Psoas muscle cross sectional area relates to bone density and microarchitecture in candidates for spine fusion surgery.

Prior studies demonstrate that muscle and bone health are integrally related, and both independently impact orthopedic surgery outcomes. However, relationships between bone density, in vivo microarchitecture, and muscle area have not been previously investigated in orthopedic surgery patients. This study assessed associations between psoas cross sectional area (CSA), bone mineral density (BMD), and microstructure in a cohort undergoing spine fusion. Pre-operatively, bilateral psoas CSA was measured on axial lumbar spine CT in the L3-L4 disc space. To adjust for body size, Psoas Muscle Index (PMI) was calculated (CSA divided by the square of patient height). High resolution peripheral quantitative CT (HR-pQCT, XtremeCT2) assessed volumetric BMD (vBMD), cortical (Ct) and trabecular (Tb) microarchitecture at the distal radius and tibia. Areal BMD (aBMD) was measured by DXA at the lumbar spine (LS), total hip (TH), femoral neck (FN), and the 1/3 radius (1/3R). Pearson correlations related psoas CSA and bone imaging parameters before and after correcting for height and weight. Among 88 patients included, mean age was 63 ± 12 years, BMI was 28 ± 7 kg/m2, 47 (53 %) were female. Larger psoas CSA was associated with higher vBMD, greater Ct thickness and better Tb microarchitecture (higher Tb number and lower Tb separation) at the tibia and radius. Larger psoas CSA was also associated with greater aBMD at TH and FN bilaterally and 1/3R (r 0.33 to 0.61; p < 0.002 for all comparisons). Psoas CSA was not associated with aBMD at the LS. Similar results were observed when relating PMI, and adjusting for age, height and weight to HR-pQCT and DXA measurements. Investigation of subgroups by sex demonstrated that relationships were similar magnitude among women but not the men. Patients who underwent primary compared to revision spine surgery had similar associations. Our results demonstrate a link between psoas muscle size and peripheral bone microarchitecture among patients undergoing posterior lumbar spinal fusion. Given the importance of both muscle and skeletal integrity to the success of spine surgery, further study regarding the associations between measurements of psoas muscle, bone microarchitecture, and surgical outcomes is warranted.

Higher Glycemic Index and Glycemic Load Diet Is Associated with Slower Disease Progression in Amyotrophic Lateral Sclerosis.

OBJECTIVE: High-caloric diets may slow the progression of amyotrophic lateral sclerosis; however, key macronutrients have not been identified. We examined whether dietary macronutrients are associated with the rate of progression and length of survival among the prospective cohort study participants. METHODS: Participants with a confirmed diagnosis of sporadic amyotrophic lateral sclerosis enrolled in the Multicenter Cohort Study of Oxidative Stress were included (n = 304). We evaluated baseline macronutrient intake assessed by food frequency questionnaire in relation to change in revised amyotrophic lateral sclerosis functional rating scale total-score, and tracheostomy-free survival using linear regression and Cox proportional hazard models. Baseline age, sex, disease duration, diagnostic certainty, body mass index, bulbar onset, revised amyotrophic lateral sclerosis functional rating scale total-score, and forced vital capacity were included as covariates. RESULTS: Baseline higher glycemic index and load were associated with less decline of revised amyotrophic lateral sclerosis functional rating scale total score at 3-month follow-up (ß = -0.13, 95% CI -0.2, -0.01, p = 0.03) and (ß = -0.01, 95% CI -0.03, -0.0007, p = 0.04), respectively. Glycemic index second-quartile, third-quartile, and fourth-quartile groups were associated with less decline at 3 months by 1.9 (95% CI -3.3, -0.5, p = 0.008), 2.0 (95% CI -3.3, -0.6, p = 0.006), and 1.6 (95% CI -3.0, -0.2, p = 0.03) points compared with the first-quartile group; the glycemic load fourth-quartile group had 1.4 points less decline compared with the first-quartile group (95% CI -2.8, 0.1, p = 0.07). Higher glycemic index was associated with a trend toward longer tracheostomy-free survival (HR 0.97, 95% CI 0.93, 1.00, p = 0.07). INTERPRETATION: Higher dietary glycemic index and load are associated with slower disease progression in amyotrophic lateral sclerosis. ANN NEUROL 2024;95:217-229.

Vitamin D and SARS-CoV-2 Infection: SERVE Study (SARS-CoV-2 Exposure and the Role of Vitamin D among Hospital Employees).

BACKGROUND: Recognition of the role of vitamin D in immune function has led to interest in its relationship with SARS-CoV-2 infection. Although clinical studies to date have had conflicting results, many individuals currently take high doses of vitamin D to prevent infection. OBJECTIVE: The goal of this study was to investigate the relationship between serum 25-hydroxyvitamin D (25OHD) and vitamin D supplement use with incident SARS-CoV-2 infection. METHODS: In this prospective cohort study, 250 health care workers were enrolled at a single institution and observed for 15 mo. Participants completed questionnaires every 3 mo regarding new SARS-CoV-2 infection, vaccination, and supplement use. Serum was drawn at baseline, 6, and 12 mo for 25OHD and SARS-CoV-2 nucleocapsid antibodies. RESULTS: The mean age of the participants was 40 y, BMI 26 kg/m2, 71% were Caucasian, and 78% female. Over 15 mo, 56 participants (22%) developed incident SARS-CoV-2 infections. At baseline, ∼50% reported using vitamin D supplements (mean daily dose 2250 units). Mean serum 25OHD was 38 ng/mL. Baseline 25OHD did not predict incident SARS-CoV-2 infection (OR: 0.98; 95% CI: 0.80, 1.20). Neither the use of vitamin D supplements (OR: 1.18; 95% CI: 0.65, 2.14) or supplement dose was associated with incident infection (OR: 1.01 per 100-units increase; 95% CI: 0.99, 1.02). CONCLUSION: In this prospective study of health care workers, neither serum 25OHD nor the use of vitamin D supplements was associated with the incident SARS-CoV-2 infection. Our findings argue against the common practice of consuming high-dose vitamin D supplements for the presumed prevention of COVID-19.

Opportunistic Evaluation of Trabecular Bone Texture by MRI Reflects Bone Mineral Density and Microarchitecture.

CONTEXT: Many individuals at high risk for fracture are never evaluated for osteoporosis and subsequently do not receive necessary treatment. Utilization of magnetic resonance imaging (MRI) is burgeoning, providing an ideal opportunity to use MRI to identify individuals with skeletal deficits. We previously reported that MRI-based bone texture was more heterogeneous in postmenopausal women with a history of fracture compared to controls. OBJECTIVE: The present study aimed to identify the microstructural characteristics that underlie trabecular texture features. METHODS: In a prospective cohort, we measured spine volumetric bone mineral density (vBMD) by quantitative computed tomography (QCT), peripheral vBMD and microarchitecture by high-resolution peripheral QCT (HRpQCT), and areal BMD (aBMD) by dual-energy x-ray absorptiometry. Vertebral trabecular bone texture was analyzed using T1-weighted MRIs. A gray level co-occurrence matrix was used to characterize the distribution and spatial organization of voxelar intensities and derive the following texture features: contrast (variability), entropy (disorder), angular second moment (ASM; uniformity), and inverse difference moment (IDM; local homogeneity). RESULTS: Among 46 patients (mean age 64, 54% women), lower peripheral vBMD and worse trabecular microarchitecture by HRpQCT were associated with greater texture heterogeneity by MRI-higher contrast and entropy (r ∼ -0.3 to 0.4, P < .05), lower ASM and IDM (r ∼ +0.3 to 0.4, P < .05). Lower spine vBMD by QCT was associated with higher contrast and entropy (r ∼ -0.5, P < .001), lower ASM and IDM (r ∼ +0.5, P < .001). Relationships with aBMD were less pronounced. CONCLUSION: MRI-based measurements of trabecular bone texture relate to vBMD and microarchitecture, suggesting that this method reflects underlying microstructural properties of trabecular bone. Further investigation is required to validate this methodology, which could greatly improve identification of patients with skeletal fragility.

Bone loss after denosumab discontinuation is prevented by alendronate and zoledronic acid but not risedronate: a retrospective study.

A retrospective study of 121 patients who stopped denosumab (Dmab) then received no treatment (NT), risedronate (RIS), alendronate (ALN), or zoledronic acid (ZOL). Bone density (spine and hip) during and after Dmab discontinuation was measured. Treatment with ALN or ZOL, not NT and RIS, mitigated BMD loss after Dmab discontinuation. INTRODUCTION: Denosumab (Dmab) discontinuation is associated with bone loss and multiple vertebral fractures. The purpose was to compare bone mineral density (BMD) change in patients following Dmab discontinuation with no subsequent treatment (NT) and three bisphosphonate (BP) treatments: risedronate (RIS), alendronate (ALN), and zoledronic acid (ZOL). METHODS: In a review of 121 patients aged 71.2 ± 8.1 years, discontinuing Dmab (mean 5.4 doses), 33 received NT and 88 received BP (22 RIS; 34 ALN; 32 ZOL). BMD change after 1 year was compared between groups at the lumbar spine (LS), femoral neck (FN), and total hip (TH). Risk factors for bone loss after Dmab discontinuation were compared between groups and incidence of vertebral fractures was determined. RESULTS: Following Dmab discontinuation, LS mean change (g/cm2; 95% CI) was for NT: - 0.041 (- 0.062 to - 0.021); RIS: - 0.035 (- 0.052 to - 0.017); ALN: - 0.005 (- 0.020 to 0.009); and ZOL: - 0.009 (- 0.025 to 0.008). Differences in LS were found between NT and ALN (p =  0.015), and NT and ZOL (p=0.037), but not between NT and RIS. The only significant difference in TH was found between NT and ZOL (p 0.034) with no group differences in FN. BMD gains during Dmab treatment were associated with BMD loss after Dmab discontinuation. In a subset, discontinuation after Dmab treatment (> 5 doses) followed by ALN (n = 22) and ZOL (n = 11) showed no difference in BMD. Five of 7 vertebral fractures occurred after Dmab discontinuation in NT. CONCLUSION: Subsequent treatment with ALN or ZOL but not NT and RIS mitigates BMD loss after Dmab discontinuation.

Effects of four-year cyclic versus two-year daily teriparatide treatment on volumetric bone density and bone strength in postmenopausal women with osteoporosis.

PURPOSE: To evaluate the effects of cyclic vs daily teriparatide treatment (TPTD) on volumetric bone mineral density (vBMD) and bone strength at the hip and spine in women who were previously untreated. METHODS: A total of 86 women were randomized to a 24-month open label treatment of either daily TPTD (20 µg daily) or cyclic TPTD (20 µg daily for 3 months followed by 3 months off). During a 2-year extension, women in the daily TPTD group were switched to alendronate (ALN) and those in the cyclic TPTD group continued on cyclic TPTD (without any ALN). QCT images were acquired at baseline, 2-years (n = 54) and 4-years (n = 35) and analyzed for volumetric integral, cortical and trabecular bone mineral density (vBMD) and bone strength (by finite element analysis) at the hip and spine. The primary analysis presented here compared the responses across equal total TPTD doses (2 years daily vs 4 years cyclic). RESULTS: In the spine, integral vBMD and strength increased substantially after 2 years daily and 4 years cyclic TPTD, with no significant differences (vBMD +12 % vs +11 %, respectively, p = 0.70; spine strength +21 % vs +16 %, respectively, p = 0.35). At the hip, the gains were smaller, but again no significant differences were detected between the groups for the increases in either vBMD (+2 % in both groups, p = 0.97) or hip strength (3 % vs 3 %, p = 0.91). In the spine, the vBMD increment was about twice as large in the trabecular vs peripheral compartment; in the hip, significant vBMD gain was seen only in the trabecular compartment. CONCLUSIONS: The gains in volumetric BMD and bone strength for an equivalent dose of TPTD did not depend on whether it was administered every day over two years or cyclically over four years.

Understanding Physicians' Perceptions of Patient-Identified Barriers to Osteoporosis Medication Initiation: A Cognitive Mapping Approach.

Objective: Interventions to initiate medication and increase adherence for postmenopausal women who have had a fragility fracture were not always successful. The purpose of this study was to derive an empirical framework for patient-identified barriers to osteoporosis medication initiation and adherence from physician experts. Methods: A cognitive mapping approach involving nominal group technique (NGT) meetings and a card sorting and rating task were used to obtain formative data. We first conducted four NGT meetings with 18 women patients who were not on osteoporosis treatment to identify barriers to osteoporosis medication, then invited 27 osteoporosis physicians to sort and rate 25 patients identified barriers. Descriptive analysis, multidimensional scaling analysis, and hierarchical cluster analysis were applied for data analysis. Results: A two-dimensional five-cluster cognitive map was derived to provide an organizational framework for understanding patients perceived barriers to medication initiation and adherence. The five clusters were concerns about side effects, experience of side effects, lifestyle changes, medication access and complexity, and patient uncertainty about treatment and trust in the provider. The two dimensions were interpreted as internal to patients (X-axis) and external to patients (Y-axis). Conclusions/Implications: Views of patients solicited in a structured format provided directions to help in designing interventions to improve osteoporosis medication initiation and adherence.

Effects of teriparatide and loading modality on modeling-based and remodeling-based bone formation in the human femoral neck.

PURPOSE: We have previously shown that a brief course of teriparatide (TPTD) stimulates bone formation in the cancellous and endocortical envelopes of the human femoral neck, and the regions of tension and compression respond differently. The purpose of the present study was to determine how much of the new bone was formed by modeling-based formation (MBF) or remodeling-based formation (RBF). METHODS: We performed a double-blind trial of TPTD vs. placebo (PBO) in patients about to undergo a total hip replacement (THR) for osteoarthritis. Participants were randomized to receive daily TPTD 20 µg or PBO for an average of 6.1 weeks (range 4.1-11.8 weeks) prior to THR. After an average of 3 weeks of study drug, double tetracycline labels were administered per standard protocol. During the THR an intact sample of the mid-femoral neck (FN) was procured; this was fixed, embedded, and sectioned transversely. Histomorphometric analysis was performed in the cancellous, endocortical, and periosteal envelopes. Additionally, separate analyses were performed in the tensile and compressive regions of the endocortical and periosteal envelopes. Sites of new bone formation were identified by the presence of tetracycline labels and designated as MBF if the underlying cement line was smooth and as RBF if it was scalloped. New bone formation on smooth cement lines adjacent to scalloped reversal lines was designated as overflow RBF (oRBF). The referent for all indices was bone surface (BS). RESULTS: In the cancellous and endocortical envelopes, the proportion of mineralizing surface engaged in RBF and oRBF was higher in the TPTD-treated than the PBO-treated subjects. There was also a trend toward higher MBF in TPTD vs. PBO in both envelopes. In linear mixed-effects models, TPTD was predicted to increase formation differently on the tensile and compressive surfaces depending on patient-specific anatomy, including body weight, FN angle, offset, and cortical width and porosity. Eroded surface was not different between groups in either envelope and no significant differences were observed in any parameter in the periosteal envelope. CONCLUSION: We conclude that the predominant early effect of TPTD in the human femoral neck is to stimulate RBF and oRBF with a trend toward an increase in MBF in the endocortical and cancellous envelopes.

Case-control study in ALS using the National ALS Registry: lead and agricultural chemicals are potential risk factors.

Objective: To identify occupational risk factors for ALS using well-characterized participants with ALS (P-ALS), sibling controls (S-controls), and matched population controls (P-controls) within the National ALS Registry. We also compared oxidative stress (OS) biomarkers between groups. Methods: P-ALS were recruited over 4 years. Demographic, socioeconomic, and medical data were ascertained from medical records and structured interviews. P-ALS were followed prospectively for 2 years or until death, whichever came sooner. S-controls and age-, sex-, race/ethnicity-, and residential location-matched P-controls were recruited over 3 years. Occupational exposure to lead and agricultural chemicals (ACs) were assigned by an occupational hygienist, blinded to case status. OS biomarkers in urine were measured. Results: P-ALS (mean age 62.8 years; 63% males) resided across the United States. Demographic and socioeconomic variables did not differ among P-ALS, S-controls, and P-controls. P-ALS were more likely to report occupations with exposure to lead (adjusted OR (aOR)=2.3, 95% CI 1.1, 4.6) and ACs (aOR = 2.4, 95% CI 1.2, 4.6) compared to pooled controls. Among those with occupations with exposure to both lead and ACs, aOR was 7.2 (95% CI 2.0, 26.1). Urinary 8-oxo-dG was significantly elevated among P-ALS (11.07 ± 5.42 ng/mL) compared to S-controls, P-controls, or pooled controls (pooled 7.43 ± 5.42 ng/mL; p < 0.0001) but was not associated with occupational exposure to either lead or ACs. Conclusions: Findings reveal increased risk of ALS diagnosis among those with occupational exposure to lead and ACs and increased OS biomarkers among cases compared to controls. OS may be an important pathogenic mechanism in ALS.

Metabolic Abnormalities, Dietary Risk Factors and Nutritional Management in Amyotrophic Lateral Sclerosis.

Amyotrophic Lateral Sclerosis (ALS) is a devastating progressive neurodegenerative disease that affects motor neurons, leading to a relentless paralysis of skeletal muscles and eventual respiratory failure. Although a small percentage of patients may have a longer survival time (up to 10 years), in most cases, the median survival time is from 20 to 48 months. The pathogenesis and risk factors for ALS are still unclear: among the various aspects taken into consideration, metabolic abnormalities and nutritional factors have been the focus of recent interests. Although there are no consistent findings regarding prior type-2 diabetes, hypercholesterolemia and ALS incidence, abnormalities in lipid and glucose metabolism may be linked to disease progression, leading to a relatively longer survival (probably as a result of counteract malnutrition and cachexia in the advanced stages of the disease). Among potential dietary risk factors, a higher risk of ALS has been associated with an increased intake of glutamate, while the consumption of antioxidant and anti-inflammatory compounds, such as vitamin E, n-3 polyunsaturated fatty acids, and carotenoids, has been related to lower incidence. Poor nutritional status and weight loss in ALS resulting from poor oral intake, progressive muscle atrophy, and the potential hypermetabolic state have been associated with rapid disease progression. It seems important to routinely perform a nutritional assessment of ALS patients at the earliest referral: weight maintenance (if adequate) or gain (if underweight) is suggested from the scientific literature; evidence of improved diet quality (in terms of nutrients and limits for pro-inflammatory dietary factors) and glucose and lipid control is yet to be confirmed, but it is advised. Further research is warranted to better understand the role of nutrition and the underlying metabolic abnormalities in ALS, and their contribution to the pathogenic mechanisms leading to ALS initiation and progression.

Perspective: US Documentation and Regulation of Human Nutrition Randomized Controlled Trials.

Training to ensure good documentation practices and adherence to regulatory requirements in human nutrition randomized controlled trials has not been given sufficient attention. Furthermore, it is difficult to find this information conveniently organized or in a form relevant to nutrition protocols. Current gaps in training and research surveillance exist in clinical nutrition research because training modules emphasize drugs and devices, promote reliance on monitoring boards, and lack nutrition expertise on human nutrition research teams. Additionally, because eating is essential, ongoing, and highly individualized, it is difficult to distinguish risks associated with interventions from eating under free-living conditions. Controlled-feeding trials provide an option to gain more experimental control over food consumed, but at a price of less external validity, and may pose human behavior issues that are unrelated to the intervention. This paper covers many of the expected practices for documentation and regulation that may be encountered in planning and conducting nutrition intervention trials with examples and references that should be useful to clinical nutrition researchers, funders of research, and research institutions. Included are definitions and guidance on clinical nutrition research oversight (institutional review boards, data safety and monitoring boards, US FDA); participant safety; standard operating procedures; training of investigators, staff, and students; and local culture and reporting requirements relevant to diet-related clinical research conduct and documentation.

Nutrition and Sarcopenia-What Do We Know?

Muscle health is important for the functionality and independence of older adults, and certain nutrients as well as dietary patterns have been shown to offer protective effects against declines in strength and function associated with aging. In this paper, micronutrients, macronutrients, and food groups have been reviewed, along with their studied effects on the prevalence and incidence of sarcopenia, as well as their ability to preserve muscle mass and optimize physical performance. Randomized controlled trials appear to suggest a critical role for dietary intake of protein in preventing sarcopenia and muscle loss, although the optimal dose and type of protein is unknown. There are some promising data regarding the role of vitamin D and sarcopenia, but it is unclear whether the dose, frequency of dose, or length of treatment impacts the efficacy of vitamin D on improving muscle mass or function. Selenium, magnesium, and omega 3 fatty acids have been studied as supplements in clinical trials and in the diet, and they appear to demonstrate a potential association with physical activity and muscle performance in older individuals. Following the Mediterranean diet and higher consumption of fruits and vegetables have been associated with improved physical performance and protection against muscle wasting, sarcopenia, and frailty.

Loading modality and age influence teriparatide-induced bone formation in the human femoral neck.

Teriparatide (TPTD) reduces risk of both vertebral and nonvertebral fracture, but increases bone mineral density (BMD) much more at the spine than the hip. TPTD and mechanical loading may have a synergistic anabolic effect on BMD, which may help explain these site-specific differences. Under normal daily activity, the femoral neck (FN) is under bending, placing one side under tension and the other under compression. We sought to further understand the relationship between mechanical loading and TPTD at the hip by investigating the effect of tensile versus compressive loading on TPTD stimulated bone formation indices in the human FN. Thirty-eight patients receiving total hip replacements for osteoarthritis were randomized to receive placebo (PBO) or TPTD for a mean treatment duration of 6 weeks prior to surgery, and double tetracycline labeling was administered to allow assessment of bone formation. The FN was harvested during surgery and analyzed for dynamic bone formation indices in the compressive and tensile regions of the endocortical and periosteal envelopes. Regression models relating outcome measures to patient characteristics including sex, age, body weight, and FN geometry were also analyzed. Overall, bone formation was higher with TPTD versus placebo on the endocortical surface, but not the periosteal surface. The level of bone formation in both TPTD and placebo groups was greater on the tensile endocortical surface and the compressive periosteal surface. There was a trend toward decreased endocortical eroded surface with TPTD in the compressive but not the tensile region. Patient age and sex explained the greatest variability in endocortical bone formation, and patient body mass and sex explained the greatest variability in periosteal bone formation. Our data represent the first dynamic comparison of teriparatide treatment under two loading modalities in human FN samples. Future work could determine whether specific hip loading intervention could amplify the benefits of teriparatide on the hip in clinical settings.

Identification of prevalent vertebral fractures using Vertebral Fracture Assessment (VFA) in asymptomatic postmenopausal women: A systematic review and meta-analysis.

BACKGROUND: Vertebral fracture (VF) is the most common osteoporotic fracture in postmenopausal women, although most VFs are subclinical. Prevalent VFs are a significant predictor of subsequent fracture and therefore, identification of VF improves the identification of those with high fracture risk. The aim of present study was to systematically review the literature that assessed the prevalence of VF in asymptomatic postmenopausal women, using Vertebral Fracture Assessment (VFA) by dual-energy X-ray absorptiometry. METHOD: Medline, Web of Science and Cochrane databases were searched between Jan 1st, 2000 and Jan 31st, 2018, for publications in English that reported the prevalence of VFA-detected VF in asymptomatic postmenopausal women. We also searched for reports, conference papers and grey literature. Reviewers screened studies for eligibility and extracted data for included studies. Random effects meta-analyses were performed to calculate the prevalence of VF. The presence of publication bias was assessed using funnel plots by precision and Egger's Test of the Intercept. RESULTS: A total of 1777 articles were identified, 94 studies were fully reviewed and 28 studies (n = 25,418) met the inclusion criteria and were analyzed. More than two thirds of the studies were cross-sectional and the sample size varied widely across the studies (from 63 to 5156). The mean age ranged from 59.5 to 86.2 years old. The prevalence of osteoporosis and osteopenia varied between 6-57.0% and 25.1-58.9%, respectively. However, among women who had prevalent VFs, up to 43% had osteopenia and as many as 32% had normal bone density. The weighted pooled prevalence of VFA-detected VF in asymptomatic women was 28% (95% CI: 23%-32%). CONCLUSION: VFA is able to identify prevalent VF in asymptomatic postmenopausal women. The use of VFA identified an average of 28% of asymptomatic women with VFs, many of whom did not have a diagnosis of osteoporosis. Implementation of VFA as a routine screening tool may detect high risk women. Detection of VF might lead to pharmacological treatment in individuals who may not otherwise be treated.

No evidence for alteration in early secondary mineralization by either alendronate, teriparatide or combination of both in transiliac bone biopsy samples from postmenopausal osteoporotic patients.

The influence of treatment with alendronate (ALN), teriparatide (TPTD) or concurrent treatment with both on the human bone matrix mineralization has not yet been fully elucidated. For this purpose we analyzed quadruple fluorochrome labelled transiliac bone biopsy samples (n = 66) from postmenopausal osteoporotic women with prior and ongoing ALN (ALN-Rx arm) or without ALN (Rx-Naïve arm) after 7 months treatment with cyclic or daily TPTD or without TPTD using quantitative backscattered electron imaging and confocal scanning laser microscopy. Additionally to the bone mineralization density distribution (BMDD) of entire cancellous and cortical compartments, we measured the mineralization kinetics, i.e. the calcium concentration between the younger (Ca_DL2) and older double labels (Ca_DL1), and in interstitial bone (Ca_int) in a subset of the biopsy cohort. We found the BMDD from the patients with prior and ongoing ALN generally shifted to higher calcium concentrations compared to those without ALN (average degree of mineralization in cancellous bone Cn.CaMean + 3.1%, p<0.001). The typical BMDD changes expected by cyclic or daily TPTD treatment due to the increased bone turnover/formation, e.g. an increase in low mineralized bone area were not observed. Additionally, we found no influence of treatment with ALN or TPTD or combination thereof on Ca_DL2, Ca_DL1, or Ca_int. Pooling the information from all groups, Ca_DL1 was +5.9% (p<0.001) higher compared to Ca_DL2, corresponding to a mineralization rate of 0.18 wt% Ca per week during the early secondary mineralization process. Our data suggest that the patients in the ALN-Rx arm had more highly mineralized bone matrix than those without ALN due to their lower bone turnover. The reason for the unexpected BMDD findings in the TPTD treated remain unknown and cannot be attributed to altered mineralization kinetics as no differences in the time course of early secondary mineralization were observed between the treatment groups.

Modeling-Based Bone Formation in the Human Femoral Neck in Subjects Treated With Denosumab.

Denosumab is associated with continued gains in hip and spine BMD with up to 10 years of treatment in postmenopausal women with osteoporosis. Despite potent inhibition of bone remodeling, findings in nonhuman primates suggest modeling-based bone formation (MBBF) may persist during denosumab treatment. This study assessed whether MBBF in the femoral neck (FN) is preserved in the context of inhibited remodeling in subjects receiving denosumab. This open-label study enrolled postmenopausal women with osteoporosis who had received two or more doses of denosumab (60 mg subcutaneously every 6 months [Q6M]) per standard of care and were planning elective total hip replacement (THR) owing to osteoarthritis of the hip. Transverse sections of the FN were obtained after THR and analyzed histomorphometrically. MBBF, based on fluorochrome labeling and presence of smooth cement lines, was evaluated in cancellous, endocortical, and periosteal envelopes of the FN. Histomorphometric parameters were used to assess MBBF and remodeling-based bone formation (RBBF) in denosumab-treated subjects (n = 4; mean age = 73.5 years; range, 70 to 78 years) and historical female controls (n = 11; mean age = 67.8 years; range, 62 to 80 years) obtained from the placebo group of a prior study and not treated with denosumab. All analyses were descriptive. All subjects in both groups exhibited MBBF in the periosteal envelope; in cancellous and endocortical envelopes, all denosumab-treated subjects and 81.8% of controls showed evidence of MBBF. Compared with controls, denosumab-treated subjects showed 9.4-fold and 2.0-fold higher mean values of MBBF in cancellous and endocortical envelopes, respectively, whereas RBBF mean values were 5.0-fold and 5.3-fold lower. In the periosteal envelope, MBBF and RBBF rates were similar between subjects and controls. These results demonstrate the occurrence of MBBF in the human FN and suggest that denosumab preserves MBBF while inhibiting remodeling, which may contribute to the observed continued gains in BMD over time after remodeling is maximally inhibited. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.

Standard Versus Cyclic Teriparatide and Denosumab Treatment for Osteoporosis: A Randomized Trial.

In the absence of an intervening antiresorptive agent, cyclic administration of teriparatide does not increase bone mineral density (BMD) more than standard daily therapy. Because denosumab is a potent antiresorptive agent with a rapid off-effect, we hypothesized that it might be the optimal agent to help maximize bone gains with cyclic teriparatide. In this 3-year protocol, 70 postmenopausal women with osteoporosis were randomized to 18 months of teriparatide followed by 18 months of denosumab (standard) or three separate 12-month cycles of 6 months of teriparatide followed by 6 months of denosumab (cyclic). BMD (dual-energy X-ray absorptiometry [DXA]) measurements of lumbar spine (LS), total hip (TH), femoral neck (FN), and 1/3 radius (RAD) were performed every 6 months and total body bone mineral (TBBM) at 18 and 36 months. Baseline descriptive characteristics did not differ between groups except for a minimal difference in LS BMD but not T-score (mean age 65 years, mean LS T-score - 2.7). In the standard group, BMD increments at 36 months were: LS 16%, TH 4%, FN 3%, and TBBM 4.8% (all p < 0.001 versus baseline). In the cyclic group, 36-month BMD increments were similar: LS 12%, TH 4%, FN 4%, and TBBM 4.1% (all p < 0.001 versus baseline). At 36 months, the LS BMD increase with standard was slightly larger than with cyclic (p = 0.04), but at 18 months, in the cyclic group, there was no decline in RAD or TBBM (p = 0.007 and < 0.001, respectively, versus standard). Although the cyclic regimen did not improve BMD compared with standard at 36 months, there appeared to be a benefit at 18 months, especially in the highly cortical skeletal sites. This could be clinically relevant in patients at high imminent risk of fracture, particularly at nonvertebral sites. © 2019 American Society for Bone and Mineral Research. © 2019 American Society for Bone and Mineral Research.

Abnormal microarchitecture and stiffness in postmenopausal women with isolated osteoporosis at the 1/3 radius.

BACKGROUND: Postmenopausal women with isolated osteoporosis at the 1/3 radius (1/3RO) present a therapeutic dilemma. Little is known about whether these patients have generalized skeletal fragility, and whether this finding warrants treatment. The aim of this study was to investigate the biochemical and microarchitectural phenotype of women with 1/3RO compared to women with classic postmenopausal osteoporosis by DXA at the spine and hip (PMO), and controls without osteoporosis at any site. METHODS: This cross-sectional study enrolled 266 postmenopausal women, who were grouped according to densitometric pattern. Subjects had serum biochemistries, areal BMD (aBMD) measured by DXA, trabecular and cortical vBMD, microarchitecture, and stiffness by high resolution peripheral QCT (HR-pQCT, voxel size ~82 µm) of the distal radius and tibia. RESULTS: Mean age was 68 ± 7 years. DXA T-Scores reflected study design. By HR-pQCT, 1/3RO had abnormalities at both radius and tibia compared to controls: lower total, cortical and trabecular vBMD, cortical thickness and trabecular number, higher trabecular separation and heterogeneity, and lower whole bone stiffness. In contrast, the magnitude and pattern of abnormalities in vBMD, microarchitecture and stiffness in 1/3RO were similar to those in PMO; the difference compared to controls was similar among the two groups. Serum calcium, creatinine, parathyroid hormone, 25-hydroxyvitamin D, and 24-hour urine calcium did not differ. CONCLUSIONS: Although aBMD appeared relatively preserved at the spine and hip by DXA, women with 1/3RO had significant microarchitectural and biomechanical deficits comparable to those in women with typical PMO. Further study is required to guide treatment decisions in this population.