The effect of vitamin D on bone and osteoporosis

Bone strength and surrogate markers: The first, second, and third fiddle

Surrogates for fracture endpoints in clinical trials.

The aim of this paper is to show one of the most important intervention ways to improve the school climate currently: the Conflict Resolution Education. First of all, we show the contents to teach resolving conflicts correctly. Conflict Resolution Education supposes to teach children negotiating, mediating or reaching collective consensus. About that, we should teach process steps and necessary attitudes, principles and skills. Secondly, we show the principal ways to integrate these contents in educative curricula. They can be inserted in schools by mean of four

Bisphosphonates are the current mainstay of treatment for postmenopausal osteoporosis. Although daily oral dosing is effective, it is associated with poor compliance, partly because of the pre and postdose fasting and posture requirements. This negatively impacts treatment outcomes, leading to a reduced clinical benefit. Improved, yet still suboptimal adherence has been noticed with less frequent bisphosphonate dosing e.g. once-weekly and once-monthly oral regimens. The recently approved quarterly intravenous (i.v.) injection regimen of ibandronate and yearly i.v. infusion of zoledronic acid are attractive options in the management of postmenopausal osteoporosis. These regimens may assure quarterly and year long compliance.

Osteoporosis is a major cause of morbidity and death in older persons. For women who are 50 years of age, the estimated lifetime risk for osteoporotic fracture is 54%, and studies suggest that the ...

Some, but not all, antiresorptive agents have been shown to reduce the risk of nonvertebral fractures. Agents that significantly reduced nonvertebral fracture risk also appear to produce larger mean increases in bone mineral density (BMD) and reductions in biochemical markers (BCM) of bone turnover, compared with other agents. To examine the extent to which increases in BMD and reductions in BCM during antiresorptive therapy are associated with reductions in risk of nonvertebral fractures, we performed a meta-analysis of all randomized, placebo-controlled trials of antiresorptive agents conducted in postmenopausal women with osteoporosis (i.e. prior vertebral fracture or low BMD) with available relevant data. A total of 18 such trials with usable data were identified, including a total of 2,415 women with incident nonvertebral fractures over 69,369 women-years of follow-up. Poisson regression was used to estimate the association between changes in BMD or BCM during the first year and overall reductions in risk of nonvertebral fractures (vs. the placebo group) across all trials. Larger increases in BMD and larger reductions in BCM were significantly associated with greater reductions in nonvertebral fracture risk. For example, each 1% increase in spine BMD at 1 yr was associated with an 8% reduction in nonvertebral fracture risk (P = 0.02). Mean BMD changes at the hip were smaller than at the spine, but the predicted net effect on fracture risk was the same; an agent that increases spine BMD by 6% at 1 yr reduces nonvertebral fracture risk by about 39%, and an agent that increases hip BMD by 3% at 1 yr reduces nonvertebral fracture risk by about 46%. The results also predict that a 70% reduction in resorption BCM would reduce risk by 40%, and a 50% reduction in formation BCM would reduce risk by 44%. It appears that either BMD or BCM changes are able to explain the effect of treatment, because a separate variable for treatment was not independently significant in any models. These data demonstrate that larger increases in BMD at both the spine and hip and larger reductions in both formation and resorption BCM are associated with greater reductions in the risk of nonvertebral fractures. Antiresorptive agents that do not produce large increases in BMD or large reductions in BCM do not appear to and would not be expected to decrease the risk of nonvertebral fractures.

Introduction HIV mainly replicates in CD4+ T lymphocytes and monocyte/macrophages causing severe immunological impairment. In addition to the immune system, HIV infection affects tissues and organs such as kidney, liver, the central nervous system, heart and bone showing a complex pathogenesis [1]. The advent and widespread use of highly active antiretroviral therapy (HAART) in the last two decades has led to a marked improvement in the treatment of HIV disease even though viral infection cannot be eradicated because HAART does not completely eliminate the viral reservoirs [2]. HAART has dramatically changed the course of HIV infection from a fatal infection to a chronic and relatively manageable disease. The increased life expectancy of HIV patients and the effects of HAART have changed the management of HIV infection. Nowadays medical treatment is no longer focused solely on HIV infection, opportunistic diseases and monitoring immune derangement, but also includes the control of metabolic, cardiovascular, liver, bone and kidney complications. In particular, bone alterations have been observed in the course of HIV disease representing a pivotal clinical problem in the management of HIV patients especially for a possible development of bone fractures [3]. The major bone lesions detectable in HIV patients are related to bone demineralization (osteopenia/osteoporosis and osteomalacia) and osteonecrosis ([4] for a review). This report will discuss the pathogenesis, diagnosis and treatment of major bone complications represented by bone demineralization diseases during HIV infection and HAART treatment. Osteopenia/osteoporosis in HIV-infected patients Bone alterations have been observed in the course of HIV disease since for nearly two decades (Table 1). In particular, reduced bone mineral density (BMD) is the most common bone lesion found in HIV-infected individuals [5,6]. BMD is a parameter that predicts fracture risk, which in turn correlates with a shorter life expectancy [7]. BMD is measured by the dual X-ray absorptiometry scan (DXA). According to the WHO Classification, BMD is commonly reported in terms of DXA T-score, which represents the number of standard deviations below the mean of a young, sex-matched control population. T-score values are considered normal above the limit of −1. Values between −1 and −2.5 indicate osteopenia (low bone mass) whereas a T-score value below −2.5 signifies osteoporosis [8,9]. Osteoporosis is a systemic condition characterized by both quantitative and qualitative alterations that reduce bone strength [10].Table 1: Summary of HIV and HAART-related bone lesions.Several groups have used DXA to study BMD status during HIV infection. A meta-analysis of selected reports on bone loss in the whole HIV patient population (HAART treated plus naive) from 1994 to 2005 showed that these individuals had 6.4 fold increased odds of osteopenia and 3.7-fold increased odds of osteoporosis in comparison with uninfected individuals [11]. The relation between antiretroviral treatment and osteopenia/osteoporosis has been noted in several studies [12–18] although other reports failed to find any influence of HAART on bone loss, disclosing no major differences between naive and HAART treated patients [19–23]. A recent study on 492 patients belonging to the Aquitaine Cohort reported osteopenia in 50% and osteoporosis in 30% of HIV-positive cases but multivariate analysis did not show a significant correlation to bone loss and cumulative HAART or specific drug class [24]. In spite of these opposing findings, a meta-analysis of selected cross-sectional studies demonstrated that the odds of osteoporosis were increased 2.4 times in HAART-treated patients compared with naïve individuals [11]. In addition, the meta-analysis by Brown and Qaqish on 12 studies disclosed that patients treated with protease inhibitors have a higher prevalence of reduced BMD and the odds of osteoporosis in protease inhibitor-treated patients are 1.6 greater than in protease inhibitor-untreated individuals [11]. The controversy over the role of antiretroviral compounds in BMD decrease could be explained by shortcomings in some studies. HAART typically combines nucleoside analogue reverse transcriptase inhibitors (NRTIs) with either HIV protease inhibitors or nonnucleoside reverse transcriptase inhibitors (NNRTIs), thus, the antiretroviral cocktail composition may differ within the same cohort with conceivably different effects on bone. In addition, some DXA studies analysed only the spine (mainly confined to trabecular bone), or hip (mostly cortical bone) or both bone sites. The choice of bone for DXA assay is not negligible; the human skeleton is composed of two different types of bone tissue: trabecular bone (comprising around 20% of the bone and mainly involved in the maintenance of mineral homeostasis) and cortical bone (80% and responsible for most support functions). Plainly, high bone turnover states, such as HIV-induced osteoporosis, involve trabecular bone (spine) earlier and to a greater extent compromising cortical bone (hip) only much later [25]. Moreover, the effectiveness and duration of HAART treatment may also affect bone biology and hence the interaction between HAART and bone is noteworthy [26,27]. Mechanisms of HIV-associated osteopenia/osteoporosis The pathogenesis of reduced BMD in HIV-infected patients is probably multifactorial. Osteopenia and osteoporosis are bone lesions mainly correlated to risk factors such as sex, age, low body weight, malnutrition, immobility, lifestyle factors (smoking, alcohol abuse), glucocorticoid, hypogonadism and lipodystrophy [28]. The sum of traditional patient-related risk factors with HIV infection and HAART side effects can determine the onset of these bone lesions in HIV-infected patients. Bone cellular components Bone is a mineralized tissue composed of bone matrix and bone cells. Its homeostasis is mainly due to the tightly integrated contrasting activity of two major bone cell types: bone forming osteoblasts and bone resorbing osteoclasts. These cells are functionally connected and regulated by mediators such as hormones, vitamins and cytokines that strongly affect the skeletal biology throughout life [29]. Osteoblasts arise from mesenchymal stem cells and determine the formation and structural organization of bone extracellular matrix and its mineralization [30]. Mature osteoblasts synthesize several molecules involved either in bone formation or in regulating osteoclast activity such as type I collagen, osteocalcin, osteopontin, proteoglycans, receptor activator for nuclear factor κB ligand (RANKL) and osteoprotegerin (OPG) [31]. Notably, osteoblasts may also evolve to osteocytes when embedded in bone matrix, playing an important role in the control of architectural bone structure [32,33]. Osteoclasts are members of the monocyte/macrophage lineage originating from multiple cellular fusions of their precursors [34] that proliferate and differentiate towards mature osteoclasts by means of macrophage colony-stimulating factor (M-CSF) and RANKL [35]. M-CSF mainly induces precursor cell proliferation whereas RANKL plays a pivotal role in their differentiation, full functional activation and multiple cellular fusions of osteoclasts. Mature osteoclasts are able to resorb bone both by acid environment induction and secretion of lytic enzymes [36–38] such as cathepsin K and tartrate-resistant acid phosphatase (TRAP). The functional balance and cross-talk between osteoblasts and osteoclasts are crucial in determining bone mass (Fig. 1), which depends on the well tuned bone remodelling characterized by osteoclast bone resorption and osteoblast bone rebuilding phases [31]. An imbalance of the osteoblast/osteoclast interaction due to pathological conditions such as infection, hormonal, immunological and metabolic disorders, impairs both bone mass and structure impairment resulting in increased bone fragility and fracture risk.Fig. 1: Flow chart indicating bone mass loss after HIV infection. The well-tuned regulation between the bone resorption by osteoclasts and bone rebuilding by osteoblasts determines the bone homeostasis (a). When HIV infection occurs, this balance is impaired by increase of osteoclast differentiation and activity associated to apoptosis activation and biological activity inhibition of osteoblasts (b). Hence, HIV infection is able to elicit a preferential bone resorption with subsequent bone mass loss.The role of HIV infection As avian, feline and murine retroviruses are known to infect osteoblasts and osteocytes [39–41], early studies focused on the hypothesis that human osteoblasts may be a permissive target for HIV infection decreasing BMD through a direct viral mechanism. Some reports showed that HIV-1 transmission can occur during bone transplantation [42] and HIV-positive PCR assay has been observed in bone graft [43]. H9 cell line or peripheral blood mononuclear cells (PBMC) cocultivated with bone fragments from HIV-1-positive individuals displayed both a positive HIV RT activity and p24 detection in cell supernatants [44]. However, it was not clear whether blood or bone marrow HIV-positive cells contamination could be excluded in these studies. Mellert et al.[45] found that osteoblast-like cell lines were infected when challenged by HIV. Together, these data suggested that bone might be considered an HIV reservoir where the limited blood flow and the particular anatomical structure may also induce a poor antiretroviral concentration to tackle the HIV infection [46]. Moreover, the infection of osteoblasts may be closely related to the incomplete refilling of bone lacunae during bone remodelling with subsequent bone loss. In spite of these observations, further studies performed on human primary osteoblasts did not confirm the results obtained in osteoblast-like cell lines. The primary osteoblasts taken from HIV-positive individuals did not show viral DNA and RNA in PCR assays [47]. In addition, another study disclosed the failure of HIV productive infection when cultures of primary osteoblasts were challenged with classical HIV laboratory strains [48]. The lack of susceptibility may be partially explained by shortage of CD4 receptor and coreceptor proteins on osteoblast cell membrane [47,48]. In addition, as observed on CD34+ hematopoietic progenitor cell membrane [49], conceivably the CD4/CXCR4 complexes might be not so sterically closed to constitute the trimeric complex with gp120 essential for HIV entry. In addition to the direct effect of HIV replication, the apoptosis process plays a pivotal role in HIV pathogenesis. The progressive loss of CD4+ T lymphocytes is also related to apoptosis activated by the interaction between HIV gp120 and the CD4 receptor [50,51]. In addition, HIV-related apoptosis is a major mechanism involved in anaemia, thrombocytopenia and induction of neuronal cell death [52–54]. A recent paper showed an increased rate of apoptosis in primary osteoblasts treated by gp120 or challenged with heat-inactivated HIV laboratory strains [48]. Apoptosis activation occurs by a paracrin/autocrin mechanism due to TNF-α increase [48]. This finding may suggest that part of the bone loss detected in HIV-infected patients may be related both to apoptosis and the decreased biological activity of osteoblasts. The inhibitory effect of HIV gp120 on osteoblast function was confirmed by Cotter et al.[55] who found that gp120 (Fig. 2 and Table 2) reduces calcium deposition, alkaline phosphatase activity and bone specific Runt-related transcription factor 2 (RUNX-2) transcription factor expression after 24 h of treatment in primary osteoblast cultures. In agreement with these data, histomorphometric and serological analysis showed impairment in primary osteoblast functional activity and a consistent decrease of serum osteocalcin in HIV-infected patients [5,56,57].Fig. 2: Interaction between HIV and osteoblast lineage. (a) HIV gp120 determines Tumour necrosis factor alpha (TNF-α) expression increase in primary osteoblasts. TNF-α induces apoptosis activation in primary osteoblasts by paracrine/autocrine mechanisms. In addition, gp120 determines a downregulation of several osteoblast activity parameters inducing an inhibition of biological function of these cells. (b) The interaction between HIV and the osteoblast progenitor cells represented by the mesenchymal stem cells determines the inhibition of survival and proliferation by direct and indirect mechanisms. (c) HIV gp120 induces the inhibition of Runt-related transcription factor 2 (RUNX-2) protein and the activation of peroxisome proliferator-activated receptor gamma (PPAR-γ) with a preferential shift of mesenchymal cells differentiation from osteoblasts to fat cells.Table 2: HIV-related effects on bone cells.Osteoblasts are derived from bone marrow mesenchymal stem cells. Hence, some studies sought to establish whether mesenchymal stem cells and their differentiation towards osteoblasts are impaired by HIV infection (Fig. 2). Wang et al.[58] showed that bone marrow mesenchymal stem cells could be infected to a low extent by X4 tropic HIV strains leading to persistent harbouring of the virus inside these cells with subsequent inhibition of proliferation and survival. Several differentiation pathways from mesenchymal cells are also impaired by Tat through the upregulation of TNF-α and IL-1β expression. More recently, the interaction between specific HIV proteins and mesenchymal cells differentiating towards osteoblasts was analysed. In particular, p55gag and gp120 viral proteins elicited a derangement of specific transcription factors involved in the differentiation and activity of osteoblasts. HIV gp120 (Fig. 2) is also able to trigger the activation of peroxisome proliferator-activated receptor gamma (PPARγ) determining an MSC differentiation switch from osteoblasts to adipocytes [55,59]. Several reports have also analysed the influence of HIV on osteoclasts (Table 2). RANKL and M-CSF are key factors modulating the proliferation and differentiation of osteoclast lineage cells. A significant increase in plasma RANKL levels with an impairment of RANKL/OPG ratio was described in HIV-positive patients [60]. The RANKL increase correlated with high plasma viral RNA load indicating a direct relation between HIV infection status and RANKL synthesis [60–62]. Moreover, gp120 upregulated RANKL secretion (Fig. 3) in primary T cells [63] whereas Vpr synergized the glucocorticoid-mediated activation of RANKL in several cell systems such as primary T cells and Jurkat lymphoblastoid cell line [64]. In turn, RANKL upregulates HIV replication in acutely and chronically infected monocyte and T-lymphocyte lineages suggesting a feedback loop between HIV replication and RANKL production [65].Fig. 3: Description of main HIV-related mechanisms of osteoclast activation. HIV gp120 protein elicits the upregulation of receptor activator for nuclear factor kB ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) in T lymphocytes and macrophages respectively determining the increase of osteoclast differentiation and activity.M-CSF is a haematopoietic growth factor controlling the survival, proliferation and differentiation of the monocyte-macrophage lineage and it is closely involved in the early phases of osteoclast differentiation. The pivotal involvement of M-CSF and its receptor in osteoclast differentiation was also confirmed by osteopetrosis and bone alterations in mice mutated in the CSF-1 or c-fms gene [66,67]. HIV infection of macrophages induces a significant increase in M-CSF production and secretion [68], which in turn promotes further HIV infection of macrophages through the increase in CD4/CCR5 receptors and virus gene expression [69–72]. M-CSF elicits osteoclast differentiation also enhancing the RANKL effect (Fig. 3). In addition, Yamada et al.[73] showed that bone marrow macrophages (BMMs) cultured without M-CSF produce a large amount of OPG compared with cells cultured with M-CSF. This finding suggests that M-CSF downregulates OPG production in BMMs. As OPG, a TNF receptor family secreting glycoprotein, inhibits osteoclast differentiation by acting as a decoy RANKL receptor, the increasing level of M-CSF during HIV infection impairs the balance between RANKL/RANK and OPG, increasing osteoclasts (Table 2). The role of HAART In 1995, the introduction of HAART in the treatment of HIV infection led to a dramatic and sustained decrease in HIV-related morbidity and mortality [74]. HAART typically combines nucleoside analogue reverse transcriptase inhibitors (NRTIs) with either HIV protease inhibitors or nonnucleoside reverse transcriptase inhibitors (NNRTIs). Despite controversial results regarding antiretroviral molecules and bone loss, several groups investigated the possible bone damage mechanisms of specific antiretroviral classes. The role of N(n)RTIs The nucleoside analogues (NRTIs) are antiretroviral molecules whose chemical structure is a modified nucleoside. These compounds suppress the replication of retroviruses by interfering with the reverse transcriptase enzyme activity causing premature termination of the proviral HIV DNA chain. Abacavir, didanosine, emtricitabine, lamivudine, stavudine, zalcitabine and zidovudine are currently used in HAART. Despite the major positive impact of these molecules in HIV therapy, clinical observations disclosed severe side effects such as mitochondrial toxicity, hyperlactataemia and lactic acidosis. To varying degrees, NRTIs inhibit the DNA polymerase-γ [75], the enzyme involved in the replication of mitochondrial DNA, leading to mitochondrial damage and dysfunction [76]. In-vitro studies disclosed some differences in the induction of specific NRTI-related mitochondrial DNA depletion. The so-called 'd-drugs' ddC (zalcitabine), ddI (didanosine), and d4T (stavudine) are relatively stronger inhibitors of polymerase-γ than other nucleoside analogues, called 'non-D drugs' [77,78]. In the presence of mitochondrial dysfunction or depletion, the metabolism of pyruvate is shifted the production of with a decrease in does not to lactic even though this condition is in individuals with virus and patients plus Several studies on patients demonstrated that hyperlactataemia is a relatively common in of individuals a whereas lactic is in than of patients et analysed patients by and found an between levels and reduced BMD (Table 3). These data suggest that lactic by NRTIs may osteopenia by a mechanism related to calcium loss as the bone to chronic acidosis. This damage mainly affects the trabecular which represents the of bone and is a of calcium than cortical bone. In addition the systemic effects of a paper by et (Table 3) showed a specific interaction between zidovudine and bone. the inducing osteopenia in a murine 3: and it is commonly with is a analogue with In-vitro studies demonstrated that the of to mitochondrial is low compared with other NRTIs studies have that is the primary of by a of secretion and and some of was noted in different This is related to dysfunction due to cell and correlates with an impaired The dysfunction may elicit the of whereas the reduced is associated with a decrease in the function of the an enzyme involved in metabolism Some and reports have described a with (Table 3) in HIV-infected patients in the presence of was mainly observed in patients treated with therapy or The impaired balance and metabolism related to may determine an in HIV some studies found an between use of and bone damage and a higher of fracture was also found in patients compared with individuals The between and was not confirmed by other studies. A cohort study in showed a in patients with normal but it was not significant with to patients. The and studies performed on a large number of patients with no of found the same of serum and in the and after 24 of treatment. The a over compared a treatment of and with a treatment of stavudine, and in patients the and These controversial results may be related to cohort as the patients in the studies did not show low is that the specific HAART and functional conditions of patients the interaction between and bone. The role of protease inhibitors inhibitors HIV replication by the viral protease a pivotal in the of the viral replication The viral obtained in the presence of protease cannot infect the target cells. and are the protease inhibitors used for antiretroviral The protease interaction has been in bone cell cultures (Table 3). The effects of protease inhibitors on osteoclasts were osteoclast activity in and showed activity whereas and did studies demonstrated that and osteoclast activity through the of a to RANKL represented by gamma of TNF receptor associated factor RANKL to the of resulting in the activation of nuclear factor of activated cells and protein pathways involved in the survival and differentiation of osteoclasts. A subsequent paper showed that had effects by This finding suggested a complex in the between protease inhibitors and the osteoclast lineage. inhibitors were also on the human mesenchymal stem cells differentiating to osteoblast lineage. These that and bone formation and calcium decreasing osteoblast activity A recent paper by et protease inhibitors on primary osteoblasts and found a decreased osteoblast activity of alkaline calcium and when and were these studies suggest that some protease inhibitors may determine bone loss by increasing osteoclast resorption and the osteoblast rebuilding is noteworthy that some studies investigated the possible between use of protease inhibitors and decreased serum is essential for the maintenance of a normal bone structure increasing the bone The biological effects on bone remodelling are by a activation to in the by of in the whereas is mainly by The can determine through the of to bone The and involved in are and protease inhibitors are inhibitors of human but also and affect the enzyme to a enzyme activity production (Table 3) whereas no inhibition of is observed Some clinical studies investigated in HIV-infected was observed the advent of HAART and a severe of was associated with infection and immune studies performed on a cohort of naive and HAART-treated patients demonstrated a high prevalence of suggesting a risk of These with the effects on regulation indicate that may be an mechanism of bone depletion. could be as a of bone impairment in HIV infection. This problem is not in the because the studies that have to bone impairment have used the DXA This is a to determine bone mineral but cannot between osteoporosis (low BMD and bone and (low BMD with normal bone of osteopenia/osteoporosis in HIV-infected patients In clinical their HIV-infected such as the of and specific are not several have been to bone conditions during HIV disease and the HAART (Table on and monitoring of HIV-related bone and DXA analysis is a to determine BMD and will between cortical and trabecular two different that may to antiretroviral Hence, DXA be performed in as studies have demonstrated that it will fracture risk A meta-analysis that the risk of hip fracture increased for standard decrease in BMD the DXA are not and cannot the analysis but a major be to BMD in HIV-infected patients. The recent by the for the T-score with the value by WHO only for in data are it is that the same can be to over the of have major risk factor for individuals than diagnosis is the that the BMD with that of a and sex-matched population. However, the has no clear value for osteopenia and osteoporosis and the are patients with values than −1 are as low bone whereas a severe bone mass is by values than The may further analysis of BMD and a of this parameter in the of bone loss in HIV-infected can only be by bone that will large of bone As bone are the diagnosis of is indirect and is by DXA analysis with some blood Hence, DXA may the rate in this population as an number of patients may have been with a diagnosis be in to Osteoporosis is commonly treated with or whereas high of and spine are to be in patients with in the patients with marked and in patients with severe spine the in patients with a diagnosis of Bone biology parameters can be by laboratory and calcium calcium and In addition, bone formation osteocalcin or alkaline and bone resorption or or can with and may be obtained by and with a low inducing a decrease in the function of in the kidney and in and the of kidney function alterations may occur with normal and may an impairment of function for lactic monitoring and during may on the side effects of NRTIs on bone. et suggested that plasma RANKL and OPG may be in some cases of therapy as impairment of the RANKL/OPG is well described in patients protease HAART. though data indicate that and protease with and the RANKL/OPG and may to a in the bone resorption The of these cytokines is not part of the of HIV-infected patients. The management of osteopenia/osteoporosis in the course of HIV infection may be on a in risk calcium and and (Table and in HIV-related bone can be to and to control body In addition, patients have to an of calcium and However, be to HIV-infected patients The limit for is but this is below the that has been even with the of A of can be suggested to The only to is and when serum calcium is can be A low calcium has been demonstrated to reduce BMD and to increase the hip fracture risk The calcium for is between and but it is to this in it is important for to be to HIV-infected patients. When and low calcium have been can be are to The for is well demonstrated for and therapy, and human studies have been on the treatment of HIV-induced osteoporosis with to the low number of individuals the results obtained have a limited even though showed that increased BMD with to More recently, results were obtained in two therapy with data are on fracture studies are to the effects of both on BMD and fracture risk in HIV-related bone disease. especially in the risk of fractures is high and this is The and of treatment be for the data or be considered to bone mineral density and decrease fracture The effects associated with and osteonecrosis but the relatively low risk of this last effect does not the use of A possible in the treatment of osteoporosis may be the use of the As described RANKL induces osteoclast activation and its upregulation was noted both in HIV-positive and patients with osteopenia/osteoporosis A clinical study on for demonstrated an increase in BMD and a decrease of bone turnover This finding suggested its possible use in osteoporosis treatment even in HIV-positive compounds such as OPG interaction receptor and bone are study interaction further is these can be in HIV-infected patients (Table in diagnosis and therapy on bone in HIV-infected Bone derangement is a major clinical in the course of HIV infection The advent of HAART has led to a longer life expectancy and bone disease is to enhancing the bone loss. Some in individuals indicate that the of osteoporosis after of between and and the fracture risk for a is greater than 50% These data suggest that the number of HIV patients with bone disease and fractures can be to increase dramatically in the because these patients also have two other HIV and antiretroviral Hence, antiretroviral therapy be by the clinical management of bone disease to reduce the risk of osteoporosis and fractures in these patients. This was by of the of the study for for selected of the of and the that have no or that may constitute a dual or

Bisphosphonates can increase bone mineral density (BMD) in children with osteogenesis imperfecta (OI). In this study of adults with OI type I, risedronate increased BMD at lumbar spine (but not total hip) and decreased bone turnover. However, the fracture rate in these patients remained high. Intravenous bisphosphonates given to children with OI can increase BMD and reduce fracture incidence. Oral and/or intravenous bisphosphonates may have similar effects in adults with OI. We completed an observational study of the effect of risedronate in adults with OI type I. Thirty-two adults (mean age, 39 years) with OI type I were treated with risedronate (total dose, 35 mg weekly) for 24 months. Primary outcome measures were BMD changes at lumbar spine (LS) and total hip (TH). Secondary outcome measures were fracture incidence, bone pain, and change in bone turnover markers (serum procollagen type I aminopropeptide (P1NP) and bone ALP). A meta-analysis of published studies of oral bisphosphonates in adults and children with OI was performed. Twenty-seven participants (ten males and seventeen females) completed the study. BMD increased at LS by 3.9% (0.815 vs. 0.846 g/cm(2), p = 0.007; mean Z-score, -1.93 vs. -1.58, p = 0.002), with no significant change at TH. P1NP fell by 37% (p = 0.00041), with no significant change in bone ALP (p = 0.15). Bone pain did not change significantly (p = 0.6). Fracture incidence remained high, with 25 clinical fractures and 10 major fractures in fourteen participants (0.18 major fractures per person per year), with historical data of 0.12 fractures per person per year. The meta-analysis did not demonstrate a significant difference in fracture incidence in patients with OI treated with oral bisphosphonates. Risedronate in adults with OI type I results in modest but significant increases in BMD at LS, and decreased bone turnover. However, this may be insufficient to make a clinically significant difference to fracture incidence.

This study examined whether 24 months of weight training exercises enhanced the effectiveness of risedronate, calcium, and vitamin D in maintaining or improving bone mineral density (BMD) in 223 postmenopausal breast cancer survivors. Subjects who were > or =50% adherent to exercise had no improvement in BMD but were less likely to lose BMD. This study examined whether (1) postmenopausal breast cancer survivors (BCS) with bone loss taking 24 months of risedronate, calcium, and vitamin D had increased bone mineral density (BMD) at the total hip, femoral neck, L1-L4 spine, total radius and 33% radius, and decreased bone turnover; (2) subjects who also participated in strength/weight training (ST) exercises had greater increases in BMD and greater decreases in bone turnover; and (3) subjects who also exercised were more likely to preserve (at least maintain) BMD. Postmenopausal BCS (223) were randomly assigned to exercise plus medication or medication only groups. Both groups received 24 months of 1,200 mg of calcium and 400 IU of vitamin D daily and 35 mg of risedronate weekly, and the exercise group additionally had ST exercises twice weekly. After 24 months, women who took medications without exercising had significant improvements in BMD at the total hip (+1.81%) and spine (+2.85%) and significant decreases in Alkphase B (-8.7%) and serum NTx (-16.7%). Women who also exercised had additional increases in BMD at the femoral neck (+0.29%), total hip (+0.34%), spine (+0.23%), total radius (+0.30%), and additional decreases in Alkphase B (-2.4%) and Serum NTx (-6.5%). Additional changes in BMD and bone turnover with exercise were not significant. Subjects who were > or =50% adherent to exercise were less likely to lose BMD at the total hip (chi-square [1] = 4.66, p = 0.03) and femoral neck (chi-square [1] = 4.63, p = 0.03). Strength/weight training exercises may prevent loss of BMD in postmenopausal BCS at risk for bone loss.

Objective. The aim of the present study was to compare the effects of raloxifene and low-dose hormone replacement therapy (HRT) on bone mineral density (BMD) and bone turnover markers in the treatment of postmenopausal osteoporosis.Methods. Forty-two postmenopausal osteoporotic women, who were randomized to receive raloxifene 60 mg or estradiol 1 mg/norethisterone acetate 0.5 mg daily for 1 year, were studied. All women received calcium 600 mg/day and vitamin D 400 IU/day. BMD and markers of bone turnover were measured at baseline and at 12 months.Results. After 12 months of treatment, there were statistically significant increases in BMD in both groups at all sites (all p < 0.05). For the lumbar spine, the increase in BMD was 2.3% for raloxifene compared with 5.8% for low-dose HRT and corresponding values for total body BMD were 2.9% for raloxifene and 4.6% for low-dose HRT; the increases being significantly greater in the low-dose HRT group (p < 0.001 and p = 0.02, respectively). Although the increase in BMD at the hip was significant for both raloxifene (2.1%) and low-dose HRT (3.2%) compared with baseline, the difference between the two regimens did not reach statistical significance. The decrease in serum C-terminal telopeptide fragment of type I collagen and serum osteocalcin levels for the low-dose HRT group (−53% and −47%, respectively) was significantly greater than for the raloxifene group (−23% and −27%, respectively; both p < 0.01).Conclusions. In postmenopausal women with osteoporosis, low-dose HRT produced significantly greater increases in BMD of the lumbar spine and total body and greater decreases in bone turnover than raloxifene at 12 months.

Therapeutic management of bone demineralization in the HIV-infected population

Health Care For Our Bones: A Practical Nutritional Approach to Preventing Osteoporosis

Bone mass and bone metabolism in pediatric gastrointestinal disorders.

A theoretical analysis of the contributions of remodeling space, mineralization, and bone balance to changes in bone mineral density during alendronate treatment

To compare the relative sensitivity and specificity of bone turnover indexes for bone loss or gain in early postmenopausal women, we performed a multicenter trial in 236 menopausal women (mean age, 51 yr), who were randomized to hormone replacement therapy (HRT) or calcium supplementation (CS; 500 mg/day) for 1 yr. Two markers of bone formation, osteocalcin (OC) and bone alkaline phosphatase (BSAP), and two markers of bone resorption, urinary N-telopeptide (NTx) and urinary free deoxypyridinoline (fDpd), as well as spine and femoral neck bone mineral density (BMD) were measured at baseline and 3, 6, and 12 months after treatment. Women receiving HRT (n = 105) showed a significant increase in spine BMD (+2.5%; P < 0.0001) and hip BMD (+1.0%; P = 0.02) compared to women receiving CS, who showed a decline at both sites (-1.1%; P < 0.01). All four markers showed time-dependent decreases in women receiving HRT (P < 0.001) and no change in women receiving CS alone. When baseline indexes of turnover were stratified by quartile, there was a significantly greater increase in BMD among those with the highest NTx, OC, and BSAP levels compared to that in those with the lowest NTx, OC, and BSAP levels (P < 0.05). The highest quartile for percent change from baseline to 6 months in fDpd, BSAP, and NTx was also associated with the greatest change in spine BMD at 1 yr. Receiver operator characteristic curves for percent change from baseline to 6 months in an individual marker to 1 yr change in BMD during HRT revealed that the percent change in NTx provided the greatest discrimination between gain and loss of BMD. When subjects receiving HRT were compared by their positive or negative skeletal response at 1 yr and their baseline turnover marker, initial NTx values were significantly higher in those that gained bone than in those that lost bone (P = 0.0002). CS women in the highest quartile for NTx at baseline had significantly greater decreases in spine BMD than subjects with the lowest NTx values (P < 0.005), although this was not true for fDpd (P < 0.20). In conclusion, for early postmenopausal women there are differential responses of biochemical markers to HRT and CS. Baseline urinary NTx and serum OC were the most sensitive predictors of change in spine BMD after 1 yr of either HRT or CS. Similarly, the percent change in NTx and OC from baseline to 6 months best predicted bone gain or loss. We conclude that markers of bone formation and resorption can be used clinically to predict future BMD in early postmenopausal women.