Bone structure and turnover in the distal radius and iliac crest: a histomorphometric study.

In bone grafting procedures of the wrist, the distal radius would be a more convenient graft donor site than the conventionally used iliac crest. We compared tetracycline-labeled bone biopsies from these two sites in 18 white patients (12 males, 6 females, aged 26-66 years) undergoing bone grafting procedures of the wrist. Fourteen had had previous trauma, 1 osteonecrosis of the lunate, 2 mild rheumatoid arthritis, and 1 a brachial plexus palsy. The specimens were processed undecalcified and examined by routine histomorphometry for bone structure, static and dynamic bone turnover variables, and marrow cellularity. We found that bone from the distal radius had thinner cortices (p = 0.0001), lower bone volume (p = 0.01), thinner trabeculae (p = 0.029), greater trabecular separation (p = 0.015), and lower wall thickness (p = 0.0001), marrow cellularity (p = 0.0001), osteoid volume (p = 0.01), osteoid surface (p = 0.02), osteoid thickness (p = 0.0002), osteoblast surface (p = 0.001), eroded surface (p = 0.01), osteoclast surface (p = 0.012), mineral apposition rate (p = 0.0002), double-labeled surface (p = 0.0005), single-labeled surface (p = 0.006), bone formation rate (p = 0.0005), adjusted apposition rate (p = 0.0001), longer mineralization lag time (p = 0.012), and greater activation frequency (p = 0.003). Prolonged mineralization lag time in the radius was associated with thin osteoid seams and low adjusted apposition rates and was therefore attributable to a low level of osteoblast activity rather than to osteomalacia. We conclude that bone from the distal radius was structurally inferior to and had lower turnover than the iliac crest bone. We suggest that where a graft has to provide immediate structural integrity, the iliac crest is the preferred donor site. However, where bone graft is to be compacted into a small cavitary defect, distal radial bone may be an adequate alternative. A clinical study is needed to confirm this assumption.

Iliac bone biopsies at the time of periarticular stress fractures during fluoride therapy: comparison with pretreatment biopsies.

We attempted to establish whether systemic changes in trabecular bone explain the development of stress fractures in the lower limbs during fluoride therapy for osteoporosis. To this end we compared transiliac bone biopsies obtained before treatment with those taken around the time of stress fractures after 14.3 +/- 10.9 (SD) months of therapy in six patients (group A). Biopsies from a comparable group of six patients without stress fractures at the time of the second biopsy (after 11.9 +/- 2.7 months of treatment) served for comparison (group B). The biopsies were processed undecalcified and examined by routine histomorphometry. The second biopsies did not show any significant improvement in mean bone volume or trabecular architecture. Although the second biopsies in group A had increased erosion surfaces (p less than 0.05) and greater osteoid volume (p less than 0.05), group B biopsies showed no difference in erosion surfaces but an increase in all osteoid parameters: osteoid volume (p less than 0.05), osteoid surface (p less than 0.05), and osteoid seam thickness (p less than 0.01). We reached the following conclusions: (1) the combination of increased erosion and replacement of removed bone by as yet unmineralized osteoid in the stress fracture group must have weakened bone and allowed the development of stress fractures. (2) Stress fracture patients may have mounted a less vigorous osteoblast response to fluoride than non-stress fracture patients. Under these conditions microfractures are likely to heal poorly and propagate to develop into full stress fractures. (3) Renal failure is a contraindication to fluoride therapy.

Pharmacokinetic interaction between intravenous phenytoin and amiodarone in healthy volunteers.

To determine the mechanism of the amiodarone-phenytoin interaction, seven healthy male subjects were given intravenous phenytoin, 5 mg/kg, before (phase I) and after (phase II) 3 weeks of oral amiodarone, 200 mg/day. Serum AUC increased from 245 +/- 37.6 to 342 +/- 87.3 mg.hr/L (p = 0.007); area under the first moment curve increased from 5666 +/- 1003 to 11,632 +/- 4198 mg.hr2/L (p = 0.008); the time-averaged total body clearance decreased from 1.57 +/- 0.3 to 1.17 +/- 0.33 L/hr (p = 0.0004); and the apparent elimination half-life increased from 16.1 +/- 1.32 to 22.6 +/- 3.8 hours (p = 0.001) for phenytoin during phase II. The volume of distribution at steady state and the unbound fraction for phenytoin remained unchanged. However, the formation of p-hydroxyphenytoin as a function of serum phenytoin concentration decreased during phase II. These findings suggest that amiodarone inhibits phenytoin metabolism. These observations also suggest that phenytoin doses will need to be reduced when coadministered with amiodarone. The magnitude of this reduction is difficult to predict because of the saturable pharmacokinetics of phenytoin, and therapeutic monitoring is recommended if amiodarone is added to the phenytoin regimen.

Steady-state interaction between amiodarone and phenytoin in normal subjects.

Amiodarone has been reported to increase phenytoin levels. This study was designed to evaluate the pharmacokinetic basis of this interaction at steady-state. Pharmacokinetic parameters for phenytoin were determined after 14 days of oral phenytoin, 2 to 4 mg/kg/day, before and after oral amiodarone, 200 mg daily for 6 weeks in 7 healthy male subjects. During amiodarone therapy, area under the serum concentration time curve for phenytoin was increased from 208 +/- 82.8 (mean +/- standard deviation) to 292 +/- 108 mg.hr/liter (p = 0.015). Both the maximum and 24-hour phenytoin concentrations were increased from 10.75 +/- 3.75 and 6.67 +/- 3.51 micrograms/ml to 14.26 +/- 3.97 (p = 0.016) and 10.27 +/- 4.67 micrograms/ml (p = 0.012), respectively, during concomitant amiodarone treatment. Amiodarone caused a decrease in the oral clearance of phenytoin from 1.29 +/- 0.30 to 0.93 +/- 0.25 liters/hr (p = 0.002). These results were due to a reduction in phenytoin metabolism by amiodarone as evidenced by a decrease in the urinary excretion of the principal metabolite of phenytoin, 5-(p-hydroxyphenyl)-5-phenylhydantoin, 149 +/- 39.7 to 99.3 +/- 40.0 mg (p = 0.041) and no change in the unbound fraction of the total phenytoin concentration expressed as a percentage, 10.3 +/- 2.7 versus 10.7 +/- 2.1% (p = 0.28) during coadministration of amiodarone. The alterations in phenytoin pharmacokinetics suggest that steady-state doses of phenytoin of 2 to 4 mg/kg/day should be reduced at least 25% when amiodarone is concurrently administered. All dosage reductions should be guided by clinical and therapeutic drug monitoring.

Ethmozine for ventricular premature complexes.

Twenty patients with an average of more than 30 ventricular premature complexes (VPCs) per hour were treated with ethmozine. Eighteen had either not responded or had adverse reactions to at least 1 other antiarrhythmic drug. Patients were treated with 200 to 300 mg 3 times daily (8.25 to 11.7 mg/kg) and were followed for up to 6 months. Three patients were withdrawn from ethmozine therapy because of unwanted effects before evaluation of efficacy. One of these patients had sustained ventricular tachycardia (VT) after a loading dose of ethmozine. Eleven of the remaining 17 patients (65%) experienced more than a 75% reduction in ventricular ectopic activity. Six patients had a smaller or no decrease in VPC frequency. Eleven of 16 patients (68%) with paired VPCs had a more than 90% reduction in paired VPC frequency. Eleven of 13 patients (84%) with VT events of 3 beats or more had more than a 90% reduction in VT events. Of the 11 patients in whom a more than 75% reduction in VPC frequency occurred, 1 patient died suddenly after 133 days of effective drug therapy. Three patients discontinued ethmozine therapy for reasons not related to the drug. Of the 6 patients in whom there was less than a 75% reduction in VPC frequency, 2 patients discontinued treatment, 1 patient because of hyperanxiety and 1 because of drug-related left anterior hemiblock. Ethmozine lengthened PR and QRS intervals but not the JT interval. Thus, ethmozine is effective and clinically useful for suppression of frequency VPCs in 50% (10 of 20 patients) of a selected population.

Effect of phenytoin on the clinical pharmacokinetics of amiodarone.

Five healthy male volunteers were given oral amiodarone hydrochloride, 200 mg per day for 6 1/2 weeks, to determine its effects on the pharmacokinetics of both intravenous and oral phenytoin. Predose amiodarone and N-desethylamiodarone serum concentrations were obtained weekly during weeks 2-6. Amiodarone serum concentrations (ASC) increased during weeks 2-4 and then decreased sharply during weeks 5-6 when oral phenytoin, 2-4 mg/kg/day, was co-administered. In addition, N-desethylamiodarone serum concentrations (DEASC) exceeded corresponding ASC during weeks 5-6 whereas during weeks 2-4, DEASC were less than ASC. Because of the long elimination half-life for amiodarone previously reported in healthy volunteers after single doses of amiodarone and the frequent administration of amiodarone associated with this half-life, a modified equation for a continuous infusion was used to describe each subject's ASC versus time data. Pre-phenytoin ASC were fitted to an appropriate function to predict ASC during weeks 5-6 assuming no interaction. Observed versus predicted ASC were compared for weeks 5 and 6. Observed ASC during weeks 5 and 6 were (mean +/- SD) 0.25 +/- 0.09 micrograms/mL and 0.19 +/- 0.07 micrograms/mL, respectively. Corresponding predicted ASC were 0.36 +/- 0.12 micrograms/mL (P = .011) and 0.38 +/- 0.13 micrograms/mL (P = .004). These represented percent differences of 32.2 +/- 12.5% and 49.3 +/- 5.6% for weeks 5 and 6, respectively. Assuming there were no changes in the bioavailability of amiodarone during continuous administration, these findings strongly suggest induction of amiodarone metabolism by phenytoin. The clinical significance of this interaction remains to be determined.

Accelerometer systolic time intervals as fast-response sensors of upright posture in the young.

BACKGROUND: Sensors of posture may improve rate-adaptive pacing in syndromes where syncope occurs in the upright posture, particularly in the young. No sensor of posture has been described to date. Previous studies suggest that two sensors currently under investigation (preejection period [PEP] and left ventricular ejection time [LVET] systolic time intervals [STIs] and accelerometers) may be affected by posture. A PEP-sensing pacemaker is available commercially in which heart rate (HR) decreases with an increase in PEP (delta(HR)/delta[PEP]< 0). In patients with upright syncope, it is not known how such algorithms respond to posture. Also, it is not known whether STIs correlate with posture independent of autonomic tone. METHODS AND RESULTS: We studied accelerometer-derived STIs in head-upright tilt-testing with beta-blockade and catecholamine stimulation in patients with syncope or presyncope using an ultra-low-frequency accelerometer placed on the chest. Thirty-two patients age 6 to 22 years with unexplained recurrent syncope or presyncope underwent tilt-testing involving two to four tilts (60 degrees) at baseline, during esmolol infusion (500 micrograms/kg load, 50 to 140 micrograms/kg per minute), after esmolol withdrawal, and during isoproterenol infusion if not contraindicated. PEP, LVET, and other indexes were quantified, and their relations to posture and to autonomic state were determined. With tilt, PEP increased from 98.9 +/- 2.2 to 109.1 +/- 2.8 msec (P < .0001), and LVET decreased (supine-to-upright) from 295.5 +/- 4.5 to 247.2 +/- 4.7 msec (P < .0001). PEP/LVET changed from 0.337 +/- 0.01 to 0.45 +/- 0.02 (P < .0001). Similar postural changes were observed during tilt with beta-blockade and esmolol withdrawal, and during isoproterenol infusion. STI changes occurred immediately on postural change and were stable. Postural change of PEP was greater than the beta-adrenergic effect by 6:1. Postural change of STIs was independent of vagal tone. CONCLUSIONS: First, accelerometer-derived STIs detect postural changes. Because these changes are independent of autonomic tone and are rapid and stable, they may be useful as fast-response sensors of upright posture in rate-adaptive pacemakers. Second, with postural change, HR increases when PEP increases. However, PEP-sensing pacemakers presently under investigation assume the opposite (inverse) mathematical relationship. Therefore, current PEP-sensing pacemakers use an incorrect algorithm for physiological postural responses in syncope patients. These data predict a paradoxical tachycardic response to the supine posture in patients implanted with these devices.

Bone fragility of the peripheral skeleton during fluoride therapy for osteoporosis.

Bone fragility during fluoride therapy for osteoporosis was observed in 24 (37.5%) of 64 patients treated with sodium fluoride, calcium, and vitamin D for 2.5 years who developed episodes of lower-limb pain during treatment. Eighteen (28%) of these patients had clinical and roentgenographic features of 41 stress fractures and 12 new spinal fractures. There were 26 periarticular, six femoral neck, three pubic rami, three tibia and fibula, one greater trochanter, and two subtrochanteric fractures. Vertebral fractures appeared first, then periarticular, then femoral neck, and lastly long-bone shaft fractures. All fractures were spontaneous in onset. The peripheral fracture rate during treatment was three times that in untreated osteoporosis. Roentgenograms must be repeated at intervals of three to four weeks before the pathognomonic callus becomes visible, and the diagnosis can be made. Trabecular stress fractures tend to occur in the first 18 months of treatment, and cortical stress fractures occur after 30 months of therapy.

Comparison of the radiographic vertebral trabecular pattern with the vertebral fracture prevalence and spinal bone density.

Spinal bone densitometry allows accurate and precise measurement of the severity of bone loss. Where densitometry is not yet available medical practitioners have to continue to rely on clinical radiography. Since the grey levels of the radiographic image are highly inaccurate we studied the radiographic vertebral trabecular pattern for its suitability as a semiquantitative assessment of vertebral bone loss. We defined four vertebral trabecular pattern indices (VTPI 4 = normal, VTPI 1 = severe bone loss) and tested these for correlations with the prevalence of vertebral fractures, and with spinal and hip bone mineral density measured by dual-energy X-ray absorptiometry (DXA). We found negative correlations between VTPI and the percentage of patients with vertebral fractures (p = 0.0001), between VTPI and the number of vertebral fractures per patient (r = 0.606, p = 0.001) and between VTPI and the severity of vertebral fractures, and a positive correlation between VTPI and spinal (r2 = 0.556, p = 0.0001) and hip DXA values (r2 = 0.315, p = 0.0001). We conclude that the vertebral trabecular pattern index can be used to assess the severity of spinal bone loss when a bone densitometer is not available.

Resolution of pace mapping stimulus site separation using body surface potentials.

BACKGROUND: Several studies have related 12-lead ECG waveform during ventricular tachycardia to ECG waveform during ventricular pacing to identify ablation sites for therapy of ventricular tachycardia. QRS isopotential maps and QRS isointegral maps derived from body surface isopotential maps have also been correlated with left ventricular pacing sites with the same objective. The comparison process used is subjective and only semiquantitative. Improved accuracy of catheter placement may improve success rates of ablation therapy. METHODS AND RESULTS: This animal study was performed to determine the spatial resolution with which left ventricular pacing sites could be distinguished by body surface isopotential mapping. Potentials were recorded from 64 evenly spaced thoracic leads. Hexapolar or octapolar pacing catheters with 2-mm interelectrode spacing were placed percutaneously in the left ventricle in each of six dogs, and bipolar endocardial pacing was performed using each pair of adjacent electrodes. QRS isopotential maps of each pacing site for each catheter placement were cross-correlated by computer. Difference maps for each pair of pacing sites were calculated lead by lead and time instant by time instant, and root-mean-square voltage differences were calculated. Results indicated that correlation coefficients and root-mean-square error of voltage differences monotonically decrease and increase, respectively, with stimulus site separation. Both measures were significantly different (P < .05) for separations of 4 mm or more. CONCLUSIONS: A method of quantitative comparison of body surface potential maps can be used in normal hearts to localize ventricular pacing sites within a 4-mm range. The method may have utility in determining potential ablation sites for therapy of ventricular tachycardia or preexcitation syndromes.

Fewer bone histomorphometric abnormalities with intermittent than with continuous slow-release sodium fluoride therapy.

To help resolve the uncertainty whether sodium fluoride (NaF) therapy should be given intermittently or continuously, we examined iliac crest bone biopsies (before and after treatment) and fragility fracture rates in 35 intermittently treated (group I) and 69 continuously treated (group C) patients; all received calcium. The following statistically significant results were obtained. Reduction in vertebral fracture rate was similar in the two groups. Trabecular thickness and the structurally more important mineralized thickness increased only in group I. Group I also accumulated less excess osteoid (surface, volume). Mean osteoid thickness did not change in either group because of a bimodal distribution of wide seams with osteoblasts and double tetracycline labels, and thin seams without osteoblasts or labels. Osteoid was lamellar. Osteoid in abnormal sites (within bone marrow or bone, or around osteocytes) was found less frequently in group I. Adjusted apposition rate declined and mineralization lag time increased in both groups because of extended unlabelled osteoid seams. Erosion surface increased only in group C. Hook and/or tunnel erosion was seen less frequently in group I; it was closely associated with osteoid in abnormal sites and correlated with osteoid surface. Extended osteoid surface may have forced osteoclasts to hollow out trabeculae, leaving the empty osteoid shell in marrow. Excess osteoid volume and eroded surface and osteoid and erosion in abnormal sites correlated with bone fragility in group C. We conclude that intermittent therapy is to be preferred because it (1) increased mineralized trabecular thickness, (2) did not cause excessive osteoid accumulation and erosion, (3) showed less osteoid and erosion in abnormal sites and (4) led to a similar reduction in the vertebral fracture rate as did continuous treatment. The question of whether intermittency of therapy has some other effect independent of the cumulative dose of fluoride administered cannot be answered by this study.