

Early stage (7-10 days): Appears as photopenic area due to lack of blood flow^[18][7][3]
Later stages: May show “doughnut sign” with central photopenia surrounded by rim of increased uptake^[7][18][3]

Common causes of avascular necrosis include:

• Trauma, particularly femoral neck fractures^[3]
• Corticosteroid therapy causing bone ischemia^[7][3]
• Sickle cell disease and other hemoglobinopathies^[10][3]
• Renal transplantation and immunosuppressive therapy^[18][3]

Bone Infarction

Bone infarcts typically present as photopenic areas, especially in acute phases:

• Acute infarction shows relative photopenia helping differentiate from malignancy^[19]
• Chronic infarcts may show normal or increased uptake during revascularization^[19]
• Can be confused with osteomyelitis or malignancy clinically^[19]

Radiation-Related Causes

Osteoradionecrosis

Radiation necrosis of bone creates cold defects through:

• Direct bone tissue damage from therapeutic radiation^[20][21]
• Vascular injury leading to compromised blood supply^[20]
• Most commonly affects the mandible but can involve ribs, clavicle, and other bones^[21]

Interestingly, the classic “photopenic defect with surrounding hypermetabolism” described for bisphosphonate-related osteonecrosis is not characteristic of osteoradionecrosis.^[20]

Traumatic Causes

Fractures

While most fractures show increased uptake, certain fracture patterns can present as cold defects:

• Acute severe fractures with significant vascular compromise^[1]
• Non-union fractures with poor healing response^[1]
• Pathological fractures through pre-existing cold lesions^[13][14]

Prosthetic and Hardware-Related Causes

• Joint prostheses and orthopedic hardware can create photopenic areas^[22][1]
• Metallic implants causing attenuation artifacts^[1]
• Post-surgical changes affecting local blood supply^[1]

Metabolic and Systemic Causes

Iron Storage Disorders

Conditions with excessive iron deposition cause characteristic patterns:

• Thalassemia major: Generalized decreased skeletal uptake with increased renal activity^[23][24]
• Hemochromatosis: Altered radiopharmaceutical distribution^[24]
• Iron interferes with bone tracer uptake mechanisms^[23][24]

Age-Related Changes

• Advanced age can cause focal cold defects due to decreased bone metabolism^[1]
• Senile osteoporosis may reduce overall scan sensitivity^[5]

Pharmacological Effects

• Corticosteroid therapy: Suppresses osteoblastic activity and can create cold areas^[25][5]
• Bisphosphonate therapy: Can alter normal bone uptake patterns^[20]

Anatomical Variants and Pitfalls

Sternal Foramina

• Sternal foramina cause photopenic defects in the lower sternum in approximately 3% of patients^[22]
• Not all patients with sternal foramina show photopenia, and not all sternal photopenia is due to foramina^[22]
• Important to exclude metastasis when detected^[22]

Diagnostic Approach and Clinical Significance

When cold defects are identified on bone scans, the differential diagnosis should be systematically approached:

1. Clinical correlation is essential, including patient history, physical examination, and other imaging studies
2. Multiple cold defects are more likely to represent systemic processes like metastatic disease or hematological malignancies^[16][17]
3. Solitary cold defects require careful evaluation to exclude malignancy^[11][12]
4. Follow-up imaging may help differentiate benign from malignant processes^[16][19]

The recognition of cold defects is clinically important because:

• They may represent the earliest sign of certain pathological processes^[3][7]
• Cold osteomyelitis requires aggressive treatment to prevent complications^[2][6]
• Malignant causes need prompt evaluation and staging^[12][11][16]
• Some conditions like avascular necrosis benefit from early intervention^[7][3]

Cold or photopenic defects on bone scans represent a diverse group of pathological processes unified by their common presentation of decreased radiotracer uptake. While less common than “hot” lesions, their recognition and appropriate interpretation are crucial for optimal patient care and management.

Bone can also be affected by radiation therapy, in which there is an overall decrease in radiotracer uptake in a focal area.

Soft tissue structures such as the breasts (or breast implants) can reduce activity observed in underlying bones such as the ribs.

Finally, there have been several reports of cold defects occurring at the site of acute osteomyelitis.

Cold or photopenic defects on bone scans refer to areas of reduced or absent radioactive tracer uptake during nuclear medicine bone scanning.

These defects can indicate various conditions affecting the bones.

It’s important to note that cold or photopenic defects on bone scans do not provide a definitive diagnosis. Additional imaging studies, laboratory tests, and clinical evaluations are usually necessary to determine the underlying cause of the abnormalities seen on the bone scan. A team of healthcare professionals, including nuclear medicine physicians, radiologists, and orthopedic specialists, will collaborate to interpret the findings and make a comprehensive diagnosis.

As with any medical imaging test, it’s essential for individuals to discuss the results and their implications with their healthcare provider to develop an appropriate treatment plan based on the underlying condition.

Any metal objects—either external, such as jewelry, or internal, such as a pacemaker or joint prosthesis—can attenuate or block emitted radiation from reaching the scan detector.

On the basis of CT morphometry of the sternum, the possible causes of photopenia in the lower sternum in patients without sternal foramen are as follows: thin middle portion of sternum bone marrow, a focal defect or notch in the posterior sternal cortex, high accumulation of peripheral lesions, and bone metastasis.

A “cold” or photopenic defect on bone scintigraphy is a well recognized phenomenon and has been described in several conditions affecting bone. An unusual case of multiple “cold” defects in a patient with stage IV neuroblastoma is presented. A follow-up scan with the patient in clinical remission shows resolution of these “cold” defects. The patient subsequently relapsed and again multiple new “cold” defects were noted on bone scintigraphy. 

As an incidental finding in an [111In]WBC scan performed in search of an infectious focus, photon deficient areas were found in several skeletal locations, characterized by bone and gallium scintigraphy and confirmed radiographically as sites of active Paget’s disease. The literature concerning cold bone defects in the [111In]WBC scintiscan is reviewed. Loss of marrow component in the bone appears to be the underlying mechanism for such an abnormality.

Sources

1. Datz FL, Thorne DA. Cause and significance of cold bone defects on indium-111-labeled leukocyte imaging. J Nucl Med. 1987;28(5):820-823.
2. Trackler RT, Miller KE, Sutherland DH, Chadwick DL. Childhood pelvic osteomyelitis presenting as a “cold” lesion on bone scan: case report. J Nucl Med. 1976;17(7):620-622.
3. Agrawal K, Tripathy SK, Sen RK, Santhosh S, Bhattacharya A. Nuclear medicine imaging in osteonecrosis of hip: old and current concepts. World J Orthop. 2017;8(10):747-753.
4. Adams C, Banks K. Bone scan. In: StatPearls. StatPearls Publishing; August 14, 2023. https://www.ncbi.nlm.nih.gov/books/NBK531486/
5. Scott SM, Manaster BJ, Alazraki N, Wooten WW, Murphy K. Technetium-99m imaging of bone trauma: reduced sensitivity caused by hydrocortisone in rabbits. AJR Am J Roentgenol. 1987;148(6):1175-1178.
6. Annen MJ, Johnston MJ, Gormley JP, Silverman E. Acute hematogenous osteomyelitis presenting as a “cold” rib in a child. World J Nucl Med. 2017;16(2):160-162.
7. Osteonecrosis. Radiopaedia.org. Updated February 14, 2025. https://radiopaedia.org/articles/osteonecrosis-2
8. Bastawrous S, Bhargava P, Behnia F, Haseley DR. Skeletal metastases and benign mimics on NaF PET/CT: a pictorial review. AJR Am J Roentgenol. 2018;211(1):W64-W74.
9. Lytic bone metastases. Radiopaedia.org. Updated December 23, 2024. https://radiopaedia.org/articles/lytic-bone-metastases-1
10. “Cold” lesions on bone imaging – PubMed. PubMed. 1975. https://pubmed.ncbi.nlm.nih.gov/1185258/
11. Diagnostic oncology case study: lytic spine lesion and cold bone scan. AJR Am J Roentgenol. 2012. https://ajronline.org/doi/10.2214/ajr.136.1.129
12. Malignant fibrous histiocytoma: etiology for a cold defect … – PubMed. PubMed. https://pubmed.ncbi.nlm.nih.gov/2161452/
13. Lapa C, Linz C, Bluemel C, et al. Infarct-associated bone sarcomas: multimodality imaging findings. AJR Am J Roentgenol. 2015;205(3):W320-W329.
14. Lapa C, Linz C, Bluemel C, et al. Infarct-associated bone sarcomas: multimodality imaging findings. AJR Am J Roentgenol. 2015;205(3):W320-W329.
15. Krishnamurthy GT, Tubis M, Hiss J, Blahd WH. The cause and clinical significance of central tumor photopenia on bone scan. AJR Am J Roentgenol. 2006;187(6):1385-1390.
16. Multiple “cold” areas demonstrated on bone scintigraphy in a patient … PubMed. https://pubmed.ncbi.nlm.nih.gov/7060292/
17. Thamake SI, Ramshanker N, Chaturbhuj DN. Differential diagnosis of reduced uptake images revealed by bone scintigraphy. Indian J Nucl Med. 2016;31(3):177-183.
18. Avascular necrosis. Radiopaedia.org. November 24, 2022. https://radiopaedia.org/cases/avascular-necrosis-10
19. Laasri K, Marrakchi S, Halfi MI, et al. Bone infarcts mimicking malignancy: avoiding misdiagnosis. J Orthop Case Rep. 2021;11(7):102-106.
20. Lapa C, Linz C, Bluemel C, et al. Three-phase bone scintigraphy for imaging osteoradionecrosis of the jaw. Clin Nucl Med. 2014;39(1):21-25.
21. Osteoradionecrosis. Radiopaedia.org. https://radiopaedia.org/articles/osteoradionecrosis
22. Yilmaz S, Cermik TF, Unsalan O, et al. Causes of photopenic defects in the lower sternum on bone scintigraphy. Clin Nucl Med. 2011;36(5):356-360.
23. Krishnan SS, Krishnan J, Balachandran K, Shanthly N. Decreased bone uptake of technetium-99m polyphosphate in thalassemia major. J Nucl Med. 1981;22(7):630-633.
24. Bone scintigraphy. Radiopaedia.org. Updated September 1, 2024. https://radiopaedia.org/articles/bone-scintigraphy-1
25. Hussain M, Mansberg R, Loh SW, et al. Technetium‑99m‑methylene diphosphonate uptake in hepatic metastases on bone scan: a case series. World J Nucl Med. 2021;20(4):369-374.
26. Nuclear medicine bone scan study identifies prevalence and outcomes cardiac amyloidosis. DI Cardiology. January 17, 2023. https://www.dicardiology.com/content/nuclear-medicine-bone-scan-study-identifies-prevalence-and-outcomes-cardiac-amyloidosis
27. Bone scan. Mayo Clinic. Updated April 2, 2024. https://www.mayoclinic.org/tests-procedures/bone-scan/about/pac-20393136
28. Boccalatte LA, Heldmann M, Shuaib W, et al. Radionuclide imaging in orthopedic infections. Semin Nucl Med. 2017;47(6):681-691.
29. Howard AD, Barron BJ, Smith GG. Skeletal scintigraphy in pediatric sports medicine. AJR Am J Roentgenol. 2012;199(5):1099-1107.
30. Liu Y, Tang GY, Tang RB, et al. Research progress in the pathogenic mechanisms and imaging of bone tumors. Eur Radiol. 2021;31(11):8517-8526.
31. Coelho PC, Pinheiro DC, Silva GF, Silveira CE. Bone scan in metabolic bone diseases. Review. Nucl Med Rev Cent East Eur. 2019;22(1):33-42.
32. Anconina J, Harvey WC, Davis MA. A pictorial review of benign causes of increased isotope uptake on bone scintigraphy. Can Assoc Radiol J. 2011;62(3):178-189.
33. Avascular necrosis (osteonecrosis) – symptoms & causes. Mayo Clinic. Updated July 28, 2025. https://www.mayoclinic.org/diseases-conditions/avascular-necrosis/symptoms-causes/syc-20369859
34. Wong KK, Piert M. Extraosseous findings on bone scintigraphy using fusion SPECT/CT. AJR Am J Roentgenol. 2015;205(1):W1-W14.
35. Zanglis A, Andreopoulos D, Zapanti E, et al. Metastatic mimics on bone scan: “All that glitters is not gold.” Hell J Nucl Med. 2004;7(2):108-116.
36. Hussain M, Mansberg R, Loh SW, et al. Technetium‑99m‑methylene diphosphonate uptake in hepatic metastases on bone scan: a case series. World J Nucl Med. 2021;20(4):369-374.
37. Cook AM, Waller S, Loken MK. Multiple “cold” areas demonstrated on bone scintigraphy in a patient with neuroblastoma. Clin Nucl Med. 1982 Jan;7(1):21-4. doi: 10.1097/00003072-198201000-00006. PMID: 7060292. https://pubmed.ncbi.nlm.nih.gov/7060292/