Significant bone loss after stopping long-term denosumab treatment: a post FREEDOM study.

We evaluate 38 elderly women who had received long-term denosumab treatment after stopping the drug. Taking into account the gain during treatment and the loss after stopping treatment, they lost 35.5% of the total gain in the spine, 44.6% of the total gain in the femoral neck, and 103.3% in the total hip. INTRODUCTION: Denosumab (DMAb) is a soluble inhibitor of the receptor activator of nuclear factor-kappaB ligand (RANKL) and, therefore, does not incorporate into the bone matrix. Consistently, DMAb discontinuation is associated with reversal of the effects attained with treatment. PURPOSE: The aim of this study is to assess changes in BMD after a year of discontinuation of DMAb in a group of postmenopausal women treated with DMAb for 7 or 10 years. Secondly, is to evaluate the occurrence of fragility fractures. METHODS: Women who had participated in the FREEDOM study and its extension were invited to participate in this follow-up study. BMD at LS and hip and spine X-rays were obtained. Results were compared to the last value obtained while in treatment to assess changes after discontinuation. RESULTS: Thirty-eight women, mean age: 81 ± 3.4 years completed study procedures; none had received bisphosphonates after stopping DMAb. Mean gap time between DMAb last dose and the follow-up visit was 17 months (range 16-20 months). Bone mineral density (BMD) decreased significantly in all regions: - 8.1% in LS, - 6% in FN, and - 8.4% in TH. Five (5/38, 13.15%) patients had a fragility fracture, one suffered a wrist fracture, and four experienced vertebral fractures. Three patients suffered one vertebral fracture and one of them had two vertebral fractures. Laboratory results showed the following mean values: CTX = 996 ± 307 pg/ml (normal values 550 ± 226 pg/ml); osteocalcin = 55.2 ± 18.6 ng/ml (normal value 42 ng/ml); and 25 OH vitamin D = 23.7 ± 6.9 ng/ml. CONCLUSION: Our results describe the rapid bone loss occurring after cessation of denosumab treatment. Further studies are needed to assess if patients have a higher risk of fracture after stopping DMAb and if so, which patients have the highest risk, and assess the role of transitioning to bisphosphonates in the long term.

Abaloparatide-SC improves trabecular microarchitecture as assessed by trabecular bone score (TBS): a 24-week randomized clinical trial.

In a phase 2 trial of 222 postmenopausal women with osteoporosis aged 55 to 85 years randomized to one of three different doses of abaloparatide-SC, subcutaneous teriparatide, or placebo for 24 weeks, abaloparatide-SC resulted in improvements in skeletal microarchitecture as measured by the trabecular bone score. INTRODUCTION: Subcutaneous abaloparatide (abaloparatide-SC) increases total hip and lumbar spine bone mineral density and reduces vertebral and non-vertebral fractures. In this study, we analyzed the extent to which abaloparatide-SC improves skeletal microarchitecture, assessed indirectly by trabecular bone score (TBS). METHODS: This is a post hoc analysis of a phase 2 trial of 222 postmenopausal women with osteoporosis aged 55 to 85 years randomized to abaloparatide-SC (20, 40, or 80 µg), subcutaneous teriparatide (20 µg), or placebo for 24 weeks. TBS was measured from lumbar spine dual X-ray absorptiometry (DXA) images in 138 women for whom the DXA device was TBS software compatible. Assessments were made at baseline, 12 and 24 weeks. Between-group differences were assessed by generalized estimating equations adjusted for relevant baseline characteristics, and a pre-determined least significant change analysis was performed. RESULTS: After 24 weeks, TBS increased significantly by 2.27, 3.14, and 4.21% versus baseline in participants on 20, 40, and 80 µg abaloparatide-SC daily, respectively, and by 2.21% in those on teriparatide (p < 0.05 for each). The TBS in the placebo group declined by 1.08%. The TBS increase in each treatment group was significantly higher than placebo at 24 weeks (p < 0.0001 for each) after adjustment for age, BMI, and baseline TBS. A dose-response was observed at 24 weeks across the three doses of abaloparatide-SC and placebo (p = 0.02). The increase in TBS in the abaloparatide-SC 80 µg group was significantly greater than TPTD (p < 0.03). CONCLUSIONS: These results are consistent with an effect of abaloparatide-SC to improve lumbar spine skeletal microarchitecture, as assessed by TBS.

Retreatment with teriparatide: our experience in three patients with severe secondary osteoporosis.

Teriparatide is a drug for the treatment of osteoporosis which is licensed for use for up to 24 months. There is little experience with retreatment. The aim of this study was to evaluate, in three patients with severe secondary osteoporosis, the response to a second cycle of teriparatide regarding bone mineral density (BMD) and osteocalcin. Case 1 : A 62-year-old woman with multiple vertebral fractures has received corticoids for a long time. After starting teriparatide, her BMD and osteocalcin increased. She then received ibandronate for 3 years but her BMD declined. After a second treatment with teriparatide, her BMD increased again (18%). Case 2 : A 60-year-old woman with severe osteoporosis in lumbar spine (LS) (T-score - 4.5) had received corticoids for a long time and had celiac disease. After starting teriparatide, her BMD improved by 11.7%. She then received zoledronic acid for 15 months, but bone density decreased, so she was retreated with teriparatide. BMD had a slightly higher increase than after the first cycle (12.6%). Case 3 : A 60-year-old woman consulted for osteoporosis (LS T-score - 5.3), several fractures, and hyperthyroidism. She started teriparatide with improvement in BMD (39%). After 24 months, she received ibandronate for 1 year, but as her BMD declined, she was retreated with teriparatide. BMD showed an increase of 15%. The indication of a second cycle of treatment with teriparatide in three patients was effective in increasing BMD. Additional studies are needed to further identify the benefits and safety of retreatment with teriparatide.

Effect of denosumab on trabecular bone score in postmenopausal women with osteoporosis.

Trabecular bone score (TBS) assesses bone quality in the lumbar spine using dual-energy X-ray absorptiometry (DXA) scans. In postmenopausal women with osteoporosis, denosumab significantly improved TBS independently of bone mineral density (BMD). This practical technique may have a role in managing patients with osteoporosis. INTRODUCTION: TBS, a gray-level texture index determined from lumbar spine DXA scans, correlates with bone microarchitecture and enhances assessment of vertebral fracture risk independently of BMD. In the FREEDOM study, denosumab increased BMD and reduced new vertebral fractures in postmenopausal women with osteoporosis. This retrospective analysis explored the effect of denosumab on TBS and the association between TBS and BMD in FREEDOM. METHODS: Postmenopausal women with lumbar spine or total hip BMD T-score <-2.5 and -4.0 or higher at both sites received placebo or denosumab 60 mg subcutaneously every 6 months. TBS indices were determined from DXA scans at baseline and months 12, 24, and 36 in a subset of 285 women (128 placebo, 157 denosumab) who had TBS values at baseline and ≥1 postbaseline visit. RESULTS: Baseline characteristics were comparable between treatment groups; mean (SD) lumbar spine BMD T-score was -2.79 (0.64), and mean (standard deviation [SD]) TBS was 1.200 (0.101) overall. In the placebo group, BMD and TBS increased by ≤0.2% or decreased from baseline at each visit. In the denosumab group, progressive increases from baseline at 12, 24, and 36 months were observed for BMD (5.7, 7.8, and 9.8%) and TBS (1.4, 1.9, and 2.4%). Percentage changes in TBS were statistically significant compared with baseline (p < 0.001) and placebo (p ≤ 0.014). TBS was largely unrelated to BMD, regardless of treatment, either at baseline or for annual changes from baseline (all r 2 ≤ 0.06). CONCLUSIONS: In postmenopausal women with osteoporosis, denosumab significantly improved TBS independently of BMD.

Bone microarchitecture in Rett syndrome and treatment with teriparatide: a case report.

We present the case of a 28-year-old female Rett syndrome patient with low bone mass and a recent fracture who was successfully treated with teriparatide. Bone mineral density and microarchitecture substantially improved after treatment. Rett syndrome (RTT), an X-linked progressive neuro-developmental disorder caused by mutations in the methyl-CpG-binding 2 (MECP2) gene, has been consistently associated with low bone mass. Consequently, patients with RTT are at increased risk of skeletal fractures. Teriparatide is a bone-forming agent for the treatment of osteoporosis that has demonstrated its effectiveness in increasing bone strength and reducing the risk of fractures in postmenopausal women, but, recently, its positive action has also been reported in premenopausal women. We present the case of a 28-year-old female RTT patient with low bone mass and a recent fracture who was successfully treated with teriparatide. Both bone mass measured by DXA and microarchitecture assessed by high resolution peripheral computed tomography (HR pQCT) were substantially improved after treatment.

Efficacy and safety of risedronate 150-mg once a month in the treatment of postmenopausal osteoporosis: 2-year data.

UNLABELLED: This study showed that risedronate 150-mg once a month provides similar efficacy and safety at 2 years compared with risedronate 5-mg daily for the treatment of postmenopausal osteoporosis. This adds to the range of risedronate dosing options and provides an alternative for patients who prefer once-a-month dosing. INTRODUCTION: Risedronate is effective in the treatment of postmenopausal osteoporosis in oral daily, weekly, or on two consecutive days per month doses. This 2-year randomized, double-blind, multicenter study assesses the efficacy and safety of a single risedronate 150-mg once-a-month oral dose compared with the 5-mg daily regimen. METHODS: Women with postmenopausal osteoporosis were randomly assigned to receive risedronate 5-mg daily (n = 642) or 150-mg once a month (n = 650) for 2 years. Bone mineral density (BMD), bone turnover markers, new vertebral fractures, and adverse events were evaluated. The primary efficacy endpoint was the mean percent change from baseline in lumbar spine BMD after 1 year. RESULTS: Four hundred ninety-eight subjects in the daily group (77.6 %) and 513 subjects in the once-a-month group (78.9 %) completed the study. After 24 months, the mean percent change in lumbar spine BMD was 3.9 % (95 % confidence interval [CI], 3.43 to 4.42 %) and 4.2 % (95 % CI, 3.68 to 4.65 %) in the daily and once-a-month groups, respectively. The once-a-month regimen was determined to be non-inferior to the daily regimen. The mean percent changes in BMD at the hip were similar in both dose groups, as were changes in biochemical markers of bone turnover. The incidence of adverse events, adverse events leading to withdrawal, and upper gastrointestinal tract adverse events were similar in the two treatment groups. CONCLUSIONS: After 2 years, treatment with risedronate 150-mg once a month provided similar efficacy and tolerability to daily dosing and provides an alternative for patients who prefer once-a-month oral dosing.

Evaluation of bone microarchitecture by high-resolution peripheral quantitative computed tomography (HR-pQCT) in hemodialysis patients.

UNLABELLED: Hemodialyzed patients have decreased bone strength not completely characterized. We evaluated bone microarchitecture in hemodialysis patients and compared it to that of subjects without renal disease by high-resolution peripheral quantitative computed tomography (HR-pQCT). Hemodialysis patients have a marked decreased in cortical density, thickness, and area with significant reduction in trabecular parameters that correlated with the severity of secondary hyperparathyroidism only in women. INTRODUCTION: Although fracture risk is greatly increased in dialysis patients, the corresponding decreased in bone strength has not been completely characterized. METHODS: We evaluated volumetric bone mineral density (vBMD) and bone microstructure by HR-pQCT at the distal radius and tibia in 50 hemodialyzed (HD) patients (30 females, mean age 53.2 ± 6 years and 20 males, mean age 59.1 ± 11 years) and 50 sex- and age-matched controls. RESULTS: At the distal radius HD, women showed a 29% reduction in total and trabecular density and trabecular bone volume fraction (p < 0.0001) compared to controls. Trabecular number was reduced by 25% (p < 0.0001), while trabecular separation was increased by 51%. Cortical thickness (-40%, p < 0.0001) and cortical area (-42%, p < 0.0001) were the parameters most reduced, while compact density was the parameter least reduced (-15%, p < 0.0001). Similar findings were found at the tibia. In HD men, HR-pQCT at the distal radius and tibia showed a reduction in volumetric density and microstructure parameters to a lesser extent than in women. In the hemodialyzed group, cortical thickness at the radius was negatively correlated with age both in women and men. At the distal radius and tibia, we found significant negative correlations between Log iPTH and total alkaline phosphatase with cortical vBMD(r = -0.48, p < 0.01; r = -0.69, p < 0.001), thickness (-0.37, p < 0.05; r = -0.60, p < 0.001), and area ((r = -0.43, p = 0.02; r = -0.65, p < 0.001) but only in women. CONCLUSION: We conclude that hemodialysis patients have a marked decreased in cortical density, thickness, and area with significant reduction in trabecular parameters that correlated with the severity of secondary hyperparathyroidism only in women.

The effect of teriparatide compared with risedronate on reduction of back pain in postmenopausal women with osteoporotic vertebral fractures.

UNLABELLED: The effect of teriparatide and risedronate on back pain was tested, and there was no difference in the proportion of patients experiencing a reduction in back pain between groups after 6 or 18 months. Patients receiving teriparatide had greater increases in bone mineral density and had fewer vertebral fractures. INTRODUCTION: This study aimed to understand the effect of teriparatide in reducing back pain in patients with prevalent back pain and vertebral fracture compared to risedronate. METHODS: In an 18-month randomized, double-blind, double-dummy trial, we investigated the effects of teriparatide (20 µg/day) vs. risedronate (35 mg/week) in postmenopausal women with back pain likely due to vertebral fracture. The primary objective was to compare the proportion of subjects reporting ≥30% reduction in worst back pain severity from baseline to 6 months as assessed by a numeric rating scale in each treatment group. Pre-specified secondary and exploratory outcomes included assessments of average and worst back pain at additional time points, disability and quality of life, bone mineral density, incidence of fractures, and safety. RESULTS: At 6 months, 59% of teriparatide and 57% of risedronate patients reported ≥30% reduction in worst back pain and there were no differences between groups in the proportion of patients experiencing reduction in worst or average back pain at any time point, disability, or quality of life. There was a greater increase from baseline in bone mineral density at the lumbar spine (p = 0.001) and femoral neck (p = 0.02) with teriparatide compared to risedronate and a lower incidence of vertebral fractures at 18 months (4% teriparatide and 9% risedronate; p = 0.01). Vertebral fractures were less severe (p = 0.04) in the teriparatide group. There was no difference in the overall incidence of adverse events. CONCLUSIONS: Although there were no differences in back pain-related endpoints, patients receiving teriparatide had greater skeletal benefit than those receiving risedronate.

Teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis: an analysis by gender and menopausal status.

SUMMARY: The effects of teriparatide versus alendronate were compared by gender and menopausal status in patients with glucocorticoid-induced osteoporosis. At 18 months, increases in lumbar spine BMD were significantly greater in the teriparatide versus alendronate group in postmenopausal women (7.8% versus 3.7%, p < 0.001), premenopausal women (7.0% versus 0.7%, p < 0.001), and men (7.3% versus 3.7%, p = 0.03). INTRODUCTION: In patients with glucocorticoid-induced osteoporosis (GIO), teriparatide significantly increased bone mineral density (BMD) and decreased vertebral fractures compared with alendronate. We examined effects of teriparatide versus alendronate by gender and menopausal status. METHODS: This was a multicenter, randomized, double-blind study of teriparatide 20 microg/day versus alendronate 10 mg/day in patients with GIO (277 postmenopausal women, 67 premenopausal women, 83 men). Primary outcome was change in lumbar spine BMD. Secondary outcomes included change in hip BMD, change in bone biomarkers, fracture incidence, and safety. RESULTS: At 18 months, mean percent increases from baseline in lumbar spine BMD were significantly greater in the teriparatide versus alendronate group in postmenopausal women (7.8% versus 3.7%, p < 0.001), premenopausal women (7.0% versus 0.7%, p < 0.001), and men (7.3% versus 3.7%, p = 0.03). Radiographic vertebral fractures occurred in one teriparatide (one postmenopausal) and ten alendronate patients (six postmenopausal, four men), and nonvertebral fractures occurred in 12 teriparatide (nine postmenopausal, two premenopausal, one man) and eight alendronate patients (six postmenopausal, two men). The proportion of patients reporting adverse events in teriparatide versus alendronate groups was consistent across subgroups. CONCLUSION: Among men and pre- and postmenopausal women with GIO, lumbar spine BMD increased more in patients receiving teriparatide compared with alendronate.

The prevalence of radiographic vertebral fractures in Latin American countries: the Latin American Vertebral Osteoporosis Study (LAVOS).

UNLABELLED: In the first population-based study of vertebral fractures in Latin America, we found a 11.18 (95% CI 9.23-13.4) prevalence of radiographically ascertained vertebral fractures in a random sample of 1,922 women from cities within five different countries. These figures are similar to findings from studies in Beijing, China, some regions of Europe, and slightly lower than those found in the USA using the same standardized methodology. INTRODUCTION: We report the first study of radiographic vertebral fractures in Latin America. METHODS: An age-stratified random sample of 1,922 women aged 50 years and older from Argentina, Brazil, Colombia, Mexico, and Puerto Rico were included. In all cases a standardized questionnaire and lateral X-rays of the lumbar and thoracic spine were obtained after informed consent. RESULTS: A standardized prevalence of 11.18 (95% CI 9.23-13.4) was found. The prevalence was similar in all five countries, increasing from 6.9% (95% CI 4.6-9.1) in women aged 50-59 years to 27.8% (95% CI 23.1-32.4) in those 80 years and older (p for trend < 0.001). Among different risk factors, self-reported height loss OR = 1.63 (95% CI: 1.18-2.25), and previous history of fracture OR = 1.52 (95% CI: 1.14-2.03) were significantly (p < 0.003 and p < 0.04 respectably) associated with the presence of radiographic vertebral fractures in the multivariate analysis. In the bivariate analyses HRT was associated with a 35% lower risk OR = 0.65 (95% CI: 0.46-0.93) and physical activity with a 27% lower risk of having a vertebral fracture OR = 0.73 (95% CI: 0.55-0.98), but were not statistically significant in multivariate analyses CONCLUSION: We conclude that radiographically ascertained vertebral fractures are common in Latin America. Health authorities in the region should be aware and consider implementing measures to prevent vertebral fractures.

[Relationship between renal function and bone mineral density in postmenopausal women that undergo bone mass evaluation]. / Relación entre función renal y densidad mineral ósea en mujeres posmenopáusicas que realizan evaluación de masa ósea.

As osteoporosis and renal insufficiency are two prevalent pathologies in the aging population we decided to evaluate retrospectively the renal function (estimated by formula) in postmenopausal women who came to our Institute for bone mass determination to establish the relationship between them. Thus, we studied 300 postmenopausal women with a mean age of 66.9 +/- 6.8 years who had a bone densitometry performed; we chose total femur bone mineral density (TFBMD) for defining osteopenia and osteoporosis as this measurement included substantial amounts of both trabecular and cortical bone; osteopenia/osteoporosis was diagnosed using T score criteria recommended by the WHO. We also measured BMD at the femoral neck. Renal function was estimated by the Cockcroft-Gault formula using serum creatinine determination. We found osteoporosis in 61 patients (20.3%). Of them, el 81.9% have renal insufficiency (estimated creatinine clearance-ECrC < or = 60 ml/min), compared to 54% of 239 women who had normal BMD/osteopenia (p < 0.001). Six of 61 (9.8%) women with osteoporosis had severe renal insufficiency (ECrC < or = 36 ml/min) versus 4/239 (1.6%) women with normal BMD/osteopenia (p = 0.001). Women with osteoporosis were older, and had a significantly lower weight and ECrC compared to patients without osteoporosis (ECrC 52 +/- 11 ml/min vs 59 +/- 12 ml/min; p < 0.0001). We found a significant positive correlation between TFBMD and ECrC (r = 0.389) as well as with weight (r = 0.422) and a negative correlation between age and ECrCE (r = -0.51) and with TFBMD (r = -0.22). In the multiple regression analysis only weight continued to correlate significantly with TFBMD (Beta = 0.344). When FNBMD was considered as the dependent variable, we found a significantly negative correlation with age (r = -0.30) and significantly positive correlations with height (r = 0. 16), weight (r = 0.33) and ECcr (r = 0.39). In the multiple regression analysis only age (Beta = -0.20) and weight (Beta = 0.20) continued having an independent correlation FNBMD. We conclude that our data confirm that there exists a substantial prevalence of renal insufficiency, even severe, among patients with densitometric osteoporosis that should be kept in mind when one is considering the prescription of medications as bisphosphonates that have renal clearance, so as not to jeopardize the efficacy and the security of these drugs.

Evaluation of cortical bone by peripheral quantitative computed tomography in renal transplant recipients.

BACKGROUND: The absolute risk of fractures in renal transplant patients is 3 times that of matched controls. Most of the symptomatic fractures are peripheral, suggesting a greater compromise of cortical bone. Peripheral quantitative computed tomography (pQCT) is a new imaging technique that allows separate noninvasive evaluations of cortical and trabecular bones. We investigated cortical bone by pQCT in 12 renal transplant patients (seven men and five women) for comparison with 27 normal controls. METHODS: pQCT (XCT 960, Stratec, Pforheim, Germany) was performed upon the distal radius of the nondominant forearm (15% the length of the ulna, proximal from the radius end plate). We evaluated total and cortical bone mineral density (TBMD, cBMD), total (cross-sectional) and cortical area (TA, cA), cortical thickness (cThk), endosteal and periosteal circumferences, and the buckling ratio (r/cThK). RESULTS: Compared with normal controls transplant patients as a whole showed a significant increase in TA, in endosteal circumference (P < .001), and in the buckling ratio (P < .001) with a significant reduction in cThK (P < .001). Female patients had a marked decrease in cA (51.4 vs 69.3 [pixel n]; P < .0001) and cThK (2.08 vs 2.78 mm; P < .0001). Male patients also had a decrease in cThK (2.54 vs 3.30 mm; P = .0001) and an increase in endosteal perimeter (31.2 vs 26.4 mm; P < .0001). Total time on dialysis prior to renal graft correlated negatively with cortical thickness (r = .62; P < .01). CONCLUSIONS: Our results suggest that a marked thinning of cortical bone may explain the increased incidence of peripheral fractures among renal transplant patients.

[Relationship between weight, body composition and bone mass in peritoneal dialysis]. / Relación entre peso, composición corporal y masa osea en diálisis peritoneal.

Patients in chronic dialysis show a decrease in total bone mass. The factors that determine this decrease are not well known. In normal populations weight and its compartments are important determinants of bone mass. We studied total bone mineral content (TBMC), a measure of bone mass, and body composition using DEXA densitometry in 65 patients (45 females and 20 males) who had been in peritoneal dialysis for a mean of 40.3 +/- 23.2 months. Forty-eight patients (73.8%) had been previously in hemodialysis. The mean total time in dialysis for these patients was 76.8 months. As a group patients showed a very significant positive correlation between TBMC and weight, height, and lean body mass. A negative correlation was found between TBMC with the time in dialysis and iPTH. In men we found significant simple positive correlations between TBMC and weight, height and lean body mass. In women we found simple positive correlations of TBMC with weight, height and lean body mass and a negative correlation with iPTH. In the multiple regression analysis, lean body mass was the only body composition parameter that had a significantly positive correlation with TBMC in men; in women only height correlated positively with TBMC and iPTH continued to correlate negatively with bone mass. When we considered pre and postmenopausal women separately, bone mass was correlated positively with height and lean body mass and negatively with iPTH in postmenopausal women and only with height in pre-menopausal females. We conclude that the lean body mass compartment. is the most important component of weight that determines TBMC in peritoneal dialysis patients particularly in males and postmenopausal women. In postmenopausal women, secondary hyperparathyroidism seems to be particularly detrimental on bone mass.

Interrelationships between densitometric, geometric, and mechanical properties of rat femora: inferences concerning mechanical regulation of bone modeling.

A compensation for differences in bone material quality by bone geometric properties in femora from two different strains of rats was previously shown by us. A feedback mechanism controlling the mechanical properties of the integrated bones was then proposed, in accordance with Frost's mechanostat theory. Evidence of such a system is now offered by the finding of a negative correlation between the modeling-dependent cross-sectional architecture (moment of inertia) and the mineral-dependent stiffness (elastic modulus) of bone material in the femoral diaphyses of 45 normal Wistar rats of different sexes, ages, and sizes. The strength and stiffness of the integrated diaphyses were found to depend on both cross-sectional inertia and body weight, not on bone mineral density. These findings are interpreted as supporting the hypothesis that the architectural efficiency of diaphyseal cross-sectional design resulting from the spatial orientation of bone modeling during growth is optimized as a function of the body weight-dependent bone strain history, within the constraints imposed by bone stiffness. Results suggest a modulating role of biomass, related to the system set point determination, and explain the usually observed lack of a direct correlation between mineral density and strength or stiffness of long bones in studies of geometrically inhomogeneous populations.

Interrelationships between geometric and mechanical properties of long bones from three rodent species with very different biomass: phylogenetic implications.

In femora from rats or mice, the area and moment of inertia (but not the wall-lumen ratio) of a diaphyseal section correlated with biomass and were determinants of the strength and stiffness of the integrated bone. In otter metacarpals, however, the geometric variable typically associated with body weight and mechanical ability of the integrated bone was the wall-lumen ratio (not the sectional moment of inertia). These differences may be associated with the meaningfulness of body density for natural selection in diving species like otters. A negative relationship between wall-lumen ratio and material modulus of elasticity in bones from the three species pointed out the impossibility of increasing diaphyseal thickness and stiffness at the same time. The results are compatible with the hypothesis that ecologic habits are selectively more important than phylogenetic relationships between species for the determination of bone mechanical properties in the upper vertebrates.

Effects of teriparatide [recombinant human parathyroid hormone (1-34)] on cortical bone in postmenopausal women with osteoporosis.

Treatment with teriparatide (rDNA origin) injection [teriparatide, recombinant human parathyroid hormone (1-34) [rhPTH(1-34)]] reduces the risk of vertebral and nonvertebral fragility fractures and increases cancellous bone mineral density in postmenopausal women with osteoporosis, but its effects on cortical bone are less well established. This cross-sectional study assessed parameters of cortical bone quality by peripheral quantitative computed tomography (pQCT) in the nondominant distal radius of 101 postmenopausal women with osteoporosis who were randomly allocated to once-daily, self-administered subcutaneous injections of placebo (n = 35) or teriparatide 20 microg (n = 38) or 40 microg (n = 28). We obtained measurements of moments of inertia, bone circumferences, bone mineral content, and bone area after a median of 18 months of treatment. The results were adjusted for age, height, and weight. Compared with placebo, patients treated with teriparatide 40 microg had significantly higher total bone mineral content, total and cortical bone areas, periosteal and endocortical circumferences, and axial and polar cross-sectional moments of inertia. Total bone mineral content, total and cortical bone areas, periosteal circumference, and polar cross-sectional moment of inertia were also significantly higher in the patients treated with teriparatide 20 microg compared with placebo. There were no differences in total bone mineral density, cortical thickness, cortical bone mineral density, or cortical bone mineral content among groups. In summary, once-daily administration of teriparatide induced beneficial changes in the structural architecture of the distal radial diaphysis consistent with increased mechanical strength without adverse effects on total bone mineral density or cortical bone mineral content.

Mechanical validation of a tomographic (pQCT) index for noninvasive estimation of rat femur bending strength.

Cross-sectional moment of inertia (CSMI) and volumetric cortical bone mineral density (vCtBMD) were assessed by peripheral quantitative computed tomography (pQCT) at femur midshafts from 103 Wistar female rats receiving 0 (n = 12) or 15-1000 mu g/kg/day sc of dexamethasone (n = 46) from 5 to 9 weeks of age, or 0 or 80 mg/kg 3/wk of AI(OH)(3) IP (n = 23,22) from 4 to 10 months of age. A bone strength index (BSI), calculated as the product CSMI x vCtBMD, was found to closely correlate (r = 0.94, R(2) = 0.89, p < 0.001) with the actual, mechanically tested bending breaking force of all bones. Correlation and determination coefficients obtained were higher than those usually reported employing different long-bone strength predictive formulae. The curve approached the origin and was linear throughout the wide range of CSMI, vCtBMD and BSI achieved because of age- and treatment-induced differences, showing a very low standard error of the estimate. Instead, different curve slopes and/or intercepts were found in separate analysis between data from each of the experiments when breaking force was correlated with CSMI or vCtBMD alone, or with the DEXA-assessed BMD of the mechanically assayed bone portion. Results suggest that noninvasive assessment of the BSI by means of pQCT technology provides an original tool for a precise and accurate estimation of long-bone bending strength that can be advantageously applied in crosssectional as well as longitudinal, in vivo studies employing animal models.

Bone mass in children: normative values for the 2-20-year-old population.

Normative values for bone mass were assessed for whole body bone mineral content (WBBMC), anterior-posterior and lateral lumbar spine, radius, femoral neck, trochanter, and Ward's triangle bone mineral density in 778 healthy children and adolescents (433 females and 345 males) from 2-20 years of age from Argentina. Bone mineral content was assessed by dual energy X-ray absorptiometry (DEXA) (Norland XR-26 HS with dynamic filtration). All subjects were Caucasian. WBBMC maximum mean value for girls was found to be in the 16-year-old group with difference between gender becoming significant in the 17-year-old (p < 0.05) group. The femoral neck, trochanter, and Ward's triangle BMD values in females increased until 14 years of age, with no significant difference between age groups older than 13. In males, no difference between age groups was seen in groups older than 16 years of age. The radius BMD showed a mild increment through infancy and adolescence in boys and girls. In lumbar spine, the gender differences were significant only in those groups over 16 years old, with boys showing a greater BMD than girls (p < 0.001). When Tanner stage was considered, the anova analysis showed in males that there were significant differences between stages (1-2, 2-3, and 4-5 (p < 0.01), but no differences between stages 3-4 for all the sites. In females, there were significant differences between stages 1-2 and 2-3 (p < 0.01), but not between stages 3-4 and 4-5 for WBBMC, FNBMD and LSBMD.(ABSTRACT TRUNCATED AT 250 WORDS)

Intravenous olpadronate restores ovariectomy-affected bone strength. A mechanical, densitometric and tomographic (pQCT) study.

Female Wistar rats aged 3 months were ovariectomized (OX, n = 27). Three months later they were given i.v. doses of 150 (6), 300 (7), or 600 (6) ug/kg 2/wk of olpadronate during 12 weeks or left as OX controls (OXc). Bending fracture load of femur diaphyses, reduced in OXc, was recovered by olpadronate. This effect was paralleled by changes in material quality indicators as DEXA-BMD, tomographic (volumetric) BMD, elastic modulus, and maximum elastic stress of cortical bone. No changes were induced by any of the treatments on cross-sectional area or moment of inertia. Diaphyseal stiffness, not reduced by OX, was enhanced to overnormal values by olpadronate at any dose. None of the treatments affected the normal mechanostatic interrelationships between cross-sectional architecture and bone material quality indicators. The positive effects described point out important differences in bisphosphonate action on bone biomechanics according to the experimental conditions assayed.

Effects of large doses of olpadronate (dimethyl-pamidronate) on mineral density, cross-sectional architecture, and mechanical properties of rat femurs.

As part of a safety-assessment study, doses of 8, 40, and 200 mg/kg per day, 6 days per week, of sodium olpadronate (dimethyl-APD, Me2-APD) were given by gavage to 10-week-old male and female rats during 27 weeks. Only the 200 mg/kg per day dose provoked toxic effects and a meaningful growth depression, regardless of the animal gender. In male animals, doses of 40 or 200 mg/kg per day improved strength, stiffness, and cross-sectional moment of inertia (CSMI) of femur diaphyses despite the toxic effects observed at the highest dose. Changes in bone mechanical properties were a consequence of those induced in CSMI. Regression analyses showed a treatment-induced improvement in bone modeling (as assessed by CSMI) for the same level of bone material stiffness (as expressed by calculated values of elastic modulus). The high dependency of results on body mass bearing suggested that these effects were exerted through an increase in the efficiency of bone mechanostat. Strikingly, they were not evident in female rats. If not related to a lower bone bioavailability of bisphosphonates in female rats as described by others, this phenomenon may have reflected: (1) their a smaller biomass; and/or (2) a less effective mechanostatic regulation of bone architecture derived from a higher bone material stiffness related to male animals. An increase of BMD with a predominance toward the distal region was observed in all femurs studied. This effect, unrelated to the observed changes in mechanical properties, seems to express a lack of remodeling of primary cartilage or bone tissue.