22-oxacalcitriol suppresses secondary hyperparathyroidism without inducing low bone turnover in dogs with renal failure.
BACKGROUND: Calcitriol therapy suppresses serum levels of parathyroid hormone (PTH) in patients with renal failure but has several drawbacks, including hypercalcemia and/or marked suppression of bone turnover, which may lead to adynamic bone disease. A new vitamin D analogue, 22-oxacalcitriol (OCT), has been shown to have promising characteristics. This study was undertaken to determine the effects of OCT on serum PTH levels and bone turnover in states of normal or impaired renal function. METHODS: Sixty dogs were either nephrectomized (Nx, N = 38) or sham-operated (Sham, N = 22). The animals received supplemental phosphate to enhance PTH secretion. Fourteen weeks after the start of phosphate supplementation, half of the Nx and Sham dogs received doses of OCT (three times per week); the other half were given vehicle for 60 weeks. Thereafter, the treatment modalities for a subset of animals were crossed over for an additional eight months. Biochemical and hormonal indices of calcium and bone metabolism were measured throughout the study, and bone biopsies were done at baseline, 60 weeks after OCT or vehicle treatment, and at the end of the crossover period. RESULTS: In Nx dogs, OCT significantly decreased serum PTH levels soon after the induction of renal insufficiency. In long-standing secondary hyperparathyroidism, OCT (0.03 microg/kg) stabilized serum PTH levels during the first months. Serum PTH levels rose thereafter, but the rise was less pronounced compared with baseline than the rise seen in Nx control. These effects were accompanied by episodes of hypercalcemia and hyperphosphatemia. In animals with normal renal function, OCT induced a transient decrease in serum PTH levels at a dose of 0.1 microg/kg, which was not sustained with lowering of the doses. In Nx dogs, OCT reversed abnormal bone formation, such as woven osteoid and fibrosis, but did not significantly alter the level of bone turnover. In addition, OCT improved mineralization lag time, (that is, the rate at which osteoid mineralizes) in both Nx and Sham dogs. CONCLUSIONS: These results indicate that even though OCT does not completely prevent the occurrence of hypercalcemia in experimental dogs with renal insufficiency, it may be of use in the management of secondary hyperparathyroidism because it does not induce low bone turnover and, therefore, does not increase the risk of adynamic bone disease. (+info)
Osteopenia in the patient with cancer.
Osteopenia is defined as a reduction in bone mass. It is commonly known to occur in elderly people or women who are postmenopausal due to hormonal imbalances. This condition, however, can result because of many other factors, such as poor nutrition, prolonged pharmacological intervention, disease, and decreased mobility. Because patients with cancer experience many of these factors, they are often predisposed to osteopenia. Currently, patients with cancer are living longer and leading more fulfilling lives after treatment. Therefore, it is imperative that therapists who are responsible for these patients understand the risk factors for osteopenia and their relevance to a patient with cancer. (+info)
A Cbfa1-dependent genetic pathway controls bone formation beyond embryonic development.
The molecular mechanisms controlling bone extracellular matrix (ECM) deposition by differentiated osteoblasts in postnatal life, called hereafter bone formation, are unknown. This contrasts with the growing knowledge about the genetic control of osteoblast differentiation during embryonic development. Cbfa1, a transcriptional activator of osteoblast differentiation during embryonic development, is also expressed in differentiated osteoblasts postnatally. The perinatal lethality occurring in Cbfa1-deficient mice has prevented so far the study of its function after birth. To determine if Cbfa1 plays a role during bone formation we generated transgenic mice overexpressing Cbfa1 DNA-binding domain (DeltaCbfa1) in differentiated osteoblasts only postnatally. DeltaCbfa1 has a higher affinity for DNA than Cbfa1 itself, has no transcriptional activity on its own, and can act in a dominant-negative manner in DNA cotransfection assays. DeltaCbfa1-expressing mice have a normal skeleton at birth but develop an osteopenic phenotype thereafter. Dynamic histomorphometric studies show that this phenotype is caused by a major decrease in the bone formation rate in the face of a normal number of osteoblasts thus indicating that once osteoblasts are differentiated Cbfa1 regulates their function. Molecular analyses reveal that the expression of the genes expressed in osteoblasts and encoding bone ECM proteins is nearly abolished in transgenic mice, and ex vivo assays demonstrated that DeltaCbfa1-expressing osteoblasts were less active than wild-type osteoblasts. We also show that Cbfa1 regulates positively the activity of its own promoter, which has the highest affinity Cbfa1-binding sites characterized. This study demonstrates that beyond its differentiation function Cbfa1 is the first transcriptional activator of bone formation identified to date and illustrates that developmentally important genes control physiological processes postnatally. (+info)
Glucocorticoid-induced secondary osteopenia in female rats: a time course study as compared with ovariectomy-induced osteopenia and response to salmon calcitonin.
Previously we reported that 8-week treatment with methylprednisolone acetate (MPA: 0.1 mg/kg, s.c., 3 days a week) of male rats caused a novel type of osteopenia whose development was prevented by salmon calcitonin (SCT) in a dose-dependent manner. In this study, to compare the MPA-inducible osteopenia with the ovariectomy (OVX)-inducible one, female rats were used instead of male rats and a time-course study of development was made. MPA treatments for 1, 2, 4 and 8 weeks histologically induced characteristic osteopenic changes in a time-dependent manner that were histomorphometrically detectable in tibiae within 4 weeks as reduced bone mass, accelerated bone resorption, and suppressed bone formation and mineralization. Node-strut analysis revealed that the connectivity of the trabecular structure remained unaffected. Such MPA-induced changes in the trabecular structure, to be defined as thinned-but-uncut, is in a good contrast with OVX-induced unthinned-but-cut structure, although the latter osteopenic changes became detectable 2 weeks earlier. Another previous finding confirmed herein was that MPA-induced osteopenia in female rats was also completely masked by SCT (10 U/kg, s.c., 5 days a week). The results indicate that the MPA-inducible secondary osteopenic model in either sex of rats would be usable for testing anti-osteopenic drugs. (+info)
Bone loss in long-term renal transplantation: histopathology and densitometry analysis.
BACKGROUND: There is little information of the spectrum and factors implicated in the bone loss in long-term renal transplantation, and virtually no data using both histomorphometric and densitometric analysis. METHODS: Twenty-three males and 22 females (13 postmenopausal) were studied with a bone biopsy and densitometry. Sixteen patients were on cyclosporine A monotherapy, 20 on azathioprine + prednisolone, and 9 on cyclosporine A + prednisolone or triple therapy. The mean time after transplantation was 127 +/- 70 months. RESULTS: No group had a significant decrease in bone mineral density (BMD) of the axial skeleton compared with an age- and sex-matched normal population. Compared with sex-matched young controls, osteopenia was observed in all groups at the femoral neck (except premenopausal women and triple therapy) and in the triple-therapy group at the L1-L4 spine region. At the distal radius, osteopenia was found in all the groups. Histopathological diagnosis was mixed uremic osteodystrophy in 46.5%, adynamic bone in 23.2%, hyperparathyroid disease in 13.9%, and normal bone in 16.3%. The diagnosis was not different according to immunosuppressive therapy, but men tended to show more mixed uremic bone disease. There was no significant difference in BMD between histopathological subtypes. In general, patients showed slight osteoclast function increase, osteoblast function decrease, and marked retardation of dynamic parameters. The cyclosporine A monotherapy group had a significantly lower appositional rate than azathioprine + prednisolone. Men had a significantly lower bone volume than women, and premenopausal women had a significantly lower mineralizing surface than postmenopausal women and men. In the multivariate analysis, male gender, time after transplantation, old age, and time on dialysis prior to transplantation were significant predictive factors for a negative effect on bone mass. CONCLUSIONS: Long-term renal transplant-patients showed reduced BMD in both trabecular and cortical bone. This reduction in BMD was not as severe as in short-term reports and was associated with osteoclast stimulation, osteoblast suppression, and retardation of mineral apposition and bone formation rates. Bone mass loss was not different between the immunosuppression therapy groups. Male gender and age were the strongest predictive factors for low bone mass. (+info)
Reduced bone density at completion of chemotherapy for a malignancy.
OBJECTIVES: Osteoporosis and pathological fractures occur occasionally in children with malignancies. This study was performed to determine the degree of osteopenia in children with a malignancy at completion of chemotherapy. METHODS: Lumbar spine (L2-L4) bone mineral density (BMD; g/cm2) and femoral neck BMD were measured by dual energy x ray absorptiometry in 22 children with acute lymphoblastic leukaemia (ALL), and in 26 children with other malignancies. Apparent volumetric density was calculated to minimise the effect of bone size on BMD. Results were compared with those of 113 healthy controls and expressed as age and sex standardised mean Z scores. RESULTS: Patients with ALL had significantly reduced lumbar volumetric (-0.77) and femoral areal and volumetric BMDs (-1.02 and -0.98, respectively). In patients with other malignancies, femoral areal and apparent volumetric BMDs were significantly decreased (-0.70 and -0.78, respectively). CONCLUSIONS: The results demonstrate that children with a malignancy are at risk of developing osteopenia. A follow up of BMD after the completion of chemotherapy should facilitate the identification of patients who might be left with impaired development of peak bone mass, and who require specific interventions to prevent any further decrease in their skeletal mass and to preserve their BMD. (+info)
Is low plasma 25-(OH)vitamin D a major risk factor for hyperparathyroidism and Looser's zones independent of calcitriol?
BACKGROUND: Recent reports suggest that calcitriol might not be the sole active metabolite of vitamin D and that plasma concentrations of 25-(OH)vitamin D (25OHD) are often abnormally low in hemodialysis patients. We have therefore evaluated plasma 25OHD as a risk factor for parathyroid hormone (PTH) hypersecretion and radiological bone disease. We carried out a cross-sectional study during the month of September in an Algerian dialysis center of 113 patients who were not taking supplements of alphacalcidol or calcitriol. METHODS: Plasma 25OHD, calcitriol, PTH, calcium, phosphate, bicarbonate, and aluminum were measured, and x-rays of the hands and pelvis were obtained for evaluation of subperiosteal resorption and Looser's zones. RESULTS: The median plasma 25OHD was 47.5 nmol/liter (range 2.5 to 170.0). Univariate analysis showed that plasma PTH was correlated positively with months on maintenance dialysis and negatively with plasma 25OHD, calcitriol, calcium, bicarbonate and aluminum, but not with that of phosphate. plasma 25OHD was positively correlated with calcium and calcitriol. Using multiple regression analysis, only plasma 25OHD (negative) and the duration on maintenance dialysis (positive) were independently linked to plasma PTH. The prevalence of isolated subperiosteal resorption (ISR) was 34%, and that of the combination of resorption with Looser's zones (CRLZ) was 9%; thus, only 57% of the patients had a normal x-ray appearance. These groups were comparable with regards to age, gender, and duration on dialysis. When the biochemical measurements of the patients with CRLZ were compared with those from patients without radiological lesions, plasma 25OHD was the only parameter to show a statistically significant difference, being significantly lower in the CRLZ group (26 +/- 18 vs. 57 nmol/liter, ANOVA, P < 0.004). Plasma 25OHD was also significantly lower in the ISR group (44, P < 0.05) than in the normal x-ray group, and plasma Ca (P < 0.003) and bicarbonate (P < 0.02) were lower. Logistical analysis showed that the presence of resorption was independently linked only with plasma PTH. Looser's zones and subperiosteal resorption were not seen in patients with plasma 25OHD of more than 40 (Looser's zones) and more than 100 nmol/liter (subperiosteal resorption). The optimal range for intact PTH in hemodialysis patients with mild aluminum overload is 10 to 25 pmol/liter. We found that plasma PTH was inappropriately high only when plasma 25OHD was less than 100 nmol/liter. With a plasma 25OHD of between 100 and 170 nmol/liter, hypercalcemia was present with a plasma PTH of less than 10 pmol/liter in only one case. CONCLUSIONS: This cross sectional study shows that low plasma 25OHD is a major risk factor for hyperparathyroidism and Looser's zones. In dialysis patients, we suggest that the plasma levels of 25OHD are maintained around the upper limit of the reference range of sunny countries. (+info)
Effects of XT-44, a phosphodiesterase 4 inhibitor, in osteoblastgenesis and osteoclastgenesis in culture and its therapeutic effects in rat osteopenia models.
We have reported that denbufylline, a phosphodiesterase 4 (PDE4) inhibitor, inhibits bone loss in Walker256/S tumor-bearing rats, suggesting therapeutic potentiality of a PDE4 inhibitor in osteopenia. In the present study, effects of a new PDE4 inhibitor, 1-n-butyl-3-n-propylxanthine (XT-44), in bone were evaluated in cell cultures and animal experiments. In rat bone marrow culture, XT-44 stimulated mineralized-nodule formation, whereas it inhibited osteoclast-like cell formation in mouse bone marrow culture. In Walker256/S-bearing rats (6-week-old female Wistar Imamichi rats), rapid decrease in bone mineral density (BMD) was prominent, and oral administration of XT-44 (0.3 mg/kg, every 2 days) inhibited the decrease in BMD. In the second animal experiment, female Wistar rats (6-week-old) were sciatic neurectomized, and XT-44 was orally administered to these rats every 2 days for 4 weeks. XT-44 administration (0.3 mg/kg) recovered BMD in these neurectomized animals. Furthermore, 19-week-old, female Wistar rats were ovariectomized (OVX), and 15 weeks after surgery, these rats were orally administered XT-44 every 2 days for 8 weeks. XT-44 treatment (1 mg/kg) increased the BMD of OVX rats. These results indicate that XT-44 could be a candidate as a therapeutic drug for treating osteopenia including osteoporosis. (+info)