One small step in time, one giant leap for DMPK kind - a CRO perspective of the evolving core discipline of drug development.

As the Space Race or Formula 1 drives innovation, efficiency and progress in home technology and home car markets, Drug Metabolism and Pharmacokinetics (DMPK) drives scientific innovation and value for drug development companies. Stand still and fall behind as the saying goes, and these analogies are true as much in the design and conduct of DMPK studies as they are in the technology and manufacturing sectors.This short review showcases the impact that DMPK has had on drug development and how it has changed in the last 10 years, illustrating the value added scientific benefit, cost and time saving, that innovative DMPK program design and study conduct have. Examples and case studies spanning novel in vitro alternatives such as organ-on-a-chip (OOAC) developments; use of in vivo microsampling across small and large animal species; challenging historical paradigms in Absorption, Distribution, Metabolism and Excretion (ADME) studies; and embracing new technologies to address regulatory concerns, are presented.The continual pace of change has kept DMPK at the core of pharmaceutical, crop and chemical evaluation, and this is set to continue as regulators use this discipline to inform decision-making. With new modalities and new scientific questions, DMPK will continue to evolve, with the likes of new in vitro, in vivo and in silico models becoming central to candidate selection and progression.

Relationships of Bone Mineral Density to Whole Body Mass, Fat Mass and Fat-free Mass in Long-term Survivors of Acute Lymphoblastic Leukemia in Childhood.

Body size influences bone mineral density (BMD) in health. Relationships of BMD with body mass index, fat mass (FM), fat-free mass, and appendicular lean mass were explored in acute lymphoblastic leukemia (ALL) survivors (n=75; 41 males; 45 standard risk ALL) >10 years from diagnosis. Dual energy radiograph absorptiometry performed body composition analysis. Relationships were assessed by regression analyses and Pearson correlation coefficients (r). Twenty subjects (26.3%) were osteopenic; lumbar spine (LS) BMD Z score <-1.00. Age at diagnosis, sex, ALL risk-category, type of post-induction steroid or cranial radiation did not correlate with LS or whole body (WB) BMD. Body mass index correlated significantly with LS BMD (r=0.333, P=0.004) and WB BMD (r=0.271, P=0.033). FM index (FM/height²) Z score showed no significant correlation with LS or WB BMD. Fat-free mass index Z score correlated strongly with LS BMD (r=0.386, P=0.013) and WB BMD (r=0.605, P<0.001) in males but not in females. The appendicular lean mass index, a surrogate for skeletal muscle mass, correlated significantly with LS BMD (r=0.367, P=0.018) and WB BMD (r=0.604, P<0.001) in males but not in females. Future studies to evaluate interventions to enhance BMD focused on improving body composition particularly skeletal muscle mass are warranted.

Body composition in long-term survivors of acute lymphoblastic leukemia diagnosed in childhood and adolescence: A focus on sarcopenic obesity.

BACKGROUND: The late effects of treatment for acute lymphoblastic leukemia (ALL) include disordered body composition, especially obesity. Less attention has been focused on the loss of skeletal muscle mass (SMM) and the combined morbidity of sarcopenic obesity. METHODS: A cross-sectional study of body composition was undertaken via dual-energy x-ray absorptiometry in 75 long-term survivors of ALL (more than 10 years after the diagnosis). Measures were obtained of the fat mass (FM), fat-free mass (equivalent to the lean body mass [LBM]), and whole-body bone mineral content. Health-related quality of life (HRQL) was measured with the Health Utilities Index. RESULTS: The sum of the FM, LBM, and whole-body bone mineral content matched the total body weight measured directly (r = 0.998). The appendicular lean mass (ALM) was derived from the LBM in all 4 limbs and accounted for approximately 75% of the SMM. According to the fat mass index (FMI; ie, FM/height2 ), 12% of females and 18% of males were frankly obese by World Health Organization criteria. The median FMI z score was + 0.40, whereas the median z score for the appendicular lean mass index (ALMI; ie, ALM/height2 ) was -0.40. Sarcopenic obesity, defined as a positive FMI z score with a negative ALMI z score, was present in 32 subjects (43%). There were statistically significant and clinically important differences in overall HRQL between subjects with and without sarcopenic obesity. CONCLUSIONS: Sarcopenic obesity is prevalent in long-term survivors of ALL, and this places them in double jeopardy from excess body fat and inadequate SMM (eg, a combination of metabolic and frailty syndromes). It is associated with an adverse impact on overall HRQL. Cancer 2018;124:1225-31. © 2017 American Cancer Society.

A trimodality comparison of volumetric bone imaging technologies. Part I: Short-term precision and validity.

In vivo peripheral quantitative computed tomography (pQCT) and peripheral magnetic resonance imaging (pMRI) modalities can measure apparent bone microstructure at resolutions 200 µm or higher. However, validity and in vivo test-retest reproducibility of apparent bone microstructure have yet to be determined on 1.0 T pMRI (196 µm) and pQCT (200 µm). This study examined 67 women with a mean age of 74±9 yr and body mass index of 27.65±5.74 kg/m2, demonstrating validity for trabecular separation from pMRI, cortical thickness, and bone volume fraction from pQCT images compared with high-resolution pQCT (hr-pQCT), with slopes close to unity. However, because of partial volume effects, cortical and trabecular thickness of bone derived from pMRI and pQCT images matched hr-pQCT more only when values were small. Short-term reproducibility of bone outcomes was highest for bone volume fraction (BV/TV) and densitometric variables and lowest for trabecular outcomes measuring microstructure. Measurements at the tibia for pQCT images were more precise than at the radius. In part I of this 3-part series focused on trimodality comparisons of precision and validity, it is shown that pQCT images can yield valid and reproducible apparent bone structural outcomes, but because of longer scan time and potential for more motion, the pMRI protocol examined here remains limited in achieving reliable values.

A Trimodality Comparison of Volumetric Bone Imaging Technologies. Part III: SD, SEE, LSC Association With Fragility Fractures.

Part II of this 3-part series demonstrated 1-yr precision, standard error of the estimate, and 1-yr least significant change for volumetric bone outcomes determined using peripheral (p) quantitative computed tomography (QCT) and peripheral magnetic resonance imaging (pMRI) modalities in vivo. However, no clinically relevant outcomes have been linked to these measures of change. This study examined 97 women with mean age of 75 ± 9 yr and body mass index of 26.84 ± 4.77 kg/m(2), demonstrating a lack of association between fragility fractures and standard deviation, least significant change and standard error of the estimate-based unit differences in volumetric bone outcomes derived from both pMRI and pQCT. Only cortical volumetric bone mineral density and cortical thickness derived from high-resolution pQCT images were associated with an increased odds for fractures. The same measures obtained by pQCT erred toward significance. Despite the smaller 1-yr and short-term precision error for measures at the tibia vs the radius, the associations with fractures observed at the radius were larger than at the tibia for high-resolution pQCT. Unit differences in cortical thickness and cortical volumetric bone mineral density able to yield a 50% increase in odds for fractures were quantified here and suggested as a reference for future power computations.

A Trimodality Comparison of Volumetric Bone Imaging Technologies. Part II: 1-Yr Change, Long-Term Precision, and Least Significant Change.

The previous article in this 3-part series demonstrated short-term precision and validity for volumetric bone outcome quantification using in vivo peripheral (p) quantitative computed tomography (pQCT) and magnetic resonance imaging (MRI) modalities at resolutions 200 µm or higher. However, 1-yr precision error and clinically significant references are yet to be reported for these modalities. This study examined 59 women with mean age of 75 ± 9 yr and body mass index of 26.84 ± 4.77 kg/m², demonstrating the lowest 1-yr precision error, standard errors of the estimate, and least significant change values for high-resolution (hr) pQCT followed by pQCT, and 1.0-T pMRI for all volumetric bone outcomes except trabecular number. Like short-term precision, 1-yr statistics for trabecular separation were similar across modalities. Excluding individuals with a previous history of fragility fractures, or who were current users of antiresorptives reduced 1-yr change for bone outcomes derived from pQCT and pMR images, but not hr-pQCT images. In Part II of this 3-part series focused on trimodality comparisons of 1-yr changes, hr-pQCT was recommended to be the prime candidate for quantifying change where smaller effect sizes are expected, but pQCT was identified as a feasible alternative for studies expecting larger changes.

Sarcopenia in children with acute lymphoblastic leukemia.

Children with acute lymphoblastic leukemia experience musculoskeletal morbidity during therapy. We examined the patterns of change in skeletal muscle mass (SMM) and the relationship between change in SMM and the burden of illness as reflected in days of hospitalization. Ninety-one children had dual energy x-ray absorptiometry (DXA scans) during treatment, yielding the sum of lean tissue mass in all 4 limbs; the appendicular lean mass. SMM was derived from appendicular lean mass. The number of inpatient days was recorded. DXA scans at 5 time points showed a profile of change in SMM characterized by a drop in the mean Z score from -0.18 at diagnosis to -1.08 after 6 months of therapy, with a partial recovery 12 to 24 months after diagnosis. Levels of serum creatinine, a surrogate measure of SMM, were mainly unchanged. The extent of the drop in SMM during early therapy was associated with the duration of hospitalization (r=0.31, P<0.05). Children with acute lymphoblastic leukemia experience a notable reduction in SMM early in treatment, with incomplete recovery. The degree of loss is associated with the burden of illness. These findings provide a target for a therapeutic intervention and a measure to determine its efficacy.

The prediction of lean body mass and fat mass from arm anthropometry at diagnosis in children with cancer.

Maintenance of adequate nutrition is important in the care of children with cancer. In clinical practice, determination of nutritional status can be accomplished with measurement of body composition by dual-energy x-ray absorptiometry (DXA). However, DXA is seldom available in low-income countries where most children with cancer live. This study sought to provide predictive equations for lean body mass and fat mass, measured by DXA, on the basis of simple arm anthropometry providing measures of mid-upper arm circumference and triceps skin-fold thickness in a population (N=99) of children diagnosed with cancer. Such equations were derived successfully with the inclusion of absolute body weight, the body weight Z-score, and the predicted whole-body bone mineral content on the basis of age and sex. Attempted validation in a small sample (N=7) of children who completed therapy for acute lymphoblastic leukemia revealed disparities reflective of the prevalence of obesity in such survivors. Further validation must be undertaken in large samples of children with a variety of malignant diseases to assess the robustness of the equations predictive of body composition.

The Changing Landscape for Human Absorption, Metabolism, and Excretion: Practical Experiences From a Data Analysis of 500 Studies.

Coincidental with the intensified regulatory and industry focus on the design and conduct of human absorption, metabolism, and excretion (hAME) studies in the past 12 months, we have recently completed our 500th cohort involving radiolabeled test item administration to humans. Here, we build upon a recent industry white paper in this journal1 and share some of our own experiences as a Contract Research Organization based upon collaborations with numerous pharma companies and their differing approaches to design and timing, to add further context to the discussion regarding hAME studies and the pivotal role that drug metabolism and pharmacokinetics plays. In this article, we explore how both changing relationships within the industry and shifting regulatory guidelines are impacting strategies, and compare EU and US pre-study approval requirements, before evaluating the trends from over 500 studies conducted at our global facilities conducted over more than 30 years. We conclude with a review of how improved technical capabilities and strategies are influencing the design and conduct of hAME studies, before speculating on some of the driving factors which may shape the direction they take in the future.

Predictors of bony morbidity in children with acute lymphoblastic leukemia.

BACKGROUND: To evaluate the relationship between lumbar spine (LS) bone mineral density (BMD) and patient-, disease-, and therapy-related variables, and to define the risk-factors for fractures in children receiving therapy on Dana-Farber Cancer Institute acute lymphoblastic leukemia (ALL) protocols. METHODS: Children (≤18 years) diagnosed with ALL during the period 1995-2006, who are in first clinical remission, were included (n = 124). Dual-energy X-ray absorptiometry provided LS-BMD at diagnosis (n = 46) and during continuation therapy. LS-BMD was expressed as Z scores based on local population norms. Regression analyses evaluated the risk of osteopenia (Z-score -1.01 to -1.99, osteoporosis (Z-score -2.00 or less) and fractures. RESULTS: At diagnosis, 14 0f 46 (30%) patients had osteopenia and 5 (11%) had osteoporosis; whereas, during continuation therapy, 47 of 124 (39.5%) patients had osteopenia, and 10 (8%) had osteoporosis. LS-BMD at diagnosis had a positive linear relationship with LS-BMD during continuation therapy (Pearson correlation coefficient 0.619, P < 0.0001). Multivariable analyses identified age ≥10 years and LS-BMD at diagnosis as independent predictors of LS-BMD during continuation therapy. Twenty-three (18.5%) patients developed fractures. Dexamethasone therapy (OR 3.4, 95% CI 1.31, 7.52, P = 0.01) and lower LS-BMD during the continuation therapy (OR 1.8, 95% CI 1.2, 2.8, P = 0.01) were independent predictors of fracture. CONCLUSIONS: Older age and lower LS-BMD at diagnosis are predictors of lower LS-BMD during continuation therapy. Dexamethasone and lower LS-BMD during continuation therapy are associated with fractures. Using these variables it is feasible to develop a predictor model to define the risk of bony morbidity in children receiving ALL therapy.

Intrarater reliability of dual-energy X-ray absorptiometry-based measures of vertebral height in postmenopausal women.

The primary purpose was to estimate intrarater reliability of vertebral body height (VH) measures in postmenopausal women based on duplicate analyses of vertebral fracture assessment (VFA) images. The secondary purpose was to determine the consistency in classification of vertebral deformity on duplicate analyses. Thirty-two VFA were randomly selected from a database of 464 scans acquired in postmenopausal women using dual-energy X-ray absorptiometry (Discovery A; Hologic Inc., Waltham, MA). Visible endplates were marked on each image on 2 occasions (4 wk apart) by a single rater; the semiautomated software derived measures of anterior, middle, and posterior VH and classified severity of vertebral deformity. Intrarater reliability was assessed using the intraclass correlation coefficient (with 95% confidence interval [CI]) when ≥ 22 VFA could be analyzed. Reliability of grading deformity of 267 vertebrae was assessed using Cohen's unweighted kappa (with 95% CI). Reliability of anterior, middle, and posterior height measures from T8 to L4 was 0.85 and greater except for T8 anterior VH and T9 posterior VH (0.76 [0.43, 0.90] and 0.62 [0.15, 0.83], respectively). Chance-corrected agreement for 4 grades of vertebral deformity was 0.48 (0.30, 0.66) and for 2 categories (normal/mild and moderate/severe) was 0.70 (50, 0.90). Intrarater reliability was acceptable for VH measures from T10 to L4. Reliability in grading severity of deformity was improved by classifying as <25% deformity (nonfracture) and as >25% deformity (fracture).

Creatinine as a measure of lean body mass during treatment of acute lymphoblastic leukemia in childhood.

Protein energy malnutrition is well-recognized in children with acute leukemia and may result in loss of lean body mass (LBM) with attendant morbidities. Much of the LBM consists of skeletal muscle, the mass of which is reflected in urinary creatinine excretion. As accurate 24 hours urine collections are challenging in children, we investigated the prospect that serum creatinine concentration provides a measure of LBM. Eleven children with acute lymphoblastic leukemia were assessed at 7 time points (6-mo intervals) from diagnosis to 1 year after the completion of therapy. LBM was measured as fat-free mass by dual energy x-ray absorptiometry (DXA scans) and correlated with serum creatinine concentration and 24 hours urine creatinine excretion. As expected, there was a strong correlation between 24 hours urinary creatinine excretion and LBM from DXA scans (r=0.79, P<0.001). Serum creatinine concentration also correlated with LBM (r=0.52, P<0.001). Serum creatinine concentration provides a surrogate measure of LBM in children with acute lymphoblastic leukemia. This will be especially useful in countries with limited resources in which more sophisticated measures, such as DXA scans, are seldom available.

Nutritional status at diagnosis in children with cancer. 2. An assessment by arm anthropometry.

Assessment of nutritional status in children with cancer is important but measures based on weight can be problematic at diagnosis, especially in those with advanced disease. Likewise, dual energy x-ray absorptiometry may be confounded by other radiological procedures and is not commonly available in low-income countries where most children with cancer live. Arm anthropometry is not subject to these constraints. In a study sample of 99 Canadian patients with cancer at diagnosis, mid-upper arm circumference correlated well with lean body mass as measured by dual energy x-ray absorptiometry but triceps skin fold thickness was a poor predictor of fat mass. Arm anthropometry can be a useful tool for the measurement of nutritional status in children with cancer. However, further studies, particularly in low-income countries and in children with solid tumors at diagnosis, are required to determine the full extent of its utility.

Radiation doses originating from diagnostic procedures during the treatment and follow-up of children and adolescents with malignant lymphoma.

Children with malignant lymphoma undergo many diagnostic procedures that involve exposure to ionising radiation. In addition, many, but by no means all, undergo further exposure to ionising radiation during radiotherapy. While therapeutic radiation exposures are prescribed, the extent of radiation exposure arising from diagnostic procedures utilised in such children is largely unknown. We completed an audit of the radiation doses arising from diagnostic imaging procedures performed in a cohort of children with malignant lymphoma. The cumulative effective radiation dose associated with radiographic and radioisotopic procedures was derived for 81 children and adolescents with malignant lymphoma during their diagnosis, treatment and follow-up. Thirty-eight of the 42 patients (90%) with Hodgkin lymphoma were alive at study termination, with follow-up periods ranging from 1.9 to 11.7 years (median 5.3). Thirty-three of the 39 patients (85%) with non-Hodgkin lymphoma were alive at study termination with follow-up periods ranging from 2.4 to 12.3 years (median 7.5). The median effective dose was 518 mSv for patients with Hodgkin lymphoma and 309 mSv for those with non-Hodgkin lymphoma. The maximum effective dose was 1.7 Sv. The principal contributors to the effective dose were computed tomography (CT) and nuclear medicine imaging procedures using (67)Ga. Protocols for the management of children and adolescents with malignant lymphoma should be reviewed in order to reduce the radiation detriment without loss of essential diagnostic information.

Nutritional status at diagnosis in children with cancer I. An assessment by dietary recall--compared with body mass index and body composition measured by dual energy X-ray absorptiometry.

The nutritional status of children with cancer is clinically important. In an effort to separate the influences of disease and treatment, we studied children at the time of diagnosis. A total of 99 children underwent assessment by 24 hours dietary recall, measurement of body mass index (BMI), and analysis of body composition by dual energy x-ray absorptiometry (DXA scan). The group averages for calorie intake and BMI were close to the median population norms but ranged widely among individuals. As a group the study participants exceeded the Dietary Reference Intake for protein. Nine children (9%) had a BMI

Is a fixed value for the least significant change appropriate?

The least significant change (LSC) represents the smallest difference between successive measurements of bone mineral density (BMD) that can be considered to be a real change and not attributable to chance. The LSC is derived from same-day in vivo BMD precision measurements. Our first objective was to determine if the LSC differs between technologists. Our second objective was to determine if patient body size influenced the LSC. Each of 8 technologists measured same-day precision in groups of 30 patients for the lumbar spine and the total trochanter and neck regions of the proximal femur. At the spine, precision ranged from 0.008 to 0.011g/cm(2) and did not differ between technologists. Precision for the total region of the left proximal femur ranged from 0.006 to 0.016g/cm(2) and did differ between technologists. For the trochanter and neck regions, precision ranged from 0.008 to 0.013g/cm(2) for the former and from 0.010 to 0.020g/cm(2) for the latter, again, with inter-technologist differences. The LSC for the lumbar spine increased linearly from 0.022 to 0.031g/cm(2) when body mass index (BMI) increased from 19.5 to 31.3kg/m(2). In contrast, there was no discernable impact of BMI on the LSC for any of the proximal femur regions. The LSC at the spine is determined by the patient, whereas the LSC at the femur is determined by the technologist. Use of a single value for the LSC will lead to misinterpretations of the significance of BMD changes at both the spine and the proximal femur.

Normative bone mineral density z-scores for Canadians aged 16 to 24 years: the Canadian Multicenter Osteoporosis Study.

The objectives of the study were to develop bone mineral density (BMD) reference norms and BMD Z-scores at various skeletal sites, to determine whether prior fracture and/or asthma were related to BMD, and to assess possible geographic variation of BMD among Canadian youth aged 16-24 yr. Z-Scores were defined as the number of standard deviations from the mean BMD of a healthy population of the same age, race, and sex. Z-Scores were calculated using the reference sample defined as Canadian Caucasian participants without asthma or prior fracture. Reference standards were created for lumbar spine (L1-L4), femoral neck, total hip, and greater trochanter, by each year of age (16-24 yr), and by sex. The Z-score norms were developed for groups noted earlier. Mean Z-scores between the asthma or fracture subgroups compared with the mean Z-scores in the reference sample were not different. There were minor differences in mean BMD across different Canadian geographic regions. This study provides age, sex, and skeletal site-specific Caucasian reference norms and formulae for the calculation of BMD Z-scores for Canadian youth aged 16-24 yr. This information will be valuable to help to identify individuals with clinically meaningful low BMD.

Alendronate once weekly for the prevention and treatment of bone loss in Canadian adult cystic fibrosis patients (CFOS trial).

BACKGROUND: Patients with cystic fibrosis (CF) are at risk for early bone loss, and demonstrate increased risks for vertebral fractures and kyphosis. A multicenter, randomized, controlled trial was conducted to assess the efficacy, tolerability, and safety of therapy with oral alendronate (FOSAMAX; Merck; Whitehouse Station, NJ) in adults with CF and low bone mass. METHODS: Participants received placebo or alendronate, 70 mg once weekly, for 12 months. All participants received 800 IU of vitamin D and 1,000 mg of calcium daily. Adults with confirmed CF with a bone mineral density (BMD) T score of < - 1.0 were eligible for inclusion. Participants who had undergone organ transplantation or had other reported contraindications were excluded from the study. The primary outcome measure was the mean (+/- SD) percentage change in lumbar spine BMD after 12 months. Secondary measures included the percentage change in total hip BMD, the number of new vertebral fractures (grade 1 or 2), and changes in quality of life. RESULTS: A total of 56 participants were enrolled in the study (mean age, 29.1 +/- 8.78 years; 61% male). The absolute percentage changes in lumbar spine and total hip BMDs at follow-up were significantly higher in the alendronate therapy group (5.20 +/- 3.67% and 2.14 +/- 3.32%, respectively) than those in the control group (- 0.08 +/- 3.93% and - 1.3 +/- 2.70%, respectively; p < 0.001). At follow-up, two participants (both in the control group) had a new vertebral fracture (not significant), and there were no differences in quality of life or the number of adverse events (including serious and GI-related events). CONCLUSION: Alendronate therapy was well tolerated and produced a significantly greater increase in BMD over 12 months compared with placebo.

Longitudinal analysis of vertebral fracture and BMD in a Canadian cohort of adult cystic fibrosis patients.

BACKGROUND: Vertebral fractures in patients with cystic fibrosis (CF) may contribute to an accelerated decline in lung function and can be a contraindication to lung transplantation. In this study, we examined longitudinal change in bone mineral density (BMD) and the prevalence of vertebral fractures in adult CF patients, without lung-transplant, attending a Canadian specialty clinic. METHODS: Retrospective chart review of all patients attending an Adult Cystic Fibrosis Clinic at Hamilton Health Sciences in Hamilton, Canada. Forty-nine of 56 adults met inclusion criteria. Chest radiographs were graded by consensus approach using Genant's semi-quantitative method to identify and grade fractured vertebrae. Dual x-ray absorptiometry (DXA) scans were also reviewed. RESULTS: The mean age of the cohort was 25.2 years (SD 9.4), 43% were male. The mean body mass index (BMI) was 19.8 (2.8) for males and 21.7 (5.1) for females. At baseline, the rate of at least one vertebral fracture was 16.3%; rising to 21.3% (prevalent and incident) after a 3-year follow-up. The mean BMD T-or Z-scores at baseline were -0.80 (SD 1.1) at the lumbar spine, -0.57 (SD 0.97) at the proximal femur, and -0.71 (SD 1.1) at the whole body. Over approximately 4-years, the mean percent change in BMD was -1.93% at the proximal femur and -0.73% at the lumbar spine. CONCLUSION: Approximately one in five CF patients demonstrated at least one or more vertebral fractures. Moderate declines in BMD were observed. Given the high rate of vertebral fractures noted in this cohort of adult CF patients, and the negative impact they have on compromised lung functioning, regular screening for vertebral fractures should be considered on routine chest radiographs.

Minimum joint space width and tibial cartilage morphology in the knees of healthy individuals: a cross-sectional study.

BACKGROUND: The clinical use of minimum joint space width (mJSW) and cartilage volume and thickness has been limited to the longitudinal measurement of disease progression (i.e. change over time) rather than the diagnosis of OA in which values are compared to a standard. This is primarily due to lack of establishment of normative values of joint space width and cartilage morphometry as has been done with bone density values in diagnosing osteoporosis. Thus, the purpose of this pilot study is to estimate reference values of medial joint space width and cartilage morphometry in healthy individuals of all ages using standard radiography and peripheral magnetic resonance imaging. DESIGN: For this cross-sectional study, healthy volunteers underwent a fixed-flexion knee X-ray and a peripheral MR (pMR) scan of the same knee using a 1T machine (ONI OrthOne, Wilmington, MA). Radiographs were digitized and analyzed for medial mJSW using an automated algorithm. Only knees scoring 0.05) in either sex. Females had a mean (SD) medial mJSW of 4.8 (0.7) mm compared to males with corresponding larger value of 5.7 (0.8) mm. Cartilage morphometry results showed similar trends with mean (SD) tibial cartilage volume and thickness in females of 1.50 (0.19) microL/mm2 and 1.45 (0.19) mm, respectively, and 1.77 (0.24) microL/mm2 and 1.71 (0.24) mm, respectively, in males. CONCLUSION: These data suggest that medial mJSW values do not decrease with aging in healthy individuals but remain fairly constant throughout the lifespan with "healthy" values of 4.8 mm for females and 5.7 mm for males. Similar trends were seen for cartilage morphology. Results suggest there may be no need to differentiate a t-score and a z-score in OA diagnosis because cartilage thickness and JSW remain constant throughout life in the absence of OA.