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.     

The mechanical consequence of actual bone loss and simulated bone recovery in acute spinal cord injury

IntroductionSpinal cord injury (SCI) is characterized by rapid bone loss and an increased risk of fragility fracture around regions of the knee. Our purpose was to quantify changes in torsional stiffness K and strength T_ult at the proximal tibia due to actual bone loss and simulated bone recovery in acute SCI.MethodsComputed tomography scans were acquired on ten subjects with acute SCI at serial time points separated by a mean of 3.9 months (range 3.0 to 4.8 months). Reductions in bone mineral were quantified and a validated subject-specific finite element modeling procedure was used to predict changes in K and T_ult. The modeling procedure was subsequently used to examine the effect of simulated hypothetical treatments, in which bone mineral of the proximal tibiae were restored to baseline levels, while all other parameters were held constant.ResultsDuring the acute period of SCI, subjects lost 8.3 ± 4.9% (p < 0.001) of their bone mineral density (BMD). Reductions in K (− 9.9 ± 6.5%; p = 0.002) were similar in magnitude to reductions in BMD, however reductions in T_ult (− 15.8 ± 13.8%; p = 0.005) were some 2 times greater than the reductions in BMD. Owing to structural changes in geometry and mineral distribution, T_ult was not necessarily recovered when bone mineral was restored to baseline, but was dependent upon the degree of bone loss prior to hypothetical treatments (r ≥ 0.719; p ≤ 0.019).ConclusionsTherapeutic interventions to halt or attenuate bone loss associated with SCI should be implemented soon after injury in an attempt to preserve mechanical integrity and prevent fracture.     

Reduced physical activity corresponds with greater bone loss at the trabecular than the cortical bone sites in men

Previous research has been inconclusive as to whether high peak bone mineral density (BMD, g/cm²) resulting from previous physical activity is retained with reduced activity later in life. The aim of this 12-year longitudinal study was to investigate the association between BMD loss and reduced physical activity (h/wk) at trabecular and cortical bone sites in men. Three groups with a mean age of 17 years at baseline were investigated: i) 51 athletes who discontinued their active careers during the follow-up period (former athletes), ii) 16 athletes who were active throughout the follow-up period (active athletes), and iii) 25 controls. BMD loss at the hip, spine, and pelvis (mainly trabecular bone) was compared to BMD loss at femur, humerus, and legs (mainly cortical bone) during a 12-year follow-up period. Across the total follow-up period in the total cohort, reduced physical activity was more strongly associated with changes at trabecular BMD sites, i.e. hip, spine, and pelvis (B = 0.008–0.005 g/cm² per weekly hour physical activity (h), p < 0.001), than at cortical bone sites, i.e. humerus, legs (B = 0.002–0.003 g/cm²/h, p < 0.05), and femur (p > 0.05). At the final follow-up, former athletes showed higher BMD than controls only at the cortical bone sites of the humerus, legs, and femur (difference 0.05–0.10 g/cm², p < 0.05). In conclusion, this study indicates that predominantly trabecular bone is lost with reduced physical activity levels in young men. Benefits were still evident at the more cortical sites eight years after the discontinuation of an active sports career.     

The high bone mass phenotype is characterised by a combined cortical and trabecular bone phenotype: Findings from a pQCT case–control study

High bone mass (HBM), detected in 0.2% of DXA scans, is characterised by a mild skeletal dysplasia largely unexplained by known genetic mutations. We conducted the first systematic assessment of the skeletal phenotype in unexplained HBM using pQCT in our unique HBM population identified from screening routine UK NHS DXA scans.pQCT measurements from the mid and distal tibia and radius in 98 HBM cases were compared with (i) 65 family controls (constituting unaffected relatives and spouses), and (ii) 692 general population controls.HBM cases had substantially greater trabecular density at the distal tibia (340 [320, 359] mg/cm³), compared to both family (294 [276, 312]) and population controls (290 [281, 299]) (p < 0.001 for both, adjusted for age, gender, weight, height, alcohol, smoking, malignancy, menopause, steroid and estrogen replacement use). Similar results were obtained at the distal radius. Greater cortical bone mineral density (cBMD) was observed in HBM cases, both at the midtibia and radius (adjusted p < 0.001). Total bone area (TBA) was higher in HBM cases, at the distal and mid tibia and radius (adjusted p < 0.05 versus family controls), suggesting greater periosteal apposition. Cortical thickness was increased at the mid tibia and radius (adjusted p < 0.001), implying reduced endosteal expansion. Together, these changes resulted in greater predicted cortical strength (strength strain index [SSI]) in both tibia and radius (p < 0.001). We then examined relationships with age; tibial cBMD remained constant with increasing age amongst HBM cases (adjusted β ? 0.01 [? 0.02, 0.01], p = 0.41), but declined in family controls (? 0.05 [? 0.03, ? 0.07], p < 0.001) interaction p = 0.002; age-related changes in tibial trabecular BMD, CBA and SSI were also divergent. In contrast, at the radius HBM cases and controls showed parallel age-related declines in cBMD and trabecular BMD.HBM is characterised by increased trabecular BMD and by alterations in cortical bone density and structure, leading to substantial increments in predicted cortical bone strength. In contrast to the radius, neither trabecular nor cortical BMD declined with age in the tibia of HBM cases, suggesting attenuation of age-related bone loss in weight-bearing limbs contributes to the observed bone phenotype.     

A well-balanced diet combined or not with exercise induces fat mass loss without any decrease of bone mass despite bone micro-architecture alterations in obese rat

The association of a well-balanced diet with exercise is a key strategy to treat obesity. However, weight loss is linked to an accelerated bone loss. Furthermore, exercise is known to induce beneficial effects on bone. We investigated the impact of a well-balanced isoenergetic reducing diet (WBR) and exercise on bone tissue in obese rats. Sixty male rats had previously been fed with a high fat/high sucrose diet (HF/HS) for 4 months to induce obesity. Then, 4 regimens were initiated for 2 months: HF/HS diet plus exercise (treadmill: 50 min/day, 5 days/week), WBR diet plus exercise, HF/HS diet plus inactivity and WBR diet plus inactivity. Body composition and total BMD were assessed using DXA and visceral fat mass was weighed. Tibia densitometry was assessed by Piximus. Bone histomorphometry was performed on the proximal metaphysis of tibia and on L2 vertebrae (L2). Trabecular micro-architectural parameters were measured on tibia and L2 by 3D microtomography. Plasma concentration of osteocalcin and CTX were measured. Both WBR diet and exercise had decreased global weight, global fat and visceral fat mass (p < 0.05). The WBR diet alone failed to alter total and tibia bone mass and BMD. However, Tb.Th, bone volume density and degree of anisotropy of tibia were decreased by the WBR diet (p < 0.05). Moreover, the WBR diet had involved a significant lower MS/BS and BFR/BS in L2 (p < 0.05). Exercise had significantly improved BMD of the tibia possibly by inhibiting the bone resorption, as evidenced by no change in plasma osteocalcin levels, a decrease of CTX levels (p < 0.005) and trabecular osteoclast number (p < 0.05). In the present study a diet inducing weight and fat mass losses did not affected bone mass and BMD of obese rats despite alterations of their bone micro-architecture. The moderate intensity exercise performed had improved the tibia BMD of obese rats without any trabecular and cortical adaptation.     

Contribution of Serum Inflammatory Markers to Changes in Bone Mineral Content and Density in Postmenopausal Women: A 1-Year Investigation

Bone formation and resorption are influenced by inflammatory processes. We examined the relationships among inflammatory markers and bone mineral content (BMC) and density (BMD) and determined the contribution of inflammatory markers to 1-yr changes in BMC and BMD in healthy postmenopausal women. This analysis included 242 women at baseline from our parent Soy Isoflavones for Reducing Bone Loss project who were randomly assigned to 1 of 3 treatment groups: placebo, 80 mg/d soy isoflavones, or 120 mg/d soy isoflavones. BMD and BMC from the lumbar spine (LS), total proximal femur (hip), and whole body were measured by dual energy X-ray absorptiometry and the 4% distal tibia by peripheral quantitative computed tomography. Serum inflammatory markers (C-reactive protein, interleukin [IL]-1β, IL-6, tumor necrosis factor-alpha [TNF-α], and white blood cell count [WBC]) were measured at baseline, 6, and 12 mo. Because of attrition or missing values, data analysis at 12 mo includes only 235 women. Significant associations among IL-6, TNF-α, and WBC were observed with percent change in LS, hip, and whole body BMC and BMD. Multiple regression analysis indicated that in combination inflammatory markers accounted for 1.1–6.1% of the variance to the observed 12-mo changes in BMC and BMD. Our results suggest that modifying inflammatory markers, even in healthy postmenopausal women, may possibly reduce bone loss.     

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.     

Bone lead (Pb) content at the tibia is associated with thinner distal tibia cortices and lower volumetric bone density in postmenopausal women

Conflicting evidence suggests that bone lead or blood lead may reduce areal bone mineral density (BMD). Little is known about how lead at either compartment affects bone structure. This study examined postmenopausal women (N = 38, mean age 76 ± 8, body mass index (BMI): 26.74 ± 4.26 kg/m²) within the Hamilton cohort of the Canadian Multicentre Osteoporosis Study (CaMos), measuring bone lead at 66% of the non-dominant leg and at the calcaneus using ¹⁰⁹Cadmium X-ray fluorescence. Volumetric BMD and structural parameters were obtained from peripheral quantitative computed tomography images (200 μm in-plane resolution, 2.3 ± 0.5 mm slice thickness) of the same 66% site and of the distal 4% site of the tibia length. Blood lead was measured using atomic absorption spectrometry and blood-to-bone lead partition coefficients (P_BB, log ratio) were computed. Multivariable linear regression examined each of bone lead at the 66% tibia, calcaneus, blood lead and P_BB as related to each of volumetric BMD and structural parameters, adjusting for age and BMI, diabetes or antiresorptive therapy. Regression coefficients were reported along with 95% confidence intervals. Higher amounts of bone lead at the tibia were associated with thinner distal tibia cortices (− 0.972 (− 1.882, − 0.061) per 100 μg Pb/g of bone mineral) and integral volumetric BMD (− 3.05 (− 6.05, − 0.05) per μg Pb/g of bone mineral). A higher P_BB was associated with larger trabecular separation (0.115 (0.053, 0.178)), lower trabecular volumetric BMD (− 26.83 (− 50.37, − 3.29)) and trabecular number (− 0.08 (− 0.14, − 0.02)), per 100 μg Pb/g of bone mineral after adjusting for age and BMI, and remained significant while accounting for diabetes or use of antiresorptives. Total lead exposure activities related to bone lead at the calcaneus (8.29 (0.11, 16.48)) and remained significant after age and antiresorptives-adjustment. Lead accumulated in bone can have a mild insult on bone structure; but greater partitioning of lead in blood versus bone revealed more dramatic effects on both microstructure and volumetric BMD.     

Effects of 16-month treatment with the cathepsin K inhibitor ONO-5334 on bone markers,mineral density,strength and histomorphometry in ovariectomized cynomolgus monkeys

We examined the effects of ONO-5334, a cathepsin K inhibitor, on bone markers, BMD, strength and histomorphometry in ovariectomized (OVX) cynomolgus monkeys. ONO-5334 (1.2, 6 and 30 mg/kg/day, p.o.), alendronate (0.05 mg/kg/2 weeks, i.v.), or vehicle was administered to OVX monkeys (all groups N = 20) for 16 months. A concurrent Sham group (N = 20) was also treated with vehicle for 16 months. OVX significantly increased bone resorption and formation markers and decreased BMD in lumbar vertebra, femoral neck, proximal tibia and distal radius. Alendronate suppressed these parameters to a level similar to that in the Sham-operated monkeys. ONO-5334 at doses 6 and 30 mg/kg decreased bone resorption markers to a level roughly half of that in the Sham group, while keeping bone formation markers level above that in the Sham monkeys. Changes in DXA BMD confirmed that ONO-5334 at doses 6 and 30 mg/kg increased BMD to a level greater than that in the Sham group in all examined sites. In the proximal tibia, in vivo pQCT analysis showed that ONO-5334 at doses 6 and 30 mg/kg suppressed trabecular BMD loss to the sham level. However, ONO-5334 increased cortical BMD, cortical area and cortical thickness to a level greater than that in the Sham group, suggesting that ONO-5334 improves both cortical BMD and cortical geometry. Histomorphometric analysis revealed that ONO-5334 suppressed bone formation rate (BFR) at osteonal site in the midshaft femur but did not influence OVX-induced increase in BFR at either the periosteal or endocortical surfaces. Unlike alendronate, ONO-5334 increased osteoclasts surface (Oc.S/BS) and serum tartrate-resistant acid phosphatise 5b (TRAP5b) activity, highlighting the difference in the mode of action between these two drugs. Our results suggest that ONO-5334 has therapeutic potential not only in vertebral bones, but also in non-vertebral bones.     

Improvements in hip trabecular,subcortical, and cortical density and mass in postmenopausal women with osteoporosis treated with denosumab

In the FREEDOM study, denosumab treatment (60 mg every 6 months) decreased bone resorption, increased bone mineral density (BMD), and reduced new vertebral, nonvertebral, and hip fractures over 36 months in postmenopausal women with osteoporosis. In a subset of these women, hip quantitative computed tomography (QCT) was performed at baseline and months 12, 24, and 36. These scans were analyzed using Medical Image Analysis Framework (MIAF) software, which allowed assessment of total hip integral, trabecular, subcortical, and cortical compartments; the cortical compartment was further divided into 2 areas of interest (outer and inner cortex). This substudy reports changes in BMD and bone mineral content (BMC) from baseline and compared placebo with denosumab over 36 months of treatment (placebo N = 26; denosumab N = 36). Denosumab treatment resulted in significant improvements in total hip integral volumetric BMD (vBMD) and BMC from baseline at each time point. At month 36, the mean percentage increase from baseline in total hip integral vBMD and BMC was 6.4% and 4.8%, respectively (both p < 0.0001). These gains were accounted for by significant increases in vBMD and BMC in the trabecular, subcortical, and cortical compartments. In the placebo group, total hip integral vBMD and BMC decreased at month 36 from baseline by − 1.5% and − 2.6%, respectively (both p < 0.05). The differences between denosumab and placebo were also significant at months 12, 24, and 36 for integral, trabecular, subcortical, and cortical vBMD and BMC (all p < 0.05 to < 0.0001). While the largest percentage differences occurred in trabecular vBMD and BMC, the largest absolute differences occurred in cortical vBMD and BMC. In summary, denosumab significantly improved both vBMD and BMC from baseline and placebo, assessed by QCT MIAF, in the integral, trabecular, subcortical, and cortical hip compartments, all of which are relevant to bone strength.     

Aging diminishes lamellar and woven bone formation induced by tibial compression in adult C57BL/6

Aging purportedly diminishes the ability of the skeleton to respond to mechanical loading, but recent data show that old age did not impair loading-induced accrual of bone in BALB/c mice. Here, we hypothesized that aging limits the response of the tibia to axial compression over a range of adult ages in the commonly used C57BL/6. We subjected the right tibia of old (22 month), middle-aged (12 month) and young-adult (5 month) female C57BL/6 mice to peak periosteal strains (measured near the mid-diaphysis) of − 2200 με and − 3000 με (n = 12–15/age/strain) via axial tibial compression (4 Hz, 1200 cycles/day, 5 days/week, 2 weeks). The left tibia served as a non-loaded, contralateral control. In mice of every age, tibial compression that engendered a peak strain of − 2200 με did not alter cortical bone volume but loading to a peak strain of − 3000 με increased cortical bone volume due in part to woven bone formation. Both loading magnitudes increased total volume, medullary volume and periosteal bone formation parameters (MS/BS, BFR/BS) near the cortical midshaft. Compared to the increase in total volume and bone formation parameters of 5-month mice, increases were less in 12- and 22-month mice by 45–63%. Moreover, woven bone incidence was greatest in 5-month mice. Similarly, tibial loading at − 3000 με increased trabecular BV/TV of 5-month mice by 18% (from 0.085 mm³/mm³), but trabecular BV/TV did not change in 12- or 22-month mice, perhaps due to low initial BV/TV (0.032 and 0.038 mm³/mm³, respectively). In conclusion, these data show that while young-adult C57BL/6 mice had greater periosteal bone formation following loading than middle-aged or old mice, aging did not eliminate the ability of the tibia to accrue cortical bone.     

Administration of romosozumab improves vertebral trabecular and cortical bone as assessed with quantitative computed tomography and finite element analysis

Romosozumab inhibits sclerostin, thereby increasing bone formation and decreasing bone resorption. This dual effect of romosozumab leads to rapid and substantial increases in areal bone mineral density (aBMD) as measured by dual-energy X-ray absorptiometry (DXA). In a phase 1b, randomized, double-blind, placebo-controlled study, romosozumab or placebo was administered to 32 women and 16 men with low aBMD for 3 months, with a further 3-month follow-up: women received six doses of 1 or 2 mg/kg every 2 weeks (Q2W) or three doses of 2 or 3 mg/kg every 4 weeks (Q4W); men received 1 mg/kg Q2W or 3 mg/kg Q4W. Quantitative computed tomography (QCT) scans at lumbar (L1–2) vertebrae and high-resolution QCT (HR-QCT) scans at thoracic vertebra (T12) were analyzed in a subset of subjects at baseline, month 3, and month 6. The QCT subset included 24 romosozumab and 9 placebo subjects and the HR-QCT subset included 11 romosozumab and 3 placebo subjects. The analyses pooled the romosozumab doses. Linear finite element modeling of bone stiffness was performed. Compared with placebo, the romosozumab group showed improvements at month 3 for trabecular BMD by QCT and HR-QCT, HR-QCT trabecular bone volume fraction (BV/TV) and separation, density-weighted cortical thickness, and QCT stiffness (all p < 0.05). At month 6, improvements from baseline were observed in QCT trabecular BMD and stiffness, and in HR-QCT BMD, trabecular BV/TV and separation, density-weighted cortical thickness, and stiffness in the romosozumab group (all p < 0.05 compared with placebo). The mean (SE) increase in HR-QCT stiffness with romosozumab from baseline was 26.9% ± 6.8% and 35.0% ± 6.8% at months 3 and 6, respectively; subjects administered placebo had changes of − 2.7% ± 13.4% and − 6.4% ± 13.4%, respectively. In conclusion, romosozumab administered for 3 months resulted in rapid and large improvements in trabecular and cortical bone mass and structure as well as whole bone stiffness, which continued 3 months after the last romosozumab dose.     

Economic loss due to traumatic injury in Uganda: The patient's perspective

IntroductionTraumatic injury is a growing public health concern globally, and is a major cause of death and disability worldwide. The purpose of this study was to quantify the socioeconomic impact of lower extremity fractures in Uganda.MethodsAll adult patients presenting acutely to Uganda's national referral hospital with a single long bone lower extremity fracture in October 2013 were recruited. Consenting patients were surveyed at admission and again at six-months and 12-months post-injury. The primary outcome was the cumulative 12-month post-injury loss in income. Secondary outcome measures included the change in health-related quality of life (HRQoL) and the injury's effect on school attendance for the patients’ dependents.ResultsSeventy-four patients were recruited during the study period. Sixty-four (86%) of the patients were available for 12-months of follow-up. Compared to pre-injury earnings, patients lost 88.4% ($1822 USD) of their annual income in the 12-months following their injury. To offset this loss in income, patients borrowed an average of 28% of their pre-injury annual income. Using the EuroQol-5D instrument, the mean HRQoL decreased from 0.91 prior to the injury to 0.39 (p < 0.0001) at 12-months post-injury. Ninety-three percent of school-aged dependents missed at least one month of school during their guardian's recovery and only 61% had returned to school by 12-months post-injury.ConclusionThis study demonstrates that lower extremity fractures in Uganda had a profound impact on the socioeconomic status of the individuals in our sample population, as well as the socioeconomic health of the family unit.     

Cortical and trabecular bone adaptation to incremental load magnitudes using the mouse tibial axial compression loading model

The mouse tibial axial compression loading model has recently been described to allow simultaneous exploration of cortical and trabecular bone adaptation within the same loaded element. However, the model frequently induces cortical woven bone formation and has produced inconsistent results with regards to trabecular bone adaptation. The aim of this study was to investigate bone adaptation to incremental load magnitudes using the mouse tibial axial compression loading model, with the ultimate goal of revealing a load that simultaneously induced lamellar cortical and trabecular bone adaptation. Adult (16 weeks old) female C57BL/6 mice were randomly divided into three load magnitude groups (5, 7 and 9 N), and had their right tibia axially loaded using a continuous 2-Hz haversine waveform for 360 cycles/day, 3 days/week for 4 consecutive weeks. In vivo peripheral quantitative computed tomography was used to longitudinally assess midshaft tibia cortical bone adaptation, while ex vivo micro-computed tomography and histomorphometry were used to assess both midshaft tibia cortical and proximal tibia trabecular bone adaptation. A dose response to loading magnitude was observed within cortical bone, with increasing load magnitude inducing increasing levels of lamellar cortical bone adaptation within the upper two thirds of the tibial diaphysis. Greatest cortical bone adaptation was observed at the midshaft where there was a 42% increase in estimated mechanical properties (polar moment of inertia) in the highest (9 N) load group. A dose response to load magnitude was not clearly evident within trabecular bone, with only the highest load (9 N) being able to induce measureable adaptation (31% increase in trabecular bone volume fraction at the proximal tibia). The ultimate finding was that a load of 9 N (engendering a tensile strain of 1833 με on medial surface of the midshaft tibia) was able to simultaneously induce measurable lamellar cortical and trabecular bone adaptation when using the mouse tibial axial compression loading model in 16 week old female C57BL/6 mice. This finding will help plan future studies aimed at exploring simultaneous lamellar cortical and trabecular bone adaptation within the same loaded element.     

Changes in bone mineral density after allogenic stem cell transplantation

ObjectiveOsteoporosis is a complication after allogenic stem cell transplantation (alloSCT). The purpose of this study was to assess changes in bone mineral density (BMD) 6 months and 3 years after alloSCT, as well as predictors of bone loss.MethodsA longitudinal, prospective, single-center study was conducted at Lille University Hospital between 2005 and 2016. Clinical, biological, radiologic (thoracic and lumbar spine) and densitometric (DXA) assessments were carried out at baseline (pre-transplant), 6 months and 3 years. Patients with myeloma were not included.ResultsTwo hundred and fifty-eight patients were included (144 men). Among them, 60.1% had leukemia and 65.8% of them, acute myeloid leukemia. At baseline, 6 months and 3 years, DXA-confirmed that osteoporosis was observed in 17%, 22.8% and 17.5% of the patients, respectively, mainly at the femoral neck. At baseline, 6 months and 3 years, 9 (8.5%), 53 (21.5%) and 38 (16.7%) patients, respectively, were receiving anti-osteoporotic treatment. From baseline to 6-month follow-up, BMD decreased significantly (p < 0.001) at the lumbar spine (?36 [95%CI; ?51 to ?20] mg/cm² of hydroxyapatite), femoral neck (?43 [95%CI; ?57 to ?29] mg/cm² of hydroxyapatite) and total hip (?53 [95%CI; ?68 to ?39] mg/cm² of hydroxyapatite). From 6-month to 3-year follow-up, a significant increase in BMD was observed at the lumbar spine only (+31 [95%CI; 20 to 42] mg/cm² of hydroxyapatite, p < 0.001). At all 3 sites, changes in BMD did not differ between patients treated or untreated by anti-osteoporotic treatment from 6-month to 3 year follow-up. Incident fractures were found in 4.1% and 5.7% of the patients at 6 months and 3 years, respectively. Between baseline and 6 months, bone loss at all 3 sites was associated with corticosteroid intake. At the total hip, 23.3% of the decrease in BMD from baseline to 6 months was due to an active hematological disease (p < 0.05), a bone marrow stem cells (p < 0.01) and a corticosteroid intake (p < 0.01).ConclusionOur study found evidence of bone fragility in alloSCT patients. Low BMD persisted at the hip 3 years after transplantation due to slower improvement at this site.     

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.     

Structural analysis of the human tibia in men with spinal cord injury by tomographic (pQCT) serial scans

Spinal cord injury (SCI), as a primarily neurological disorder that causes muscular atrophy, is well known to be associated with sub-lesional bone losses. These losses are more pronounced from epiphyseal than from diaphyseal regions. We hypothesized that this discrepancy may be explained by anatomical variation in endocortical circumference.Nine men who had attracted SCI 9 to 32 (mean 21.4) years prior to study inclusion were matched to able bodied control (Ctrl) people by age, height and weight. Serial scans by peripheral quantitative computed tomography were obtained from the tibia at steps corresponding to 5%-steps of the tibias length (s05 to s95, from distal to the proximal end of the tibia).As expected, SCI people had lower total bone mineral content (vBMC.tot) than able bodied control people (P < 0.001 at all sites). This group difference (ΔvBMC.tot) was more pronounced at the distal and proximal tibia than in the shaft (P < 0.001), and it amounted to 51% at s05, to 22% at s40, and to 47% at s95. Both endocortical and periosteal circumference were better predictors of ΔvBMC.tot (R² = 0.98 and R² = 0.97, respectively; P < 0.001 in both cases) than vBMC.tot (R² = 0.58, P < 0.001), suggesting that anatomical variation in geometry, rather than in bone mass can explain differential rates of bone loss after SCI. Moreover, the s04:s38 ratio in vBMC.tot was found to be 1.00 (95% confidence interval: 0.95–1.05) in the Ctrl group, and 0.63 in the SCI group (P < 0.001, 95% confidence interval: 0.54–0.68).These findings offer a rationale to account for the discrepancy between epiphyseal and diaphyseal bone losses following SCI. The suggestion is that the bone adaptive responses involved are limited in time, and that the reduced surface:volume ratio constitutes a limit within the available time window, in particular in the diaphysis. Finally, the drastically reduced s04:s38 vBMC.tot ratio observed in the SCI group in this study provides a rationale to scrutinize this Capozza index also in other studies as a general indicator of immobilisation-induced bone loss.     

Muscle volume is related to trabecular and cortical bone architecture in typically developing children

IntroductionMuscle is strongly related to cortical bone architecture in children; however, the relationship between muscle volume and trabecular bone architecture is poorly studied. The aim of this study was to determine if muscle volume is related to trabecular bone architecture in children and if the relationship is different than the relationship between muscle volume and cortical bone architecture.Materials and methodsForty typically developing children (20 boys and 20 girls; 6 to 12 y) were included in the study. Measures of trabecular bone architecture [i.e., apparent trabecular bone volume to total volume (appBV/TV), trabecular number (appTb.N), trabecular thickness (appTb.Th) and trabecular separation (appTb.Sp)] in the distal femur, cortical bone architecture [cortical volume, total volume, section modulus (Z) and polar moment of inertia (J)] in the midfemur, muscle volume in the midthigh and femur length were assessed using magnetic resonance imaging. Total physical activity and moderate-to-vigorous physical activity were assessed using an accelerometer-based activity monitor worn around the waist for four days. Calcium intake was assessed using diet records. Relationships among the measures were tested using multiple linear regression analysis.ResultsMuscle volume was moderately-to-strongly related to measures of trabecular bone architecture [appBV/TV (r = 0.81), appTb.N (r = 0.53), appTb.Th (r = 0.67), appTb.Sp (r = − 0.71); all p < 0.001] but more strongly related to measures of cortical bone architecture [cortical volume (r = 0.96), total volume (r = 0.94), Z (r = 0.94) and J (r = 0.92; all p < 0.001)]. Similar relationships were observed between femur length and measures of trabecular (p < 0.01) and cortical (p < 0.001) bone architecture. Sex, physical activity and calcium intake were not related to any measure of bone architecture (p > 0.05). Because muscle volume and femur length were strongly related (r = 0.91, p < 0.001), muscle volume was scaled for femur length (muscle volume/femur length^2.77). When muscle volume/femur length^2.77 was included in a regression model with femur length, sex, physical activity and calcium intake, muscle volume/femur length^2.77 was a significant predictor of appBV/TV, appTb.Th and appTb.Sp (partial r = 0.44 to 0.49, p < 0.05) and all measures of cortical bone architecture (partial r = 0.47 to 0.54; p < 0.01).ConclusionsThe findings suggest that muscle volume in the midthigh is related to trabecular bone architecture in the distal femur of typically developing children. The relationship is weaker than the relationship between muscle volume in the midthigh and cortical bone architecture in the midfemur, but the discrepancy is driven, in large part, by the greater dependence of cortical bone architecture measures on femur length.     

Effects of Exemestane and Tamoxifen Treatment on Bone Texture Analysis Assessed by TBS in Comparison With Bone Mineral Density Assessed by DXA in Women With Breast Cancer

We performed an analysis of a substudy of the randomized Tamoxifen Exemestane Adjuvant Multinational trial to determine the effects of exemestane (EXE) and tamoxifen (TAM) adjuvant treatment on bone mineral density (BMD) measured by dual-energy X-ray absorptiometry compared with the trabecular bone score, a novel grey-level texture measurement that correlates with 3-dimensional parameters of bone texture in postmenopausal women with hormone receptor–positive breast cancer for the first time. In total, 36 women were randomized to receive TAM (n = 17) or EXE (n = 19). Patients receiving TAM showed a mean increase of BMD in lumbar spine from baseline of 1.0%, 1.5%, and 1.9% and in trabecular bone score of 2.2%, 3.5%, and 3.3% at 6-, 12-, and 24-mo treatment, respectively. Conversely, patients receiving EXE showed a mean decrease from baseline in lumbar spine BMD of −2.3%, −3.6%, and −5.3% and in trabecular bone score of −0.9%, −1.7%, and −2.3% at 6-, 12-, and 24-mo treatment, respectively. Changes in trabecular bone score from baseline at spine were also significantly different between EXE and TAM: p = 0.05, 0.007, and 0.006 at 6, 12, and 24 mo, respectively. TAM induced an increase in BMD and bone texture analysis, whereas EXE resulted in decreases. The results were independent from each other.