High Turnover Bone Loss Research Articles

One versus 2years of alendronate following denosumab: the CARD extension.

When denosumab is discontinued, antiresorptive therapy is critical to attenuate high-turnover bone loss. The ideal choice and duration of antiresorptive therapy are not yet defined, however. In the Comparison of Alendronate or Raloxifene following Denosumab (CARD) study, we demonstrated that 12months of alendronate was better able to maintain the bone mineral density (BMD) gains achieved with 12months of denosumab versus 12months of raloxifene. In this extension, we wished to determine if 12months of alendronate would be sufficient in maintaining these denosumab-induced BMD gains. In the CARD study, postmenopausal osteoporotic women aged 60-79 at high fracture risk received 12months of denosumab 60-mg SC every 6months followed by 12months of either alendronate 70mg weekly (N = 26) or raloxifene (N = 25). All subjects in the alendronate arm were then offered participation in a 1-year extension in which they were randomized to continue alendronate for an additional 12months (N = 10) or to receive calcium and vitamin D alone (N = 8). The primary outcome was change in spine BMD between months 24 and 36. Exploratory endpoints included changes in areal BMD (aBMD) at other anatomic sites as well as changes in serum bone turnover markers. The CARD study demonstrated the effectiveness of 12months alendronate in preserving denosumab-induced BMD gains. In the extension, aBMD was maintained at the spine, total hip, and femoral neck in both those randomized to an additional year of alendronate and those randomized to calcium/vitamin D alone. We did, however, observe a transient comparative decrease between months 24-30 in the calcium/vitamin D group at the total hip (P = 0.008) and femoral neck (P = 0.040). At the end of 24months of the CARD study, bone turnover markers serum c-telopeptide (CTX) and procollagen N-propeptide of type I collagen (PINP) were suppressed in both groups and then increased more between months 24-36 in the calcium/vitamin D group than the alendronate group (P = 0.051 for CTX, P = 0.030 for P1NP). Both CTX and PINP remained below the month 0 baseline in both groups (P < 0.05 for all comparisons). With the limitations of our small sample size, these data suggest that both 1 and 2years of alendronate effectively maintain BMD gains achieved with 1year of denosumab and prevented any rebound in bone turnover marker levels above pre-denosumab baseline. This is the first randomized trial to assess minimum duration of bisphosphonate after short-term denosumab and may be helpful to guide clinical care. Similar studies performed after longer durations of denosumab would be helpful to further define optimal management. ClinicalTrials.gov registration number: NCT03623633.

Roxadustat improves renal osteodystrophy by dual regulation of bone remodeling.

Renal osteodystrophy (ROD), a component of chronic kidney disease-mineral and bone disorder (CKD-MBD) can lead to bone loss increasing fracture risks in CKD patients. Therefore, it is important to prevent and treat ROD. Activation of hypoxia-inducible factor-1α (HIF-1α) signaling was reported to prevent osteoporotic bone loss. Roxadustat, which is used to treat renal anemia in the clinic, is a novel HIF stabilizer. In our study, we aimed to investigate the effects of roxadustat on ROD. We established an adenine-induced CKD rat model. Roxadustat was administered intragastrically to normal and CKD rats for 4 weeks. Hemoglobin concentrations and serum biochemical parameters were tested, and bone histomorphometric analysis was performed. CKD rats exhibited impaired renal function with anemia, secondary hyperparathyroidism and high-turnover ROD-induced significant bone loss. Roxadustat ameliorated renal anemia and attenuated the extreme increase in intact parathyroid hormone (iPTH) and fibroblast growth factor 23 (FGF23) in CKD rats. Bone histomorphometric analysis showed that roxadustat significantly alleviated bone loss and bone microarchitecture deterioration in CKD rats by increasing osteoblast activity and inhibiting osteoclast activity. We did not find that roxadustat had significant effects on bone metabolism in normal rats. Roxadustat can improve ROD via dual regulation of bone remodeling. The use of roxadustat may be a promising strategy to treat osteoporotic bone disorders, such as ROD.

Bariatric surgery and skeletal health: A narrative review and position statement for management by the European Calcified Tissue Society (ECTS).

Numerous studies have demonstrated detrimental skeletal consequences following bariatric surgery. A working group of the European Calcified Tissue Society (ECTS) performed an updated review of existing literature on changes of bone turnover markers (BTMs), bone mineral density (BMD), and fracture risk following bariatric surgery and provided advice on management based on expert opinion. Based on observational studies, bariatric surgery is associated with a 21-44% higher risk of all fractures. Fracture risk is time-dependent and increases approximately 3years after bariatric surgery. The bariatric procedures that have a malabsorptive component (including Roux-en-Y Gastric bypass (RYGB) and biliopancreatic diversion (BPD)) have clearly been associated with the highest risk of fracture. The extent of high-turnover bone loss suggests a severe skeletal insult. This is associated with diminished bone strength and compromised microarchitecture. RYGB was the most performed bariatric procedure worldwide until very recently, when sleeve gastrectomy (SG) became more prominent. There is growing evidence that RYGB is associated with greater reduction in BMD, greater increase in BTMs, and higher risk of fractures compared with SG but RCTs on optimal management are still lacking. In all patients, it is mandatory to treat vitamin D deficiency, to achieve adequate daily calcium and protein intake and to promote physical activity before and following bariatric surgery. In post-menopausal women and men older than 50years, osteoporosis treatment would be reasonable in the presence of any of the following criteria: i) history of recent fragility fracture after 40years of age, ii) BMD T-score≤-2 at hip or spine, iii) FRAX score with femoral neck BMD exceeding 20% for the 10-year major osteoporotic fracture probability or exceeding 3% for hip fracture. Zoledronate as first choice should be preferred due to intolerance of oral formulations and malabsorption. Zoledronate should be used with caution due to hypocemia risk. It is recommended to ensure adequate 25-OH vitamin D level and calcium supplementation before administering zoledronate. The bariatric procedures that have a malabsorptive component have been associated with the highest turnover bone loss and risk of fracture. There is a knowledge gap on osteoporosis treatment in patients undergoing bariatric surgery. More research is necessary to direct and support guidelines.

Bariatric Surgery and Osteoporosis.

It has been increasingly acknowledged that bariatric surgery adversely affects skeletal health. After bariatric surgery, the extent of high-turnover bone loss is much greater than what would be expected in the absence of a severe skeletal insult. Patients also experience a significant deterioration in bone microarchitecture and strength. There is now a growing body of evidence that suggests an association between bariatric surgery and higher fracture risk. Although the mechanisms underlying the high-turnover bone loss and increase in fracture risk after bariatric surgery are not fully understood, many factors seem to be involved. The usual suspects are nutritional factors and mechanical unloading, and the roles of gut hormones, adipokines, and bone marrow adiposity should be investigated further. Roux-en-Y gastric bypass (RYGB) was once the most commonly performed bariatric procedure worldwide, but sleeve gastrectomy (SG) has now become the predominant bariatric procedure. Accumulating evidence suggests that RYGB is associated with a greater reduction in BMD, a greater increase in markers of bone turnover, and a higher risk of fracture than SG. These findings should be taken into consideration in determining the most appropriate bariatric procedure for patients, especially those at higher fracture risk. Before and after all bariatric procedures, sufficient calcium, vitamin D and protein intake, and adequate physical activity, are needed to counteract negative impacts on bone. There are no studies to date that have evaluated the effect of osteoporosis treatment on high-turnover bone loss after bariatric surgery. However, in patients with a diagnosis of osteoporosis, anti-resorptive agents may be considered.

Bone Density and Trabecular Morphology at Least 10 Years After Gastric Bypass and Gastric Banding.

Roux-en-Y gastric bypass (RYGB) instigates high-turnover bone loss in the initial 5 years after surgery, whereas skeletal changes after adjustable gastric banding (AGB) are less pronounced. Long-term skeletal data are scarce, and the mechanisms of bone loss remain unclear. We sought to examine bone density and microarchitecture in RYGB and AGB patients a decade after surgery and to determine whether prior published reports of bone loss represent an appropriate adaptation to new postsurgical weight. In this cross-sectional study, 25 RYGB and 25 AGB subjects who had bariatric surgery ≥10 years ago were matched 1:1 with nonsurgical controls for age, sex, and current body mass index (BMI). We obtained bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA), volumetric BMD and microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT), trabecular morphology by individual trabecular segmentation, and metabolic bone laboratory results. As compared with BMI-matched controls, RYGB subjects had significantly lower hip BMD, and lower total volumetric BMD at the distal radius and tibia. Substantial deficits in cortical and trabecular microarchitecture were observed in the RYGB group compared to controls, with reduced trabecular plate bone volume fraction and estimated failure load at both the radius and tibia, respectively. Bone turnover markers CTX and P1NP were 99% and 77% higher in the RYGB group than controls, respectively, with no differences in serum calcium, 25-hydroxyvitamin D, or parathyroid hormone. In contrast, the AGB group did not differ from their BMI-matched controls in any measured bone density, microarchitecture, or laboratory parameter. Thus, RYGB, but not AGB, is associated with lower than expected hip and peripheral BMD for the new weight setpoint, as well as deleterious changes in bone microarchitecture. These findings suggest that pathophysiologic processes other than mechanical unloading or secondary hyperparathyroidism contribute to bone loss after RYGB, and have important clinical implications for the long-term care of RYGB patients. © 2020 American Society for Bone and Mineral Research.

Denosumab to Prevent High-Turnover Bone Loss After Bariatric Surgery

Denosumab to Prevent High-Turnover Bone Loss After Bariatric Surgery

Osteoclast-Released Wnt-10b Underlies Cinacalcet Related Bone Improvement in Chronic Kidney Disease.

Secondary hyperparathyroidism (SHPT) relates to high turnover bone loss and is responsible for most bone fractures among chronic kidney disease (CKD) patients. Changes in the Wingless/beta-catenin signaling (Wnt/β-catenin) pathway and Wnt inhibitors have been found to play a critical role in CKD related bone loss. A calcimimetic agent, cinacalcet, is widely used for SHPT and found to be similarly effective for parathyroidectomy clinically. A significant decrease in hip fracture rates is noted among US hemodialysis Medicare patients since 2004, which is probably related to the cinacalcet era. In our previous clinical study, it was proven that cinacalcet improved the bone mineral density (BMD) even among severe SHPT patients. In this study, the influence of cinacalcet use on bone mass among CKD mice was determined. Cinacalcet significantly reduced the cortical porosity in femoral bones of treated CKD mice. It also improved the whole-bone structural properties through increased stiffness and maximum load. Cinacalcet increased femoral bone wingless 10b (Wnt10b) expression in CKD mice. In vitro studies revealed that cinacalcet decreased osteoclast bone resorption and increased Wnt 10b release from osteoclasts. Cinacalcet increased bone mineralization when culturing the osteoblasts with cinacalcet treated osteoclast supernatant. In conclusion, cinacalcet increased bone quantity and quality in CKD mice, probably through increased bone mineralization related with osteoclast Wnt 10b secretion.

SAT-518 Long-term Impact of Gastric Bypass on Bone Density &gt;10 years after Bariatric Surgery: Exceeding Physiologic Expectations

Introduction: In the initial years after bariatric surgery, Roux-en-Y gastric bypass (RYGB) leads to high-turnover bone loss and an increased risk of fractures. The long-term effects of RYGB on bone density and microarchitecture have not been defined beyond 5 years. Furthermore, there remains an open question of whether bone loss exceeds physiologic expectations for surgical weight loss. Thus, we evaluated bone mineral density (BMD) and bone microarchitecture in adults who received RYGB at least 10 years ago compared to BMI-matched controls. Methods: In this ongoing study, we recruited 24 adults who received RYGB ≥10 years ago, along with nonsurgical controls who were matched 1:1 by age, sex, race/ethnicity, and current BMI. Total body composition and areal BMD (aBMD) of the lumbar spine and proximal femur were assessed by dual energy x-ray absorptiometry (DXA). Volumetric BMD (vBMD) and bone microarchitecture at the distal radius and tibia were evaluated with high resolution peripheral QCT. Serum calcium, 25-OH vitamin D, and PTH were available in 2/3 of subjects; additional analyses are ongoing. Paired t-tests were used to compare outcomes between groups. Results: By design, the RYGB group was well-matched with controls for BMI (33 ± 6 kg/m2), age (56 ± 10 yr), sex (88% female), and race (65% white). Fat mass and lean mass were similar between RYGB and controls. Mean time since surgery was 13.7 ± 2.2 yrs in the RYGB group, and self-reported weight loss was 45 ± 19 kg. As compared to BMI-matched controls, RYGB patients had 17% lower femoral neck aBMD (p<0.001) and 13% lower total hip aBMD (p<0.001), but lumbar spine aBMD was not significantly different between groups. RYGB patients had lower cortical and trabecular vBMD than BMI-matched controls at both the radius and tibia (p≤0.02 for all), leading to a total vBMD that was 27% lower at the radius (p<0.001) and 20% lower at the tibia (p<0.001). Cortical area and thickness were significantly lower in the RYGB group at the radius and tibia (p<0.05 for all). In addition, the RYGB group had lower trabecular number and thickness, wider trabecular separation, and increased trabecular heterogeneity at both the radius and tibia (p≤0.02 for all). Serum calcium and 25-OH vitamin D levels were similar to BMI-matched controls, although PTH levels tended to be higher in the RYGB group (71 vs 52 pg/mL, p=0.07). Conclusions: Adults who received RYGB at least 10 years ago have femoral and peripheral BMD that is lower than expected given their new weight set point, despite comparable serum calcium and vitamin D levels as BMI-matched controls. Furthermore, both the radius and tibia showed a similar magnitude of deterioration in bone microarchitecture, suggesting that bone loss is driven by a systemic process rather than confined to weight-bearing sites. These data indicate that the effects of RYGB on bone are pathophysiologic, and may be attributed to factors beyond skeletal unloading.

Longitudinal 5-Year Evaluation of Bone Density and Microarchitecture After Roux-en-Y Gastric Bypass Surgery.

Bone health declines in the initial years after Roux-en-Y gastric bypass (RYGB), but long-term skeletal effects are unclear. To document longitudinal changes in bone mineral density (BMD) and microarchitecture 5 years after RYGB. Prospective 5-year observational study of 21 adults with severe obesity receiving RYGB at an academic medical center. Spine and hip areal BMD were measured by dual-energy X-ray absorptiometry, and trabecular volumetric BMD (vBMD) of the spine was assessed by quantitative CT (QCT). We measured vBMD and microarchitecture of the distal radius and tibia by high-resolution peripheral QCT in a subset of subjects. Serum type I collagen C-terminal telopeptide (CTX) and procollagen type I N-terminal propeptide (P1NP) were also measured. Areal BMD declined by -7.8% ± 7.6% at the spine and -15.3% ± 6.3% at the total hip by 5 years after RYGB (P ≤ 0.001), although the rate of bone loss slowed in later years. Trabecular spine vBMD decreased by -12.1% ± 12.3% by 5 years (P ≤ 0.001). At peripheral sites, vBMD continued to decrease steadily throughout 5 years, with parallel declines in cortical and trabecular microarchitecture, leading to decreases in estimated failure load of -20% and -13% at the radius and tibia, respectively (P < 0.001). Five years after RYGB, CTX and P1NP were 150% and 34% above baseline (P < 0.001 and P = 0.017, respectively). Sustained high-turnover bone loss and bone microarchitectural deterioration occur in the 5 years after RYGB. Adults receiving RYGB warrant assessment of bone health.

Effects of the calcineurin inhibitors cyclosporine and tacrolimus on bone metabolism in rats.

Immunosuppressive therapy is considered as one of the factors inducing to the onset of osteoporosis after organ transplantation. Chronic immunosuppressive therapy after transplantation is required for organ transplant patients, and it is important to prevent the occurrence of osteoporotic fractures to maintain the quality of life in patients. In this study, we examined the effects of cyclosporine and tacrolimus on bone metabolism in rats. Five-week-old male Wistar rats were treated orally with 15 mg/kg cyclosporine or 1.5 mg/kg tacrolimus daily for 4 weeks. Each of cyclosporine and tacrolimus significantly reduced the bone strength of the femoral mid-diaphysis and bone mineral density of the tibia and femur. Bone histomorphometry showed that the administration of both drugs resulted in a decrease in bone volume, number and thickness of trabeculae, and an increase in trabecular separation. Bone formation parameters such as osteoid volume, osteoblast surface, mineralizing surface, mineral apposition rate, and bone formation rate significantly increased in the cyclosporine-treated group. Bone resorption parameters such as eroded surface, osteoclast surface, and osteoclast number significantly increased in both the cyclosporine- and the tacrolimus- treated groups. These results showed that cyclosporine increases both bone formation and bone resorption, leading to a high-turnover bone loss, and that tacrolimus increases bone resorption without affecting bone formation, leading to bone loss.

The wakefulness promoting drug Modafinil causes adenosine receptor-mediated upregulation of receptor activator of nuclear factor κB ligand in osteoblasts: Negative impact of the drug on peak bone accrual in rats

Modafinil is primarily prescribed for treatment of narcolepsy and other sleep-associated disorders. However, its off-prescription use as a cognition enhancer increased considerably, specially among youths. Given its increasing use in young adults the effect of modafinil on peak bone accrual is an important issue but has never been investigated. Modafinil treatment to young male rats caused trabecular and cortical bone loss in tibia and femur, and reduction in biomechanical strength. Co-treatment of modafinil with alendronate (a drug that suppresses bone resorption) reversed the trabecular bone loss but failed to prevent cortical loss. Modafinil increased serum type 1 pro-collagen N-terminal protein (P1NP) and collagen type 1 cross-linked C-telopeptide (CTX-1) indicating a high turnover bone loss. The drug also increased receptor activator of nuclear factor κB ligand (RANKL) to osteoprotegerin (OPG) ratio in serum which likely resulted in increased osteoclast number per bone surface. Furthermore, conditioned medium from modafinil treated osteoblasts increased the expression of osteoclastogenic genes in bone marrow-derived macrophages and the effect was blocked by RANKL neutralizing antibody. In primary osteoblasts, modafinil stimulated cAMP production and using pharmacological approach, we showed that modafinil signalled via adenosine receptors (A2AR and A2BR) which resulted in increased RANKL expression. ZM-241,385 (an A2AR inhibitor) and MRS 1754 (an A2BR inhibitor) suppressed modafinil-induced upregulation of RANKL/OPG ratio in the calvarium of new born rat pups. Our data suggests that by activating osteoblast adenosine receptors modafinil increases the production of osteoclastogenic cytokine, RANKL that in turn results in high turnover bone loss in young rats.

Bariatric Surgery: Weighing In on Bone Loss.

Bariatric Surgery: Weighing In on Bone Loss.

Attenuation of Postmenopausal Bone Loss in Patients with Transient Hypoparathyroidism After Total Thyroidectomy

Increased bone mineral density (BMD) has been reported in patients with postsurgical permanent hypoparathyroidism. Hypoparathyroidism may attenuate the high-turnover bone loss in postmenopausal women. We reported previously that patients who had transient hypoparathyroidism postoperatively were at subclinical hypoparathyroid (hP) status even 5 years after surgery. We hypothesized that patients with transient hypoparathyroidism (ThP) may have altered BMD. A total of 140 women who underwent total thyroidectomy had BMD measurements of the lumbar spine, femoral neck, and radius 3 years after surgery. At surgery, 99 patients were ≥50 years and 41 were <50 years. They were divided into three groups according to their postoperative parathyroid function: There were 80 patients in the no hP (NhP) group, 54 in the ThP group, and 6 in the permanent hP (PhP) group. Among the 99 patients aged ≥50 years, 36 ThP patients had median Z scores of the BMD in all three areas (lumbar spine, femoral neck, radius) that were significantly higher (by 1.083, 0.533, and 1.047, respectively) than those in the 60 NhP patients aged ≥50 years. The BMDs in the three PhP patients ≥50 years were higher than those in the NhP and ThP patients, but the difference did not reach significance except for in the femoral neck. Multivariate logistic regression analyses showed that Z scores > 0 were significantly associated only with the presence of ThP postoperatively. In the patients <50 years, the BMD values were not significantly different among the three groups except at the radius in PhP patients, which was significantly lower than those of the other patients. We found that ThP was associated with increased BMD in postmenopausal women. This may be due to attenuation of the high-turnover bone loss in postmenopausal women.

Developmental Exposure to As, Cd, and Pb Mixture Diminishes Skeletal Growth and Causes Osteopenia at Maturity via Osteoblast and Chondrocyte Malfunctioning in Female Rats

We studied the effect of metal mixture (MM), comprising As, Cd, and Pb, in developing female rat skeleton from gestation day 5 until postnatal day 60 (P-60). MM resulted in synergistic inhibition in viability and differentiation of osteoblasts in vitro, likely induced by reactive oxygen species. MM, administered at their most frequently occurring concentrations present in the groundwater of India, i.e., As: 0.38 ppm, Pb: 0.22 ppm, and Cd: 0.098 ppm or 10× of the ratio to developing rats, exhibited a synergistic decrease in ex vivo mineralization of bone marrow stromal (osteoprogenitor) cells. MM group showed a dose-dependent attenuation in weight and axial lengths and shortening of tibias at P-60. Furthermore, the growth plate was shortened, which was associated with shorter proliferative and hypertrophic zones, decreased parathyroid hormone-related protein and Indian hedgehog expression in the chondrocytes, reduced primary and secondary spongiosa, and hypomineralized osteoids-a major characteristic of osteomalacia. In addition, compared with the control, MM-treated rats were clearly osteopenic based on bone mineral density, microarchitecture, biomechanical strength, and particularly the biochemical profile, that suggested high turnover bone loss. Finally, in comparison to the control, the fracture-healing ability of MM group was delayed and accompanied by inferior quality of the healed bone. Together, these data demonstrated that the mixture of As, Cd, and Pb induced synergistic toxicity to developing skeleton, thereby diminishing modeling-directed bone accrual, inducing osteopenia and dampening fracture healing.

Longitudinal Assessment of In Vivo Bone Dynamics in a Mouse Tail Model of Postmenopausal Osteoporosis

Recently, it has been shown that transient bone biology can be observed in vivo using time-lapse micro-computed tomography (μCT) in the mouse tail bone. Nevertheless, in order for the mouse tail bone to be a model for human disease, the hallmarks of any disease must be mimicked. The aim of this study was to investigate whether postmenopausal osteoporosis could be modeled in caudal vertebrae of C57Bl/6mice, considering static and dynamic bone morphometry as well as mechanical properties, and to describe temporal changes in bone remodeling rates. Twenty C57Bl/6mice were ovariectomized (OVX, n=11) or sham-operated (SHM, n=9) and monitored with in vivo μCT on the day of surgery and every 2weeks after, up to 12weeks. There was a significant decrease in bone volume fraction for OVX (-35%) compared to SHM (+16%) in trabecular bone (P<0.001). For OVX, high-turnover bone loss was observed, with the bone resorption rate exceeding the bone formation rate (P<0.001). Furthermore there was a significant decrease in whole-bone stiffness for OVX (-16%) compared to SHM (+11%, P<0.001). From these results we conclude that the mouse tail vertebra mimics postmenopausal bone loss with respect to these parameters and therefore might be a suitable model for postmenopausal osteoporosis. When evaluating temporal changes in remodeling rates, we found that OVX caused an immediate increase in bone resorption rate (P<0.001) and a delayed increase in bone formation rate (P<0.001). Monitoring transient bone biology is a promising method for future research.

Ovine modeling of dietary induced metabolic acidosis and bone loss

A challenge in studying the development of osteoporosis is controlling all of the varying factors that contribute to its development. Such factors include genetic predisposition, age at the onset of menopause, surgically induced menopause, lifestyle choices such as alcohol consumption and smoking and dietary influences. An ideal animal model would be one in which many of the aforementioned factors could be controlled in addition to having the osteopenia develop in a practically short period of time with the resulting bone having similar quality as human bone with osteoporosis. No single animal model fulfills all of these criteria. This paper provides a brief review of our laboratories investigations into the use of dietary induced metabolic acidosis in an ovine model of osteopenia that shows promise in providing a model for high turnover bone loss.

Follicle-stimulating hormone stimulates TNF production from immune cells to enhance osteoblast and osteoclast formation

Declining estrogen production after menopause causes osteoporosis in which the resorption of bone exceeds the increase in bone formation. We recently found that mice deficient in the beta-subunit of follicle-stimulating hormone (FSHbeta) are protected from bone loss despite severe estrogen deficiency. Here we show that FSHbeta-deficient mice have lowered TNFalpha levels. However, TNFalpha-deficient mice are resistant to hypogonadal bone loss despite having elevated FSH, suggesting that TNFalpha is critical to the effect of FSH on bone mass. We find that FSH directly stimulates TNFalpha production from bone marrow granulocytes and macrophages. We also explore how TNFalpha up-regulation induces bone loss. By modeling the known actions of TNFalpha, we attribute the high-turnover bone loss to an expanded osteoclast precursor pool, together with enhanced osteoblast formation. TNFalpha inhibits osteoblastogenesis in the presence of ascorbic acid in culture medium, but in its absence this effect becomes stimulatory; thus, ascorbic acid reverses the true action of TNFalpha. Likewise, ascorbic acid blunts the effects of TNFalpha in stimulating osteoclast formation. We propose that hypogonadal bone loss is caused, at least in part, by enhanced FSH secretion, which in turn increases TNFalpha production to expand the number of bone marrow osteoclast precursors. Ascorbic acid may prevent FSH-induced hypogonadal bone loss by modulating the catabolic actions of TNFalpha.

Reduced Expression of Thrombospondins and Craniofacial Dysmorphism in Mice Overexpressing Fra1

Fra1 transgenic (Tg) mice develop osteosclerosis and exhibit altered expression of bone matrix proteins. We found that expression of Thbs1 and Thbs2 was reduced in Fra1 Tg osteoblasts. Fra1 Tg and non-osteosclerotic Thbs1-/-Thbs2-/- mice share an edge-to-edge bite. Therefore, reduced expression of thrombospondins may contribute to craniofacial dysmorphism independently of osteosclerosis. Tg mice overexpressing Fra1, a component of the transcription factor activator protein-1 (AP-1), show progressive osteosclerosis caused by cell autonomous abnormalities in osteoblasts. The expression of several bone matrix proteins, including matrix gla protein, is dysregulated in Fra1 Tg osteoblasts. In osteoblastogenic cultures, altered bone matrix production by Fra1 overexpression was monitored using Alizarin red staining, quantitative RT-PCR, and Western blotting. Responsiveness to ovariectomy was examined by bone histomorphometry. Craniofacial parameters were measured on radiographs and using CT. Thrombospondin-1 (Thbs1) and thrombospondin-2 (Thbs2) were reduced in Fra1 Tg osteoblasts differentiated in vitro and in bones from Fra1 Tg mice. Despite alterations in bone matrix proteins, ovariectomy induces high turnover bone loss in Fra1 Tg mice as in wildtype mice. Fra1 Tg mice, as well as Thbs1-/- Thbs2-/- mice, which do not show osteosclerosis, exhibit an edge-to-edge bite phenotype associated with craniofacial dysmorphism. These data suggest that reduced expression of thrombospondins in Fra1 Tg mice underlies craniofacial dysmorphism, independent of osteosclerosis.

Hypertrophy of vascularized bone isograft in rats treated with cyclosporine A.

The aim of this study was to investigate the effects of cyclosporine A (CsA) on vascularized tibio-fibula isograft between 12-week-old male Lewis rats. After transplantation, 45 rats were randomly allocated to one of the following 7 treatment groups: (1) 4-week vehicle (n = 5), (2) 4-week CsA (n = 5), (3) 8-week vehicle (n = 10), (4) 8-week CsA (n = 10), (5) 4-week CsA followed by 4-week vehicle (n = 5), (6) 16-week vehicle (n = 5), or (7) 4-week CsA followed by 12-week vehicle (n = 5). In soft X-ray and micro-computed tomography examination, hypertrophic change of the grafted bones was apparent in the 4- and 8-week CsA groups. Mineral apposition rate and bone formation rate of the grafted bones in the 4-week CsA group were markedly higher than those in the 4-week vehicle group. In the 4- and 8-week CsA groups, however, bone mineral density (BMD) of the grafted bones was lower and strength of the reconstructed bones was weaker than the 4- and 8-week vehicle groups. Urinary deoxypyridinoline (DPD) level was higher in the 4- and 8-week CsA groups than in the 4- and 8-week vehicle groups. The group of 4-week CsA followed by 4-week vehicle had a level of urinary DPD equal to the 8-week vehicle group, but their BMD of the grafted bones was lower and strength of the reconstructed bones was weaker than the 8-week vehicle group. By contrast, the group of 4-week CsA followed by 12-week vehicle had BMD of the grafted bones and strength of the reconstructed bones similar to the 16-week vehicle group. These findings demonstrate that short-term CsA treatment induces hypertrophic change of vascularized bone graft with high-turnover bone loss, and strength of the reconstructed bone is gradually restored after the cessation of CsA treatment.

バセドウ病術後発生の飢餓骨症候群例

A 25-year-old woman with a more than 16-month history of hyperthyroidism due to Graves' disease visited to our clinic for surgical treatment. Due to hyperthyroidism, accelerated bone formation and resorption resulted in high turn-over bone loss. Total thyroidectomy without parathyroid resection was performed, because anti-thyroid agents thiamazole (MMI), propylthiouracil (PTU) failed to control thyroid function. After thyroidectomy, hypocalcemia appeared and persisted over 2 weeks despite normal parathyroid function. We considered this hypocalcemia in the early post-operative period was due to the pre operative state of the bone, and consider this to be a case of hungry bone syndrome.