Neurotransmitters in cerebrospinal fluid reflect pathological activity

Reduced bone mineral density (BMD), termed diabetic osteopenia, has been reported in patients with insulin-dependent (Type 1) diabetes mellitus (IDDM). To examine BMD in long-term IDDM patients with normal kidney function, but with different degrees of urinary albumin excretion rate (UAER), compared to that of patients with elevated plasma creatinine, 36 IDDM male patients (mean duration 27 years) were subdivided according to UAER (<30, 30-300, >300, >300 mg 24 h(-1) and plasma creatinine 0.120-0.350 mmol l(-1)) and 15 controls were recruited. BMD was measured by dual energy X-ray absorptiometry and UAER by enzyme linked immunosorbent assay. BMD was normal in IDDM patients with normal UAER and reduced in the femoral neck, the trochanter major, and the Wards triangle in patients with increased UAER (p < 0.01, p < 0.05, p < 0.02). BMD correlated to creatinine clearance in both cortical and cancellous bone sites (p < 0.001, p < 0.0001), and inversely to the levels of plasma PTH (p < 0.0005). We conclude that BMD is normal in long-term IDDM male patients with normal kidney function and normal UAER and reduced in patients with increased UAER. Diabetic osteopenia seems to be a progressive phenomenon related to diabetic nephropathy and associated with the decrease in creatinine clearance and with the resulting rise in plasma PTH.     

Bone mineral affection in asymptomatic adult patients with celiac disease

OBJECTIVES: Osteopenia is a well-known complication of overt celiac disease, but whether such defective bone mineralization is present among asymptomatic or silent patients is not known. Our objectives were: 1) to examine bone mineralization of a group of asymptomatic celiac patients; 2) to compare these results with those of symptomatic patients. METHODS: Bone mineral density of the spine and total skeleton by dual energy x-ray absorptiometry and serum parameters of mineral metabolism of eight recently diagnosed asymptomatic patients with celiac disease were studied. Results were compared with those obtained in 20 untreated symptomatic celiacs, 14 patients treated with gluten-free diet for a mean time of 15 yr, and 153 healthy adult subjects, matched by sex and age. RESULTS: Four and five out of eight asymptomatic patients presented with reduced mineralization of the spine and the total skeleton, respectively (> 1 SD below normal values for sex and age). Two patients presented with severe osteopenia of the spine, and the other three presented with severe osteopenia of the whole skeleton (> 2 SD below mean normal values). Osteopenia at plane bone level (total skeleton) was significantly lower when compared to healthy controls (p < 0.02). Symptomatic untreated patients had significantly more severe deterioration of bone mineralization than did asymptomatics (p < 0.05) and treated patients (p < 0.05). No difference in bone mineral density was observed between treated patients and asymptomatic celiacs. Serum levels of calcium, alkaline phosphatase, 25-OH vitamin D, and parathormone did not show conclusive abnormalities. CONCLUSIONS: Our findings provide direct evidence that reduced bone mineralization occurs in asymptomatic celiac patients before any other symptom becomes evident. Only early diagnosis and treatment of celiac disease can avoid the deterioration of the bone structure observed in all clinical status of celiac disease.     

Developing a research culture for palliative care

The aim of study was to evaluate, during 2-year follow-up, bone mineral density in sites with different cortical/cancellous bone ratios (lumbar spine, total body, distal site of radius) and selected markers of bone turnover (total alkaline phoshatase, osteocalcin, pyridinoline and deoxypirydinoline) in patients with long-standing insulin-dependent diabetes mellitus in comparison with healthy controls. Additionally, the influence of age, sex, smoking, duration of diabetes, the degree of metabolic control, or coexisting chronic complications of diabetes (retinopathy, incipient nephropathy, polyneuropathy) on the studied indices of bone metabolism in patients with insulin-dependent diabetes mellitus were evaluated. It was found that patients with long-standing diabetes mellitus had significantly lower bone mineral density than healthy controls (p < 0.003 in lumbar spine and p < 0.001 in total body). The incidence rate of osteopenia and osteoporosis was significantly higher in this group of patients in comparison with the controls (p < 0.005 for lumbar spine and total body and p < 0.001 for radius). In comparison with healthy subjects, diabetic patients and significantly higher, but within normal reference range, serum alkaline phosphate (p < 0.005) and osteocalcin (p < 0.05), accompanied by similar pyridinoline and not significantly increased deoxypyridinoline. Duration and metabolic control of diabetes, or the coexistence of its chronic complications, did not correlate with bone mineral density or the studied indices of bone turnover. In conclusion, diabetic osteopenia seems to be a normal bone turnover state, not influenced by the duration or degree of metabolic control of diabetes.     

Bone size and mechanics at the femoral diaphysis across age and sex

The reasons for the increase in fracture rates with age are not fully understood. It is known that there is a decrease in bone mass with a presumed loss of strength. This decrease may possibly be compensated for by changes in cross-sectional geometry. Previous studies, which have been limited by lack of information on subjects' heights and weights, were not able to resolve this issue. In this study, measurements of cross-sectional geometry (area and second moments of area) from 107 specimens of human femoral diaphysis from subjects aged 21-92 years were analysed. Mathematical models of the variation in bone geometry with age were developed. These models included the effects of sex, height and weight. Values of parameters from these models were then used in a biomechanical analysis of the static stresses at the mid-shaft of the femur. Results indicate that although there was a reduction in cortical area in old age, bone tissue was redistributed so that neither bending stresses in the coronal plane nor torsional stresses were higher in old age than in young adulthood. An additional finding was that at any age women had smaller bones, less cortical bone area and higher bone stresses than men. This finding may have some bearing on the higher fracture incidence seen in older women.     

Attachment loss with postmenopausal age and smoking

To determine whether postmenopausal bone loss and factors associated with osteoporosis affect tooth retention, we examined vertebral and proximal femoral (postcranial) bone mineral density in relation to tooth loss and attachment loss in a cross-sectional study of 135 postmenopausal women (age range 41-70 yr). Women had at least 10 teeth and no evidence of moderate or severe periodontal disease. Full-mouth attachment loss measurements were made using a pressure-sensitive probe, and bone density was determined by dual-energy X-ray absorptiometry. Attachment loss was correlated with tooth loss (number of remaining teeth, radiologically determined), but not with vertebral or proximal femur bone density. Multivariate analysis showed current smoking (p = 0.01), years since menopause (p = 0.02) and the interaction of age and current smoking (p < 0.01), to be statistically significant predictors of attachment loss in our study population.     

Reduced speed of sound in tibial bone of haemodialysed patients: association with serum PTH level

BACKGROUND: In end-stage renal disease, average bone mineral density has been reported to be normal or only modestly reduced, more so in the cortical bone. The purpose of the present study was to explore the potential use of quantitative ultrasound, a method reflecting both quantitative and qualitative properties of bone, in assessing bone status in patients on maintenance haemodialysis. METHODS: We studied 71 patients (age 17-81 years, time on dialysis 0-18 years). The speed of sound waves (tSOS; m/s) propagating along the cortical bone has been determined at the tibial shaft. tSOS results were expressed as Z scores, i.e. units of standard deviations from age- and sex-matched normal mean values, and correlated with relevant clinical and biochemical variables. RESULTS: SOS Z score averaged -2. 0 (range -6.8 to 0.6; P<0.001) and was negative in 93% of the patients. Significant inverse correlations were found between SOS Z score and both time on dialysis (r=-0.52; P<0.0001) and serum PTH (r=-0.39; P=0.0002). Markedly reduced SOS Z score, below -2, was found in 80% of the patients whose PTH levels exceeded 34 pmol/l (five times the upper normal limit), compared with 43% of the patients whose PTH levels were below 34 pmol/l(P=0.04). Compared to patients without bone pain (n=51), subjects with bone pain (n=20) had somewhat lower SOS Z scores -2.5+/-2.0 versus -1.8+/-1.4; P=0. 08), but this could be accounted for by longer time on dialysis. CONCLUSIONS: tSOS is substantially reduced in the majority of haemodialysed patients and is related to time on dialysis and serum PTH level. The clinical value of this novel method needs further exploration.     

Bone disease in patients with primary sclerosing cholangitis: prevalence, severity and prediction of progression

BACKGROUND/AIMS: Osteopenia is a common complication in some chronic cholestatic liver diseases. Our aims were to determine the prevalence and severity of bone disease in patients with primary sclerosing cholangitis; and identify risk factors to predict the presence and progression of osteopenia. METHODS: Eighty-one patients involved in a randomized trial of ursodeoxycholic acid were analyzed. Bone mineral density of the lumbar spine was determined at entry and at annual intervals. RESULTS: Bone mineral density of the lumber spine in primary sclerosing cholangitis patients was significantly lower than expected when compared to normal values adjusted for age, sex and ethnic group at entry (p<0.005), and after 1 year (p<0.05), 2 years (p<0.05), 4 years (p<0.005) and 5 years of follow-up (p<0.005). Seven patients (8.6%) had bone mineral density of the lumber spine below the fracture threshold at entry. These patients were significantly older, had a longer duration of inflammatory bowel disease and more advanced primary sclerosing cholangitis. The rate of bone loss in primary sclerosing cholangitis patients and expected in normal controls was 0.01+/-0.02 g x cm(-2) x year(-1) and 0.003+/-0.003 g x cm(-2) x year(-1), respectively (p = NS), and was similar in patients receiving placebo and ursodeoxycholic acid. Age was the only variable inversely related with baseline bone mineral density of the lumber spine (p<0.0001). None of the variables predicted progression of the bone disease. CONCLUSIONS: Severe osteoporosis occurs in few patients with primary sclerosing cholangitis, but it should be suspected in patients with longer duration of inflammatory bowel disease and more advanced liver disease. Its presence, severity and progression cannot be accurately evaluated by routine clinical, biochemical, or histological variables. Ursodeoxycholic acid does not affect the rate of bone loss in primary sclerosing cholangitis.     

Load-bearing capacity of corticocancellous bone grafts in the spine

We investigated the relationship between the densities and areas of commonly used autogenous tricortical bone grafts from the iliac crest and the fibula and their mechanical load-bearing abilities. Intact corticocancellous grafts, seven millimeters thick, were obtained during elective spinal arthrodeses from fifty-six patients: from the anterior part of the pelvis in twenty-four patients, the posterior part of the pelvis in twenty-nine patients, and the fibula in three patients. The apparent densities and cross-sectional areas of the cortical and cancellous bone were measured with use of a specific computed-tomographic technique before the specimens were mechanically tested to failure in uniaxial compression. Specimens from the anterior superior iliac spine were able to bear significantly higher axial loads (average, 3230 newtons; range, 430 to 8112 newtons) than were those from the posterior superior iliac spine (average, 1458 newtons; range, 350 to 4639 newtons) (p < 0.001). The cancellous density was the most significant single factor in the prediction of the load to failure of the grafts from the iliac crest (adjusted r2 = 0.58; p < 0.0001). When all of the physical variables (the cancellous and cortical densities and areas) were entered into a multiple-regression model, the combination of the cortical and cancellous densities and the cortical area was a good predictor (adjusted r2 = 0.68; p < 0.001) of the load to failure. The fibular grafts were stronger than those from the other two sites, but they had the least over-all cross-sectional area and cancellous bone.(ABSTRACT TRUNCATED AT 250 WORDS)     

Assessment of bone in Ehlers Danlos syndrome by ultrasound and densitometry

OBJECTIVE: Ehlers Danlos syndrome (EDS) is an inherited disorder of connective tissue characterised by hyperextensible skin, joint laxity, and easy bruising. There are phenotypic similarities with osteogenesis imperfecta, but in EDS a tendency to fracture or altered bone mass has not previously been considered to be a cardinal feature. METHOD: This case-control design study investigates whether 23 patients with EDS had differences in fracture rates, bone mass, and calcaneal ultrasound parameters compared with age and sex matched controls. RESULTS: 23 cases of EDS (mean (SD) age 38.5 (15.5)) were compared with 23 controls (mean age 37.8 (14.5)). A significant reduction in bone density measured by dual energy x ray absorptiometry was found at the neck of femur by 0.9 SD, p = 0.05, and lumbar spine by 0.74 SD, p = 0.02. At the calcaneum, broad band ultrasound attenuation and speed of sound were significantly reduced compared with controls by 0.95 SD (p = 0.004) and 0.49 SD (p = 0.004) for broad band ultrasound attenuation and speed of sound respectively. Broad band ultrasound attenuation and speed of sound remained significantly reduced after adjusting for bone mineral density (BMD). After adjusting for functional status (HAQ), age and sex, hypermobility was inversely correlated with broad band ultrasound attenuation and SOS, but not BMD at hip or spine. Previous fracture was 10 times more common in EDS (p < 0.001), with 86.9% of patients reporting a total of 47 low impact fractures, compared with 8.7% of controls. CONCLUSION: This study has identified a tendency of EDS patients to fracture, have low bone mass and abnormal bone structure. The aetiology is likely to be multifactorial, with an inherited structural element, accentuated by immobility or reduced exercise. This is one of the first clinical studies to suggest ultrasound can detect structural differences in bone, independent of dual energy x ray absorptiometry.     

The increase in blood pressure induced by inhibition of nitric oxide synthase in anesthetized Wistar rats is inversely related to basal blood pressure value

A marked reduction of 40-70% in regional bone mineral density (BMD) has been reported after fractures of long bones, and this post-traumatic osteopenia may to some extent persist for several years, perhaps lifelong. In this cross-sectional study, we investigated whether prolonged alcohol abuse had any effect on the degree of post-traumatic osteopenia after isolated tibia shaft fractures, the rationale for such a suspicion being the deranged bone metabolism found in alcoholics. We also wanted to investigate whether dual energy X-ray absorptiometry (DEXA) or quantitative ultrasound technique could detect differences between abusers and non-abusers in post-traumatic bone loss. We measured the BMD in 61 male patients with isolated tibia shaft fractures (1984-94) with the Lunar DPX-L and the Lunar Achilles. Twenty-four of the patients were verified to be high consumers of alcohol. After correction for differences in age and the time elapsed since the fracture event, we found significantly lower (11%; P = 0.017) BMD in the femoral neck of the fractured leg in abusers when utilizing the DEXA technique. No differences between abusers and non-abusers in BMD were detectable when using the ultrasound technique. We found a fair correlation (r = 0.63-0.81) between the DEXA and the ultrasound techniques in regions with spongious bone. Our findings suggest that alcohol abuse has some, albeit a limited, effect on the degree of post-traumatic osteopenia and that ultrasound measurements in the calcaneus are of little use in detecting an increased post-traumatic osteopenia in this patient group.     

High turnover osteopenia in preterm babies

Osteopenia is common in preterm babies, but its pathogenesis is uncertain. In this study bone density in babies was quantitated, postnatal bone mineralization compared to expected intrauterine bone mineralization and the pathogenesis of osteopenia investigated. Healthy babies (103 term, 76 preterm) were examined clinically, biochemically and radiologically the day after birth and at a time corresponding to expected full term gestation. Appendicular bone density was quantitated by magnification radiogrammetry, using the humeral cortical index (CI). The CI of preterm and term babies was similar the day after birth. In preterm babies elevated serum alkaline phosphatase and high urinary hydroxyproline indicated increased bone turnover. The CI of preterm babies at expected full term gestation was lower (p = 0.0001) than that of term babies at birth, implying that postnatal bone mineralization lagged behind expected intrauterine bone mineralization. Radiologic data suggested increased endosteal resorption rather than decreased bone formation. At expected full term gestation the preterm babies had higher serum alkaline phosphatase and urinary calcium, phosphate, c-AMP and hydroxyproline (p = 0.0001) than term babies at birth, and 15% had periosteal reactions. The biochemical as well as the radiologic data therefore indicated high turnover osteopenia in preterm babies. We conclude that postnatal bone mineralization in preterm babies lagged significantly behind expected intrauterine bone mineralization and that the osteopenia observed in preterm babies is caused by increased bone resorption and not by decreased bone formation. The cause(s) of this high turnover osteopenia, however, remains to be ascertained.     

Considerations on correct diagnosis of atypical electrocardiographic T-wave findings in young subjects

This study was designed to determine the fate of new parathyroid hormone (PTH)-induced cortical bone after withdrawal of PTH treatment, and to evaluate whether subsequent treatment with a bisphosphonate would influence this. Six groups of 21-month-old rats were used: a baseline group killed at the beginning of the experiment, three groups injected with human PTH (1-34) (62 mug/kg) daily for 8 weeks (day 1-56), then one group was killed and the other two groups were injected for another 8 weeks (day 57-112) with either saline or bisphosphonate (risedronate 5 mug/kg twice a week). Two control groups were injected with vehicle for the first 8 weeks, then one group was killed and the other group injected with saline the next 8 weeks. All animals were labeled with tetracycline and calcein on day 35 and day 49 of the experiment, respectively. PTH increased periosteal (35%) and in particular endosteal mineralizing surfaces (188%), mineral appositional rates, and bone formation rates at the femur diaphysis, leading to an increase in cortical cross-sectional area of 31%. Withdrawal of PTH induced a fast and pronounced endosteal bone resorption whereas risedronate prevented this resorption. No differences were seen in apparent density of dry defatted bone and ash among the groups. PTH increased the mechanical strength of the femur diaphysis; ultimate load increased by 64% and ultimate stress by 25%. A pronounced decrease in mechanical strength and competence was found after withdrawal of PTH: ultimate load decreased by 31% and ultimate stress by 21%. Risedronate, however, prevented this decrease in mechanical strength and competence in these 2-year-old rats.     

The effect of enhanced milk yield of dairy cows by frequent milking or suckling on intake and digestibility of the diet

The prevalence of osteoporosis and the incidence of fractures are substantially lower in black than in white subjects, a finding generally attributed to racial differences in adult bone mass. Whether these racial differences are present in childhood is the subject of considerable interest, as the amount of bone gained during growth is a major determinant of future susceptibility to fractures. We measured the density and size of the vertebrae and femurs of 80 black and 80 white healthy children, 8-18 yr of age, matched for age, gender, height, weight, and stage of sexual development, using computed tomography. Race had a significant and differential effect on the bones in the axial and appendicular skeletons. In the axial skeleton, black children had greater cancellous bone density, but similar cross-sectional area of the vertebral bodies. In contrast, in the appendicular skeleton, black children had greater femoral cross-sectional area, but similar cortical bone area and cortical bone density. Compared to white children, vertebral bone density and femoral cross-sectional area at sexual maturity were, on the average, 10.75% and 5.7% higher, respectively, in black children. Such significant variations may contribute to the racial differences in the prevalence of osteoporosis between black and white adults.     

In times of survival, the right of silence

The purpose of this study was to assess cortical and cancellous bone responses to unilateral limb immobilization and, subsequently, to remobilization with exercise, in a young adult canine model. Right forelimbs of 14 1-2-year old mongrel dogs were immobilized in a non-weight-bearing position by a bandage for 16 weeks. Six control dogs were untreated. At 16 weeks, seven immobilized and three control dogs were euthanized. The remaining seven immobilized dogs began a recovery protocol consisting of 16 weeks of kennel confinement (without the right forelimb bandaged) followed by 16 weeks of treadmill exercise conducted three times per week. These seven dogs and three control dogs were euthanized at 48 weeks. Bone mineral density of the proximal radii was determined with dual-energy X-ray absorptiometry and humeral middiaphyseal cross-sectional areas were determined with computed tomography. Humeri were tested in cranio-caudal three-point bending to failure. Cancellous bone cores from the lateral humeral condyles had wet apparent density determined and were tested to failure in compression. Mechanical properties, bone density, and cross-sectional areas were compared between immobilized (right forelimb), contralateral weight bearing (left forelimb), and control forelimbs with Kruskal-Wallis and post hoc tests. At 16 weeks, bone mineral density, cortical load, yield, and stiffness as well as cancellous bone failure stress, yield stress, and modulus were significantly lower (p < 0.02) for immobilized limbs than control limbs. Immobilized limb cancellous bone mechanical properties were 28%-74% of control values, and cortical bone mechanical properties were 71%-98% of control values. After 32 weeks of remobilization, cortical and cancellous bone mechanical properties were not different from control values except that cortical bone failure stress and modulus were significantly higher (p < 0.01) between remobilized and control limbs. In summary, 16 weeks of forelimb immobilization was associated with significantly lower mechanical properties, and with greater differences in cancellous than cortical bone properties. Mechanical properties were not different from control values after 32 weeks of recovery that included 16 weeks of treadmill exercise.     

Altered instantaneous and calcium-modulated oscillatory PTH secretion patterns in patients with secondary hyperparathyroidism

The relative contributions of increased parathyroid cell mass and altered control mechanisms of parathyroid hormone (PTH) secretion in secondary hyperparathyroidism are still controversial. In this study, endogenous pulsatile PTH secretion was analyzed by the multiparameter deconvolution technique to differentiate alterations in cell mass-dependent (PTH burst mass) and regulation-dependent (frequency, synchrony, calcium responsiveness) PTH release in uremic patients. PTH concentration versus time profiles were obtained in 13 uremic and 16 healthy adults under baseline conditions and during acute hypo- and hypercalcemia. Plasma PTH half-life was increased in patients compared with control subjects (4.7+/-1.9 versus 2.6+/-0.1 min, P < 0.005). The baseline PTH secretion rate was elevated eightfold in the patients as a result of an increased PTH mass secreted per burst (17.1+/-4.7 versus 2.0+/-0.4 pM, P = 0.0001), higher burst frequency (8.0+/-0.3 versus 6.8+/-0.3 h(-1), P < 0.01), and a higher tonic secretion rate (343+/-99 versus 30+/-4 pM/h, P = 0.0001). Acute hypocalcemia elicited an immediate, frequency- and amplitude-mediated selective increase in the pulsatile secretory component, which was fractionally weaker in patients (+595%) than control subjects (+1755%, P < 0.001). The acceleration and the amplification of PTH bursts were 35 and 60% lower in the patient group. Acute hypercalcemia suppressed total PTH secretion by 79% in control subjects but only by 63% in patients (P < 0.002). PTH burst frequency was reduced during hypercalcemia by 30% in control subjects, but remained unchanged in patients. In conclusion, uremic hyperparathyroidism is mediated by a marked increase in glandular secretion, but also by reduced PTH elimination. The increased spontaneous PTH burst frequency and the blunted responsiveness to changes in Ca2+ indicate partial uncoupling of hyperplastic parathyroid glands from the physiologic regulatory mechanisms that direct pulsatile PTH release.     

Epidermal growth factor receptor ectodomain in the urine of patients with squamous cell carcinoma

Female Sprague-Dawley rats were ovariectomized (OVX) or sham-operated at 3 months of age and maintained untreated for 1 year after surgery. Baseline control and OVX rats were killed at the beginning of treatment when the rats were 15 months of age and 1 year postovariectomy. The remaining rats were treated with hPTH 1-34 (80 micrograms/kg BW, 5 days/week) or vehicle for 10 weeks. Quantitative bone histomorphometry was performed on undecalcified longitudinal sections of the proximal femur from each rat. Baseline OVX rats exhibited cancellous and cortical osteopenia at the femoral neck as their mean cancellous bone volume and cortical width were significantly decreased compared to the means for baseline control rats. In addition, baseline OVX rats had increased osteoblast and osteoclast surfaces and a greater cancellous bone formation rate than baseline control rats. OVX rats remained osteopenic with no further bone loss from the femoral neck after 10 weeks of vehicle treatment. In contrast, cancellous bone volume and cortical width in OVX rats treated with PTH were increased to the level of vehicle-treated control rats. The hormone restored lost bone in the femoral neck of OVX rats by markedly stimulating both cancellous and cortical bone formation. These histomorphometric findings in concert with recent biomechanical studies of bone strength indicate that the femoral neck of aged OVX rats is a promising sample site for studies of the prevention and treatment of bone loss induced by estrogen depletion.     

LY353381 x HCl: an improved benzothiophene analog with bone efficacy complementary to parathyroid hormone-(1-34)

LY353381 x HCl is a benzothiophene analog that is structurally related to raloxifene with potent selective estrogen receptor modulator activity in the ovariectomized rat model of postmenopausal osteoporosis. The effects of LY353381 x HCl on bones, body weight, and uterine weight were evaluated in 7-month-old rats with osteopenia that was induced by ovariectomizing animals for 1 month before initiation of treatment with several agents individually, in combination, or in sequence. LY353381 x HCl was administered daily by itself for 90 days, in combination with the amino-terminal fragment of PTH-(1-34) (PTH) for 90 days, or sequentially after PTH when PTH was discontinued after 45 days of treatment. Additionally, comparisons were made of animals treated with PTH alone, 17alpha-ethynyl estradiol alone, equine estrogens (Premarin) alone, raloxifene alone, or combinations of PTH and equine estrogens or raloxifene. Ovariectomy induced increases in the rate of bone turnover and body weight while decreasing bone mineral density, bone mineral content, bone strength, trabecular bone volume, trabecular thickness, trabecular number, and uterine weight. LY353381 x HCl at 0.01-1 mg/kg had marginal effects on body weight and no effect on uterine weight compared with those in ovariectomized controls, in contrast to 17alpha-ethynyl estradiol or equine estrogens. LY353381 x HCl prevented further bone loss due to ovariectomy in tibia, femora, and lumbar vertebra, like 17alpha-ethynyl estradiol but unlike equine estrogens. LY353381 x HCl prevented the resorption of trabecular bone spicules, like 17alpha-ethynyl estradiol, but inhibited bone formation activity to a lesser extent than 17alpha-ethynyl estradiol. In this model, 17alpha-ethynyl estradiol appeared to be more efficacious after 3 months of treatment than equine estrogens in the proximal tibia metaphysis, suggesting efficacy differences between metabolites of 17beta-estradiol in bone. PTH at 10 microg/kg had no effect on body weight or uterine weight, but significantly increased bone mass to beyond those in sham-operated controls, baseline controls, and groups receiving other individual treatments at both axial and appendicular sites. The combination of LY353381 x HCl and PTH increased bone mass at a faster rate and to a greater extent than PTH alone or the combinations of equine estrogens/PTH and raloxifene/PTH at trabecular bone sites. The LY353381 x HCl/PTH combination improved bone mass and quality beyond any agent alone in regions enriched for cancellous bone, but was not significantly better than PTH alone on cortical bone. Additionally, when PTH was discontinued at 45 days, LY353381 x HCl prevented the rapid loss of bone observed in controls. Therefore, LY353381 x HCl appears to be useful by itself, in combination, or in sequence with PTH to replace lost bone in postmenopausal women.     

Randomised controlled study of effect of parathyroid hormone on vertebral-bone mass and fracture incidence among postmenopausal women on oestrogen with osteoporosis

BACKGROUND: Small increases in bone mass are commonly seen with existing treatments for osteoporosis, which reduce bone remodelling and primarily prevent bone loss. Since these drugs reduce but do not eliminate risk of fractures, an anabolic agent that would increase bone mass and potentially cure the underlying skeletal problem is needed. METHODS: We did a 3-year randomised controlled trial to find out the effects of 1-34 human parathyroid hormone (hPTH [1-34], 400 U/25 micrograms daily subcutaneously) in postmenopausal women with osteoporosis taking hormone-replacement therapy (n = 17). The controls were women taking hormone-replacement therapy only (n = 17). The primary outcome was bone-mineral density of the lumbar vertebrae, with bone-mineral density at other sites and vertebral fractures as secondary endpoints. FINDINGS: Patients taking hormone-replacement therapy and PTH (1-34) had continuous increase in vertebral bone-mineral density during the 3 years, whereas there was no significant change in the control group. The total increase in vertebral bone-mineral density was 13.0% (p < 0.001); 2.7% at the hip (p = 0.05); and 8.0% in total-body bone mineral (p = 0.002). No loss of bone mass was found at any skeletal site. Increased bone mass was associated with a reduction in the rate of vertebral fractures, which was significant when fractures were taken as a 15% reduction in vertebral height (p = 0.04). During the first 6 months of treatment, serum osteocalcin concentration, which reflects bone formation, increased by more than 55%, whereas excretion of crosslinked n-telopeptide, which reflects bone resorption, increased by only 20%, which suggests some uncoupling of bone formation and resorption. By 6 months, there were similar increases in both markers, which gradually returned towards baseline as the study progressed. Vertebral bone-mineral density increased most during the first year of PTH treatment. INTERPRETATION: We found that PTH has a pronouned anabolic effect on the central skeleton in patients on hormone-replacement therapy. PTH also increases total-body bone mineral, with no detrimental effects at any skeletal site. The increased vertebral mass was associated with a reduced rate of vertebral fracture, despite increased bone turnover. Bone-mass changes may be consistent with a reduction in all osteoporotic fractures. If confirmed in larger studies, these data have important implications for the treatment of postmenopausal osteoporosis.     

The use of antibiotic-impregnated cement in infected reconstructions after resection for bone tumours

Bone mobilization, lowering of bone mineral density (BMD), and osteoporotic fractures are recognized in postmenopausal women with weight loss. Because a high-calcium intake suppresses bone loss in peri- and postmenopausal women, the present randomized, double-blind, placebo-controlled study was designed to test the hypothesis that calcium supplementation prevents net bone mobilization and consequent bone mineral loss during voluntary weight reduction in obese postmenopausal women. Subjects were placed on a moderate energy-restricted diet and either calcium supplementation (1 g/day) or placebo for 6 months. Body weight, bone turnover markers (pyridinium cross-links), osteocalcin, and parathyroid hormone (PTH) were measured at treatment weeks 1-5, 7, 10, 13, 16, 20, and 25. Total body BMD, insulin-like growth factor, 25-hydroxyvitamin D, and sex hormone binding globulin (SHBG) were measured at baseline and week 25. The calcium supplemented (n = 15; age 60.9 +/- 9.4 years, body mass index [BMI] 33.2 +/- 4.6 kg/m2) and placebo (n = 16; age 55.8 +/- 8.3 years, BMI 32.9 +/- 4.5 kg/m2) groups lost similar amounts of weight over the study interval (10.2 +/- 5.3% vs. 10.0 +/- 5.2%) and both groups increased SHBG (p < 0.001). There was a statistical effect of calcium supplementation during weight loss to suppress pyridinium cross-links, osteocalcin, and PTH (p < 0.05, < 0.01, and < 0.05, respectively). Loss of BMD tended to be greater in the placebo group by 1.4% (p < 0.08) after weight loss. One gram per day calcium supplementation normalizes the increased calcium-PTH axis activity and the elevated bone turnover rate observed during moderate voluntary energy restriction in postmenopausal women.