Characteristics of bone metabolism markers during the healing of osteoporotic versus nonosteoporotic metaphyseal long bone fractures: a matched pair analysis

Purpose

The activity and metabolism of fracture healing can be monitored quantitatively by measuring bone turnover markers (BTMs) in serum or urine. However, in osteoporotic bone, the exact metabolism processes during the healing of metaphyseal fractures remain unknown. There is no diagnostic approach which currently allows dynamic insight into the fracture healing processes in order to monitor the progression of healing and to assist in therapeutic decision making.

Methods

Between March 2007 and February 2009, 30 patients over 50?years of age who suffered a metaphyseal fracture were included in our study. The levels of the osteoanabolic marker BAP (bone-specific alkaline phosphatase) and osteocatabolic marker β-CTX [crosslinked C-(CTX)-telopeptide-of-type-I-collagen] were monitored during the fracture healing of osteoporotic and nonosteoporotic fractures for a duration of 8?weeks.

Results

After an initial decrease of BAP in the first week, the BAP level steadily increased through the fourth week in both groups. The levels of BAP in the osteoporotic group surpassed the healthy group. β-CTX steadily increased in healthy bone up to the fourth week; in osteoporotic bone, β-CTX first increased and, thereafter, decreased from the first week onwards.

Conclusions

In this work, the first molecular biological aspects of osteoporotic fracture healing have been uncovered, helping to explain the mechanisms of delayed fracture healing in osteoporotic bone. The early decrease of reduced β-CTX as well as elevated BAP during the healing process may be the first aspects within the delayed healing of osteoporotic bone. Further studies are necessary in order to achieve more detailed insight to fracture healing and to ascertain the progression of fracture healing as being essential (criteria) for therapeutic decision making.     

血清脂质运载蛋白2、骨代谢指标与中年女性骨密度相关性研究

目的 观察血清脂质运载蛋白2 (lipocalin 2,LCN2)、骨代谢指标与中年女性骨密度的相关性。方法 分析253名汉族女性资料,通过双能X线吸收测定法测量其腰椎和股骨颈的骨密度（bone mineral density, BMD）,测量LCN2、I型胶原的羧基末端交联端肽(type I collage cross-linked-telopeptide, CTX)、骨钙蛋白(osteocalcin ,OCN)和肌酸酐(screatinine ,Scr)的血清水平。结果 LCN2与腰椎和股骨颈的BMD呈负相关。LCN2和CTX、OCN、年龄、Scr之间呈显著正相关。调整年龄和Scr后,LCN2、BMDs和OCN之间的相关性消失,但LCN2仍与CTX呈正相关。LCN2的血清浓度在有和没有骨质疏松性骨折的受试者之间没有显示出显著差异。在多变量回归分析中,LCN2是血清CTX变化的主要决定因素之一。结论 在中年女性中,血清LCN2水平、BMD和OCN之间的关系受到年龄和Scr的干扰。虽然LCN2与CTX呈正相关,但相关性非常小。     

Effects of denosumab on bone turnover markers in postmenopausal osteoporosis

Denosumab, a fully human monoclonal antibody to RANKL, decreases bone remodeling, increases bone density, and reduces fracture risk. This study evaluates the time course and determinants of bone turnover marker (BTM) response during denosumab treatment, the percentage of denosumab‐treated women with BTMs below the premenopausal reference interval, and the correlations between changes in BTMs and bone mineral density (BMD). The BTM substudy of the Fracture REduction Evaulation of Denosumab in Osteoporosis every 6 Months (FREEDOM) Trial included 160 women randomized to subcutaneous denosumab (60 mg) or placebo injections every 6 months for 3 years. Biochemical markers of bone resorption (serum C‐telopeptide of type I collagen [CTX] and tartrate‐resistant acid phosphatise [TRACP‐5b]) and bone formation (serum procollagen type I N‐terminal propeptide [PINP] and bone alkaline phosphatase [BALP]) were measured at baseline and at 1, 6, 12, 24, and 36 months. Decreases in CTX were more rapid and greater than decreases in PINP and BALP. One month after injection, CTX levels in all denosumab‐treated subjects decreased to levels below the premenopausal reference interval. CTX values at the end of the dosing period were influenced by baseline CTX values and the dosing interval. The percentage of subjects with CTX below the premenopausal reference interval before each subsequent injection decreased from 79% to 51% during the study. CTX and PINP remained below the premenopausal reference interval at all time points in 46% and 31% denosumab‐treated subjects, respectively. With denosumab, but not placebo, there were significant correlations between CTX reduction and BMD increase (r = ?0.24 to ?0.44). The BTM response pattern with denosumab is unique and should be appreciated by physicians to monitor this treatment effectively. © 2011 American Society for Bone and Mineral Research.     

Relative contributions of bone density, bone turnover, and clinical risk factors to long-term fracture prediction.

Long-term fracture prediction using bone mineral density remains controversial, as does the additional contribution from assessing bone turnover or clinical risk factors. We measured bone mineral density at various sites, along with biochemical markers of bone turnover, sex steroid levels, and over 100 clinical variables, at baseline on an age-stratified sample of 304 Rochester, MN women in 1980. The 225 postmenopausal women were subsequently followed for 3146 person-years (median, 16.2 years per subject), wherein they experienced 302 new fractures: 81% resulted from minimal or moderate trauma and 60% of these involved the proximal femur, thoracic or lumbar vertebrae, or distal forearm. Accounting for multiple fractures per subject, these osteoporotic fractures together were best predicted by baseline femoral neck bone mineral density (age-adjusted hazard ratio [HR] per SD decrease, 1.37; 95% CI, 1.10-1.70); 19 moderate trauma forearm fractures were best predicted by distal radius bone mineral content, whereas 28 hip fractures and 100 vertebral fractures were best predicted by femoral neck bone mineral density. Femoral neck bone mineral density performed comparably in predicting osteoporotic fracture risk within the first decade of follow-up (HR, 1.38; 95% CI, 1.10-1.74) as well as more than 10 years after baseline (HR, 1.39; 95% CI, 1.05-1.84). The older biochemical markers were not associated with fractures, but serum "free" estradiol index was independently predictive of short- and long-term fracture risk. Consistent clinical risk factors were not identified, but statistical power was limited. Identifying patients at increased long-term risk of fracture is challenging, but it is reassuring that femoral neck bone mineral density can predict osteoporotic fractures up to 20 years later.     

Metaphyseal fracture healing in a sheep model of low turnover osteoporosis induced by hypothalamic–pituitary disconnection (HPD)

We recently established a large animal model of osteoporosis in sheep using hypothalamic–pituitary disconnection (HPD). As central regulation is important for bone metabolism, HPD‐sheep develop severe osteoporosis because of low bone turnover. In this study we investigated metaphyseal fracture healing in HPD‐sheep. To elucidate potential pathomechanisms, we included a treatment group receiving thyroxine T4 and 17β‐estradiol. Because clinically osteoporotic fractures often occur in the bone metaphysis, HPD‐sheep and healthy controls received an osteotomy in the distal femoral condyle. Half of the HPD‐sheep were systemically treated with thyroxine T4 and 17β‐estradiol during the healing period. Fracture healing was evaluated after 8 weeks using pQCT, µCT, and histomorphometrical analysis. Bone mineral density (BMD) and bone volume/total volume (BV/TV) were considerably reduced by 30% and 36%, respectively, in the osteotomy gap of the HPD‐sheep compared to healthy sheep. Histomorphometry also revealed a decreased amount of newly formed bone (?29%) and some remaining cartilage in the HPD‐group, suggesting that HPD disturbed fracture healing. Thyroxine T4 and 17β‐estradiol substitution considerably improved bone healing in the HPD‐sheep. Our results indicate that fracture healing requires central regulation and that thyroxine T4 and 17β‐estradiol contribute to the complex pathomechanisms of delayed metaphyseal bone healing in HPD‐sheep. © 2013 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:1851–1857, 2013

     

The challenges of promoting osteogenesis in segmental bone defects and osteoporosis

Conventional clinical management of complex bone healing scenarios continues to result in 5–10% of fractures forming non‐unions. Additionally, the aging population and prevalence of osteoporosis‐related fractures necessitate the further exploration of novel ways to augment osteogenesis in this special population. This review focuses on the current clinical modalities available, and the ongoing clinical and pre‐clinical research to promote osteogenesis in segmental bone defects, delayed unions, and osteoporosis. In summary, animal models of fracture repair are often small animals as historically significant large animal models, like the dog, continue to gain favor as companion animals. Small rodents have well‐documented limitations in comparing to fracture repair in humans, and few similarities exist. Study design, number of studies, and availability of funding continue to limit large animal studies. Osteoinduction with rhBMP‐2 results in robust bone formation, although long‐term quality is scrutinized due to poor bone mineral quality. PTH 1‐34 is the only FDA approved osteo‐anabolic treatment to prevent osteoporotic fractures. Limited to 2 years of clinical use, PTH 1‐34 has further been plagued by dose‐related ambiguities and inconsistent results when applied to pathologic fractures in systematic human clinical studies. There is limited animal data of PTH 1‐34 applied locally to bone defects. Gene therapy continues to gain popularity among researchers to augment bone healing. Non‐integrating viral vectors and targeted apoptosis of genetically modified therapeutic cells is an ongoing area of research. Finally, progenitor cell therapies and the content variation of patient‐side treatments (e.g., PRP and BMAC) are being studied. © 2017 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 36:1559–1572, 2018.     

Osteoporosis influences the early period of fracture healing in a rat osteoporotic model

Osteoporotic fractures commonly occur in the elderly. Although current therapies are aimed at the prevention and treatment of osteoporotic fractures, studies examing the fracture healing process in osteoporotic bone are limited. We produced an osteoporotic rat model by ovariectomy (ovx) and maintained a low calcium diet (LCD) in order to evaluate the influence of osteoporosis on fracture healing. Callus formation and strength was monitored over a 3 week period by histological and biomechanical assessment. Data collected simultaneously on a group of rats undergoing sham surgery (sx) were used for comparison. A 40% reduction in fracture callus cross-sectional area and a 23% reduction in bone mineral density in the healing femur of the ovx rats was observed on day 21 following fracture as compared with the sx group (p < 0.01). Biomechanical data from the healing femur of the ovx rats revealed a fivefold decrease in the energy required to break the fracture callus, a threefold decrease in peak failure load, a twofold decrease in stiffness and a threefold decrease in stress as compared with the sx group (p < 0.01, respectively). Histomorphological analysis revealed a delay in fracture callus healing with poor development of mature bone in the ovx rats. This study provides physical evidence of altered fracture healing in osteoporotic bone, which may have important implications in evaluating the effects of new treatments for osteoporosis on fracture healing.     

Effects of sclerostin antibody on healing of a non‐critical size femoral bone defect

Sclerostin is a glycoprotein secreted by osteocytes and inhibits osteoblastogenesis via inhibition of Wnt signaling. We hypothesized that sclerostin antibody (Scl‐AbIII) would accelerate the healing of a murine femoral non‐critical size bone defect model. A unilateral and unicortical 0.8 mm‐sized drill hole was made in the proximal femoral shaft of adult female nude mice. One group of mice received subcutaneous injections of Scl‐AbIII and a second group received vehicle only. Reporter MC3T3 osteoprogenitor cells were injected via the tail vein 3 days after surgery to monitor systemic trafficking of exogenous osteoprogenitors. Bioluminescence imaging (BLI), microcomputed tomography (microCT), micropositron emission tomography (microPET) and histological analysis were used to compare the bone healing responses to Scl‐AbIII treatment. Bone mineral density (BMD) significantly increased at the defect site after week 1, and was significantly higher in the treatment compared with the control group at all time points. This finding was also confirmed on histological analysis by increased deposition of new woven bone. MicroPET scanning showed a trend for greater activity in the control group at day 21 compared with the Scl‐AbIII group, indicating early bone maturation following treatment with Scl‐AbIII. Whereas the BLI signals derived from the injected osteoprogenitor cells showed no differences between vehicle and Scl‐AbIII treated groups, systemic migration of MC3T3 cells to the bone defect was clearly identified in both groups using immunohistochemistry. Systemic administration of Scl‐AbIII resulted in earlier healing and maturation of a non‐critical size bone defect. These findings underscore the potential use of Scl‐AbIII for treatment of complicated fractures, non‐unions, and other clinical scenarios. © 2012 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 31:155–163, 2012     

Women with previous stress fractures show reduced bone material strength

Background and purpose — Bone fragility is determined by bone mass, bone architecture, and the material properties of bone. Microindentation has been introduced as a measurement method that reflects bone material properties. The pathogenesis of underlying stress fractures, in particular the role of impaired bone material properties, is still poorly understood. Based on the hypothesis that impaired bone material strength might play a role in the development of stress fractures, we used microindentation in patients with stress fractures and in controls.

Patients and methods — We measured bone material strength index (BMSi) by microindentation in 30 women with previous stress fractures and in 30 normal controls. Bone mineral density by DXA and levels of the bone markers C-terminal cross-linking telopeptide of type-1 collagen (CTX) and N-terminal propeptide of type-1 procollagen (P1NP) were also determined.

Results — Mean BMSi in stress fracture patients was significantly lower than in the controls (SD 72 (8.7) vs. 77 (7.2); p = 0.02). The fracture subjects also had a significantly lower mean bone mineral density (BMD) than the controls (0.9 (0.02) vs. 1.0 (0.06); p = 0.03). Bone turnover—as reflected in serum levels of the bone marker CTX—was similar in both groups, while P1NP levels were significantly higher in the women with stress fractures (55?μg/L vs. 42?μg/L; p = 0.03). There was no correlation between BMSi and BMD or bone turnover.

Interpretation — BMSi was inferior in patients with previous stress fracture, but was unrelated to BMD and bone turnover. The lower values of BMSi in patients with previous stress fracture combined with a lower BMD may contribute to the increased propensity to develop stress fractures in these patients.     

Mechanical property and tissue mineral density differences among severely suppressed bone turnover (SSBT) patients, osteoporotic patients, and normal subjects

Pathogenesis of atypical fractures in patients on long term bisphosphonate therapy is poorly understood, and the type, the manner in which they occur and the fracture sites are quite different from the usual osteoporotic fractures. We hypothesized that the tissue-level mechanical properties and mean degree of mineralization of the iliac bone would differ among 1) patients with atypical fractures and severely suppressed bone turnover (SSBT) associated with long-term bisphosphonate therapy, 2) age-matched, treatment-na?ve osteoporotic patients with vertebral fracture, 3) age-matched normals and 4) young normals. Large differences in tissue-level mechanical properties and/or mineralization among these groups could help explain the underlying mechanism(s) for the occurrence of typical osteoporotic and the atypical femoral shaft fractures. Elastic modulus, contact hardness, plastic deformation resistance, and tissue mineral densities of cortical and trabecular bone regions of 55 iliac bone biopsies--12 SSBT patients (SSBT; aged 49-77), 11 age-matched untreated osteoporotic patients with vertebral fracture (Osteoporotic), 12 age-matched subjects without bone fracture (Age-Matched Normal), and 20 younger subjects without bone fracture (Young Normal)--were measured using nanoindentation and quantitative backscattered electron microscopy. For cortical bone nanoindentation properties, only plastic deformation resistance was different among the groups (p<0.05), with greater resistance to plastic deformation in the SSBT group compared to all other groups. For trabecular bone, all nanoindentation properties and mineral density of the trabecular bone were different among the groups (p<0.05). The SSBT group had greater plastic deformation resistance and harder trabecular bone compared to the other three groups, stiffer bone compared to the Osteoporotic and Young Normal groups, and a trend of higher mineral density compared to the Age-Matched Normal and Osteoporotic groups. Lower heterogeneity of modulus and contact hardness for cortical bone of the SSBT and trabecular bone of the Osteoporotic fracture groups, respectively, compared to the non-fractured groups, may contribute to fracture susceptibility due to lowered ability to prevent crack propagation. We tentatively conclude that, in addition to extremely low bone formation rate, atypical fractures in SSBT and/or long-term bisphosphonate treatment may be associated with greater mean plastic deformation resistance properties and less heterogeneous elastic properties of the bone.     

绝经后女性骨质疏松性椎体骨折与腰椎体骨密度的相关性

随着我国步入老龄化社会,骨质疏松症的患病率明显升高。骨质疏松症最严重的危害来自骨质疏松性骨折,绝经后女性尤其多见。由于脊柱独特的解剖学和生物力学特点,骨质疏松患者更易发生椎体骨折。骨密度测量是诊断骨质疏松的金标准。本文通过回顾近年来相关文献,探讨腰椎体骨密度检测对绝经后女性骨质疏松性椎体骨折的意义,发现:绝经后骨质疏松性椎体骨折患者的BMD水平比绝经后骨质疏松症但无脊椎骨折者明显减少;绝经后骨质疏松症患者的BMD水平越低,其发生椎体骨折的风险越高;有椎体骨折史的绝经后骨质疏松症患者的BMD水平与发生再次椎体骨折的风险呈负相关。药物干预通常可明显提高绝经后骨质疏松症患者的BMD水平,同时还可减少椎体骨折的发生。尚存在一些不足:腰椎骨密度可能出现假性增高;需进一步探讨预测骨质疏松性椎体骨折的骨密度阈值;药物干预的研究中BMD水平与椎体骨折发生的相关性并没有得到深入研究;缺少大规模的绝经后骨质疏松性椎体骨折的流行病学,现有研究也大都存在病例收集方法不规范、样本量小、年龄分布存在差异等不足。对绝经后骨质疏松性椎体骨折的深入研究需要多学科共同协作。     

Prediction of Incident Major Osteoporotic and Hip Fractures by Trabecular Bone Score (TBS) and Prevalent Radiographic Vertebral Fracture in Older Men

Trabecular bone score (TBS) has been shown to predict major osteoporotic (clinical vertebral, hip, humerus, and wrist) and hip fractures in postmenopausal women and older men, but the association of TBS with these incident fractures in men independent of prevalent radiographic vertebral fracture is unknown. TBS was estimated on anteroposterior (AP) spine dual‐energy X‐ray absorptiometry (DXA) scans obtained at the baseline visit for 5979 men aged ≥65 years enrolled in the Osteoporotic Fractures in Men (MrOS) Study and its association with incident major osteoporotic and hip fractures estimated with proportional hazards models. Model discrimination was tested with Harrell's C‐statistic and with a categorical net reclassification improvement index, using 10‐year risk cutpoints of 20% for major osteoporotic and 3% for hip fractures. For each standard deviation decrease in TBS, there were hazard ratios of 1.27 (95% confidence interval [CI] 1.17 to 1.39) for major osteoporotic fracture, and 1.20 (95% CI 1.05 to 1.39) for hip fracture, adjusted for FRAX with bone mineral density (BMD) 10‐year fracture risks and prevalent radiographic vertebral fracture. In the same model, those with prevalent radiographic vertebral fracture compared with those without prevalent radiographic vertebral fracture had hazard ratios of 1.92 (95% CI 1.49 to 2.48) for major osteoporotic fracture and 1.86 (95% CI 1.26 to 2.74) for hip fracture. There were improvements of 3.3%, 5.2%, and 6.2%, respectively, of classification of major osteoporotic fracture cases when TBS, prevalent radiographic vertebral fracture status, or both were added to FRAX with BMD and age, with minimal loss of correct classification of non‐cases. Neither TBS nor prevalent radiographic vertebral fracture improved discrimination of hip fracture cases or non‐cases. In conclusion, TBS and prevalent radiographic vertebral fracture are associated with incident major osteoporotic fractures in older men independent of each other and FRAX 10‐year fracture risks, and these data support their use in conjunction with FRAX for fracture risk assessment in older men. © 2015 American Society for Bone and Mineral Research.     

Fracture healing in osteoporotic fractures: is it really different? A basic science perspective

Osteoporosis is a major health problem characterized by compromised bone strength that predisposes patients to an increased risk of fracture. Osteoporotic patients differ from normal subjects in bone mineral composition, bone mineral content, and crystallinity. Poor bone quality in patients with osteoporosis presents the surgeon with difficult treatment decisions. Much effort has been expended on improving therapies that are expected to preserve bone mass and thus decrease fracture risk. Manipulation of both the local fracture environment in terms of application of growth factors, scaffolds and mesenchymal cells, and systemic administration of agents promoting bone formation and bone strength has been considered as a treatment option from which promising results have recently been reported. Surprisingly, less importance has been given to investigating fracture healing in osteoporosis. Fracture healing is a complex process of bone regeneration, involving a well-orchestrated series of biological events that follow a definable temporal and spatial sequence that may be affected by both biological factors, such as age and osteoporosis, and mechanical factors such as stability of the osteosynthesis. Current studies mainly focus on preventing osteoporotic fractures. In recent years, the literature has provided evidence of altered fracture healing in osteoporotic bone, which may have important implications in evaluating the effects of new osteoporosis treatments on fracture healing. However, the mechanics of this influence of osteoporosis on fracture healing have not yet been clarified and clinical evidence is still lacking.     

骨转换标志物CTX-1和PINP预测骨质疏松骨折的研究进展

骨质疏松性骨折作为老年人群中的常见病,已成为全球性公共卫生问题,但目前对其发生风险的预测方法有限且准确度不足。近期研究发现骨转换标志物可能对预测骨质疏松性骨折发生有应用前景,现综述近年来有关骨转换标志物(CTX-1和PINP)对骨质疏松性骨折风险预测的研究进展,为临床筛查骨质疏松性骨折发生的高风险人群提供新思维。     

Relationship of early changes in bone resorption to the reduction in fracture risk with risedronate.

Changes in the level of biochemical markers of bone resorption with risedronate treatment for osteoporosis were examined as a surrogate for the decrease in fracture risk. Greater decreases in bone resorption markers were associated with greater decreases in vertebral (and nonvertebral) fractures. Antifracture efficacy of antiresorptive therapies is only partially explained by increases in bone mineral density. Early decreases in bone resorption may also play a role. We tested this hypothesis by measuring two bone resorption markers, the C-telopeptide of type I collagen (CTX) and the N-telopeptide of type I collagen (NTX), in osteoporotic patients in risedronate vertebral fracture trials. We studied 693 women with at least one vertebral deformity (mean age, 69 +/- 7 years) who received calcium (and vitamin D if required) and placebo or risedronate 5 mg daily for 3 years. The reductions in urinary CTX (median, 60%) and NTX (51%) at 3-6 months with risedronate therapy were significantly associated (p < 0.05) with the reduction in vertebral fracture risk (75% over 1 year and 50% over 3 years). The changes in both CTX and NTX accounted for approximately one-half (CTX, 55%; NTX, 49%) of risedronate's effect in reducing the risk of vertebral fractures in the first year and approximately two-thirds (CTX, 67%; NTX, 66%) over 3 years compared with placebo. The changes in CTX and NTX accounted for 77% and 54%, respectively, of risedronate's effect in reducing the risk of nonvertebral fractures over 3 years compared with placebo. The relationships between vertebral fracture risk and changes from baseline in CTX and NTX were not linear (p < 0.05). There was little further improvement in fracture benefit below a decrease of 55-60% for CTX and 35-40% for NTX. The decrease in bone resorption in patients taking risedronate accounts for a large proportion of the reduction in fracture risk. There may be a level of bone resorption reduction below which there is no further fracture benefit.     

Biochemical markers of bone turnover, endogenous hormones and the risk of fractures in postmenopausal women: the OFELY study.

The mechanisms leading to increased bone loss and skeletal fragility in women with postmenopausal osteoporosis are still poorly understood. Increased bone resorption, low serum estradiol and high serum sex-hormone-binding globulin (SHBG) recently have been reported as predictors of vertebral and hip fractures in elderly women. In a cohort of healthy untreated younger postmenopausal women aged 50-89 years (mean, 64 years), we compared baseline levels of bone markers and endogenous hormones in 55 women who subsequently had a fracture (20 vertebral and 35 peripheral fractures) with levels in the 380 women who did not fracture during a mean 5 years of follow-up. Women with levels in the highest quartile of four bone resorption markers including urinary-free deoxypyridinoline (D-Pyr), urinary type I collagen N-telopeptides (NTX), and urinary and serum type I collagen C-telopeptides (CTX) had about a 2-fold increased risk of fractures compared with women with levels in the three lowest quartiles with relative risk (RR) and 95% CI of 1.8 (1.0-3.4) for free D-Pyr, 1.7 (0.9-3.2) for urinary NTX, 2.3 (1.3-4.1) for urinary CTX, and 2.1 (1.2-3.8) for serum CTX. Serum levels of bone alkaline phosphatase (BAP) in the highest quartile were associated with an RR of fracture of 2.4 (1.3-4.2). Women with serum levels of estradiol and dehydroepiandrosterone (DHEA) sulfate in the lowest quartile had an RR of fracture of 2.2 (1.2-4.0) and 2.1 (1.2-3.8), respectively. Increased levels of SHBG and intact parathyroid hormone (PTH) were moderately associated with an increased risk of fracture. Similar results were obtained when the analysis was restricted to symptomatic vertebral and nonvertebral fractures. Adjustment of biochemical markers by hormone levels did not significantly alter the results. Women with both high bone resorption markers and low estradiol (or low DHEA sulfate) had a higher risk of fracture with RRs of 3.0-3.3 (p < 0.001). After adjustment for bone mineral density (BMD) of the hip, spine, radius, or total body, bone markers and hormones were still predictive of fracture risk with similar RRs. We conclude that high levels of some biochemical markers of bone turnover, low serum estradiol, low DHEA sulfate, high SHBG, and high PTH are associated with increased risk of osteoporotic fracture in postmenopausal women, independently of each other and of BMD. The mechanism by which some postmenopausal women have an increased rate of bone turnover leading to an increased risk of fracture remains to be elucidated.     

Influence of defective bone marrow osteogenesis on fracture repair in an experimental model of senile osteoporosis

Bone marrow osteogenesis in senile osteoporotic bone is impaired and, as such, may have significant implications on the successful outcome of fracture repair. Here we utilize a well‐established murine model of senile osteoporosis, the P6 strain of senescence‐accelerated mice (SAMP6), to investigate fracture healing in aged osteoporotic bone. A femoral osteotomy was created in SAMP6 and in non‐osteoporotic age‐matched control R1 senescence‐resistant mice (SAMR1). The course of fracture healing was evaluated over a period of 42 days using quantitative µCT and histological analysis. The differentiation capabilities of bone mesenchymal progenitor cells derived from SAMP6 and SAMR1 mice was examined, and their osteogenic potential determined. Although preliminary in vitro analysis confirmed that bone marrow‐derived stem cells (BMSC) isolated from SAMP6 mice had a reduced osteogenic capacity, no significant deficit in fracture repair as determined by quantitative µCT could be detected. This was supported by histology assessment, where complete bridging of the fracture gap was evident by day 28 and was fully healed day 42 in both SAMP6 and SAMR1 mice. Further in vitro studies revealed that periosteal‐derived progenitor cells (PDPC) isolated from SAMP6 mice had an osteogenic potential comparable to that observed in SAMR1 mice. In conclusion, fracture healing in SAMP6 mice is not detrimentally affected by impairment of BMSC osteogenesis, suggesting that bone marrow‐mediated repair processes are dispensable for normal bone healing in this senile osteoporotic fracture model. Furthermore, the influence of PDPC in the repair process may partly explain the absence of any detectable deficits in fracture repair in SAMP6 mice. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:798–804, 2010     

Micro‐CT analysis with multiple thresholds allows detection of bone formation and resorption during ultrasound‐treated fracture healing

Multiple threshold algorithms applied to microcomputed tomography analysis were used to probe the effects of low‐intensity pulsed ultrasound on fracture healing. Rat femurs were fractured in accordance with IACUC guidelines. Ultrasound treatment was administered daily to one femur; the contralateral bone was treated with a sham transducer. Each week for 3 weeks healing fractures were harvested and scanned by micro‐CT. Remodeling activity was confirmed by evaluation of TRAP activity. Using thresholds of 331–700 and 225–330, area of cortical bone, and new bone formation, respectively, were identified, and by inference, regions of bone resorption. The increased sensitivity of this multithresholding procedure revealed that ultrasound treatment significantly increased the rate of fracture healing in vivo by activating both new bone formation and by increasing the removal of cortical bone in a time‐ and site‐specific manner. At week 1, compared to the proximal side, there was a significant increase in new bone formation distal to the fracture site. Removal of the existing cortical bone followed the same pattern at week 2. Results of the study indicate that at sites of bone turnover, this multithresholding analytical technique can be used to provide quantitative information on bone formation, as well as resorption. © 2008 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 27: 673–679, 2009     

Elevated levels of macrophage colony‐stimulating factor in human fracture healing

Macrophage colony‐stimulating factor (M‐CSF) plays a unique role in bone remodeling. However, to our knowledge, no data on the role of M‐CSF in fracture healing in humans have been published so far. This study addressed this issue. One hundred and thirteen patients with long‐bone fractures were included in the study and divided into two groups, according to their course of fracture healing. The first group contained 103 patients with normal fracture healing. Ten patients with impaired fracture healing formed the second group of the study. Volunteers donated blood samples as control. Serum samples were collected over a period of 6 months, following a standardized time schedule. In addition, M‐CSF levels were measured in fracture hematoma and serum of 11 patients with bone fractures. M‐CSF concentrations were measured by enzyme‐linked immunosorbent assay (ELISA). Fracture hematoma contained significantly higher M‐CSF concentrations compared to M‐CSF concentrations in patient's serum. M‐CSF levels in fracture hematoma and in patient's serum were both significantly higher than M‐CSF concentrations measured in serum of healthy controls. Highly elevated M‐CSF serum concentrations were found in patients with physiological fracture healing over the entire observation period. Significant differences in the M‐CSF serum concentration between patients with normal fracture healing and patients with impaired fracture healing were not observed. This study indicates, for the first time, to our knowledge, a possible local and systemic involvement of M‐CSF in humans during fracture healing. © 2009 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 28:671–676, 2010     

Spatial Differences in the Distribution of Bone Between Femoral Neck and Trochanteric Fractures

There is little knowledge about the spatial distribution differences in volumetric bone mineral density and cortical bone structure at the proximal femur between femoral neck fractures and trochanteric fractures. In this case‐control study, a total of 93 women with fragility hip fractures, 72 with femoral neck fractures (mean ± SD age: 70.6 ± 12.7 years) and 21 with trochanteric fractures (75.6 ± 9.3 years), and 50 control subjects (63.7 ± 7.0 years) were included for the comparisons. Differences in the spatial distributions of volumetric bone mineral density, cortical bone thickness, cortical volumetric bone mineral density, and volumetric bone mineral density in a layer adjacent to the endosteal surface were investigated using voxel‐based morphometry (VBM) and surface‐based statistical parametric mapping (SPM). We compared these spatial distributions between controls and both types of fracture, and between the two types of fracture. Using VBM, we found spatially heterogeneous volumetric bone mineral density differences between control subjects and subjects with hip fracture that varied by fracture type. Interestingly, femoral neck fracture subjects, but not subjects with trochanteric fracture, showed significantly lower volumetric bone mineral density in the superior aspect of the femoral neck compared with controls. Using surface‐based SPM, we found that compared with controls, both fracture types showed thinner cortices in regions in agreement with the type of fracture. Most outcomes of cortical and endocortical volumetric bone mineral density comparisons were consistent with VBM results. Our results suggest: 1) that the spatial distribution of trabecular volumetric bone mineral density might play a significant role in hip fracture; 2) that focal cortical bone thinning might be more relevant in femoral neck fractures; and 3) that areas of reduced cortical and endocortical volumetric bone mineral density might be more relevant for trochanteric fractures in Chinese women. © 2017 American Society for Bone and Mineral Research.