Risedronate on 2 Consecutive Days a Month Reduced Vertebral Fracture Risk at 1 Year Compared With Historical Placebo

The use of historical controls may be a viable alternative for comparing antifracture efficacy in osteoporosis fracture endpoint trials that do not have a placebo control group. The risedronate 2 consecutive days a month (2CDM) study showed that risedronate 75 mg on 2 consecutive days had similar increases in bone mineral density compared with risedronate 5 mg/d. To assess the antifracture efficacy of this regimen, data collected in the 2CDM study were analyzed using historical control data matched for key clinical characteristics from 2 placebo-controlled trials. Fracture rates in historical groups were compared with those of the 2CDM study treatment groups. At 12 mo, vertebral fractures occurred in 5.1% and 1.0% of the placebo and 5-mg risedronate historical patients, respectively. In the risedronate 5 mg/d and 75 mg 2CDM groups, fracture incidence was 1.5% and 1.1%, respectively. Based on comparisons with the historical control group, risedronate 75 mg 2CDM appears as effective as the 5-mg/d dose in reducing the risk of new vertebral fractures in the first year of treatment. The use of appropriate historical control data may provide an alternative design to assess fracture effects in osteoporosis trials for which simultaneous placebo-controlled data are unavailable.     

Distinct effect of zoledronate and clodronate on circulating levels of DKK1 and sclerostin in women with postmenopausal osteoporosis

The coupling of bone formation to bone resorption during treatment of postmenopausal osteoporosis with antiresorbers might be related to changes in Wnt/b-catenin signaling. We compared the effects of two bisphosphonate treatments on two Wnt-inhibitors Sclerostin (SOST) and Dickkopf-related protein 1 (DKK1).The study population included 74 women with postmenopausal osteoporosis participating simultaneously in two multicenter, placebo controlled trials. The patients were randomized to: intramuscular clodronate 100 mg/week (CLO) (N = 36), and yearly intravenous therapy with 5 mg zoledronate (ZOL) (N = 18) and placebo (N = 20).Bone turnover markers (intact N-propeptide of type I collagen [P1NP], C-terminal telopeptide of type I collagen [CTX]) remained unchanged in the placebo group while they significantly decreased during treatment with the two bisphosphonates, versus both placebo and baseline. In CLO treated patients serum DKK1 remained stable over the entire period of observation while serum SOST levels increased significantly after 12 months of treatment both versus placebo group (p < 0,005), baseline (p < 0,001) and ZOL treated group.In the ZOL group, DKK1 levels increased significantly within one month and for the following 6 months and it fell back to baseline values at 12 months. The second ZOL infusion was again associated with an increase in DKK1 a month later, although to a lesser extent.In conclusion, in this study we have found that the treatment of postmenopausal osteoporosis with intermittent yearly ZOL is associated with transient and declining increases in DKK1 while continuous treatment with CLO, results in a late increase in serum SOST. These preliminary results and further ad hoc studies might contribute to shed light on our understanding of the bone coupling effects taking place during treatment of osteoporosis with different anti-resorbers or with different treatment regimens.     

Risedronate may preserve bone microarchitecture in breast cancer survivors on aromatase inhibitors: A randomized,controlled clinical trial

This study provides preliminary evidence that risedronate not only preserves BMD but may also attenuate the loss of bone microarchitecture over 2 years during a time of accelerated bone loss in post-menopausal breast cancer survivors on aromatase inhibitors.IntroductionAccelerated bone loss and elevated fracture risk are associated with the use of aromatase inhibitors (AIs) in women with breast cancer. We previously reported that the oral bisphosphonate, risedronate, can maintain bone mineral density (BMD) in the hip and spine over 2-years in post-menopausal breast cancer survivors on AIs. In this study, we examined whether oral bisphosphonates can also preserve bone microarchitecture as measured by the trabecular bone score (TBS) in this population.MethodsThis 2-year randomized, double-blind, placebo-controlled trial included postmenopausal women over age 55 with breast cancer on an AI who had low bone mass. Participants provided informed consent and were randomized to risedronate 35 mg once weekly or placebo. We examined 12- and 24-month changes in spine TBS, analyzed using linear mixed models.ResultsOne-hundred and nine women with a mean age of 70.5 years were included in the analysis. In the placebo group, BMD declined at the spine and hip over the 24-month period but was preserved in the active treatment group (data previously reported). TBS declined in the placebo group by − 2.1% and − 2.3% at 12- and 24-months, respectively (p < 0.005). The TBS percent change in bisphosphonate-treated patients was − 0.9% and − 1.3% at 12 and 24-months but did not reach statistical significance (p = 0.24 and 0.14). The 12- and 24-month between-group differences were 0.9 (p = 0.38) and 0.8 (p = 0.44) percentage points. TBS change correlated with spine BMD changes in the placebo group at 12- and 24-months (r = 0.33 and 0.34, p < 0.01) but not in the active treatment group.ConclusionThe oral bisphosphonate risedronate preserves BMD and may attenuate loss of bone microarchitecture over 2 years during a time of accelerated bone loss in breast cancer survivors on AIs, but more definitive evidence is needed.     

Loss of milk fat globule-epidermal growth factor 8 (MFG-E8) in mice leads to low bone mass and accelerates ovariectomy-associated bone loss by increasing osteoclastogenesis

Milk fat globule-epidermal growth factor 8 (MFG-E8) is a glycoprotein that controls the engulfment of apoptotic cells and exerts inflammation-modulatory effects. Recently, it has been implicated in osteoclastogenesis and the pathogenesis of inflammatory periodontal bone loss, but its role in physiological bone homeostasis is still not well defined. Here, we evaluated the influence of MFG-E8 on osteoblasts and osteoclasts and its impact on bone remodeling in healthy and ovariectomized mice as a model for post-menopausal osteoporosis.Total and trabecular bone mineral densities at the lumbar spine in 6-week-old MFG-E8 KO mice were reduced by 11% (p < 0.05) and 17% (p < 0.01), respectively, as compared to wild-type (WT) mice. Accordingly, serum levels of the bone formation marker P1NP were decreased by 37% (p < 0.01) in MFG-E8 KO mice as were the ex vivo mineralization capacity and expression of osteoblast genes (Runx2, alkaline phosphatase, osteocalcin) in MFG-E8 KO osteoblasts. In contrast, serum bone resorption markers CTX1 and TRAP5b were increased by 30% and 60% (p < 0.05), respectively, in MFG-E8 KO mice. Furthermore, bone marrow macrophages from MFG-E8-KO mice differentiated more effectively into osteoclasts, as compared to WT cells. MFG-E8-deficient osteoclasts displayed increased bone resorption ex vivo, which could be reversed by the presence of recombinant MFG-E8. To determine the significance of the enhanced osteoclastogenesis in MFG-E8 KO mice, we performed an ovariectomy, which is associated with bone loss due to increased osteoclast activity. Indeed, MFG-E8 KO mice lost 12% more trabecular bone density than WT mice after ovariectomy.Together, these data indicate that MFG-E8 controls steady-state and pathological bone turnover and may therefore represent a new target gene in the treatment of bone diseases.     

Odanacatib,effects of 16-month treatment and discontinuation of therapy on bone mass,turnover and strength in the ovariectomized rabbit model of osteopenia

Odanacatib (ODN) a selective and reversible cathepsin K inhibitor, inhibits bone resorption, increases bone mass and reduces fracture risk in women with osteoporosis. A 16-month (~ 7-remodeling cycles) study was carried out in treatment mode to assess the effects of ODN versus ALN on bone mass, remodeling status and biomechanical properties of lumbar vertebrae (LV) and femur in ovariectomized (OVX) rabbits. This study also evaluated the impact of discontinuing ODN on these parameters. Rabbits at 7.5 months post-OVX were dosed for 16-months with ODN (7.5 μM·h_0–24, in food) or ALN (0.2 mg/kg/wk, s.c.) and compared to vehicle-treated OVX- (OVX + Veh) or Sham-operated animals. After 8 months, treatment was discontinued in half of the ODN group. ODN treatment increased in vivo LV aBMD and trabecular (Tb) vBMD until reaching plateau at month 12 by 16% and 23% vs. baseline, respectively, comparable levels to that in Sham and significantly above OVX + Veh. LV BMD was also higher in ALN that plateaued around month 8 to levels below that in ODN or Sham. ODN treatment resulted in higher BMD, structure and improved biomechanical strength of LV and central femur (CF) to levels similar to Sham. ALN generally showed less robust efficacy compared to ODN. Neither ODN nor ALN influenced material properties at these bone sites following ODN or ALN treatment for 7 remodeling cycles in rabbits. ODN and ALN persistently reduced the bone resorption marker urinary helical peptide over study duration. While ALN reduced the bone formation marker BSAP, ODN treatment did not affect this marker. ODN also preserved histomorphometry-based bone formation indices in LV trabecular, CF endocortical and intracortical surfaces, at the levels of OVX + Veh. Discontinuation of ODN returned bone mass, structure and strength parameters to the comparable respective levels in OVX + Veh. Together, these data demonstrate efficacy and bone safety profile of ODN and suggests the potential long-term benefits of this agent over ALN with respect to accrued bone mass without long-term effects on bone formation.     

A reversal phase arrest uncoupling the bone formation and resorption contributes to the bone loss in glucocorticoid treated ovariectomised aged sheep

Large animals as sheep are often used as models for human osteoporosis. Our aim was therefore to determine how glucocorticoid treatment of ovariectomised sheep affects the cancellous bone, determining the cellular events within the bone remodelling process that contributes to their bone loss. Twenty female sheep were assigned for two groups; an untreated control group and an ovariectomised group treated with glucocorticoids (0.6 mg/kg/day, 5 times weekly) for 7 months.At 7 months the glucocorticoid-treated ovariectomised sheep showed a significant change in the bone microstructure revealed by a decreased trabecular bone volume and thickness compared to the control sheep. The treatment led to a temporary elevation of the bone resorption marker CTX (c-terminal collagen telopeptide), while the bone formation marker osteocalcin remained suppressed all 7 months. Histomorphometrically, the treated sheep had a complete absence of osteoid surfaces, and a 5-fold increase in the extent of eroded/reversal surfaces after 7 months. Most of these reversal surfaces were actually arrested reversal surfaces, defined as reversal surfaces without the presence of neighbouring osteoid surfaces or osteoclasts, which is classically observed next to active reversal surfaces. As in humans, these arrested reversal surfaces had compared to active reversal surfaces a reduced canopy coverage, a significantly decreased cell density, and a decreased immunoreactivity for the osteoblastic markers osterix, runx2 and smooth muscle actin in the mononuclear reversal cells colonising the surfaces.In conclusion, glucocorticoid treatment of ovariectomised sheep induced a significant bone loss, caused by an arrest of the reversal phase, resulting in an uncoupling of the bone formation and resorption during the reversal phase, as recently demonstrated in postmenopausal women with glucocorticoid-induced osteoporosis. This supports the relevance of the sheep model to the pathophysiology of glucocorticoid-induced osteoporosis in postmenopausal women, making it a relevant preclinical model for orthopaedic implant and biomaterial research.     

An oral cathepsin K inhibitor ONO-5334 inhibits N-terminal and C-terminal collagen crosslinks in serum and urine at similar plasma concentrations in postmenopausal women

Relationships between the plasma concentration of a cathepsin K inhibitor (ONO-5334) and inhibition of bone resorption markers N-telopeptide of type I collagen (NTX) and C-telopeptide of type I collagen (CTX) in serum and urinary NTX/creatinine and CTX/creatinine were examined in 10 postmenopausal women. The subjects received slow-release tablets of 100 mg ONO-5534 under fasted or fed conditions in a study with a crossover design. Inhibition of serum NTX and CTX levels and plasma concentrations of ONO-5334 were monitored at 0, 24, 48 and 168 h after dosing. Changes in urinary NTX/creatinine and CTX/creatinine levels in second morning urine were evaluated on 0, 1, 2 and 7 days after dosing. Data were analyzed using sigmoid maximal drug effect (E_max) models. The maximal inhibition, estimated E_max values, were − 31.8% for serum NTX, − 53.1% for serum CTX, − 67.2% for urinary NTX/creatinine, and − 95.2% for urinary CTX/creatinine. The estimated half maximal effective plasma concentrations (EC₅₀) of ONO-5334 and confidence intervals were 1.79 (1.01 to 3.16) ng/mL for serum NTX, 2.07 (1.63 to 2.62) ng/mL for serum CTX, 1.85 (1.30 to 2.61) ng/mL for urinary NTX/creatinine, and 1.98 (0.94 to 3.76) ng/mL for urinary CTX/creatinine. EC₅₀ values for the four crosslinks did not significantly differ, as indicated by the overlapping 95% confidence intervals. The highest signal-to-noise ratio was achieved with serum CTX, and was 2-fold higher than that on serum NTX. Inhibition for serum NTX and CTX, and urinary NTX/creatinine and CTX/creatinine by ONO-5334 were all correlated with correlation coefficients ranging from 0.55 to 0.80. In conclusion, data of ONO-5334 slow-releasing tablets in postmenopausal women were well fitted in E_max model. In all measured telopeptides, the maximal inhibition was obtained at urinary CTX/creatinine level, but serum CTX had the highest signal-to-noise ratio. Inhibition for all measured telopeptides by ONO-5334 were all correlated. The estimated half maximal effective plasma concentrations were not significantly different between all measured telopeptides.     

Zoledronic acid for treatment of osteopenia and osteoporosis in women with primary breast cancer undergoing adjuvant aromatase inhibitor therapy

BackgroundPostmenopausal women with osteoporosis/osteopenia are at increased risk of fracture. Aromatase inhibitors further increase bone loss in these patients. This study evaluates whether zoledronic acid prevents the bone loss expected when these patients initiate letrozole.Patients and methodsPostmenopausal women with estrogen and/or progesterone receptor-positive breast cancer and a bone mineral density (BMD) T-score <?2.0 were given letrozole 2.5 mg/vitamin D 400 international units daily, calcium 500 mg twice daily, and 4 mg zoledronic acid every 6 months. The BMD was assessed at baseline and 1 year. The primary endpoint was the mean change in lumbar spine (LS) BMD at 1 year.ResultsForty-six patients completed 1 year of treatment. LS BMD increased by 2.66% (p = 0.01), femoral neck (FN) by 4.81% (p = 0.01), and any measured endpoint by 4.55% (p = 0.0052).ConclusionsZoledronic acid prevents bone loss in postmenopausal women with osteoporosis/osteopenia starting letrozole and is associated with improvements in BMD.     

Denosumab: A cost-effective alternative for older men with osteoporosis from a Swedish payer perspective

ObjectiveTo assess the cost-effectiveness of denosumab versus other treatments in men with osteoporosis who are ≥ 75 years old from a payer perspective in Sweden.MethodsA lifetime cohort Markov model was developed with seven health states: well, hip fracture, vertebral fracture, other osteoporotic fracture, post-hip fracture, post-vertebral fracture, and dead. During each cycle, patients could have a fracture, remain healthy, remain in a post-fracture state or die. Background fracture risks, mortality rates, persistence rates, utilities, medical and drug costs were derived using published sources. Estimates of fracture efficacy were drawn from available studies in post-menopausal osteoporotic (PMO) women as BMD improvements have been shown to be similar across male osteoporosis (MOP) and PMO populations, and a recent clinical trial suggested that the fracture risk reduction from bisphosphonate therapy in men is similar to that seen in women in comparable studies. Lifetime expected costs and quality-adjusted life-years (QALYs) were estimated for denosumab, generic alendronate, generic risedronate, ibandronate, zoledronate, strontium ranelate and teriparatide. On average, patients in the model were 78 years old, with bone mineral density T-score at the femoral neck of − 2.12. Prevalent vertebral fractures were present in 23% of patients. In the base-case, the model assumed that patients would experience treatment-related effects up to 2 years after discontinuation. Costs and QALYs were discounted at 3% annually. Extensive sensitivity analyses were conducted.ResultsTotal lifetime costs for denosumab, alendronate, strontium ranelate, zoledronate, risedronate, ibandronate and teriparatide were €31,004, €33,731, €34,788, €34,796, €34,826, €35,983 and €37,461, respectively. Total QALYs were 5.23, 5.15, 5.15, 5.17, 5.13, 5.12 and 5.22, respectively. Compared to other treatments, denosumab had the lowest costs and highest QALYs. In the one-way sensitivity analyses, when compared to alendronate (next least expensive strategy), the ICER for denosumab was most sensitive to the relative risk of hip fracture on denosumab. The probability of denosumab being cost-effective compared to the other treatments at a threshold of €66,000/QALY was 96.1%.ConclusionDenosumab dominated all comparators, including generic bisphosphonates, in the treatment of osteoporosis in men who were ≥ 75 years old in Sweden.     

The effects of thyrotropin-suppressing therapy on bone metabolism in patients with well-differentiated thyroid carcinoma

Studies on the effects of levothyroxine (LT4) therapy on bone and bone metabolism have yielded conflicting results. This 1-year prospective study examined whether LT4 in patients with well-differentiated thyroid carcinoma (DTC) is a risk factor for bone mass loss and the subsequent development of osteoporosis.We examined 93 patients with DTC over 12 months after initiating LT4 therapy (early postoperative period). We examined another 33 patients on long-term LT4 therapy for DTC (late postoperative period). Dual energy X-ray absorptiometry was performed at baseline and after 1 year.The mean bone losses during the early postoperative period in the lumbar spine, femoral neck, and total hip, calculated as the percentage change between levels at baseline and 12 months, were − 0.88, − 1.3 and − 0.81%, respectively. Bone loss was more evident in postmenopausal women (lumbar spine − 2.1%, femoral neck − 2.2%, and hip − 2.1%; all P < 0.05). We compared the changes in annual bone mineral density (BMD) in postmenopausal women according to calcium/vitamin D supplementation. Bone loss tended to be higher in the postmenopausal women receiving no supplementation. There was no decrease in BMD among patients during the late postoperative period. The mean bone loss was generally greater in the early than in the late postoperative group, and this was significant at the lumbar spine (P = 0.041) and femoral neck (P = 0.010).TSH-suppressive levothyroxine therapy accelerates bone loss, predominantly in postmenopausal women and exclusively during the early post-thyroidectomy period.     

Urinary γ-glutamyltransferase (GGT) as a potential marker of bone resorption

We recently identified γ-glutamyltransferase (GGT) as a novel bone-resorbing factor. The present study was undertaken to determine whether GGT is a marker of bone resorption in two genetic models of hyper- and hypo-function of osteoclasts, as well as in postmenopausal women with accelerated bone resorption, using type I collagen N-telopeptide (NTX) and deoxypyridinoline (DPD) as established biochemical markers. Urinary excretion of GGT, corrected for creatinine, was found to be increased in osteoprotegerin (OPG)-deficient osteoporotic mice as well as in patients with postmenopausal osteoporosis (67–83 years of age); in both cases the urinary level decreased after treatment of patients or mice with alendronate, a selective inhibitor of bone resorption, concomitantly with a reduction in DPD and NTX. Conversely, in osteopetrotic op/op mice, urinary GGT increased in parallel with DPD after induction of osteoclasts with M-CSF injection. Constant infusion of parathyroid hormone (PTH) also increased urinary GGT along with DPD. In a survey of 551 postmenopausal women (50–89 years of age) at their regular health checkup, urinary GGT excretion exhibited a high correlation with DPD (ρ = 0.49, p < 0.0001). The calculated sensitivity and specificity for diagnosing elevated bone resorption, as determined by a DPD value higher than 7.6 nM/mM Cr, were 61% and 92%, respectively, when a cut-off value of 40 IU/g Cr was assigned for urinary GGT. Since GGT activity can be measured inexpensively in large numbers in a very short time, the measurement of urinary level may provide a convenient and useful method for mass screening to identify those with increased bone turnover and hence at increased risk for bone fracture.     

TBS reflects trabecular microarchitecture in premenopausal women and men with idiopathic osteoporosis and low-traumatic fractures

Transiliac bone biopsies, while widely considered to be the standard for the analysis of bone microstructure, are typically restricted to specialized centers. The benefit of Trabecular Bone Score (TBS) in addition to areal bone mineral density (aBMD) for fracture risk assessment has been documented in cross-sectional and prospective studies. The aim of this study was to test if TBS may be useful as a surrogate to histomorphometric trabecular parameters of transiliac bone biopsies. Transiliac bone biopsies from 80 female patients (median age 39.9 years — interquartile range, IQR 34.7; 44.3) and 43 male patients (median age 42.7 years — IQR 38.9; 49.0) with idiopathic osteoporosis and low traumatic fractures were included. Micro-computed tomography values of bone volume fraction (BV/TV), trabecular thickness (Tb.Th), trabecular number (Tb.N), trabecular separation (Tb.Sp), structural model index (SMI) as well as serum bone turnover markers (BTMs) sclerostin, intact N-terminal type 1 procollagen propeptide (P1NP) and cross-linked C-telopeptide (CTX) were investigated. TBS values were higher in females (1.282 vs 1.169, p <  0.0001) with no differences in spine aBMD, whereas sclerostin levels (45.5 vs 33.4 pmol/L) and aBMD values at the total hip (0.989 vs 0.971 g/cm², p < 0.001 for all) were higher in males. Multiple regression models including: gender, aBMD and BTMs revealed TBS as an independent, discriminative variable with adjusted multiple R² values of 69.1% for SMI, 79.5% for Tb.N, 68.4% for Tb.Sp, and 83.3% for BV/TV. In univariate regression models, BTMs showed statistically significant results, whereas in the multiple models only P1NP and CTX were significant for Tb.N. TBS is a practical, non-invasive, surrogate technique for the assessment of cancellous bone microarchitecture and should be implemented as an additional tool for the determination of trabecular bone properties.     

Effects of rhIGF-1 administration on surrogate markers of bone turnover in adolescents with anorexia nervosa

BackgroundAdolescents with anorexia nervosa (AN) have low bone density and low levels of surrogate markers of bone formation. Low bone density is a consequence of hormonal alterations that include hypogonadism and decreases in IGF-1, a bone trophic factor. Although IGF-1 is key to pubertal bone accretion, and effects have been demonstrated in adults, there are no data regarding the effect of recombinant human (rh) IGF-1 administration in adolescents with AN.ObjectivesWe hypothesized that rhIGF-1 would cause an increase in PINP, a bone formation marker, in girls with AN, without any effect on CTX, a bone resorption marker.Subjects and methodsRhIGF-1 was administered at a dose of 30–40 mcg/k twice daily to 10 consecutive girls with AN 12–18 years old for 7–9 days. Ten age-matched girls with AN were followed without rhIGF-1 for a similar period. IGF-1, PINP and CTX levels were measured.ResultsRhIGF-1 administration caused an increase in IGF-1 from day-1 to day-4/5 (p < 0.0001) and day-1 to day-8/9 (p < 0.0001). Simultaneously, PINP increased from day-1 to day-4/5 (p = 0.004) and day-1 to day-8/9 (p = 0.004), with a smaller increase from day-4/5 to day-8/9 (p = 0.048). CTX levels did not change with rhIGF-1 administration. No changes occurred in IGF-1 or PINP levels in girls not receiving rhIGF-1; however, CTX levels increased significantly (p = 0.01). Percent change in PINP was significantly higher (p = 0.02) and percent change in CTX was significantly lower (p = 0.006) in girls who received rhIGF-1 compared to those who did not receive any intervention. RhIGF-1 was well tolerated without hypoglycemia.ConclusionShort-term administration of rhIGF-1 causes an increase in a surrogate bone formation markers in girls with AN without significant side effects.     

Calcium intake and the risk of osteoporosis and fractures in French women

ObjectivesTo evaluate dietary calcium intake in postmenopausal women over 45 years of age and compare intake according to osteoporosis diagnosis and fracture history.MethodsA cross-sectional epidemiological survey of osteoporosis in postmenopausal women over 45 years in the general population was conducted using a stratified random sampling method and face-to-face interviews. Information was collected on osteoporosis diagnosis, fracture history and risk factors. Information on dietary calcium intake was collected using a validated questionnaire.ResultsTwo thousand six hundred and thirty-one women (mean age: 67.9 ± 10.0 years) were included. Two hundred and fifty-four (9.7%) had received a diagnosis of osteoporosis by bone densitometry, of whom 154 (45.3%) reported at least one previous fracture. Total mean daily dietary calcium intake was 754 mg/day, of which dairy products (milk, cheese and others) were the principal source. Overall, 37.2% of the sample consumed < 600 mg/day and 20.1% > 1000 mg/d. The proportion of women consuming < 600 mg/day increased with age (p = 0.0028). No difference in mean daily calcium intake was observed between women with or without a diagnosis of osteoporosis or with or without fractures.ConclusionsMean dietary calcium intake in this population is well below that recommended in current national guidelines (≥ 1500 mg/day), notably in those most at risk for fractures, such as women with a diagnosis of osteoporosis or those in older age groups. Intake does not appear to be influenced by osteoporosis diagnosis or fracture experience.     

Prevalence of Low Bone Mineral Density in Men and Women Infected With Human Immunodeficiency Virus 1 and a Proposal for Screening Strategy

We analyzed data collected during screening for eligibility in the ANRS-120 FOSIVIR clinical trial to estimate the prevalence of osteoporosis in patients infected with human immunodeficiency virus 1 (HIV-1), to study its risk factors, and to develop a screening strategy. McNemar test was used to compare the estimated prevalence of osteoporosis, using 3 different definitions. We then derived a screening strategy for HIV-infected men.We analyzed data for 700 men and 192 women. The prevalence of osteoporosis differed markedly according to the definition used. Based on the “T-score ≤ ?2.5” definition, 14.9% of men and 1.0% of women had osteoporosis. Factors associated with low bone mineral density comprised not only classical risk factors for osteoporosis such as low body mass index (BMI) or older age but also factors associated with HIV infection such as lower CD4 T-cell nadir in men and AIDS in women, and with antiretroviral treatment such as recent tenofovir therapy.In addition to postmenopausal women, we recommend osteoporosis screening for HIV-infected men older than 60 yr, men younger than 60 yr with BMI <20 kg/m², and men younger than 60 yr with both BMI 20–23 kg/m² and a CD4 T-cell nadir ≤200/mm³.     

Effects of combined treatment with eldecalcitol and alendronate on bone mass,mechanical properties,and bone histomorphometry in ovariectomized rats: A comparison with alfacalcidol and alendronate

Eldecalcitol (ELD), a 2β-hydroxypropyloxy derivative of 1α,25 (OH) 2D3, inhibits bone resorption more potently than alfacalcidol (ALF) while maintaining osteoblastic function in an ovariectomized (OVX) osteoporosis rat model. Alendronate (ALN), which is the most common bisphosphonate used for the treatment of osteoporosis, increases the bone mineral density (BMD) by suppressing bone resorption. In this study, we investigated the effects of combination treatments with ELD and ALN or with ALF and ALN on bone mass and strength in OVX rats. Seventy female rats, 32 weeks old, were assigned to seven groups: (1) a sham-operated control group; (2) an OVX-control group; (3) an ELD group; (4) an ALF group; (5) an ALN group; (6) an ELD + ALN group; and (7) an ALF + ALN group. OVX rats were orally treated with ELD (0.015 μg/kg), ALF (0.0375 μg/kg), or ALN (0.2 mg/kg) daily for 12 weeks. In both the lumbar spine and the femur, ELD and ALF monotherapy significantly increased the BMD, and ELD + ALN and ALF + ALN significantly increased the BMD, compared with ALN monotherapy, as an additive effect. In particular, ELD + ALN resulted in a significantly higher BMD than ALF + ALN in the femur. On mechanical testing of the lumbar spine, ELD and ALF monotherapy significantly increased the ultimate load, and ELD + ALN and ALF + ALN significantly increased the ultimate load compared with ALN monotherapy. In the femur, ELD, ELD + ALN, and ALF + ALN treatment significantly increased the ultimate load, compared with the OVX-control group, and ELD + ALN resulted in a significantly higher ultimate load than ALN monotherapy. A histomorphometric analysis showed that ELD monotherapy and ELD + ALN combination therapy had a potent inhibitory effect on bone resorption parameters (osteoclast surface and eroded surface), while maintaining bone formation parameters (osteoblast surface and osteoid surface). By contrast, ALF and ALF + ALN significantly lowered the histological parameters of both bone resorption and formation. These results suggested that ELD or ALF used in combination with ALN has therapeutic advantages over ALN monotherapy, with ELD + ALN combination treatment producing an especially beneficial anti-osteoporotic effect by inhibiting osteoclastic bone resorption and maintaining osteoblastic function, compared with ALF + ALN combination treatment.     

The Utility of Changes in Serum Levels of C-Terminal Telopeptide of Type I Collagen in Predicting Patient Response to Oral Monthly Ibandronate Therapy

Bone turnover markers may provide a more rapid indication of patient response to osteoporosis treatment than bone mineral density (BMD) measurements. This post hoc analysis of data from the MOBILE (Monthly Oral iBandronate In LadiEs) study assessed the relationship between increases in BMD at 12 mo from baseline after starting ibandronate treatment and changes in bone resorption marker serum C-terminal telopeptide of type I collagen (sCTX) from baseline at 3 and 6 mo. MOBILE enrolled postmenopausal women aged 55–80 yr with mean lumbar spine (LS) BMD T-score of ?2.5 to ?5.0. This analysis included women who received 150-mg monthly oral ibandronate (n = 323). A high proportion of women were classified as BMD responders after 1 yr (BMD increase was ≥0%, i.e., 74–91% depending on skeletal site; BMD increase was ≥3%, i.e., 34–67%). Women with larger decreases in sCTX were more likely to be BMD responders. The percent increase in LS BMD at 12 mo was significantly associated with the percent decrease in sCTX at 3 mo from baseline (Pearson correlation coefficient: ?0.19, p = 0.0016). In linear regression models, percent decrease in sCTX at 3 mo from baseline was a significant predictor of 1-yr LS BMD response (R² = 0.61, p = 0.0007). These data suggest that 3-mo changes in sCTX levels are associated with 1-yr LS BMD increases in postmenopausal women treated with once-monthly oral ibandronate.     

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

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

There is still a care gap in osteoporosis management for patients with rheumatoid arthritis

ObjectivesTo assess compliance rates with the current Canadian osteoporosis guidelines and whether the Fracture Risk Assessment Tool score in patients with rheumatoid arthritis correlated with the likelihood of receiving osteoporosis treatment and having a bone mineral density test.MethodsCharts of serial outpatients with rheumatoid arthritis were reviewed to collect bone mineral density test data and patients’ use of calcium, vitamin D, and osteoporosis treatment. Odds ratios (OR) were calculated to determine if a higher Fracture Risk Assessment Tool score increased the likelihood of osteoporosis treatment or having a bone mineral density test.ResultsUsing the Fracture Risk Assessment Tool, the 10-year risk of major osteoporotic fracture was high in 92 (12.5%), moderate in 216 (29.3%), and low in 429 (58.2%) patients. Compared to those at low risk, patients identified as high risk were more likely to receive osteoporosis treatment (OR 16.31, 95% CI 9.45–28.13, P < 0.001); calcium (OR 3.89, 95% CI 2.43–6.25, P < 0.001); vitamin D (OR 3.46, 95% CI 2.12–5.64, P < 0.001); and to have had a bone mineral density test (OR 10.22, 95% CI 5.50–18.96, P < 0.001). Among 124 patients currently taking prednisone, half (46.8%) were prescribed a bisphosphonate.ConclusionsAlthough compliance with current osteoporosis guidelines remains low among all patients with rheumatoid arthritis, higher risk patients were more likely to have a bone mineral density test and receive treatment for osteoporosis, as indicated by the clear dose response seen along the 10-year fracture risk from low to high-risk groups.     

TBS and BMD at the end of AI-therapy: A prospective study of the B-ABLE cohort

IntroductionPatients with breast cancer under aromatase inhibitor (AI) treatment often develop osteoporosis and their average bone loss rate is twice that of natural reduction during menopause, increasing fracture risk. As the current diagnostic technique based on bone mineral density (BMD) provides no information on bone quality, the Trabecular Bone Score (TBS) has been proposed to reflect bone microarchitecture status. The present study was designed to assess prospective changes in TBS and lumbar spine (LS) BMD in postmenopausal women with breast cancer at completion of AI treatment.MethodsB-ABLE is a prospective cohort of 735 women with breast cancer treated with AIs according to American Society of Clinical Oncology recommendations: 5 years of AI starting within 6 weeks post-surgery or 1 month after the last cycle of chemotherapy (5y-AI group), or switching to an AI to complete 5-year therapy after 2–3 years of tamoxifen (pTMX-AI group). Patients with osteoporosis were treated with oral bisphosphonates (BP). TBS and LS-BMD changes at completion of AI therapy were evaluated by Student t-test for paired samples. Pearson correlation coefficients were computed for correlations between LS-BMD and TBS.ResultsAI treatment was completed by 277 women. Of these, 70 (25.3%) were allocated to BP therapy. The non-BP-treated patients (74.7%) showed significant decreases in TBS (− 2.94% in pTMX-AI and − 2.93% in 5y-AI groups) and in LS-BMD (− 4.14% in pTMX-AI and − 2.28% in 5y-AI groups) at the end of AI treatment. In BP-treated patients, TBS remained stable at the end of AI treatment, whereas LS-BMD showed significant increases (+ 2.30% in pTMX-AI and + 5.33% in 5y-AI groups). Moderate associations between TBS and LS-BMD values at baseline and at the end of AI treatment (r = 0.4; P < 0.001) were observed. At the end of treatment, changes in spine BMD and TBS were weakly correlated (r = 0.1, P < 0.01).ConclusionsAI therapy induces significant decreases in TBS, comparable to BMD loss. BP-treated patients maintained TBS values, whereas BMD increased. AI treatment leads to deterioration of bone microarchitecture, which seems to be attenuated by BP therapy.