Legg‐Calvé‐Perthes Disease Produces Chronic Hip Synovitis and Elevation of Interleukin‐6 in the Synovial Fluid

Legg‐Calvé‐Perthes disease (LCPD) is a childhood hip disorder of ischemic osteonecrosis of the femoral head. Hip joint synovitis is a common feature of LCPD, but the nature and pathophysiology of the synovitis remain unknown. The purpose of this study was to determine the chronicity of the synovitis and the inflammatory cytokines present in the synovial fluid at an active stage of LCPD. Serial MRI was performed on 28 patients. T2‐weighted and gadolinium‐enhanced MR images were used to assess synovial effusion and synovial enhancement (hyperemia) over time. A multiple‐cytokine assay was used to determine the levels of 27 inflammatory cytokines and related factors present in the synovial fluid from 13 patients. MRI analysis showed fold increases of 5.0 ± 3.3 and 3.1 ± 2.1 in the synovial fluid volume in the affected hip compared to the unaffected hip at the initial and the last follow‐up MRI, respectively. The mean duration between the initial and the last MRI was 17.7 ± 8.3 months. The volume of enhanced synovium on the contrast MRI was increased 16.5 ± 8.5 fold and 6.3 ± 5.6 fold in the affected hip compared to the unaffected hip at the initial MRI and the last follow‐up MRI, respectively. In the synovial fluid of the affected hips, IL‐6 protein levels were significantly increased (LCPD: 509 ± 519 pg/mL, non‐LCPD: 19 ± 22 pg/mL; p = 0.0005) on the multi‐cytokine assay. Interestingly, IL‐1β and TNF‐α levels were not elevated. In the active stage of LCPD, chronic hip synovitis and significant elevation of IL‐6 are produced in the synovial fluid. Further studies are warranted to investigate the role of IL‐6 on the pathophysiology of synovitis in LCPD and how it affects bone healing. © 2015 American Society for Bone and Mineral Research     

Ischemic femoral head osteonecrosis in a piglet model causes three dimensional decrease in acetabular coverage

Legg‐Calve‐Perthes disease (LCPD) is a childhood form of ischemic osteonecrosis marked by development of severe femoral head deformity and premature osteoarthritis. The pathogenesis of femoral head deformity has been studied extensively using a piglet model of ischemic osteonecrosis, however, accompanying acetabular changes have not been investigated. The purpose of this study was to determine if acetabular changes accompany femoral head deformity in a well‐established piglet model of LCPD and to define the acetabular changes using three dimensional computed tomography (3‐D CT) and modeling. Twenty‐four piglets were surgically induced with ischemic osteonecrosis on the right side. The contralateral hip was used as control. At 8 weeks postoperative, pelvi were retrieved and imaged with CT. Custom software was used to measure acetabular morphologic parameters on 3‐D CT images. Moderate to severe femoral head deformities were present in all animals. Acetabula with accompanying femoral head deformity had a significant decrease in acetabular version and tilt (p < 0.001) and in coverage angle in the superior, posterior, and inferior quadrants (p < 0.05). These findings indicate that the development of femoral head deformity following ischemic osteonecrosis produces specific and predictable changes to the shape of the acetabulum. Acetabular changes described in patients with LCPD were observed in the piglet model. This model may serve as a valuable tool to elucidate the relationship between femoral head and acetabular deformities. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1173–1177, 2018.

     

Bone Loss After Bariatric Surgery: Discordant Results Between DXA and QCT Bone Density

Several studies, using dual‐energy X‐ray absorptiometry (DXA), have reported substantial bone loss after bariatric surgery. However, profound weight loss may cause artifactual changes in DXA areal bone mineral density (aBMD) results. Assessment of volumetric bone mineral density (vBMD) by quantitative computed tomography (QCT) may be less susceptible to such artifacts. We assessed changes in BMD of the lumbar spine and proximal femur prospectively for 1 year using DXA and QCT in 30 morbidly obese adults undergoing Roux‐en‐Y gastric bypass surgery and 20 obese nonsurgical controls. At 1 year, subjects who underwent gastric bypass surgery lost 37 ± 2 kg compared with 3 ± 2 kg lost in the nonsurgical controls (p < 0.0001). Spine BMD declined more in the surgical group than in the nonsurgical group whether assessed by DXA (?3.3 versus ?1.1%, p = 0.034) or by QCT (?3.4 versus 0.2%, p = 0.010). Total hip and femoral neck aBMD declined significantly in the surgical group when assessed by DXA (?8.9 versus ?1.1%, p < 0.0001 for the total hip and ?6.1 versus ?2.0%, p = 0.002 for the femoral neck), but no changes in hip vBMD were noted using QCT. Within the surgical group, serum P1NP and CTX levels increased by 82% ± 10% and by 220% ± 22%, respectively, by 6 months and remained elevated over 12 months (p < 0.0001 for all). Serum calcium, vitamin D, and PTH levels remained stable in both groups. We conclude that moderate vertebral bone loss occurs in the first year after gastric bypass surgery. However, striking declines in DXA aBMD at the proximal femur were not confirmed with QCT vBMD measurements. These discordant results suggest that artifacts induced by large changes in body weight after bariatric surgery affect DXA and/or QCT measurements of bone, particularly at the hip. © 2014 American Society for Bone and Mineral Research.     

Combined Tantalum Implant with Bone Grafting for the Treatment of Osteonecrosis of the Femoral Head

ABSTRACT

Background: The purpose of this study was to evaluate the short-term clinical outcome of using a tantalum implant in combination with bone grafting for the treatment of osteonecrosis of the femoral head. Methods: Sixty-nine patients with 94 osteonecrotic hips were treated with this method from March 2006 to March 2011. All the patients were treated with tantalum rod implantation in combination with bone grafting, and were followed for an average 35.4 months. Harris hip score and the survival rate were analyzed according to stage, etiology, and osteonecrosis part. Results: Patients with stage I and stage II diseases had significant greater Harris hip score improvement than patients having stage III disease (p < .05). The survival rate was also significantly higher in patients with stage I and stage II diseases than in patients having stage III disease (p < .05). Patients with type A and type B necrotic lesions had better recovery than patients with type C1 and type C2 having lateral column lesions (p < .05). No significant differences were detected in the clinical outcome among patients with different etiologies. Conclusion: Combined tantalum implant with bone grafting provided good short-term clinical outcomes for early stage I and stage II patients with type A and type B necrotic lesions. However, this treatment modality was not so effective for patients with stage III or type C1 and type C2 necrotic lesions.     

Microcrack density and nanomechanical properties in the subchondral region of the immature piglet femoral head following ischemic osteonecrosis

Development of a subchondral fracture is one of the earliest signs of structural failure of the immature femoral head following ischemic osteonecrosis, and this eventually leads to a flattening deformity of the femoral head. The mechanical and mineralization changes in the femoral head preceding subchondral fracture have not been elucidated. We hypothesized that ischemic osteonecrosis leads to early material and mechanical alterations in the bone of the subchondral region. The purpose of this investigation was to assess the bone of the subchondral region for changes in the histology of bone cells, microcrack density, mineral content, and nanoindentation properties at an early stage of ischemic osteonecrosis in a piglet model. This large animal model has been shown to develop a subchondral fracture and femoral head deformity resembling juvenile femoral head osteonecrosis. The unoperated, left femoral head of each piglet (n = 8) was used as a normal control, while the right side had a surgical ischemia induced by disrupting the femoral neck vessels with a ligature. Hematoxylin and eosin (H&E) staining and TUNEL assay were performed on femoral heads from 3 piglets. Quantitative backscattered electron imaging, nanoindentation, and microcrack assessments were performed on the subchondral region of both control and ischemic femoral heads from 5 piglets. H&E staining and TUNEL assay showed extensive cell death and an absence of osteoblasts in the ischemic side compared to the normal control. Microcrack density in the ischemic side (3.2 ± 0.79 cracks/mm²) was significantly higher compared to the normal side (0.27 ± 0.27 cracks/mm²) in the subchondral region (p < 0.05). The weighted mean of the weight percent distribution of calcium (CaMean) also was significantly higher in the ischemic subchondral region (p < 0.05). Furthermore, the nanoindentation modulus within localized areas of subchondral bone was significantly increased in the ischemic side (16.8 ± 2.7 GPa) compared to the normal control (13.3 ± 3.2 GPa) (p < 0.05). Taken together, these results support the hypothesis that the nanoindentation modulus of the subchondral trabecular bone is increased in the early stage of ischemic osteonecrosis of the immature femoral head and makes it more susceptible to microcrack formation. We postulate that continued loading of the hip joint when there is a lack of bone cells to repair the microcracks due to ischemic osteonecrosis leads to microcrack accumulation and subsequent subchondral fracture.     

Forearm Bone Mineral Densitometry Cannot be Used to Monitor Response to Alendronate Therapy in Postmenopausal Women

Alendronate significantly increases bone mass and reduces hip and spine fractures in postmenopausal women. To determine whether forearm densitometry could be used to monitor the efficacy of alendronate, we examined changes in bone mineral density (BMD) at the forearm (one-third distal, mid-distal, ultradistal radius) versus changes at the hip (femoral neck, total hip) and spine (posteroanterior and lateral) in a double-masked, randomized, placebo-controlled clinical trial of 120 elderly women (mean age 70 ± 4 years) treated with alendronate for 2.5 years. We found that among women in the treatment group, BMD increased by 4.0–12.2% at the hip and spine sites (all p<0.001), whereas BMD increased only nominally at the one-third distal radius (1.3%, p<0.001) and mid-radius (0.8%, p<0.05), and remained stable at the ultradistal radius. At baseline, forearm BMD correlated with that of the hip (r= 0.55–0.64, p<0.001), femoral neck (r= 0.54–0.61, p<0.001) and posteroanterior spine (r= 0.56–0.63, p<0.001). Changes in radial BMD after 1 year of therapy were not correlated with changes in hip and spine BMD after 2.5 years of therapy. In contrast, short-term changes in total hip and spine BMD were generally positively associated with long-term changes in total hip, femoral neck and spine BMD (r= 0.30–0.71, p<0.05). Furthermore, long-term BMD changes at the forearm did not correlate with long-term hip and spine BMD changes, in contrast to the moderate correlations seen between spine and hip BMD at 2.5 years (r= 0.38–0.45, p<0.01). We conclude that neither short- nor long-term changes in forearm BMD predict long-term changes in overall BMD for elderly women on alendronate therapy, suggesting that measurements of clinically relevant central sites (hip and spine) are necessary to assess therapeutic efficacy. Received: 18 February 1999 / Accepted: 20 May 1999     

RANKL inhibition: a novel strategy to decrease femoral head deformity after ischemic osteonecrosis.

A novel therapeutic strategy to decrease the development of femoral head deformity after ischemic osteonecrosis was studied in a large animal model of total head infarction. RANKL inhibition through exogenous osteoprotegerin administration significantly decreased pathologic bone resorption and deformity during repair of the infarcted head. INTRODUCTION: Legg-Calvé-Perthes disease (LCPD) is a juvenile form of osteonecrosis of the femoral head that can produce permanent femoral head deformity (FHD) and premature osteoarthritis. The development of FHD in LCPD is closely associated with the repair process, characterized by a predominance of bone resorption in its early stage that produces a fragmented appearance and collapse of the femoral head. We present here a novel strategy to preserve the femoral head structure after ischemic osteonecrosis based on inhibition of interaction between RANK and RANKL using exogenous administration of osteoprotegerin (OPG-Fc) in a large animal model of ischemic osteonecrosis. MATERIALS AND METHODS: Ischemic osteonecrosis was surgically induced in 18 male piglets by placing a ligature tightly around the right femoral neck to disrupt the blood flow to the right femoral head. Two weeks after the induction of total head infarction, OPG-Fc or saline was administered subcutaneously to nine animals per group for 6 weeks. The contralateral, normal (left) femoral heads from the animals treated with saline served as normal, nondisease controls. All animals were killed at 8 weeks when severe FHD has been previously shown to occur because of the repair process dominated by osteoclastic bone resorption. Radiographic, histomorphometric, and immunohistochemical assessments were performed. RESULTS: Radiographic assessment showed significantly better preservation of the femoral head structure in the OPG-Fc group compared with the saline group. Epiphyseal quotient (the ratio of epiphyseal height to diameter) was significantly higher in the OPG-Fc group (0.41 +/- 0.09) compared with the saline group (0.24 +/- 0.08, p < 0.001). Histomorphometric assessment revealed a significant reduction in the number of osteoclasts present in the OPG-Fc group (5.9 +/- 5.3mm(-2)) compared with the saline group (39.6 +/- 13.8 mm(-2), p < 0.001). Trabecular bone volume, number, and separation were significantly better preserved in the OPG-Fc group compared with the saline group (p < 0.001). No significant difference in femoral length was observed between the OPG-Fc and saline groups. Immunostaining revealed the presence of OPG-Fc only within the blood vessels, with no apparent staining of bone matrix or trabecular bone surfaces. CONCLUSIONS: To our knowledge, this is the first study to show that RANKL inhibition decreases bone resorption and FHD after ischemic osteonecrosis. Because RANKL inhibitors do not bind to bone, their effects on resorption are reversible as the drug is cleared from circulation. The reversible nature of RANKL inhibitors is very appealing for treating pediatric bone diseases such as LCPD, where the resorptive stage of the disease lasts for 1-2 years.     

Sex Differences in the Association Between Adiponectin and BMD,Bone Loss,and Fractures: The Rancho Bernardo Study

We evaluated sex differences in the prospective association between adiponectin with BMD, bone loss, and fractures. Adiponectin, an adipose‐derived protein with insulin‐sensitizing properties, is also expressed in bone‐forming cells. Conflicting results and sex differences in the adiponectin‐BMD association have been reported in cross‐sectional studies. Serum adiponectin was measured in fasting blood samples obtained in 1984–1987 in 447 postmenopausal women (mean age: 76 yr) and 484 men (mean age: 75 yr). Four years later, BMD was measured at the midshaft radius by single photon absorptiometry and at the femoral neck, total hip, and lumbar spine by DXA. In 1992–1996, axial BMD was remeasured in 261 women and 264 men. Multivariable analysis adjusted for age, weight, calcium intake, type 2 diabetes, alcohol intake, and exercise. Among women, adiponectin was inversely associated with BMD at the femoral neck (β = ?0.002, p = 0.007), total hip (β = ?0.002, p = 0.009), lumbar spine (β = ?0.003, p = 0.008), and midshaft radius (β = ?0.002, p = 0.01) after 4.4 yr and at the femoral neck and total hip 8.6 yr later. Among men, adiponectin was inversely associated with BMD at the femoral neck, (β = ?0.002, p = 0.03), total hip (β = ?0.004, p < 0.001), and midshaft radius (β = ?0.003, p < 0.001) after 4.4 yr and at the hip 8.6 yr later. Adiponectin was not associated with 4‐yr bone loss in either sex but was associated with vertebral fractures (adjusted OR: 1.13; 95% CI: 1.08–1.23; p = 0.009) among men only. Adiponectin was inversely associated with BMD; however, sex differences were observed by anatomical site and with regards to vertebral fractures.     

Biochemical Markers of Bone Turnover Reflect Femoral Bone Loss in Elderly Women

Although over 90% of hip fractures occur in patients over age 70, few data are available on femoral bone loss in this age group. To examine the relationship between biochemical markers of bone turnover and femoral bone loss in the elderly, 36 female and 17 male, healthy, community-dwelling elderly over age 65 (mean ± SD age: women 71 ± 4 years, men 75 ± 5 years) were followed for 3 years. Annual bone mineral density measurements of the hip and lumbar spine by dual-energy x-ray absorptiometry (DXA) were obtained and biochemical markers of bone resorption (urinary N-telopeptide crosslinks, free pyridinoline, total pyridinoline, total deoxypyridinoline, and hydroxyproline) and bone formation (serum osteocalcin, bone-specific alkaline phosphatase) were obtained at the end of year 3. In elderly women, longitudinal bone loss at the total hip was negatively correlated with markers of bone resorption (r =−0.39 to −0.52, P < 0.05), bone formation (r =−0.38, P < 0.05), and age (r =−0.39, P < 0.05). Markers of bone resorption were correlated with markers of bone formation (r = 0.63 to 0.74, P < 0.01). In multiple regression analysis, urinary N-telopeptide crosslinks (marker of resorption), serum osteocalcin (marker of formation), and serum parathyroid hormone explained 43% of the variability of bone loss at the total hip in women. These parameters were not related to bone loss in men. We conclude that femoral bone loss increases with age in women over 65. Measurements of specific biochemical markers of bone turnover are correlated with longitudinal bone loss in elderly women. These markers may help identify women at greatest risk for bone loss who would benefit most from therapeutic interventions. Received: 28 January 1996 / Accepted: 3 May 1996     

Prediction of Human Femoral Bone Strength Using Ultrasound Velocity and BMD: An In Vitro Study

The stiffness and strength of cancellous bone are important in the management of skeletal diseases such as osteoporosis. These properties are a function not only of bone density but also of bone architecture, some measure of which can be provided by quantitative ultrasound. The ability of quantitative ultrasound and bone mineral density (BMD) to predict stiffness and strength of human femoral heads removed from live subjects during hip replacement was assessed. Stiffness and strength were measured using a uniaxial compression test. Ultrasound velocity was measured using the pulse-submersion technique (McClue CUBAResearch) and BMD using DXA (Lunar DPX-L). Ultrasound velocity (quantitative ultrasound) and stiffness varied with the three orthogonal directions, the highest significance being between the proximo-distal (PD) and antero-posterior (AP) directions (p < 0.0001) for stiffness and p = 0.0003 for velocity). Ultrasound velocity was significantly correlated with compressive bone strength (r = 0.76, p < 0.0001) and stiffness (r = 0.79–0.83, p < 0.0001). BMD was also significantly correlated with compressive strength (r = 0.82, p < 0.0001) and stiffness (r = 0.66–0.81, p < 0.001). Using multiple regression analysis both BMD and velocity were significant predictors of strength (r = 0.88, p = 0.0004 and 0.0054 respectively) and stiffness r = 0.92, p = 0.0001 and 0.0003 respectively). BMD and velocity were still independent significant predictors of both stiffness (r = 0.93, p < 0.0001 and 0.0001 respectively) and strength (r = 0.89, p < 0.0001 and 0.02) when they combined as a product (BMDⁿ*V^m). This suggests that BMD measured using DXA, if used in conjunction with ultrasound velocity, may be able to improve osteoporosis risk assessment. The information about femur anisotropy may also be important for hip prosthesis and in vivo modelling.     

Longitudinal Evaluation of Perimenopausal Femoral Bone Loss: Effects of a Low-Dose Oral Contraceptive Preparation on Bone Mineral Density and Metabolism

To characterize the pattern of biochemical markers of bone metabolism and femoral bone mineral density in eumenorrheic and oligomenorrheic perimenopausal women, and assess the effects of a low-dose oral contraceptive (OC) on bone metabolism and femoral bone density, bone biochemical markers and femoral bone density (measured at the neck, Ward’s triangle and trochanter regions) were evaluated in a longitudinal 2-year follow-up study. The study was conducted in healthy, normally menstruating perimenopausal women (n= 18), perimenopausal oligomenorrheic women (n= 18), and perimenopausal oligomenorrheic women treated with an OC containing 20 mg ethinylestradiol plus 0.15 mg desogestrel (n= 19). The results were analyzed by factorial or repeated measures analysis of variance, as appropriate. During the observation period, in normally menstruating women there were no changes in the menstrual cycle, plasma FSH and estradiol levels, biochemical markers of bone turnover or femoral bone density. In oligomenorrheic untreated women an increase in cycle length with a concomitant decrease in plasma estradiol and an increase in plasma FSH levels were found (p < 0.05). In this group a significant increase in urinary excretion of hydroxyproline and in plasma osteocalcin levels with a concomitant significant decrease in femoral bone density (p < 0.05) occurred. In OC-treated women, osteocalcin plasma levels and urinary excretion of hydroxyproline significantly (p < 0.05) decreased, leading to a significant (p < 0.05) increase in femoral bone density. It is concluded that perimenopausal OC administration can avoid the increase in bone turnover and the decrease in femoral bone density due to the perimenopausal impairment of ovarian function. Received: 20 July 1999 / Accepted: 28 December 1999     

Platelet-Rich Plasma-Incorporated Autologous Granular Bone Grafts Improve Outcomes of Post-Traumatic Osteonecrosis of the Femoral Head

BackgroundTo investigate the effects of platelet-rich plasma (PRP)-incorporated autologous granular bone grafts for treatment in the precollapse stages (Association of Research Circulation Osseous stage II–III) of posttraumatic osteonecrosis of the femoral head.MethodsA total of 46 patients were eligible and enrolled in the study. Twenty-four patients were treated with core decompression and PRP-incorporated autologous granular bone grafting (treatment group), and 22 patients were treated with core decompression and autologous granular bone grafting (control group). During a minimum follow-up duration of 36 months, X-ray and computed tomography were used to evaluate the radiological results, and the Harris hip score (HHS) and visual analog scale were chosen to assess the clinical results.ResultsBoth the treatment and control groups had a significantly improved HHS (P < .001). The minimum clinically important difference for the HHS was reached in 91.7% of the treatment group and 68.2% of the control group (P < .05). The HHS and visual analog scale in the treatment group were significantly improved than that in the control group at the last follow-up (P < .05). Successful clinical and radiological results were achieved 87.5% and 79.2% in the treatment group compared with 59.1% and 50.0% in the control group (P < .05), respectively. The survival rates based on the requirement for further hip surgery as an endpoint were higher in the treatment group in comparison to those in the control group (P < .05).ConclusionPRP-incorporated autologous granular bone grafting is a safe and effective procedure for treatment in the precollapse stages (Association of Research Circulation Osseous stage II–III) of posttraumatic osteonecrosis of the femoral head.     

Effects of Romosozumab Compared With Teriparatide on Bone Density and Mass at the Spine and Hip in Postmenopausal Women With Low Bone Mass

Romosozumab, a monoclonal antibody that binds sclerostin, has a dual effect on bone by increasing bone formation and reducing bone resorption, and thus has favorable effects in both aspects of bone volume regulation. In a phase 2 study, romosozumab increased areal BMD at the lumbar spine and total hip as measured by DXA compared with placebo, alendronate, and teriparatide in postmenopausal women with low bone mass. In additional analyses from this international, randomized study, we now describe the effect of romosozumab on lumbar spine and hip volumetric BMD (vBMD) and BMC at month 12 as assessed by QCT in the subset of participants receiving placebo, s.c. teriparatide (20 µg once daily), and s.c. romosozumab (210 mg once monthly). QCT measurements were performed at the lumbar spine (mean of L₁ and L₂ entire vertebral bodies, excluding posterior processes) and hip. One year of treatment with romosozumab significantly increased integral vBMD and BMC at the lumbar spine and total hip from baseline, and compared with placebo and teriparatide (all p < 0.05). Trabecular vertebral vBMD improved significantly and similarly from baseline (p < 0.05) with both romosozumab (18.3%) and teriparatide (20.1%), whereas cortical vertebral vBMD gains were larger with romosozumab compared with teriparatide (13.7% versus 5.7%, p < 0.0001). Trabecular hip vBMD gains were significantly larger with romosozumab than with teriparatide (10.8% versus 4.2%, p = 0.01), but were similar for cortical vBMD (1.1% versus –0.9%, p = 0.12). Cortical BMC gains were larger with romosozumab compared with teriparatide at both the spine (23.3% versus 10.9%, p < 0.0001) and hip (3.4% versus 0.0%, p = 0.03). These improvements are expected to result in strength gains and support the continued clinical investigation of romosozumab as a potential therapy to rapidly reduce fracture risk in ongoing phase 3 studies. © 2016 American Society for Bone and Mineral Research.     

Long-Term Persistence of Low Bone Density in Orthotopic Liver Transplantation

We determined bone density and metabolism in 46 patients (35 males, 11 females) who had undergone liver transplantation 1–48 months previously. Twenty-one patients were then followed for the next 24 months. At each visit, blood and urine samples for bone and liver metabolism parameters, as well as spinal and femoral dual-energy X-ray absorptiometry (DXA) scans, were obtained. Basal spinal and femoral density was low (p<0.001). Patients with pre-transplant cholestatic diseases had lower spinal density than all the other subjects (p<0.05) and the cumulative methylprednisolone intake was an independent negative predictor of total hip density (p<0.02). At baseline, urinary hydroxyproline and N-telopeptide were at the upper normal level and decreased only after 24 months of follow-up (p<0.05). During the first year of follow-up, femoral density decreased (p<0.05) and a partial recovery was observed for both spine and femur after 24 months. After 12 months, femoral bone density was negatively associated with serum cyclosporin A levels (p<0.005) and cumulative methylprednisolone intake (p<0.05), while the percent decrease in spinal density after the first 12 months was negatively predicted by mean daily methylprednisolone intake (p<0.05). In patients with pre-transplant cholestatic diseases, femoral and spinal density increased after the first (p<0.05) and second year (p<0.05), respectively. In patients with previous post-necrotic cirrhosis, femoral density decreased after 12 months (p<0.05) and was still lower than baseline after 24 months (p<0.05). However, at the end of the study the cumulative percentage of femoral neck osteoporosis was 43%. In conclusion, an elevated prevalence of spinal and femoral osteoporosis is present even many years after liver transplantation, with immunosuppressive treatment and pre-transplant liver disease being the most important pathogenetic factors. Received: 15 April 1999 / Accepted: 29 October 1999     

Knee loading protects against osteonecrosis of the femoral head by enhancing vessel remodeling and bone healing

Osteonecrosis of the femoral head is a serious orthopedic problem. Moderate loads with knee loading promote bone formation, but their effects on osteonecrosis have not been investigated. Using a rat model, we examined a hypothesis that knee loading enhances vessel remodeling and bone healing through the modulation of the fate of bone marrow-derived cells. In this study, osteonecrosis was induced by transecting the ligamentum teres followed by a tight ligature around the femoral neck. For knee loading, 5 N loads were laterally applied to the knee at 15 Hz for 5 min/day for 5 weeks. Changes in bone mineral density (BMD) and bone mineral content (BMC) of the femur were measured by pDEXA, and ink infusion was performed to evaluate vessel remodeling. Femoral heads were harvested for histomorphometry, and bone marrow-derived cells were isolated to examine osteoclast development and osteoblast differentiation. The results showed that osteonecrosis significantly induced bone loss, and knee loading stimulated both vessel remodeling and bone healing. The osteonecrosis group exhibited the lowest trabecular BV/TV (p < 0.001) in the femoral head, and lowest femoral BMD and BMC (both p < 0.01). However, knee loading increased trabecular BV/TV (p < 0.05) as well as BMD (p < 0.05) and BMC (p < 0.01). Osteonecrosis decreased the vessel volume (p < 0.001), vessel number (p < 0.001) and VEGF expression (p < 0.01), and knee loading increased them (p < 0.001, p < 0.001 and p < 0.01). Osteonecrosis activated osteoclast development, and knee loading reduced its formation, migration, adhesion and the level of “pit” formation (p < 0.001, p < 0.01, p < 0.001 and p < 0.001). Furthermore, knee loading significantly increased osteoblast differentiation and CFU-F (both p < 0.001). A significantly positive correlation was observed between vessel remodeling and bone healing (both p < 0.01). These results indicate that knee loading could be effective in repair osteonecrosis of the femoral head in a rat model. This effect might be attributed to promoting vessel remodeling, suppressing osteoclast development, and increasing osteoblast and fibroblast differentiation. In summary, the current study suggests that knee loading might potentially be employed as a non-invasive therapy for osteonecrosis of the femoral head.     

Increased hepatic cytochrome P4503A activity decreases the risk of developing steroid‐induced osteonecrosis in a rabbit model

Low hepatic cytochrome P4503A (CYP3A) activities might play an important role for inducing osteonecrosis of the femoral head (ONFH) by corticosteroids. However, the relationship between hepatic CYP3A activity and steroid‐induced ONFH is unknown. We have examined the relationship between hepatic CYP3A activity and the inducibility of ONFH in a rabbit model. Sixty rabbits were divided into three groups. Hepatic CYP3A inducer (phenobarbital, group P; n = 15), inhibitor (itraconazole, group I; n = 15), or saline (group C, n = 30) was administrated for 3 weeks before intramuscular methylprednisolone. In groups P and I, hepatic CYP3A levels were measured by midazolam clearance before treatment (baseline) and before methylprednisolone injection. All animals were sacrificed 3 weeks after methylprednisolone injection and both femurs were harvested and examined histologically for osteonecrosis. Midazolam clearance was significantly increased and decreased, compared with baseline in groups P and I respectively (p < 0.0005, p < 0.002). The incidence of osteonecrosis in group P (33%) was significantly lower than in group I (100%) and group C (83%; p < 0.001 for both). The percentage necrotic area to whole bone marrow area on cross sections in group P (8.2 ± 5.9%) was significantly lower than in group I (69.8 ± 20.8%) and group C (51.5 ± 30.7%; p < 0.005 for both). Hepatic CYP3A activity inversely correlated with the incidence of osteonecrosis and extent of the necrotic area caused by the same dose of corticosteroids, suggesting possible prevention of the steroid‐induced osteonecrosis by reducing steroid dose in poor corticosteroid metabolizers. © 2007 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 26:91–95, 2008     

Importance of Albumin, 25(OH)-Vitamin D and IGFBP-3 as Risk Factors in Elderly Women and Men with Hip Fracture

The relative importance of vitamin D deficiency, secondary hyperparathyroidism, nutritional deficiency and low bone mineral density (BMD) as risk factors for hip fracture is not definitely established. In the framework of a case-control study of risk factors for hip fractured, biochemical markers of bone metabolism and nutrition and femoral BMD data were compared in 136 female and 43 male hip fracture patients, 126 female and 44 male age-matched hospitalized controls, and 47 healthy elderly women (8 men). Patients with hip fracture had lower albumin (−10%9 and 25(OH)-vitamin D (25(OH)D; −19%) compared with hospitalized controls, and lower albumin (−28%) and 25(OH)D levels (−52%) compared with the elderly controls. Serum values of IGFBP-3 were also significantly lower (−33%) in hip fracture patients than in community controls. BMD of femoral neck was lower (p < 0.001) in patients than in hospitalized and community controls. In hip fracture patients, parathyroid hormone (PTH) correlated weakly with BMD (neck: r = −0.19, trochanter: r = −0.17; both p < 0.05). When all women were pooled (n = 233), albumin correlated significantly (age-adjusted) with BMD at all sites (neck: r = 0.27, trochanter: r = 0.25; all p < 0.001). Albumin, but not 25(OH)D, also correlated with skinfold thickness (r = 0.19, p < 0.0025) and with body mass index (BMI) (r = 0.14, p < 0.05). Male patients with hip fracture had lower BMD and albumin (both p < 0.001), 25(OH)D (p = 0.02) and IGFBP-3 levels (p <: 0.005) compared with the controls. When male patients and controls were pooled together, albumin, skinfold thickness and BMI were significantly correlated with each other, but not with BMD. IGFBP-3 was highly correlated with albumin (p < 0.0001), 25(OH)D (p < 0.005) and, less significantly, with PTH (p < 0.05), but not with BMI or skinfold thickness. IGFBP-3 was significantly correlated with BMD at all sites (neck: r = 0.27, p < 0.05); trochanter: r = 0.40, p < 0.0005). In conclusion, low albumin and low BMD were both important risk factors for hip fracture. Low serum albumin was the strongest independent variable correlated with hip fractures. In men, IGFBP-3 was correlated with BMD. The femoral BMD depended only weakly on PTH and 25(OH)D, but was correlated at all sites with albumin, a non-specific parameter of nutrition and general health.     

Muscular Maximal Strength Indices and Bone Variables in a Group of Elderly Women

The aim of the present study was to explore the relations between muscular maximal strength indices and bone parameters (bone mineral density [BMD], hip geometry indices, and trabecular bone score [TBS]) in a group of elderly women. This study included 35 healthy elderly women whose ages range between 65 and 75 yr (68.1 ± 3.1 yr). BMD (in gram per square centimeter) was determined for each individual by dual-energy X-ray absorptiometry at the whole body, lumbar spine (L1–L4), total hip (TH), and femoral neck (FN). L1–L4 TBS and hip geometry indices were also evaluated by dual-energy X-ray absorptiometry. Maximal muscle strength of bench press (1-repetition maximum [RM] bench press), maximal muscle strength of leg press (1-RM leg press), and handgrip were measured using validated methods. 1-RM bench press was positively correlated to TH BMD (r = 0.40; p < 0.05), FN BMD (r = 0.41; p < 0.05), FN section modulus (r = 0.33; p < 0.05), and FN cross-sectional moment of inertia (r = 0.35; p < 0.05). 1-RM leg press was positively correlated to TH BMD (r = 0.50; p < 0.01), FN BMD (r = 0.35; p < 0.05), FN cross-sectional area (r = 0.38; p < 0.05), and TBS (r = 0.37; p < 0.05). Handgrip was correlated only to FN cross-sectional moment of inertia (r = 0.43; p < 0.01). This study suggests that 1-RM bench press and 1-RM leg press are positive determinants of BMD in elderly women.     

Abdominal Aortic Calcification,BMD, and Bone Microstructure: A Population‐Based Study

To better define the relationship between vascular calcification and bone mass/structure, we assessed abdominal aortic calcification (AAC), BMD, and bone microstructure in an age‐stratified, random sample of 693 Rochester, MN, residents. Participants underwent QCT of the spine and hip and high‐resolution pQCT (HRpQCT) of the radius to define volumetric BMD (vBMD) and microstructural parameters. AAC was quantified with the Agatston scoring method. In men, AAC correlated with lower vertebral trabecular and femoral neck vBMD (p < 0.001), but not after age or multivariable (age, body mass index, smoking status) adjustment. Separation into <50 and ≥50 yr showed this pattern only in the older men. BV/TV and Tb.Th inversely correlated with AAC in all men (p < 0.001), and Tb.Th remained significantly correlated after age adjustment (p < 0.05). Tb.N positively correlated with AAC in younger men (p < 0.001) but negatively correlated in older men (p < 0.001). The opposite was true with Tb.Sp (p = 0.01 and p < 0.001, respectively). Lower Tb.N and higher Tb.Sp correlated with AAC in older men even after multivariable adjustment. Among all women and postmenopausal women, AAC correlated with lower vertebral and femoral neck vBMD (p < 0.001) but not after adjustment. Lower BV/TV and Tb.Th correlated with AAC (p = 0.03 and p = 0.04, respectively) in women, but not after adjustment. Our findings support an age‐dependent association between AAC and vBMD. We also found that AAC correlates with specific bone microstructural parameters in older men, suggesting a possible common pathogenesis for vascular calcification and deterioration in bone structure. However, sex‐specific differences exist.     

Systemic effects of zoledronic acid in children with traumatic femoral head avascular necrosis and Legg–Calve–Perthes disease

Background: Intravenous bisphosphonate therapy is associated with preservation of femoral head sphericity and congruence in 77% of children with traumatic avascular necrosis. The aim was to describe the systemic effects of intravenous zoledronic acid (ZA) on bone and mineral metabolism in otherwise normal children and adolescents with femoral head AVN.Material and methods: 37 children (age 10.8 ± 2.76 years) diagnosed with avascular necrosis AVN (Slipped Capital Femoral Epiphysis (SCFE), N = 20 or Legg–Calve–Perthes disease (LCPD), N = 17) were treated with at least 12 months of ZA. Bone mineral density (BMD) by DXA, bone morphometry and mineral homeostasis were evaluated at baseline, 6, 12 and 18 months. Data was retrieved retrospectively.Results: All children maintained height SD during treatment. BMI SD increased in the SCFE subgroup during the first 12 month period. Bone age increased appropriately. Age adjusted total body BMD, lumbar spine BMD and lean tissue mass adjusted bone mineral content (BMC) Z-scores increased significantly over the 18 months of treatment. The LS.BMD increase was greater in LCPD than in SCFE leading to more individuals with LCPD having a LS.BMD_(age) Z-score over 2 SD at 12 months follow-up. Biochemical markers of bone turnover were decreased and PTH increased during the first 12 months of treatment and bone modeling was reduced. All markers stabilised over the next 6 months. There were no incidences of fracture, spondylolisthesis or osteonecrosis of the jaw.Conclusion: We here report that ZA in otherwise healthy children with femoral head AVN increases BMD – most pronounced in the LCPD group – and reduces bone modeling and turnover. Further efficacy and safety data are required before this therapy can be widely recommended.