Prof. Daniele Diacinti

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Morphometric vertebral fractures in postmenopausal women with primary hyperparathyroidism.

Ricerche Osteoporosi


Context: An increased risk of fracture in patients with primary hyperparathyroidism (PHPT) compared to the general population has been reported, but available data are controversial.

Objective: The aim of the study was to evaluate the rate of vertebral fractures (VFs) by dual-energy x-ray absorptiometry in postmenopausal women with sporadic PHPT and compare the results with a control group.

Design and Setting: A case-control study was performed at a referral center.

Participants: A total of 150 consecutive patients and 300 healthy women matched for age and menopausal age participated in the study.

Results: VFs were detected in 37 of 150 (24.6%) patients and 12 of 300 (4.0%) controls (P < 0.0001). The majority of VFs were mild. Stepwise multiple logistic regression analysis showed that in PHPT patients lumbar spine bone mineral density was the only variable independently associated with the prevalence of VFs (P = 0.003). The rate of fracture was higher in symptomatic (34.1%) than asymptomatic (21.1%) patients, but this difference was not statistically significant (P = 0.15). Among asymptomatic patients, fracture rate was significantly higher in those who met the criteria for parathyroidectomy (28.1%) than in those who did not (11.1%) (P = 0.03). Compared to controls, the fracture rate was significantly higher in patients with symptomatic and asymptomatic PHPT who met the criteria for surgery (P < 0.0001), but not in those who did not meet the criteria (P = 0.06).

Conclusions: VF rate is increased in postmenopausal women with PHPT compared to controls, independently of whether they are classified as symptomatic or asymptomatic. The question of whether the finding of mild morphometric VFs in the latter represents an indication for parathyroid surgery remains to be established.
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Primary hyperparathyroidism is associated with an increased risk of morphometric vertebral fractures both in symptomatic and asymptomatic patients.

The common clinical presentation of primary hyperparathyroidism (PHPT) changed after the introduction of the automated serum calcium measurement from a disease that was primarily symptomatic and characterized by hypercalcemic symptoms, kidney stones, overt bone disease, and specific neuromuscular symptoms to one that is primarily asymptomatic at the time of diagnosis (1). Although PHPT occurs at all ages, the majority of patients are postmenopausal women (1). A variable degree of bone loss is commonly found, with a greater involvement of cortical sites, such as the forearm, than at trabecular sites, such as the lumbar spine (1,2). An increased risk of fracture compared with the general population has also been reported in most studies, but to what extent the risk of fracture is increased in PHPT is still controversial (3,4,5,6,7,8,9,10,11,12,13,14). Several factors, such as the retrospective nature of all studies, the selection of the patients and controls, and the methods to define vertebral fractures may account for the discrepant data. In all these studies vertebral fractures were defined on the basis of x-rays.

Despite the preferential involvement of cortical bone in PHPT, an increased rate of vertebral fractures has been reported in most studies, some of which also included patients with asymptomatic PHPT (3,5,6,7,10,13,14). Two thirds of vertebral fractures are clinically silent, but they are associated with the same increased risk of additional vertebral and nonvertebral fractures as are clinically symptomatic vertebral fractures (15). Vertebral x-ray examination is the gold standard by which vertebral fractures are detected, but vertebral fracture assessment (VFA) by dual-energy x-ray absorptiometry (DXA) has been recognized recently as an acceptable alternative. VFA is more convenient compared with the standard vertebral spine x-ray because it is performed at the same time as bone mineral density (BMD) measurement by DXA with less radiation exposure (16).

The aim of the present study was to evaluate the presence of vertebral fractures using VFA in a series of postmenopausal women with sporadic PHPT and compare the results with an appropriate control group.
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Subjects and Methods

Between January 2004 and December 2006, 230 consecutive Caucasian postmenopausal women with PHPT were evaluated at the Department of Endocrinology at the University of Pisa (Fig. 1​1).). The diagnosis of PHPT was based on elevated ionized [>5.3 mg/dl (>1.32 mmol/liter); normal range, 4.5–5.3 mg/dl (1.12–1.32 mmol/liter), respectively] or albumin-corrected serum calcium [>10.2 mg/dl (>2.55 mmol/liter); normal range, 8.2–10.2 mg/dl (2.05–2.55 mmol/liter), respectively)] with increased [>75 pg/ml (>75 ng/liter); normal range, 15–75 pg/ml (15–75 ng/liter), respectively] or inappropriately normal intact PTH on at least three separate occasions.
Figure 1

Figure 1
Flow diagram of patient recruitment. Symptomatic patients had symptoms of hypercalcemia, nephrolithiasis, osteitis fibrosa cystica, or low-trauma clinical fractures. Criteria for parathyroid surgery were those established by the 2002 Workshop on Asymptomatic ...

All women underwent clinical, biochemical, and densitometric evaluations (see below). Patients with familial hypocalciuric hypercalcemia (n = 3) or identified by the screening of kindreds with PHPT (n = 1) and patients treated with antiosteoporotic drugs (n = 41), or with previous or concomitant diseases (n = 13) or therapies affecting the skeleton (n = 6), were all excluded. Of the remaining 166 women with PHPT, 150 agreed to assessment of the vertebral spine by VFA. PHPT was diagnosed in 21 (14.0%) patients because of classical manifestations of PHPT, in 22 (14.7%) in the course of an evaluation for low BMD (n = 4) or osteoporosis (n = 18), and in 107 (71.3%) in the course of a routine biochemical screening test.

A total of 148 had sporadic PHPT, and two had familial PHPT that was later diagnosed by the measurement of serum calcium and PTH in first-degree relatives (one multiple endocrine neoplasia type 1, and one familial isolated PHPT).

Patients were grouped as symptomatic (n = 41; 27.3%), defined by the presence of symptoms of hypercalcemia, nephrolithiasis, osteitis fibrosa cystica, and low-trauma clinical fractures (n = 4, 31, 0, 13, respectively) or asymptomatic (n = 109; 72.7%) in the absence of previous features (Fig. 1​1).). X-ray was used to detect osteitis fibrosa cystica in patients with bone pain and/or fractures. Asymptomatic patients were further grouped according to whether they met (n = 64) or did not meet (n = 45) the criteria for surgery as established by the 2002 Workshop on Asymptomatic PHPT (17). A BMD T-score below −2.5 at any site was the criterion that defined an asymptomatic patient as meeting indications for surgery in 52 (47.7%) patients and the unique criterion in 32 (29.4%). The diagnosis of PHPT was confirmed by surgery in 108 patients.

The control group consisted of 300 healthy postmenopausal women matched (2:1) for age (± 2 yr) and menopausal age (± 5 yr). They were selected from a series of ambulatory postmenopausal women with no diseases or therapies affecting the skeleton. They underwent a densitometric evaluation (lumbar spine and hip) during the same period of time, as a part of the menopause screening and agreed to a VFA evaluation. Routine blood tests in these control subjects were normal, including a serum calcium and PTH determination.

The study was approved by the local Institutional Review Board. Written informed consent was obtained from all patients.
Laboratory methods

Serum calcium, creatinine, and urinary calcium and creatinine clearance were determined using standard methods. Ionized calcium was measured as previously described (18). Serum PTH was measured by immunoradiometric assay (DiaSorin, Saluggia, Italy), bone-specific alkaline phosphatase (BSAP) by immunoenzymatic assay (OCTEIA Ostase BAP; IDS Ltd., Boldon, Tyne & Wear, UK), and serum 25-hydroxyvitamin D (25-OHD) by RIA (DiaSorin). Serum N-MID osteocalcin (IDS Ltd., Boldon, UK) and serum C-terminal telopeptides of type 1 collagen (CTX) (Nordic Bioscience Diagnostics A/S, Herlew, Denmark) were measured by ELISA. The estimated glomerular filtration rate (eGFR) was evaluated from serum creatinine using the four-variable version of the Modification of Diet in Renal Disease index (19).


BMD (grams per square centimeter) was measured by DXA (QDR-4500; Hologic Inc., Waltham, MA) at the lumbar spine in posterior-anterior projection (L1–L4) (LS-BMD), femoral sites [femoral neck (FN-BMD) and total femur], and nondominant forearm (one third distal). BMD was expressed as T-score (difference from the mean BMD value of healthy young people in sd units) or Z-score (age-matched comparison in sd units). The coefficients of variations were 1.1% at lumbar spine, 1.2% femoral neck, and 1.4% distal third radius (20). On the basis of their BMD, patients and controls were classified as normal (T-score ≥ −1.0), osteopenic (T-score < −1.0 and > −2.5), or osteoporotic (T-score ≤ −2.5) according to the World Health Organization criteria (21).

For VFA, two lateral scans of the vertebrae from T4 to L4 were performed using the single-energy and the dual-energy high-definition scan modes, with the patients in the supine position (with the C-arm of the scanner rotated through 90°). DXA images were evaluated by a trained operator using the standard semiautomatic analysis performed by the software supplied by the manufacturer. Markings of vertebral bodies and semiquantitative analyses were performed on single-energy scans, using the high definition images to aid placement of vertebral markers.

A lateral radiograph of the thoracic and lumbar spine was obtained in the first 50 patients for internal validation of the VFA methodology.

The operator performing the VFA was blinded to the subject’s clinical status.

Vertebral fractures were defined using the Genant’s semiquantitative method (combination of morphometric and visual assessment), which is commonly used for diagnosis of vertebral fractures (22). Accordingly, fractures were classified as mild (20–25% loss of vertebral height), moderate (25–40% loss of vertebral height), and severe (greater than 40% loss of vertebral height).

Hereinafter, the abbreviation “VF” will be used to indicate a vertebral fracture detected by VFA, independently of whether it was x-ray confirmed or not. The abbreviation will be used only when we refer to our study groups.
Data presentation and statistical analyses

Data are expressed as mean ± sd or prevalence, unless otherwise specified. Univariate statistical analyses were performed by unpaired t test, χ2, or odds ratios (ORs), as appropriate. Stepwise forward logistic models were used to identify potential predictors of the prevalence of VF. LS-BMD values of the entire study population (patients and controls) were divided into quartiles to estimate the association between VF and LS-BMD. Receiver operating characteristics (ROC) curves and quartile distribution were used to evaluate the relationship between LS-BMD values and VFs. The analysis was performed using Statistical Package for Social Science, version 15.00 (SPSS, Inc., Chicago, IL). P < 0.05 was considered significant.
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Demographic and biochemical data

Selected clinical and biochemical data of the 150 postmenopasual PHPT patients and controls are reported in Table 1​1.. There was no statistically significant difference in age, menopausal age, years since menopause, 25-OHD, LS-BMD, or FN-BMD between patients and controls. Both groups, however, were deficient in vitamin D with mean 25-OHD levels of only 16.2 ng/ml. Serum total calcium and PTH levels were higher in patients than controls. Weight and body mass index (BMI) were slightly, but significantly higher in patients than in controls. Twenty-five PHPT women (16.7%) and 28 controls (9.3%) had a history of previous nonvertebral clinical fractures, which were classified as low-trauma fracture in 13 (8.7%) patients and 15 (5.0%) controls. No patient or control had a history of clinical vertebral fractures. Low-trauma fractures were the presenting symptom in two symptomatic patients (femur in one case, and rib in the other).
Table 1

Table 1
Baseline clinical, biochemical, and densitometric (mean ± sd) data of the 150 patients and 300 controls enrolled in the study

Validation of the VFA vs. x-ray

To validate VFA as a reliable method to detect vertebral fractures, the first 50 patients had both VFA and lateral x-rays of vertebral spine. Vertebral fractures were detected by VFA in 15 patients, with a total of 21 fractures (16 mild and five moderate). All but one had vertebral fractures also detected by x-ray evaluation. Of the remaining 35 patients, who were scored as negative by VFA, three had vertebral fractures at x-ray evaluation. All four discrepant cases had mild fractures at the upper thoracic vertebrae. An independent evaluation of VFA and spine radiographs by another radiologist entirely confirmed the above data. The accuracy of VFA compared with x-ray was 92% (83.3% among cases with mild vertebral fractures). Thus, sensitivity and specificity of VFA were 82.4% [95% confidence interval (CI), 55.8–95.3] and 97.0% (82.5–99.8), respectively.
VFA in PHPT and controls

VFs were detected in 37 of 150 (24.6%) patients and 12 of 300 (4.0%) controls [χ2 = 41.9, P < 0.0001; OR = 7.86 (95% CI, 3.96–15.61)]. All VFs were asymptomatic. The prevalence of VFs in patients vs. controls was still higher even if patients referred for evaluation of clinical nonvertebral fractures (n = 2) or low BMD (n = 22) were excluded [χ2 = 34.6, P < 0.0001; OR = 6.86 (CI, 3.36–14.00)]. One VF was found in 25 patients and six controls; two or more VFs were found in 12 patients and six controls. The total number of VFs was 52 in patients and 24 in controls. In both groups, all VFs were scored as mild or moderate (39 and 13 in PHPT patients and 19 and 5 in controls, respectively); no severe VFs were observed. It has been argued that isolated, mild deformities as determined by VFA are questionable because they are not a reliable index of vertebral fractures. Indeed, only two or more mild deformities have been associated with significant incident fracture risk independent of BMD in randomized clinical trials in postmenopausal osteoporosis (23). In this regard, when cases with only one mild deformity were excluded, the fracture rate was still significantly higher in patients (20 of 150 or 13.3%) compared with controls (8 or 300 or 2.7%) [χ2 = 17.7, P < 0.0001; OR = 5.61 (95% CI, 2.41–13.08)].

To identify whether risk factor relationships for VFs among PHPT patients differed from those of controls, a stepwise logistic regression analysis was performed, using the variables that were available in both groups (age, menopausal age, years since menopause, BMI, total serum calcium, PTH, 25-OHD, LS-BMD, and FN-BMD). Risk factors associated with VFs were LS-BMD (P = 0.002) in PHPT patients and LS-BMD (P = 0.004) and age (P = 0.04) in controls. To examine whether PHPT conveys an additional risk of VFs, a logistic regression analysis was performed in the entire sample (patients and controls) using PHPT status as covariate. Age (P = 0.015) and LS-BMD (P = 0.01) remained significantly associated with VFs, with a strong interaction of LS-BMD and PHPT status (P < 0.0001).

ROC curves were constructed to further evaluate the relationship between LS-BMD and VFs in PHPT patients and controls (Fig. 2​2).). The area under the ROC curve was greater in controls [0.90 ± 0.03 (95% CI, 0.84–0.96)] than in PHPT patients [0.68 ± 0.05 (0.57–0.78)], suggesting that LS-BMD may be a better predictor of VFs in the former than in the latter. Similar results were also obtained for FN-BMD (data not shown).

Fracture distribution was also evaluated in patients and controls according to LS-BMD quartiles of the overall study group (Table 2​2).). In both groups, the rate of fractures was higher in the lowest quartile. No VFs were detected in controls with LS-BMD in the upper two quartiles. In contrast, in PHPT patients, VFs were found throughout all quartiles, although the fracture rate decreased at increasing LS-BMD values, as expected.

Correlates of VF prevalence in PHPT patients

In the following analyses, variables that were available only in PHPT patients and not in controls were also included.

As shown in Table 3​3,, patients who had fractures were significantly older, had menopause earlier, and had been in the menopausal state for a longer period of time. Moreover, BMD at all sites was significantly lower in those who had sustained a fracture in comparison to those who had not.

When patients were classified as osteoporotic (n = 82) or nonosteoporotic (n = 68) on the basis of T-scores at any site, the rate of VF was significantly higher in the former compared with the latter [χ2 = 10.5, P = 0.0012; OR = 4.25 (95% CI, 1.79–10.11)].

Fourteen variables (age, BMI, menopausal age, years since menopause, LS-BMD, FN-BMD, forearm BMD, total serum calcium, PTH, 25-OHD, BASP, osteocalcin, CTX, and eGFR) were entered into a stepwise logistic regression analysis. The final model showed that LS-BMD was the only variable associated with VFs (P = 0.003).
VFA in PHPT according to severity of the disease

As indicated in Fig. 3​3,, left panel, the rate of VFs was higher in patients with symptomatic PHPT (34.1%) compared with the rate of fracture in asymptomatic subjects (21.1%), but this difference was not statistically significant [OR = 1.94 (95% CI, 0.88–4.28); P = 0.15]. When the same analysis was performed in asymptomatic patients classified according to whether they met or did not meet criteria for parathyroidectomy, the VF rate was significantly higher in the former (28.1%) compared with the latter (11.1%) [OR = 3.1 (95% CI, 1.06–9.19); P = 0.032; Fig. 3​3,, right panel]. The fracture rate in patients with symptomatic PHPT and in those with asymptomatic PHPT who met the criteria for surgery was significantly higher than in controls (4.0%) [OR = 12.4 (95% CI, 5.23–25.59), P < 0.0001; and OR = 9.39 (95% CI, 4.25–20.78), P < 0.0001]. But when asymptomatic subjects who did not meet criteria for surgery were compared with controls, there was no significant difference in fracture rate [OR = 3.0 (95% CI, 1.00–8.96); P = 0.06].
Figure 3
Figure 3
Rate of VF in patients and controls. Left, Symptomatic and asymptomatic patients and controls. Right, Asymptomatic patients, grouped according to whether they met or did not meet the criteria for surgery established by the 2002 Workshop on Asymptomatic ...
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In the present study, the number of morphometric VFs was evaluated in a series of patients with PHPT diagnosed between 2004 and 2006. This series mostly included patients with asymptomatic PHPT (72.7%) and therefore generally reflects the current most common presentation of the disease.

Vertebral fractures were evaluated using the Genant semiquantitative method, which is the current technique of choice for diagnosis of vertebral fractures by VFA (24). As demonstrated by the validation study in 50 patients in whom VFA and standard spine radiographs were compared, concordant results were obtained in the majority of cases (92%), even among cases with mild deformities (83.3%). It can be argued that sensitivity to detect vertebral fractures by VFA is lower than that of standard radiography. Moreover, accuracy of VFA may be influenced by scoliosis and disc space osteoarthritis. Thus, the use of a follow-up radiography has been advocated in these cases to avoid false-positive results by VFA (25). As far as our study is concerned, although x-rays were not obtained in all cases, we believe that this limitation should have a minimal impact, if any, on our results. This is because the rate of false-positive cases by VFA in the first 50 patients who also underwent x-ray evaluation was low. Another limitation of the study, however, is the point that we did not take into account patients who might have had vertebral fractures by x-ray but who were not detected first by VFA.

Several lines of evidence indicate that cancellous bone mass is relatively preserved in postmenopausal women with mild PHPT (26), suggesting that the hyperparathyroid state affords relative protection against the cancellous bone loss associated with the menopause. This has been recently confirmed by micro-computed tomography studies (27). Based on these observations, it might be argued that postmenopausal women with PHPT might have a reduced risk of vertebral fractures compared with postmenopausal women without PHPT. This assumption is not supported by our data that document an increased rate of vertebral fractures in postmenopausal women with PHPT compared with controls. It is worth noting that our control population was not a historical series but rather consisted of postmenopausal women who were being evaluated at the same time. The rather low rate of vertebral deformities in the control group compared with the reported rate in the general population (28,29) is likely due to the fact that our control group did not include women with diseases or therapies affecting the skeleton. It may therefore represent a “low-risk” population.

Several studies have dealt with the risk of vertebral fractures in patients with untreated PHPT (3,5,6,7,10,13,14) and, with few exceptions (4,12), an increased rate of vertebral fractures compared with controls was demonstrated. However, all previous studies were retrospective and mostly included patients with either symptomatic or asymptomatic PHPT in whom the rate of vertebral fractures was not evaluated separately. The wide range of fracture rates reported in PHPT patients [from 1.7% (Ref. 12) to 46.9% (Ref. 3)] is likely due to differences in patient selection, ethnicity, and methods used for the definition of vertebral fractures.

Multivariate analysis showed that age and LS-BMD were associated with the rate of VFs in controls, whereas LS-BMD was the only variable associated with VF in PHPT patients. The finding that age was not a risk factor of VFs in PHPT patients could be due to the relative protective effect of the disease on cancellous bone. Indeed, in PHPT patients trabecular plates and their connection are maintained over time more effectively than in normal aging individuals (26,27,30).

LS-BMD values were significantly lower in subjects who fractured than in those who did not fracture. Moreover, when PHPT patients were grouped according to quartiles of LS-BMD, VF rate was significantly higher in the lowest compared with the highest quartile. Different from controls, VFs occurred in the two highest quartiles among those with PHPT. Thus, PHPT patients fractured at LS-BMD values (>0.792 g/cm2) where no fractures occurred in controls. ROC curves were plotted to evaluate further the relationship between LS-BMD and VFs in patients and controls and showed that LS-BMD may be a better predictor of VFs in the latter than in the former. Thus, LS-BMD may not be as good a measure of bone strength in PHPT as it is in postmenopausal women without PHPT. The expected positive effects of PTH on bone geometry and trabecular connectivity may help to account for these observations (26,27,30). Cortical bone is preferentially affected in PHPT, and vertebrae contain approximately 25% cortical bone. Thus, thinning of the cortical envelope could contribute to vertebral fracture risk, although cancellous architecture is relatively well preserved. Moreover, increased bone turnover, like reduced bone density, might lead to reduced mineralization density and an increase in risk of fracture (31). Finally, it has also been recently observed that collagen maturity is reduced among subjects with PHPT (Zoehrer, R., unpublished data). Reduced mineralization density and reduced collagen maturity might be expected to contribute to increased rate of fracture. These findings are in keeping with the observation that some phalangeal ultrasound parameters reflecting bone mineralization are lower in PHPT patients compared with controls (32) and, as found in a subset of our patients, also in fractured more than in unfractured cases (data not shown). Other correlates of vertebral fracture risk associated with PHPT status remain to be identified.

VF rate was increased independently of whether patients were classified as symptomatic or asymptomatic, although VFs occurred more frequently in the former than in the latter group. An important observation related to those who did not meet criteria for surgery. Presumably, these patients, also with asymptomatic PHPT, do not present the same risk for fracture as do those who do meet criteria for surgery. The rate of VFs was not increased in asymptomatic patients who did not meet the criteria for parathyroidectomy. Thus, these results help to validate the criteria upon which recommendations are made for surgery in asymptomatic PHPT.

Although LS-BMD predicted fracture rate and the prevalence of fracture was graded according to quartile, it is noteworthy that a substantial percentage of patients fractured with T-scores greater than −2.5 (10 of 62 or 16.1%), whereas this was not seen in those without PHPT. This observation raises the question of whether the cut-point of −2.5 in PHPT is as useful as it is in postmenopausal women who do not have PHPT. It is currently unknown whether in postmenopausal women with PHPT, the presence of vertebral fractures represents a risk factor for further fragility fractures as has been shown in women with postmenopausal osteoporosis but without PHPT (15). On the other hand, we do know that after parathyroidectomy, the risk of fracture in PHPT returns to control levels within 1 yr after surgery (6).

Based on these considerations, the routine assessment of vertebral fractures by VFA might be appropriate in the evaluation of patients with asymptomatic PHPT. The question of whether the finding of a mild morphometric vertebral fracture represents an indication for parathyroid surgery in patients with mild asymptomatic PHPT remains to be established.
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We thank Maria Laura Manca (Department of Neuroscience, University of Pisa, Pisa, Italy) for statistical analysis assistance.
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This work was partly supported by grants from MIUR (Ministero dell’Istruzione, dell’Università e della Ricerca Scientifica) Rome, Italy (to C.M.) and by grants from the University of Pisa (Fondi di Ateneo per la Ricerca; to C.M.).

Disclosure Summary: The authors have nothing to disclose.

First Published Online April 28, 2009

Abbreviations: BMD, Bone mineral density; BMI, body mass index; BSAP, bone-specific alkaline phosphatase; CI, confidence interval; CTX, C-terminal telopeptides of type 1 collagen; DXA, dual-energy x-ray absorptiometry; eGFR, estimated glomerular filtration rate; FN-BMD, femoral neck BMD; LS-BMD, lumbar spine BMD; 25-OHD, 25-hydroxyvitamin D; OR, odds ratio; PHPT, primary hyperparathyroidism; ROC, receiver operating characteristics; VFA, vertebral fracture assessment.

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