Hormonal Control of Bone Architecture Throughout the Lifespan: Implications for Fracture Prediction and Prevention.

BACKGROUND: Skeletal modeling in childhood and adolescence and continuous remodeling throughout the lifespan are designed to adapt to a changing environment and resist external forces and fractures. The flux of sex steroids in men and women, beginning from fetal development and evolving through infancy, childhood, puberty, young adulthood, peri/menopause transition, and postmenopause, is critical for bone size, peak bone mass, and fracture resistance. OBJECTIVE: This review will highlight how changes in sex steroids throughout the lifespan affect bone cells and the consequence of these changes on bone architecture and strength. METHODS: Literature review and discussion. RESULTS: The contributions of estrogen and testosterone on skeletal development have been difficult to study due to the reciprocal and intertwining contributions of one on the other. Although orchiectomy in men renders circulating testosterone absent, circulating estrogen also declines due to testosterone being the substrate for estradiol. The discovery of men with absent estradiol or resistance to estrogen and the study of mouse models led to the understanding that estrogen has a larger direct role in skeletal development and maintenance in men and women. The mechanistic reason for larger bone size in men is incompletely understood but related to indirect effects of testosterone on the skeleton, such as higher muscle mass leading to larger mechanical loading. Declines in sex steroids during menopause in women and androgen deprivation therapies in men have profound and negative effects on the skeleton. Therapies to prevent such bone loss are available, but how such therapies can be tailored based on bone size and architecture remains an area of investigation. CONCLUSION: In this review, the elegant interplay and contribution of sex steroids on bone architecture in men and women throughout the lifespan is described.

Structural differences contributing to sex-specific associations between FN BMD and whole-bone strength for adult White women and men.

Hip areal BMD (aBMD) is widely used to identify individuals with increased fracture risk. Low aBMD indicates low strength, but this association differs by sex with men showing greater strength for a given aBMD than women. To better understand the structural basis giving rise to this sex-specific discrepancy, cadaveric proximal femurs from White female and male donors were imaged using nano-CT and loaded in a sideways fall configuration to assess strength. FN pseudoDXA images were generated to identify associations among structure, aBMD, and strength that differ by sex. Strength correlated significantly with pseudoDXA aBMD for females (R2 = 0.468, P < .001) and males (R2 = 0.393, P < .001), but the elevations (y-intercepts) of the linear regressions differed between sexes (P < .001). Male proximal femurs were 1045 N stronger than females for a given pseudoDXA aBMD. However, strength correlated with pseudoDXA BMC for females (R2 = 0.433, P < .001) and males (R2 = 0.443, P < .001) but without significant slope (P = .431) or elevation (P = .058) differences. Dividing pseudoDXA BMC by FN-width, total cross-sectional area, or FN-volume led to significantly different associations between strength and the size-adjusted BMC measures for women and men. Three structural differences were identified that differentially affected aBMD and strength for women and men: First, men had more bone mass per unit volume than women; second, different cross-sectional shapes resulted in larger proportions of bone mass orthogonal to the DXA image for men than women; and third, men and women had different proportions of cortical and trabecular bone relative to BMC. Thus, the proximal femurs of women were not smaller versions of men but were constructed in fundamentally different manners. Dividing BMC by a bone size measure was responsible for the sex-specific associations between hip aBMD and strength. Thus, a new approach for adjusting measures of bone mass for bone size and stature is warranted.

A skeleton in a huff: insights in etiologies of osteosclerosis.

A 30-yr-old man developed right lower leg pain and a palpable solid mass. Radiographic imaging revealed a periosteal reaction with an exostotic mass arising from the right distal fibula. Generalized skeletal osteosclerosis with periosteal reaction was discovered on a radiographic skeletal survey. A biopsy of the right fibular mass revealed reactive woven bone. The patient was referred to a metabolic bone disease clinic, where laboratory values were consistent with secondary hyperparathyroidism and increased bone turnover. A DXA bone density scan revealed high bone density, with an L1-4 spine Z-score of +9.3, a left femoral neck Z-score of +8.5, and a total hip Z-score of +6.5. A dental exam revealed generalized gingival inflammation, teeth mobility, generalized horizontal alveolar bone loss and widening of the periodontal ligament space, increased bone density around the teeth, and thickening of the radicular lamina dura. An extensive evaluation was performed, with the result of a single test revealing the diagnosis. The differential diagnoses of osteosclerosis affecting the skeleton, teeth, and oral cavity are discussed.

A 30-yr-old man developed, over a short period, pain in his lower right leg accompanied by a hard mass. He also reported weight loss and night sweats for the past 6 months. After evaluation by his primary physician, an X-ray was ordered that reported a bony mass arising from the right fibula bone. A biopsy was performed of the mass, but no evidence of cancer or any other specific abnormality was found. The patient was then referred to a bone disease specialty clinic. Laboratory tests revealed a large increase in how quickly the patient's skeleton was remodeling, affecting the balance of bone formation and removal involved in maintaining a healthy skeleton. A bone density scan reported that the patient had very dense bones. Other unusual changes were also discovered in a dental exam, suggesting bone thickening. After an extensive evaluation, a single blood test revealed the cause of the fibular bone mass and dense bones.

Perspective: A multi-trait integrative approach to understanding the structural basis of bone fragility for pediatric conditions associated with abnormal bone development.

Bone development is a highly orchestrated process that establishes the structural basis of bone strength during growth and functionality across the lifespan. This developmental process is generally robust in establishing mechanical function, being adaptable to many genetic and environmental factors. However, not all factors can be fully accommodated, leading to abnormal bone development and lower bone strength. This can give rise to early-onset bone fragility that negatively impacts bone strength across the lifespan. Current guidelines for assessing bone strength include measuring bone mineral density, but this does not capture the structural details responsible for whole bone strength in abnormally developing bones that would be needed to inform clinicians on how and when to treat to improve bone strength. The clinical consequence of not operationalizing how altered bone development informs decision making includes under-detection and missed opportunities for early intervention, as well as a false positive diagnosis of fragility with possible resultant clinical actions that may actually harm the growing skeleton. In this Perspective, we emphasize the need for a multi-trait, integrative approach to better understand the structural basis of bone growth for pediatric conditions with abnormal bone development. We provide evidence to showcase how this approach might reveal multiple, unique ways in which bone fragility develops across and within an array of pediatric conditions that are associated with abnormal bone development. This Perspective advocates for the development of new translational research aimed at informing better ways to optimize bone growth, prevent fragility fractures, and monitor and treat bone fragility based on the child's skeletal needs.

Treatment of Hypercalcemia of Malignancy in Adults: An Endocrine Society Clinical Practice Guideline.

BACKGROUND: Hypercalcemia of malignancy (HCM) is the most common metabolic complication of malignancies, but its incidence may be declining due to potent chemotherapeutic agents. The high mortality associated with HCM has declined markedly due to the introduction of increasingly effective chemotherapeutic drugs. Despite the widespread availability of efficacious medications to treat HCM, evidence-based recommendations to manage this debilitating condition are lacking. OBJECTIVE: To develop guidelines for the treatment of adults with HCM. METHODS: A multidisciplinary panel of clinical experts, together with experts in systematic literature review, identified and prioritized 8 clinical questions related to the treatment of HCM in adult patients. The systematic reviews (SRs) queried electronic databases for studies relevant to the selected questions. The Grading of Recommendations Assessment, Development and Evaluation (GRADE) methodology was used to assess the certainty of evidence and make recommendations. An independent SR was conducted in parallel to assess patients' and physicians' values and preferences, costs, resources needed, acceptability, feasibility, equity, and other domains relevant to the Evidence-to-Decision framework as well as to enable judgements and recommendations. RESULTS: The panel recommends (strong recommendation) in adults with HCM treatment with denosumab (Dmab) or an intravenous (IV) bisphosphonate (BP). The following recommendations were based on low certainty of the evidence. The panel suggests (conditional recommendation) (1) in adults with HCM, the use of Dmab rather than an IV BP; (2) in adults with severe HCM, a combination of calcitonin and an IV BP or Dmab therapy as initial treatment; and (3) in adults with refractory/recurrent HCM despite treatment with BP, the use of Dmab. The panel suggests (conditional recommendation) the addition of an IV BP or Dmab in adult patients with hypercalcemia due to tumors associated with high calcitriol levels who are already receiving glucocorticoid therapy but continue to have severe or symptomatic HCM. The panel suggests (conditional recommendation) in adult patients with hypercalcemia due to parathyroid carcinoma, treatment with either a calcimimetic or an antiresorptive (IV BP or Dmab). The panel judges the treatments as probably accessible and feasible for most recommendations but noted variability in costs, resources required, and their impact on equity. CONCLUSIONS: The panel's recommendations are based on currently available evidence considering the most important outcomes in HCM to patients and key stakeholders. Treatment of the primary malignancy is instrumental for controlling hypercalcemia and preventing its recurrence. The recommendations provide a framework for the medical management of adults with HCM and incorporate important decisional and contextual factors. The guidelines underscore current knowledge gaps that can be used to establish future research agendas.

Five-year risk of fracture and subsequent fractures among adults with cerebral palsy.

Background: Epidemiologic evidence documenting the incidence of fracture and subsequent fractures among adults with cerebral palsy (CP) is lacking, which could inform fracture prevention efforts. The objective was to characterize the 5-year rate of initial and subsequent fragility fractures among adults with CP. Methods: This retrospective cohort study used Medicare claims from 01/01/2008-12/31/2019 from adults ≥18 years old with CP (n = 44,239) and elderly ≥65 years old without CP (n = 2,176,463) as a comparison. The incidence rate (IR), IR ratio (IRR), and site distribution were estimated for the initial and subsequent fragility fractures over 5-years by sex and age. Results: The IR of fragility fracture at any site over the 5-year follow-up was similar for 18-30-year-old men with CP (IR = 5.2; 95%CI = 4.4-5.9) and 30-34-year-old women with CP (IR = 6.3; 95%CI = 5.3-7.2) compared to the same sex youngest-old (65-74 years old) without CP (IRR = 1.09 and 0.94, respectively, both P > 0.05), and increased with older age for those with CP. The number of fragility fractures and IR of subsequent fragility fractures was similar for young men and middle-aged women with CP compared to elderly without CP, and increased with older age for those with CP. The proportion of fragility fracture at the tibia/fibula decreased while the vertebral column and multiple simultaneous sites (most involved hip/lower extremities) increased with older age. Conclusion: Young and middle-aged adults with CP had similar-to-worse initial and subsequent fragility fracture profiles compared to the general elderly population- a well characterized group for bone fragility. Findings emphasize the need for fracture prevention efforts at younger ages for CP, possibly by ~5 decades younger.

Differential immune landscapes in appendicular versus axial skeleton.

Roughly 400,000 people in the U.S. are living with bone metastases, the vast majority occurring in the spine. Metastases to the spine result in fractures, pain, paralysis, and significant health care costs. This predilection for cancer to metastasize to the bone is seen across most cancer histologies, with the greatest incidence seen in prostate, breast, and lung cancer. The molecular process involved in this predilection for axial versus appendicular skeleton is not fully understood, although it is likely that a combination of tumor and local micro-environmental factors plays a role. Immune cells are an important constituent of the bone marrow microenvironment and many of these cells have been shown to play a significant role in tumor growth and progression in soft tissue and bone disease. With this in mind, we sought to examine the differences in immune landscape between axial and appendicular bones in the normal noncancerous setting in order to obtain an understanding of these landscapes. To accomplish this, we utilized mass cytometry by time-of-flight (CyTOF) to examine differences in the immune cell landscapes between the long bone and vertebral body bone marrow from patient clinical samples and C57BL/6J mice. We demonstrate significant differences between immune populations in both murine and human marrow with a predominance of myeloid progenitor cells in the spine. Additionally, cytokine analysis revealed differences in concentrations favoring a more myeloid enriched population of cells in the vertebral body bone marrow. These differences could have clinical implications with respect to the distribution and permissive growth of bone metastases.

Clinical bone health among adults with cerebral palsy: moving beyond assessing bone mineral density alone.

AIM: To understand associations among bone mineral density (BMD), bone mineral content (BMC), and bone area, and their association with fractures in adults with cerebral palsy (CP). METHOD: This retrospective cohort study included 78 adults with CP with a hip dual energy X-ray absorptiometry (DXA) from 1st December 2012 to 3rd May 2021 performed at the University of Michigan. Data-driven logistic regression techniques identified which, if any, DXA-derived bone traits (e.g. age/sex/ethnicity-based z-scores) were associated with fracture risk by sex and severity of CP. BMC-area associations were examined to study the structural mechanisms of fragility. RESULTS: Femoral neck area was associated with lower age-adjusted odds ratios (ORs) of fracture history (OR 0.72; 95% confidence interval [CI] 0.49-1.06; p=0.098), while higher BMD was associated with higher odds of incident fracture (OR 3.08; 95% CI 1.14-8.33; p=0.027). Females with fracture had lower area than females without fracture but similar BMC, whereas males with fracture had larger area and higher BMC than males without fracture. The paradoxical BMD-fracture association may be due to artificially elevated BMD from BMC-area associations that differed between females and males (sex interaction, p˂0.05): males had higher BMC at lower area values and lower BMC at higher area values compared to females. INTERPRETATION: BMD alone may not be adequate to evaluate bone strength for adults with CP. Further research into associations (or integration) between BMC and area is needed.

Ca2+-independent phospholipase A2ß-derived PGE2 contributes to osteogenesis.

Bone modeling can be modulated by lipid signals such as arachidonic acid (AA) and its cyclooxygenase 2 (COX2) metabolite, prostaglandin E2 (PGE2), which are recognized mediators of optimal bone formation. Hydrolysis of AA from membrane glycerophospholipids is catalyzed by phospholipases A2 (PLA2s). We reported that mice deficient in the Ca2+- independent PLA2beta (iPLA2ß), encoded by Pla2g6, exhibit a low bone phenotype, but the cause for this remains to be identified. Here, we examined the mechanistic and molecular roles of iPLA2ß in bone formation using bone marrow stromal cells and calvarial osteoblasts from WT and iPLA2ß-deficient mice, and the MC3T3-E1 osteoblast precursor cell line. Our data reveal that transcription of osteogenic factors (Bmp2, Alpl, and Runx2) and osteogenesis are decreased with iPLA2ß-deficiency. These outcomes are corroborated and recapitulated in WT cells treated with a selective inhibitor of iPLA2 ß (10 µM S-BEL), and rescued in iPLA2ß-deficient cells by additions of 10 µM PGE2. Further, under osteogenic conditions we find that PGE2 production is through iPLA2ß activity and that this leads to induction of Runx2 and iPLA2ß transcription. These findings reveal a strong link between osteogenesis and iPLA2ß-derived lipids and raise the intriguing possibility that iPLA2ß-derived PGE2 participates in osteogenesis and in the regulation of Runx2 and also iPLA2ß.

Osteoblasts Generate Testosterone From DHEA and Activate Androgen Signaling in Prostate Cancer Cells.

Bone metastasis is a complication of prostate cancer in up to 90% of men afflicted with advanced disease. Therapies that reduce androgen exposure remain at the forefront of treatment. However, most prostate cancers transition to a state whereby reducing testicular androgen action becomes ineffective. A common mechanism of this transition is intratumoral production of testosterone (T) using the adrenal androgen precursor dehydroepiandrosterone (DHEA) through enzymatic conversion by 3ß- and 17ß-hydroxysteroid dehydrogenases (3ßHSD and 17ßHSD). Given the ability of prostate cancer to form blastic metastases in bone, we hypothesized that osteoblasts might be a source of androgen synthesis. RNA expression analyses of murine osteoblasts and human bone confirmed that at least one 3ßHSD and 17ßHSD enzyme isoform was expressed, suggesting that osteoblasts are capable of generating androgens from adrenal DHEA. Murine osteoblasts were treated with 100 nM and 1 µM DHEA or vehicle control. Conditioned media from these osteoblasts were assayed for intermediate and active androgens by liquid chromatography-tandem mass spectrometry. As DHEA was consumed, the androgen intermediates androstenediol and androstenedione were generated and subsequently converted to T. Conditioned media of DHEA-treated osteoblasts increased androgen receptor (AR) signaling, prostate-specific antigen (PSA) production, and cell numbers of the androgen-sensitive prostate cancer cell lines C4-2B and LNCaP. DHEA did not induce AR signaling in osteoblasts despite AR expression in this cell type. We describe an unreported function of osteoblasts as a source of T that is especially relevant during androgen-responsive metastatic prostate cancer invasion into bone. © 2021 American Society for Bone and Mineral Research (ASBMR). This article has been contributed to by US Government employees and their work is in the public domain in the USA.

Dura promotes metastatic potential in prostate cancer through the CXCR2 pathway.

PURPOSE: Spinal metastases are common in cancer. This preferential migration/growth in the spine is not fully understood. Dura has been shown to affect the surrounding microenvironment and promote cancer growth. Here, we investigate the role of dural cytokines in promoting the metastatic potential of prostate cancer (PCa) and the involvement of the CXCR2 signaling pathway. METHODS: The role of dural conditioned media (DCM) in proliferation, migration and invasion of five PCa cell lines with various hormone sensitivities was assessed in the presence or absence of the CXCR2 inhibitor, SB225002. CXCR2 surface protein was examined by FACS. Cytokine levels were measured using a mouse cytokine array. RESULTS: We observed high levels of cytokines produced by dura and within the vertebral body bone marrow, namely CXCL1 and CXCL2, that act on the CXCR2 receptor. All prostate cell lines treated with DCM demonstrated significant increase in growth, migration and invasion regardless of androgen sensitivity, except PC3, which did not significantly increase in invasiveness. When treated with SB225002, the growth response to DCM by cells expressing the highest levels of CXCR2 as measured by FACS (LNCaP and 22Rv1) was blunted. The increase in migration was significantly decreased in all lines in the presence of SB225002. Interestingly, the invasion increase seen with DCM was unchanged when these cells were treated with the CXCR2 inhibitor, except PC3 did demonstrate a significant decrease in invasion. CONCLUSION: DCM enhances the metastatic potential of PCa with increased proliferation, migration and invasion. This phenomenon is partly mediated through the CXCR2 pathway.

Adrenal metastasis as the initial diagnosis of synchronous papillary and follicular thyroid cancer.

BACKGROUND: Differentiated thyroid cancer uncommonly presents with distant metastases. Adrenal metastasis from differentiated thyroid cancer presenting as the initial finding is even less common. CASE PRESENTATION: A 71-year-old male was incidentally found on chest CT to have bilateral thyroid nodules, which were confirmed on ultrasound. Fine needle aspiration of the dominant right 3.3 cm nodule contained histologic features most consistent with Bethesda classification III, and repeat fine needle aspiration revealed pathology consistent with Bethesda classification II. Follow-up thyroid ultrasound showed 1% increase and 14% increase in nodule volume at one and two years, respectively, compared to baseline. Prior to the second annual thyroid ultrasound, the patient was incidentally found to have a 4.1 cm heterogeneously enhancing mass in the right adrenal gland on CT of the abdomen and pelvis. Biochemical evaluation was unremarkable with the exception of morning cortisol of 3.2 µg/dL after dexamethasone suppression. The patient then underwent laparoscopic right adrenal gland excision, which revealed metastatic follicular thyroid carcinoma. Total thyroidectomy was then performed, with pathology showing a 4.8 cm well-differentiated follicular thyroid carcinoma of the right lobe, a 0.5 cm noninvasive follicular thyroid neoplasm with papillary-like nuclear features of the left lobe, and a 0.1 cm papillary microcarcinoma of the left lobe. Thyrotropin-stimulated whole body scan showed normal physiologic uptake of the remnant thyroid tissue without evidence of other iodine avid disease. The patient then received radioactive iodine. At follow-up 14 months after total thyroidectomy, he remains free of recurrent disease. CONCLUSION: Despite following the recommended protocol for evaluation and surveillance of thyroid nodules, thyroid cancer can be challenging to diagnose, and may not be diagnosed until distant metastases are identified.

A rare cause of atraumatic fractures: case series of four patients with tumor-induced osteomalacia.

BACKGROUND: Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome that presents with hypophosphatemia, bone pain, muscle weakness and fractures. We report a case series of four patients with TIO that resulted in significant muscle weakness and multiple atraumatic fractures. CASE PRESENTATION: Four patients were referred to an endocrinology clinic for the evaluation of multiple atraumatic fractures, muscle weakness, generalized muscle and joint pain. Laboratory evaluation was notable for persistent hypophosphatemia due to urinary phosphate wasting, low to low-normal 1,25-dihydroxyvitamin D, elevated alkaline phosphatase and elevated fibroblast growth factor 23 (FGF23). Tumor localization was successful, and all four patients underwent resection of phosphaturic mesenchymal tumors. Post-operatively, patients exhibited normalization of serum phosphorus, in addition to significant improvement in their ambulatory function. CONCLUSION: Hypophosphatemia with elevated FGF23 and low 1,25-dihydroxyvitamin D level in the setting of multiple atraumatic fractures necessitates careful evaluation for biochemical evidence of tumor-induced osteomalacia.

A case report of T-box 1 mutation causing phenotypic features of chromosome 22q11.2 deletion syndrome.

BACKGROUND: The heterozygous microdeletion of chromosome 22q11.2 results in a spectrum of disorders, including DiGeorge syndrome (DGS) and velocardiofacial syndrome (VCFS), with phenotypic features that can include the classic triad of congenital heart disease (CHD), thymic aplasia and hypoparathyroidism. Such microdeletions are usually detectable by fluorescence in situ hybridization (FISH). CASE PRESENTATION: We report a case of a twenty-three year-old female who presented with clinical features of chromosome 22q11.2 deletion syndrome including cardiac anomalies, hypoparathyroidism and dysmorphic facial features. FISH did not reveal a 22q11.2 microdeletion. Further genetic analysis showed T box-1 (TBX1) heterozygous mutation. CONCLUSIONS: The TBX1 gene plays a significant role in the development of fourth pharyngeal arch structures. Mutations of TBX1, which is found at chromosome 22q11.21 can be responsible for the development of syndromes classically associated with chromosome 22q11.2 deletions. This case emphasizes that the TBX1 gene, among other genes, can be responsible for the developmental anomalies seen in these syndromes.

Castration Determines the Efficacy of ETAR Blockade in a Mouse Model of Prostate Cancer Bone Metastasis.

Bone metastasis is a painful complication of advanced prostate cancer. Endothelin-1 is a tumor-secreted factor that plays a central role in osteoblast activation and the osteosclerotic response of prostate cancer metastatic to bone. Antagonists that block the activation of the endothelin A receptor (ETAR), located on osteoblasts, reduce osteoblastic bone lesions in animal models of bone metastasis. However, ETAR antagonists demonstrated limited efficacy in clinical trials of men with advanced prostate cancer who also received standard androgen deprivation therapy (ADT). Previous data from our group suggested that, in a mouse model, ETAR antagonists might only be efficacious when androgen signaling in the osteoblast is lowered beyond the ability of standard ADT. This notion was tested in a mouse model of prostate cancer bone metastasis. Castrated and sham-operated male athymic nude mice underwent intracardiac inoculation of the ARCaPM castration-resistant prostate cancer cell line. The mice were then treated with either the ETAR antagonist zibotentan or a vehicle control to generate four experimental groups: vehicle+sham (Veh+Sham), vehicle+castrate (Veh+Castr), zibotentan+sham (Zibo+Sham), and zibotentan+castrate (Zibo+Castr). The mice were monitored radiographically for the development of skeletal lesions. The Zibo+Castr group had significantly longer survival and a single incidental lesion. Mice in the Zibo+Sham group had the shortest survival and the largest number of skeletal lesions. Survival and skeletal lesions of the Veh+Sham and Veh+Castr groups were intermediate compared with the zibotentan-treated groups. We report a complex interaction between ETAR and androgen signaling, whereby ETAR blockade was most efficacious when combined with complete androgen deprivation.

Predominance of Spinal Metastases Involving the Posterior Vertebral Body.

BACKGROUND: Spinal metastases pose significant morbidity. For many histologies, the spine is a frequent site for bone metastases. This predilection is not fully understood, and there are conflicting reports regarding the distribution within the vertebral body itself. Knowing this distribution will give clues as to the underlying biologic reason for this increased incidence in the spine and lead to a better understanding of tumor dispersion and growth. METHODS: We retrospectively examined magnetic resonance imaging scans of patients undergoing radiation to the spine from 2015 to 2017 for spinal metastases. The anatomical distribution of lesions was categorized. Lesions were sorted along the sagittal plane into 5 groups: anterior only, anterior + middle, middle only, posterior + middle, and posterior only. Lesions that covered all groups were discarded. χ2 and post-hoc analyses were used for statistical analyses. RESULTS: Three hundred metastatic lesions were examined in 89 patients; 203 lesions were used for analysis. Sixty-five percent of all lesions were found in posterior only and posterior + middle aspects of the vertebral body (P < 0.0001). This localization was significant regardless of histology: lung (67%, P < 0.0001), kidney (66%, P < 0.0001), sarcoma (67%, P < 0.0001), prostate (63%, P = 0.01), and breast (63%, P = 0.01). This was consistent across thoracic (n = 96) and lumbar (n = 63) regions (72% and 64%, respectively, P < 0.0001). CONCLUSIONS: Metastatic lesions of the thoracolumbar spine have a greater propensity to localize to the posterior aspect of the vertebral body. These data support the hypothesis that there may be differences within the vertebral body leading to differential tumor dispersion and growth.

The challenges of diagnosing osteoporosis and the limitations of currently available tools.

Dual-energy X-ray absorptiometry (DXA) was the first imaging tool widely utilized by clinicians to assess fracture risk, especially in postmenopausal women. The development of DXA nearly coincided with the availability of effective osteoporosis medications. Although osteoporosis in adults is diagnosed based on a T-score equal to or below - 2.5 SD, most individuals who sustain fragility fractures are above this arbitrary cutoff. This incongruity poses a challenge to clinicians to identify patients who may benefit from osteoporosis treatments. DXA scanners generate 2 dimensional images of complex 3 dimensional structures, and report bone density as the quotient of the bone mineral content divided by the bone area. An obvious pitfall of this method is that a larger bone will convey superior strength, but may in fact have the same bone density as a smaller bone. Other imaging modalities are available such as peripheral quantitative CT, but are largely research tools. Current osteoporosis medications increase bone density and reduce fracture risk but the mechanisms of these actions vary. Anti-resorptive medications (bisphosphonates and denosumab) primarily increase endocortical bone by bolstering mineralization of endosteal resorption pits and thereby increase cortical thickness and reduce cortical porosity. Anabolic medications (teriparatide and abaloparatide) increase the periosteal and endosteal perimeters without large changes in cortical thickness resulting in a larger more structurally sound bone. Because of the differences in the mechanisms of the various drugs, there are likely benefits of selecting a treatment based on a patient's unique bone structure and pattern of bone loss. This review retreats to basic principles in order to advance clinical management of fragility fractures by examining how skeletal biomechanics, size, shape, and ultra-structural properties are the ultimate predictors of bone strength. Accurate measurement of these skeletal parameters through the development of better imaging scanners is critical to advancing fracture risk assessment and informing clinicians on the best treatment strategy. With this information, a "treat to target" approach could be employed to tailor current and future therapies to each patient's unique skeletal characteristics.

DKK1 and Kremen Expression Predicts the Osteoblastic Response to Bone Metastasis.

Bone metastasis is a complication of advanced breast and prostate cancer. Tumor-secreted Dickkopf homolog 1 (DKK1), an inhibitor of canonical Wnt signaling and osteoblast differentiation, was proposed to regulate the osteoblastic response to metastatic cancer in bone. The objectives of this study were to compare DKK1 expression with the in vivo osteoblastic response in a panel of breast and prostate cancer cell lines, and to discover mechanisms that regulate cancer DKK1 expression. DKK1 expression was highest in MDA-MB-231 and PC3 cells that produce osteolytic lesions, and hence a suppressed osteoblastic response, in animal models of bone metastasis. LnCaP, C4-2B, LuCaP23.1, T47D, ZR-75-1, MCF-7, ARCaP and ARCaPM cancer cells that generate osteoblastic, mixed or no bone lesions had the lowest DKK1 expression. The cell lines with negligible expression, LnCaP, C4-2B and T47D, exhibited methylation of the DKK1 promoter. Canonical Wnt signaling activity was then determined and found in all cell lines tested, even in the MDA-MB-231 and PC3 cell lines despite sizeable amounts of DKK1 protein expression expected to block canonical Wnt signaling. A mechanism of DKK1 resistance in the osteolytic cell lines was investigated and determined to be at least partially due to down-regulation of the DKK1 receptors Kremen1 and Kremen2 in the MDA-MB-231 and PC3 cell lines. Combined DKK1 and Kremen expression in cancer cells may serve as predictive markers of the osteoblastic response of breast and prostate cancer bone metastasis.

Dural Cells Release Factors Which Promote Cancer Cell Malignancy and Induce Immunosuppressive Markers in Bone Marrow Myeloid Cells.

BACKGROUND: Thirty per cent of cancer patients develop spine metastases with a substantial number leading to spinal cord compression and neurological deficits. Many demonstrate a propensity toward metastasis to the posterior third of the vertebral body. The dura, the outer layer of the meninges, lies in intimate contact with the posterior border of the vertebral body and has been shown to influence adjacent bone. The effects of the dura on bone marrow and cancer cells have not been examined. Understanding the biology of spinal metastasis will provide insights into mechanisms of cancer growth and allow for new treatment strategies. OBJECTIVE: To examine the extent to which dura influences bone marrow/tumor cell metastatic characteristics. METHODS: Dura conditioned media (DCM) from primary dura was examined for the ability to stimulate tumor cell proliferation/invasion and to alter bone marrow cell populations. RNA sequencing of dural fibroblasts was performed to examine expression of cytokines and growth factors. RESULTS: DCM induced a significant increase in invasion and proliferation of multiple tumor cell lines, and of patient-derived primary spinal metastatic cells. DCM also increased the proliferation of bone marrow myeloid cells, inducing expression of immunosuppressive markers. RNA sequencing of dural fibroblasts demonstrated abundant expression of cytokines and growth factors involved in cancer/immune pathways. CONCLUSION: Factors released by primary dural cells induce proliferation of tumor cells and alter bone marrow to create a fertile environment for tumor growth. The dura therefore may play an important role in the increased incidence of metastases to adjacent bone.