Cesar R. Libanati

Relationship between trabecular vertebral body density and fractures: A quantitative definition of spinal osteoporosis

To evaluate the relationship between vertebral fractures and trabecular vertebral body density (TVBD), as measured by computed tomography (CT), we evaluated 110 female and 38 male patients referred consecutively to our clinic for an osteoporosis evaluation. Number of fractures per patient and TVBD was negatively correlated in both males and females (r = -.64, P less than .001 and r = -.69, P less than .001, respectively). Based on this relationship and that between percent of patients with fracture and TVBD, we devised four different approaches to calculate the fracture threshold. (1) Because the x-axis intercept of this regression line represents the TVBD value at zero fractures, this intercept can be considered the fracture threshold, which was 103 mg/cm3 for females and 132 mg/cm3 for males. (2) Breakpoint analysis of the relationship between the number of vertebral fractures per patient v TVBD gave a fracture threshold value of 98 mg/cm3 for females, but for males we were unable to compute a threshold value because of the small sample size. The percentage of patients with fractures was also negatively correlated with TVBD for males and females (r = -.98, P less than .001, and r = -.94, P less than .001, respectively). (3) the x-axis intercept of this relationship, which represents the fracture threshold, was 123 mg/cm3 for males and 101 mg/cm3 for females. (4) The fracture threshold, calculated as the mean TVBD + 2 SD for patients with fracture(s), was 120 and 92 mg/cm3 for males and females, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)

Reproducibility of DXA in Obese Women

Dual-energy X-ray absorptiometry (DXA) measurements were analyzed using two versions of software (Hologic V8.1a and V8.21) to compare the short- and long-term precisions of the measurements. Software V8.21 was designed by the manufacturer to better address magnification effects on estimations of soft tissue lean mass. Twenty weight-stable, obese postmenopausal Caucasian women aged 40-70 yr participated in the study. Total and regional body composition measurements were obtained at baseline and after 3 mo, using a fan beam Hologic QDR 4500A absorptiometer. For the estimation of precision, duplicate scans obtained on the same day for nine women were analyzed using both versions of the software. The correlations between duplicate scans ranged from 0.886 to 0.998 and were similar between software versions. The CVs for fat and lean weights and bone mineral content (BMC) were 1.2%, 1.1%, and 1.7%, respectively, for software V8.21 compared to 1.3%, 1.3%, and 2.1%, respectively, for V8.1a. Systematic differences were found between software versions with higher values for fat and lean weights for software version V8.21. The 3-mo, long-term reproducibility of body composition estimates from DXA was only slightly less than short-term reproducibility for both software versions (coefficient of variation [CV] range from 1.3% for BMC weight to 11.0% for arm fat). Software V8.21 yielded smaller percentage mean differences between scale and DXA-estimated weights (-2.4% and -7.2% at baseline and -2.9% and -7.6% at 3 mo, respectively) and higher fat and lean weights (49.12 and 47.1 kg and 49.6 and 44.6 kg, respectively) than V8.1a. Reproducibility of all variables was comparable between software versions.

Comparison of Body Composition by Bioelectrical Impedance and Dual-Energy X-Ray Absorptiometry in Overweight/Obese Postmenopausal Women

The purpose of this study was to compare the Rudolph J. Liedtke (RJL) Sciences Quantum II system bioelectrical impedance analyzer (BIA) with the fan beam Hologic dual-energy X-ray absorptiometry (DXA, software V8.26a) for assessing body composition in postmenopausal obese women. Thirty-three postmenopausal overweight/obese females (mean age: 53.9+/-6.0 yr; mean weight: 91.3+/-17.5 kg; and mean body mass index [BMI]: 33.1+/-5.7 kg/m2) were evaluated for comparison of body weight (BW), fat mass (FM), percent FM (%FM), and fat free mass (FFM). The comparison was assessed by RJL Quantum 2 Cyprus 2.6 (Clinton Township, MI) BIA vs fan beam DXA Hologic QDR-4500A software V8.26a (ODR 4500 Hologic, Inc., Waltham, Mass). RJL-BIA and DXA measurements were performed at the same time. BW was measured using a balance scale (Detecto; Web City, MO) and these results were used for the RJL-BIA analysis. Balance weight was compared with DXA BW. Correlations between DXA and RJL-BIA for BW, FM, %FM, and FFM were 0.998, 0.980, 0.782, and 0.926 (p<0.01), respectively. Bland-Altman plots demonstrated general agreement between methods for BW, FM, %FM, and FFM. However, for the latter 3 metrics of body composition, one unit change using BIA does not correspond to one unit change using DXA, as there were systematic disagreements at either end of the range of values. But RJL-BIA could be a valid method for assessing body composition of overweight/obese postmenopausal women once appropriate validated regression equations have been developed.

Fixation of humeral prostheses and axial micromotion.

Surgeons often avoid cementing a proximal humeral prosthesis. Occasionally bony augmentation is needed. This study was undertaken to compare proximal cementation in combination with distal press with total cementation or press fit alone. In phase 1 axial micromotion with axial loading was measured in 15 pairs of humeri: 5 fully cemented versus proximally cemented, 5 fully cemented versus press fit, and 5 proximally cemented versus press fit. X-ray films of the specimens were obtained to assess canal fill. In phase 2 axial micromotion was measured in 5 pairs of high mineral density and 5 pairs of low mineral density to compare proximal cementation with press fit. The 3 M modular prosthesis was used in both phases. No difference was found in phase 1 among the 3 fixation techniques. A strong reverse statistical correlation (P = .007) (r = .55) was seen between axial micromotion and fill of the canal with the prosthesis. In the second phase no statistically significant difference was found between the techniques of fixation or between the 2 bone densities. Fill of the canal at the distal end of the prosthesis was the only variable found that affected axial micromotion, but it accounted for only approximately 30% of the variance. Bone quality and augmentation of the proximal bone with cement did not affect axial micromotion in this experiment but warrant further study.

Fluoride therapy for osteoporosis: a review of dose response, duration of treatment, and skeletal sites of action.

SummaryOsteoporosis is a disease characterized by a reduction in bone density which predisposes to fracture after even minimal trauma. Fluoride, because it has consistently been shown to stimulate bone formation and increase trabecular bone density, has been widely studied for the treatment of osteoporosis. The article focuses on the dose response, duration of treatment, and skeletal sites of action of fluoride; we also include comments on the effect of fluoride on vertebral and appendicular fracture rates. The skeletal response to fluoride doses, ranging from 15 to 43 mg elemental fluoride per day, included a linear increase in spinal bone density at an average rate of 1.25±0.91 mg/cm3 per month. The rate of increase in spinal bone density was related to the dose of fluoride (r=0.34,P<0.03). Spinal bone density had increased above the fracture threshold in 44% of patients treated with fluoride for 32±10 months. The time required to achieve this goal was, however, influenced by the pretreatment spinal bone density and interpatient variation in response to fluoride treatment. Patients whose spinal bone density remained below the fracture threshold had lower pretreatment bone densities and/or slower rates of increase in spinal bone density (P<0.001). The osteogenic effect of fluoride was not limited to the spine. After 2 years of fluoride therapy, we found bone density in the femoral condyle (measured by QCT) to have increased by 13±2.6 mg/cm3 (n=38,P<0.001); bone density in the hip (measured by DPA) was increased by 0.0261±0.015 g/cm2 (n=55,P<0.025). The efficacy of fluoride therapy to reduce fractures is not well established. Recently, investigators from the Mayo Clinic and Henry Ford Hospital reported fluoride had no effect on the vertebral fracture rate despite a significant increase in spinal bone density, but this finding has not been supported by findings in other studies. Moreover, our preliminary analysis of over 500 fluoride-treated patients found a time-dependent decrease in vertebral fracture rate related to a corresponding increase in spinal bone density. We conclude that these data, together with the many other positive international findings related to fluoride, justify continued investigation of this potent agent for the treatment of osteoporosis.

The increase in spinal bone density that occurs in response to fluoride therapy for osteoporosis is not maintained after the therapy is discontinued

In 44 osteoporotic subjects who had been treated with fluoride for 37±16 months, the fluoride was discontinued because they had shown fluoride-dependent increases in trabecular spinal bone densities from low initial levels (below the fracture threshold) to values that were equivalent to normal peak bone densities in the spines of young adults. During the subsequent period, after discontinuation of the fluoride therapy (i.e. 19±9 months), spinal bone density decreased in 73% of the subjects (i.e. 32 of 44,p<0.03), at a rate that was comparable to the rate of the previous gain that had occurred during the treatment with fluoride (i.e. −3.23±2.39 mg/cm3 per month, compared with +3.91±1.96 mg/cm3 per month in this subgroup of patients,p<0.001). Although 9 of the 44 subjects showed continuing increases in spinal bone density after discontinuation of the fluoride therapy, spinal bone density decreased in the entire group of 44 at an average rate of −1.02±4.72 mg/cm3 per month (p<0.001, compared with the rate of the previous gain during the treatment with fluoride; i.e. +3.83±1.82 mg/cm3 per month). Surprisingly, our data showed that the rate of decrease in spinal bone density during the post-fluoride period was not affected by concurrent (undesigned) treatment with calcium, calcium plus estrogen, or calcium plus calcitriol. The cessation of fluoride therapy was also associated with a decrease in serum alkaline phosphatase activity (i.e. a decrease from the elevated levels that were observed during the period of fluoride therapy, back to the original, pre-treatment levels;p<0.001), and that the rate of spinal bone loss after cessation of fluoride could be correlated with the prior rate of increase in serum alkaline phosphatase activity that had occurred during the treatment with fluoride (n=44,r=0.312,p=0.039). Together, the observations from this retrospective analysis of data obtained from our clinical subjects suggest that fluoride-treated osteoporotic subjects who have exhibited increases in trabecular spinal bone density are at risk for bone loss after discontinuation of the fluoride therapy.

Effect of a Weight-Reduction Program on Total and Regional Body Composition in Obese Postmenopausal Women

The association of body fat and its distribution with risk for chronic disease is well documented.1–4 Some complications of obesity improve with a reduction in weight.5 In premenopausal women whose weight was lowered, an analysis of fat distribution by computerized tomography (CT) scan demonstrated that a decrease in the visceral/subcutaneous (V/S) ratio and in visceral fat volume was more strongly correlated with an improvement in plasma glucose and lipid metabolism than was a decrease in body weight, BMI, total fat volume, and abdominal subcutaneous fat volume. Accurate measurement of body fat and fat distribution is essential to assess the relation of regional fat mass to risk of chronic disease.6,7 The purpose of this study was to assess the impact of a weight-reduction program on total body weight loss in postmenopausal women, using indices of total and regional body composition as measured by DXA fan beam technology.

Acute Effects of Calcitonin Nasal Spray on Serum C-telopeptide of Type 1 Collagen (CTx) Levels in Elderly Osteopenic Women with Increased Bone Turnover

Salmon calcitonin is a potent inhibitor of osteoclastic activity. The effect of calcitonin in elderly women with high bone turnover at higher risk of developing osteoporosis has not been studied. To investigate acute effects of calcitonin treatment on bone resorption markers in elderly women, we conducted a randomized trial in women >65 years of age with high bone turnover assessed as urinary N-telopeptide of type-I collagen (NTx) levels 1 SD higher than mean premenopausal levels, which was irrespective of bone density. A total of 98 elderly women were randomly assigned to receive either 200 IU calcitonin nasal spray (n = 75) with calcium (500 mg) and vitamin D (200 IU) or calcium and vitamin D (n = 23) alone for 6 months. Blood and urine samples were collected at 0, 2, 4, and 6 months and analyzed for urinary NTx and serum C-telopeptide of type-1 collagen (CTx). At baseline, mean age was 72.1 ± 4.7 (mean ± SD) in the calcitonin group and 72.2 ± 6 years in the control group. The spine and total hip BMD, serum PTH levels and urinary calcium/creatinine ratios were similar in both groups. Mean BMD was in the osteopenic range in both groups. Calcitonin treatment resulted in significant decreases in serum CTx levels, 2, 4 and 6 months after treatment as compared to baseline, and after 4 and 6 months as compared to controls. A maximum decrease from baseline of 33% was seen at 6 months. The urinary resorption marker, urine NTx, showed a significant decrease in the calcitonin group when compared to baseline only at the 6-month time point. Analysis of least significance change (LSC) showed that 70% of calcitonin patients were categorized as responders using serum CTx after 6 months of treatment. We conclude that 200 IU calcitonin effectively decreases bone resorption within 60 days of therapy, thus preventing further bone loss in elderly women who are at a high risk of developing osteoporosis.

Serum fluoride and serum osteocalcin levels in response to a novel sustained-release monofluorophosphate preparation: comparison with plain monofluorophosphate.

In a previous study we found that sustained-release monofluorophosphate (MFP-SR), a novel, sustained-release MFP preparation, acutely maintained the basal therapeutic serum fluoride levels without causing the high serum peak levels associated with plain MFP administration. The objective of the present study was to determine (a) whether chronic MFP-SR administration would provide therapeutic serum fluoride levels, and (b) whether treatment with this new preparation would result in an increase in bone formation similar to that achieved with plain MFP. Bone formation was assessed by serum osteocalcin (OC) determination. We studied 17 postmenopausal women older than 60 years and suffering from primary osteoporosis. All had received a minimum of 6 months of continuous treatment with plain MFP at a dose of 152 mg/day (76 mg b.i.d.). Upon entering the study, the subjects were randomized, in a double-masked protocol, to receive either MFP-SR (76 mg b.i.d.) (n=9) or placebo (n=8) for 2 months, after which all subjects returned to the original plain MFP regimen. Serum fluoride and serum OC levels were determined monthly for 3 months. At the beginning of the study serum fluoride levels were in the accepted therapeutic range (5–10 µM) in all patients. Serum fluoride levels were maintained in the patients switched to MFP-SR. In contrast, serum fluoride levels decreased significantly (p<0.005) in the placebo-treated control subjects and returned to therapeutic levels upon switching back to plain MFP. Similarly, serum OC levels remained elevated in the subjects switched to MFP-SR but dropped significantly (p<0.001) in the placebo-treated group. Our results demonstrate that chronic MFP-SR administration, at a dose of 152 mg/day, results in maintenance of therapeutic serum fluoride levels and in stimulation of bone formation. Because we have previously reported that high, supratherapeutic post-absorptive serum fluoride levels are avoided by MFP-SR administration, this novel preparation may prevent side effects associated with plain MFP by reducing the amount of fluoride deposited in bone.

Pharmacokinetic profile of a new fluoride preparation : sustained-release monofluorophosphate

The pharmacokinetic profiles of a sustained-release monofluorophosphate (MFP-SR) preparation (76 mg) and of plain MFP (76 mg) were compared in six osteoporotic females. These studies were performed in a randomized, crossover, double-blind design to select a preparation that would result in therapeutic serum levels while avoiding high serum peak values. Following a single dose of 76 mg MFP-SR, the serum fluoride levels remained within the accepted therapeutic range (5–10 μM/liter) for 24 hours. In contrast, following a single dose of 76 mg plain MFP, serum fluoride levels exhibited a wide circadian fluctuation and serum levels approximately threefold higher than those of the MFP-SR preparation (9.5±1.6 vs 3.5±0.8 μM/liter, P<0.005). Compared with plain MFP, the sustained-release MFP had a significantly lower peak concentration (Cmax MFP-SR: 10.6 ±3 vs CmaxMFP: 18.9±5 μM/liter, P<0.005) and a significantly longer absorption lag time (TmaxMFP-SR 7.3±1.6 vs TmaxMFP: 3.0±0.6 h, P<0.05). Twenty-four-hour urinary fluoride excretion after ingestion of plain or SR fluoride was significantly increased from pretreatment values documenting absorption with either MFP formulation. Our results show that the use of sustained-release MFP preparation that we tested prevents the development of high peak levels associated with the use of plain MFP preparations. Furthermore, a single dose of MFP-SR resulted in serum fluoride levels within the accepted range of 5–10 μM/liter for 24 hours.