Mechanotransduction in bone--role of the lacuno-canalicular network.
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The capacity of bone tissue to alter its mass and structure in response to mechanical demands has long been recognized but the cellular mechanisms involved remained poorly understood. Over the last several years significant progress has been made in this field, which we will try to summarize. These studies emphasize the role of osteocytes as the professional mechanosensory cells of bone, and the lacuno-canalicular porosity as the structure that mediates mechanosensing. Strain-derived flow of interstitial fluid through this porosity seems to mechanically activate the osteocytes, as well as ensuring transport of cell signaling molecules and nutrients and waste products. This concept allows an explanation of local bone gain and loss, as well as remodeling in response to fatigue damage, as processes supervised by mechanosensitive osteocytes. (+info)
Is low plasma 25-(OH)vitamin D a major risk factor for hyperparathyroidism and Looser's zones independent of calcitriol?
(18/2466)
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)
Double-blind, randomised, placebo-controlled, dose-finding study of oral ibandronate in patients with metastatic bone disease.
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BACKGROUND: Bisphosphonates are an important component of the treatment of metastatic bone disease but more potent, oral formulations are required to improve the effectiveness and convenience of treatment. An oral formulation of the new bisphosphonate, ibandronate (BM 21.0955) has recently been developed. PATIENTS AND METHODS: One hundred ten patients with bone metastases (77 breast, 16, prostate, 3 myeloma, 14 others) were recruited from a single institution to this double blind placebo-controlled evaluation of four oral dose levels (5, 10, 20 and 50 mg) of ibandronate. No changes in systemic anti-cancer treatment were allowed in the month before commencing treatment or during the study period. After an initial four-week tolerability phase, patients could continue on treatment for a further three months without unblinding; patients initially allocated to placebo received ibandronate 50 mg. The primary endpoint was urinary calcium excretion (UCCR). Bone resorption was also assessed by measurement of pyridinoline (Pyr), deoxypyridinoline (Dpd), and the N-terminal (NTX) and C-terminal (Crosslaps) portions of the collagen crosslinking molecules. RESULTS: Two patients did not receive any trial medication thus, 108 patients were evaluable for safety. Ninety-two patients were evaluable for efficacy. A dose dependent reduction was observed in both UCCR and collagen crosslink excretion. At the 50 mg dose level, the percentage reductions from baseline in UCCR, Pyr, Dpd, Crosslaps and NTX were 71%, 28%, 39%, 80% and 74% respectively. One or more gastrointestinal (GI) adverse events occurring in the first month of treatment were reported by six (30%), seven (33%), nine (39%), nine (41%) and eleven (50%) patients at the placebo, 5, 10, 20 and 50 mg dose levels respectively. One patient (20 mg dose) developed radiographically confirmed oesophageal ulceration. GI tolerability may have been adversely affected by concomitant administration of non-steroidal anti-inflammatory agents. Nine (8%) patients stopped treatment within the first month due to GI intolerability but these patients were evenly distributed across the five treatment groups. There was no difference in non-GI adverse events between groups. CONCLUSIONS: Oral ibandronate has potent effects on the rate of bone resorption at doses which are generally well tolerated. Further development is appropriate to evaluate the effects of long-term administration in the prevention of metastatic bone disease and the management of established skeletal metastases. (+info)
Treatment with calcitonin suppresses the responses of bone, cartilage, and synovium in the early stages of canine experimental osteoarthritis and significantly reduces the severity of the cartilage lesions.
(20/2466)
OBJECTIVE: To relate the rate of bone resorption to serum levels of both hyaluronan (HA) and antigenic keratan sulfate (KS) in canine experimental osteoarthritis (OA) and to evaluate the effects of calcitonin on these parameters and the OA lesions of the unstable knee. METHODS: Twenty-two dogs underwent anterior cruciate ligament transection (ACLT) and 6 dogs underwent sham operation. Urinary pyridinium crosslinks were quantified by high-performance liquid chromatography. Immunoassays quantified hyaluronan (HA) and antigenic KS. Macroscopic and histologic OA lesions were scored. Calcitonin treatment was started on day 14 postsurgery and stopped on either day 49 or day 104 postsurgery. Control dogs and all treated dogs were killed on day 105. RESULTS: All ACLT joints developed OA. In contrast to sham-operated animals, all operated dogs exhibited an early and sustained rise in the levels of their urinary and serum markers. Calcitonin markedly reduced the levels of these markers and the severity of OA lesions. Furthermore, the longer the period of calcitonin therapy, the lower the score of the OA lesions. CONCLUSION: Bone, synovium, and articular cartilage all appear to be involved in the state of hypermetabolism that develops in unstable joints. Furthermore, the rate of bone resorption increases markedly in the early stages of this OA model and is likely to contribute to cartilage breakdown. Since calcitonin reduced the severity of OA changes, this form of therapy may have benefits for humans who have recently experienced a traumatic knee injury. (+info)
Congenital osteoclast deficiency in osteopetrotic (op/op) mice is improved by ovariectomy and orchiectomy.
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We examined the changes in the appearance of osteoclasts in the femora of ovariectomized (OVX) or orchiectomized (ORX) op/op mice. Osteoclasts on the trabecular bone surface of the OVX or ORX op/op mice significantly increased in number seven or eight times in comparison with sham-operated op/op mice. Furthermore, TRAP-positive cells increased about four times in 100-week-old females and males, compared with sham-operated groups. These results have indicated that a sex hormone reduction due to OVX or ORX induces prominent recruitment of osteoclasts in op/op mice. (+info)
Skeletal effects of constant and terminated use of sodium risedronate in ovariectomized rats.
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AIM: To study the skeletal effects of constant and terminated use of sodium risedronate (Ris) treatment in the ovariectomized (Ova) rats. METHODS: Ris 5 micrograms.kg-1, s.c., twice a wk. The proximal tibial metaphysis (PTM) were processed undecalcified for quantitive bone histomorphometry. RESULTS: (1) Placebo-treated (normal saline) Ova rats were characterized by decreased trabecular area (TA) on d 60, d 81, and d 150 compared with aging controls, and bone resorption was over formation with high bone turnover. (2) Ova rats were treated with Ris for 60, 81, and 150 d (Ris-on) increased. (TA 217%, 108%, and 101%) respectively, vs Ova rats and depressed bone turnover indices to aging control level, but bone mass did not maintain at high level in 150-d group as in the early stage. (3) Ova rats were pretreated with Ris for 60 d and then terminated (Ris-on/off), followed by sequential sacrifice of rats on 21 and 90 d. Withdrawal on 21 d showed the same results as the match-age Ris-on group. Withdrawal on 90 d still maintained cancellous bone mass at a high level vs 150 d Ris-on groups (+26%) and aging control group (+27%). CONCLUSION: Regimen of Ris 60 d on then 90 d off prevented the development of osteoporosis in Ova rats. (+info)
Functional heterogeneity of osteoclasts: matrix metalloproteinases participate in osteoclastic resorption of calvarial bone but not in resorption of long bone.
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Data in the literature suggest that site-specific differences exist in the skeleton with respect to digestion of bone by osteoclasts. Therefore, we investigated whether bone resorption by calvarial osteoclasts (intramembranous bone) differs from resorption by long bone osteoclasts (endochondral bone). The involvement of two major classes of proteolytic enzymes, the cysteine proteinases (CPs) and matrix metalloproteinases (MMPs), was studied by analyzing the effects of selective low molecular weight inhibitors of these enzymes on bone resorption. Mouse tissue explants (calvariae and long bones) as well as rabbit osteoclasts, which had been isolated from both skeletal sites and subsequently seeded on bone slices, were cultured in the presence of inhibitors and resorption was analyzed. The activity of the CP cathepsins B and K and of MMPs was determined biochemically (CPs and MMPs) and enzyme histochemically (CPs) in explants and isolated osteoclasts. We show that osteoclastic resorption of calvarial bone depends on activity of both CPs and MMPs, whereas long bone resorption depends on CPs, but not on the activity of MMPs. Furthermore, significantly higher levels of cathepsin B and cathepsin K activities were expressed by long bone osteoclasts than by calvarial osteoclasts. Resorption of slices of bovine skull or cortical bone by osteoclasts isolated from long bones was not affected by MMP inhibitors, whereas resorption by calvarial osteoclasts was inhibited. Inhibition of CP activity affected the resorption by the two populations of osteoclasts in a similar way. We conclude that this is the first report to show that significant differences exist between osteoclasts of calvariae and long bones with respect to their bone resorbing activities. Resorption by calvarial osteoclasts depends on the activity of CPs and MMPs, whereas resorption by long bone osteoclasts depends primarily on the activity of CPs. We hypothesize that functionally different subpopulations of osteoclasts, such as those described here, originate from different sets of progenitors. (+info)
The impact of mammalian reproduction on cancellous bone architecture.
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Pregnancy and lactation make demands on maternal calcium homeostasis which may affect bone strength. Recently, changes in cancellous architecture have been described in iliac crest bone biopsies from normal pregnant women but the rarity of such human material means an animal model is essential. The microanatomy of cancellous bone was compared in uniparous and multiparous rats using undecalcified histological sections of lumbar and caudal vertebrae and also proximal femora. An automated trabecular analysis system (TAS) measured a comprehensive range of structural variables including the trabecular number, connectivity and width. In the first pregnancy cycle an early stimulation of bone formation (which quadrupled at some sites) was indicated by an increase in the skeletal uptake and spacing of double calcein labels and the immediate generation of thicker more numerous and interconnected trabeculae. A 40% increase in cancellous bone volume was observed in the lumbar spine in comparison with age-matched virgin controls. In contrast, a rapid succession of 3 pregnancy cycles (including lactation) culminated in cancellous atrophy of 15% at the same site, with a loss in trabecular number ranging from 20% (caudal vertebra) to 30% (lumbar vertebrae). In comparison, the proximal femur lost 40% of its struts but, nevertheless, uniquely sustained its cancellous bone volume. When lactation was excluded the number of struts lost was halved although trabecular thinning then took place which was sufficient to maintain the previous 15% deficit in bone volume. It was concluded that a single pregnancy strengthens the cancellous component of the maternal skeleton while a quick succession of pregnancies weakens it. Lactation influences the pattern of bone loss but not its amount. (+info)