PET for bone imaging

(a) Coronal PET slice of lumbar spine (LS); (b) Transaxial PET-CT showing ROI (orange) capturing trabecular bone only; (c) Coronal PET of upper femur with kidney/bladder signals removed for clarity; (d) Dynamic [¹⁸F]NaF PET of LS, transaxial slice over 0–60 min post-injection.

Positron emission tomography for bone imaging, as an in vivo tracer technique, allows the measurement of the regional concentration of radioactivity proportional to the image pixel values averaged over a region of interest (ROI) in bones. Positron emission tomography is a functional imaging technique that uses [¹⁸F]NaF radiotracer to visualise and quantify regional bone metabolism and blood flow. [¹⁸F]NaF has been used for imaging bones for the last 60 years. This article focuses on the pharmacokinetics of [¹⁸F]NaF in bones, and various semi-quantitative and quantitative methods for quantifying regional bone metabolism using [¹⁸F]NaF PET images.

Use of [¹⁸F]NaF PET

The measurement of regional bone metabolism is critical to understand the pathophysiology of metabolic bone diseases.

• Bone biopsy is considered the gold standard to quantify bone turnover; however, it is invasive, complex and costly to perform and subject to significant measurement errors. ^[2]
• Measurements of serum or urine biomarkers of bone turnover are simple, cheap, quick, and non-invasive in measuring changes in bone metabolism, but only provide information on the global skeleton. ^[3]
• The functional imaging technique of dynamic [¹⁸F]NaF PET scans can quantify regional bone turnover at specific sites of clinical importance such as the lumbar spine and hip ^[4] and has been validated by comparison with the gold standard of bone biopsy. ^{[5] [6] [7]}

Pharmacokinetics of [¹⁸F]NaF

Bone remodeling is a six-stage cycle: (1) Quiescent phase with no activity; (2) Activation by osteocytes; (3) Resorption by osteoclasts; (4) Reversal phase prepares surface; (5) Formation by osteoblasts; (6) Mineralization deposits hydroxyapatite. Bone-targeting radionuclides integrate during mineralization. The cycle then returns to quiescence.

The chemically stable anion of Fluorine-18-Fluoride is a bone-seeking radiotracer in skeletal imaging. [¹⁸F]NaF has an affinity to deposit at areas where the bone is newly mineralizing. ^{[6] [9] [10] [11] [12]} Many studies have [¹⁸F]NaF PET to measure bone metabolism at the hip, ^[4] lumbar spine, and humerus. ^[13] [¹⁸F]NaF is taken-up in an exponential manner representing the equilibration of tracer with the extracellular and cellular fluid spaces with a half-life of 0.4 hours, and with kidneys with a half-life of 2.4 hours. ^[14] The single passage extraction of [¹⁸F]NaF in bone is 100%. ^[15] After an hour, only 10% of the injected activity remains in the blood. ^[16]

¹⁸F- ions are considered to occupy extracellular fluid spaces because, firstly, they equilibrate with transcellular fluid spaces and secondly, they are not entirely extracellular ions. ^{[17] [18] [19]} Fluoride undergoes equilibrium with hydrogen fluoride, which has a high permeability allowing fluoride to cross the plasma blood membrane. ^[20] The fluoride circulation in red blood cells accounts for 30%. ^[21] However, it is freely available to the bone surface for uptake because the equilibrium between erythrocytes and plasma is much faster than the capillary transit time. This is supported by studies reporting 100% single-passage extraction of whole-blood ¹⁸F- ion by bone ^[15] and the rapid release of ¹⁸F- ions from erythrocytes with a rate constant of 0.3 per second. ^[22]

[¹⁸F]NaF is also taken-up by immature erythrocytes in the bone marrow, ^[23] which plays a role in fluoride kinetics. ^[24] The plasma protein binding of [¹⁸F]NaF is negligible. ^[25] [¹⁸F]NaF renal clearance is affected by diet ^[26] and pH level, ^[27] due to its re-absorption in the nephron, which is mediated by hydrogen fluoride. ^[28] However, large differences in urine flow rate ^[21] are avoided for controlled experiments by keeping patents well hydrated. ^[23]

The exchangeable pool and the size of the metabolically active surfaces in bones determines the amount of tracer accumulated or exchanged ^[29] with bone extracellular fluid, ^[30] chemisorption onto hydroxyapatite crystals to form fluorapatite, ^{[16] [31] [11]} as shown in Equation-1: ^{[32] [33]}

${\displaystyle Ca_{10}(PO_{4})_{6}(OH)_{2}+2F-=>Ca_{10}(PO_{4})_{6}F_{2}+2.OH-}$Equation (1)

Fluoride ions from the crystalline matrix of bone are released when the bone is remodelled, thus providing a measure of the rate of bone metabolism. ^{[34] [35] [36]}

Use of [18F]NaF in PET imaging and radiation dosimetry

In the context of PET bone imaging using [18F]NaF, the estimated radiation dose to patients is approximately 4.3 millisieverts (mSv) for a typical injected activity of 250 megabecquerels (MBq). This estimate aligns with international radiation protection standards. However, the actual dose delivered to a patient depends on several variables, including how different organs absorb the tracer, the biological clearance rates, and anatomical differences such as organ size and position. These estimates are typically based on reference models of average adult males and females. It's important to note that additional radiation exposure may occur from associated imaging procedures, such as the CT scan that often accompanies PET in combined PET/CT scans. The contribution from the CT scan varies depending on the scan settings, including tube current and exposure time. Recent studies have demonstrated that lower doses of [18F]NaF, such as 90 MBq, may still provide adequate image quality, especially in targeted regions like the lumbar spine. Research is also ongoing into ways to reduce dosage even further, particularly in preclinical studies. However, radiation dosimetry is a complex field and not the primary focus here.

Imaging procedure and patient preparation

The Bone metabolic flux (Ki) can be measured using either: (a) a 60-min dynamic PET scan, or (b) a static PET scan. The static method captures one bed position in 4 minutes; two positions are used to cover L1–L4. For reliable Ki values, static scans should occur 30–60 minutes post-injection.

Before the scan, patients are advised to stay relaxed and well-hydrated to promote consistent renal clearance of the tracer. They are typically asked to empty their bladder just before imaging to reduce variability in tracer uptake. During the scan, the patient lies in a supine position so that the target region (such as the hip or spine) is fully within the scanner’s field of view. The imaging session begins with a CT scan, followed by the injection of [18F]NaF. The tracer is administered intravenously within seconds of starting the scan, followed by a saline flush. Imaging data are collected continuously, and blood samples are taken at specific time points to measure tracer concentration in both whole blood and plasma. These measurements are necessary for quantifying tracer kinetics. Blood samples are processed to separate plasma from cells, and radioactivity is measured. Accurate measurements require weighing the tubes before and after sample collection to calculate the actual volume based on fluid density. Tracer concentrations in plasma and whole blood are compared over time to adjust the estimated arterial input function (AIF), which is used in modeling how the tracer behaves in the body.

Dose correction and data accuracy

To ensure consistent analysis, all tracer concentration values—whether from imaging or blood samples—are corrected to a single reference time point, typically the time of injection. The residual tracer left in the syringe after injection is also measured and adjusted for radioactive decay to calculate the actual amount of tracer delivered to the patient. [18F]NaF does not undergo metabolism or significant protein binding, so the tracer concentration in plasma reflects the parent compound directly. This simplifies the calculation of tracer kinetics.

Image reconstruction and quantification

The PET data are processed using various frame durations to accurately capture both the early rapid changes and the later slower changes in tracer distribution. Corrections for physical factors such as scatter, random coincidences, dead time, and attenuation are applied during reconstruction. Quantitative analysis can be performed using either two-dimensional (2D) or three-dimensional (3D) image reconstruction methods. Each has strengths and limitations. 3D reconstruction generally provides better visualization due to higher sensitivity but may introduce variability in measured activity across the field of view. In contrast, 2D reconstruction offers more uniform sensitivity, which may make it more reliable for quantitative analysis. Thus, the choice of reconstruction method can impact the accuracy of tracer uptake measurements.

Measuring SUV using static PET images

Definition

Top row: Spectral analysis output on log (left) and linear (right) scales, showing frequency clusters—high, intermediate, and low—corresponding to plasma, bone ECF, and bone mineral in the Hawkins model. Bottom: IRF plotted using these frequency components.

The standardized uptake value (SUV) is defined as tissue concentration (KBq/ml) divided by activity injected normalized for body weight. ^[38]

Appropriateness

The SUV measured from the large ROI smooths out the noise and, therefore, more appropriate in [¹⁸F]NaF bone studies as the radiotracer is fairly uniformly taken up throughout the bone. The measurement of SUV is easy, ^[39] cheap, and quicker to perform, making it more attractive for clinical use. It has been used in diagnosing and assessing the efficacy of therapy. ^{[40] [41]} SUV can be measured at a single site, or the whole skeleton using a series of static scans and restricted by the small field-of-view of the PET scanner. ^[34]

Known Issues

The SUV has emerged as a clinically useful, albeit controversial, semi-quantitative tool in PET analysis. ^[42] Standardizing imaging protocols and measuring the SUV at the same time post-injection of the radiotracer, is necessary to obtain a correct SUV ^[43] because imaging before the uptake plateau introduces unpredictable errors of up to 50% with SUVs. ^[44] Noise, image resolution, and reconstruction do affect the accuracy of SUVs, but correction with phantom can minimize these differences when comparing SUVs for multi-centre clinical trials. ^{[45] [46]} SUV may lack sensitivity in measuring response to treatment as it is a simple measure of tracer uptake in bone, which is affected by the tracer uptake in other competing tissues and organs in addition to the target ROI. ^{[47] [48]}

Measuring K_i using serial/dynamic PET images

The quantification of dynamic PET studies to measure Ki requires the measurement of the skeletal time-activity curves (TAC) from the region of interest (ROI) and the arterial input function (AIF), which can be measured in various different ways. However, the most common is to correct the image-based blood time-activity curves using several venous blood samples taken at discrete time points while the patient is scanned. The calculation of rate constants or K_i requires three steps: ^[4]

• Measurement of the arterial input function (AIF), which acts as the first input to the mathematical model of tracer distribution.
• Measurement of the time-activity curve (TAC) within the skeletal region of interest, which acts as the second input to the mathematical model of tracer distribution.
• Kinetic modelling of AIF and TAC using mathematical modelling to obtain net plasma clearance (K_i) to the bone mineral.

A bone TAC is modeled as the convolution of the arterial input function with the IRF. IRF estimates are iteratively refined to minimize differences between the measured bone curve and the convolution. The green curve shows the initial IRF estimate; the blue curve is the final optimized IRF. Ki is derived from the intercept of the linear fit to the slow exponential component, where the red line crosses the y-axis, representing plasma clearance to bone mineral.

Spectral method

The method was first described by Cunningham & Jones ^[49] in 1993 for the analysis of dynamic PET data obtained in the brain. It assumes that the tissue impulse response function (IRF) can be described as a combination of many exponentials. Since A tissue TAC can be expressed as a convolution of measured arterial input function with IRF, C_bone(t) can be expressed as:

${\displaystyle C_{bone}(t)=\sum _{k=1}^{n}\alpha _{i}.{\bigl (}C_{plasma}(t)\otimes exp(-\beta _{i}.t){\bigr )}}$

where, ${\displaystyle \otimes }$ is a convolution operator, C_bone(t) is the bone tissue activity concentration of tracer (in units: MBq/ml) over a period of time t, C_plasma(t) is the plasma concentration of tracer (in units: MBq/ml) over a period of time t, IRF(t) is equal to the sum of exponentials, β values are fixed between 0.0001 sec⁻¹ and 0.1 sec⁻¹ in intervals of 0.0001, n is the number of α components that resulted from the analysis and β₁, β₂,..., β_n corresponds to the respective α₁, α₂,..., α_n components from the resulted spectrum. The values of α are then estimated from the analysis by fitting multi-exponential to the IRF. The intercept of the linear fit to the slow component of this exponential curve is considered the plasma clearance (K_i) to the bone mineral.

Deconvolution method

The method was first described by Williams et al. in the clinical context. ^[50] The method was used by numerous other studies. ^{[51] [52] [53]} This is perhaps the simplest of all the mathematical methods for the calculation of K_i but the one most sensitive to noise present in the data. A tissue TAC is modelled as a convolution of measured arterial input function with IRF, the estimates for IRF are obtained iteratively to minimise the differences between the left- and right-hand side of the following Equation:

${\displaystyle C_{bone}(t)=C_{plasma}(t)\otimes IRF(t)}$

where, ${\displaystyle \otimes }$ is a convolution operator, C_bone(t) is the bone tissue activity concentration of tracer (in units: MBq/ml) over a period of time t, C_plasma(t) is the plasma concentration of tracer (in units: MBq/ml) over a period of time t, and IRF(t) is the impulse response of the system (i.e., a tissue in this case). The K_i is obtained from the IRF in a similar fashion to that obtained for the spectral analysis, as shown in the figure.

Hawkins model

A diagrammatic view of the process of kinetic modelling using Hawkins model used to calculate the rate of bone metabolism at a skeletal site. C_p refers to the plasma concentration of the tracer, C_e refers to the tracer concentration in ECF compartment, C_b refers to the concentration of tracer in bone mineral compartment, M1 refers to mass of tracer in the C_e compartment, M2 refers to the mass of tracer in the C_b compartment, C_T is the total mass in the C_e+C_b, PVE refers to the partial volume correction, FA refers to the femoral artery, ROI refers to region of the interest, B-Exp refers to the bi-exponential, .

The measurement of Ki from dynamic PET scans require tracer kinetic modelling to obtain the model parameters describing the biological processes in bone, as described by Hawkins et al. ^[24] Since this model has two tissue compartments, it is sometimes called a two-tissue compartmental model. Various different versions of this model exist; however, the most fundamental approach is considered here with two tissue compartments and four tracer-exchange parameters. The whole kinetic modelling process using Hawkins model can be summed up in a single image as seen on the right-hand-side. The following differential equations are solved to obtain the rate constants:

${\displaystyle {\operatorname {d} \!C_{e}(t) \over \operatorname {d} \!t}=K_{1}*C_{p}(t)-(k_{2}+k_{3})*C_{e}(t)+k_{4}*C_{b}(t)}$

${\displaystyle {\operatorname {d} \!C_{b}(t) \over \operatorname {d} \!t}=k_{3}*C_{e}(t)-k_{4}*C_{b}(t)}$

The rate constant K₁ (in units: ml/min/ml) describes the unidirectional clearance of fluoride from plasma to the whole of the bone tissue, k₂ (in units: min⁻¹) describes the reverse transport of fluoride from the ECF compartment to plasma, k₃ and k₄ (in units min⁻¹) describe the forward and backward transportation of fluoride from the bone mineral compartment.

K_i represents the net plasma clearance to bone mineral only. K_i is a function of both K₁, reflecting bone blood flow, and the fraction of the tracer that undergoes specific binding to the bone mineral k₃ / (k₂ + k₃). Therefore, ${\displaystyle K_{i}=\left({\frac {K_{1}*k_{3}}{k_{2}+k_{3}}}\right)}$

Hawkins et al. found that the inclusion of an additional parameter called fractional blood volume (BV), representing the vascular tissue spaces within the ROI, improved the data fitting problem, although this improvement was not statistically significant. ^[54]

Patlak method

Patlak analysis where a linear regression is fitted between the data on y- and x-axis to obtain the estimates of the Ki, which is the slope of the fitted regression line.

Patlak method ^[55] is based on the assumption that the backflow of tracer from bone mineral to bone ECF is zero (i.e., k₄=0). The calculation of K_i using Patlak method is simpler than using non-linear regression (NLR) fitting the arterial input function and the tissue time-activity curve data to the Hawkins model. The Patlak method can only measure bone plasma clearance (K_i), and cannot measure the individual kinetic parameters, K₁, k₂, k₃, or k₄.

The concentration of tracer in tissue region-of-interest can be represented as a sum of concentration in bone ECF and the bone mineral. It can be mathematically represented as

${\displaystyle {\frac {C_{bone}(T)}{C_{plasma}(T)}}=K_{i}*{\frac {\int \limits _{0}^{T}C_{plasma}(t)dt}{C_{plasma}(T)}}+V_{o}}$

where, within the tissue region-of-interest from the PET image, C_bone(T) is the bone tissue activity concentration of tracer (in units: MBq/ml) at any time T, C_plasma(T) is the plasma concentration of tracer (in units: MBq/ml) at time T, V_o is the fraction of the ROI occupied by the ECF compartment, and ${\displaystyle \int \limits _{0}^{T}C_{plasma}(t)dt}$ is the area under the plasma curve is the net tracer delivery to the tissue region of interest (in units: MBq.Sec/ml) over time T. The Patlak equation is a linear equation of the form ${\displaystyle Y=m*X+c}$

The Patlak plot method for estimating Ki involves plotting normalized bone tracer uptake against normalized time, using data collected between 10 and 60 minutes after tracer injection. A straight line is fitted to the data, where the slope represents Ki, and the intercept (V₀) corresponds to the volume of distribution of the tracer within the bone extracellular fluid (ECF) compartment. (B) Siddique-Blake Method: It is a simplified version of the Patlak method, using a single data point typically taken around 60 minutes post-injection. The intercept (V₀) is a population-average value.

Therefore, linear regression is fitted to the data plotted on Y- and X-axis between 4–60 minutes to obtain m and c values, where m is the slope of the regression line representing K_i and c is the Y-intercept of the regression line representing V_o. ^[55]

Siddique–Blake method

The calculation of Ki using arterial input function, time-activity curve, and Hawkins model was limited to a small skeletal region covered by the narrow field-of-view of the PET scanner while acquiring a dynamic scan.

However, Siddique et al. ^[57] showed that it was possible to measure K_i values in bones using a 4-minute static [¹⁸F]NaF PET scans obtained at a single bed position. Blake et al. ^[34] later showed that the K_i obtained using the Siddique–Blake method has precision errors of less than 10%. The Siddique–Blake approach is based on the combination of the Patlak method, ^[55] the semi-population based arterial input function, ^[58] and the information that V_o does not significantly change post-treatment. This method uses the information that a linear regression line can be plotted using the data from a minimum of two time-points, to obtain m and c as explained in the Patlak method. However, if V_o is known or fixed, only one single static PET image is required to obtain the second time-point to measure m, representing the K_i value. This method should be applied with great caution to other clinical areas where these assumptions may not hold true.

A visual overview of the Excel spreadsheet illustrates how values of [18F] NaF bone metabolic flux (Ki) are calculated using 4-min static PET scan.

This method has potential for clinical translation due to its simplicity. The Siddique-Blake method requires data to be collected using a specific protocol, allowing an Excel file to be used to calculate the Ki value at any skeletal region within the PET image.

The blood sampling protocol worksheet, the Excel file required to perform these calculations, and instructions on how to use the Excel file can be downloaded from the Supplemental Section of this paper by Puri et al. ^[60]

SUV vs K_i

The most fundamental difference between SUV and K_i values is that SUV is a simple measure of uptake, which is normalized to body weight and injected activity. The SUV does not take into consideration the tracer delivery to the local region of interest from where the measurements are obtained, therefore, affected by the physiological process consuming [¹⁸F]NaF elsewhere in the body. On the other hand, K_i measures the plasma clearance to bone mineral, taking into account the tracer uptake elsewhere in the body affecting the delivery of tracer to the region of interest from where the measurements are obtained. The difference in the measurement of K_i and SUV in bone tissue using [¹⁸F]NaF are explained in more detail by Blake et al. ^[36]

It is critical to note that most of the methods for calculating K_i require dynamic PET scanning over an hour, except, the Siddique–Blake methods. Dynamic scanning is complicated and costly. However, the calculation of SUV requires a single static PET scan performed approximately 45–60 minutes post-tracer injection at any region imaged within the skeleton.

Many researchers have shown a high correlation between SUV and K_i values at various skeletal sites. ^{[61] [62] [63]} However, SUV and K_i methods can contradict for measuring response to treatment. ^[48] Since SUV has not been validated against the histomorphometry, its usefulness in bone studies measuring response to treatment and disease progression is uncertain.

An additional advantage of using the metabolic flux parameter Ki from dynamic PET imaging, rather than relying solely on standardized uptake values (SUV) from static scans, is its greater sensitivity to treatment-related changes in bone turnover. In one study, postmenopausal women with low bone mineral density at the spine or hip were treated for six months with teriparatide, a parathyroid hormone analog that stimulates bone formation. Tracer uptake in the lumbar spine was assessed both before and after treatment using two approaches: a kinetic modeling method to derive Ki, and static PET imaging to calculate SUV. The average increase in Ki was 23.8%, compared to only a 3.0% increase in SUV. This discrepancy was attributed to a decrease in plasma tracer concentration following treatment, as a greater proportion of the tracer was absorbed by cortical bone in the peripheral skeleton. Since SUV does not account for changes in tracer input function, Ki provides a more reliable measure of treatment response in such contexts. A follow-up study using similar methods found that treatment effects varied by skeletal site: after 12 weeks of teriparatide, Ki increased by 50.7% at the femoral shaft and 17.8% at the lumbar spine. These imaging results were consistent with changes observed in biochemical markers of bone turnover, which also indicated a peak treatment response around 12 weeks. As a result, it is generally recommended to perform PET imaging assessments of therapeutic efficacy no earlier than 12 weeks after initiating bone-forming treatments. ^[64]

Interpreting model parameters

^[65]

Ki

In [¹⁸F]sodium fluoride PET imaging, the parameter Ki quantifies the net influx rate of fluoride tracer from plasma into the bone mineral compartment and is widely used as a biomarker of bone turnover. It reflects the efficiency with which the tracer is delivered to bone tissue and irreversibly incorporated into the mineral phase. Mathematically, Ki is defined by the equation

A scatter plot illustrating the relationship between Ki values at the lumbar spine, obtained from [18F]NaF PET imaging and histomorphometry - the bone formation rate per unit bone surface area, determined through tetracycline-labeled bone biopsy at the iliac crest.

Ki = K₁ × k₃ / (k₂ + k₃),

where K₁ is the rate of delivery of the tracer from plasma to bone, k₂ represents the rate at which the tracer returns from bone to plasma, and k₃ corresponds to the rate of tracer binding to bone mineral. This expression captures the proportion of delivered tracer that becomes fixed in the bone matrix, providing a mechanistic representation of local skeletal metabolic activity.

The units of Ki are typically expressed as mL/min/mL, which may be interpreted as the volume of plasma cleared of tracer per minute for each milliliter of bone tissue. For instance, a Ki value of 0.01 mL/min/mL means that each milliliter of bone tissue incorporates fluoride tracer at a rate equivalent to that contained in 0.01 milliliters of plasma every minute. This gives Ki a direct physiological meaning: it measures how much tracer is being deposited in the bone over time relative to the available tracer in circulation. In practical terms, higher Ki values indicate greater bone metabolic activity, which may be due to increased bone formation, remodeling, or both.

Ki is considered more reliable than the standardized uptake value (SUV) when evaluating dynamic changes in bone turnover, particularly in response to treatment. SUV measurements are influenced by changes in systemic tracer distribution and plasma concentration, which can lead to misleading results in cases where treatment alters the overall biodistribution of the tracer. In contrast, Ki accounts for changes in plasma tracer concentration, making it more accurate for detecting true biological changes at the imaging site. This is particularly important in diseases or therapies that affect the skeleton broadly, such as metastatic bone disease, Paget's disease, or systemic osteoporosis treatments.

Clinically, Ki has been shown to increase following anabolic therapies such as teriparatide, reflecting enhanced bone formation, and to decrease with antiresorptive agents like bisphosphonates, which suppress bone turnover. Because Ki captures site-specific remodeling activity, it is valuable for monitoring regional treatment responses, assessing bone quality, and stratifying fracture risk. Its quantitative nature and strong correlation with histomorphometric bone formation rates make Ki a central parameter in the noninvasive assessment of metabolic bone diseases using PET imaging.

K1

In dynamic [¹⁸F]NaF PET imaging, the parameter K₁ quantifies the rate at which fluoride tracer is transferred from the blood plasma into the bone’s extracellular fluid space, reflecting the local blood flow to bone tissue. It is expressed in units of mL/min/mL, indicating how much plasma is cleared of tracer per minute per milliliter of bone tissue. This metric is especially important in assessing regional bone perfusion, which plays a critical role in bone metabolism and remodeling.

The relationship between K₁ and actual blood flow is defined by the equation

K₁ = E × F × (1 − PVC),

where E is the extraction efficiency of the tracer during a single capillary pass, F is the local blood flow, and PVC represents the plasma volume correction accounting for red blood cell volume. The extraction efficiency E itself is derived from the formula

E = 1 − exp(−P×S/F),

where P denotes capillary permeability to the tracer, S is the surface area of the capillary bed, and F is again the blood flow. In bone, fluoride has a high extraction efficiency due to its small molecular size and ability to rapidly diffuse into surrounding tissues, allowing K₁ to closely approximate actual blood flow in low-flow conditions.

Empirical studies have shown that K₁ values below approximately 0.16 mL/min/mL correspond well with bone blood flow values measured by [¹⁵O]H₂O PET, the gold standard for perfusion imaging. However, at higher flow rates, the limited diffusivity of fluoride leads to an underestimation of actual perfusion, as the tracer cannot fully equilibrate with the bone compartment within the short capillary transit time. Despite this limitation, measured K₁ values at metabolically active skeletal sites, such as the lumbar spine, are generally within this reliable range in both healthy individuals and those with bone diseases, supporting its utility as a biomarker for bone perfusion.

K₁ is physiologically meaningful because bone blood flow is intricately linked to bone remodeling. Adequate perfusion supports osteoblast and osteoclast function and regulates the delivery of nutrients and removal of waste products in bone tissue. With aging, reductions in bone blood supply contribute to increased bone loss and the progression of osteoporosis, particularly in trabecular-rich regions. Studies have demonstrated correlations between K₁ and calcium uptake rates, as well as new bone formation in patients with osteoporosis. Although the precise mechanisms connecting perfusion and bone metabolism remain under investigation, impaired vascular regulation—such as reduced nitric oxide or prostaglandin PGI₂ signaling—is believed to play a role in age-related declines in bone blood flow.

Regional differences in K₁ also help explain site-specific variations in bone metabolic activity. For instance, the spine tends to show higher K₁ values compared to the proximal femur or humerus, aligning with the higher metabolic activity and richer red marrow content of the vertebral bones. In contrast, peripheral bones often show reduced K₁ values, partly due to marrow composition changes with age, including the replacement of red marrow with fatty yellow marrow. These findings underscore the role of vascular supply in maintaining bone health and highlight K₁ as a key parameter in evaluating site-specific bone perfusion and metabolism, particularly in aging and disease contexts.

k2 & k3

In dynamic [¹⁸F]NaF PET imaging, the parameters k₂ and k₃ represent the rates at which the sodium fluoride tracer moves between the extravascular extracellular fluid (ECF) compartment and other compartments of the bone. Specifically, k₂ describes the rate of efflux, or movement of tracer from the ECF back into the plasma, while k₃ reflects the forward flux of tracer from the ECF into the bone mineral matrix, where it binds to hydroxyapatite crystals. Although the exact physiological interpretation of k₂ and k₃ remains partially unclear, they collectively contribute to understanding the efficiency of fluoride tracer extraction and its incorporation into bone tissue.

These parameters are essential components of compartmental kinetic models used to estimate the net influx rate constant (Ki), which is derived from the equation Ki = K₁ × k₃ / (k₂ + k₃). Thus, k₂ and k₃ play key roles in governing how the tracer is distributed and retained within bone, particularly in the context of metabolic bone diseases and treatment response.

In clinical studies, antiresorptive treatments—such as bisphosphonates—have been shown to increase k₂, likely reflecting reduced tracer retention within bone tissue due to suppressed bone remodeling. Conversely, in high-turnover bone diseases such as Paget’s disease, pathological changes in bone structure significantly alter these kinetic parameters. In Pagetic bone, the extracellular fluid space is often enlarged and structurally complex, contributing to an atypical tracer distribution pattern. Clinical PET studies have observed elevated k₃ values—indicating increased tracer uptake into mineralizing surfaces—alongside decreased k₂ values, suggesting slower return of the tracer to the bloodstream. These patterns reflect the increased bone turnover and altered vascular and cellular environment characteristic of Paget’s disease.

The interpretation of k₂ and k₃ is also influenced by changes in bone architecture. For instance, in pathological bone, marrow space may be replaced with fibrotic tissue, limiting the volume and permeability of the ECF compartment and affecting tracer availability. Since k₂ quantifies how quickly the tracer leaves the ECF, and k₃ measures how efficiently it binds to mineral, the balance between these rates can indicate how tracer is partitioned between temporary residence in fluid and permanent incorporation into bone.

Overall, k₂ and k₃ offer important insight into the microenvironmental dynamics of bone tissue, including cellular activity, vascular function, and mineralization processes. Their values can change significantly in response to both therapeutic interventions and disease-related remodeling, making them useful indicators in the study of bone metabolism under both normal and pathological conditions. Although less frequently discussed than K₁ or Ki, these parameters help refine our understanding of how the tracer is handled within the bone, enhancing the utility of dynamic PET in clinical and research applications.

k4

The parameter k₄ represents the backward rate constant describing the movement of the [¹⁸F]fluoride tracer from the bone mineral compartment back into the extravascular extracellular fluid (ECF). This rate characterizes the reversibility of tracer binding to bone mineral surfaces. Although fluoride ions bind to hydroxyapatite crystals within the bone matrix, not all binding interactions are permanent; some are relatively weak and reversible. This is evidenced by the fact that multiple studies have consistently reported nonzero values for k₄, indicating that a fraction of the tracer can dissociate from the mineralized matrix and re-enter the surrounding fluid compartment. Typically, measured k₄ values are low, around 0.01 min⁻¹, which corresponds to a tracer half-life in the bone mineral compartment of approximately 70 minutes.

Because of the small magnitude of k₄, certain analytical methods—such as the Patlak graphical approach—simplify the model by assuming k₄ = 0. While this assumption facilitates data analysis, it can lead to a systematic underestimation of the Ki parameter by as much as 25%, since Ki reflects the net influx of tracer into bone mineral and disregarding k₄ overlooks the reversible component of binding. Therefore, even though k₄ is small, it can significantly impact the accuracy of bone metabolic flux measurements in dynamic PET studies. Clinical data suggest that k₄ does not vary significantly between skeletal regions such as the lumbar spine and the hip, making it a relatively stable parameter across different bone sites.

From a modeling perspective, k₄ serves a critical role in distinguishing strongly bound tracer (which remains fixed in mineralized bone) from weakly bound or exchangeable tracer that may leave the mineral surface over time. Its value provides insight into the dynamic equilibrium between tracer deposition and release at the bone surface, adding temporal resolution to the interpretation of bone turnover and fluoride retention. As such, accurate estimation of k₄ is essential for refining Ki measurements, especially in advanced kinetic models that go beyond simplified assumptions. In summary, although k₄ is often small, its inclusion in compartmental models enhances the physiological accuracy of PET-based assessments of bone metabolism and tracer kinetics in both clinical and research contexts.

K1/k2

The K₁/k₂ ratio represents the effective volume of distribution for a tracer within the bone extracellular fluid space. It reflects the fraction of the skeletal volume of interest that corresponds to the extracellular fluid compartment, under the assumption of passive fluoride diffusion between plasma and extracellular fluid. This assumption is considered reasonable due to the low atomic weight and diffusibility of fluoride ions. Fluoride-18 can form electrically neutral hydrogen fluoride (HF) by binding with hydrogen atoms, resulting in a small, highly diffusible molecule capable of crossing cell membranes.

Within the bone extracellular fluid space, the sodium fluoride tracer may exhibit reduced inter-compartmental exchange due to binding within marrow spaces, which can limit access to bone mineral surfaces. Empirical data suggest that the K₁/k₂ ratio corresponds to approximately 48% of the vertebral bone volume and 34% of the humeral bone volume. These values are consistent with earlier estimates indicating approximately 10% of bone extracellular fluid and 24% of bone marrow extracellular fluid in tibial bone samples. These findings support the understanding that trabecular-rich bone, which contains more marrow, has a larger extracellular fluid space compared to cortical bone.

Clinically, Ki values—a measure of fluoride incorporation into bone mineral—are observed to be approximately three times lower at the hip than at the lumbar spine. While this difference may partly reflect variations in K₁ due to differences in marrow fat content, the higher K₁/k₂ ratios in vertebrae also likely contribute. The lumbar spine contains a greater proportion of red marrow, increasing the accessible extracellular fluid volume for fluoride diffusion, whereas the hip is characterized by predominantly fatty marrow, with a smaller extracellular fluid compartment and reduced tracer availability for bone uptake.

Therapeutic studies have shown that K₁/k₂ ratios at the lumbar spine decrease in osteoporotic patients following antiresorptive treatment, which may reflect a reduction in extracellular fluid space due to increased bone mineral density and filling of remodeling spaces. In contrast, elevated K₁/k₂ ratios are observed in Paget’s disease, indicating expansion of both bone and non-bone extracellular fluid compartments. This enlargement, combined with increased tracer delivery and clearance, contributes to enhanced overall uptake of sodium fluoride in affected bone tissue.

k₃/(k₂ + k₃)

The k₃ / (k₂ + k₃) ratio represents the proportion of a radiotracer delivered to the bone extracellular fluid space that subsequently becomes bound within the bone mineral matrix. Mathematically, this ratio is equivalent to Ki/K₁ and serves as an index of the fraction of tracer undergoing specific incorporation into bone mineral. Studies have shown that k₃ / (k₂ + k₃) values are similar between the lumbar spine and hip in healthy postmenopausal individuals.

This parameter has been investigated as a biomarker for treatment response in osteoporosis and other metabolic bone conditions. Anabolic therapies, such as teriparatide, are associated with increased values of the k₃ / (k₂ + k₃) ratio, reflecting enhanced mineral binding. In contrast, antiresorptive agents, such as risedronate, typically reduce the ratio, indicating a lower proportion of tracer undergoing mineral incorporation. These distinct patterns highlight the potential of this parameter to differentiate between therapeutic mechanisms and to monitor treatment efficacy.

Compared to other kinetic parameters derived from the Hawkins model, k₃ / (k₂ + k₃) has demonstrated superior sensitivity to treatment-related changes relative to its measurement precision. Because it directly reflects the fraction of tracer incorporated into bone mineral, this ratio serves as a useful surrogate for changes in bone formation rate. As such, it is considered a valuable endpoint for non-invasive assessment of skeletal metabolic activity using dynamic [^18F] sodium fluoride positron emission tomography (NaF PET).

The combination of specificity for mineral-bound tracer, statistical robustness, and correlation with clinical outcomes supports the use of the k₃ / (k₂ + k₃) ratio—alongside Ki—as a key parameter in both clinical trials and research studies evaluating bone formation dynamics.

Measuring response to treatment using [18F]NaF PET

Average T-scores of biochemical markers for (A) bone resorption (NTX) and (B) bone formation (BSAP) measured at six time points in 85 postmenopausal women treated with alendronic acid. Scores are referenced to 46 healthy premenopausal controls, where T-score = 0..

Monitoring treatment response in bone diseases requires methods that can detect changes quickly and accurately. Biochemical markers found in blood and urine offer one approach for measuring bone metabolism changes within weeks of starting treatment. These markers fall into two categories: those indicating bone breakdown and those showing bone formation activity.

For bone breakdown, doctors commonly measure serum carboxy-terminal collagen crosslinks and N-terminal telopeptide. For bone formation, they track serum bone-specific alkaline phosphatase and serum procollagen 1 N-terminal propeptide. When patients begin treatment with bone-preserving medications like alendronic acid, the breakdown markers drop rapidly within the first month. However, formation markers take longer to change, typically showing decreases only after 3 to 6 months due to the natural bone renewal cycle.

Sodium fluoride PET scanning provides another method for tracking treatment effects by measuring changes in bone metabolism parameters. Research has examined how different osteoporosis treatments affect these measurements in postmenopausal women. In studies with the bone-preserving drug risedronate, the Ki parameter decreased by approximately 18% after six months of treatment, matching similar decreases seen in blood markers of bone formation. The k3/(k2 + k3) ratio also dropped by about 18%, while k2 values increased significantly.

Conversely, treatment with bone-building medications like teriparatide produced opposite effects. The Ki parameter increased by nearly 24% after six months, with the k3/(k2 + k3) ratio showing similar increases. These changes demonstrate that sodium fluoride PET can effectively detect both bone-preserving and bone-building treatment responses.

(a) Scatter plot of Hawkins model Ki at the lumbar spine in 18 postmenopausal women before and after 6 months of teriparatide treatment, showing a 23.8% average increase. (b) Similar plot of SUVmean values, with a 3.0% mean increase at follow-up.

The timing for measuring treatment response using 18F-NaF PET is particularly advantageous, with quantitative sodium fluoride PET-CT capable of detecting changes in regional bone formation within approximately 12 weeks after treatment initiation. ^[69] This represents a significant advantage over bone mineral density measurements by DXA scanning, which typically require much longer periods to show detectable changes. The ability to assess treatment effectiveness within three months allows clinicians to make earlier decisions about continuing, modifying, or changing therapeutic approaches.

An important finding from these studies involves the comparison between Ki measurements and standardized uptake values. While Ki showed significant changes with teriparatide treatment at the spine, standardized uptake values remained essentially unchanged at this location. However, standardized uptake values did increase significantly at hip locations. This difference highlights why Ki measurements provide more accurate assessments of local bone changes, especially when treatments affect the entire skeleton or when patients have widespread bone disease. In such cases, the total amount of tracer gets distributed across many active bone sites, making standardized uptake values less reliable indicators of true regional changes in bone metabolism.

Measurement accuracy of model parameters in [18F]NaF PET

Plotted [18F]NaF PET Coefficient of Variation (CoV) data based on info available in Puri, T.; Frost, M.L.; Cook, G.J.; Blake, G.M. [18F] Sodium Fluoride PET Kinetic Parameters in Bone Imaging. Tomography 2021, 7, 843-854. https://doi.org/10.3390/tomography7040071,  published under © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

The measurement accuracy of individual parameters within the Hawkins model, expressed through coefficient of variation values, along with therapeutic response shown as percentage changes from initial measurements to six months following bone anabolic agent teriparatide treatment, were reported in clinical research. Parameters demonstrating substantial therapeutic response combined with minimal measurement error represent the most reliable indicators for assessing treatment effectiveness and need fewer study participants to achieve statistically meaningful differences in clinical trials.

In the referenced teriparatide investigation, only Ki and k3/(k2 + k3) possessed adequate measurement reliability and therapeutic response to provide clinical value. The other parameters (K1, k2, k3, k4, and Fbv) showed measurement errors of approximately 30% or higher, rendering them insufficiently reliable for most research applications.

The measurement precision data reveals significant variability across different parameters. K1 demonstrated a coefficient of variation of 36%, while k2 showed the poorest precision at 52%. Parameter k3 exhibited 28% variation, k4 showed 33%, and Fbv displayed 55% coefficient of variation. In contrast, the k3/(k2 + k3) ratio achieved much better precision at 19%, and Ki demonstrated the best measurement reliability with only 15% coefficient of variation. For comparison, standardized uptake value measurements showed 11% coefficient of variation. ^[71]

These precision characteristics explain why Ki and k3/(k2 + k3) emerge as the most practical parameters for clinical monitoring. Their superior measurement consistency, combined with meaningful changes in response to treatment, makes them ideal candidates for tracking therapeutic effectiveness in bone metabolism studies. The high variability in other parameters limits their utility despite their potential physiological significance, highlighting the importance of balancing theoretical relevance with practical measurement capabilities in clinical applications.

Clinical applications of [18F]NaF PET

1. Metabolic Bone Disorders

> Osteoporosis: [18F]NaF PET has demonstrated utility in evaluating treatment efficacy in osteoporosis by quantifying regional bone turnover. Frost et al. (2013) showed that it provides sensitive detection of treatment response to bone-active agents, especially at the hip, offering a noninvasive biomarker for monitoring therapeutic impact. ^[72]

> Paget’s Disease: In Paget’s disease, [18F]NaF PET is effective for assessing disease activity and monitoring response to therapy. Installé et al. (2005) found that fluoride uptake patterns correlate with disease extent and therapeutic changes, making it a reliable imaging tool for disease management. ^[73]

2. Chronic Kidney Disease–Mineral and Bone Disorder (CKD-MBD)

> [18F]NaF PET provides insight into altered bone metabolism in CKD-MBD, where standard imaging may fall short. Feng et al. (2021) highlighted its role in evaluating early kinetic changes, enabling noninvasive assessment of skeletal complications in CKD patients. ^[74]

3. Metastatic Bone Disease

> In patients with breast cancer, [18F]NaF PET can assess skeletal metastases with high sensitivity. Azad et al. (2019) showed that measuring fluoride metabolic flux offers superior assessment of treatment response compared to conventional SUV measurements, improving clinical decision-making. ^[75]

4. Autoimmune Diseases

> [18F]NaF PET/CT aids in evaluating disease activity in rheumatoid arthritis by detecting bone remodeling and joint involvement. Park et al. (2021) demonstrated its utility in estimating inflammatory burden and tracking treatment response, particularly when traditional markers are inconclusive. ^[76]

5. Fracture Healing & Orthopedic Applications

> [18F]NaF PET is valuable in assessing fracture healing, including challenging cases like atypical femoral shaft fractures. It helps distinguish between viable and nonviable bone, enabling early detection of impaired healing and guiding orthopedic management. ^[77]

6. Atherosclerosis

> Joshi et al. (2014) demonstrated that [18F]NaF PET can identify active, high-risk coronary plaques that are prone to rupture — outperforming traditional imaging by detecting microcalcification activity. ^[78]

> Syed et al. (2022) showed that [18F]NaF PET/CT detects disease activity in acute aortic syndromes, providing critical insight into vascular wall remodeling and potential instability in real time. ^[79]

7. Osteogenic Bone Disorder

> Fibrodysplasia Ossificans Progressiva (FOP): [18F]NaF PET/CT can detect early heterotopic ossification in FOP. Eekhoff et al. (2018) found it effective in identifying subclinical disease activity before structural changes appear on conventional imaging. ^[80]

8. Medication-Related Bone Pathology

> Osteonecrosis of the Jaw (ONJ): In patients receiving bisphosphonates or antiresorptive therapies, [18F]NaF PET helps detect osteonecrosis of the jaw early. Raje et al. (2008) showed that it offers valuable metabolic and structural information, aiding in the diagnosis and monitoring of ONJ in cancer patients. ^[81]

See also

• Bone
• Positron emission tomography
• Time-activity curve
• Arterial input function
• Medical Imaging
• Radiology
• Molecular Imaging
• Medical Imaging
• Bone scintigraphy

References

1. Puri, Tanuj; Frost, Michelle L.; Moore, Amelia E. B.; Cook, Gary J. R.; Blake, Glen M. (2023). "Input function and modeling for determining bone metabolic flux using [18F] sodium fluoride PET imaging: A step-by-step guide". Medical Physics. 50 (4): 2071–2088. Bibcode:2023MedPh..50.2071P. doi:10.1002/mp.16125. ISSN   2473-4209. PMID   36433629.
2. Compston, J.E.; Croucher, P.I. (August 1991). "Histomorphometric assessment of trabecular bone remodelling in osteoporosis". Bone and Mineral. 14 (2): 91–102. doi:10.1016/0169-6009(91)90086-f. ISSN   0169-6009. PMID   1912765.
3. Beck Jensen, J. E.; Kollerup, G.; Ørensen, H. A.; Nielsen, S. Pors; Sørensen, O. H. (January 1997). "A single measurement of biochemical markers of bone turnover has limited utility in the individual person". Scandinavian Journal of Clinical and Laboratory Investigation. 57 (4): 351–359. doi:10.3109/00365519709099408. ISSN   0036-5513. PMID   9249882.
4. Puri, T.; Frost, M. L.; Curran, K. M.; Siddique, M.; Moore, A. E. B.; Cook, G. J. R.; Marsden, P. K.; Fogelman, I.; Blake, G. M. (2012-05-12). "Differences in regional bone metabolism at the spine and hip: a quantitative study using 18F-fluoride positron emission tomography". Osteoporosis International. 24 (2): 633–639. doi:10.1007/s00198-012-2006-x. ISSN   0937-941X. PMID   22581294. S2CID   22146999.
5. Aaltonen, Louise; Koivuviita, Niina; Seppänen, Marko; Tong, Xiaoyu; Kröger, Heikki; Löyttyniemi, Eliisa; Metsärinne, Kaj (May 2020). "Correlation between 18F-Sodium Fluoride positron emission tomography and bone histomorphometry in dialysis patients". Bone. 134 115267. doi: 10.1016/j.bone.2020.115267 . ISSN   8756-3282. PMID   32058018.
6. Messa, C. (1993-10-01). "Bone metabolic activity measured with positron emission tomography and [18F]fluoride ion in renal osteodystrophy: correlation with bone histomorphometry". Journal of Clinical Endocrinology & Metabolism. 77 (4): 949–955. doi:10.1210/jcem.77.4.8408470. ISSN   0021-972X. PMID   8408470.
7. Piert, Morand; Zittel, Tilman T.; Machulla, Hans-Jurgen; Becker, Georg Alexander; Jahn, Michael; Maier, Gerhard; Bares, Roland; Becker, Horst Dieter (1998-08-01). "Blood Flow Measurements with [15O]H2O and [18F]Fluoride Ion PET in Porcine Vertebrae". Journal of Bone and Mineral Research. 13 (8): 1328–1336. doi: 10.1359/jbmr.1998.13.8.1328 . ISSN   0884-0431. PMID   9718202. S2CID   19824951.
8. Puri, Tanuj; Frost, Michelle L.; Moore, Amelia E. B.; Choudhury, Ananya; Vinjamuri, Sobhan; Mahajan, Abhishek; Fynbo, Claire; Vrist, Marie; Theil, Jørn; Kairemo, Kalevi; Wong, James; Zaidi, Habib; Revheim, Mona-Elisabeth; Werner, Thomas J.; Alavi, Abass (2023-09-13). "Utility of a simplified [18F] sodium fluoride PET imaging method to quantify bone metabolic flux for a wide range of clinical applications". Frontiers in Endocrinology. 14 1236881. doi: 10.3389/fendo.2023.1236881 . ISSN   1664-2392. PMC   10534005 . PMID   37780613.
9. Piert, Morand; Machulla, Hans-Jürgen; Jahn, Michael; Stahlschmidt, Anke; Becker, Georg A.; Zittel, Tilman T. (2002-04-13). "Coupling of porcine bone blood flow and metabolism in high-turnover bone disease measured by [15O]H2O and [18F]fluoride ion positron emission tomography". European Journal of Nuclear Medicine and Molecular Imaging. 29 (7): 907–914. doi:10.1007/s00259-002-0797-2. ISSN   1619-7070. PMID   12111131. S2CID   2591493.
10. Schumichen, C.; Rempfle, H.; Wagner, M.; Hoffmann, G. (1979). "The short-term fixation of radiopharmaceuticals in bone". European Journal of Nuclear Medicine. 4 (6): 423–428. doi:10.1007/bf00300839. ISSN   0340-6997. PMID   520356. S2CID   23813593.
11. Narita, Naoki; Kato, Kazuo; Nakagaki, Haruo; Ohno, Norikazu; Kameyama, Yoichiro; Weatherell, John A. (March 1990). "Distribution of fluoride concentration in the rat's bone". Calcified Tissue International. 46 (3): 200–204. doi:10.1007/bf02555045. ISSN   0171-967X. PMID   2106380. S2CID   2707183.
12. REEVE, J.; ARLOT, M.; WOOTTON, R.; EDOUARD, C.; TELLEZ, M.; HESP, R.; GREEN, J. R.; MEUNIER, P. J. (June 1988). "Skeletal Blood Flow, Iliac Histomorphometry, and Strontium Kinetics in Osteoporosis: A Relationship Between Blood Flow and Corrected Apposition Rate". The Journal of Clinical Endocrinology & Metabolism. 66 (6): 1124–1131. doi:10.1210/jcem-66-6-1124. ISSN   0021-972X. PMID   3372678.
13. Cook, Gary J. R.; Lodge, Martin A.; Blake, Glen M.; Marsden, Paul K.; Fogelman, Ignac (2010-02-18). "Differences in Skeletal Kinetics Between Vertebral and Humeral Bone Measured by 18F-Fluoride Positron Emission Tomography in Postmenopausal Women". Journal of Bone and Mineral Research. 15 (4): 763–769. doi:10.1359/jbmr.2000.15.4.763. ISSN   0884-0431. PMID   10780868. S2CID   10630967.
14. Krishnamurthy, GT; Huebotter, RJ; Tubis, M; Blahd, WH (February 1976). "Pharmaco-kinetics of current skeletal-seeking radiopharmaceuticals". American Journal of Roentgenology. 126 (2): 293–301. doi:10.2214/ajr.126.2.293. ISSN   0361-803X. PMID   175699.
15. Wootton, R; Dore, C (November 1986). "The single-passage extraction of 18 F in rabbit bone". Clinical Physics and Physiological Measurement. 7 (4): 333–343. Bibcode:1986CPPM....7..333W. doi:10.1088/0143-0815/7/4/003. ISSN   0143-0815. PMID   3791879.
16. Blau, Monte; Ganatra, Ramanik; Bender, Merrill A. (January 1972). "18F-fluoride for bone imaging". Seminars in Nuclear Medicine. 2 (1): 31–37. doi:10.1016/s0001-2998(72)80005-9. ISSN   0001-2998. PMID   5059349.
17. Edelman, I.S.; Leibman, J. (August 1959). "Anatomy of body water and electrolytes". The American Journal of Medicine. 27 (2): 256–277. doi:10.1016/0002-9343(59)90346-8. ISSN   0002-9343. PMID   13819266.
18. Pierson, R. N.; Price, D. C.; Wang, J.; Jain, R. K. (1978-09-01). "Extracellular water measurements: organ tracer kinetics of bromide and sucrose in rats and man". American Journal of Physiology. Renal Physiology. 235 (3): F254 –F264. doi:10.1152/ajprenal.1978.235.3.f254. ISSN   1931-857X. PMID   696835.
19. Staffurth, J. S.; Birchall, I. (January 1959). "The Significance of the Protein Bound Radioactive Iodine Determination in Hyperthyroidism". Acta Endocrinologica. 30 (1): 42–52. doi:10.1530/acta.0.0300042. ISSN   0804-4643. PMID   13605561.
20. Whitford, G.M. (June 1994). "Intake and Metabolism of Fluoride". Advances in Dental Research. 8 (1): 5–14. doi:10.1177/08959374940080011001. ISSN   0895-9374. PMID   7993560. S2CID   21763028.
21. Hosking, D. J.; Chamberlain, M. J. (1972-02-01). "Studies in Man with 18F". Clinical Science. 42 (2): 153–161. doi:10.1042/cs0420153. ISSN   0009-9287. PMID   5058570.
22. TOSTESON, D. C. (January 1959). "Halide Transport in Red Blood Cells". Acta Physiologica Scandinavica. 46 (1): 19–41. doi:10.1111/j.1748-1716.1959.tb01734.x. ISSN   0001-6772.
23. Blake, Glen M.; Park-Holohan, So-Jin; Cook, Gary J.R.; Fogelman, Ignac (January 2001). "Quantitative studies of bone with the use of 18F-fluoride and 99mTc-methylene diphosphonate". Seminars in Nuclear Medicine. 31 (1): 28–49. doi:10.1053/snuc.2001.18742. ISSN   0001-2998. PMID   11200203.
24. Hoh, Carl K.; Hawkins, Randall A.; Dahlbom, Magnus; Glaspy, John A.; Seeger, Leanne L.; Choi, Yong; Schiepers, Christiaan W.; Huang, Sung-cheng; Satyamurthy, Nagichettiar; Barrio, Jorge R.; Phelps, Michael E. (January 1993). "Whole Body Skeletal Imaging with [18F]Fluoride Ion and PET". Journal of Computer Assisted Tomography. 17 (1): 34–41. doi:10.1097/00004728-199301000-00005. ISSN   0363-8715. PMID   8419436. S2CID   42563084.
25. TAVES, DONALD R. (November 1968). "Electrophoretic Mobility of Serum Fluoride". Nature. 220 (5167): 582–583. Bibcode:1968Natur.220..582T. doi:10.1038/220582a0. ISSN   0028-0836. PMID   5686731. S2CID   4220484.
26. Ekstrand, J.; Spak, C. J.; Ehrnebo, M. (2009-03-13). "Renal Clearance of Fluoride in a Steady State Condition in Man: Influence of Urinary Flow and pH Changes by Diet". Acta Pharmacologica et Toxicologica. 50 (5): 321–325. doi:10.1111/j.1600-0773.1982.tb00982.x. ISSN   0001-6683. PMID   7113707.
27. Ekstrand, Jan; Ehrnebo, Mats; Boréus, Lars O. (March 1978). "Fluoride bioavailability after intravenous and oral administration: Importance of renal clearance and urine flow". Clinical Pharmacology & Therapeutics. 23 (3): 329–337. doi:10.1002/cpt1978233329. ISSN   0009-9236. PMID   627140. S2CID   26176903.
28. Whitford, GM; Pashley, DH; Stringer, GI (1976-02-01). "Fluoride renal clearance: a pH-dependent event". American Journal of Physiology. Legacy Content. 230 (2): 527–532. doi:10.1152/ajplegacy.1976.230.2.527. ISSN   0002-9513. PMID   1259032.
29. Costeas, A.; Woodard, H. Q.; Laughlin, J. S. (May 1971). "Comparative Kinetics of Calcium and Fluoride in Rabbit Bone". Radiation Research. 46 (2): 317–333. Bibcode:1971RadR...46..317C. doi:10.2307/3573023. ISSN   0033-7587. JSTOR   3573023. PMID   5564840.
30. Walker, P. G. (November 1958). "THE CHEMICAL DYNAMICS OF BONE MINERAL. By William F. Neuman and Margaret W. Neuman. 9¼x5½ in. Pp. xi+209, with 51 figures and 24 tables. Index. 1958. Chicago: The University of Chicago Press. London: Cambridge University Press. Price 37s. 6d". The Journal of Bone and Joint Surgery. British Volume. 40-B (4): 846. doi: 10.1302/0301-620x.40b4.846 . ISSN   0301-620X.
31. Ishiguro, Koji; Nakagaki, Haruo; Tsuboi, Shinji; Narita, Naoki; Kato, Kazuo; Li, Jianxue; Kamei, Hideo; Yoshioka, Ikuo; Miyauchi, Kenichi; Hosoe, Hiroyo; Shimano, Ryouyu (April 1993). "Distribution of fluoride in cortical bone of human rib". Calcified Tissue International. 52 (4): 278–282. doi:10.1007/bf00296652. ISSN   0171-967X. PMID   8467408. S2CID   31137242.
32. Grynpas, Marc D. (2010-02-25). "Fluoride effects on bone crystals". Journal of Bone and Mineral Research. 5 (S1): S169 –S175. doi:10.1002/jbmr.5650051362. ISSN   0884-0431. PMID   2187325. S2CID   22713623.
33. Jones, Alun G.; Francis, Marion D.; Davis, Michael A. (January 1976). "Bone scanning: Radionuclidic reaction mechanisms". Seminars in Nuclear Medicine. 6 (1): 3–18. doi:10.1016/s0001-2998(76)80032-3. ISSN   0001-2998. PMID   174228.
34. Blake, Glen M.; Puri, Tanuj; Siddique, Musib; Frost, Michelle L.; Moore, Amelia E. B.; Fogelman, Ignac (February 2018). "Site specific measurements of bone formation using [18F] sodium fluoride PET/CT". Quantitative Imaging in Medicine and Surgery. 8 (1): 47–59. doi: 10.21037/qims.2018.01.02 . PMC   5835654 . PMID   29541623.
35. Grant, F. D.; Fahey, F. H.; Packard, A. B.; Davis, R. T.; Alavi, A.; Treves, S. T. (2007-12-12). "Skeletal PET with 18F-Fluoride: Applying New Technology to an Old Tracer". Journal of Nuclear Medicine. 49 (1): 68–78. doi: 10.2967/jnumed.106.037200 . ISSN   0161-5505. PMID   18077529.
36. Blake, Glen M.; Siddique, Musib; Frost, Michelle L.; Moore, Amelia E.B.; Fogelman, Ignac (September 2011). "Radionuclide studies of bone metabolism: Do bone uptake and bone plasma clearance provide equivalent measurements of bone turnover?". Bone. 49 (3): 537–542. doi:10.1016/j.bone.2011.05.031. ISSN   8756-3282. PMID   21689803.
37. Puri, Tanuj; Frost, Michelle L.; Moore, Amelia E. B.; Cook, Gary J. R.; Blake, Glen M. (2023). "Input function and modeling for determining bone metabolic flux using [18F] sodium fluoride PET imaging: A step-by-step guide". Medical Physics. 50 (4): 2071–2088. Bibcode:2023MedPh..50.2071P. doi:10.1002/mp.16125. ISSN   2473-4209. PMID   36433629.  This article incorporates textfrom this source, which is available under the CC BY 4.0 license.
38. Huang, (Henry) Sung-Cheng (October 2000). "Anatomy of SUV". Nuclear Medicine and Biology. 27 (7): 643–646. doi:10.1016/s0969-8051(00)00155-4. ISSN   0969-8051. PMID   11091106.
39. Basu, Sandip; Zaidi, Habib; Houseni, Mohamed; Bural, Gonca; Udupa, Jay; Acton, Paul; Torigian, Drew A.; Alavi, Abass (May 2007). "Novel Quantitative Techniques for Assessing Regional and Global Function and Structure Based on Modern Imaging Modalities: Implications for Normal Variation, Aging and Diseased States". Seminars in Nuclear Medicine. 37 (3): 223–239. doi:10.1053/j.semnuclmed.2007.01.005. ISSN   0001-2998. PMID   17418154.
40. Lucignani, G.; Paganelli, G.; Bombardieri, E. (July 2004). "The use of standardized uptake values for assessing FDG uptake with PET in oncology: a clinical perspective". Nuclear Medicine Communications. 25 (7): 651–656. doi:10.1097/01.mnm.0000134329.30912.49. ISSN   0143-3636. PMID   15208491. S2CID   38728335.
41. Frost, M. L.; Blake, G. M.; Park-Holohan, S.-J.; Cook, G. J.R.; Curran, K. M.; Marsden, P. K.; Fogelman, I. (2008-04-15). "Long-Term Precision of 18F-Fluoride PET Skeletal Kinetic Studies in the Assessment of Bone Metabolism". Journal of Nuclear Medicine. 49 (5): 700–707. doi: 10.2967/jnumed.107.046987 . ISSN   0161-5505. PMID   18413385.
42. Visser, E. P.; Boerman, O. C.; Oyen, W. J.G. (2010-01-15). "SUV: From Silly Useless Value to Smart Uptake Value". Journal of Nuclear Medicine. 51 (2): 173–175. doi: 10.2967/jnumed.109.068411 . ISSN   0161-5505. PMID   20080897.
43. Halama, J; Sadjak, R; Wagner, R (June 2006). "SU-FF-I-82: Variability and Accuracy of Standardized Uptake Values in FDG PET Scans". Medical Physics. 33 (6Part4): 2015–2016. Bibcode:2006MedPh..33.2015H. doi:10.1118/1.2240762. ISSN   0094-2405.
44. Fischman, Alan J.; Alpert, Nathaniel M.; Babich, John W.; Rubin, Robert H. (January 1997). "The Role of Positron Emission Tomography in Pharmacokinetic Analysis". Drug Metabolism Reviews. 29 (4): 923–956. doi:10.3109/03602539709002238. ISSN   0360-2532. PMID   9421680.
45. Krak, Nanda C.; Boellaard, R.; Hoekstra, Otto S.; Twisk, Jos W. R.; Hoekstra, Corneline J.; Lammertsma, Adriaan A. (2004-10-15). "Effects of ROI definition and reconstruction method on quantitative outcome and applicability in a response monitoring trial". European Journal of Nuclear Medicine and Molecular Imaging. 32 (3): 294–301. doi:10.1007/s00259-004-1566-1. ISSN   1619-7070. PMID   15791438. S2CID   22518269.
46. Westerterp, Marinke; Pruim, Jan; Oyen, Wim; Hoekstra, Otto; Paans, Anne; Visser, Eric; van Lanschot, Jan; Sloof, Gerrit; Boellaard, Ronald (2006-10-11). "Quantification of FDG PET studies using standardised uptake values in multi-centre trials: effects of image reconstruction, resolution and ROI definition parameters". European Journal of Nuclear Medicine and Molecular Imaging. 34 (3): 392–404. doi:10.1007/s00259-006-0224-1. ISSN   1619-7070. PMID   17033848. S2CID   1521701.
47. Blake, G. M.; Frost, M. L.; Fogelman, I. (2009-10-16). "Quantitative Radionuclide Studies of Bone". Journal of Nuclear Medicine. 50 (11): 1747–1750. doi: 10.2967/jnumed.109.063263 . ISSN   0161-5505. PMID   19837752.
48. Frost, Michelle L; Siddique, Musib; Blake, Glen M; Moore, Amelia EB; Schleyer, Paul J; Dunn, Joel T; Somer, Edward J; Marsden, Paul K; Eastell, Richard; Fogelman, Ignac (May 2011). "Differential effects of teriparatide on regional bone formation using 18F-fluoride positron emission tomography". Journal of Bone and Mineral Research. 26 (5): 1002–1011. doi: 10.1002/jbmr.305 . ISSN   0884-0431. PMID   21542003. S2CID   40840920.
49. Cunningham, Vincent J.; Jones, Terry (January 1993). "Spectral Analysis of Dynamic PET Studies". Journal of Cerebral Blood Flow & Metabolism. 13 (1): 15–23. doi: 10.1038/jcbfm.1993.5 . ISSN   0271-678X. PMID   8417003.
50. Spedding, V. (2001). "Live laboratory will analyse real-time market data". Quantitative Finance. 1 (6): 568–570. doi:10.1088/1469-7688/1/6/606. ISSN   1469-7688. S2CID   154537213.
51. Liberati, D.; Turkheimer, F. (1999). "Linear spectral deconvolution of catabolic plasma concentration decay in dialysis". Medical & Biological Engineering & Computing. 37 (3): 391–395. doi:10.1007/bf02513317. ISSN   0140-0118. PMID   10505392. S2CID   25080033.
52. Lau, Chi-hoi Lun, Pak-kong Daniel Feng, D. David (1998). Non-invasive quantification of physiological processes with dynamic PET using blind deconvolution. IEEE. OCLC   697321031.
53. Chi-Hoi Lau; Lun, D.P.-K.; Dagan Feng (1998). "Non-invasive quantification of physiological processes with dynamic PET using blind deconvolution". Proceedings of the 1998 IEEE International Conference on Acoustics, Speech and Signal Processing, ICASSP '98 (Cat. No.98CH36181). Vol. 3. IEEE. pp. 1805–1808. doi:10.1109/icassp.1998.681811. hdl: 10397/1882 . ISBN   0-7803-4428-6. S2CID   5947145.
54. Puri, Tanuj; Blake, Glen M.; Frost, Michelle L.; Siddique, Musib; Moore, Amelia E.B.; Marsden, Paul K.; Cook, Gary J.R.; Fogelman, Ignac; Curran, Kathleen M. (June 2012). "Comparison of six quantitative methods for the measurement of bone turnover at the hip and lumbar spine using 18F-fluoride PET-CT" . Nuclear Medicine Communications. 33 (6): 597–606. doi:10.1097/MNM.0b013e3283512adb. ISSN   0143-3636. PMID   22441132. S2CID   23490366.
55. Patlak, Clifford S.; Blasberg, Ronald G.; Fenstermacher, Joseph D. (March 1983). "Graphical Evaluation of Blood-to-Brain Transfer Constants from Multiple-Time Uptake Data". Journal of Cerebral Blood Flow & Metabolism. 3 (1): 1–7. doi: 10.1038/jcbfm.1983.1 . ISSN   0271-678X. PMID   6822610.
56. Puri, Tanuj; Frost, Michelle L.; Moore, Amelia E. B.; Choudhury, Ananya; Vinjamuri, Sobhan; Mahajan, Abhishek; Fynbo, Claire; Vrist, Marie; Theil, Jørn; Kairemo, Kalevi; Wong, James; Zaidi, Habib; Revheim, Mona-Elisabeth; Werner, Thomas J.; Alavi, Abass (2023-09-13). "Utility of a simplified [18F] sodium fluoride PET imaging method to quantify bone metabolic flux for a wide range of clinical applications". Frontiers in Endocrinology. 14 1236881. doi: 10.3389/fendo.2023.1236881 . ISSN   1664-2392.
57. Siddique, Musib; Blake, Glen M.; Frost, Michelle L.; Moore, Amelia E. B.; Puri, Tanuj; Marsden, Paul K.; Fogelman, Ignac (2011-11-08). "Estimation of regional bone metabolism from whole-body 18F-fluoride PET static images". European Journal of Nuclear Medicine and Molecular Imaging. 39 (2): 337–343. doi:10.1007/s00259-011-1966-y. ISSN   1619-7070. PMID   22065012. S2CID   23959977.
58. Blake, Glen Mervyn; Siddique, Musib; Puri, Tanuj; Frost, Michelle Lorraine; Moore, Amelia Elizabeth; Cook, Gary James R.; Fogelman, Ignac (August 2012). "A semipopulation input function for quantifying static and dynamic 18F-fluoride PET scans". Nuclear Medicine Communications. 33 (8): 881–888. doi:10.1097/mnm.0b013e3283550275. ISSN   0143-3636. PMID   22617486. S2CID   42973690.
59. Puri, Tanuj; Frost, Michelle L.; Moore, Amelia E. B.; Cook, Gary J. R.; Blake, Glen M. (2023). "Input function and modeling for determining bone metabolic flux using [18F] sodium fluoride PET imaging: A step-by-step guide". Medical Physics. 50 (4): 2071–2088. doi:10.1002/mp.16125. ISSN   2473-4209.
60. Puri, Tanuj; Frost, Michelle L.; Moore, Amelia E. B.; Cook, Gary J. R.; Blake, Glen M. (2023). "Input function and modeling for determining bone metabolic flux using [18F] sodium fluoride PET imaging: A step-by-step guide". Medical Physics. 50 (4): 2071–2088. doi:10.1002/mp.16125. ISSN   2473-4209.
61. Puri, Tanuj; Blake, Glen M.; Frost, Michelle L.; Siddique, Musib; Moore, Amelia E.B.; Marsden, Paul K.; Cook, Gary J.R.; Fogelman, Ignac; Curran, Kathleen M. (June 2012). "Comparison of six quantitative methods for the measurement of bone turnover at the hip and lumbar spine using 18F-fluoride PET-CT". Nuclear Medicine Communications. 33 (6): 597–606. doi:10.1097/mnm.0b013e3283512adb. ISSN   0143-3636. PMID   22441132. S2CID   23490366.
62. BRENNER, W. (2004). "Comparison of different quantitative approaches to 18F-fluoride PET scans". J Nucl Med. 45 (9): 1493–500. PMID   15347716.
63. Brenner, Winfried; Vernon, Cheryl; Conrad, ErnestU.; Eary, JanetF. (2004-06-10). "Assessment of the metabolic activity of bone grafts with 18F-fluoride PET". European Journal of Nuclear Medicine and Molecular Imaging. 31 (9): 1291–8. doi:10.1007/s00259-004-1568-z. ISSN   1619-7070. PMID   15197502. S2CID   10000344.
64. Frost, Michelle L; Siddique, Musib; Blake, Glen M; Moore, Amelia EB; Schleyer, Paul J; Dunn, Joel T; Somer, Edward J; Marsden, Paul K; Eastell, Richard; Fogelman, Ignac (2011-05-01). "Differential effects of teriparatide on regional bone formation using 18F-fluoride positron emission tomography". Journal of Bone and Mineral Research. 26 (5): 1002–1011. doi:10.1002/jbmr.305. ISSN   0884-0431.
65. Puri, Tanuj; Frost, Michelle L.; Cook, Gary J.; Blake, Glen M. (2021-12-01). "[18F] Sodium Fluoride PET Kinetic Parameters in Bone Imaging". Tomography. 7 (4): 843–854. doi: 10.3390/tomography7040071 . ISSN   2379-139X. PMC   8708178 . PMID   34941643.
66. Aaltonen, Louise; Koivuviita, Niina; Seppänen, Marko; Tong, Xiaoyu; Kröger, Heikki; Löyttyniemi, Eliisa; Metsärinne, Kaj (May 2020). "Correlation between 18F-Sodium Fluoride positron emission tomography and bone histomorphometry in dialysis patients". Bone. 134 115267. doi:10.1016/j.bone.2020.115267. PMID   32058018.
67. Puri, Tanuj; Frost, Michelle L.; Moore, Amelia E. B.; Choudhury, Ananya; Vinjamuri, Sobhan; Mahajan, Abhishek; Fynbo, Claire; Vrist, Marie; Theil, Jørn; Kairemo, Kalevi; Wong, James; Zaidi, Habib; Revheim, Mona-Elisabeth; Werner, Thomas J.; Alavi, Abass (2023-09-13). "Utility of a simplified [18F] sodium fluoride PET imaging method to quantify bone metabolic flux for a wide range of clinical applications". Frontiers in Endocrinology. 14 1236881. doi: 10.3389/fendo.2023.1236881 . ISSN   1664-2392. PMC   10534005 . PMID   37780613.  This article incorporates textfrom this source, which is available under the CC BY 4.0 license.
68. Puri, Tanuj; Frost, Michelle L.; Moore, Amelia E. B.; Cook, Gary J. R.; Blake, Glen M. (2023). "Input function and modeling for determining bone metabolic flux using [18F] sodium fluoride PET imaging: A step-by-step guide". Medical Physics. 50 (4): 2071–2088. Bibcode:2023MedPh..50.2071P. doi:10.1002/mp.16125. ISSN   2473-4209. PMID   36433629.  This article incorporates textfrom this source, which is available under the CC BY 4.0 license.
69. Puri, Tanuj; Frost, Michelle L.; Moore, Amelia E. B.; Choudhury, Ananya; Vinjamuri, Sobhan; Mahajan, Abhishek; Fynbo, Claire; Vrist, Marie; Theil, Jørn; Kairemo, Kalevi; Wong, James; Zaidi, Habib; Revheim, Mona-Elisabeth; Werner, Thomas J.; Alavi, Abass (2023-09-13). "Utility of a simplified [18F] sodium fluoride PET imaging method to quantify bone metabolic flux for a wide range of clinical applications". Frontiers in Endocrinology. 14 1236881. doi: 10.3389/fendo.2023.1236881 . ISSN   1664-2392. PMC   10534005 . PMID   37780613.  This article incorporates textfrom this source, which is available under the CC BY 4.0 license.
70. Puri, Tanuj; Frost, Michelle L.; Cook, Gary J.; Blake, Glen M. (2021-12-01). "[18F] Sodium Fluoride PET Kinetic Parameters in Bone Imaging". Tomography. 7 (4): 843–854. doi: 10.3390/tomography7040071 . ISSN   2379-139X. PMC   8708178 . PMID   34941643.
71. Puri, Tanuj; Frost, Michelle L.; Cook, Gary J.; Blake, Glen M. (2021-12-01). "[18F] Sodium Fluoride PET Kinetic Parameters in Bone Imaging". Tomography. 7 (4): 843–854. doi: 10.3390/tomography7040071 . ISSN   2379-139X. PMC   8708178 . PMID   34941643.
72. Frost, Michelle L; Moore, Amelia E; Siddique, Musib; Blake, Glen M; Laurent, Didier; Borah, Babul; Schramm, Ursula; Valentin, Marie-Anne; Pellas, Theodore C; Marsden, Paul K; Schleyer, Paul J; Fogelman, Ignac (2013-06-01). "18F-fluoride PET as a noninvasive imaging biomarker for determining treatment efficacy of bone active agents at the hip: A prospective, randomized, controlled clinical study". Journal of Bone and Mineral Research. 28 (6): 1337–1347. doi:10.1002/jbmr.1862. ISSN   0884-0431. PMID   23322666.
73. Installé, Johanne; Nzeusseu, Adrien; Bol, Anne; Depresseux, Geneviève; Devogelaer, Jean-Pierre; Lonneux, Max (October 2005). "(18)F-fluoride PET for monitoring therapeutic response in Paget's disease of bone". Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine. 46 (10): 1650–1658. ISSN   0161-5505. PMID   16204715.
74. Feng, Tao; Zhao, Yizhang; Shi, Hongcheng; Li, Hongdi; Zhang, Xuezhu; Wang, Guobao; Price, Patricia M.; Badawi, Ramsey D.; Cherry, Simon R.; Jones, Terry (2021-05-10). "Total-Body Quantitative Parametric Imaging of Early Kinetics of 18 F-FDG". Journal of Nuclear Medicine. 62 (5): 738–744. doi:10.2967/jnumed.119.238113. ISSN   0161-5505. PMC   8844261 . PMID   32948679.
75. Azad, Gurdip K.; Siddique, Musib; Taylor, Benjamin; Green, Adrian; O'Doherty, Jim; Gariani, Joanna; Blake, Glen M.; Mansi, Janine; Goh, Vicky; Cook, Gary J. R. (March 2019). "Is Response Assessment of Breast Cancer Bone Metastases Better with Measurement of 18F-Fluoride Metabolic Flux Than with Measurement of 18F-Fluoride PET/CT SUV?". Journal of Nuclear Medicine: Official Publication, Society of Nuclear Medicine. 60 (3): 322–327. doi:10.2967/jnumed.118.208710. ISSN   1535-5667. PMC   6424232 . PMID   30042160.
76. Park, Hee Jin; Chang, Sung Hae; Lee, Jeong Won; Lee, Sang Mi (April 2021). "Clinical utility of F-18 sodium fluoride PET/CT for estimating disease activity in patients with rheumatoid arthritis". Quantitative Imaging in Medicine and Surgery. 11 (4): 1156–1169. doi: 10.21037/qims-20-788 . PMC   7930669 . PMID   33816157.
77. van Rijsewijk, N. D.; Wouthuyzen-Bakker, M.; van Snick, J. H.; van Sluis, J.; Duis, K. Ten; Glaudemans, A. W. J. M.; IJpma, F. F. A. (August 2025). "[18F]NaF PET/CT to assess bone healing capacity in orthopaedic trauma surgery: a feasibility study". European Journal of Nuclear Medicine and Molecular Imaging. 52 (10): 3903–3914. doi:10.1007/s00259-025-07209-y. ISSN   1619-7089. PMC   12316756 . PMID   40214741.
78. Joshi, Nikhil V; Vesey, Alex T; Williams, Michelle C; Shah, Anoop S V; Calvert, Patrick A; Craighead, Felicity H M; Yeoh, Su Ern; Wallace, William; Salter, Donald; Fletcher, Alison M; van Beek, Edwin J R; Flapan, Andrew D; Uren, Neal G; Behan, Miles W H; Cruden, Nicholas L M (February 2014). "18F-fluoride positron emission tomography for identification of ruptured and high-risk coronary atherosclerotic plaques: a prospective clinical trial". The Lancet. 383 (9918): 705–713. doi:10.1016/S0140-6736(13)61754-7. PMID   24224999.
79. Syed, Maaz B.J.; Fletcher, Alexander J.; Debono, Samuel; Forsythe, Rachel O.; Williams, Michelle C.; Dweck, Marc R.; Shah, Anoop S.V.; Macaskill, Mark G.; Tavares, Adriana; Denvir, Martin A.; Lim, Kelvin; Wallace, William A.; Kaczynski, Jakub; Clark, Tim; Sellers, Stephanie L. (July 2022). "18F-Sodium Fluoride Positron Emission Tomography and Computed Tomography in Acute Aortic Syndrome". JACC: Cardiovascular Imaging. 15 (7): 1291–1304. doi:10.1016/j.jcmg.2022.01.003. PMID   35798405.
80. Eekhoff, E. Marelise W.; Botman, Esmée; Coen Netelenbos, J.; de Graaf, Pim; Bravenboer, Nathalie; Micha, Dimitra; Pals, Gerard; de Vries, Teun J.; Schoenmaker, Ton; Hoebink, Max; Lammertsma, Adriaan A.; Raijmakers, Pieter G.H.M. (April 2018). "[18F]NaF PET/CT scan as an early marker of heterotopic ossification in fibrodysplasia ossificans progressiva". Bone. 109: 143–146. doi:10.1016/j.bone.2017.08.012. PMID   28826841.
81. Raje, Noopur; Woo, Sook-Bin; Hande, Karen; Yap, Jeffrey T.; Richardson, Paul G.; Vallet, Sonia; Treister, Nathaniel; Hideshima, Teru; Sheehy, Niall; Chhetri, Shweta; Connell, Brendan; Xie, Wanling; Tai, Yu-Tzu; Szot-Barnes, Agnieszka; Tian, Mei (2008-04-15). "Clinical, Radiographic, and Biochemical Characterization of Multiple Myeloma Patients with Osteonecrosis of the Jaw". Clinical Cancer Research. 14 (8): 2387–2395. doi:10.1158/1078-0432.CCR-07-1430. ISSN   1078-0432. PMID   18413829.