Bone material quality in transiliac bone biopsies of postmenopausal osteoporotic women after 3 years of strontium ranelate treatment

Strontium ranelate (SrR) is a relatively new treatment for osteoporosis. In this study we investigated its potential impact on human bone material quality in transiliac bone biopsies from postmenopausal osteoporotic women treated 3 years with calcium and vitamin D plus either 2 g SrR per day or placebo. Bone mineralization density distribution (BMDD), strontium (Sr) concentration, collagen cross‐link ratio, and indentation modulus were analyzed by quantitative backscattered electron imaging, electron‐induced X‐ray fluorescence analysis, synchrotron radiation induced micro X‐ray fluorescence elemental mapping, Fourier transform infrared imaging, and nanoindentation, respectively. The BMDD of SrR‐treated patients was shifted to higher atomic numbers (Z_mean +1.5%, p < .05 versus placebo). We observed Sr being preferentially incorporated in bone packets formed during SrR treatment up to 6% atom fraction [Sr/(Sr + Ca)] depending on the SrR serum levels of the individuals (correlation r = 0.84, p = .018). Collagen cross‐link ratio was preserved in SR‐treated bone. The indentation modulus was significantly decreased in younger versus older bone packets for both placebo‐ (?20.5%, p < .0001) and SrR‐treated individuals (?24.3%, p < .001), whereas no differences were found between the treatment groups. In conclusion, our findings indicate that after SrR treatment, Sr is heterogeneously distributed in bone and preferentially present in bone packets formed during treatment. The effect of SrR on BMDD seems to be due mainly to the uptake of Sr and not to changes in bone calcium content. Taken together, these data provide evidence that the investigated bone quality determinants at tissue level were preserved in postmenopausal osteoporotic women after 3‐year treatment with 2 g SrR per day plus calcium and vitamin D. © 2010 American Society for Bone and Mineral Research     

Effects of Growth Hormone Administration on Bone Mineral Metabolism,PTH Sensitivity and PTH Secretory Rhythm in Postmenopausal Women With Established Osteoporosis

Introduction : Growth hormone (GH) replacement improves target organ sensitivity to PTH, PTH circadian rhythm, calcium and phosphate metabolism, bone turnover, and BMD in adult GH‐deficient (AGHD) patients. In postmenopausal women with established osteoporosis, GH and insulin like growth factor‐1 (IGF‐1) concentrations are low, and administration of GH has been shown to increase bone turnover and BMD, but the mechanisms remain unclear. We studied the effects of GH administration on PTH sensitivity, PTH circadian rhythm, and bone mineral metabolism in postmenopausal women with established osteoporosis. Materials and Methods : Fourteen postmenopausal women with osteoporosis were compared with 14 healthy premenopausal controls at baseline that then received GH for a period of 12 mo. Patients were hospitalized for 24 h before and 1, 3, 6, and 12 mo after GH administration and half‐hourly blood and 3‐h urine samples were collected. PTH, calcium (Ca), phosphate (PO₄), nephrogenous cyclic AMP (NcAMP), β C‐telopeptide of type 1 collagen (βCTX), procollagen type I amino‐terminal propeptide (PINP), and 1,25‐dihydroxyvitamin D [1,25(OH)₂D] were measured. Circadian rhythm analysis was performed using Chronolab 3.0 and Student's t‐test and general linear model ANOVAs for repeated measures were used where appropriate. Results : IGF‐1 concentration was significantly lower in the women with established osteoporosis compared with controls (101.5 ± 8.9 versus 140.9 ± 10.8 μg/liter; p < 0.05) and increased significantly after 1, 3, 6, and 12 mo of GH administration (p < 0.001). Twenty‐four‐hour mean PTH concentration was higher in the osteoporotic women (5.4 ± 0.1 pM) than in healthy controls (4.4 ± 0.1 pM, p < 0.001) and decreased after 1 (5.2 ± 0.1 pM, p < 0.001), 3 (5.0 ± 0.1 pM, p < 0.001), 6 (4.7 ± 0.1 pM, p < 0.001), and 12 mo (4.9 ± 0.1 pM, p < 0.05) of GH administration compared with baseline. NcAMP was significantly lower in osteoporotic women (17.2 ± 1.2 nM glomerular filtration rate [GFR]) compared with controls (21.4 ± 1.4 nM GFR, p < 0.05) and increased after 1 (24.2 ± 2.5 nM GFR, p < 0.05), 3 (27.3 ± 1.5 nM GFR, p < 0.001), and 6 mo (32.4 ± 2.5 nM GFR, p < 0.001) compared with baseline. PTH secretion was characterized by two peaks in premenopausal women and was altered in postmenopausal women with a sustained increase in PTH concentration. GH administration also restored a normal PTH secretory pattern in the osteoporotic women. The 24‐h mean adjusted serum calcium (ACa) concentration increased at 1 and 3 mo (p < 0.001) and PO₄ at 1, 3, 6, and 12 mo (p < 0.001). 1,25(OH)₂D concentration increased after 3, 6, and 12 mo of GH (p < 0.05). An increase in urine Ca excretion was observed at 3 and 6 mo (p < 0.05), and the renal threshold for maximum tubular phosphate reabsorption rate (TmPO4/GFR) increased after 1, 3, 6, and 12 mo (p < 0.05). βCTX concentration increased progressively from 0.74 ± 0.07 μg/liter at baseline to 0.83 ± 0.07 μg/liter (p < 0.05) at 1 mo and 1.07 ± 0.09 μg/liter (p < 0.01) at 3 mo, with no further increase at 6 or 12 mo. PINP concentration increased progressively from baseline (60 ± 5 μg/liter) to 6 mo (126 ± 11 μg/liter, p < 0.001), with no further increase at 12 mo. The percentage increase in PINP concentration was significantly higher than βCTX (p < 0.05). Conclusions : Our study shows that GH has a regulatory role in bone mineral metabolism. GH administration to postmenopausal osteoporotic women improves target organ sensitivity to PTH and bone mineral metabolism and alters PTH secretory pattern with greater increases in bone formation than resorption. These changes, resulting in a net positive bone balance, may partly explain the mechanism causing the increase in BMD after long‐term administration of GH in postmenopausal women with osteoporosis shown in previous studies and proposes a further component in the development of age‐related postmenopausal osteoporosis.     

Comparative Effects of Teriparatide,Denosumab, and Combination Therapy on Peripheral Compartmental Bone Density,Microarchitecture, and Estimated Strength: the DATA‐HRpQCT Study

Combined teriparatide and denosumab increases spine and hip bone mineral density more than either drug alone. The effect of this combination on skeletal microstructure and microarchitecture, however, is unknown. Because skeletal microstructure and microarchitecture are important components of skeletal integrity, we performed high‐resolution peripheral quantitative computed tomography (HR‐pQCT) assessments at the distal tibia and radius in postmenopausal osteoporotic women randomized to receive teriparatide 20 µg daily (n = 31), denosumab 60 mg every 6 months (n = 33), or both (n = 30) for 12 months. In the teriparatide group, total volumetric bone mineral density (vBMD) did not change at either anatomic site but increased in both other groups at both sites. The increase in vBMD at the tibia was greater in the combination group (3.1 ± 2.2%) than both the denosumab (2.2 ± 1.9%) and teriparatide groups (–0.3 ± 1.9%) (p < 0.02 for both comparisons). Cortical vBMD decreased by 1.6 ± 1.9% at the tibia and by 0.9 ± 2.8% at the radius in the teriparatide group, whereas it increased in both other groups at both sites. Tibia cortical vBMD increased more in the combination group (1.5 ± 1.5%) than both monotherapy groups (p < 0.04 for both comparisons). Cortical thickness did not change in the teriparatide group but increased in both other groups. The increase in cortical thickness at the tibia was greater in the combination group (5.4 ± 3.9%) than both monotherapy groups (p < 0.01 for both comparisons). In the teriparatide group, radial cortical porosity increased by 20.9 ± 37.6% and by 5.6 ± 9.9% at the tibia but did not change in the other two groups. Bone stiffness and failure load, as estimated by finite element analysis, did not change in the teriparatide group but increased in the other two groups at both sites. Together, these findings suggest that the use of denosumab and teriparatide in combination improves HR‐pQCT measures of bone quality more than either drug alone and may be of significant clinical benefit in the treatment of postmenopausal osteoporosis. © 2014 American Society for Bone and Mineral Research.     

Bone Loss After Bariatric Surgery: Discordant Results Between DXA and QCT Bone Density

Several studies, using dual‐energy X‐ray absorptiometry (DXA), have reported substantial bone loss after bariatric surgery. However, profound weight loss may cause artifactual changes in DXA areal bone mineral density (aBMD) results. Assessment of volumetric bone mineral density (vBMD) by quantitative computed tomography (QCT) may be less susceptible to such artifacts. We assessed changes in BMD of the lumbar spine and proximal femur prospectively for 1 year using DXA and QCT in 30 morbidly obese adults undergoing Roux‐en‐Y gastric bypass surgery and 20 obese nonsurgical controls. At 1 year, subjects who underwent gastric bypass surgery lost 37 ± 2 kg compared with 3 ± 2 kg lost in the nonsurgical controls (p < 0.0001). Spine BMD declined more in the surgical group than in the nonsurgical group whether assessed by DXA (?3.3 versus ?1.1%, p = 0.034) or by QCT (?3.4 versus 0.2%, p = 0.010). Total hip and femoral neck aBMD declined significantly in the surgical group when assessed by DXA (?8.9 versus ?1.1%, p < 0.0001 for the total hip and ?6.1 versus ?2.0%, p = 0.002 for the femoral neck), but no changes in hip vBMD were noted using QCT. Within the surgical group, serum P1NP and CTX levels increased by 82% ± 10% and by 220% ± 22%, respectively, by 6 months and remained elevated over 12 months (p < 0.0001 for all). Serum calcium, vitamin D, and PTH levels remained stable in both groups. We conclude that moderate vertebral bone loss occurs in the first year after gastric bypass surgery. However, striking declines in DXA aBMD at the proximal femur were not confirmed with QCT vBMD measurements. These discordant results suggest that artifacts induced by large changes in body weight after bariatric surgery affect DXA and/or QCT measurements of bone, particularly at the hip. © 2014 American Society for Bone and Mineral Research.     

Effects of Denosumab and Teriparatide Transitions on Bone Microarchitecture and Estimated Strength: the DATA‐Switch HR‐pQCT study

In postmenopausal osteoporosis, switching from teriparatide to denosumab results in continued bone mineral density (BMD) gains whereas switching from denosumab to teriparatide results in BMD loss. To assess the effects of these transitions on bone microarchitecture and strength, we performed high‐resolution peripheral QCT (HR‐pQCT) at the distal tibia and radius in postmenopausal osteoporotic women who received 24 months of teriparatide 20 μg daily followed by 24 months of denosumab 60 mg every 6 months, 24 months of denosumab followed by 24 months of teriparatide, or 24 months of both medications followed by 24 months of denosumab. The 77 women who completed at least one post‐switch visit are included in this analysis. Tibial cortical volumetric BMD (vBMD) increased between months 24 and 48 in the teriparatide‐to‐denosumab (net 48‐month change –0.8% ± 2.4%) and combination‐to‐denosumab groups (net 48‐month changes +2.4% ± 4.1%) but decreased in the denosumab‐to‐teriparatide group (net 48‐month change –3.4% ± 3.2%, p < 0.001 for all between‐group comparisons). Changes in total vBMD, cortical thickness, and estimated stiffness (by micro–finite element analysis [µFEA]) followed a similar pattern, as did changes at the radius. Conversely, tibial cortical porosity remained stable between months 24 and 48 in the teriparatide‐to‐denosumab and combination‐to‐denosumab groups (net 48‐month changes +7.2% ± 14.8% and –3.4% ± 12.1%, respectively) but increased in the denosumab‐to‐teriparatide group (net 48‐month change +16.2% ± 11.5%, p < 0.05 versus other groups). Trabecular vBMD changes did not differ among groups. Together, these findings demonstrate that in women treated with denosumab, switching to teriparatide is associated with a reduction in total and cortical vBMD, cortical thickness, and estimated strength, whereas switching to denosumab from teriparatide or combination therapy results in improvements in these parameters with the greatest improvements observed in women treated with combined therapy followed by denosumab. These findings strongly suggest that the use of teriparatide after denosumab should be avoided and that the use of combined teriparatide/denosumab followed by denosumab alone may be a useful treatment strategy in those with severe osteoporosis. © 2017 American Society for Bone and Mineral Research.     

Effects of intravenous zoledronic acid plus subcutaneous teriparatide [rhPTH(1–34)] in postmenopausal osteoporosis

Clinical data suggest concomitant therapy with bisphosphonates and parathyroid hormone (PTH) may blunt the anabolic effect of PTH; rodent models suggest that infrequently administered bisphosphonates may interact differently. To evaluate the effects of combination therapy with an intravenous infusion of zoledronic acid 5 mg and daily subcutaneous recombinant human (rh)PTH(1–34) (teriparatide) 20 µg versus either agent alone on bone mineral density (BMD) and bone turnover markers, we conducted a 1‐year multicenter, multinational, randomized, partial double‐blinded, controlled trial. 412 postmenopausal women with osteoporosis (mean age 65 ± 9 years) were randomized to a single infusion of zoledronic acid 5 mg plus daily subcutaneous teriparatide 20 µg (n = 137), zoledronic acid alone (n = 137), or teriparatide alone (n = 138). The primary endpoint was percentage increase in lumbar spine BMD (assessed by dual‐energy X‐ray absorptiometry [DXA]) at 52 weeks versus baseline. Secondary endpoints included change in BMD at the spine at earlier time points and at the total hip, trochanter, and femoral neck at all time points. At week 52, lumbar spine BMD had increased 7.5%, 7.0%, and 4.4% in the combination, teriparatide, and zoledronic acid groups, respectively (p < .001 for combination and teriparatide versus zoledronic acid). In the combination group, spine BMD increased more rapidly than with either agent alone (p < .001 versus both teriparatide and zoledronic acid at 13 and 26 weeks). Combination therapy increased total‐hip BMD more than teriparatide alone at all times (all p < .01) and more than zoledronic acid at 13 weeks (p < .05), with final 52‐week increments of 2.3%, 1.1%, and 2.2% in the combination, teriparatide, and zoledronic acid groups, respectively. With combination therapy, bone formation (assessed by serum N‐terminal propeptide of type I collagen [PINP]) increased from 0 to 4 weeks, declined minimally from 4 to 8 weeks, and then rose throughout the trial, with levels above baseline from 6 to 12 months. Bone resorption (assessed by serum β‐C‐telopeptide of type I collagen [β‐CTX]) was markedly reduced with combination therapy from 0 to 8 weeks (a reduction of similar magnitude to that seen with zoledronic acid alone), followed by a gradual increase after week 8, with levels remaining above baseline for the latter half of the year. Levels for both markers were significantly lower with combination therapy versus teriparatide alone (p < .002). Limitations of the study included its short duration, lack of endpoints beyond DXA‐based BMD (e.g., quantitative computed tomography and finite‐element modeling for bone strength), lack of teriparatide placebo, and insufficient power for fracture outcomes. We conclude that while teriparatide increases spine BMD more than zoledronic acid and zoledronic acid increases hip BMD more than teriparatide, combination therapy provides the largest, most rapid increments when both spine and hip sites are considered. © 2011 American Society for Bone and Mineral Research.     

Effects of Romosozumab Compared With Teriparatide on Bone Density and Mass at the Spine and Hip in Postmenopausal Women With Low Bone Mass

Romosozumab, a monoclonal antibody that binds sclerostin, has a dual effect on bone by increasing bone formation and reducing bone resorption, and thus has favorable effects in both aspects of bone volume regulation. In a phase 2 study, romosozumab increased areal BMD at the lumbar spine and total hip as measured by DXA compared with placebo, alendronate, and teriparatide in postmenopausal women with low bone mass. In additional analyses from this international, randomized study, we now describe the effect of romosozumab on lumbar spine and hip volumetric BMD (vBMD) and BMC at month 12 as assessed by QCT in the subset of participants receiving placebo, s.c. teriparatide (20 µg once daily), and s.c. romosozumab (210 mg once monthly). QCT measurements were performed at the lumbar spine (mean of L₁ and L₂ entire vertebral bodies, excluding posterior processes) and hip. One year of treatment with romosozumab significantly increased integral vBMD and BMC at the lumbar spine and total hip from baseline, and compared with placebo and teriparatide (all p < 0.05). Trabecular vertebral vBMD improved significantly and similarly from baseline (p < 0.05) with both romosozumab (18.3%) and teriparatide (20.1%), whereas cortical vertebral vBMD gains were larger with romosozumab compared with teriparatide (13.7% versus 5.7%, p < 0.0001). Trabecular hip vBMD gains were significantly larger with romosozumab than with teriparatide (10.8% versus 4.2%, p = 0.01), but were similar for cortical vBMD (1.1% versus –0.9%, p = 0.12). Cortical BMC gains were larger with romosozumab compared with teriparatide at both the spine (23.3% versus 10.9%, p < 0.0001) and hip (3.4% versus 0.0%, p = 0.03). These improvements are expected to result in strength gains and support the continued clinical investigation of romosozumab as a potential therapy to rapidly reduce fracture risk in ongoing phase 3 studies. © 2016 American Society for Bone and Mineral Research.     

Higher Milk Requirements for Bone Mineral Accrual in Adolescent Girls Bearing Specific Caucasian Genotypes in the VDR Promoter

Low milk intakes hamper bone mineral acquisition during adolescence, especially in European girls. We hypothesized that ethnic‐specific polymorphisms of the vitamin D receptor gene promoter (VDRp) influence this milk/bone association. We evaluated lumbar spine BMC and BMD, milk/dairy products and calcium intakes, markers of P‐Ca metabolism, and VDRp polymorphisms at the Cdx‐2 binding (rs11568820) and ?1012 (rs4516035) loci in 117 healthy European peri‐ and postmenarcheal girls (14.9 ± 1.6 yr) during a 4‐yr follow‐up. Calcium intakes from milk, nonmilk dairy products, and nondairy products averaged 199, 243, and 443 mg/d at the initiation of the study. Results show no association between milk intakes and bone mass accrual in girls bearing an A/A genotype at the ?1012 VDRp locus (30% of the cohort). In contrast, A/G or G/G girls had lower spine BMC (?13%, p = 0.031), BMD (?10%, p = 0.004), and BMD Z‐score (?0.84 SD, p = 0.0003) when their milk intakes were <260 ml/d compared with genotype‐matched girls with higher milk intakes and with girls with an A/A genotype. The negative impact of low milk intake persisted up to 19.0 ± 1.7 yr. These findings suggest that European girls bearing a ?1012 A/G or G/G VDRp genotype should have higher milk/calcium intakes for optimal vertebral mass accrual during adolescence than girls bearing an A/A genotype, a genotype found in 30% of European and 98% of Asian and Sub‐Saharan African populations. VDRp genotype diversity may contribute to the ethnic differences observed in milk requirements for bone health during adolescence.     

Bone density and structure in long-term survivors of pediatric allogeneic hematopoietic stem cell transplantation

Children requiring allogeneic hematopoietic stem cell transplantation (alloHSCT) have multiple risk factors for impaired bone accrual. The impact of alloHSCT on volumetric bone mineral density (vBMD) and cortical structure has not been addressed. Tibia peripheral quantitative computed tomography (pQCT) scans were obtained in 55 alloHSCT recipients, ages 5 to 26 years, a median of 7 (range, 3–16) years after alloHSCT. pQCT outcomes were converted to sex‐ and race‐ specific Z‐scores relative to age based on reference data in >700 concurrent healthy participants. Cortical section modulus (Zp; a summary measure of cortical bone structure and strength), and muscle and fat area Z‐scores were further adjusted for tibia length for age Z‐scores. AlloHSCT survivors had lower height Z‐scores (?1.21 ± 1.25 versus 0.23 ± 0.92; p < 0.001), versus reference participants; BMI Z‐scores did not differ. AlloHSCT survivors had lower trabecular vBMD (?1.05; 95% confidence interval [CI], ?1.33 to ?0.78; p < 0.001), cortical Zp (?0.63; 95% CI, ?0.91 to ?0.35; p < 0.001), and muscle (?1.01; 95% CI, ?1.30 to ?0.72; p < 0.001) Z‐scores and greater fat (0.82; 95% CI, 0.54–1.11; p < 0.001) Z‐scores, versus reference participants. Adjustment for muscle deficits eliminated Zp deficits in alloHSCT. Total body irradiation (TBI) was associated with lower trabecular vBMD (?1.30 ± 1.40 versus ?0.49 ± 0.88; p = 0.01) and muscle (?1.34 ± 1.42 versus ?0.34 ± 0.87; p < 0.01) Z‐scores. Growth hormone deficiency (GHD) was associated with lower Zp Z‐scores (?1.64 ± 2.47 versus ?0.28 ± 1.24; p = 0.05); however, muscle differences were not significant (?1.69 ± 1.84 versus ?0.78 ± 1.01; p = 0.09). History of graft versus host disease was not associated with pQCT outcomes. In summary, alloHSCT was associated with significant deficits in trabecular vBMD, cortical geometry, and muscle area years after transplantation. TBI and GHD were significant risk factors for musculoskeletal deficits. Future studies are needed to determine the metabolic and fracture implications of these deficits, and to identify therapies to improve bone accrual following alloHSCT during childhood. © 2012 American Society for Bone and Mineral Research.     

In Vivo Magnetic Resonance Detects Rapid Remodeling Changes in the Topology of the Trabecular Bone Network After Menopause and the Protective Effect of Estradiol

Introduction : Estrogen depletion after menopause is accompanied by bone loss and architectural deterioration of trabecular bone. The hypothesis underlying this work is that the μMRI‐based virtual bone biopsy can capture the temporal changes of scale and topology of the trabecular network and that estrogen supplementation preserves the integrity of the trabecular network. Materials and Methods : Subjects studied were early postmenopausal women, 45–55 yr of age (N = 65), of whom 32 were on estrogen (estradiol group), and the remainder were not (control group). Early menopause was defined by amenorrhea for 6–24 mo and elevated serum follicle‐stimulating hormone (FSH) concentration. The subjects were evaluated with three imaging modalities at baseline and 12 and 24 mo to determine the temporal changes in trabecular and cortical architecture and density. μMRI of the distal radius and tibia was performed at 137 × 137 × 410‐μm³ voxel size. The resulting bone volume fraction maps were Fourier interpolated to a final voxel size of 45.7 × 45.7 × 136.7 μm³, binarized, skeletonized, and subjected to 3D digital topological analysis (DTA). Skeletonization converts trabecular rods to curves and plates to surfaces. Parameters quantifying scale included BV/TV, whereas DTA parameters included the volume densities of curves (C) and surface (S)‐type voxels, as well as composite parameters: the surface/curve ratio (S/C), and erosion index (EI, ratio of the sum of parameters expected to increase with osteoclastic resorption divided by the sum of those expected to decrease). For comparison, pQCT of the same peripheral locations was conducted, and trabecular density and cortical structural parameters were measured. Areal BMD of the lumbar vertebrae and hip was also measured. Results : Substantial changes in trabecular architecture of the distal tibia, in particular as they relate to topology of the network, were detected after 12 mo in the control group. S/C decreased 5.6% (p < 0.0005), and EI increased 7.1% (p < 0.0005). Most curve‐ and profile‐type voxels (representative of trabecular struts), increased significantly (p < 0.001). Curve and profile edges resulting from disconnection of rod‐like trabeculae increased by 9.8% and 5.1% (p = 0.0001 and <0.001, respectively). Similarly, DXA BMD in the spine and hip decreased 2.6% and 1.3% (p < 0.0001 and <0.005, respectively), and pQCT cortical area decreased 3.6% (p = 0.0001). However, neither trabecular density nor BV/TV changed. Furthermore, none of the parameters measured in the estradiol group were significantly different after 12 mo. Substantial differences in the mean changes from baseline between the estradiol treatment and control groups, in particular after 24 mo, were observed, with relative group differences as large as 13% (S/C, p = 0.005), and the relative changes in the two groups had the opposite sign for most parameters. The observed temporal alterations in architecture are consistent with remodeling changes that involve gradual conversion of plate‐like to rod‐like trabecular bone along with disconnection of trabecular elements, even in the absence of a net loss of trabecular bone. The high‐resolution 3D rendered images provide direct evidence of the above remodeling changes in individual subjects. The radius structural data indicated similar trends but offered no definitive conclusions. Conclusions : The short‐term temporal changes in trabecular architecture after menopause, and the protective effects of estradiol ensuring maintenance of a more plate‐like TB architecture, reported here, have not previously been observed in vivo. This work suggests that MRI‐based in vivo micromorphometry of trabecular bone has promise as a tool for monitoring osteoporosis treatment.     

Bone involvement in aldosteronism

In rats with aldosteronism, a reduction of bone mineral density (BMD) and cortical bone strength has been reported. Our study was aimed to evaluate bone involvement in patients with primary aldosteronism (PA). A total of 188 consecutive subjects with adrenal incidentaloma, observed between November 2009 and October 2011, were screened for PA with aldosterone‐to‐renin ratio. After confirmatory tests, in those who screened positive, 11 patients were diagnosed as PA and 15 patients were not (nPA). A serum/urinary biochemical profile, parathyroid hormone (PTH), BMD measured at lumbar spine (LS) and total and femoral neck (TN and FN) by dual X‐ray absorptiometry, and conventional spinal radiographs (T₄–L₄) were obtained in all subjects. PA patients had a significantly higher 24‐hour urinary calcium (6.28 ± 1.85 versus 4.28 ± 1.18 mmol/d; p < 0.01), and PTH (9.8 [5.8‐14.6], median [range] versus 5.3 [2.5‐10.8] pmol/L; p < 0.01) than nPA patients. BMD expressed as Z‐value at LS (?1.18 ± 0.99 versus 0.22 ± 1.12), FN (?0.85 ± 0.73 versus 0.01 ± 0.82), and TN (?0.49 ± 0.61 versus 0.39 ± 0.93) was lower in PA than in nPA (p = 0.003, p = 0.011, and p = 0.012, respectively). The prevalence of osteoporosis was higher in PA than in nPA (8/11, 72.7% versus 3/15, 20.0%; Fisher's exact test: p = 0.015). Vertebral fractures tended to be more prevalent in PA than in nPA (5/11, 45.5% versus 2/15, 13.3%; Fisher's exact test: p = 0.095). Logistic regression analysis showed that osteoporosis and morphometric vertebral fractures were associated with PA (odds ratio [OR], 15.4; 95% confidence interval [CI] = 1.83–130, p = 0.012; and OR, 30.4; 95%CI, 1.07–862, p = 0.045, respectively) regardless of age, body mass index (BMI), and LS‐BMD. In 9 of 11 PA patients, 6 months after beginning of treatment (surgery or spironolactone) there was a significant reduction of urinary calcium excretion (p < 0.01) and PTH (p < 0.01), whereas in 5 of 11 PA patients, 1 year after beginning of treatment, BMD was significantly increased at LS, p < 0.01). In conclusion, PA is associated with osteoporosis, vertebral fractures, and increased urinary calcium excretion. © 2012 American Society for Bone and Mineral Research.     

Gene Expression Profiling in Paget's Disease of Bone: Upregulation of Interferon Signaling Pathways in Pagetic Monocytes and Lymphocytes

We examined the gene expression profile of genes involved in bone metabolism in 23 patients with PD compared with 23 healthy controls. We found a significant overexpression of the genes of the IFN pathway along with a downregulation of tnf‐α. Our result suggest that IFN‐mediated signaling may play important roles in aberrant osteoclastogenesis of PD. Introduction: Paget's disease of bone (PD) is characterized by focal regions of highly exaggerated bone remodeling and aberrant osteoclastogenesis. Under physiological conditions, circulating monocytes may serve as early progenitors of osteoclasts and along with peripheral blood lymphocytes produce a wide variety of factors important in bone metabolism. Nevertheless, little is known about the roles of circulating monocytes and lymphocytes in relation to the pathological bone turnover in PD. Materials and Methods: In this study, we aimed at investigating the gene expression pattern of PD using quantitative real‐time PCR in monocytes and lymphocytes isolated from peripheral blood mononuclear cells (PBMCs). Fifteen genes known to be involved in osteoclastogenesis were studied in cells from 23 patients with PD and in cells from 23 healthy controls. Eight human genes including ifn‐α (3.48‐fold, p < 0.001), ifn‐β (2.68‐fold, p < 0.001), ifn‐γ (1.98‐fold, p = 0.002), p38 β2 mapk (2.47‐fold, p = 0.002), ifn‐γr1 (2.03‐fold, p = 0.01), ifn‐γr2 (1.81‐fold, p = 0.02), stat1 (1.57‐fold, p = 0.037), and tnf‐α (?2.34, p < 0.001) were found to be significantly altered in pagetic monocytes compared with monocytes of healthy controls. Results: In pagetic lymphocytes, significant changes in the expression of ifn‐α (2.17‐fold, p < 0.001), ifn‐β (2.13‐fold, p = 0.005), ifn‐γ (1.89‐fold, p < 0.001), ifn‐γr1 (1.02‐fold, p = 0.04), ifn‐γr2 (1.01‐fold, p = 0.031), stat2 (1.79‐fold, p < 0.001), and tnf‐α (?1.49, p < 0.001) were found compared with lymphocytes of healthy controls. Furthermore, IFN‐γ protein was significantly elevated in the sera of PD patients (18.7 ± 6.69 pg/ml) compared with healthy controls (3.87 ± 6.48 pg/ml, p = 0.042). Conclusions: In conclusion, our data suggest that novel pathways mainly related to the IFN‐mediated signaling may play important roles in the aberrant osteoclastogenesis of PD.     

Vertebral Fracture Risk Is Reduced in Women Who Lose Femoral Neck BMD With Teriparatide Treatment

Response to osteoporosis therapy is often assessed by serial BMD testing. Patients who lose BMD without secondary causes of bone loss may be considered to be “nonresponders” to treatment. We examined vertebral fracture (VF) risk, change in lumbar spine (LS) BMD, and change in amino‐terminal extension peptide of procollagen type I (PINP) in postmenopausal women whose femoral neck (FN) BMD decreased, increased, or was unchanged after receiving teriparatide (TPTD) or placebo (PL) in the Fracture Prevention Trial. FN and LS BMD were measured at baseline and 12 mo. VFs were assessed by lateral spine radiographs at baseline and study endpoint. A BMD change from baseline of >4% was considered to be clinically significant. Decreases of >4% FN BMD were less common in women receiving TPTD (10%) versus PL (16%, p < 0.05), yet women on TPTD who lost FN BMD still had significant reductions in VF risk compared with PL (RR = 0.11; 95% CI = 0.03–0.45). VF risk reduction with TPTD compared with PL was similar across categories of FN BMD change from baseline at 12 mo (loss >4%, loss 0–4%, gain 0–4%, or gain >4%; interaction p = 0.40). Irrespective of FN BMD loss or gain, TPTD‐treated women had statistically significant increases in LS BMD and PINP compared with PL. In both groups, losses or gains in FN BMD at 12 mo corresponded to losses or gains in BMC rather than changes in bone area. In conclusion, loss of FN BMD at 12 mo in postmenopausal women with osteoporosis treated with TPTD is nevertheless consistent with a good treatment response in terms of VF risk reduction.     

Overlapping and Continued Alendronate or Raloxifene Administration in Patients on Teriparatide: Effects on Areal and Volumetric Bone Mineral Density—The CONFORS Study

Nine month teriparatide (TPTD) monotherapy followed by co‐administration of raloxifene (RAL) or alendronate (ALN) for another nine 9 months resulted in incremental bone mineral density (BMD) increase. The aim of this study was to investigate the effects of continued antiresorptive treatments for 12 months in the extension phase. Postmenopausal women (n = 125) with severe osteoporosis on ongoing TPTD treatment for 9 months were randomized into three open‐label groups for another 9 months: ALN (70 mg/week, n = 41), RAL (60 mg/d, n = 37) in addition to TPTD or no additional medication (n = 47) except Ca and vitamin D. After discontinuation of TPTD the respective antiresorptives were continued for a further 12 months, while patients in the TPTD monotherapy group received Ca and vitamin D. Amino‐terminal propeptide of type I procollagen (P1NP) and cross‐linked C‐telopeptide (CTX), areal and volumetric BMD at the lumbar spine (LS) and hip were assessed. ALN resulted in continued BMD increase in LS (4.3 ± 1.5%; mean ± SD), femoral neck (4.2 ± 1.6%) and total hip (4 ± 1.6%; p < 0.001 for all), while RAL was only effective at the LS (2.4 ± 1.7%, p < 0.001) but no changes at the femoral neck (0.4 ± 1.4%) or total hip (?0.8 ± 1.5%) were observed. Cortical bone only increased in the ALN group (femoral neck 6.7 ± 2.7% and ?1.3 ± 2.5%; total hip 13.8 ± 2.9% and ?2.3 ± 2.5% for ALN and RAL, p < 0.001 for all; respectively). Analyzing the entire 30 months of therapy, the ALN group revealed the largest BMD increase in all regions. Our results suggest that the addition of ALN to ongoing TPTD and continuing ALN after TPTD was stopped may be beneficial for patients in terms of areal and volumetric BMD increase. Further research is warranted to determine the optimal timing of the initiation of the combination treatment, the respective antiresorptive medication and the potential benefit of this BMD increase regarding fracture prevention. © 2014 American Society for Bone and Mineral Research     

Differing effects of PTH 1–34, PTH 1–84, and zoledronic acid on bone microarchitecture and estimated strength in postmenopausal women with osteoporosis: An 18‐month open‐labeled observational study using HR‐pQCT

Whereas the beneficial effects of intermittent treatment with parathyroid hormone (PTH) (intact PTH 1–84 or fragment PTH 1–34, teriparatide) on vertebral strength is well documented, treatment may not be equally effective in the peripheral skeleton. We used high‐resolution peripheral quantitative computed tomography (HR‐pQCT) to detail effects on compartmental geometry, density, and microarchitecture as well as finite element (FE) estimated integral strength at the distal radius and tibia in postmenopausal osteoporotic women treated with PTH 1–34 (20 µg sc daily, n = 18) or PTH 1–84 (100 µg sc daily, n = 20) for 18 months in an open‐label, nonrandomized study. A group of postmenopausal osteoporotic women receiving zoledronic acid (5 mg infusion once yearly, n = 33) was also included. Anabolic therapy increased cortical porosity in radius (PTH 1–34 32 ± 37%, PTH 1–84 39 ± 32%, both p < 0.001) and tibia (PTH 1–34 13 ± 27%, PTH 1–84 15 ± 22%, both p < 0.001) with corresponding declines in cortical density. With PTH 1–34, increases in cortical thickness in radius (2.0 ± 3.8%, p < 0.05) and tibia (3.8 ± 10.4%, p < 0.01) were found. Trabecular number increased in tibia with both PTH 1–34 (4.2 ± 7.1%, p < 0.05) and PTH 1–84 (5.3 ± 8.3%, p < 0.01). Zoledronic acid did not impact cortical porosity at either site but increased cortical thickness (3.0 ± 3.5%, p < 0.01), total (2.7 ± 2.5%, p < 0.001) and cortical density (1.5 ± 2.0%, p < 0.01) in tibia as well as trabecular volume fraction in radius (2.5 ± 5.1%, p < 0.05) and tibia (2.2 ± 2.2%, p < 0.01). FE estimated bone strength was preserved, but not increased, with PTH 1–34 and zoledronic acid at both sites, whereas it decreased with PTH 1–84 in radius (?2.8 ± 5.8%, p < 0.05) and tibia (–3.9 ± 4.8%, p < 0.001). Conclusively, divergent treatment‐specific effects in cortical and trabecular bone were observed with anabolic and zoledronic acid therapy. The finding of decreased estimated strength with PTH 1–84 treatment was surprising and warrants confirmation. © 2013 American Society for Bone and Mineral Research.     

Bone quality, as measured by trabecular bone score in patients with adrenal incidentalomas with and without subclinical hypercortisolism

Patients with adrenal incidentalomas (AIs) and subclinical hypercortisolism (SH) have increased risk of fracture independent of bone mineral density (BMD) and possibly due to reduced bone quality. The trabecular bone score (TBS) has been proposed as a index of bone microarchitecture. The aim of the study was to investigate TBS in AI. In 102 AI patients, SH was diagnosed in the presence of at least two of the following: (1) urinary free cortisol >70 µg/24 h (193.1 nmol/L); (2) cortisol after 1‐mg dexamethasone suppression test (1‐mg DST) >3.0 µg/dL (82.8 nmol/L); or (3) adrenocorticotropic hormone (ACTH) <10 pg/mL (<2.2 pmol/L). In patients and in 70 matched controls, BMD was measured at lumbar spine (LS) and femur (neck [FN] and total [FT]) by dual X‐ray absorptiometry and TBS was assessed in the region of LS‐BMD; BMD and TBS data were reported as Z‐scores. In patients, vertebral deformities were assessed by radiograph. Patients with SH (n = 34) had lower LS‐BMD (?0.31 ± 1.17), FT‐BMD (?0.29 ± 0.91), and TBS (?3.18 ± 1.21) than patients without SH (n = 68, 0.31 ± 1.42, p = 0.03; 0.19 ± 0.97, p = 0.01; ?1.70 ± 1.54, p < 0.0001, respectively) and controls (0.42 ± 1.52, p = 0.02; 0.14 ± 0.76, p = 0.02; ?1.19 ± 0.99, p < 0.0001, respectively). TBS was inversely correlated with 1‐mg DST (β = ?0.26, t = ?2.79, p = 0.006) regardless of age, LS‐BMD, body mass index (BMI), and gender. The presence of fracture was associated with low TBS alone (odds ratio [OR], 4.8; 95% confidence interval [CI], 1.85–12.42, p = 0.001) and with the cluster low TBS plus low LS‐BMD (OR, 4.37; 95% CI, 1.71–11.4, p = 0.002), after adjustment for age, BMI, and gender. Low TBS plus low LS‐BMD showed a good specificity (79%) for predicting fractures, whereas normal TBS (ie, > ?1.5) plus normal LS‐BMD high specificity (88.1%) for excluding fractures. Finally, TBS predicted the occurrence of a new fracture in 40 patients followed for 24 months (OR, 11.2; 95%CI, 1.71–71.41, p = 0.012) regardless of LS‐BMD, BMI, and age. In SH, bone quality, as measured by TBS, is altered. TBS is useful in detecting AI patients at risk of fractures. © 2012 American Society for Bone and Mineral Research.     

Effect of Two‐Year Caloric Restriction on Bone Metabolism and Bone Mineral Density in Non‐Obese Younger Adults: A Randomized Clinical Trial

Although caloric restriction (CR) could delay biologic aging in humans, it is unclear if this would occur at the cost of significant bone loss. We evaluated the effect of prolonged CR on bone metabolism and bone mineral density (BMD) in healthy younger adults. Two‐hundred eighteen non‐obese (body mass index [BMI] 25.1 ± 1.7 kg/m²), younger (age 37.9 ± 7.2 years) adults were randomly assigned to 25% CR (CR group, n = 143) or ad libitum (AL group, n = 75) for 2 years. Main outcomes were BMD and markers of bone turnover. Other outcomes included body composition, bone‐active hormones, nutrient intake, and physical activity. Body weight (–7.5 ± 0.4 versus 0.1 ± 0.5 kg), fat mass (–5.3 ± 0.3 versus 0.4 ± 0.4 kg), and fat‐free mass (–2.2 ± 0.2 versus –0.2 ± 0.2 kg) decreased in the CR group compared with AL (all between group p < 0.001). Compared with AL, the CR group had greater changes in BMD at 24 months: lumbar spine (–0.013 ± 0.003 versus 0.007 ± 0.004 g/cm²; p < 0.001), total hip (–0.017 ± 0.002 versus 0.001 ± 0.003 g/cm²; p < 0.001), and femoral neck (–0.015 ± 0.003 versus –0.005 ± 0.004 g/cm²; p = 0.03). Changes in bone markers were greater at 12 months for C‐telopeptide (0.098 ± 0.012 versus 0.025 ± 0.015 μg/L; p < 0.001), tartrate‐resistant acid phosphatase (0.4 ± 0.1 versus 0.2 ± 0.1 U/L; p = 0.004), and bone‐specific alkaline phosphatase (BSAP) (–1.4 ± 0.4 versus –0.3 ± 0.5 U/L; p = 0.047) but not procollagen type 1 N‐propeptide; at 24 months, only BSAP differed between groups (–1.5 ± 0.4 versus 0.9 ± 0.6 U/L; p = 0.001). The CR group had larger increases in 25‐hydroxyvitamin D, cortisol, and adiponectin and decreases in leptin and insulin compared with AL. However, parathyroid hormone and IGF‐1 levels did not differ between groups. The CR group also had lower levels of physical activity. Multiple regression analyses revealed that body composition, hormones, nutrients, and physical activity changes explained ～31% of the variance in BMD and bone marker changes in the CR group. Therefore, bone loss at clinically important sites of osteoporotic fractures represents a potential limitation of prolonged CR for extending life span. Further long‐term studies are needed to determine if CR‐induced bone loss in healthy adults contributes to fracture risk and if bone loss can be prevented with exercise. © 2015 American Society for Bone and Mineral Research.     

Deleterious Effect of Late Menarche on Distal Tibia Microstructure in Healthy 20‐Year‐Old and Premenopausal Middle‐Aged Women

Late menarche is a risk factor for fragility fractures. We hypothesized that pubertal timing–dependent alterations in bone structural components would persist from peak bone mass to menopause, independent of premenopausal bone loss. We studied the influence of menarcheal age (MENA) on femoral neck BMD (FN aBMD) by DXA and microstructure of distal tibia by HR‐pQCT in healthy young adult (YAD; 20.4 ± 0.6 [SD] yr, n = 124) and premenopausal middle‐aged (PREMENO; 45.8 ± 3.4 yr, n = 120) women. Median of MENA was 13.0 ± 1.2 and 13.1 ± 1.7 yr in YAD and PREMENO, respectively. In YAD and PREMENO (n = 244), FN aBMD (R = ?0.29, p = 0.013), as well as total volumetric BMD (Dtot; R = ?0.23, p = 0.006) and cortical thickness (Ct.Th; R = ?0.18, p = 0.011) of distal tibia were inversely correlated to MENA. After segregation by the median of MENA in EARLY and LATE subgroups, the significant influences of both MENA (p = 0.004) and chronological age (p < 0.0001) were observed for FN aBMD and trabecular bone volume fraction of the distal tibia with similar differences in T‐scores between LATE and EARLY subgroups in YAD (?0.36 and ?0.31 T‐scores) and PREMENO (?0.35 and ?0.42 T‐scores) women. Ct.Th was negatively influenced by MENA, whereas trabecular thickness (Tb.Th) was negatively influenced by chronological age. There was a striking inverse relationship between cross‐sectional area and Ct.Th (R = ?0.57, p < 0.001). In conclusion, the negative influence of late menarcheal age at weight‐bearing sites as observed by the end of skeletal growth remains unattenuated a few years before menopause and is independent of premenopausal bone loss. Alterations in both bone mineral mass and microstructural components may explain the increased risk of fragility fractures associated with later menarcheal age.     

Histomorphometric and μCT Analysis of Bone Biopsies From Postmenopausal Osteoporotic Women Treated With Strontium Ranelate

Strontium ranelate is a new anti‐osteoporotic treatment. On bone biopsies collected from humans receiving long‐term treatment over 5 yr, it has been shown that strontium ranelate has good bone safety and better results than placebo on 3D microarchitecture. Hence, these effects may explain the decreased fracture rate. Introduction: Strontium ranelate's mode of action involving dissociation of bone formation and resorption was shown in preclinical studies and could explain its antifracture efficacy in humans. Materials and Methods: One hundred forty‐one transiliac bone biopsies were obtained from 133 postmenopausal osteoporotic women: 49 biopsies after 1–5 yr of 2 g/d strontium ranelate and 92 biopsies at baseline or after 1–5 yr of placebo. Results and Conclusions: Histomorphometry provided a 2D demonstration of the bone safety of strontium ranelate, with significantly higher mineral apposition rate (MAR) in cancellous bone (+9% versus control, p = 0.019) and borderline higher in cortical bone (+10%, p = 0.056). Osteoblast surfaces were significantly higher (+38% versus control, p = 0.047). 3D analysis of 3‐yr biopsies with treatment (20 biopsies) and placebo (21 biopsies) using μCT showed significant changes in microarchitecture with, in the strontium ranelate group, higher cortical thickness (+18%, p = 0.008) and trabecular number (+14%, p = 0.05), and lower structure model index (?22%, p = 0.01) and trabecular separation (?16%, p = 0.04), with no change in cortical porosity. The changes in 3D microarchitecture may enhance bone biomechanical competence and explain the decreased fracture rate with strontium ranelate.     

Effect of teriparatide on bone mineral density and biochemical markers in Japanese women with postmenopausal osteoporosis: a 6-month dose-response study

The dose-response efficacy and safety with three doses of teriparatide and placebo was assessed, using oncedaily subcutaneous injections for 24 weeks, in Japanese postmenopausal women with osteoporosis at high risk of fracture for reasons of preexisting fracture(s), advanced age, and/or low bone mineral density (BMD). In this multicenter, randomized, placebo-controlled study, 159 subjects were randomized and 154 subjects were included for analysis. Teriparatide (10-μg, 20-μg, and 40-μg doses) showed a statistically significant increase with increasing treatment dose as assessed by the percent change of lumbar spine BMD from baseline to endpoint using Williams’ test when compared with placebo (P < 0.001). The mean (±SD) percent change in lumbar spine, femoral neck, and total hip BMD with the 20-μg dose from baseline to endpoint was 6.40% ± 4.76%, 1.83% ± 7.13%, and 1.91% ± 3.60%, respectively. Rapid and sustained increases in bone formation markers [type I procollagen N-terminal propeptide (PINP), type I procollagen C-terminal propeptide (PICP), and bone-specific alkaline phosphatase (BAP)], followed by late increases in a bone resorption marker [type I collagen cross-linked C-telopeptide (CTX)], were observed for the teriparatide treatment groups (20-μg, 40-μg), suggesting a persistent, positive, balanced anabolic effect of teriparatide. Optimal adherence was achieved by this daily self-injection treatment. Regarding safety, most of the adverse events were mild to moderate in severity. No study drug-or study procedure-related serious adverse events were reported during the treatment period. These results observed in Japanese patients may support the observation that teriparatide stimulates bone formation in patients with osteoporosis at a high risk of fracture.