Remodeling Space Research Articles

Selective Modification of Bone Quality by PTH, Pamidronate, or Raloxifene

Bone strength, a determinant of resistance to fracture, depends on BMD, geometry, microarchitecture, bone turnover rates, and properties of the bone at the material level. Despite comparable antifracture efficacy, anti-catabolics and bone anabolic agents are likely to modify the various determinants of bone strength in very different ways. Eight weeks after ovariectomy (OVX), 8-mo-old osteoporotic rats received pamidronate (APD; 0.6 mg/kg, 5 days/mo, SC), raloxifene (3 mg/kg, 5/7 days, tube feeding), PTH(1-34) (10 mug/kg, 5/7 days, SC), or vehicle for 16 wk, and we measured vertebral BMD, maximal load, stiffness and energy, microarchitecture, and material properties by nanoindentation, which allows the calculation of the elastic modulus, tissue hardness, and working energy. Markers of bone turnover, plasma osteocalcin, and urinary deoxypyridinoline (Dpd) were also determined. PTH induced greater maximal load than APD or raloxifene, as well as greater absorbed energy, BMD, and increased bone turnover markers. PTH markedly increased trabecular bone volume and connectivity to values higher than sham. Animals treated with APD had BV/TV values significantly higher than OVX but lower than sham, whereas raloxifene had no effect. Tissue hardness was identical in PTH-treated and OVX untreated controls. In contrast, APD reversed the decline in strength to levels not significantly different to sham, reduced bone turnover, and increased hardness. Raloxifene markedly increased material level cortical hardness and elastic modulus. These results show the different mechanisms by which anti-catabolics and bone anabolics reduce fracture risk. PTH influences microarchitecture, whereas bisphosphonates alter material-level bone properties, with probable opposite effects on remodeling space. Raloxifene primarily improved the material stiffness at the cortical level.

The impact of immobilization and strength exercise strategy to bone change: An animal study

Objective: The aim of this study is to evaluate whether an immobilization model can be used in studies of the mechanism of structural adaptation to mechanical usage. Methods: Six-week-oldmale rats were subjected to right hindlimb immobilization or served as control for 0, 4, 6, 8, 12 or 24 weeks. They were double-labeled with bone markers prior to sacrifice. The right hindlimb was immobilized by sciatic nerve denervation and considered unloaded, while the left hindlimb was overloaded during ambulation, such as strengthening exercise. Static and dynamic histormorphometric studies were performed on 20-μm-thick Villanueva stained, undercalcified sections of the proximal tibia metaphysis and the tibia shaft. Results: In the unloaded limb, immobilization induced cancellous and cortical bone loss. The bone loss was accompanied by poorer trabecular architecture. Unloading shut off nearly both peri-osteal bone formation and accelerated bone marrow expansion. In the overloaded limb, significant changes occurred in proximal tibial metaphyses: trabecular area increased, trabecular number increased, and trabecular separation decreased. A significant increase in mineral apposition rate was found only at 4 weeks of overloading. Significant decrease in both eroded and labeled bone surfaces occurred at all time periods. These histomorphometric changes indicated that increased cancellous bone mass was caused by an increase in bone formation activity (i.e., increase in mineral apposition rate) and a decrease in remodeling space (i.e., decrease in bone eroded surface). Although cortical bone mass was unchanged, increased peri-osteal bone formation activity (i.e., increases in mineral apposition and bone formation rates) was detectable. Conclusions: These findings indicate that the rat skeleton can quickly adapt to mechanical usage. Therefore, the one-legged immobilization model can be used in studies of the mechanism of structural adaptation to mechanical usage.

A computational assessment of the independent contribution of changes in canine trabecular bone volume fraction and microarchitecture to increased bone strength with suppression of bone turnover

This study addressed the effects of changes in trabecular microarchitecture induced by suppressed bone turnover—including changes to the remodeling space—on the trabecular bone strength–volume fraction characteristics independent of changes in tissue material properties. Twenty female beagle dogs, aged 1–2 years, were treated daily with either oral saline ( n=10 control) or high doses of oral risedronate (0.5 mg/kg/day, n=10 suppressed) for a period of 1 year, the latter designed (and confirmed) to substantially suppress bone turnover. High-resolution micro-CT-based finite element models (18-μm voxel size) of canine trabecular bone cores ( n=2 per vertebral body) extracted from the T-10 vertebrae were analyzed in both compressive and torsional loading cases. The same tissue-level material properties were used in all models, thus providing measures of tissue-normalized strength due only to changes in the microarchitecture. Suppressed bone turnover resulted in more plate-like architecture with a thicker and more dense trabecular structure, but the relationship between the microarchitectural parameters and volume fraction was unaltered ( p>0.05). Though the suppressed group had a greater tissue-normalized strength as compared to the control group ( p<0.001) for both compressive and torsional loading, the relationship between tissue-normalized strength and volume fraction was not significantly altered for compression ( p>0.13) or torsion ( p>0.09). In this high-density, non-osteoporotic animal model, the increases in tissue-normalized strength seen with suppression of bone turnover were entirely commensurate with increases in bone volume fraction and thus, no evidence of microarchitecture-related or “stress-riser” effects which may disproportionately affect strength were found.

Effect of pamidronate on bone turnover and implant migration after total hip arthroplasty: a randomized trial

In this trial we studied the effect of pamidronate on periprosthetic bone turnover and pelvic implant migration over 2 years after hybrid total hip arthroplasty (THA). Twenty-two patients received 90 mg of pamidronate and 22 received placebo at randomization 5 days after surgery. Rapid periprosthetic bone loss occurred in the placebo group over the first 6 months and was accompanied by transient increases in biochemical markers of bone turnover. Partial recovery in bone mass occurred in most regions after this period. No recovery of bone mass occurred at the femoral calcar or the medial wall of the acetabulum. Femoral calcar bone loss at 2 years was strongly predicted by acute biomarker changes at week 6. Pamidronate therapy reduced femoral bone loss in the region of the femoral calcar ( P=0.01), but did not affect pelvic bone loss. Pamidronate therapy also inhibited the transient rise in biochemical markers of bone turnover during this period. Pamidronate therapy did not affect acetabular cup migration. Cup migration was inversely related to subject age, but unrelated to initial post-operative bone mineral density, or subsequent bone loss. In summary, early periprosthetic bone loss is associated with a transient expansion of the bone remodeling space. Bisphosphonate therapy reduces femoral calcar bone loss and bone turnover after THA, but did not influence cup migration in this study. Acute changes in biochemical markers predict femoral periprosthetic bone loss.

Estrogen and "exercise" have a synergistic effect in preventing bone loss in the lumbar vertebra and femoral neck of the ovariectomized rat.

This study was designed to study the individual or combined effects of estrogen and bipedal stance "exercise" on the lumbar vertebral body (LVB) and femoral neck (FN). At 6 months of age, six rats were sacrificed as baseline controls and all the others were either bilateral sham-ovariectomized or ovariectomized (OVX). Groups of OVX rats were housed in normal height cage (NC, 28 cm) or raised height cages (RC, 33 cm) and received biweekly s.c. injections of 10 microg/kg 17 beta estradiol (E2) or vehicle for 4 and 8 weeks. Histomorphometric measurements were performed on the undecalcified mid-transverse sections of the 4th LVB and FN. Ovariectomy alone induced cancellous bone loss by 21% and 39% in the LVB and FN, respectively; intracortical porosity area of the FN increased by 108% while total bone area did not change significantly because of the periosteal expansion following OVX. E2 alone partially prevented cancellous bone loss in the LVB and FN and prevented increased intracortical porosity area in the FN by reducing eroded surface and activation frequency. RC alone partially prevented the decrease of cancellous bone in the LVB and FN by reducing the bone-eroded surface but increased wall width. E2 plus RC completely preserved cancellous bone by having an additive effect on reducing eroded surface and activation frequency. RC helped to partially prevent decreased periosteal bone formation after estrogen administration. In conclusion, apart from inducing cancellous bone loss in the LVB and FN, OVX also increased intracortical remodeling in the FN. Estrogen prevented the overall activation of remodeling space induced by OVX. Apart from having similar effects as estrogen on remodeling space, RC induced positive bone balance within each remodeling unit. Combination treatment increased total bone mass beyond that of sham-control level by having an additive effect on lowering bone remodeling and increasing wall in both the LVB and FN.

The Effects of Growth Hormone Replacement Therapy on Bone Metabolism in Adult-Onset Growth Hormone Deficiency: A 2-Year Open Randomized Controlled Multicenter Trial

Adult hypopituitary patients with growth hormone deficiency (GHD) show a significant decrease in bone mass and an increased fracture rate. Replacement therapy with GH increases bone turnover. Most of the long-term data on bone mineral content (BMC) and bone mineral density (BMD) have been acquired in open, noncontrolled trials involving limited numbers of patients. To determine whether long-term GH therapy is beneficial for bone despite the increased bone turnover, 100 patients (59 men and 41 women), aged 25-65 years (mean, 49.7 years) with adult-onset GHD were randomized to treatment with GH (40 men and 28 women; mean dose, 0.18 IU/kg per week) or to a nontreated control group (19 men and 13 women) for 24 months. Despite a similar increase in parameters of bone turnover (osteocalcin [OC], procollagen type I carboxy-terminal propeptide [PICP], and pyridinolines ([PYD]) in male and female GH-treated patients compared with controls, the effects on BMC and BMD as evaluated by dual-energy X-ray absorptiometry were gender specific. A significant increase in spine BMC and BMD and total hip BMD and a decrease in BMD at the ultradistal radius over time was observed in male GH-treated patients compared with the evolution in controls (mean +/- SEM change at 24 months: +6.8 +/- 1.1% and p = 0.009, +5.1 +/- 0.8% and p = 0.005, +3.5 +/- 0.7% and p = 0.02, and -2.6 +/- 0.8% and p = 0.008, respectively). No significant treatment effects were observed in female patients. Despite the increase in the total remodeling space induced by GH treatment, prolonged GH therapy in adult-onset GHD has a positive effect on bone balance, maintaining bone mass in women, and even increasing it in men over a 2 year-period.

A theoretical analysis of the contributions of remodeling space, mineralization, and bone balance to changes in bone mineral density during alendronate treatment

In patients with osteoporosis, alendronate treatment causes an increase in bone mineral density (BMD) and a decrease in fracture incidence. Alendronate acts by changing the bone remodeling process. Changes in bone remodeling resulting in decreased remodeling space, increased bone balance per remodeling cycle, and increased mineralization (ash mass/bone mass) have all been associated with alendronate treatment. Understanding the relative contributions of these parameters to BMD increases could help predict the utility of long-term (>10 years) or intermittent treatment strategies, as well as treatment strategies in which another pharmaceutical is administered concurrently. We have developed a computer simulation of bone remodeling to compare the contributions of focal bone balance and mineralization on BMD by simulating alendronate treatment using a bone balance method (decreased remodeling space, increased focal bone balance, uniform bone mineralization) and a mineralization method (decreased remodeling space, neutral focal bone balance, varying bone mineralization). Although both methods are able to predict BMD increases caused by alendronate over short periods, our findings suggest that the mineralization method may be more descriptive of long-term alendronate treatment. This implies that mineralization may be a larger contributor to BMD changes caused by alendronate than the focal bone balance. Based on this finding we offer a hypothesis to describe how remodeling space, focal bone balance, and mineralization each contribute to alendronate-induced BMD changes. Future analyses with this method could be used to identify improved dosing regimens and to predict which osteoporosis treatments would best complement each other.

The influence of calcium intake and physical activity on bone mineral content and bone size in healthy children and adolescents.

Studies of determinants of bone mineralization during growth are relevant to the attempt to increase peak bone mass. The aim of this study was to examine how calcium intake and physical activity influence bone size (bone area, BA), accretion in BA, whole body bone mineral content (BMC) and accretion in BMC. BA and BMC were examined by dual-energy X-ray absorptiometry (Hologic 1000/W) in healthy girls (n = 192) and boys (n = 140) aged 5-19 years at baseline and 1 year later. Calcium intake was assessed three times by a food frequency questionnaire and physical activity three times by a 24 h recall questionnaire. The influence of calcium intake and physical activity was examined by multiple regression. BA was size-adjusted by including height and weight in all analyses, and BMC was size-adjusted by including BA, height and weight in all analyses. Size-adjusted average BA was associated neither with average calcium intake nor with average physical activity. Size-adjusted accretion in BA was borderline associated with the average calcium intake in boys only (p = 0.07). Size-adjusted average BMC was positively associated with average calcium intake (p) = 0.03 girls; p = 0.07 boys) and borderline associated with average physical activity level in boys (p = 0.07) but not girls (p = 0.7). Size-adjusted accretion in BMC was significantly associated neither with average calcium intake nor with average physical activity level, but was associated with change in calcium intake over the 1 year observation period in boys (p = 0.03) but not girls (p = 0.9). In conclusion, we found that size-adjusted BMC in school-aged children was positively associated with average calcium intake. Size-adjusted accretion in BMC was positively associated with change in dietary calcium intake in boys only. To what degree this is caused by a reduction in remodeling space is unknown.

A three-dimensional simulation of age-related remodeling in trabecular bone.

After peak bone mass has been reached, the bone remodeling process results in a decrease in bone mass and strength. The formation deficit, the deficit of bone formation compared with previous resorption, results in bone loss. Moreover, trabeculae disconnected by resorption cavities probably are not repaired. The contributions of these mechanisms to the total bone loss are unclear. To investigate these contributions and the concomitant changes in trabecular architecture and mechanical properties, we made a computer simulation model of bone remodeling using microcomputed tomography (micro-CT) scans of human vertebral trabecular bone specimens. Up to 50 years of physiological remodeling were simulated. Resorption cavities were created and refilled 3 months later. These cavities were not refilled completely, to simulate the formation deficit. Disconnected trabeculae were not repaired; loose fragments generated during the simulation were removed. Resorption depth, formation deficit, and remodeling space were based on biological data. The rate of bone loss varied between 0.3% and 1.1% per year. Stiffness anisotropy increased, and morphological anisotropy (mean intercept length [MIL]) was almost unaffected. Connectivity density increased or decreased, depending on the remodeling parameters. The formation deficit accounted for 69-95%, disconnected trabeculae for 1-21%, and loose fragments for 1-17% of the bone loss. Increasing formation deficit from 1.8% to 5.4% tripled bone loss but only doubled the decrease in stiffness. Increasing resorption depth from 28 to 56 microm slightly increased bone loss but drastically decreased stiffness. Decreasing the formation deficit helps to prevent bone loss, but reducing resorption depth is more effective in preventing loss of mechanical stiffness.

Growth and hormone deficiency and peak bone mass.

In order to define the relationship between growth hormone (GH) and peak bone mass, and the importance of the role played by GH in reaching optimal peak bone mass, several questions, discussed in this article, have first to be answered. Although the answers to some of these questions are already becoming apparent, some await the findings of further research. It is doubtful whether the results of these studies, which by definition should be long-term because of the long lag between the end of linear growth and the attainment of peak bone mass, will soon be available. In the absence of evidence-based medicine one can, however, conclude that long-term GH replacement therapy for GH deficiency in adults has no deleterious effects on bone. Indeed, despite an increase in bone turnover and an increase in remodeling space, bone mineral density and bone mineral content have been shown to increase slowly over time and to the same degree in both controlled and uncontrolled studies.

Effect of calcium supplementation on bone mineral accretion in Gambian children accustomed to a low-calcium diet

Rural Gambian children have poor growth, delayed puberty, a low bone mineral content, and a low calcium intake. We investigated the effect of a calcium supplement on bone mineral accretion in rural Gambian children. A randomized, double-blind, placebo-controlled study was conducted in 160 children (80 boys, 80 girls) aged 8.3-11.9 y. Bone mineral content (BMC), bone mineral density (BMD), and BMC adjusted for bone width, body weight, and height (size-adjusted BMC) were measured at the midshaft and distal radius. Each child received either 1000 mg Ca/d (as calcium carbonate) or a placebo 5 d/wk for 12 mo. Supplementation increased calcium intake from 342 to 1056 mg/d (8.6 to 26.4 mmol/d). Calcium supplementation resulted in a higher BMC, BMD, and size-adjusted BMC (&xmacr; difference +/- SE): midshaft radius-BMC (3.0 +/- 1.4%; P = 0.034), BMD (4.5 +/- 0.9%; P </= 0.0001), and size-adjusted BMC (4.6 +/- 0.9%; P </= 0.0001); distal radius-BMC (8. 4 +/- 3.2%; P = 0.009), BMD (7.0 +/- 2.7%; P = 0.011), and size-adjusted BMC (5.5 +/- 2.7%; P = 0.042). Supplementation had no significant effect on height, weight, or bone width at the midshaft radius or distal radius. At the end of the study, the calcium group had a significantly lower mean plasma osteocalcin concentration than the placebo group after adjustment for baseline concentration, sex, and pubertal status (-21.9 +/- 6.5%; P = 0.001). Increased calcium intake resulted in increased bone mineral status, possibly in association with a decreased bone remodeling space. Further studies are needed to determine whether an increased calcium intake has long-term benefits in Gambian children.

Early Estrogen Replacement Therapy Reverses the Rapid Loss of Trabecular Bone Volume and Prevents Further Deterioration of Connectivity in the Rat

To evaluate the ability of estrogen replacement therapy (ERT) to prevent changes in trabecular bone volume (BV/TV) and connectivity beginning either at ovariectomy (OVX) or 5-13 days after OVX in adult female rats, the right proximal tibial was examined by three-dimensional X-ray tomographic microscopy (XTM) in vivo. Animals had XTM scans of the right tibia and then were randomized into six groups (n = 9). Groups 2-6 had bilateral (OVX), while group 1 was sham-ovariectomized (OVXd) on day 0. Animals were treated with vehicle (groups 1 and 2) or 17beta-estradiol therapy (ERT) at 10 microg/kg three times per week starting at days 0, 5, 8, and 13 post-OVX (groups 3, 4, 5, and 6), until day 50 when they were rescanned by XTM and sacrificed. Trabecular bone structural variables were calculated from XTM data (BV/TVx and beta1/BV/TVx) and standard histomorphometry. Trabecular bone volume (BV/TVx) and the trabecular connections per cubic millimeter of trabecular bone (beta1/BV/TVx) were maintained in both sham-OVXd animals and OVX animals given ERT from the time of OVX. However, OVX + vehicle-treated animals lost 54% BV/TVx and 46% beta1/BV/TVx (p < 0. 01 from day 0). BV/TVx and beta1/BV/TVx decreased rapidly post-OVX to -22% and -25% at day 13 (p < 0.01 from day 0). ERT initiated at day 5, 8, and 13 post-OVX restored BV/TVx to baseline values at day 50 by modestly increasing trabecular plate thickness; however, beta1/BV/TVx was reduced in all OVX groups when compared with their baseline values. ERT also caused a significant reduction in bone turnover compared with OVX + vehicle; however, resorption was suppressed more than formation. These results demonstrate that ERT can restore the lost trabecular bone, but not trabecular connectivity, that occurs soon after OVX by allowing bone formation to continue in previously activated bone remodeling units while suppressing the production of new remodeling units. This may be the mechanism by which prompt intervention with estrogen and other antiresorptive agents can restore bone mass that has been lost from the increase in remodeling space, and thereby reduce the risk of osteoporotic fractures in postmenopausal women.

The role of parathyroid hormone in the pathogenesis, prevention and treatment of postmenopausal osteoporosis.

Parathyroid hormone (PTH) is the principal regulator of bone remodeling in the adult skeleton. The acute in vivo effect of PTH is to increase bone resorption, although sustained increases in its circulating levels accelerate both formation and resorption. These divergent effects have focused attention on PTH as a factor contributing to bone loss in some postmenopausal women, as well as interest in its role as therapy for the disease. Sustained increases in PTH are classically seen in primary hyperparathyroidism. While still controversial, increasing evidence suggests that primary hyperparathyroidism is associated with increased rates of bone loss, particularly from cortical sites in the skeleton. It is clear that the remodeling space is increased in primary hyperparathyroidism, and that surgical correction of the disease leads to substantial increases in bone mass in patients with osteoporosis. Recently, secondary hyperparathyroidism has emerged as an important contributor to increased rates of bone turnover and bone loss in postmenopausal women. The etiology of secondary hyperparathyroidism in postmenopausal women is complex, and is probably related to alterations in vitamin D metabolism and tissue responsiveness to 1,25(OH)2vitamin D. PTH has emerged at the forefront of anabolic therapies for the treatment of postmenopausal osteoporosis. When given as a single agent, intermittent daily subcutaneous administration of PTH induces consistent gains in trabecular bone mass with more varying effects on the cortical envelope. However, recent therapeutic trials employing a second agent, most notably estrogen, give hope that this approach may provide the first truly efficacious anabolic therapy for this devastating disease.

Bone microdamage and skeletal fragility in osteoporotic and stress fractures.

The accumulation of bone microdamage has been proposed as one factor that contributes to increased skeletal fragility with age and that may increase the risk for fracture in older women. This paper reviews the current status and understanding of microdamage physiology and its importance to skeletal fragility. Several questions are addressed: Does microdamage exist in vivo in bone? If it does, does it impair bone quality? Does microdamage accumulate with age, and is the accumulation of damage with age sufficient to cause a fracture? The nature of the damage repair mechanism is reviewed, and it is proposed that osteoporotic fracture may be a consequence of a positive feedback between damage accumulation and the increased remodeling space associated with repair.

Quantification of remodeling parameter sensitivity—assessed by a computer simulation model

During normal aging and menopause, cancellous bone is lost at all skeletal sites due to remodeling-related factors: negative formation balance; temporarily increased remodeling space; and osteoclastic perforations. The relative importance of the various factors in inducing bone mass loss and perforations is still controversial. We have previously used a computer simulation model to describe the effect of several bone remodeling parameters on vertebral cancellous bone loss. The model focused on two different scenarios for the menopause and three different treatment regimens. The aim of the present study was to extend the previous study by quantifying remodeling parameter sensitivity for changes in the bone mass with the use of the computer model we had previously formulated. The menopause scenario, with increased activation frequency and increased resorption depth, was chosen as the base case scenario, and the following parameters were investigated in the sensitivity analysis: activation frequency; formation balance; resorption depth; and critical trabecular thickness. Simulations were performed for a period of 20 years starting at the age of 48 years. The analyses showed that the number of perforations and the perforation-related mass loss both exhibited a large sensitivity toward variations in the final resorption depth. However, the formation balance was the factor that was responsible for the greater part of the bone mass loss. The computer model allowed us to quantify the sensitivity of different output variables with respect to changes in some of the model parameters. This can give information about the biological mechanisms responsible for bone mass loss around the surgically induced or natural menopause and also provide an indication of the type of treatment that would be most useful in preventing the deterioration of the cancellous network.

Cortical bone remodeling in autosomal dominant osteopetrosis: A study of two different phenotypes

Previous analyses of cancellous bone remodeling in autosomal dominant osteopetrosis (ADO) have suggested a diminished osteoclastic resorption at the endocortical surface. Consequently, cortical width increases with age in both ADO type I and II. By means of histomorphometric methods, the remodeling cycle of the Haversian surface in the iliac crest has recently been reconstructed in normal individuals. The aim of the present investigation was to study cortical bone remodeling in ADO type I and II. Transcortical iliac crest bone biopsies obtained from 21 ADO patients were studied. Of these, 14 had ADO type I and seven had ADO type II. Twenty of the patients had received intravital double labeling with tetracycline before the biopsies were obtained. The static histomorphometric parameters for cortical bone mass and structure were compared with a control group of 21 sex- and age-matched individuals. Regarding the dynamic histomorphometric parameters for reconstruction of the cortical bone remodeling cycle, the ADO type I material was compared with control material from 14 sex- and age-matched individuals, whereas the ADO type II material was compared with control material from six sex-matched but younger individuals. Significant increases were seen in absolute as well as fractional cortical widths in both ADO types. Furthermore, an age-related increase was observed in both absolute and fractional cortical widths in ADO type I, whereas ADO type II was nonsignificant with regard to age. The fractional cancellous width was reduced in both type I and type II. However, only in ADO type I did the fractional cancellous width significantly correlate inversely with age. In the control group, neither cortical dimensions nor cancellous width correlated significantly with age. No significant differences were observed between patients and the control group in osteon dimensions; fractional resorptive, formative, or quiescent sites; resorptive or formative remodeling rates; remodeling periods; or activation frequency. An age-related increase in cortical porosity was seen in the group of normal individuals, but not in the two patient groups. The fractional remodeling space was increased in the ADO type II group. In conclusion, cortical dimensions are increased in both ADO type I and II and positively correlated to age in type I. However, cortical remodeling at the Haversian surface is essentially normal in both ADO type I and II. This could be explained by a defective endocortical bone resorption, as no periosteal accretion was observed, and because cancellous bone remodeling previously has been described to be normal.

Reconstruction of cortical bone remodeling in untreated primary hyperparathyroidism and following surgery

Iliac crest bone biopsies from 39 patients (23 women, 16 men) with untreated primary hyperparathyroidism (PHP) were examined. Static histomorphometric parameters for cortical bone was compared with values obtained from 39 age- and sex-matched normal controls. Thirty-five of the patients were double-labeled with tetracycline before biopsy. The cortical remodeling cycle was reconstructed in these patients and compared with 24 sex-matched but younger normal controls. In 9 patients, a second intact bone biopsy was obtained 6–12 months after successful surgery for PHP. In these patients, pre- and post-treatment biopsies were compared. Cortical porosity was increased in PHP ( p < 0.001) due to a high turnover state with expansion of the remodeling space ( p < 0.001). The net balance of the remodeling cycle on the haversian surface was found unchanged in PHP, since the average haversian canal diameter remained unchanged. In the female PHP-patients, a significant increase in the final resorption depth ( p < 0.01) was balanced by a proportional increase in the wall width ( p < 0.001). Among all PHP patients, no significant decrease in cortical width was found. However, a significant reduction in absolute ( p < 0.05) and fractional cortical width ( p < 0.05) was seen in postmenopausal PHP women giving rise to a cortical bone loss. Reconstruction of the cortical remodeling cycle revealed a doubling in activation frequency from 0.6#/year in normals to 1.2#/year in PHP ( p < 0.001), giving rise to a high turnover state. Surgical cure of PHP was accompanied by marked changes in cortical bone metabolism. Activation frequency ( p < 0.005), porosity ( p < 0.05), and remodeling space ( p < 0.001) all decreased, indicating a normalization of the enhanced bone turnover in untreated PHP.

Reconstruction of cortical bone remodeling in untreated primary hyperparathyroidism and following surgery.

Iliac crest bone biopsies from 39 patients (23 women, 16 men) with untreated primary hyperparathyroidism (PHP) were examined. Static histomorphometric parameters for cortical bone was compared with values obtained from 39 age- and sex-matched normal controls. Thirty-five of the patients were double-labeled with tetracycline before biopsy. The cortical remodeling cycle was reconstructed in these patients and compared with 24 sex-matched but younger normal controls. In 9 patients, a second intact bone biopsy was obtained 6-12 months after successful surgery for PHP. In these patients, pre- and post-treatment biopsies were compared. Cortical porosity was increased in PHP (p < 0.001) due to a high turnover state with expansion of the remodeling space (p < 0.001). The net balance of the remodeling cycle on the haversian surface was found unchanged in PHP, since the average haversian canal diameter remained unchanged. In the female PHP-patients, a significant increase in the final resorption depth (p < 0.01) was balanced by a proportional increase in the wall width (p < 0.001). Among all PHP patients, no significant decrease in cortical width was found. However, a significant reduction in absolute (p < 0.05) and fractional cortical width (p < 0.05) was seen in postmenopausal PHP women giving rise to a cortical bone loss. Reconstruction of the cortical remodeling cycle revealed a doubling in activation frequency from 0.6#/year in normals to 1.2#/year in PHP (p < 0.001), giving rise to a high turnover state. Surgical cure of PHP was accompanied by marked changes in cortical bone metabolism.(ABSTRACT TRUNCATED AT 250 WORDS)

Stochastic simulation of vertebral trabecular bone remodeling

Bone remodeling changes bone mass, architecture, and thereby bone strength, during normal aging. These changes seem to be accelerated during the menopause. Several therapeutic agents have been used in order to delay the onset of the menopause-related changes. The effects of these agents on the remodeling process have been determined histomorphometrically in several short-term clinical studies, but data from long-term clinical studies are difficult to achieve, as are data on the influence on bone strength. The aim of this study was to develop a computer simulation model that could assist in predicting the long-term effects of changes in the remodeling process on bone mass, trabecular thickness, and perforations. The paper presents such a stochastic model of the remodeling process in human vertebral trabecular bone. The computer model is based on histomorphometric and structural data from human studies. It is presented in terms of flow charts, and simulations performed with the model are discussed in relation to measurements on human vertebral bone samples. The results show that a menopause-related doubling of the activation frequency causes a transient, mainly reversible bone loss. If the menopause is accompanied by an increase in both activation frequency and resorption depth, then the resulting bone loss will be more pronounced and with a larger part being irreversible bone loss (perforations). The two antiresorptive agents Etidronate and estrogen both cause a slight increase in bone mass (reducing remodeling space), and Etidronate also seems capable of preventing perforations. During fluoride therapy, an initial increase in remodeling space followed by a reduction is seen. Very few perforations are found to take place during fluoride therapy. The present model has been validated by assessing the effects of the menopause and treatment with antiresorptive or anabolic agents. It was found that the results mirrored very closely the results (bone mass measurements) from short-term clinical studies. It is therefore concluded that the model provides a tool for evaluating existing and new therapeutic regimens.

Management of Osteoporosis and Paget??s Disease

Osteoporosis is a major public health problem occurring primarily among the postmenopausal population. Osteoporosis is a preventable disease, but despite several advances in its prevention, treatment of the established disease to date remains a major challenge to be managed by primary care physicians. Stabilisation of bone mass and prevention of falls are of paramount importance in any therapeutic programme for osteoporotic patients with established vertebral fractures. Drug therapy for osteoporosis can be divided operationally into 2 main categories: those that inhibit bone resorption, and thus reduce bone turnover, and those that stimulate bone formation, exerting an anabolic effect. Therapeutic agents that inhibit bone remodeling would appear to be best suited to those patients with high turnover osteoporosis (about 30%). Included in this category are calcium, vitamin D and its metabolites, gonadal steroids, calcitonin, ipriflavone and bisphosphonates. Although estrogen replacement therapy has been proven to be effective in older females, calcitonin appears to be the treatment of choice for this population since it stabilises or increases bone mass and also has reported analgesic properties. Drugs that stimulate bone remodeling or bone formation would be best suited to patients with low turnover osteoporosis (about 70%). The agent in this class that is widely used is sodium fluoride. New therapies include intermittent injections of synthetic parathyroid hormone, and cyclic bisphosphonates to activate then depress resorption and formation. Any attempts to stabilise the skeleton with any drug regimen must be accompanied by an adequate calcium supply, i.e. 1200 to 1500 mg/day). The theoretical basis of tailoring treatment for osteoporosis to the underlying histology has not yet been fully proven, but there is increasing experimental support to this approach. Drugs that inhibit bone turnover, such as calcitonin, appear to be effective in increasing bone mass for 1.5 to 2 years, about the time it would take to replenish the remodeling space in a patient with high turnover osteoporosis. In contrast, although bone mass appears to increase for as long as 5 years in patients treated with sodium fluoride, there has been no consistent reduction in occurrence of vertebral or hip fractures. Paget' disease of bone is a focal disorder of the skeleton characterised by excessive resorption and subsequently disorganised formation of bone. The aetiology of the disease is unknown. Paget's disease may be mono-ostotic or polyostotic; pain and bone deformities due to enlargement of skeletal segments represent the main clinical aspects. However, in many patients the disease may be asymptomatic.(ABSTRACT TRUNCATED AT 400 WORDS)