Chronic opioid therapy in long-term cancer survivors.

PURPOSE: Long-term cancer survivors develop special health issues and specific needs. Chronic pain, whether the consequence of their cancer or as a side effect of treatment, is one of their most prevalent concerns. METHODS: We conducted a review of the English-language literature on long-term cancer survivorship and chronic opioid therapy, with the objective of determining the efficacy, safety and tolerability in this group of patients. Practical management recommendations are made on the basis of this review. RESULTS: Pain syndromes encountered in the long-term cancer survivors are diverse. Opioid receptor pathways possess complex and pleiotropic functions and continuous over-activation may lead to de novo endocrinopathies, immunosuppression, neurocognitive impairment, or cell cycle disturbances with potential clinical connotations. However, there are insufficient data to support evidence-based decision making with respect to patient selection, doses, administration, monitoring and follow-up. Data about long-term treatment effectiveness and safety are limited and often aggravated by the overlapping of several diseases prevalent among long-term cancer survivors, as well as chronic opiate-induced toxicity. CONCLUSIONS: Chronic opioid therapy is frequent in long-term cancer survivors, and may negatively affect the immune system, and produce health problems such as endocrinopathies, osteoporosis, neurological or cardiopulmonary effects, alterations of cell cycle kinetics, abuse and addiction. This review highlights the need for specialized teams to treat chronic pain in long-term cancer survivors from an integrative perspective.

[News in osteogenesis imperfecta: from research to clinical management]. / Nouveautés dans l'ostéogenèse imparfaite: de la recherche à la prise en charge multidisciplinaire.

Osteogenesis imperfecta (OI) is a rare genetic disease. Today we are able to propose an adapted and efficient management to the patients with this rare disorder (and their families) thanks to a strong collaboration of clinicians and researchers. Recent knowledge regarding the genetics of OI permits an accurate diagnosis of the specific type of OI and its own molecular mechanism, a genetic counseling for family planning and prenatal diagnosis, and in addition more targeted therapeutic options. A specific support with re-education for patients with OI is necessary and efficient. To optimize patient care, a multidisciplinary consultation is proposed at the CHUV, moreover a web site is available for patients, families and therapists: www.infomaladiesrares.ch

Differences in skeletal and muscle mass with aging in black and white women.

Previous cross-sectional studies using delayed gamma neutron activation analysis and whole body counting suggested that the relationship of total body calcium (TBCa) to total body potassium (TBK) (muscle mass, body cell mass) remained constant with age. This led to the hypothesis that the muscle mass and skeletal mass compartments are integrated in their response to aging. It had also been hypothesized that loss of skeletal and muscle mass was similar between races. In the current study, delayed gamma neutron activation analysis and whole body counting were performed on 90 black and 143 white women 20-69 yr of age. Black women had higher TBCa and TBK values than white women, even when the data were adjusted for age, height, and weight. TBCa was correlated with height and TBK with weight. The estimated decline of skeletal mass (TBCa) from 20 to 70 yr was 18% in black women and 19% in white women. However, the lifetime decline of TBK was only 8% for black women, compared with 22% for white women. Black women may lose TBK more slowly than TBCa with aging, compared with white women. In particular, correlation of TBCa and age was similar for blacks and whites (r = -0.44 and r = -0.54, respectively). However, for TBK these correlations were r = -0.14 and r = -0.42. These data confirm a higher musculoskeletal mass in black women and suggest that the loss of muscle mass with age may be lower in black than in white women. These ethnic differences do not support the hypothesis of an integrated musculoskeletal system, so that these two components should be considered separately. A prospective study is needed to confirm these findings.

Body composition by dual-energy X-ray absorptiometry in black compared with white women.

Dual-energy X-ray absorptiometry (DXA) has recently been applied to the measurement of body composition using a three-compartment model consisting of fat, lean and bone mineral. The mass of skeletal muscle may be approximated by measurement of the lean tissue mass of the extremities. In addition, body fat distribution can be estimated by determining the ratio of fat in the trunk to the fat in the extremities. In the current study, DXA was used to compare body composition and fat distribution between black (n = 162) and white women (n = 203). Black women had a higher mineral mass and a higher skeletal muscle mass. The ratio of mineral to muscle mass was higher in black women, even when the data were adjusted for age, height and weight. Both total body bone mineral and muscle mass declined with age in both races, with evidence for an accelerated loss of bone mineral after menopause. Body size (height and weight) was generally a significant variable in developing regressions of each compartment against age. Their higher musculoskeletal mass may lead to misclassification of 12% of black women as obese if body mass index is used as an index of obesity. Body fat distribution (trunk/leg) did not differ between races in the raw data. However, for women of the same age, height and weight, white women have a significantly higher trunk/leg fat ratio. Body composition values for fat, lean and bone mineral obtained from DXA should be adjusted not only for gender but also for age, height, weight and ethnicity.

Cancellous bone of the spine is greater in black women.

The bone mineral density (BMD) of the spine was measured in the posteroanterior (PA) and lateral projections as well as the total body BMD in 447 black and white women. The lateral projection is comprised predominantly of cancellous bone whereas the total body BMD is predominantly cortical bone, and the PA spine is intermediate in composition. Black women had a higher BMD than white women for each measurement, but the difference was greatest in the lateral spine. Similarly, black women showed less decline in cancellous bone density with aging. The development of a high peak cancellous bone mass with reduced involutional loss may provide a major contribution towards protection against osteoporotic fractures in black women. Metabolic and pharmacologic studies in black and white women should consider the possibility of the influence of a larger cancellous bone mass.

Total-body calcium estimated by delayed gamma neutron activation analysis and dual-energy X-ray absorptiometry.

Total body calcium (TBCa) in 270 black and white women age 21-79 years was measured concurrently by delayed gamma neutron activation analysis (DGNA) and dual-energy X-ray absorptiometry (DXA). The mean value for TBCa calculated from DXA was 933 g compared with 730 g for DGNA. By regression, TBCa(DXA(g)) = 1.35 x TBCa(DGNA(g)) -54 (r = 0. 90, r(2) = 81.4%, SEE = 66.9 g). This remarkable difference of 203 g suggests that one or both these methods is not accurate. Adjustment of the regression of DXA versus DGNA for body mass index or trunk thickness explained 8.5-10% of the variability between methods. The unadjusted slope for the DXA values regressed against the DGNA values was 1.35, indicating significant discordance between the methods. There is greater agreement between the two DGNA facilities (Brookhaven National Laboratory and Baylor College of Medicine) and between the various DXA instruments. Either DGNA underestimates TBCa or DXA overestimates total-body bone mineral content. Resolution of these disparate results may possibly be achieved by concurrent measurement of whole human cadavers of different sizes with chemical determination of the calcium content of the ash. In the interim, cross-calibration equations between DGNA and standardized values for DXA for total-body bone mineral content may be used, which will permit reporting of consistent values for TBCa from the two technologies.

Relationship of body water compartments to age, race, and fat-free mass.

Water compartments were studied in 72 black and 128 white women, aged 20 to 70 years. Total body water (TBW) was measured by tritiated water dilution, and extracellular water (ECW) was measured by using delayed gamma neutron activation for the determination of total body chloride. Intracellular water (ICW) was assessed as the difference between TBW and ECW. Fat-free mass (FFM) was estimated by the measurement of total body potassium (TBK) and total body fat (TBF) by measurement of total body carbon (TBC). Total body protein was calculated from total body nitrogen (TBN). TBW was found to decline with age and to also be significantly influenced by body size. The extracellular water space was 41.5% of TBW. The decline of TBW with age is due primarily to a decline in ICW. The hydration of the FFM increased with age for the overall population because of a decline in TBK and TBN and an increase in ECW. Body composition models that have assumed constancy of hydration should be adjusted not only for gender but for age and body size.

Discordance between ultrasound of the calcaneus and bone mineral density in black and white women.

Black women have 40% of the incidence rate for hip fracture and have a higher bone mineral density (BMD) than white women. The possibility was raised that bone quality may be disproportionately greater than the advantage in bone density in protection against osteoporotic fractures in black versus white women. Ultrasound (US) of the calcaneus is believed to measure properties of bone in addition to its density. We performed bone density measurements and US of the calcaneus in 108 black and 177 healthy white women, aged 20-70 years. The highest correlation was seen between total body bone density and speed of sound (r = 0.75). The interracial differences in BMD were all statistically significant and varied from 3.4 to 7.6%. The US measurements had lesser interracial differences than the bone density measurements, with velocity barely different between races. These findings suggest that US of the calcaneus measures properties of bone different from density. Fracture prediction data using US from prospective data in white women should not be extrapolated to black women because of the discordance between bone density and US measurements. Prospective studies are needed comparing US measurements in black women to the occurrence of osteoporotic fractures.

Thyroid disease among the Rongelap and Utirik population--an update.

In 1954, 253 Marshallese were accidentally exposed to fallout radiation from the hydrogen bomb, BRAVO. The Marshall Islands Medical Program (MIMP) was established by the Department of Energy in 1955 to monitor and treat radiation-related disease pursuant to this accident. Medical teams from Brookhaven National Laboratory, a federal institution, regularly visit the Marshall Islands to give medical care to the exposed population. The most significant complication of the exposure has been found to be thyroid disease due to the ingestion of radioactive iodides from the fallout. In 1963 the first thyroid nodules were found in Rongelap subjects and in 1969 in Utirik. Non-neoplastic adenomatous nodules were associated with higher doses of radiation and neoplastic nodules developed in individuals receiving lower doses of radiation. Women were more susceptible to the development of palpable thyroid nodules than men. In 1994 the MIMP initiated examination of the thyroid by ultrasound to supplement the clinical examination. One hundred and sixty-four patients were evaluated. No significant differences were found in the incidence of thyroid nodules or the mean nodule count between the three groups of Rongelap and Utirik exposed and a comparison patient population. There was no significant difference in the incidence of thyroid nodules in males vs. females. Five exposed patients were referred for surgical excision of a nodule detected only by ultrasound. These ultrasound findings are unexpected in that females are known to have a higher incidence of thyroid disease than males and we expected that the incidence of ultrasound nodules would be higher in the exposed population.

A multi-center comparison of dual energy X-ray absorptiometers: in vivo and in vitro soft tissue measurement.

OBJECTIVE: To assess intra- and inter-site soft tissue variability by dual energy X-ray absorptiometry (DXA). DESIGN: Cross-sectional trial. SETTING: Three medical research institutions. SUBJECTS: Five humans (in vivo) and four phantoms (in vitro), configured from two whole body phantoms with artificial skeletons and thickness overlays. INTERVENTIONS: Duplicate total-body DXA scans were performed on all subjects at each institution within a 15 d period. RESULTS: All intra-site coefficients of variation (CV) were < 0.5% for total tissue mass, but in vitro and in vivo Cvs were 7.2% and 2.3% for fat mass (FM) and 2.5% and 0.9% for lean mass (LM), respectively. Several total-body and regional FM and LM measurements were significantly different between sites (P < 0.05), with percent differences between sites ranging from 2.6-13.3% for FM and from 1.6-13.6% for LM. Site 2 was consistently lower for FM and Site 3 was consistently lower for LM. CONCLUSIONS: These results stress the need for both rigorous and standardized cross-calibration procedures for soft tissue measurement by DXA.

Comparison of body composition in black and white premenopausal women.

We examined 23 pairs of black and white premenopausal women to determine whether there were ethnic differences in body composition. The pairs were matched on weight and height. Each woman had measurements of total body water taken by a tritiated water dilution technique, total body nitrogen, and total body carbon by neutron-activation, mineral ash by dual x-ray absorptiometry, and body potassium by whole body counting. Differences between blacks and whites were compared with the use of both the two-compartment and four-compartment models. The two-compartment model showed that in premenopausal black and white women of similar age, heights, and weights, blacks had significantly more lean mass. The four-compartment model resulted in similar conclusions. The black women had larger protein, mineral, and water compartments and less fat than whites. It may be that body weight measurements as an indicator of obesity should be adjusted for black versus white women.

Sodium distribution in black and white women.

Delayed gamma neutron activation analysis (DGNA) was performed on 99 black and 168 healthy white women, aged 20-80 years, to examine sodium distribution in the two ethnic groups. Elements measured included total body levels of sodium (TBNa) and chlorine (TBCl). The black women were heavier, and consequently had a higher body surface area. Sodium excess (Naes) was calculated from TBNa and TBCl. Total body water was measured by tritiated water dilution. TBNa was higher in black than white women, and this difference persisted when the values were corrected for body surface area. TBNa and Naes declined significantly with age in white women, whereas extracellular fluid sodium (ECFNa) remained constant. The change with age was not statistically significant in black women for TBNa, Naes or ECFNa. Our sample of healthy black women had a higher TBNa and Naes than healthy white women. This difference persisted after adjustment for body surface area, so that values for sodium distribution need to be adjusted for race. The change in TBNa with age in white women appears to be due to their decline of skeletal tissue mass with a consequent decline in nonexchangeable sodium.

Risk for osteoporosis in black women.

Models of involutional bone loss and strategies for the prevention of osteoporosis have been developed for white women. Black women have higher bone densities than white women, but as the black population ages there will be an increasingly higher population of black women with osteoporosis. Strategies should be developed to reduce the risk of black women for fragility fractures. Dual energy X-ray absorptiometry measurements of the total body, femur, spine, and radius were performed on 503 healthy black and white women aged 20-80 years. Indices of bone turnover, the calcitrophic hormones, and radioisotope calcium absorption efficiency were also measured to compare the mechanisms of bone loss.The black women had higher BMD values at every site tested than the white women throughout the adult life cycle. Black women have a higher peak bone mass and a slightly slower rate of adult bone loss from the femur and spine, which are skeletal sites comprised predominantly of trabecular bone. Indices of bone turnover are lower in black women as are serum calcidiol levels and urinary calcium excretion. Serum calcitriol and parathyroid hormone levels are higher in black women and calcium absorption efficiency is the same in black and white women, but dietary calcium intake is lower in black women. Black and white women have a similar pattern of bone loss, with substantial bone loss from the femur and spine prior to menopause and an accelerated bone loss from the total skeleton and radius after menopause. The higher values for bone density in black women as compared with white women are caused by a higher peak bone mass and a slower rate of loss from skeletal sites comprised predominantly of trabecular bone. Low-risk strategies to enhance peak bone mass and to lower bone loss, such as calcium and vitamin D augmentation of the diet, should be examined for black women. The risk vs. benefits of hormonal replacement therapy should be determined, especially in older women.

Body composition in normal black women: the four-compartment model.

The four-compartment model of body composition was studied in 112 healthy black women to develop normative data to be used to assess deviations in illness. Each compartment was measured by an independent method: tritiated water dilution, prompt-gamma neutron activation analysis (for nitrogen), inelastic neutron scattering (for carbon) and dual energy x-ray absorptiometry (for calcium). The mean age of the population was 43.2 years. Race was self-declared. The mean values for the four compartments were [kg SE] protein: 9.6 (0.07); mineral 3.0 (0.03); fat 24.2 (0.70); and water 33.1 (0.29). Each of the compartments changed significantly with age (P < .0001). There were declines in total body water, mineral, and protein, whereas fat increased linearly with age. Linear regressions performed on pre- and postmenopausal women showed a significant difference only for the mineral compartment. Various models were fit to the data to adjust for body size and age. The equation y = age + height + weight fits the data as well as the other models. Equations and graphs were developed to assess each compartment using this linear model and may be used to assess the body composition status of healthy and ill black women. Although black women tended to be heavier than white women, after controlling for differences in body weight (and age) black women had a greater mass of protein, mineral, and water and a similar fat store. These differences, while statistically significant, were not of great magnitude. This was a cross-sectional study and suspected trends with aging must be confirmed by a longitudinal study.

Calibration of the delayed-gamma neutron activation facility.

The delayed-gamma neutron activation facility at Brookhaven National Laboratory was originally calibrated using an anthropomorphic hollow phantom filled with solutions containing predetermined amounts of Ca. However, 99% of the total Ca in the human body is not homogeneously distributed but contained within the skeleton. Recently, an artificial skeleton was designed, constructed, and placed in a bottle phantom to better represent the Ca distribution in the human body. Neutron activation measurements of an anthropomorphic and a bottle (with no skeleton) phantom demonstrate that the difference in size and shape between the two phantoms changes the total body calcium results by less than 1%. To test the artificial skeleton, two small polyethylene jerry-can phantoms were made, one with a femur from a cadaver and one with an artificial bone in exactly the same geometry. The femur was ashed following the neutron activation measurements for chemical analysis of Ca. Results indicate that the artificial bone closely simulates the real bone in neutron activation analysis and provides accurate calibration for Ca measurements. Therefore, the calibration of the delayed-gamma neutron activation system is now based on the new bottle phantom containing an artificial skeleton. This change has improved the accuracy of measurement for total body calcium. Also, the simple geometry of this phantom and the artificial skeleton allows us to simulate the neutron activation process using a Monte Carlo code, which enables us to calibrate the system for human subjects larger and smaller than the phantoms used as standards.

A multicenter comparison of dual-energy X-ray absorptiometers: in vivo and in vitro measurements of bone mineral content and density.

As part of a multicenter research project, we compared dual-energy X-ray absorptiometry (DXA) instruments at three research centers (sites 1, 2 and 3) to determine both intra- and intersite variability of bone mineral content (BMC), bone mineral density (BMD), and bone area (BA). Scans of the total body and lumbar spine were performed in duplicate on five humans (in vivo), and scans of the total body were performed on two whole body phantoms with artificial skeletons and thickness overlays (in vitro) at all sites over 15 days. The average intrasite variability in two consecutive total body BMD measurements, expressed as a percent difference, was significantly higher in vitro, 1.74 +/- 1.97%, than in vivo, 0.71 +/- 0.38% (p < 0.05). Average intrasite variability of the in vivo lumbar spine BMD was 1.08 +/- 1.12%. The intersite coefficients of variation for all BMD, BMC, and BA measurements were < 2.0%. The total body BMD from site 2 was systematically lower than at sites 1 and 3 both in vivo and in vitro (p < 0.05) with no differences in BMC and BA. Although significant, the total body BMD differences between sites were small (< 1.2%) in vivo compared with in vitro (< 2.6%) and are encouraging for the comparison and pooling of human data from multicenter trials, provided that appropriate standardized cross-calibration and analysis procedures are applied.

Aging in women--the four-compartment model of body composition.

The four-compartment model of body composition was examined in 155 white women through measurement of total body carbon (TBC), nitrogen (TBN), calcium (TBCa), and water levels. The age (mean +/- SD) of the population was 51.4 +/- 13.5 years, and values for the four compartments were as follows (in kilograms): protein 8.9 +/- 1.0, water 30.9 +/- 3.5, mineral 2.6 +/- 0.4, and fat 22.6 +/- 7.3. There was a linear change with age for protein and water, whereas mineral and fat were curvilinear. These latter two compartments also showed differences in premenopausal and postmenopausal rates of change. Various models were fit to the data to adjust for body size and age. Each of the four compartments (mineral, water, fat, and protein) changed with age, with fat increasing and the other compartments declining. The equation, y = age + age2 + height + weight, fit the data as well as the other models. Equations are provided to assess body composition in populations with disorders of nutrition, as well as other illnesses, using height, weight, and age as covariates. Since this was a cross-sectional study, longitudinal studies will have to be performed to confirm the accuracy of rates of change with age predicted with each compartment.

Racial differences in femoral dimensions and their relation to hip fracture.

White women have a higher rate of age-specific hip fractures than black women. Recently, femoral dimensions have been implicated in osteoporotic fractures. To study racial differences in femoral dimensions, dual X-ray absorptiometry scans were obtained for two similar groups of 50 white women and 50 black women. We measured the hip axis length (the distance from below the lateral aspect of the greater trochanter to the inner pelvic brim), the neck width and the neck/shaft angle on the scan print-out. The observer was masked to the race of the subject. The results were analyzed using the independent t-test and showed that the hip axis length and the neck width were significantly longer in the white women than in the black women (p values < 0.05 and < 0.02 respectively) but that the neck/shaft angle was not statistically different in the two groups. We conclude that femoral geometry differs among races. Whether this contributes to the lower risk of hip fracture in black women will require prospectively based studies.

Differential effects of dietary calcium augmentation and hormone replacement therapy on bone turnover and serum levels of calcitrophic hormones.

The mechanism of action of retardation of postmenopausal bone loss may be different for dietary calcium augmentation and hormonal replacement therapy (HRT). We performed a three-arm, placebo-controlled, randomized clinical trial comparing an intake of calcium of 1700 mg with: (1) calcium augmentation with HRT and (2) placebo. One hundred and eighteen women entered the study; 17 patients dropped out of the study. The vast majority of women were less than 2 years postmenopause. Bone mineral density declined significantly in the placebo group. The previously reported rates of change in the HRT group were significantly positive for total body calcium and the trochanter and not significantly different from zero for the others. The rate of change in the calcium augmentation group was intermediate between that in the two other groups, and achieved statistical significance compared with placebo for the total body calcium measurement and for the neck of the femur. Measurements were made prior to treatment and at the end of the study (2.9 years +/- 1.1 SD) for parameters of bone turnover and the calcitrophic hormones, to examine whether the mechanism of action was different for calcium augmentation versus hormonal therapy. There were no changes in the placebo group. The calcium augmentation group had a significant increase in 24-h urinary calcium and declining values for urinary collagen cross-links (pyridinium and deoxypyridinium), urinary hydroxyproline and calcitriol. The group treated with HRT and dietary calcium augmentation also had an increase in urinary calcium and a decline in collagen cross-links and urinary hydroxyproline and skeletal alkaline phosphatase; serum calcitriol did not change. The HRT group also displayed a drop in serum osteocalcin, and an increase in nephrogenous cAMP. Serum parathyroid hormone remained unchanged in all groups. Dietary calcium augmentation retards postmenopausal bone loss by decreasing resorption. The addition of HRT results in a more marked decline in bone resorption parameters and a suppression of parameters of bone formation. Whereas calcium augmentation suppressed calcitriol levels, the addition of HRT resulted in maintenance of calcitriol levels, possibly through enhancement of the renal effects of parathyroid hormone, although other mechanisms are possible.

Comparative study of body composition by dual-energy x-ray absorptiometry.

UNLABELLED: Dual-energy x-ray absorptiometry (DEXA) is a readily available technique that has recently been applied to measurement of body composition. In order to validate this technique, results from DEXA were compared with fat-free mass (FFM) and fat mass (FM) measured by total body levels of potassium (TBK), nitrogen (TBN), water (TBW) and carbon (TBC). METHODS: A healthy population of 127 white women and 38 black women with a body mass index of 18-30 were recruited. RESULTS: Compared with each of the other methods, DEXA overestimated FM and underestimated FFM. The slopes of the FM by DEXA versus the FM from each of the four methods were approximately the same, with a s.e.e. ranging from 2.4 to 3.0 units. The slopes of DEXA in comparison to FFM, however, ranged from 0.61 to 0.74 and were significantly less than unity, with a s.e.e. of 1.6 to 2.4 units. CONCLUSION: These findings suggest that at high values of FFM, DEXA is measuring something different from the FFM measured by TBW, TBN and TBK. The program for separating bone and soft tissue and for separating soft tissue into fat and lean at higher values in the DEXA method may need to be adjusted.