Involutional Osteoporosis Research Articles

Fragility fractures of the acetabulum

There are limited epidemiological data dedicated to geriatric acetabular fractures. The incidence in individuals older than 60 years of age has more than doubled in the past three decades and expected to double further over the next 20 years. These fractures represent a challenging subset of acetabular trauma patients to treat. Conservative treatment is a valid option in those with minimal displaced fractures and a preserved congruent hip joint. Similarly the frail patient with multiple medical co-morbidities and those unlikely to tolerate surgical intervention should have appropriate analgesia and their fracture managed or ignored by watchful neglect. Surgical treatment options include percutaneous fixation or open reduction and internal fixation techniques. Good outcomes may be expected should a concentric reduction be achieved. Age-related involutional osteoporosis associated with fracture comminution and acetabular dome impaction complicate surgical fixation with higher complication rates and the need for further surgery recognised. Historically described as central fracture dislocations, stoved in hip or burst fracture, acute arthroplasty is advocated in the setting of femoral head damage and in significant acetabular impaction injuries. Controversy remains whether geriatric patients should be treated by open reduction and internal fixation or total hip arthroplasty either acute or delayed and needs to be assessed based on the patient and personality of the fracture.

REDUCTION OF BONE MINERAL DENSITY IN WOMEN OF REPRODUCTIVE AGE, DESCENDANTS OF THOSE IRRADIATED AS A RESULT OF NUCLEAR TESTS

Aim of research: To determine the frequency and degree of decrease in bone mineral density in women of reproductive age who are descendants of persons exposed to radiation as a result of nuclear tests at the Semipalatinsk test site. The study included 383 women, descendants of non-irradiated and irradiated II and III generations in the female line. The parameters of bone mineral density in 2 age groups (II generation - 1962-1987 year of birth and III generation – 1988-1996 year of birth) were studied by ultrasound densitometry. It was revealed that women of reproductive age with irradiated ancestors of the second and third generation, who lived in areas of maximum and extreme radiation risk, had a relative decrease in bone mineral density, which was statistically significant in relation to the descendants of persons who were not exposed to chronic anthropogenic sources of ionizing radiation. There were statistically significant relationship between exposure ancestors II and III generation and indicators BMD their offspring, women of reproductive age. It is possible to predict the rapid development of involutional osteoporosis in women-descendants of irradiated patients in the ІІ and ІІІ generation.

Increased marrow adipogenesis does not contribute to age-dependent appendicular bone loss in female mice.

Marrow adipocytes and osteoblasts differentiate from common mesenchymal progenitors in a mutually exclusive manner, and diversion of these progenitors toward adipocytes in old age has been proposed to account for the decline in osteoblasts and the development of involutional osteoporosis. This idea has been supported by evidence that thiazolidinedione (TZD)‐induced activation of PPARγ, the transcription factor required for adipocyte differentiation, increases marrow fat and causes bone loss. We functionally tested this hypothesis using C57BL/6J mice with conditional deletion of PPARγ from early mesenchymal progenitors targeted by the Prx1‐Cre transgene. Using a longitudinal littermate‐controlled study design, we observed that PPARγ is indispensable for TZD‐induced increase in marrow adipocytes in 6‐month‐old male mice, and age‐associated increase in marrow adipocytes in 22‐month‐old female mice. In contrast, PPARγ is dispensable for the loss of cortical and trabecular bone caused by TZD or old age. Instead, PPARγ restrains age‐dependent development of cortical porosity. These findings do not support the long‐standing hypothesis that increased marrow adipocyte differentiation contributes to bone loss in old age but reveal a novel role of mesenchymal cell PPARγ in the maintenance of cortical integrity.

Fragility fractures of the acetabulum

There are limited epidemiological data dedicated to geriatric acetabular fractures. The incidence in individuals older than 60 years of age has more than doubled in the past three decades and expected to double further over the next 20 years. These fractures represent a challenging subset of acetabular trauma patients to treat. Conservative treatment is a valid option in those with minimal displaced fractures and a preserved congruent hip joint. Similarly the frail patient with multiple medical co-morbidities and those unlikely to tolerate surgical intervention should have appropriate analgesia and their fracture managed or ignored by watchful neglect. Surgical treatment options include percutaneous fixation or open reduction and internal fixation techniques. Good outcomes may be expected should a concentric reduction be achieved. Age-related involutional osteoporosis associated with fracture comminution and acetabular dome impaction complicate surgical fixation with higher complication rates and the need for further surgery recognised. Historically described as central fracture dislocations, stoved in hip or burst fracture, acute arthroplasty is advocated in the setting of femoral head damage and in significant acetabular impaction injuries. Controversy remains whether geriatric patients should be treated by open reduction and internal fixation or total hip arthroplasty either acute or delayed and needs to be assessed based on the patient and personality of the fracture.

Parathyroid hormone-related protein exhibits antioxidant features in osteoblastic cells through its N-terminal and osteostatin domains.

ObjectivesOxidative stress plays a major role in the onset and progression of involutional osteoporosis. However, classical antioxidants fail to restore osteoblast function. Interestingly, the bone anabolism of parathyroid hormone (PTH) has been shown to be associated with its ability to counteract oxidative stress in osteoblasts. The PTH counterpart in bone, which is the PTH-related protein (PTHrP), displays osteogenic actions through both its N-terminal PTH-like region and the C-terminal domain.MethodsWe examined and compared the antioxidant capacity of PTHrP (1-37) with the C-terminal PTHrP domain comprising the 107-111 epitope (osteostatin) in both murine osteoblastic MC3T3-E1 cells and primary human osteoblastic cells.ResultsWe showed that both N- and C-terminal PTHrP peptides at 100 nM decreased reactive oxygen species production and forkhead box protein O activation following hydrogen peroxide (H2O2)-induced oxidation, which was related to decreased lipid oxidative damage and caspase-3 activation in these cells. This was associated with their ability to restore the deleterious effects of H2O2 on cell growth and alkaline phosphatase activity, as well as on the expression of various osteoblast differentiation genes. The addition of Rp-cyclic 3′,5′-hydrogen phosphorothioate adenosine triethylammonium salt (a cyclic 3',5'-adenosine monophosphate antagonist) and calphostin C (a protein kinase C inhibitor), or a PTH type 1 receptor antagonist, abrogated the effects of N-terminal PTHrP, whereas protein phosphatase 1 (an Src kinase activity inhibitor), SU1498 (a vascular endothelial growth factor receptor 2 inhibitor), or an anti osteostatin antiserum, inhibited the effects of C-terminal PTHrP.ConclusionThese findings indicate that the antioxidant properties of PTHrP act through its N- and C-terminal domains and provide novel insights into the osteogenic action of PTHrP.Cite this article: S. Portal-Núñez, J. A. Ardura, D. Lozano, I. Martínez de Toda, M. De la Fuente, G. Herrero-Beaumont, R. Largo, P. Esbrit. Parathyroid hormone-related protein exhibits antioxidant features in osteoblastic cells through its N-terminal and osteostatin domains. Bone Joint Res 2018;7:58–68. DOI: 10.1302/2046-3758.71.BJR-2016-0242.R2.

Old age causes de novo intracortical bone remodeling and porosity in mice.

Decreased cortical thickness and increased cortical porosity are the key anatomic changes responsible for osteoporotic fractures in elderly women and men. The cellular basis of these changes is unbalanced endosteal and intracortical osteonal remodeling by the osteoclasts and osteoblasts that comprise the basic multicellular units (BMUs). Like humans, mice lose cortical bone with age, but unlike humans, this loss occurs in the face of sex steroid sufficiency. Mice are therefore an ideal model to dissect age-specific osteoporotic mechanisms. Nevertheless, lack of evidence for endosteal or intracortical remodeling in mice has raised questions about their translational relevance. We show herein that administration of the antiosteoclastogenic cytokine osteoprotegerin to Swiss Webster mice ablated not only osteoclasts, but also endosteal bone formation, demonstrating the occurrence of BMU-based endosteal remodeling. Femoral cortical thickness decreased in aged male and female C57BL/6J mice, as well as F1 hybrids of C57BL/6J and BALB/cBy mice. This decrease was greater in C57BL/6J mice, indicating a genetic influence. Moreover, endosteal remodeling became unbalanced because of increased osteoclast and decreased osteoblast numbers. The porosity of the femoral cortex increased with age but was much higher in females of both strains. Notably, the increased cortical porosity resulted from de novo intracortical remodeling by osteon-like structures. Age-dependent cortical bone loss was associated with increased osteocyte DNA damage, cellular senescence, the senescence-associated secretory phenotype, and increased levels of RANKL. The demonstration of unbalanced endosteal and intracortical remodeling in old mice validates the relevance of this animal model to involutional osteoporosis in humans.

Retraction Note to: Efficacy of Antiresorptive Agents for Preventing Fractures in Japanese Patients with an Increased Fracture Risk: Review of the Literature.

The aim of the present review was to clarify the efficacy of currently available potent antiresorptive agents for preventing fractures in Japanese patients with an increased fracture risk. PubMed was used to search the literature for randomized controlled trials (RCTs), with the following search terms: fracture, etidronate, alendronate, risedronate, minodronate, raloxifene, bazedoxifene and Japan. The inclusion criteria were papers written in English, ≥50 subjects per group and a study period of ≥1 year. Fourteen RCTs met these criteria. The efficacy of antiresorptive agents for preventing vertebral, nonvertebral and hip fractures was investigated. There was evidence that raloxifene reduced the incidence of clinical vertebral fractures, while etidronate, alendronate and minodronate (but not bazedoxifene) reduced the incidence of morphometric vertebral fractures in patients with postmenopausal or involutional osteoporosis. Head-to-head trials showed that alendronate and raloxifene had similar efficacy for preventing vertebral fractures in patients with postmenopausal osteoporosis, while risedronate was not inferior to etidronate for reducing the incidence of morphometric vertebral fractures in patients with involutional osteoporosis. Alendronate reduced the incidence of hip fractures in patients with Parkinson's disease, and risedronate reduced the incidence of nonvertebral fractures and hip fractures in patients with Alzheimer's disease or stroke. In conclusion, the present review confirmed the efficacy of etidronate, minodronate and raloxifene for the prevention of vertebral fractures, the efficacy of alendronate for vertebral and hip fractures, and the efficacy of risedronate for vertebral, nonvertebral and hip fractures in Japanese patients with an increased fracture risk.

Glucocorticoid-induced osteoporosis: 2013 update.

Glucocorticoids are the most common cause of secondary osteoporosis leading to the so-called glucocorticoid-induced osteoporosis (GIO). A treatment with 10 mg/d of prednisone or equivalent for more than 3 months leads to a 7-fold increase in hip fractures and a 17-fold increase in vertebral fractures. The difference between bone quantity and quality in GIO makes bone mineral density measurements inadequate to detect patients at risk of fracture. The adverse effects of glucocorticoids on the skeleton derive from a direct impact on bone cells with a severe impairment of mechanical competence. Crucial to prevention of GIO is early timing of intervention. The World Health Organization has adopted a fracture prevention algorithm (FRAX) intended to estimate fracture risk in GIO. The American College of Rhematology modified its prevention and treatment guidelines taking into account the individual risk of fracture calculated in GIO on the basis of the FRAX algorithm. Recently, also a joint Guideline Working Group of the International Osteoporosis Foundation (IOF) and the European Calcified Tissue Society (ECTS) published a framework for the development of national guidelines for the management of GIO. Bisphosphonates are the first-line drugs to treat GIO; teriparatide counteracts several fundamental pathophysiologic aspects of GIO; denosumab is useful in patients with renal failure and in potentially pregnant young women. Vertebroplasty and kyphoplasty may be less beneficial in GIO than in primary involutional osteoporosis.

Efficacy, tolerability and safety of once-monthly administration of 75 mg risedronate in Japanese patients with involutional osteoporosis: A comparison with a 2.5 mg once-daily dosage regimen

Oral risedronate has been shown to be effective in the treatment of osteoporosis when administered once-daily or once-weekly in Japan. This randomized, double-blind, multicenter 12-month study was conducted to compare the efficacy and tolerability of oral risedronate 75mg once-monthly with 2.5mg once-daily in Japanese patients with involutional osteoporosis. Bone mineral density (BMD), biochemical markers of bone metabolism, fractures, and adverse events (AEs) were evaluated. At the end of the study (Month 12, last observation carried forward [M12, LOCF]), mean percent change (SD) from baseline in lumbar spine (L2–L4) BMD, measured by dual energy X-ray absorptiometry (primary endpoint), was increased by 5.69 (4.00)% in the 2.5mg once-daily group (n=428), and 5.98 (4.54)% in the 75mg once-monthly group (n=422). In the non-inferiority t-test (non-inferiority margin Δ=1.5%), the 75mg once-monthly group was non-inferior to the 2.5mg once-daily group (p<0.0001). The difference between treatment groups was 0.28% (95% CI, −0.31% to 0.88%). Changes in biochemical markers of bone metabolism were generally comparable in the two groups, although decreases in the percent change from baseline in urinary NTX/CRN and CTX/CRN were statistically greater in the 2.5mg once-daily group than the 75mg once-monthly group. The frequency of new vertebral fractures (including aggravation of prevalent fractures) at the end of the study (M12, LOCF) was also similar in the two groups: 1.2% in the 2.5mg once-daily group and 1.3% in the 75mg once-monthly group.The incidence of mild/moderate/severe AEs was 75.5%/6.3%/0.5% in the 2.5mg once-daily group and 77.7%/8.1%/0.7% in the 75mg once-monthly group. AEs associated with gastrointestinal symptoms occurred in approximately 30% of subjects in each group but with no severe cases. AEs potentially associated with acute phase reaction (including symptoms of influenza-like illness or pyrexia starting within 3days of the first dose of the study drug and with a duration of 7days or less) only occurred in the 75mg once-monthly group (2.1%, 9/422 subjects; influenza-like symptoms in 1 subject and pyrexia in 8 subjects), although the incidence was low without any severe cases.In conclusion, risedronate 75mg once-monthly (a dosage which is 30 times higher than risedronate 2.5mg once-daily) had non-inferior efficacy in terms of BMD and was similarly well tolerated compared to the once-daily regimen in Japanese patients with involutional osteoporosis. Consistent with the once-daily and once-weekly dosage, the once-monthly dosage of risedronate 75mg was half that used outside Japan (150mg).

Effects of denosumab on cortical and trabecular microarchitecture: evidences from clinical studies

Excess of bone remodeling is still the major pathogenic factor in involutional osteoporosis. This phenomenon is linked to an imbalance between neoformation (by osteoblasts) and resorption (by osteoclasts). Recently, research in drug development is focused on new and more "physiological" approach to balance bone remodeling. The efficacy of denosumab was proved in the prevention of vertebral and non-vertebral fractures and related to the ability of the drug to penetrate in cortical and trabecular bone. Recently, data from several clinical studies confirm that denosumab improves fracture outcomes, also at skeletal sites rich in cortical bone.

FOXOs attenuate bone formation by suppressing Wnt signaling

Wnt/β-catenin/TCF signaling stimulates bone formation and suppresses adipogenesis. The hallmarks of skeletal involution with age, on the other hand, are decreased bone formation and increased bone marrow adiposity. These changes are associated with increased oxidative stress and decreased growth factor production, which activate members of the FOXO family of transcription factors. FOXOs in turn attenuate Wnt/β-catenin signaling by diverting β-catenin from TCF- to FOXO-mediated transcription. We show herein that mice lacking Foxo1, -3, and -4 in bipotential progenitors of osteoblast and adipocytes (expressing Osterix1) exhibited increased osteoblast number and high bone mass that was maintained in old age as well as decreased adiposity in the aged bone marrow. The increased bone mass in the Foxo-deficient mice was accounted for by increased proliferation of osteoprogenitor cells and bone formation resulting from upregulation of Wnt/β-catenin signaling and cyclin D1 expression, but not changes in redox balance. Consistent with this mechanism, β-catenin deletion in Foxo null cells abrogated both the increased cyclin D1 expression and proliferation. The elucidation of a restraining effect of FOXOs on Wnt signaling in bipotential progenitors suggests that FOXO activation by accumulation of age-associated cellular stressors may be a seminal pathogenetic mechanism in the development of involutional osteoporosis.

The vertebrae of prematurely aging mice as a skeletal model of involutional osteoporosis.

Oxidative stress in bone increases with age, which leads to bone frailty and a high fracture risk. Animal models show that early changes in trabecular structure occur in age-related osteopenia. These models might be valuable to assess the contribution of oxidative stress in age-related bone loss. Premature aging mice (PAM) have previously been characterized as a model of premature immunological and neurological senescence. PAM long bones (mainly consisting of cortical bone) display features of aging bone. Thus, we aimed to evaluate the vertebrae, representing a unique poorly loaded type of trabecular bone in mice, in PAM and no PAM (NPAM) controls. PAM showed an anxious behaviour, based on physical activity evaluation. These mice had decreased bone mineral density (0.078 mg/cm² in NPAM vs 0.070 g/cm² in PAM; p⟨0.05); a decreased number of osteocytes per bone field (404±36 in NPAM vs 320±27 in PAM; p⟨0.01); and downregulation of various osteoblastic genes and low eroded surface/bone surface, 4.2±0.5 in NPAM vs 1.9±0.2 in PAM; p⟨0.01). This was associated with increased expression of oxidative stress markers, Foxo1 and GADD45, in PAM vertebrae. Mesenchymal progenitors in the bone marrow of PAM have a poor mineralization capacity (assessed by the number of mineralized nodules and suface), and showed a lower response to an osteogenic input -represented by parathormone-related protein-, compared to NPAM. Collectively, these results indicate that PAM vertebrae show osteopenia related to diminished bone formation and remodeling. Our findings further support the validity of PAM as a suitable model for involutional osteoporosis and its treatment.

Efficacy and safety of monthly oral minodronate in patients with involutional osteoporosis

SummaryMonthly minodronate at 30 or 50 mg had similar efficacy as 1 mg daily in terms of change in bone mineral density (BMD) and bone turnover markers with similar safety profiles. This new regimen provides patients with a new option for taking minodronate.IntroductionMinodronate at a daily oral dose of 1 mg has been proven to have antivertebral fracture efficacy. In the present study, the efficacy and safety of oral minodronate at monthly doses of either 30 mg or 50 mg were compared with a daily dose of 1 mg.MethodsA total of 692 patients with involutional osteoporosis were randomized to receive minodronate at either 30 or 50 mg monthly or a daily dose of 1 mg. The primary endpoint was the percent change from baseline in lumbar spine (LS) BMD at 12 months. Total hip BMD, bone turnover markers, serum calcium (Ca), and parathyroid hormone (PTH) levels were also evaluated.ResultsMinodronate at monthly doses of 30 or 50 mg were noninferior to the 1 mg daily dose in terms of change in LS-BMD. Changes in total hip BMD were also comparable. Although a transient decrease in serum Ca and increase in PTH levels were observed in all three groups at slightly different magnitudes and time courses, changes in bone turnover markers were comparable among the different dosage groups with a similar time course. Safety profiles were also comparable.ConclusionMinodronate at monthly doses of 30 or 50 mg has similar efficacy to the daily 1 mg dose in terms of BMD and bone turnover markers with similar tolerability.

The Side-To-Side Differences in Forearm Bone Mineral Density in Iranian Professional Dragon Boat Athletes

PURPOSE: Over the past 30 years dragon boating as a sport has rapidly spread beyond Asia and becoming a popular international sport for a growing global base of participants. Today, dragon boat racing is among the fastest growing of team water sports. The use of exercise to maintain bone health throughout life and prevent osteoporosis related problems has received noticeable research attention. Numerous studies have revealed that strength-based and contact-type sports are most beneficial in boosting bone mass. The aim of this study was to determine the effect of hand dominance on side-to-side difference in forearm bone mineral density in professional dragon athletes and also to compare BMD of dragon boat athletes with non-athletes. METHODS: Dual-energy X-ray absorptiometry measurements of both forearms were performed on 19 professional dragon boat athletes (mean±SD; age 23±2.48y, height 165±6.05cm, weight 57±6.45kg) and 19 non-athletes (mean±SD; age 25±1.78y, height 160±5.82cm, weight 53±5kg). RESULTS: The results of this study showed that total BMD of dragon boat athletes (0.9374±0.061 mg/cm2) was significantly higher than non-athletes (0.8854±0.075)(t=2.28,P<0.05). Forearm BMD of both dominant and non-dominant sides of athletes was significantly higher than non-athletes (P<0.05). Although forearm BMD of dominant side (0.5261) of athletes was higher than non-dominant side (0.5167) but the differences was not significant (t=1.87,P>0.05). In non-athletes BMD of dominant side (0.574) was significantly higher than non-dominant side (0.4882)(P<0.05). CONCLUSIONS: In conclusion, the participation in dragon boat is associated with increased BMD in the forearms and total body which may have implications for young people to participate in this sport to prevent involutional osteoporosis later in life. This study also suggested that long term regular dragon boating did not result in significant bilateral difference in forearm BMD.

Physiotherapy interventions for the management of whiplash injuries

Age dependent decrease in androgen levels is the main and most important mechanism responsible for involutional osteoporosis in men. Decreased physical activity may contribute to the development of osteoporosis. Supplementation with DHEA and increased physical activity may counteract the development of male osteoporosis and decrease fracture risk. DHEA may increase bone formation after conversion to testosterone, and exercise — by activation of the canonical Wnt/β-catenin pathway. The aim of the present study was to examine the effect of DHEA and moderate exercise on mechanical properties of long bones in rats with androgen deficiency induced by orchidectomy. The experiments were carried out on 3-month-old Wistar rats, divided into following groups (n=8–10 rats per group): non-orchidectomized control rats, orchidectomized (ORX) control rats, ORX rats receiving DHEA, ORX rats submitted to exercise, ORX rats receiving DHEA submitted to exercise. The rats were submitted to the moderate exercise on the treadmill once daily (1 hour) for 8 weeks. DHEA was administered at a dose 7 mg/kg p.o. once daily for 8 weeks. Mechanical properties of tibial metaphysis and femoral diaphysis (in three-point bending tests) and femoral neck (in a compression test), bone turnover markers (serum osteocalcin and C-terminal telopeptide of type I collagen fragments), geometric parameters, mass, and mass of bone mineral in the tibia and femur were studied. Androgen deficiency inhibited bone formation and resorption. It weakened mechanical properties of tibial metaphysis as well as femoral neck and diaphysis, and decreased bone mass and mass of bone mineral. Exercise increased bone formation and counteracted unfavorable changes in mechanical properties of tibial metaphysis and femoral neck, induced by androgen deficiency. DHEA increased bone formation and significantly inhibited the effect of androgen deficiency on the mechanical properties of the tibial metaphysis. Administration of DHAE combined with exercise counteracted unfavorable changes in bone mechanical properties (especially in the tibial metaphysis) induced by androgen deficiency. This article is part of a Special Issue entitled ECTS 2011. Disclosure of interest: None declared. doi:10.1016/j.bone.2011.03.670 PP540-T Physiotherapy interventions for the management of whiplash injuries V. Barkatsa ⁎, C. Iliadis , V. Moraitis , N. Syrmos , M. Tzagarakis , K. Tsipras d a Physiotherapy, Greece b Neurosurgery, Venizeleion General Hospital, Heraklion, Greece c Pathology, General Hospital, Rethymno, Greece d Endocrinology, Greek Institute of Social Security, Athens, Greece Abstract: Introduction/background: Whiplash injuries are associated with motor Introduction/background: Whiplash injuries are associated with motor vehicle accidents or in sporting mishaps after an acceleration–deceleration mechanism of energy transfer to the neck. The injury results in a series of clinical manifestations (mainly cervical pain 88% and headaches) known as Whiplash Associated Disorder. The syndrome involves trauma to amultiplicity of tissues in the cervical spine and it may affect other areas of the vertebral column. Clinicians are challenged to use different treatments in order to relieve symptoms and to improve body function. Method: systematic review of the effectiveness of physiotherapy interventions in the management of whiplash injuries using MEDLINE, CINAHL, Cochrane database systematic reviews and published guidelines. Results: In the acute stage (0 to 2 weeks after injury) physiotherapy interventions recommended for pain reduction are active exercises, manual mobilisation, use of TENS, education and advice and relaxation techniques compared to electrotherapy, traction, and the use of soft collar. There is insufficient evidence to support the use of massage and acupuncture. In the sub acute stage (2–12 weeks after injury) and in the chronic stage( after 12 weeks) a multimodal programme including active exercises, postural training, manual techniques, physical agents and psychosocial support should be used to reduce pain and enable people to return to normal activities. Conclusion: Recovery is improved by early active management and early return to pre-accidental activities. This article is part of a Special Issue entitled ECTS 2011.

Validity of the DEXA diagnosis of involutional osteoporosis in patients with femoral neck fractures

Background:There exists no study comparing dual energy X-ray absorptimetry (DEXA) with histomorphometry to evaluate its accuracy and validity as an assessment tool. A prospective study was done comparing the measurements of osteoporosis in patients with femoral neck fractures using the histological method of diagnosis and in the same patients with DEXA postoperatively.Patients and Methods:The histological method depends on histomorphometric analysis of bone biopsies taken from the neck of femur during surgical treatment of the fracture. We depend on three indices in histomorphometric analysis: these are osteoid seam width, osteoblast surface, and osteoid surface. The radiological method depends on the measurement of the bone mineral density using DEXA for fractured patients with the scan performed onto the contralateral nonfractured hips and lumbar spines.Results:We found positive histological histomorphometric parameters of osteoporosis in 68% of patients with the femoral neck fracture, and there is a moderate correlation between histological histomorphometric analysis and DEXA in the diagnosis of osteoporosis in these patients. In our study, DEXA can detect up to 88.2% of possible cases of osteoporosis (sensitivity 88.2%), but the specificity of this diagnostic tool is 62.5% at a t-score of ≤ −2, i.e., it is sensitive but less specific. The mean difference in the t-score in femoral DEXA and lumbar DEXA is almost zero.Conclusions:DEXA is a noninvasive and an affordable and easy method for the diagnosis of osteoporosis but less efficient than the histological histomorphometric method of diagnosis with a low specificity. We also found that the mean difference in the t-score in femoral DEXA and lumbar DEXA is almost zero, so DEXA of one region can reflect the change in the other region and there is no need for DEXA of both regions as a routine unless indicated for a special reason. This avoids exposing the patient to unnecessary risk of radiation and reduces cost.

From Estrogen-Centric to Aging and Oxidative Stress: A Revised Perspective of the Pathogenesis of Osteoporosis

Estrogen deficiency has been considered the seminal mechanism of osteoporosis in both women and men, but epidemiological evidence in humans and recent mechanistic studies in rodents indicate that aging and the associated increase in reactive oxygen species (ROS) are the proximal culprits. ROS greatly influence the generation and survival of osteoclasts, osteoblasts, and osteocytes. Moreover, oxidative defense by the FoxO transcription factors is indispensable for skeletal homeostasis at any age. Loss of estrogens or androgens decreases defense against oxidative stress in bone, and this accounts for the increased bone resorption associated with the acute loss of these hormones. ROS-activated FoxOs in early mesenchymal progenitors also divert ss-catenin away from Wnt signaling, leading to decreased osteoblastogenesis. This latter mechanism may be implicated in the pathogenesis of type 1 and 2 diabetes and ROS-mediated adverse effects of diabetes on bone formation. Attenuation of Wnt signaling by the activation of peroxisome proliferator-activated receptor gamma by ligands generated from lipid oxidation also contributes to the age-dependent decrease in bone formation, suggesting a mechanistic explanation for the link between atherosclerosis and osteoporosis. Additionally, increased glucocorticoid production and sensitivity with advancing age decrease skeletal hydration and thereby increase skeletal fragility by attenuating the volume of the bone vasculature and interstitial fluid. This emerging evidence provides a paradigm shift from the "estrogen-centric" account of the pathogenesis of involutional osteoporosis to one in which age-related mechanisms intrinsic to bone and oxidative stress are protagonists and age-related changes in other organs and tissues, such as ovaries, accentuate them.

Long Term Use of Glucocorticoid Induced Osteoporotic Multiple Compression Fractures in Autoimmune Diseases

Reduced bone mineral density precedes the development of vertebral fractures in patients under long term glucocorticoid therapy. Osteoporosis is a frequent complication in steroiddependent patients, and the risk of developing vertebral fractures in these patients is much higher than involutional osteoporosis. We described a 54-year-old patient who presented with autoimmune hepatitis and had a 6-year history of steroid medication. The patient had multiple compression fractures (T10∼L5) without trauma, and was treated successfully with multi-level vertebroplasty and an intravenous injection of bisphosphonate without complications.

Gone with the Wnts: β-Catenin, T-Cell Factor, Forkhead Box O, and Oxidative Stress in Age-Dependent Diseases of Bone, Lipid, and Glucose Metabolism

The Wnt/beta-catenin signaling pathway affects several biological processes ranging from embryonic development, patterning, and postembryonic stem cell fate, to bone formation and insulin secretion in adulthood. beta-Catenin mediates canonical Wnt signaling by binding to and activating members of the T-cell factor (TCF) transcription factor family. Similar to the Wnt/beta-catenin pathway, oxidative stress influences fundamental cellular processes including stem cell fate and has been linked to aging and the development of age-related diseases. However, the molecular details of the pathogenetic effects of oxidative stress on the homeostasis of many different tissues remain unclear. beta-Catenin has been recently implicated as a pivotal molecule in defense against oxidative stress by serving as a cofactor of the forkhead box O (FOXO) transcription factors. In addition, it has been shown that oxidative stress is a pivotal pathogenetic factor of age-related bone loss and strength in mice, leading to, among other changes, a decrease in osteoblast number and bone formation. These particular cellular changes evidently result from diversion of the limited pool of beta-catenin from TCF- to FOXO-mediated transcription in osteoblastic cells. Fascinatingly, attenuation of Wnt-mediated transcription, resulting from an autosomal-dominant missense mutation in LRP6, a coreceptor for the Wnt-signaling pathway, has been linked recently genetically not only to premature osteoporosis, but also to coronary artery disease as well as several features of the metabolic syndrome including hyperlipidemia, hypertension, and diabetes, but not obesity. In this minireview, we highlight evidence linking the age-associated oxidative stress with FOXOs, Wnt/beta-catenin signaling, osteoblastogenesis, adipogenesis, osteoporosis, and several features of the metabolic syndrome. We hypothesize that antagonism of Wnt signaling by oxidative stress with increasing age may be a common molecular mechanism contributing to the development not only of involutional osteoporosis, but several pathologies such as atherosclerosis, insulin resistance, and hyperlipidemia, all of which become more prevalent with advancing age.

Pathological fractures in epilepsy

Fracture rates in epilepsy are two to three times that for the general population, although the influence of gender and age is not well defined. We examined, over a 7-year period at a single health care center, 750 patients with epilepsy who sustained the fractures. Among these patients, 293 (39%) had pathological fractures and 457 (61%) had traumatic/seizure-related fractures. Pathological fractures accounted for 71% of the 146 patients >60 years, a group traditionally at risk for pathological fractures ( P < 0.02). Fractures in epilepsy are distributed with bimodal peaks in the fifth and eighth decades of life, although pathological fractures are a significant contributor across the life span, accounting for 20 to 40% of patients traditionally thought not to be at risk for involutional osteoporotic fractures. Together these findings suggest that epilepsy, and/or its treatment, is a dominant influence in the pathogenesis of fractures and may exacerbate the effects of aging-related involutional osteoporosis.