Reducing glucocorticoid dosage improves serum osteocalcin in patients with rheumatoid arthritis-results from the TOMORROW study.

UNLABELLED: Decreasing the daily dose of glucocorticoids improved bone metabolic marker levels in patients with rheumatoid arthritis. However, changes in disease activity did not influence bone metabolism. Bone metabolism might thus remain uncontrolled even if disease activity is under good control. Decreasing glucocorticoid dosage appears important for improving bone metabolism. INTRODUCTION: Patients with rheumatoid arthritis (RA) develop osteoporosis more frequently than healthy individuals. Bone resorption is increased and bone formation is inhibited in patients with RA, and glucocorticoid negatively affects bone metabolism. We aimed to investigate factors influencing bone metabolic markers in patients with RA. METHODS: We started the 10-year prospective cohort Total Management of Risk Factors in Rheumatoid Arthritis Patients to Lower Morbidity and Mortality (TOMORROW) study in 2010. We compared changes in urinary cross-linked N-telopeptide of type I collagen (uNTx) and serum osteocalcin (OC), as markers of bone resorption and formation, respectively, in 202 RA patients and age- and sex-matched volunteers between 2010 and 2011. We also investigated factors influencing ΔuNTx and ΔOC in the RA group using multivariate analysis. RESULTS: Values of ΔuNTx were significantly lower in patients with RA than in healthy controls (-0.51 vs. 7.41 nmol bone collagen equivalents (BCE)/mmol creatinine (Cr); p = 0.0013), whereas ΔOC values were significantly higher in RA patients (0.94 vs. 0.37 ng/ml; p = 0.0065). Changes in prednisolone dosage correlated negatively with ΔOC (ß = -0.229, p = 0.001), whereas changes in disease activity score, bisphosphonate therapy, and period of biologics therapy did not correlate significantly with ΔOC. No significant correlation was seen between ΔuNTx and change in prednisolone dosage. CONCLUSIONS: Decreased glucocorticoid dosage improved bone metabolic markers in RA, but disease activity, bisphosphonate therapy, and period of biologics therapy did not influence levels of bone metabolic markers. Decreasing glucocorticoid dosage appears important for improving bone metabolic marker profiles in patients with RA.

Risk factors for dysbaric osteonecrosis.

OBJECTIVES: Dysbaric osteonecrosis (DON) is a complication of ineffective decompression following exposure to high-pressure environments. This study was designed to determine risk factors for the occurrence of DON in divers. METHODS: Fifty-six male divers received skeletal examinations by radiography to assess the occurrence of DON. A questionnaire was used to obtain clinical and diving information, including diving experience and maximum diving depth. Blood samples were collected to analyse the levels of plasminogen activator inhibitor (PAI)-1, cholesterol, triglyceride, low-density lipoprotein, very low-density lipoprotein, high-density lipoprotein, apolipoprotein A1 and apolipoprotein B. RESULTS: Lesions of DON were detected in 31 of the 56 (55%) divers. Multivariate logistic regression analysis showed that high levels of PAI-1, a coagulation marker (odds ratio 4.281; P=0.0296) and great maximum diving depth (odds ratio 5.627; P=0.0231) were independent predictors of DON. CONCLUSIONS: This study has shown the presence of coagulation abnormality in divers with DON. This result suggests that a pharmacological approach incorporating the use of an anticoagulant may represent a potential strategy for the prevention of DON.

Transtrochanteric valgus osteotomy for the treatment of osteoarthritis of the hip secondary to acetabular dysplasia.

Our study describes the mid-term clinical results of the use of transtrochanteric valgus osteotomy (TVO) for the treatment of osteoarthritis of the hip secondary to acetabular dysplasia. The operation included valgus displacement at the level of the lesser trochanter, and lateral displacement of the greater trochanter by inserting a wedge of bone. We reviewed 70 hips. The mean age of the patients at operation was 44 years (14 to 59). Most (90%) had advanced osteoarthritis. The scores for pain and gait had improved significantly at a mean follow-up of 9.4 years. The rate of survival until an endpoint of a further operation during a follow-up of ten years was 82%. The survival rate was 95% in patients with unilateral involvement who were less than 50 years of age at operation. TVO is a useful form of treatment for advanced osteoarthritis of the hip, particularly in young patients with unilateral disease.

Osteonecrosis induced by a single administration of low-dose lipopolysaccharide in rabbits.

We succeeded in developing a novel rabbit model of nonsteroid and nontraumatic osteonecrosis (ON) by use of a single- and low-dose lipopolysaccharide (LPS) injection. This model is simple and highly reproducible for the frequent development of multifocal and widespread ON lesions. Male adult Japanese white rabbits intravenously injected with a single injection of 10 microg/kg body weight of LPS were histopathologically examined in the early phase (3 [n = 3], 5 [n = 3], and 24 h [n = 3]) and at 4 weeks (n = 22). Seventy-seven percent of the rabbits developed multifocal ON 4 weeks after LPS injection. ON was also observed in the femoral and humeral condyle. The average percentage of necrotic area/total area examined was 86.7 +/- 29.1% and 78.8 +/- 16.7% in the proximal one third of both the femoral and humeral bones, respectively. Organized thrombi in the intraosseous small-sized arteries and arterioles were frequently seen in and around the necrotic tissues. In the early phase, LPS treatment prominently induced thrombocytopenia, hyperlipidemia, and increased plasma levels of plasminogen activator inhibitor-1 (PAI-1). The plasma level of PAI-1 was significantly higher in the rabbits with ON than in those without ON (p < 0.01). The immunohistochemical expression of tissue factor was exaggerated in monocytes/macrophages and adipocytes in both the femoral and humeral bones of the LPS-treated rabbits. Histologically, marrow necrosis and fibrin thrombi could be observed at 24 h. In addition, pretreatment with an anticoagulant, warfarin potassium, significantly decreased the incidence of LPS-induced ON (33%, n = 9, p < 0.05) associated with elongation of prothrombin time. The results of our study show that a single administration of low-dose lipopolysaccharide induces multifocal and widespread ON characterized by the pathophysiological participation of hypercoagulability in ON development. Therefore, this model would be useful for elucidating the pathogenesis of nonsteroid ON in humans especially inflammatory hypercoagulability-induced as well as for developing preventive and therapeutic strategies.

Markers of joint tissue turnover in joint fluids from hips with osteonecrosis of the femoral head.

Osteonecrosis of the femoral head often results in secondary osteoarthritis of the hip joint; however, the pathologic processes underlying the destruction of articular cartilage are not fully understood. Molecular markers in the hip joint fluids were measured to examine the changes in turnover of cartilage and other joint tissues. Marker data were related to clinical, radiological, and histopathological changes in the articular cartilage of the hip. Forty-five patients (median age: 43 years) were studied. The median time between the onset of symptoms and sampling of hip synovial fluid was 6 months. Aggrecan fragments, C-propeptide of type-II collagen, matrix metalloproteinase-3, and tissue inhibitor of metalloproteinases-1 levels in joint fluid were determined by immunoassay. Osteonecrosis of the femoral head was graded by radiology as minimal collapse of the femoral head (stage 2: 26 patients), severe collapse (stage 3: 15 patients), or severe collapse with osteoarthritis (stage 4: four patients). Histological changes of the articular cartilage, consistent with early-stage osteoarthritis, were evident at stage 3 and were more advanced at stage 4. The average concentrations of proteoglycan fragments and C-propeptide of type-II collagen were 207 (SD 182) microg/ml and 19.6 (SD 19.3) ng/ml, respectively. The average concentrations of matrix metalloproteinase-3 and tissue inhibitor of metalloproteinases-1 were 177 (SD 291) nM and 23.0 (SD 9.9) nM, respectively. Measurable levels for all markers assayed were noted in the earliest stage of the disease, only a few months after the onset of symptoms and well before the appearance of radiological changes. Levels of matrix metalloproteinase-3 and molar ratios of matrix metalloproteinase-3/tissue inhibitor of metalloproteinases-1 were higher in early stage disease than in later stage disease.

Uptake of 99mTc-tetrofosmin, 99mTc-MIBI and 201Tl in malignant thymoma.

99mTc-tetrofosmin, Thallium-201-chloride (201Tl) and 99mTc-MIBI imagings were performed in a patient with malignant thymoma. Tracer uptake in the primary tumor was demonstrated. The tumor-to-background ratios of planar and SPECT imagings were 1.60 and 1.98 for 99mTc-tetrofosmin, 1.12 and 2.09 for 201Tl, and 1.19 and 1.80 for 99mTc-MIBI, respectively. In another patient 99mTc-tetrofosmin and 201Tl imagings were performed. Not only the primary tumor but also the direct invasions and metastatic lesions (bone metastases) were clearly detected. The tumor-to-background ratios of planar and SPECT imagings were 2.31 and 2.78 for 99mTc-tetrofosmin and 2.45 and 3.58 for 201Tl, respectively. In 99mTc-tetrofosmin scintigraphy we acquired delayed images, and the tumor-to-background ratios of planar and SPECT delayed images were 1.20 and 1.86, the retention ratios were -1.11 and -0.92 and the retention indices were -48.1 and -33.1, respectively. Our preliminary results suggest that 99mTc-tetrofosmin is useful in detecting not only the primary tumor but also metastatic lesions from malignant thymoma.

Prediction of the outcome of transtrochanteric rotational osteotomy for osteonecrosis of the femoral head.

We have studied the correlation between the prevention of progressive collapse and the ratio of the intact articular surface of the femoral head, after transtrochanteric rotational osteotomy for osteonecrosis. We used probit analysis on 125 hips in order to assess the ratio necessary to prevent progressive radiological collapse over a ten-year period. The results show that a minimum postoperative intact ratio of 34% was required. This critical ratio may be useful for surgical planning and in assessing the natural history of the condition.

Osteoporosis and years since menopause.

In Fukuoka Prefecture, in south-western Japan, a regional screening program for osteoporosis was conducted from 1994 to 1995. The screening level in the bone mineral density (BMD) at the distal non-dominant radius was equal to or less than two standard deviations below age-specific mean (< or = -2.0 SD). In 1177 examinees with natural menopause (mean age: 61.4, range: 42-88), 56 of those who were screened were subsequently radiologically confirmed by orthopedic specialists to have osteoporosis (case group). They were then compared with 802 normal BMD (> or =-1.0 SD) women (reference group) with their lifestyle and reproductive characteristics. The adjusted odds ratio (OR) and its 95% confidence interval (CI) were calculated using a logistic regression model. A significant increase in the ORs for osteoporosis based on the number of years since menopause was observed for 7-13 years since menopause (OR = 2.3; 95% CI: 1.0-5.4) compared with <7 years, however, no increasing trend in risk was evident in 14+ years since menopause (OR = 1.4; 95% CI: 0.4-5.1). Thus, the elevated risk continued up to around 10 years since menopause. These findings are consistent with previous studies that reported an alternation in the calcium metabolism and bone loss related to the length of time after menopause. Both the childhood and current milk consumption were also associated with a decreased risk: ORs were 0.4 (95% CI: 0.2-0.9) and 0.5 (95% CI: 0.3-1.0), respectively.

Increased level of apolipoprotein B/apolipoprotein A1 ratio as a potential risk for osteonecrosis.

OBJECTIVE: This study was performed to investigate whether a high ratio of apolipoprotein B to apolipoprotein A1 (apo B/apo A1 ratio) is significantly associated with the risk of developing non-traumatic osteonecrosis of the femoral head (ON). METHODS: Fifty consecutive non-traumatic ON cases were compared with 50 age and sex matched controls, using both univariate and stepwise discriminant analyses, regarding the factors of corticosteroid, alcohol, cigarettes, cholesterol, triglyceride, and apo B/apo A1 ratio. To eliminate the possibility that ON or osteoarthritic change itself can increase the apo B/apo A1 ratio, a further 32 consecutive cases comprising nine traumatic ON and 23 osteoarthritis (OA) patients were analysed using Scheffe's test. RESULTS: There was a significant association between a high apo B/apo A1 ratio and the development of non-traumatic ON with both univariate (p=0.0001) and stepwise discriminant analyses (partial r(2)=0.1239, p=0.0004). The apo B/apo A1 ratio in the non-traumatic ON group was significantly higher than that in the traumatic ON (p<0.01), control (p<0.001), or the OA groups (p<0.001). CONCLUSION: A high apo B/apo A1 ratio is significantly associated with the risk of developing ON. This ratio may be useful for assessing the potential risk of developing osteonecrosis.

Assessment of subchondral bone blood flow in the rabbit femoral condyle using the laser speckle method.

The laser speckle method is a new form of flowmetry that can obtain a two-dimensional distribution of blood flow in tissue. This method is a noncontact, simple, and rapid technique that may aid in the diagnosis of osteonecrosis. We investigated whether the subchondral bone blood flow within the femoral condyles of rabbits could be measured by the laser speckle method. The hydrogen washout method was chosen as a comparison technique because of its ability to allow repetitive measurements of blood flow in various conditions in one rabbit and because of its reliability, which already has been established. We simultaneously measured the bone blood flow in 20 femoral condyles of 10 rabbits with the laser speckle and hydrogen washout methods and found a significant correlation between the blood flow levels with use of these two methods. For the clinical application of the laser speckle method, we also investigated the influence of cartilage thickness on the measurements and the depth in the bone to which blood flow could be measured with this method. A cartilage thickness of 0.2 mm did not influence the measurement of the bone blood flow, and the depth in the bone to which the laser speckle method could be used was approximately 2 mm.

Combined NK1 and NK2 tachykinin receptor antagonists: synthesis and structure-activity relationships of novel oxazolidine analogues.

We report herein the synthesis and structure-activity relationships of a series of novel oxazolidine analogues with regards to NK1 and NK2 tachykinin receptor binding affinity. Among this series of oxazolidine analogues, some compounds exhibited excellent high binding affinities for both NK1 and NK2 receptors. In addition, we describe the inhibitory effect in vivo on SP-induced airway vascular hyperpermeability and NKA-induced bronchoconstriction in guinea pigs.

Synthesis of 2-phenylbenzofuran derivatives as testosterone 5 alpha-reductase inhibitor.

A series of 2-phenylbenzofuran derivatives with a carbamoyl, alkylamino, or alkyloxy group at the 5 or 6 position of the benzofuran ring were synthesized and evaluated for rat and human testosterone 5 alpha-reductase inhibitory activities in vitro. Against rat enzyme, the carbamoyl derivatives had more potent inhibitory activities than the alkylamino or alkyloxy derivatives, and the 6-carbamoyl derivatives tended to be more potent than the 5-carbamoyl derivatives. Against human enzyme, the 6-substituted derivatives had more potent inhibitory activities than the 5-substituted derivatives. The 6-carbamoyl and 6-alkylamino derivatives tended to show stronger inhibitory activities against human type 1 enzyme than against type 2 enzyme, but they were not largely selective.

Evaluation of blood flow within the subchondral bone of the femoral head: use of the laser speckle method at surgery for osteonecrosis.

The laser speckle method is a new form of tissue flowmetry that can analyze the interference pattern that appears when tissue is illuminated with a laser beam. During surgery for 100 cases of osteonecrosis of the femoral head, we measured the blood flow within the subchondral bone using this method. We compared the flow maps (two-dimensional distribution of the microcirculation) obtained this way with the necrotic area estimated by the preoperative magnetic resonance images and with the collapse seen during surgery. The laser speckle method was able to distinguish between the ischemic areas and the normal areas in 92 femoral heads, including five hips for which neither the magnetic resonance images nor the collapse observed during surgery demonstrated a distinct margin surrounding the necrotic area. We concluded that the laser speckle method is useful for defining the margin around a necrotic area.

Suppressed expression of hypoxanthine-guanine phosphoribosyltransferase (HGPRT) in an irradiation-attenuated Plasmodium berghei XAT strain.

Plasmodium berghei XAT (XAT) is a non-reversible, non-lethal type malaria parasite strain derived from the highly virulent lethal P. berghei NK65 (NK65) by X-irradiation. The difference in polypeptide expression between NK65 and XAT was examined in this study. Western blot patterns of the parasite polypeptides showed that a 30-kDa polypeptide was not detected in XAT. In the present paper, we focused the study on the difference in the expression of the 30-kDa polypeptide between XAT and NK65. Although several other significant differences were noted in the spots shown by two-dimensional gel electrophoresis, the 30-kDa polypeptide was isolated by means of preparative 2D-gel electrophoresis followed by HPLC, and N-terminal amino acid sequence of the polypeptide was eventually determined. Complementary DNA clones encoding the 30-kDa polypeptide were isolated and characterized. Full-length cDNA clones from XAT encoded a protein of 231 amino acid residues with a 693-bp open reading frame. The deduced amino acid sequence exhibited 67% identity with that for P. falciparum hypoxanthine-guanine phosphoribosyltransferase (HGPRT; EC 2.4.2.8), suggesting that this protein is P. berghei HGPRT. Northern blot analysis revealed that expression of HGPRT in XAT was only one-eighth of that in NK65. This finding indicates that HGPRT gene expression is markedly suppressed in XAT. The amino acid sequence of HGPRT from NK65 was identical to that from XAT. This finding showed that the amino acid sequence of XAT-HGPRT was not mutated and had not undergone deletion.

Serum 1alpha,25-dihydroxyvitamin D3 accumulates into the fracture callus during rat femoral fracture healing.

1,25-dihydroxyvitamin D3 (1,25(OH)2D3) is thought to be an important systemic factor in the fracture repair process, but the mechanism of action of 1,25(OH)2D3 has not been clearly defined. In this study, the role of 1,25(OH)2D3 in the fracture repair process was analyzed in a rat closed femoral fracture model. The plasma concentration of 1,25(OH)2D3 rapidly decreased on day 3 and continued to decrease to 10 days after fracture. We assessed whether this decrease was based on the accelerated degradation or retardation of the synthesis rate of 1,25(OH)2D3, from 25(OH)D3. After radiolabeled 3H-1,25(OH)2D3 or 3H-25(OH)D3 was injected i.v. into fractured or control (unfractured) rats, the concentrations of 25(OH)D3 and 1,25(OH)2D3 metabolites were measured by HPLC. The plasma concentrations of these radiolabeled metabolites in fractured group were similar to those in control rats early after operation. However, radioactivity in the femurs of fractured rats was higher than that of the control group. Furthermore, the radioactivity was concentrated in the callus of the fractured group analyzed by autoradiography. 1,25(OH)2D3 receptor gene expression was detected early after fracture and, additionally, both in the soft and hard callus on days 7 and 13 after fracture. These results showed that the rapid disappearance of 1,25(OH)2D3 in the early stages after fracture was not due to either increased degradation or decreased synthesis of 1,25(OH)2D3, but rather to increased consumption. Further, these results suggest the possibility that plasma 1,25(OH)2D3 becomes localized in the callus and may regulate cellular events in the process of fracture healing.

Synthesis and 5 alpha-reductase inhibitory activities of benzofuran derivatives with a carbamoyl group.

A series of 2-phenylbenzofuran derivatives with a diphenylmethylcarbamoyl group at the 5 or 6 position of the benzofuran ring were synthesized and evaluated for rat and human testosterone 5 alpha-reductase inhibitory activities in vitro. They had inhibitory activities against both enzymes and the 6-carbamoyl derivatives tended to be more potent than the 5-carbamoyl compounds.

Effects of pulse methylprednisolone on bone and marrow tissues: corticosteroid-induced osteonecrosis in rabbits.

OBJECTIVE: To investigate the effects of pulse methylprednisolone acetate on bone and bone marrow tissues and to clarify the causal factors of corticosteroid-induced osteonecrosis (ON) by using an experimental animal model. METHODS: Male adult Japanese white rabbits were injected once with 20 mg/kg of methylprednisolone into the right gluteus medius muscle. Seven rabbits were killed at 4 weeks, 4 at 6 weeks, 4 at 8 weeks, and 6 at 10 weeks. Both histopathologic and hematologic studies were performed every week. RESULTS: By 4 weeks after the steroid injection, 43% of the rabbits studied had developed multifocal ON lesions in the femur and/or humerus. In 1 rabbit, a thrombus was detected in an arteriole adjacent to the necrotic area at 4 weeks. After 6 weeks, there was also progressive histologic evidence of revascularization, with granulation tissue, and osteoblastic repair, with appositional bone formation. Hyperlipemia, fatty liver, and intraosseous fat embolism were observed in conjunction with thrombocytopenia and hypofibrinogenemia. CONCLUSION: A single injection of high-dose corticosteroids was found to be capable of inducing thrombocytopenia, hypofibrinogenemia, and hyperlipemia with multifocal ON in several bones.

Histopathologic alterations of retinacular vessels and osteonecrosis.

To probe into the pathogenesis of osteonecrosis of the femoral head, the authors obtained 37 asymptomatic human femoral heads at autopsy; of these, 13 were cases of high dosage corticosteroid therapy (steroid group) and 24 were cases without steroid therapy (nonsteroid group). The steroid group included two asymptomatic cases of osteonecrosis incidentally recognized. These femoral heads then were studied histologically and morphometrically using 2-mm stepwise tissue sections of the whole femoral head and serial sections to examine the histopathologic alterations of superior retinacular arteries and veins in detail. There was no significant difference in the luminal stenotic rate of the superior retinacular arteries between the steroid and nonsteroid groups. However, the draining veins morphometrically were more stenotic or obliterated in the steroid group than were those in the nonsteroid group. In fact, the number of stenotic veins was significantly greater in the steroid group. These findings indicate that the stenotic changes of the draining veins may participate in the development and progression of steroid induced osteonecrosis of the femoral head.

Hydroxyapatite-coating on titanium arc sprayed titanium implants.

We developed a new titanium spray technique using an inert gas shielded arc spray (titanium arc spray). Hydroxyapatite (HA)-coating can be applied to the implant without any surface pore obstruction after the rough surface is made by this technique. Scanning electron microscopy (SEM) of various porous implant surfaces after HA-coating revealed that the bead and fiber metal-coated implants had either a pore obstruction or an uneven HA-coating. On the other hand, the titanium arc sprayed implant demonstrated an even HA-coating all the way to the bottom of the surface pore. In the first set of animal experiments (Exp. 1), the interfacial shear strength to bone of four kinds of cylindrical Ti-6A1-4V (Ti) implants were compared using a canine transcortical push-out model 4 and 12 weeks after implantation. The implant surfaces were roughened by titanium arc spray (group A-C) and sand blasting (group D) to four different degrees (roughness average, Ra = group A: 56.1, B: 44.9, C: 28.3, D: 3.7 microns). The interfacial shear strength increased in a surface roughness-dependent manner at both time periods. However, the roughest implants (group A) showed some failed regions in the sprayed layers after pushout test. In the second set of animal experiments (Exp. 2), four kinds of Ti implants; HA-coated smooth Ti (sHA) with Ra of 3.4 microns, bead-coated Ti (Beads), titanium arc sprayed Ti (Ti-spray) with Ra of 38.1 microns and HA-coated Ti-spray (HA + Ti-spray) with Ra of 28.3 microns were compared using the same model as that in Exp. 1. The interfacial shear strength of HA + Ti-spray was significantly greater than that of sHA and Beads at both time periods, and that of Ti-spray at 4 weeks. Although a histological examination revealed that HA-coating enhanced bone ingrowth, sHA showed the lowest shear strength at both time periods. SEM after pushout test showed that sHA consistently demonstrated some regional failure at the HA-implant substrate interface. HA + Ti-spray had many failed regions either at the HA-bone interface or within the bone tissue rather than at the HA-implant substrate interface. These results suggested that the HA-coated smooth surfaced implants had a mechanical weakness at the HA-substrate interface. Therefore, HA should be coated on the rough surfaced implants to avoid a detachment of the HA-coating layer from the substrate and thus obtain a mechanical anchoring strength to bone. HA-coating on this new type of surface morphology may thus lead to a solution to the problems of conventional HA-coated and porous-coated implants.

Macrophage inflammatory protein-1 alpha (LD78) expressed in human bone marrow: its role in regulation of hematopoiesis and osteoclast recruitment.

Human macrophage inflammatory protein-1 alpha (hMIP-1 alpha), also known as LD78, is a member of the chemokine/ intercrine family and an inhibitor of the proliferation of the hematopoietic stem cells in vitro. Using a specific monoclonal antibody, we observed significant localization of hMIP-1 alpha in eosinophilic myelocytes in human bone marrow. We further examined the expression of hMIP-1 alpha mRNA in human bone tissue by in situ hybridization. A high level of hMIP-1 alpha mRNA expression was detected in eosinophilic myelocytes in bone marrow, confirming these cells as the site of hMIP-1 alpha synthesis. hMIP-1 alpha mRNA expression was also detected in osteoblasts in the bone-remodeling sites, and osteoclasts were frequently observed in the vicinity of these osteoblasts. hMIP-1 alpha was also able to induce osteoclastogenesis on calcified matrices in the absence of any other osteotropic hormones. These results strongly suggest that hMIP-1 alpha is involved not only in the regulation of hematopoiesis but also in the modulation of bone remodeling.