Use Of Antiresorptive Therapies Research Articles

Impact of Liver Cirrhosis on Bone Metabolism

AbstractBone loss is an early and major problem in cirrhotic patients. The majority of cirrhotic patients demonstrate evidence of hepatic osteodystrophy (HOD). This includes decreased bone volume, turnover abnormalities, and rarely mineralization defects. Moreover, the degree of bone disease usually correlates with the severity of liver dysfunction. The mechanism of HOD is multifactorial. Vitamin D insufficiency/deficiency, secondary hyperparathyroidism, hypogonadism, inhibitors of bone formation, and mediators/promoters of bone resorption are frequent findings and essential coplayers in HOD. Early and proper identification of HOD is challenging. DXA is the most widely used tool; however, it has fundamental limitations. Bone turnover biomarkers are used to understand the mechanism of bone loss. Bone biopsy with histomorphometry is the gold standard to evaluate bone structure. The evidence for the effectiveness of nonpharmacological and pharmacological management of HOD is limited. Adequate nutrition, weight-bearing exercise, smoking cessation, and limitation of alcohol consumption improve bone health and quality of life. The use of antiresorptive therapies prevents bone loss particularly in patients with high bone turnover. However, osteoanabolics are essential in patients with low bone turnover. Herein, we are discussing the magnitude of the problem, pathogenesis, diagnosis of HOD, and various interventions to improve bone health in cirrhotic patients.

Abstract P6-11-01: Adherence to guidelines for bone health in a predominantly Hispanic cohort of breast cancer patients receiving aromatase inhibitors

Abstract Introduction: Aromatase inhibitors (AI), by reducing estrogen levels, decrease the risk of recurrence of hormone receptor positive breast cancer but also lead to accelerated bone loss and increased fracture risk. This has led to guidelines for treating women on AIs with bone antiresorptive agents earlier in order to avoid fractures. The 2017 joint position statement from the International Osteoporosis Foundation, Cancer and Bone Society, European Calcified Tissue Society, International Expert Group for AI Bone Loss, European Society for Clinical and Economic Aspects of Osteoporosis, Osteoarthritis and Musculoskeletal Disease, International Menopause Society, and the International Society for Geriatric Oncology recommends treating patients on AI with either denosumab or bisphosphonates with BMD T-scores < -2.0, T-scores < -1.5 with one additional risk factor, or with ≥ 2 risk factors even without a BMD for the duration of AI therapy. The Garbar Breast Care Center at TTUHSC-El Paso serves a predominantly Hispanic patient population. As disparities in cancer care have been well documented amongst minorities, we sought to determine the adherence to the current guidelines for fracture prevention in this group. Methods: Post-menopausal women diagnosed with non-metastatic breast cancer and receiving adjuvant AIs who had a BMD done were included. Patients with pre-existing osteoporosis or already receiving antiresorptive therapy prior to cancer diagnosis were excluded. Electronic medical records of patients seen in clinic between 9/2015 and 3/2018 were reviewed to extract data regarding bone mineral density (T score, Z score), risk factors, and use of antiresorptive therapies. Study was approved by the institutional IRB. Results: A total of sixty patients were included. Median age was 65 years and 92% were Hispanic. Stage distribution was as follows: I, 40%, II, 43% and III, 17%. Thirty-eight (63%) met criteria to be treated with an antiresorptive agent. Thirty-two (53%) had T-scores < -2.0 and 6 (10%) had a T-score < -1.5 with at least 1 additional risk factor. Only 15 (39%) of the 38 patients who met guidelines for treatment were on antiresorptive therapy. Of the 15 patients who were on treatment, 10 had osteoporosis (T-score < -2.5), and 5 had osteopenia (T-score -2 to -2.5). Two additional patients were on antiresorptive therapy that did not meet the guidelines. Of the remaining 23 patients who met guidelines for treatment but were not treated, 6 had frank osteoporosis, 11 had a T-score between -2.0 and -2.5, and 6 had T-scores < -1.5 with at least one additional risk factor. Perceived barriers to appropriate institution of anti-resorptive therapy amongst oncologists were a) lack of timely dental evaluation and risk of osteonecrosis, b) cost of denosumab and zoledronic acid c) risk of myalgias and arthralgias with anti-resorptive agents potentially affecting compliance with AI therapy. Conclusion: In a predominantly Hispanic population, we found that only 39% of patients with indications for anti-resorptive therapy were on appropriate treatment. This has important implications for long term bone health amongst these cancer survivors. As adjuvant bisphosphonates have also been associated with a decrease in bone metastases and improvement of breast cancer specific survival, the low rate of adherence to guidelines can potentially contribute to inferior long-term survival. Timely access to dental services can potentially improve compliance rates. Citation Format: Tamis M. Bright, Meghan K. Mcalice, Abelardo Escriba-Omar, Sumit Gaur, Alexander V. Philipovskiy. Adherence to guidelines for bone health in a predominantly Hispanic cohort of breast cancer patients receiving aromatase inhibitors [abstract]. In: Proceedings of the 2019 San Antonio Breast Cancer Symposium; 2019 Dec 10-14; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2020;80(4 Suppl):Abstract nr P6-11-01.

Siglec-15-targeting therapy increases bone mass in rats without impairing skeletal growth.

The treatment of juvenile osteoporosis has not been established due to a lack of data regarding the efficacy and adverse effects of therapeutic agents. The possible adverse effects of the long-term use of antiresorptive therapies on skeletal growth in children is of particular concern. Sialic acid-binding immunoglobulin-like lectin 15 (Siglec-15) is an immunoreceptor that regulates osteoclast development and bone resorption, and its deficiency suppresses bone remodeling in the secondary spongiosa, but not in the primary spongiosa, due to a compensatory mechanism of osteoclastogenesis. This prompted us to develop an anti-Siglec-15 therapy for juvenile osteoporosis because most anti-resorptive drugs have potential adverse effects on skeletal growth. Using growing rats, we investigated the effects of an anti-Siglec-15 neutralizing antibody (Ab) on systemic bone metabolism and skeletal growth, comparing this drug to bisphosphonate, a first-line treatment for osteoporosis. Male 6-week-old F344/Jcl rats were randomized into six groups: control (PBS twice per week), anti-Siglec-15 Ab (0.25, 1, or 4 mg/kg every 3 weeks), and alendronate (ALN) (0.028 or 0.14 mg/kg twice per week). Treatment commenced at 6 weeks of age and continued for the next 6 weeks. Changes in bone mass, bone metabolism, bone strength, and skeletal growth during treatment were analyzed. Both anti-Siglec-15 therapy and ALN increased bone mass and the mechanical strength of both the femora and lumbar spines in a dose-dependent manner. Anti-Siglec-15 therapy did not have a significant effect on skeletal growth as evidenced by micro-CT-based measurements of femoral length and histology, whereas high-dose ALN resulted in growth retardation with histological abnormalities in the growth plates of femurs. This unique property of the anti-Siglec-15 Ab can probably be attributed to compensatory signaling for Siglec-15 inhibition in the primary spongiosa, but not in the secondary spongiosa. Thus, anti-Siglec-15 therapy could be a safe and effective for juvenile osteoporosis.

Mineral and Bone Disorders After Kidney Transplantation.

The risk of mineral and bone disorders among patients with chronic kidney disease is substantially elevated, owing largely to alterations in calcium, phosphorus, vitamin D, parathyroid hormone, and fibroblast growth factor 23. The interwoven relationship among these minerals and hormones results in maladaptive responses that are differentially affected by the process of kidney transplantation. Interpretation of conventional labs, imaging, and other fracture risk assessment tools are not standardized in the post-transplant setting. Post-transplant bone disease is not uniformly improved and considerable variation exists in monitoring and treatment practices. A spectrum of abnormalities such as hypophosphatemia, hypercalcemia, hyperparathyroidism, osteomalacia, osteopenia, and osteoporosis are commonly encountered in the post-transplant period. Thus, reducing fracture risk and other bone-related complications requires recognition of these abnormalities along with the risk incurred by concomitant immunosuppression use. As kidney transplant recipients continue to age, the drivers of bone disease vary throughout the post-transplant period among persistent hyperparathyroidism, de novo hyperparathyroidism, and osteoporosis. The use of anti-resorptive therapies require understanding of different options and the clinical scenarios that warrant their use. With limited studies underscoring clinical events such as fractures, expert understanding of MBD physiology, and surrogate marker interpretation is needed to determine ideal and individualized therapy.

Prognostic factors for skeletal complications from metastatic bone disease in breast cancer

Skeletal morbidity is common in patients with bone metastases from breast cancer (BC) and can undermine patients' functional independence and quality of life. Previously defined prognostic factors may not reflect current treatment standards and the use of antiresorptive therapies. We report a comprehensive multivariate analysis of potential prognostic factors for skeletal-related events (SREs) using data from a phase III, randomized study of zoledronic acid in patients with bone metastases from BC. The trial evaluated the number and timing of SREs (pathologic fracture, palliative radiotherapy to bone, surgery to bone to treat or prevent a fracture, and spinal cord compression) and assessed variables for prognostic significance in univariate and multivariate Cox-regression analyses. Continuous variables were categorized with predefined cutpoints. All associations with P < 0.05 were considered significant. A total of 444 zoledronic acid-treated patients with assessments of biochemical markers of bone metabolism and complete baseline variable data were included. Significant baseline prognostic factors for occurrence of a first SRE by multivariate analyses included age, pain score, prior history of an SRE, predominant lesion type, elevated bone-specific alkaline phosphatase, and lactate dehydrogenase. Prior fracture was found to be prognostic in a reduced multivariate analysis of time to first fracture, but not for time to first palliative radiotherapy. In conclusion, this model identified several prognostic factors that may be useful in routine clinical care. Validation of these factors in a separate dataset and generation of a prognostic risk score are recommended next steps.

New perspectives on parathyroid hormone therapy

The prevention and treatment of osteoporosis has traditionally involved the use of antiresorptive therapies. The introduction of parathyroid hormone, an anabolic agent that enhances bone formation, has been accompanied by new treatment strategies. This article reviews combination and sequential therapy approaches with parathyroid hormone and antiresorptive agents to optimize efficacy outcomes. The distinguishing features of the anabolic and antiresorptive therapies for the treatment of osteoporosis has led to the hypothesis that the appropriate use of both agents, either in sequence or in combination, may result in superior fracture protection compared with either anabolic or antiresorptive treatment alone. This enthusiasm has been tempered by the observations that the transition from daily bisphosphonate therapy may blunt the efficacy of teriparatide. By contrast, more recent studies suggest that once-weekly bisphosphonate therapy may provide a better option with parathyroid hormone either in combination or in sequence. These considerations are critical to understanding the benefits of sequential treatment (parathyroid hormone followed by an antiresorptive agent), which aims to maintain or build on the large gains in efficacy from short-term therapy with parathyroid hormone. Because patients may require an additional treatment course of parathyroid hormone in the future, the choice of antiresorptive agent should be carefully considered. In addition, more recent evidence suggests that the forms of parathyroid hormone may have important differences in action that influence combination and sequence outcomes. Combination and sequential therapy with parathyroid hormone offers new options to maximize efficacy in patients at risk for osteoporotic fracture.

Use of antiresorptive drugs among older women: A case study in Wisconsin

The factors contributing to the use of antiresorptive therapies (ARTs) and differentiating the ARTs used were examined. A list of names of community-dwelling persons 65 years or older living in Wisconsin was obtained, and 2100 individuals were selected (1050 men and 1050 women) to receive the 10-page survey instrument. The survey requested information on health status, prescription drug use, preferences for using prescription drugs versus self-treatment strategies, demographic characteristics, and status and type of prescription drug and medical insurance. Only the responses from female respondents were evaluated. Descriptive statistics were calculated for each variable. The simultaneous relationships among all variables were modeled sequentially using a binary logistic regression model and a multinomial logistic regression model. Usable responses were received from 629 women, yielding an adjusted response rate of 59.9%; 169 (26.9%) reported current use of at least one ART, 110 (17.5%) reported using hormone replacement therapy (HRT), and 59 (9.4%) were using newer ARTs. The typical respondent did not use any prescription medicines for the treatment or prevention of osteoporosis, was married, and did not have a four-year college degree. Married, younger women with high medical care preferences scores were more likely to use antiresorptive agents. Married women were more likely to use HRT versus no treatment. A higher number of family practice physicians per 100,000 population reduced the likelihood of the use of any ART. Lower age was also related to the use of ARTs. Marital status, age, medical care preferences, prescription drug insurance, a regular source of care, and the diagnosis of osteoporosis were all significantly associated with the use of any antiresorptive agent.

Osteoclast activation in inflammatory periodontal diseases.

In this paper, we review the mechanisms thought to be involved in the activation of osteoclasts in periodontitis. Osteoclasts are regulated by both microbial and host factors. Some factors act directly on cells of the osteoclast lineage, whereas others act indirectly through other cell types in the bone environment. The proinflammatory cytokines (interleukins 1 and 6, tumor necrosis factors) have been implicated in the stimulation of osteoclastic resorption. The roles of the immunoregulatory cytoknes (interleukins 2 and 4, interferon gamma) are less clear, but decreased levels of these factors may contribute to periodontitis. A number of lipid mediators may be involved in stimulation of bone resorption. These include bacterial lipopolysaccharide and host-derived platelet-activating factor and prostaglandins. More recently, reactive oxygen intermediates and extracellular nucleotides, both present at sites of inflammation, have been investigated as possible modulators of osteoclast activity. The potential use of antiresorptive therapies in periodontitis is reviewed. A wide range of host and bacterial factors contribute to the loss of alveolar bone in periodontitis. However, much remains to be understood about the complex mechanisms through which these factors regulate osteoclast activity. Further studies at the cellular and molecular level will lead to a better understanding of these processes and perhaps suggest new approaches for periodontal therapy.