Differing effects of denosumab and alendronate on cortical and trabecular bone.

Vertebral fractures and trabecular bone loss are hallmarks of osteoporosis. However, 80% of fractures are non-vertebral and 70% of all bone loss is cortical and is produced by intracortical remodeling. The resulting cortical porosity increases bone fragility exponentially. Denosumab, a fully human anti-RANKL antibody, reduces the rate of bone remodeling more than alendronate. The aim of this study was to quantify the effects of denosumab and alendronate on cortical and trabecular bone. Postmenopausal women, mean age 61years (range 50 to 70), were randomized double blind to placebo (n=82), alendronate 70mg weekly (n=82), or denosumab 60mg every 6months (n=83) for 12months. Porosity of the compact-appearing cortex (CC), outer and inner cortical transitional zones (OTZ, ITZ), and trabecular bone volume/total volume (BV/TV) of distal radius were quantified in vivo from high-resolution peripheral quantitative computed tomography scans. Denosumab reduced remodeling more rapidly and completely than alendronate, reduced porosity of the three cortical regions at 6months, more so by 12months relative to baseline and controls, and 1.5- to 2-fold more so than alendronate. The respective changes at 12months were [mean (95% CI)]; CC: -1.26% (-1.61, -0.91) versus -0.48% (-0.96, 0.00), p=0.012; OTZ: -1.97% (-2.37, -1.56) versus -0.81% (-1.45, -0.17), p=0.003; and ITZ: -1.17% (-1.38, -0.97) versus -0.78% (-1.04, -0.52), p=0.021. Alendronate reduced porosity of the three cortical regions at 6months relative to baseline and controls but further decreased porosity of only the ITZ at 12months. By 12months, CC porosity was no different than baseline or controls, OTZ porosity was reduced only relative to baseline, not controls, while ITZ porosity was reduced relative to baseline and 6months, but not controls. Each treatment increased trabecular BV/TV volume similarly: 0.25% (0.19, 0.30) versus 0.19% (0.13, 0.30), p=0.208. The greater reduction in cortical porosity by denosumab may be due to greater inhibition of intracortical remodeling. Head to head studies are needed to determine whether differences in porosity result in differing fracture outcomes.

Assessment of bone microarchitecture in postmenopausal women on long-term bisphosphonate therapy with atypical fractures of the femur.

Reports of atypical femoral fractures (AFFs) in patients receiving long- term bisphosphonate therapy have raised concerns regarding the genesis of this rare event. Using high-resolution peripheral quantitative computed tomography (HR-pQCT), we conducted a study to evaluate bone microarchitecture in patients who had suffered an AFF during long-term bisphosphonate treatment. The aim of our study was to evaluate if bone microarchitecture assessment could help explain the pathophysiology of these fractures. We compared bone volumetric density and microarchitectural parameters measured by HR-pQCT in the radius and tibia in 20 patients with AFFs with 35 postmenopausal women who had also received long-term bisphosphonate treatment but had not experienced AFFs, and with 54 treatment-naive postmenopausal women. Control groups were similar in age, body mass index (BMI), and bone mineral density (BMD). Mean age of the 20 patients with AFFs was 71 years, mean lumbar spine T-score was -2.2, and mean femoral neck T-score was -2. Mean time on bisphosphonate treatment was 10.9 years (range, 5-20 years). None of the patients had other conditions associated with AFFs such as rheumatoid arthritis, diabetes or glucocorticoid use. There were no statistically significant differences in any of the parameters measured by HR-pQCT between postmenopausal women with or without treatment history and with or without history of atypical fractures. We could not find any distinctive microarchitecture features in the peripheral skeleton of women who had suffered an atypical fracture of the femur while receiving bisphosphonate treatment. This suggests that risk of developing an atypical fracture is not related to bone microarchitecture deterioration. Our results indicate that there may be other individual factors predisposing to atypical fractures in patients treated with bisphosphonates, and that those are independent of bone microarchitecture. In the future, identification of those factors could help prevent and understand the complex physiopathology of these rare events.

Multicenter precision of cortical and trabecular bone quality measures assessed by high-resolution peripheral quantitative computed tomography.

High-resolution peripheral quantitative computed tomography (HR-pQCT) has recently been introduced as a clinical research tool for in vivo assessment of bone quality. The utility of this technology to address important skeletal health questions requires translation to standardized multicenter data pools. Our goal was to evaluate the feasibility of pooling data in multicenter HR-pQCT imaging trials. Reproducibility imaging experiments were performed using structure and composition-realistic phantoms constructed from cadaveric radii. Single-center precision was determined by repeat scanning over short-term (<72 hours), intermediate-term (3-5 months), and long-term intervals (28 months). Multicenter precision was determined by imaging the phantoms at nine different HR-pQCT centers. Least significant change (LSC) and root mean squared coefficient of variation (RMSCV) for each interval and across centers was calculated for bone density, geometry, microstructure, and biomechanical parameters. Single-center short-term RMSCVs were <1% for all parameters except cortical thickness (Ct.Th) (1.1%), spatial variability in cortical thickness (Ct.Th.SD) (2.6%), standard deviation of trabecular separation (Tb.Sp.SD) (1.8%), and porosity measures (6% to 8%). Intermediate-term RMSCVs were generally not statistically different from short-term values. Long-term variability was significantly greater for all density measures (0.7% to 2.0%; p < 0.05 versus short-term) and several structure measures: cortical thickness (Ct.Th) (3.4%; p < 0.01 versus short-term), cortical porosity (Ct.Po) (15.4%; p < 0.01 versus short-term), and trabecular thickness (Tb.Th) (2.2%; p < 0.01 versus short-term). Multicenter RMSCVs were also significantly higher than short-term values: 2% to 4% for density and micro-finite element analysis (µFE) measures (p < 0.0001), 2.6% to 5.3% for morphometric measures (p < 0.001), whereas Ct.Po was 16.2% (p < 0.001). In the absence of subject motion, multicenter precision errors for HR-pQCT parameters were generally less than 5%. Phantom-based multicenter precision was comparable to previously reported in in vivo single-center precision errors, although this was approximately two to five times worse than ex vivo short-term precision. The data generated from this study will contribute to the future design and validation of standardized procedures that are broadly translatable to multicenter study designs.

Mechanism of action study to evaluate the effect of rosiglitazone on bone in postmenopausal women with type 2 diabetes mellitus: rationale, study design and baseline characteristics.

OBJECTIVES: Post-hoc analyses have shown an increase incidence of fractures among type 2 diabetes (T2DM) patients treated with thiazolidinediones (TZDs). The mechanisms by which TZDs may be associated with increased fracture risk is not well understood. This article describes the study design and baseline characteristics for a prospective, randomized, double-blind, active-controlled trial to evaluate the effects of rosiglitazone on changes in measures of skeletal structure, surrogates of bone strength and metabolism. METHODS: Postmenopausal women without osteoporosis and diagnosed with T2DM were randomized in a double-blind design to either rosiglitazone or metformin for 52 weeks, then all subjects received open-label metformin for 24 weeks. Study endpoints included changes in bone mineral density (BMD), quantitative computed tomography (QCT), digitized hip radiography (HXR) and high resolution magnetic resonance imaging (hrMRI). Serum markers of bone metabolism and indices of glycemic control were assessed within and between treatment groups. RESULTS: A total of 226 subjects were randomized. Baseline characteristics included: age 63.8 ± 6.5 years; years postmenopausal 16.9 ± 8.4; duration of diabetes 3.5 (1.8-7.8) years; body mass index (BMI) 31.4 ± 5.9 kg/m(2); and glycated hemoglobin (HbA1c) 6.4 ± 0.65%. At baseline, mean T-scores were -0.95 ± 0.91 at the femoral neck, -0.02 ± 0.97 at the total hip and -0.55 ± 1.25 at the total spine. Since there are no well recognized techniques to determine bone mass and structure at the distal limbs (cortical bone sites where fractures were reported in RSG subjects), using the femoral neck as a surrogate for these areas may be a potential limitation of the study. CONCLUSION: This is the first randomized trial utilizing multiple techniques to evaluate bone mass, structure, serum markers of bone remodeling, and potential reversibility of changes after discontinuation of rosiglitazone. This study will provide information about RSG bone effects in a population of postmenopausal women at risk for bone loss and subsequent fracture. CLINICALTRIALSGOV NUMBER: NCT00679939.

Denosumab: an update.

Denosumab is a fully human monoclonal antibody that inhibits the formation, function and survival of osteoclasts, preventing the interaction of tumor necrosis factor ligand superfamily member 11 (receptor activator of nuclear factor kappa-B ligand, RANKL) with the tumor necrosis factor receptor superfamily member 11A (osteoclast differentiation factor receptor, ODFR, receptor activator of NF-KB, RANK). This results in a reduction in bone resorption and an increase in bone mineral density. In clinical studies, denosumab has been shown to decrease the risk for vertebral, hip and nonvertebral fractures in women with postmenopausal osteoporosis and the risk for new vertebral fractures in men with nonmetastatic prostate cancer receiving androgen deprivation therapy, with a rate of side effects similar to placebo. A number of clinical trials with denosumab are ongoing to demonstrate its value for other indications and to further characterize its effects on immunomodulation. Denosumab is a new alternative for the prevention and treatment of postmenopausal osteoporosis and a promising agent for the treatment of other bone diseases associated with bone loss.

Denosumab: What's new?

Denosumab is the first fully human monoclonal antibody that inhibits the formation, function, and survival of osteoclasts by blocking the interaction of receptor activator of nuclear factor-κB (RANK) ligand with its osteoclastic receptor RANK. Clinical studies have shown that the decreased bone resorption and increased bone mineral density resulting from the use of denosumab 60 mg twice yearly entail significant risk reduction of vertebral, hip, and nonvertebral fractures in women with postmenopausal osteoporosis, with an acceptable rate of side effects so far. Following its approval by the US Food and Drug Administration and the European Medicines Agency, a number of clinical trials with denosumab are ongoing to demonstrate its value for other indications and to further characterize its effects on immunomodulation. Denosumab offers a new choice for the treatment of postmenopausal osteoporosis in patients at high risk for fracture.

Treatment of postmenopausal women with osteoporosis with PTH(1-84) for 36 months: treatment extension study.

OBJECTIVE: To determine the safety and efficacy of full-length parathyroid hormone, PTH(1-84), treatment for up to 36 months by evaluating bone mineral density (BMD) changes, bone histomorphometric indices, and clinical fracture incidence in postmenopausal women with osteoporosis. BACKGROUND: The TOP trial demonstrated increased lumbar spine BMD (6.9%) versus placebo after 18 months of PTH(1-84) treatment and reduced the incidence of new vertebral fractures (61%; p = 0.001). The therapeutic benefits of long-term treatment of postmenopausal women with PTH(1-84) are unknown. METHODS: The safety and efficacy of 36 months of once-daily dosing with 100 µg PTH(1-84) in postmenopausal women with osteoporosis were assessed. Women receiving placebo during the TOP trial were eligible for PTH(1-84) in the extension study. CLINICAL TRIAL REGISTRATION: NCT00172120. RESULTS: Lumbar spine BMD increased by 8.5% above baseline (p < 0.001) at 36 months of PTH(1-84) treatment, remaining stable during the last 12 months of treatment. Increases in total hip and femoral neck BMD occurred more slowly, reaching 3.2% and 3.4%, respectively above baseline at 36 months (p < 0.001). The total hip BMD showed no signs of reaching a limiting value although the femoral neck plateaued from months 24 to 36. Seven patients had vertebral fractures during the placebo phase of the TOP trial and before entering the extension study, but this rate decreased with the introduction of PTH(1-84) therapy, resulting in a single worsened vertebral fracture in the first 6 months and no further vertebral fractures from months 6 to 36. Treatment over 36 months with PTH(1-84) was well-tolerated and iliac crest biopsies showed no adverse effects on bone. LIMITATIONS: There was no placebo group for BMD comparisons. The number of patients assessed for fracture incidence was small. CONCLUSIONS: PTH(1-84) treatment for 36 months resulted in significant increases in BMD at the lumbar spine and hip, was associated with a lower incidence of vertebral fracture when compared to before therapy initiation, and was well-tolerated. The continuous increases in total hip BMD suggest that prolonged PTH(1-84) treatment may be beneficial for postmenopausal osteoporosis. Increased BMD at the femoral neck and lumbar spine also showed favourable changes but plateaued between 24 and 36 months. Long-term treatment was not associated with abnormalities in bone biopsies.

Assessment of material, structural, and functional properties of the human skeleton by pQCT systems.

Peripheral quantitative computed tomography (pQCT) systems measure bone parameters noninvasively using low radiation doses. This limits image resolution but is practical for the diagnosis and quantitative monitoring of the properties of the peripheral human skeleton. pQCT determines volumetric bone mineral density separately in trabecular and cortical bone. It may combine densitometry determinations with geometric estimates and use strain-stress indexes, and it may be used to analyze muscle variables in some areas, allowing the study of regional fragility. Experimental and clinical ex vivo studies show that pQCT variables correlate with biomechanical predictors of fragility and/or fractures. Since pQCT was approved by the US Food and Drug Administration in 1997, new skeletal regions (human femur and mandible) have been considered in the development of the system. Basically, pQCT explores intraindividual and interindividual variations in greater detail and compares the impact of skeletal diseases, risk factors, and anabolic and catabolic treatments within a given bone cross section.

Clinical use of quantitative computed tomography and peripheral quantitative computed tomography in the management of osteoporosis in adults: the 2007 ISCD Official Positions.

The International Society for Clinical Densitometry (ISCD) has developed Official Positions for the clinical use of dual-energy X-ray absorptiometry (DXA) and non-DXA technologies. While only DXA can be used for diagnostic classification according to criteria established by the World Health Organization, DXA and some other technologies may predict fracture risk and be used to monitor skeletal changes over time. ISCD task forces reviewed the evidence for clinical applications of non-DXA techniques and presented reports with recommendations at the 2007 ISCD Position Development Conference. Here we present the ISCD Official Positions for quantitative computed tomography (QCT) and peripheral QCT (pQCT), with supporting medical evidence, rationale, controversy, and suggestions for further study. QCT is available for bone mineral density measurements at the spine, hip, forearm, and tibia. The ISCD Official Positions presented here focus on QCT of the spine and pQCT of the forearm. Measurements at the hip may have clinical relevance, as this is an important fracture site; however, due to limited medical evidence, definitive advice on its use in clinical practice cannot be provided until more data emerge.

Evaluation of cortical bone by peripheral quantitative computed tomography in continuous ambulatory peritoneal dialysis patients.

Several studies have suggested an increased prevalence of osteopenia in dialysis. Peripheral quantitative computed tomography (pQCT) is a new technique that allows the noninvasive evaluation of trabecular and cortical bone separately. The aim of the study was: (1) to evaluate cortical bone by pQCT in continuous ambulatory peritoneal dialysis (CAPD) patients and compare the data with that obtained in healthy controls; and (2) to correlate cortical bone parameters with bone mineral density (BMD) of the lumbar spine and femoral neck and total bone mineral content (TBMC). Cortical bone parameters were obtained in 22 CAPD patients and 27 healthy individuals at the distal radius using a Stratec XCT 960 pQCT machine. In the dialysis patients, we also determined BMD and TBMC by bone densitometry. Dialysis patients, compared with controls, showed a significant reduction in volumetric cortical BMD (VcBMD) (p = 0.04) and cortical thickness (cThk) (p < 0.0001) with a significant increase in radial total cross-sectional area (TA) (p = 0.006), endosteal circumference (p < 0.0001), and buckling ratio (p < 0.0001). In CAPD patients, total time on dialysis correlated negatively with radial total BMD (p < 0.01) and VcBMD (p < 0.01). Age correlated positively with TA (p < 0.01), endosteal (p < 0.01), and periosteal circumferences (p < 0.01). Serum intact parathyroid hormone (PTH) levels correlated positively with endosteal (p = 0.04) and periosteal perimeter (p = 0.01). Total alkaline phosphatase correlated negatively with VcBMD (p < 0.01), and positively with endosteal perimeter (p = 0.02). Total bone mineral content correlated significantly with radial cortical content (p < 0.001), cross-sectional cortical area (cA; p < 0.001), and cThk (p < 0.01) but not with total radial BMD, VcBMD, or buckling ratio. No correlations were found between radial cortical parameters and BMD measured at the lumbar spine or femoral neck. We conclude that dialysis patients show cortical osteopenia with marked cortical thinning partially mediated by PTH action on bone. Total bone mineral content correlated with various radial cortical parameters (content, area, and thickness) but not with others. No correlations were found between cortical bone parameters measured at the peripheral skeleton with areal bone density measured at the axial skeleton. These findings suggest that pQCT may be a new tool in the assessment of bone fragility in dialysis patients.

Parathyroid hormone (1-84) and teriparatide in the treatment of postmenopausal osteoporosis.

Osteoporosis-related fractures are a major public health problem worldwide. Antiresorptive drugs, which work principally by suppressing bone resorption, are the established therapeutic approach for the prevention of fragility fractures in patients with osteoporosis. Parathyroid hormone and its analogs represent a new class of agents with anabolic effects on the skeleton. The results of double-blind, randomized, placebo-controlled trials have shown that both the full length, 84 amino acid parathyroid hormone and teriparatide, the parathyroid hormone fragment (1-34) increase bone mineral density and reduce the risk of fracture when administered intermittently to postmenopausal osteoporotic women. Therefore, these drugs should be considered an alternative therapy in postmenopausal osteoporosis.

Effects of teriparatide [rhPTH (1-34)] treatment on structural geometry of the proximal femur in elderly osteoporotic women.

INTRODUCTION: We evaluated effects of teriparatide (rDNA origin) injection [teriparatide, rhPTH (1-34), TPTD] on hip structure among a subset 558 postmenopausal women enrolled in the Fracture Prevention Trial. METHODS: Patients were randomized to once-daily, self-administered subcutaneous injections of placebo (N = 189), teriparatide 20 mug (TPTD20; N = 186), or 40 mug (TPTD40; N = 183) for a median of 20 months. Repeated dual energy X-ray absorptiometry (DXA) hip scans were analyzed with the Hip Structure Analysis (HSA) program to derive structural geometry. RESULTS AND CONCLUSIONS: There were no significant differences in age or body size between groups at baseline, 1 year, or study termination. At the femoral neck, teriparatide increased bone mass and improved bone geometric strength in both treatment groups compared to the placebo group, with the response being dose-related. The mean difference (95% CI) in bone cross-sectional area (CSA) in the TPTD20 was 3.5% (1.8% to 5.3%), and 6.3% (4.5% to 8.2%) in TPTD40 at study termination, compared to placebo controls. Teriparatide treatment increased bending strength, with the mean difference in section modulus being 3.6% (1.4% to 5.8%) and 6.8% (4.6% to 9.1%) greater in the TPTD20 and TPTD40 groups, respectively. Compared to placebo, local cortical instability characterized by the buckling ratio decreased by 5.5% (3.5% to 7.5%) and 8.6% (6.6% to 10.5%) in the TPTD20 and TPTD40 groups, respectively, during the study period. The changes at the intertrochanteric region were comparable to those at the narrow neck although between-group differences were slightly smaller. Except for an inconsequential (1%) improvement in section modulus in TPTD20, teriparatide effects did not reach significance at the femoral shaft. In conclusion, teriparatide treatment improved axial and bending strength, and increased cortical thickness and stability at the femoral neck and intertrochanteric region. Teriparatide treatment effects were not apparent at the purely cortical femoral shaft.

Bone densitometry in a patient with hypophosphatemic osteomalacia.

A 60-year-old Caucasian woman with a 1-year history of pain at the ribs, spine, and pelvis consulted at our Institute in March 1999. She brought a bone densitometry performed using a Lunar DPX densitometer that showed bone mineral density (BMD) measurements in the osteoporotic range at both the lumbar spine and the femoral neck. As a child she had had bowed legs and had been treated with ultraviolet radiation. Results of the laboratory test performed at our institute showed normal total serum calcium, repeated low serum P levels, and a low renal phosphate threshold with elevated total and bone fraction of alkaline phosphatase with normal intact parathyroid hormone (PTH). A diagnosis of hypophosphatemic osteomalacia due to renal phosphate leak was made. She began treatment with neutral sodium phosphate at 1.5 g/day and calcitriol 0.5 microg/day. Her serum P levels normalized, and there was a progressive decrease in alkaline phosphatase levels. The densitometry showed a very rapid increase in BMD values with normalization at the lumbar spine after 10 months of treatment. This case shows the importance of bone densitometry in the follow-up of patients with suspected osteomalacia.

Bone mineral density: serum markers of bone turnover and their relationships in peritoneal dialysis.

BACKGROUND: The usefulness of bone mass measurements and bone turnover markers to estimate the risk of fracture and the type of underlying renal osteodystrophy are not well established in patients on peritoneal dialysis (PD). OBJECTIVE: To assess bone mass using total and regional bone densitometry in a group of patients on PD and to determine if serum markers of bone turnover identify patients with low bone mass. METHODS: Bone densitometry was studied by dual-energy x-ray absorptiometry (DEXA), and bone turnover using several serum markers, in 65 patients on PD. Bone mass was classified as normal, osteopenic, or osteoporotic according to World Health Organization criteria based on bone mineral density (BMD) T scores. RESULTS: T scores in the osteopenia range were present at the lumbar spine (LS) in 44.6% (45% of men and 44.4% of women) of patients and at the femoral neck (FN) in 56.9% (55% of men and 58% of women). T scores in the osteoporosis range were present at the LS in 13.8% of patients (10% of men and 15.5% of women) and at the FN in 21.5% (30% of men and 17.7% of women). Patients with BMD T scores in the osteoporosis range at both regions had increased serum intact parathyroid hormone (iPTH) levels compared to patients in the osteopenic/normal range. Bone mineral content in the whole skeleton (TBMC) correlated negatively with iPTH (r = -0.34) and with total time on dialysis (r = -0.26); in multivariate analysis, only iPTH correlated negatively with TBMC (B = -0.26, p = 0.03). No correlations were found between the other bone markers and BMD T scores at the FN or LS. There were no significant differences in absolute BMD or BMD T scores at the LS or FN between patients with and patients without fractures. CONCLUSIONS: BMD T scores in the osteopenia/osteoporosis range were observed at the LS in 58.4% of these patients on PD and at the FN in 78.4%. TBMC correlated negatively with iPTH. There were no correlations between markers of bone turnover and bone mass measurements at the two skeletal regions, although patients with BMD T scores in the osteoporosis range had increased serum iPTH levels. Bone mass measurements were not different between patients with and patients without fractures.

Medición in vivo del contenido mineral de los cálculos renales por densitometría de doble haz: correlación con su fragilidad a la litotricia extracorpórea por ondas de choque / In vivo measurement of the mineral content of renal calculi by dual-photon absorptiometry: correlation with its fragility to extracorporeal shockwave lithotripsy

After a few years of experience with extracorporeal shock wave lithotripsy (ESWL) and other fragmentation techniques, it has become apparent that stone fragility is a significant clinical distinction that should be taken into consideration when selecting a treatment program. In 30 unselected patients, stone mineral content, density and area were measured in vivo by dual-photon absorptiometry prior to perform ESWL treatment. Stone area determinations showed a median of 4.21 with a range of 0.46 to 49.7 cm2. Stone mineral content (g) and stone density (g/cm2) values were 2.47 and 0.46 with ranges of 0.37 to 13.7 and 0.167 to 1.203 respectively. The number of shocks needed for total fragmentation were 2375 with a range of 1200 to 7800. No correlation could be found between the number of shocks needed for fragmentation and the stone area or density. On the other hand, a strong linear correlation (r = 0.81, p < 0.001) (Fig. 1) could be demonstrated between stone mineral content and the number of shocks needed for fragmentation. Our results support the concept that size alone is not always a suitable criterion for selecting a stone as appropriate for ESWL, since no correlation could be found between stone area and the number of shocks needed for total fragmentation. We were also unable to find any correlation between in vivo stone density measured by dual-photon absorptiometry and the number of shocks required for stone fragmentation. Instead, a strong linear correlation between stone mineral content and its resistance to shock wave fragmentation was found. Therefore, calculation of mineral content appears to be the determinant of the amount of energy required for total fragmentation. Our results strongly suggest that in vivo stone mineral content measurement provides helpful information for predicting the fragmentation prospect of a stone.

Medición in vivo del contenido mineral de los cálculos renales por densitometría de doble haz: correlación con su fragilidad a la litotricia extracorpórea por ondas de choque / In vivo measurement of the mineral content of renal calculi by dual-photon absorptiometry: correlation with its fragility to extracorporeal shockwave lithotripsy

After a few years of experience with extracorporeal shock wave lithotripsy (ESWL) and other fragmentation techniques, it has become apparent that stone fragility is a significant clinical distinction that should be taken into consideration when selecting a treatment program. In 30 unselected patients, stone mineral content, density and area were measured in vivo by dual-photon absorptiometry prior to perform ESWL treatment. Stone area determinations showed a median of 4.21 with a range of 0.46 to 49.7 cm2. Stone mineral content (g) and stone density (g/cm2) values were 2.47 and 0.46 with ranges of 0.37 to 13.7 and 0.167 to 1.203 respectively. The number of shocks needed for total fragmentation were 2375 with a range of 1200 to 7800. No correlation could be found between the number of shocks needed for fragmentation and the stone area or density. On the other hand, a strong linear correlation (r = 0.81, p < 0.001) (Fig. 1) could be demonstrated between stone mineral content and the number of shocks needed for fragmentation. Our results support the concept that size alone is not always a suitable criterion for selecting a stone as appropriate for ESWL, since no correlation could be found between stone area and the number of shocks needed for total fragmentation. We were also unable to find any correlation between in vivo stone density measured by dual-photon absorptiometry and the number of shocks required for stone fragmentation. Instead, a strong linear correlation between stone mineral content and its resistance to shock wave fragmentation was found. Therefore, calculation of mineral content appears to be the determinant of the amount of energy required for total fragmentation. Our results strongly suggest that in vivo stone mineral content measurement provides helpful information for predicting the fragmentation prospect of a stone.(AU)