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Preclinical evidence demonstrates that senescent cells accumulate with aging and that senolytics delay multiple age-related morbidities, including bone loss. Thus, we conducted a phase 2 randomized controlled trial of intermittent administration of the senolytic combination dasatinib plus quercetin (D + Q) in postmenopausal women (n = 60 participants). The primary endpoint, percentage changes at 20 weeks in the bone resorption marker C-terminal telopeptide of type 1 collagen (CTx), did not differ between groups (median (interquartile range), D + Q -4.1% (-13.2, 2.6), control -7.7% (-20.1, 14.3); P = 0.611). The secondary endpoint, percentage changes in the bone formation marker procollagen type 1 N-terminal propeptide (P1NP), increased significantly (relative to control) in the D + Q group at both 2 weeks (+16%, P = 0.020) and 4 weeks (+16%, P = 0.024), but was not different from control at 20 weeks (-9%, P = 0.149). No serious adverse events were observed. In exploratory analyses, the skeletal response to D + Q was driven principally by women with a high senescent cell burden (highest tertile for T cell p16 (also known as CDKN2A) mRNA levels) in which D + Q concomitantly increased P1NP (+34%, P = 0.035) and reduced CTx (-11%, P = 0.049) at 2 weeks, and increased radius bone mineral density (+2.7%, P = 0.004) at 20 weeks. Thus, intermittent D + Q treatment did not reduce bone resorption in the overall group of postmenopausal women. However, our exploratory analyses indicate that further studies are needed testing the hypothesis that the underlying senescent cell burden may dictate the clinical response to senolytics. ClinicalTrials.gov identifier: NCT04313634 ., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

Competing Interests: We declare no competing interests.

Hypercalcaemia of malignancy (HCM) is a common metabolic complication of advanced malignancies with a prevalence varying from 2-30%, depending on cancer type and disease stage. HCM is associated with impaired quality of life, increased risk of hospitalisation and limited survival. Evidence-based guidelines for management of HCM have been lacking to date, despite its prevalence and detrimental impact. This concise guidance highlights key recommendations from the recent Endocrine Society Clinical Practice Guidelines on Treatment of Hypercalcaemia of Malignancy in Adults, published in December 2022. A systematic review and meta-analysis was commissioned to support the guideline development process. Key suggestions include the use of denosumab in preference to intravenous bisphosphonates as first-line treatment for HCM and the use of denosumab in cases of recurrent or refractory HCM in patients previously treated with intravenous bisphosphonates. The guideline also identifies priority areas for future research., (© Royal College of Physicians 2023. All rights reserved.)

Multiple myeloma (MM) bone disease is a significant cause of morbidity but there is a paucity of data on the impact of malignant plasma cells on adjacent trabecular bone within the BM. Here, we characterize the proteome of trabecular bone tissue from BM biopsies of 56 patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering (SMM), newly diagnosed (NDMM), relapsed MM (RMM), and normal controls. Proteins involved in extracellular matrix (ECM) formation and immunity pathways were decreased in SMM and active MM. Among the proteins most decreased were immunoglobulins, type IV collagen, and TIMP3, suggesting increased immunoparesis and decreased ECM remodelling within trabecular bone. Proteins most increased in SMM/MM were APP (enhances osteoclast activity), ENPP1 (enhances bone mineralization), and MZB1 (required for normal plasmablast differentiation). Pathway analyses showed that proteins involved in gamma -carboxylation, a pathway implicated in osteocalcin function, osteoblast differentiation, and normal hematopoiesis, were also overexpressed in SMM/MM. This study is the first comprehensive proteomic atlas of the BM bone proteome in dysproteinemias. We identify new key proteins and pathways for MM bone disease and potentially impaired hematopoiesis, and show for the first time that gamma -carboxylation pathways are increased in the bone tissue of SMM/MM., (© 2023. The Author(s).)

The 22 nd Annual Santa Fe Bone Symposium (SFBS) was a hybrid meeting held August 5-6, 2022, with in-person and virtual attendees. Altogether, over 400 individuals registered, a majority of whom attended in-person, representing many states in the USA plus 7 other countries. The SFBS included 10 plenary presentations, 2 faculty panel discussions, satellite symposia, Bone Health & Osteoporosis Foundation Fracture Liaison Service Boot Camp, and a Project ECHO workshop, with lively interactive discussions for all events. Topics of interest included fracture prevention at different stages of life; how to treat and when to change therapy; skeletal health in cancer patients; advanced imaging to assess bone strength; the state of healthcare in the USA; osteosarcopenia; vitamin D update; perioperative bone health care; new guidelines for managing primary hyperparathyroidism; new concepts on bone modeling and remodeling; and an overview on the care of rare bone diseases, including hypophosphatasia, X-linked hypophosphatemia, tumor induced osteomalacia, osteogenesis imperfecta, fibrodysplasia ossificans progressiva, and osteopetrosis. The SFBS was preceded by the Santa Fe Fellows Workshop on Osteoporosis and Metabolic Bone Diseases, a collaboration of the Endocrine Fellows Foundation and the Osteoporosis Foundation of New Mexico. From the Workshop, 4 participating fellows were selected to give oral presentations at the bone symposium. These proceedings represent the clinical highlights of 2022 SFBS presentations and the discussions that followed, all with the aim of optimizing skeletal health and minimizing the consequences of fragile bones., (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

In an effort to enhance the trustworthiness of its clinical practice guidelines, the Endocrine Society has recently adopted new policies and more rigorous methodologies for its guideline program. In this Clinical Practice Guideline Communication, we describe these recent enhancements-many of which reflect greater adherence to the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) approach to guideline development-in addition to the rationale for such changes. Improvements to the Society's guideline development practices include, but are not limited to, enhanced inclusion of nonendocrinologist experts, including patient representatives, on guideline development panels; implementation of a more rigorous conflict/duality of interest policy; a requirement that all formal recommendations must be demonstrably underpinned by systematic evidence review; the explicit use of GRADE Evidence-to-Decision frameworks; greater use and explanation of standardized guideline language; and a more intentional approach to guideline updating. Lastly, we describe some of the experiential differences our guideline readers are most likely to notice., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Introduction: Vitamin D deficiency is common, but no data have been reported on vitamin D levels in light chain (AL) amyloidosis., Patients and Methods: In this exploratory study, stored serum samples from 173 patients with newly diagnosed AL amyloidosis were analyzed for vitamin studies which included 25-hydroxyvitamin D [25(OH)D], 1,25-dihydroxyvitamin D [1,25(OH) 2 D] and vitamin D binding protein (DBP). Measurements were made by liquid chromatography-tandem mass spectrometry. Kidney survival and overall survival (OS) were assessed in association to vitamin D status., Results: Cardiac and kidney involvement occurred in 69% and 63% of patients, respectively. 25(OH)D deficiency (<20 ng/mL) was seen in 56.6% of the patients and was notably found among patients with heavy proteinuria (96%), hypoalbuminemia (84.3%) and morbidly obese patients (68.3%). Heavy proteinuria (>5 gr/24-h) and vitamin D supplementation were independent predictors of 25(OH)D level on nominal multivariate regression analysis. 1,25(0H) 2 D deficiency was noted in 37.6% of patients and was independently associated with low eGFR and hypoalbuminemia. Progression to ESRD occurred in 23.7% of evaluable patients. Patients who progressed to ESRD had lower serum 25(OH)D and 1,25(OH) 2 D levels compared to those who did not progress to ESRD. On a multivariate analysis, severe 25(OH)D deficiency was an independent predictor of progression to ESRD as was renal stage, while 1,25(OH) 2 D deficiency was not., Conclusions: Hypovitaminosis D is common in AL amyloidosis, particularly among patients with heavy proteinuria. Severe 25(OH)D deficiency at time of diagnosis predicts progression to ESRD., Competing Interests: EM: honorarium from Janssen and consultation fee from Protego (fee paid to institution). NL served on advisory board for Takeda Pharmaceuticals. AD: research funding from Celgene, Millennium Pharmaceuticals, Pfizer, and Janssen and received a travel grant from Pfizer. ML: Research Funding from Celgene. PK is a principal investigator of research studies for which Mayo Clinic has received funding from AbbVie, Takeda, Sanofi, Janssen, Karyopharm, Glaxo SmithKline, Regeneron Pharmaceuticals, Ichnos Sciences and Amgen. He has served on the Medical advisory board meetings of Sanofi, Pharmacyclics, BeiGene, Cellectar, GSK, X4 and Karyopharm. SK received research funding for clinical trials to the institution from Abbvie, Amgen, BMS, Carsgen, Janssen, Astra-Zeneca, Novartis, Roche-Genentech, Takeda, Tenebio, Molecular Templates, received consulting/Advisory Board participation (with no personal payments) from Abbvie, Amgen, BMS, Janssen, Roche-Genentech, Takeda, Astra-Zeneca, Bluebird Bio, Epizyme, Secure Biotherapeutics and (with personal payment) Oncopeptides, Beigene, Antengene. MG served as a consultant for Millennium Pharmaceuticals and received honoraria from Celgene, Millennium Pharmaceuticals, Onyx Pharmaceuticals, Novartis, GlaxoSmithKline, Prothena, Ionis Pharmaceuticals, and Amgen. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Muchtar, Drake, Leung, Dispenzieri, Lacy, Buadi, Dingli, Hayman, Kapoor, Hwa, Fonder, Hobbs, Gonsalves, Kourelis, Warsame, Russell, Go, Binder, Kyle, Rajkumar, Kumar and Gertz.)

Purpose of Review: This review provides an overview regarding osteoporosis therapies during the COVID-19 pandemic., Recent Findings: The COVID-19 pandemic has disrupted treatments for osteoporosis and resulted in decreased adherence particularly for parenteral regimens. Osteoporosis medications are safe and effective during the pandemic and should be continued whenever possible. Bisphosphonates have long-lasting effects on bone turnover such that delays in their administration are unlikely to be harmful to skeletal health. In contrast, interruption of denosumab treatment is strongly discouraged because of rapid loss of bone mass and an associated increased risk for rebound vertebral fractures. When osteoanabolic treatments cannot be continued during the pandemic, change to an oral bisphosphonate is advised. Preclinical data suggest possible beneficial effects of some therapies against COVID-19, but require validation in clinical studies. Vitamin D deficiency is associated with a more severe COVID-19 clinical course but data supporting improvements in outcomes with vitamin D supplementation are lacking., Summary: The impact of the COVID-19 pandemic on long-term bone health remains unknown but focused interventions to ensure osteoporosis treatment initiation/maintenance should be implemented. Future studies are needed to determine whether osteoporosis medications have an impact on SARS-CoV-2 pathophysiology and COVID-19 clinical outcomes., Competing Interests: Conflict of InterestET has received research funding from MSD, honoraria for lectures from Amgen, UCB, Shire, Kyowa Kirin, and educational grants from Shire and UCB. Matthew T. Drake declares that he has no conflict of interest., (© The Author(s), under exclusive licence to Springer Nature Switzerland AG 2022.)

Objective: To evaluate the antidiabetic effects of the senolytic agent dasatinib in older patients with type 2 diabetes mellitus., Methods: This retrospective cohort study included enterprise-wide Mayo Clinic patients using Informatics for Integrating Biology at the Bedside from January 1994 through December 2019. The antidiabetic outcomes (change in hemoglobin A 1c value, serum glucose concentration, and diabetic medications) after 1 year of a strongly senolytic tyrosine kinase inhibitor, dasatinib (n=16), was compared with a weakly senolytic tyrosine kinase inhibitor, imatinib (n=32)., Results: Relative to imatinib, patients treated with dasatinib had a mean reduction of 43.7 mg/dL (P=.005) in serum glucose concentration (to convert glucose values to mmol/L, multiply by 0.0555) and required 28.8 fewer total daily insulin units (P=.08) in the setting of a 4.8-kg relative weight loss (5.3% of total body weight; P=.045). Linear regression analysis suggests that the relative difference in weight accounts for 8.4 mg/dL of the 43.7 mg/dL blood glucose value decrease, or 19.2%. Relative to imatinib, patients treated with dasatinib had a mean 0.80 absolute point (P=.05) reduction in hemoglobin A 1c and required 18.2 fewer total daily insulin units (P=.16) in the setting of a 5.9-kg relative weight loss (6.3% of total body weight; P=.06)., Conclusion: Dasatinib may have antidiabetic effects comparable to contemporary diabetic treatments and may be considered for use as a novel diabetic therapy. Future studies are needed to determine whether these results are translatable to patients with type 2 diabetes mellitus without underlying malignant diseases and to determine whether the antidiabetic effects of dasatinib are due to its senolytic properties., (Copyright © 2021 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Osteoporosis is characterized by reduced bone mass leading to diminished skeletal integrity and an increased risk for fracture. Multiple agents exist that are effective for the treatment of osteoporosis. These can be broadly categorized into those that reduce the risk for additional loss of bone mass (anti-resorptive agents) and those that augment existing bone mass (anabolic agents). This article reviews the different medications within each class, and discusses more recent data regarding the combination and sequential use of these medications for optimization of skeletal health in patients at high risk for fracture., Competing Interests: Disclosure Neither D. Saul nor M.T. Drake have any relevant disclosures., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Objectives: To determine the indications for prediagnostic testing, subsequent diagnoses found, and follow-up practices in patients who were incidentally diagnosed with monoclonal gammopathy of undetermined significance (MGUS)., Patients and Methods: From our prospective MGUS database, we identified 329 patients residing in southeastern Minnesota who were diagnosed from January 1, 2011, through December 31, 2014, and followed up at Mayo Clinic., Results: Most test orders came from nonhematologists (n=310, 94.2%). The top 5 indications were neuropathy (n=65, 19.8%), renal disease (n=45, 13.7%), anemia (n=42, 12.8%), bone disorder or connective tissue pain (n=42, 12.8%), and cutaneous disease (n=19, 5.8%). Hypercalcemia was an infrequent indication (n=9, 2.7%). The final diagnosis for all neuropathy evaluations was sensory/motor neuropathy-not otherwise specified, with 18.7% having IgM MGUS. Chronic kidney disease-not otherwise specified, iron deficiency, and osteoporosis/osteopenia were the most common subsequent diagnoses for test indications of renal disease, anemia, and bone disorder or connective tissue pain, respectively. Most patients (n=213, 64.7%) had 1 or more follow-up visit during the study period. A minority were followed by hematologists (43.5%, n=143). Patients with low-risk MGUS comprised 45.0% (n=148) of the cohort. Male patients and younger patients were more likely to be followed up than their counterparts (P<.01). About one-third (n=27, 32.1%) of patients 80 years or older (n=84) continued to have regular follow-up visits. Hematologists were more likely to follow patients with MGUS more closely than nonhematologists (P<.001). However, the intensity of follow-up was not based on MGUS risk., Conclusion: Monoclonal protein testing is commonly performed for signs and symptoms not typically associated with lymphoplasmacytic malignancies. There is a significant variation in MGUS follow-up between hematologists and nonhematologists (P<.001) that is not based on risk factors or clinical practice guidelines., (Copyright © 2020 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.)

Bone remodeling consists of resorption by osteoclasts followed by formation by osteoblasts, and osteoclasts are a source of bone formation-stimulating factors. Here we utilize osteoclast ablation by denosumab (DMAb) and RNA-sequencing of bone biopsies from postmenopausal women to identify osteoclast-secreted factors suppressed by DMAb. Based on these analyses, LIF, CREG2, CST3, CCBE1, and DPP4 are likely osteoclast-derived coupling factors in humans. Given the role of Dipeptidyl Peptidase-4 (DPP4) in glucose homeostasis, we further demonstrate that DMAb-treated participants have a significant reduction in circulating DPP4 and increase in Glucagon-like peptide (GLP)-1 levels as compared to the placebo-treated group, and also that type 2 diabetic patients treated with DMAb show significant reductions in HbA1c as compared to patients treated either with bisphosphonates or calcium and vitamin D. Thus, our results identify several coupling factors in humans and uncover osteoclast-derived DPP4 as a potential link between bone remodeling and energy metabolism.

Cell-based therapies, defined here as the delivery of cells in vivo to treat disease, have recently gained increasing public attention as a potentially promising approach to restore structure and function to musculoskeletal tissues. Although cell-based therapy has the potential to improve the treatment of disorders of the musculoskeletal system, there is also the possibility of misuse and misrepresentation of the efficacy of such treatments. The medical literature contains anecdotal reports and research studies, along with web-based marketing and patient testimonials supporting cell-based therapy. Both the American Society for Bone and Mineral Research (ASBMR) and the Orthopaedic Research Society (ORS) are committed to ensuring that the potential of cell-based therapies is realized through rigorous, reproducible, and clinically meaningful scientific discovery. The two organizations convened a multidisciplinary and international Task Force composed of physicians, surgeons, and scientists who are recognized experts in the development and use of cell-based therapies. The Task Force was charged with defining the state-of-the art in cell-based therapies and identifying the gaps in knowledge and methodologies that should guide the research agenda. The efforts of this Task Force are designed to provide researchers and clinicians with a better understanding of the current state of the science and research needed to advance the study and use of cell-based therapies for skeletal tissues. The design and implementation of rigorous, thorough protocols will be critical to leveraging these innovative treatments and optimizing clinical and functional patient outcomes. In addition to providing specific recommendations and ethical considerations for preclinical and clinical investigations, this report concludes with an outline to address knowledge gaps in how to determine the cell autonomous and nonautonomous effects of a donor population used for bone regeneration. © 2019 American Society for Bone and Mineral Research., (© 2019 American Society for Bone and Mineral Research.)

Background: The importance of exercise in skeletal health is increasingly recognized by both patients and providers. However, the safety of prescribed or recreational exercise in at-risk populations remains under-reported and under-publicized. Yoga has gained widespread popularity due to its physical and psychological benefits. When practiced in a population at increased fracture risk, however, some yoga poses may increase fracture risk, particularly at the spine, rather than increasing BMD as noted in recent popular press reports., Case Report: Nine subjects (8 women) with a median age of 66 years (range 53-87), developed vertebral compression fracture (VCF) one month to six years after initiating yoga-associated spinal flexion exercises (SFE). VCF presented with back pain and occurred in the thoracicspine (N.=6), lumbar-spine (N.=4) and cervical-spine (N.=1). Four patients had osteoporosis by BMD criteria prior to VCF and 2 had osteopenia (median T-score -2.35; range -3.3 to +2.0). Interestingly, all patients had their lowest T-scores at the spine. Three patients had a history of fragility fracture prior to the index VCF. While one patient had primary hyperparathyroidism and another was treated with high dose prednisone, no other risk factors for bone loss including medications or secondary osteoporosis causes were identified in the other patients., Clinical Rehabilitation Impact: This study identified patients in whom increased torsional and compressive mechanical loading pressures occurring during yoga SFE resulted in de novo VCF. Despite the need for selectivity in yoga poses in populations at increased fracture risk, both scientific and media reports continue to advertise yoga as a bone protective activity. Accordingly, yoga is misconceived as a 'onesize-fits-all' prescription. Instead, the appropriate selection of patients likely to benefit from yoga must be a cornerstone of fracture prevention.

Background: Prior evidence of a possible link between vitamin D status and hematologic malignancy (HM) in humans comes from observational studies, leaving unresolved the question of whether a true causal relationship exists., Methods: The authors performed a secondary analysis of data from the Women's Health Initiative Calcium/Vitamin D (CaD) trial, a large randomized controlled trial of CaD supplementation compared with placebo in older women. Kaplan-Meier and Cox proportional hazards survival analysis methods were used to evaluate the relationship between treatment assignment and 1) incident HM and 2) HM-specific mortality over 10 years following randomization. HMs were classified by cell type (lymphoid, myeloid, or plasma cell) and analyzed as distinct endpoints in secondary analyses., Results: A total of 34,763 Women's Health Initiative CaD trial participants (median age, 63 years) had complete baseline covariate data and were eligible for analysis. Women assigned to CaD supplementation had a significantly lower risk of incident HM (hazard ratio [HR], 0.80; 95% confidence interval [95% CI], 0.65-0.99) but not HM-specific mortality (HR, 0.77 [95% CI, 0.53-1.11] for the entire cohort; and HR, 1.03 [95% CI, 0.70-1.51] among incident HM cases after diagnosis). In secondary analyses, protective associations were found to be most robust for lymphoid malignancies, with HRs of 0.77 (95% CI, 0.59-1.01) and 0.46 (95% CI, 0.24-0.89), respectively, for cancer incidence and mortality in those assigned to CaD supplementation., Conclusions: The current post hoc analysis of data from a large and well-executed randomized controlled trial demonstrates a protective association between modest CaD supplementation and HM risk in older women. Additional research concerning the relationship between vitamin D and HM is warranted. Cancer 2017;123:4168-4177. © 2017 American Cancer Society., (© 2017 American Cancer Society.)

Aging is associated with increased cellular senescence, which is hypothesized to drive the eventual development of multiple comorbidities. Here we investigate a role for senescent cells in age-related bone loss through multiple approaches. In particular, we used either genetic (i.e., the INK-ATTAC 'suicide' transgene encoding an inducible caspase 8 expressed specifically in senescent cells) or pharmacological (i.e., 'senolytic' compounds) means to eliminate senescent cells. We also inhibited the production of the proinflammatory secretome of senescent cells using a JAK inhibitor (JAKi). In aged (20- to 22-month-old) mice with established bone loss, activation of the INK-ATTAC caspase 8 in senescent cells or treatment with senolytics or the JAKi for 2-4 months resulted in higher bone mass and strength and better bone microarchitecture than in vehicle-treated mice. The beneficial effects of targeting senescent cells were due to lower bone resorption with either maintained (trabecular) or higher (cortical) bone formation as compared to vehicle-treated mice. In vitro studies demonstrated that senescent-cell conditioned medium impaired osteoblast mineralization and enhanced osteoclast-progenitor survival, leading to increased osteoclastogenesis. Collectively, these data establish a causal role for senescent cells in bone loss with aging, and demonstrate that targeting these cells has both anti-resorptive and anabolic effects on bone. Given that eliminating senescent cells and/or inhibiting their proinflammatory secretome also improves cardiovascular function, enhances insulin sensitivity, and reduces frailty, targeting this fundamental mechanism to prevent age-related bone loss suggests a novel treatment strategy not only for osteoporosis, but also for multiple age-related comorbidities.

The Wnt/β-catenin signaling pathway plays an essential role in osteoblast biology. Sclerostin is a soluble antagonist of Wnt/β-catenin signaling secreted primarily by osteocytes. Current evidence indicates that sclerostin likely functions as a local/paracrine regulator of bone metabolism rather than as an endocrine hormone. Nonetheless, circulating sclerostin levels in humans often reflect changes in the bone microenvironment, although there may be exceptions to this observation. Using existing assays, circulating sclerostin levels have been shown to be altered in response to both hormonal stimuli and across a variety of normal physiological and pathophysiological conditions. In both rodents and humans, parathyroid hormone provided either intermittently or continuously suppresses sclerostin levels. Likewise, most evidence from both human and animal studies supports a suppressive effect of estrogen on sclerostin levels. Efforts to examine non-hormonal/systemic regulation of sclerostin have in general shown less consistent findings or have provided associations rather than direct interventional information, with the exception of mechanosensory studies which have consistently demonstrated increased sclerostin levels with skeletal unloading, and conversely decreases in sclerostin with enhanced skeletal loading. Herein, we will review the existent literature on both hormonal and non-hormonal/systemic factors which have been studied for their impact on sclerostin regulation., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Introduction: While teriparatide is the only skeletal anabolic agent approved in the United States, treatment failure is a major concern which complicates its clinical utility. We sought to identify factors that predict response failure in patients with low bone mass., Method: We performed a retrospective study of adults with osteopenia or osteoporosis (T-scores < - 1.0 and - 2.5 SD below normal, respectively, at the total hip or lumbar spine) treated with teriparatide at the Mayo Clinic (Rochester, Minnesota) between November 2002-December 2012. Trained study investigators blinded to patient outcomes collected electronic medical record data. Potential response failure predictors were identified using univariate analysis. Multivariable logistic regression modeling was used to identify independent predictors of treatment failure based on either osteoporotic fragility fracture or BMD response., Results: During the 10-year period, 494 patients received teriparatide treatment and met eligibility criteria. Thirty-five patients had osteoporotic fractures, while 172 did not achieve a ≥ 3% BMD increase. Among predictors as defined by BMD change, both prior bisphosphonate treatment [odds ratio (95% confidence interval), 1.50 (1.01-2.24)] and vitamin D therapy [1.50 (1.01-2.22)] were significantly (P < 0.05) associated with teriparatide treatment failure. By contrast, no predictors were associated with treatment failure when fracture was the endpoint., Conclusion: These data suggest that prior bisphosphonate or vitamin D exposure may predict response failure to teriparatide therapy. Although these findings may, in part, reflect increased severity or longer duration of disease, this knowledge should help guide clinicians and patients when therapy choices are made.

Importance: Up to 20% of patients undergoing thyroidectomy develop hypocalcemia after surgery. Although usually transient, severe symptomatic hypocalcemia may occur. Teriparatide acetate (recombinant human parathyroid hormone 1-34) therapy can rapidly raise calcium levels., Objective: To test the hypothesis that teriparatide therapy in patients with postthyroidectomy hypoparathyroidism would expedite relief of symptomatic hypocalcemia and reduce the duration of hospitalization compared with standard treatment., Design, Setting, and Participants: Case series of all hospitalized patients 18 years or older treated with teriparatide for symptomatic postthyroidectomy hypocalcemia occurring immediately after thyroidectomy at Mayo Clinic, Rochester, Minnesota, between January 1, 2008, and June 30, 2014. A secondary analysis was performed with matched control and cohort groups having postthyroidectomy hypocalcemia of similar degree who received standard treatment only. Participants included 8 hospitalized patients who received teriparatide therapy after 24 hours of standard treatment (cases) and eight control patients selected from a cohort of 1193 thyroidectomies were matched for age, sex, body mass index, and nadir calcium levels., Intervention: Teriparatide acetate therapy (20 µg twice daily) subcutaneously for 1 week, with the option of continuing at 20 µg/d for up to 3 weeks., Main Outcomes and Measures: Safety, symptom resolution, calcium supplementation, and duration of hospitalization., Results: Among the 16 case and control patients the median nadir calcium level was 7.1 mg/dL in both groups. Most patients underwent thyroidectomy for thyroid cancer. Teriparatide therapy was safe, with no adverse events noted, and completely eliminated symptomatic hypocalcemia in all treated patients within 24 hours of initiation. Hospital discharge occurred at a median of 1.0 day (interquartile range, 1.0-1.0 day) after teriparatide therapy initiation among cases vs 2.5 days (interquartile range, 1.8-3.0 days) after the equivalent clinical point was reached in controls (P = .01). This value was 2.0 days in the source cohort (P = .02). On hospital discharge, patients had similar calcium levels. Six months after surgery, all patients treated with teriparatide showed partial or complete parathyroid recovery. Calcium supplementation and calcium levels were comparable between the groups., Conclusions and Relevance: In this pilot study, teriparatide therapy in patients with postthyroidectomy hypoparathyroidism was safe, rapidly eliminated hypocalcemic symptoms, and likely reduced the duration of hospitalization. Given the limitations of this small study, a large-scale randomized trial is needed to verify these results and to assess the long-term effect of teriparatide therapy on clinical outcomes.

Purpose: The objectives of this article are to review the pathophysiology of bone loss associated with aging and to review current pharmacologic approaches for the treatment of osteoporosis., Methods: A literature search with PubMed was performed with the terms osteoporosis and pathophysiology and osteoporosis and treatment and limited to studies written in English that were published within the preceding 10 years. Given the large number of studies identified, we selectively reviewed those studies that contained primary data related to osteoporosis pathophysiology or osteoporosis pharmacologic treatments and references included within selected studies identified from abstract review., Findings: Published studies have consistently reported that osteoporosis in older adults is caused by an imbalance of bone resorption in excess of bone formation. The dominant factor leading to bone loss in older adults appears to be gonadal sex steroid deficiency, with multiple genetic and biochemical factors, such as vitamin D deficiency or hyperparathyroidism, that may accelerate bone loss. Conditions that adversely affect growth and development may limit development of peak bone mass and accelerate subsequent bone loss. Studies of bone microarchitecture have shown that trabecular bone loss begins in the third decade of life, before gonadal sex steroid deficiency develops, whereas cortical loss typically begins in the sixth decade, about the time of menopause in women and about the same age in men. Antiresorptive agents for the treatment of osteoporosis act primarily by limiting osteoclast activity, whereas osteoanabolic agents, such as teriparatide, act primarily by stimulating osteoblastic bone formation. Clinical investigation of new compounds for the treatment of osteoporosis is mainly directed to those that stimulate bone formation or differentially decrease bone resorption more than bone formation. Therapies for osteoporosis are associated with adverse effects, but in patients at high risk of fracture, the benefits generally far outweigh the risks., Implications: Current osteoporosis therapies mitigate or reverse the loss of bone associated with age-related decreases of gonadal sex steroids, increase bone strength, and reduce fracture risk. With improved knowledge of the pathophysiology of osteoporosis, new targets for therapeutic intervention have been identified. Clinical investigations of potential new treatments for osteoporosis are primarily directed to stimulating osteoblastic bone formation or to modulating the balance of bone resorption and formation in ways that improve bone strength., (Copyright © 2015 Elsevier HS Journals, Inc. All rights reserved.)

Osteoporosis is now recognized as a major threat to health in aging men. Morbidity and mortality, particularly following hip fracture, are substantial. Although trabecular bone loss starts in early adulthood, loss of cortical bone only seems to occur from midlife onwards. Declining bioavailable estradiol levels plays an integral role in male age-associated bone loss. Both pharmacologic and supportive care interventions are important for optimal care in men at an increased fracture risk., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Purpose: It has been hypothesized that vitamin D mediates the inverse relationship between sun exposure and non-Hodgkin lymphoma (NHL) risk reported in several recent studies. We evaluated the association of self-reported sun exposure at ages <13, 13-21, 22-40, and 41+ years and 19 single nucleotide polymorphisms (SNPs) from 4 candidate genes relevant to vitamin D metabolism (RXR, VDR , CYP24A1, CYP27B1) with NHL risk., Methods: This analysis included 1,009 newly diagnosed NHL cases and 1,233 frequency-matched controls from an ongoing clinic-based study. Odds ratios (OR), 95 % confidence intervals (CI), and tests for trend were estimated using unconditional logistic regression., Results: There was a significant decrease in NHL risk with increased sun exposure at ages 13-21 years (OR(≥15 vs. ≤3 h/week) = 0.68; 95 % CI, 0.43-1.08; p(trend) = 0.0025), which attenuated for older ages at exposure. We observed significant main effect associations for 3 SNPs in VDR and 1 SNP in CYP24A1: rs886441 (OR(per-allele) = 0.82; 95 % CI, 0.70-0.96; p = 0.016), rs3819545 (OR(per-allele) = 1.24; 95 % CI, 1.10-1.40; p = 0.00043), and rs2239186 (OR(per-allele) = 1.22; 95 % CI, 1.05-1.41; p = 0.0095) for VDR and rs2762939 (OR(per-allele) = 0.85; 95 % CI, 0.75-0.98; p = 0.023) for CYP24A1. Moreover, the effect of sun exposure at age 13-21 years on overall NHL risk appears to be modified by germline variation in VDR (rs4516035; p(interaction) = 0.0066). Exploratory analysis indicated potential heterogeneity of these associations by NHL subtype., Conclusion: These results suggest that germline genetic variation in VDR, and therefore the vitamin D pathway, may mediate an association between early life sun exposure and NHL risk.

Context: Osteoporosis and osteopenia are associated with increased fracture incidence., Objective: The aim of this study was to determine the comparative effectiveness of different pharmacological agents in reducing the risk of fragility fractures., Data Sources: We searched multiple databases through 12/9/2011., Study Selection: Eligible studies were randomized controlled trials enrolling individuals at risk of developing fragility fractures and evaluating the efficacy of bisphosphonates, teriparatide, selective estrogen receptor modulators, denosumab, or calcium and vitamin D., Data Extraction: Reviewers working independently and in duplicate determined study eligibility and collected descriptive, methodological quality, and outcome data., Data Synthesis: This network meta-analysis included 116 trials (139,647 patients; median age, 64 yr; 86% females and 88% Caucasians; median follow-up, 24 months). Trials were at low to moderate risk of bias. Teriparatide had the highest risk reduction of fractures (odds ratios, 0.42, 0.30, and 0.50 for hip, vertebral, and nonvertebral fractures, respectively) and the highest probability of being ranked first for efficacy (probabilities of 42, 49, and 79% for hip, vertebral, and nonvertebral fractures, respectively). However, differences to denosumab, zoledronate, risedronate, ibandronate, and alendronate were not statistically significant. Raloxifene and bazedoxifene were likely less effective, although these data were limited. Calcium and vitamin D were ineffective given separately but reduced the risk of hip fractures if given in combination (odds ratio, 0.81; 95% confidence interval, 0.68–0.96)., Conclusions: Teriparatide, bisphosphonates, and denosumab are most effective in reducing the risk of fragility fractures. Differences in efficacy across drugs are small; therefore, patients and clinicians need to consider their associated harms and costs.

Context: Testing men at increased risk for osteoporotic fractures has been recommended., Objective: The aim of this study was to estimate the magnitude of association and quality of supporting evidence linking multiple risk factors with low bone mass-related fractures in men., Data Sources: We searched MEDLINE, EMBASE, Web of Science, SCOPUS and Cochrane CENTRAL through February 2010. We identified further studies by reviewing reference lists from selected studies and reviews., Study Selection: Eligible studies had to enroll men and quantitatively evaluate the association of risk factors with low bone density-related fractures., Data Extraction: Reviewers working independently and in duplicate determined study eligibility and extracted study description, quality, and outcome data., Data Synthesis: Fifty-five studies provided data sufficient for meta-analysis. The quality of these observational studies was moderate with fair levels of multivariable adjustment and adequate exposure and outcome ascertainment. Statistically significant associations were established for age, low body mass index, current smoking, excessive alcohol use, chronic corticosteroid use, history of prior fractures, history of falls, history of hypogonadism, history of stroke, and history of diabetes. Statistical heterogeneity of the meta-analytic estimates of all associations was significant except for chronic corticosteroid use. None of these associations were of large magnitude (i.e. adjusted odds ratios were generally <2). No evidence supporting a particular effective testing or screening strategy was identified., Conclusions: Multiple risk factors for fractures in men were identified, but their usefulness for stratifying and selecting men for bone density testing remains uncertain.

Bisphosphonates are chemically stable structural analogs of inorganic pyrophosphate. Owing to their ability to inhibit osteoclast activity, bisphosphonates have become the primary agents to treat conditions marked by excessive osteoclast-mediated bone resorption, such as osteoporosis, Paget's disease of bone, and cancer-associated bone disease. At the molecular level, bisphosphonates exert their anti-resorptive effects by inhibiting farnesyl pyrophosphate synthase activity within osteoclasts. Bisphosphonates are generally well tolerated, with many patients now having been treated for more than ten years. Widespread bisphosphonate use, however, has revealed both short-term and long-term side effects in some patients. Here, we review our current understanding of the mechanisms by which bisphosphonates inhibit osteoclast function, the current roles for these medications in clinical practice, and areas of concern that have emerged with widespread bisphosphonate use.

Classically, the beta 2-adrenergic receptor (beta 2AR) and other members of the seven-transmembrane receptor (7TMR) superfamily activate G protein-dependent signaling pathways in response to ligand stimulus. It has recently been discovered, however, that a number of 7TMRs, including beta 2AR, can signal via beta-arrestin-dependent pathways independent of G protein activation. It is currently unclear if among beta 2AR agonists there exist ligands that disproportionately signal via G proteins or beta-arrestins and are hence "biased." Using a variety of approaches that include highly sensitive fluorescence resonance energy transfer-based methodologies, including a novel assay for receptor internalization, we show that the majority of known beta 2AR agonists exhibit relative efficacies for beta-arrestin-associated activities (beta-arrestin membrane translocation and beta 2AR internalization) identical to the irrelative efficacies for G protein-dependent signaling (cyclic AMP generation). However, for three betaAR ligands there is a marked bias toward beta-arrestin signaling; these ligands stimulate beta-arrestin-dependent receptor activities to a much greater extent than would be expected given their efficacy for G protein-dependent activity. Structural comparison of these biased ligands reveals that all three are catecholamines containing an ethyl substitution on the alpha-carbon, a motif absent on all of the other, unbiased ligands tested. Thus, these studies demonstrate the potential for developing a novel class of 7TMR ligands with a distinct bias for beta-arrestin-mediated signaling.

Physiological effects of beta adrenergic receptor (beta2AR) stimulation have been classically shown to result from G(s)-dependent adenylyl cyclase activation. Here we demonstrate a novel signaling mechanism wherein beta-arrestins mediate beta2AR signaling to extracellular-signal regulated kinases 1/2 (ERK 1/2) independent of G protein activation. Activation of ERK1/2 by the beta2AR expressed in HEK-293 cells was resolved into two components dependent, respectively, on G(s)-G(i)/protein kinase A (PKA) or beta-arrestins. G protein-dependent activity was rapid, peaking within 2-5 min, was quite transient, was blocked by pertussis toxin (G(i) inhibitor) and H-89 (PKA inhibitor), and was insensitive to depletion of endogenous beta-arrestins by siRNA. beta-Arrestin-dependent activation was slower in onset (peak 5-10 min), less robust, but more sustained and showed little decrement over 30 min. It was insensitive to pertussis toxin and H-89 and sensitive to depletion of either beta-arrestin1 or -2 by small interfering RNA. In G(s) knock-out mouse embryonic fibroblasts, wild-type beta2AR recruited beta-arrestin2-green fluorescent protein and activated pertussis toxin-insensitive ERK1/2. Furthermore, a novel beta2AR mutant (beta2AR(T68F,Y132G,Y219A) or beta2AR(TYY)), rationally designed based on Evolutionary Trace analysis, was incapable of G protein activation but could recruit beta-arrestins, undergo beta-arrestin-dependent internalization, and activate beta-arrestin-dependent ERK. Interestingly, overexpression of GRK5 or -6 increased mutant receptor phosphorylation and beta-arrestin recruitment, led to the formation of stable receptor-beta-arrestin complexes on endosomes, and increased agonist-stimulated phospho-ERK1/2. In contrast, GRK2, membrane translocation of which requires Gbetagamma release upon G protein activation, was ineffective unless it was constitutively targeted to the plasma membrane by a prenylation signal (CAAX). These findings demonstrate that the beta2AR can signal to ERK via a GRK5/6-beta-arrestin-dependent pathway, which is independent of G protein coupling.