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PubMed2006

Bone density and markers of bone remodeling in type 1 male diabetic patients.

AIMS: To assess the prevalence and severity of bone disease in type 1 diabetic patients and to determine serum markers of bone remodeling as well as their relationship with bone mineral density (BMD). METHODS: BMD [by dual energy x-ray absorptiometry (DXA)] and serum markers of bone remodeling [osteocalcin, c-terminal telopeptide of type I collagen (CTX)], leptin and osteoprotegerin (OPG) were measured in 42 adult males with type 1 diabetes. Twenty-four non-diabetic subjects served as controls. RESULTS: In 40% of the patients, osteopenia at the lumbar spine (L1-L4) and/or at the left hip was found, and 7% met criteria for osteoporosis. L1-L4 BMD z-score was correlated with age (r=0.365, P=0.018) and a similar trend was observed at left hip. L1-L4 BMD z-score was negatively correlated with CTX and osteocalcin (r=-0.343, P=0.028; r=-0.376, P=0.024, respectively). A significant correlation was evidenced between BMD z-score at both lumbar spine and left hip and leptin values (r=0.343, P=0.03; r=0.395, P=0.012, respectively) but after adjustment for weight this correlation was no longer significant. Osteocalcin, CTX and leptin concentrations were comparable between patients and controls, while OPG concentrations tend to be higher in diabetic subjects (P=0.08). CTX was negatively correlated with age (r=-0.390, P=0.012) and positively correlated with osteocalcin (r=0.696, P<0.001). OPG was positively correlated with age (r=0.507, P=0.001). CONCLUSION: Our results suggest that in diabetic subjects osteopenia is a relatively frequent complication but bone loss is attenuated with age progression. Whether this is also mediated by OPG and/or leptin remains to be confirmed.

Adult↗
PubMed1990

The influence of materials difference on stress distribution and bone remodeling around alumina and titanium dental implants.

The long-term complications of dental implants are associated with loosening of the implant-bone interface, due to bone resorption and subsequent connective tissue interposing at the implant-bone interface. Mechanical stresses, which are induced in the surrounding bone, play a key role in the interface bone remodeling. In the present study, it is investigated how local stress patterns are associated with local bone structure. For identical geometry alumina, and titanium implants, the stress patterns, determined in the finite element models with boundary conditions, are compared with the local bone structure found in animal experiments. The results indicate that there appears to be relationship between the stress patterns and the bone remodeling at the implant-bone interface independently on the materials properties in alumina and titanium.

Aluminum Oxide↗
PubMed1992

The behavior of adaptive bone-remodeling simulation models.

The process of adaptive bone remodeling can be described mathematically and simulated in a computer model, integrated with the finite element method. In the model discussed here, cortical and trabecular bone are described as continuous materials with variable density. The remodeling rule applied to simulate the remodeling process in each element individually is, in fact, an objective function for an optimization process, relative to the external load. Its purpose is to obtain a constant, preset value for the strain energy per unit bone mass, by adapting the density. If an element in the structure cannot achieve that, it either turns to its maximal density (cortical bone) or resorbs completely. It is found that the solution obtained in generally a discontinuous patchwork. For a two-dimensional proximal femur model this patchwork shows a good resemblance with the density distribution of a real proximal femur. It is shown that the discontinuous end configuration is dictated by the nature of the differential equations describing the remodeling process. This process can be considered as a nonlinear dynamical system with many degrees of freedom, which behaves divergent relative to the objective, leading to many possible solutions. The precise solution is dependent on the parameters in the remodeling rule, the load and the initial conditions. The feedback mechanism in the process is self-enhancing, denser bone attracts more strain energy, whereby the bone becomes even more dense. It is suggested that this positive feedback of the attractor state (the strain energy field) creates order in the end configuration. In addition, the process ensures that the discontinuous end configuration is a structure with a relatively low mass, perhaps a minimal-mass structure, although this is no explicit objective in the optimization process. It is hypothesized that trabecular bone is a chaotically ordered structure which can be considered as a fractal with characteristics of optimal mechanical resistance and minimal mass, of which the actual morphology depends on the local (internal) loading characteristics, the sensor-cell density and the degree of mineralization.

Bone Density↗
PubMed1989

Bone remodeling and osteophyte formation after remission of rheumatoid arthritis.

Bone remodeling and osteophyte formation rarely take place in active rheumatoid arthritis (RA). To determine if disease inactivation leads to their occurrence, we studied 38 patients with RA whose disease had gone into drug induced remission. We looked for osteophytes at the metacarpophalangeal (MCP) joints in roentgenograms taken before and after remission, and correlated their presence to that of osteoarthritis of the distal interphalangeal (DIP) joints. There were 21 patients with RA who had a median of 3 (range 1-8) osteophytes in their "remission" films which were rarely present in their "activity" films (p less than 0.0001). The osteophytes were frequently symmetrical and most often located (41%) at the third MCP joint. In addition, we observed a peculiar remodeling of the styloid process in 13 patients, 9 of whom had developed MCP joint osteophytes. There were no other detectable differences between patients who had MCP joint osteophytes and those who did not. Presence of osteoarthritis at the DIP joints did not correlate with development of osteophytes. We were able to classify the MCP osteophytes into 3 types on the basis of their shape: hook-like that were most frequently bilateral and situated on the radial aspect of the metacarpal side of the joint, beak-like that were most often found at the ulnar aspect of the phalangeal side, and nipple-like which occurred equally on either sites. These differences in distribution indicate that they are not stages of the same process. Our findings indicate that paraarticular bone remodeling occurs upon remission of RA, even in joints where osteoarthritis is unusual. Its shape and location may depend on both their site and the mechanism of joint damage.

Adult↗
PubMed2002

Is all cortical bone remodeling initiated by microdamage?

There is increasing interest in the degree to which bone remodeling, particularly in cortical bone, is "targeted" at fatigue microdamage. The theory that microdamage initiates remodeling in close proximity to microcracks, thereby removing them, and that this accounts for a significant fraction of the overall remodeling activity, has been gaining acceptance. However, the association between the initial, resorptive stage of remodeling and microcracks in histologic sections of cortical bone is far from complete; indeed, the great majority of resorption spaces are not spatially associated with microcracks. This observation has maintained support for the older concept that most remodeling occurs primarily for such metabolic purposes as calcium homeostasis. To gain further insight regarding the degree to which microdamage governs remodeling, this study presents a mathematical analysis based on the unorthodox hypothesis that all cortical bone remodeling is initiated by, and in close proximity to, microcracks. Equations are derived showing that, because remodeling basic multicellular units (BMUs) travel several millimeters beyond their point of initiation, the relative numbers of resorption spaces and microcracks found in close spatial proximity or isolated from one another are consistent with the hypothesis. The results also predict the degree to which the spatial association between resorption spaces and microcracks should exceed that due to chance alone. There are as yet very limited experimental data suitable for testing this model, but the existing data closely correspond to the model's predictions.

Animals↗
PubMed2000

New factors controlling bone remodeling.

Two factors of crucial importance in bone cell differentiation were discovered within the last two years. One is the transcription factor Osf2/Cbfa1, which allows mesenchymal stem cells to differentiate into osteoblasts. Soluble factors, including bone morphogenetic proteins (BMPs), leptin, and TGF-beta, can modulate differentiation of mesenchymal stem cells to osteoblasts or to other cell types such as chondrocytes or adipocytes. The other recent discovery is osteoclast differentiating factor (ODF), which is specific for and indispensable to osteoclast differentiation. ODF belongs to the TNF family. Its soluble receptor, osteoprotegerin, prevents it from binding to osteoclasts, thus inhibiting its activity. A role of lymphocytes in bone remodeling has long been suspected, and it has now been shown that ODF is produced by activated T lymphocytes, which may therefore be implicated in bone loss accompanying inflammation. Finally, recent evidence supports a role for B lymphocytes in bone loss secondary to estrogen deprivation. In conclusion, these recent data may have important applications. Osteoprotegerin is a potent antiosteoclast agent that may prove useful in the treatment of bone disorders. Osf2/Cbfa1 and ODF are major targets in the treatment of osteoporosis.

Animals↗
PubMed2006

Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor-kappaB ligand concentrations and normalises indices of bone remodelling in patients with relapsed multiple myeloma.

The effect of bortezomib on bone remodelling was evaluated in 34 relapsed myeloma patients. At baseline, patients had increased serum concentrations of dickkopf-1 (DKK-1), soluble receptor activator of nuclear factor-kappaB ligand (sRANKL), sRANKL/osteoprotegerin ratio, C-telopeptide of type-I collagen (CTX) and tartrate-resistant acid phosphatase isoform-5b (TRACP-5b); bone-alkaline phosphatase and osteocalcin were reduced. Serum DKK-1 correlated with CTX and severe bone disease. Bortezomib administration significantly reduced serum DKK-1, sRANKL, CTX, and TRACP-5b after four cycles, and dramatically increased bone-alkaline phosphatase and osteocalcin, irrespective of treatment response. This is the first study showing that bortezomib reduces DKK-1 and RANKL serum levels, leading to the normalisation of bone remodelling in relapsed myeloma.

Acid Phosphatase↗
PubMed2004

Bone remodeling analysis of various dental implant surfaces using polyfluorochrome sequential labeling in rabbit tibias.

The purpose of this study is to analyze the bone remodeling process after the placement of threaded implants with rough (RBM) and hydroxyapatite coated surfaces (HA) in rabbit tibias using polyfluorochrome sequential labeling. Histomorphometry was performed in order to quantify the amount of each label deposited during the healing period. This work demonstrates the possibility of periodic identification of apatite deposition during bone remodeling around titanium and ceramic implants. It has been concluded that the polyfluorochrome sequential labeling is an important tool for identification of bone remodeling after the insertion of titanium and ceramic implants inside rabbit tibias.

Animals↗
PubMed1986

The effects of 17 beta-estradiol and progestagen on trabecular bone remodeling in oophorectomized dogs.

We present the results of the static and dynamic histomorphometric analyses of parameter measurements of trabecular bone remodeling activity in nonoophorectomized, untreated oophorectomized, 17 beta-estradiol-supplemented oophorectomized, as well as progestagen-supplemented oophorectomized beagle dams. If the spayed beagle dam can be considered a model in which one may equivalate bone changes occurring in the ovarian hormone-deficient human female, we reach the following conclusions: The presence or absence of quasi-physiological levels of single ovarian hormones do affect the status of trabecular bone. The evidence indicates that the presence or absence of individual ovarian hormones do not have a simple effect on trabecular bone remodeling. Apart from affecting the numbers of new bone remodeling units (BMUs) that are initiated in unit time, their effect is seen to be extended to the working efficiency of existing osteoclasts and osteoblasts. The effect is also manifest on the total amount of work performed by the collections of osteoclasts and osteoblasts that provide the respective resorptive and formation phases of the BMU. Finally, we are led to believe that there may be a close interdependence both in physiological activity and therapeutic response between the four active bone envelopes. Such protein effects have hitherto not received their due consideration from researchers in this field.

Animals↗
PubMed1979

Age-related variations in cortical bone-remodeling measurements in male Beagles 10 to 26 months of age.

Age-related variations in bone-remodeling rates in the male Beagle were unknown. Variations were examined in 28 male Beagles whose ages were evenly distributed between 10 and 26 months. Results were analyzed by computer and regression lines for a best fit line for each determination were given; the 95% confidence limit for the best-fit line and the 95% confidence limits for the individual measurements were calculated. The results are graphically presented in this paper. There was a slight increase in total cortical area, although there was a decrease in the ratio of total-to-cortical area. Osteoid seams showed a frank decrease. Relatively little variation was found in circumference of osteoid seams and appositional rate. The number of resorption spaces decreased. There was a decrease in radial closure rate. Marked decreases were found in activation frequencies and bone formation rate. Increases were observed in osteon formation times and ratio of resorption to formation. The width of osteoid seams and the percentage of systems labeled decreased slightly. As a result of these experiments concerning variations in bone-remodeling activity carried out on Beagles (using the same dogs as their own controls), it was concluded that results obtained should be compared with the expected age-related activity of bone remodeling and not with the initial preexperimental biopsy results.

Aging↗
PubMed2006

The roles of parathyroid hormone and calcitonin in bone remodeling: prospects for novel therapeutics.

Inappropriate regulation of the bone resorption and bone formation processes that occur as a normal part of bone remodeling can lead to net bone loss, as found in osteoporosis. Parathyroid hormone (PTH) and calcitonin (CT) are two peptide hormones that play important roles in calcium homeostasis through their actions on osteoblasts (bone forming cells) and osteoclasts (bone resorbing cells), respectively. Paradoxically, even though genetic deletion of either PTH or CT produces mice with increased bone mass (presumably through different mechanisms), derivatives of both PTH and CT have now been approved for clinical use in the treatment of bone loss in osteoporosis. In this review, we focus on the biology and pharmacology of these two peptides. Specifically, we sequentially address the following three topics in detail: (1) the biological mechanisms of action of PTH and CT, focusing on data from in vitro studies and animal models; (2) the clinical utility of PTH and CT in treating osteoporosis, examining how their pharmacological efficacy correlates with our understanding of their biological mechanism of action; and (3) future prospects for combination therapy, alternative formulation of PTH and CT into oral and transdermal therapies, and replacement of PTH and CT with modified peptides or small molecules. The past four years have witnessed dramatic advances in each of these three areas, and the review places in context the challenges that lie ahead for this complicated, but clinically-relevant field.

Animals↗
PubMed1997

Calciotropic hormones and markers of bone remodeling in age-related (type II) femoral neck osteoporosis: alterations consistent with secondary hyperparathyroidism-induced bone resorption.

BACKGROUND: Both a decrease in bone formation and the skeletal consequences of secondary hyperparathyroidism have been implied in the pathogenesis of age-related femoral neck osteoporosis. However, studies using biochemical indices of bone remodeling in hip fracture patients have yielded conflicting results. Similarly, secondary hyperparathyroidism has not been a consistent finding in this population. Some of these inconsistencies might reflect differences in the assays used as well as in the timing of the sampling. Moreover, measurements were mostly performed in a limited number of patients. In this regard, the aim of the present study was to analyze potential alterations in bone metabolism in a large population of elderly hip fracture patients. METHODS: Circulating concentrations of 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH)2D3], intact parathyroid hormone (PTH), and calcitonin were measured in 117 elderly women (within a few hours after sustaining a fracture of the proximal femur) and in 117 healthy age-matched controls. In addition, serum osteocalcin and urinary excretion of (deoxy)pyridinoline were determined as markers of bone formation and resorption, respectively. RESULTS: Serum levels of 25(OH)D and 1,25(OH)2D3 were decreased in hip fracture patients. When correcting for differences in serum vitamin D binding protein, serum 25(OH)D was still significantly lower in patients than in controls, whereas serum 1,25(OH)2D3 was not. Moreover, 25(OH)D deficiency in hip fracture patients was associated with an increase in circulating PTH and urinary excretion of (deoxy)pyridinoline. Serum osteocalcin, on the other hand, was significantly decreased in fracture patients. There was no statistically significant difference in calcitonin. CONCLUSION: These data suggest that there is reduced bone formation and increased bone resorption in patients with hip fracture. Although limited by its cross-sectional design, the present study emphasizes the role of secondary hyperparathyroidism-induced bone resorption in the pathogenesis of age-related osteoporosis, mainly due to a lack of 25(OH)D.

Aged↗
PubMed2003

Bucco-lingual bone remodeling around implants placed into immediate extraction sockets: a case series.

BACKGROUND: Implants placed immediately after tooth extraction have shown high percentages of clinical success. Few studies in the scientific literature have observed the horizontal bone remodeling in the buccal-lingual direction after immediate placement of implants. The aim of this study was to analyze bone healing and coronal bone remodeling around 15 implants placed immediately after tooth removal without the use of guided bone regeneration (GBR) techniques. METHODS: Ten patients received a total of 15 implants placed immediately after removal of 15 single-rooted teeth. All implants were placed within the alveolar confines, limiting, in most cases, small peri-implant bone defects. After implant placement, the distance from the buccal to lingual bone plate was measured. No membranes or filling materials were used. Primary flap closure was performed in all cases. RESULTS: At second-stage surgery, all peri-implant defects were completely filled and the distance from buccal to lingual bone was measured again. The pattern of bone healing around the neck of immediate implants showed an absence of peri-implant defects and a narrowing of bone crest width in a buccal-lingual direction. The mean distance between buccal bone and lingual bone at the time of implant placement was 10.5 mm (+/- 1.52) and, at second-stage surgery, 6.8 mm (+/- 1.33). CONCLUSIONS: The coronal bone remodeling around immediate implants showed a healing pattern with new bone apposition around the neck of the implants and, at the same time, bone resorption with horizontal width reduction of the bone ridge. The small peri-implant bone defects were completely healed without the use of GBR procedures. An absence of complications during the healing period was also observed, probably due to the absence of barrier membranes and grafting materials.

Adolescent↗
PubMed1976

The actions of parathyroid hormone on bone: relation to bone remodeling and turnover, calcium homeostasis, and metabolic bone disease. Part IV of IV parts: The state of the bones in uremic hyperaparathyroidism--the mechanisms of skeletal resistance to PTH in renal failure and pseudohypoparathyroidism and the role of PTH in osteoporosis, osteopetrosis, and osteofluorosis.

In early chronic renal failure, the state of the bones resembles that of type II primary hyperparathyroidism. Cortical bone becomes thinner and more porous, and there is increased extent of surface remodeling. These changes are followed in turn by osteomalacia and osteitis fibrosa, although sometimes these may be alternate rather than successive stages. Bone turnover is less than would be expected for the elevation of PTH level, probably because of 1,25 (OH)2D3 deficiency. The resorption velocity and lamellar bone appositional rates are depressed, but woven bone appositional rate may be increased, possibly because of hyperphosphatemia. Bone mass reflects the summation of three independent processes: loss of lamellar bone due to hyperparathyroidism (depending on the extent of insulation by osteoid); accumulation of partly mineralized osteoid because of osteomalacia; accumulation of woven bone because of osteitis fibrosa. Osteosclerosis may be growth-related metaphyseal, subchondral or diffuse axial, and periosteal neostosis may also occur. Some patients on hemodialysis lose bone because of planing rather than lacunar or dissecting resorption, combined with depression of both lamellar and woven bone formation. Hyperparathyroid bone disease tends to improve slowly after renal transplantation. Persistent hypocalcemia reflects a defect in the calcium homeostatic system and cannot be explained solely by the known stimuli to secondary hyperparathyroidism. The increment in plasma calcium in response to PTH infusion is subnormal, both in early chronic and in acute renal failure, probably because of 1,25(OH)2D3 deficiency. This is also the most likely explanation for the depressed level of blood-bone equilibrium. The activity of all three of the PTH responsive cell systems in bone is depressed in renal failure, probably because all three require 1,25(OH)2D3 in order to function normally. In pseudohypoparathyroidism, as in chronic renal failure, hypocalcemia results from a defect in the regulation of the blood-bone equilibrium. The bone-remodeling system shows all gradations of response, from slight depression of bone turnover to overt osteitis fibrosa, but bone turnover is never as low as in PTH deficiency. These differences may reflect the presence or absence of resistance to PTH of the osteoprogenitor cell as well as of the calcium homeostatic system, or may be due to varying degrees of 1,25(OH)2D3 deficiency, as in chronic renal failure. An increase in plasma calcium in response to PTH can occur either in the untreated state or after treatment with vitamin D because either the error-correcting or remodeling system remains responsive to PTH. Pseudohypoparathyroidism may be subdivided into three types, depending on whether the urinary cyclic-AMP response to PTH remains defective despite treatment with vitamin D, improves with treatment, or is normal before treatment. Only the former is associated with the genetic syndrome of Albright's hereditary osteodystrophy...

Bone Diseases↗
PubMed1991

Osteopenia, hematopoiesis, and bone remodelling in iliac crest and femoral biopsies: a prospective study of 102 cases of femoral neck fractures.

Cancellous microanatomy, bone remodelling, and hematopoietic tissue were studied in iliac crest and femoral neck biopsies taken intraoperatively in 102 consecutive patients with displaced intracapsular fractures. About half of the femoral biopsies had osteopenia, and most showed replacement of hematopoietic tissue by fat cells, with absence of osteoblasts and osteoclasts. In contrast, most of the iliac crest biopsies showed relatively less decrease in cancellous bone, while hematopoietic tissue and bone remodelling cells were present in approximately 75%. These results indicate that the iliac crest biopsy does not necessarily reflect cancellous microanatomy, hematopoietic tissue, and bone remodelling at other skeletal sites in any given patient.

Aged↗
PubMed2006

[Periprosthetic bone remodeling after cementless hip endoprosthesis stem implantation].

The research was aimed at determining the course of the adaptation remodelling of the bone tissue basing on the changes in periprosthetic bone density of the THA with the employment of the computer densitometric x-ray analysis. The applied research methods made it possible to describe the characteristics of the adaptation remodelling of the femoral bone tissue around the implanted stem of the endoprosthesis and allowed to distinguish the stages included in the course of this process: I--the early stage, up to 6 months after an operation, characterised by decreasing of the roentgenological bone tissue density and the appearance of rarefaction and condensation lines of the bone along the stem, II--the late stage, starting 6 months after an operation, with its increasing roentgenological bone tissue density, holding back of stem settling, and the progression of bone growth and osteointegration led to the establishment of the connection between the stem and the surrounding bone tissue. The normal course of the adaptation remodelling of the periprosthesis bone tissue is characterised by the decrease in the density of bone tissue surrounding the stem, which does not exceed 2% of it preoperative value, absence of settling of the stem or its nonprogressive settling, and gradual increase in the periprosthesis bone tissue taking part not earlier than 6 moths after an operation, which creates conditions for osteointegration and establishment of further durable connection between the stem and the bone through bone ingrow. An irregular course of the adaptation remodelling of the periprosthesis bone tissue is characterised by the decrease in bone density after an operation, which does not exceed 5% of its preoperational state, followed by the absence of increase in bone density, continuous settling of the stem, which does not exceed 3 mm a year, and atrophy of strain within the area of the small trochanter and its concentration at the stem level. These symptoms are indicative of the disturbance of osteointegration and bone growth processes and of a high risk of the aseptic loosening of an endoprosthesis.

Absorptiometry, Photon↗
PubMed2003

Jaw bone remodeling at the invasion front of gingival squamous cell carcinomas.

BACKGROUND: It is still unknown how jaw bone remodeling occurs at actual invasion sites of oral squamous cell carcinomas. Since there is no other human carcinomas which make a direct invasion of the bone, gingival carcinomas are valuable examples. METHODS: Twelve surgical specimens of gingival squamous cell carcinoma were examined histopathologically and immunohistochemically for remodeling of bone and its surrounding tissue. RESULTS: Three types of bone interfaces with carcinomatous invasion were distinguished. These included areas with bone resorption, smooth bone surface and new bone formation. In the bone-resorption area, numerous osteoclasts were located along the bone surface, which was surrounded by myxoid stroma. The myxoid stroma was characterized by immunopositivity for heparan sulfate proteoglycan (HSPG), abundant vascularity and macrophagic infiltration. In the bone-formation area, rows of osteoblasts were aligned on the bone surface. The stroma around osteoblasts was also HSPG-immunopositive, poor in vascularity but rich in activated fibroblasts. In the smooth-bone area, the stroma showed an organizing phase of granulation tissue with slender fibroblasts and mature collagen fibers but with less vascularity and inflammatory infiltrates. CONCLUSION: The results indicate that the stromal architecture, especially in terms of its inflammatory cellular, vascular and matrix compositions, is strictly regulated in the timing and site of jaw bone remodeling which is causes by carcinomatous invasion.

Antigens, CD↗
PubMed2001

Impact of the timing of indomethacin treatment in a model of synchronized bone remodelling in rats.

Prostaglandins (PGs) promote both bone resorption and formation in vitro and in vivo. In a synchronised model of bone remodelling, indomethacin, an inhibitor of PG synthesis, given from the start of the sequence, transiently impaired bone resorption. In this study we further explored the involvement of PGs in this model by treating rats with indomethacin (7.5 mg x kg(-1) x day(-1)) for 6 days from the peak of resorption (day 4 after activation in this model) or during reversal (day 6 after activation). In rats treated from day 4, the resorption surface (Oc.S/BS) and the number of osteoclasts (N.Oc/BPm) were higher on day 10 (+69 %, P < 0.01, and +60 %, P < 0.02 compared with controls, respectively); no effect on cell resorptive activity was observed. The bone formation surface (OS/BS) was reduced (-50 %, P < 0.01). The inactive surface (In/BS) was not modified. In rats treated from day 6, the Oc.S/BS was also higher than in controls (P < 0.02), as was the N.Oc/BPm (P < 0.05). Osteoclast activity appeared to be increased, as the osteoclast-bone interface was larger (P < 0.02), but the mean lacuna area was reduced (-23 %, P < 0.05). Bone formation was also strongly affected: the OS/BS was decreased (-66 %, P < 0.01), as was the osteoid seam thickness (-24 %, P < 0.05). The In/BS was increased 1.5-fold (P < 0.05). These data indicate that PGs intervene at various stages of this remodelling sequence, as both resorption and formation were affected by indomethacin. Although resorption resumed in the two treatment groups despite treatment continuation, the timing of treatment was clearly important. Only inhibition of PG synthesis at the peak of resorption delayed all phases of the remodelling sequence. In contrast, inhibition during the reversal phase prevented activation of a significant part of the bone surface usually involved at this stage of remodelling; this treatment schedule reduced the resorptive capacity of the system, and depressed osteoblast activity.

Animals↗