Long-Term Follow-Up of Denosumab Discontinuers with Multiple Vertebral Fractures in the Real-World: A Case Series.

Denosumab discontinuation is associated with rapid reversal of bone turnover suppression and with a considerable increase in fracture risk, including a risk for multiple vertebral fractures (MVF). Long-term follow-up of patients who sustained MVF after denosumab discontinuation has not been reported. This case-series was aimed to provide a long-term follow-up on the management and outcome of denosumab discontinuers who initially presented with multiple vertebral fractures. Denosumab discontinuers were identified from a computerized database of a large healthcare provider. Baseline and follow-up clinical, laboratory, and imaging data were obtained from the computerized database and electronic medical records. The post-denosumab discontinuers MVF patients consisted of 12 women aged 71±12. Osteoporotic fractures were prevalent before denosumab discontinuation in 6 of the patients. The majority received bisphosphonates before denosumab. MVF occurred 134±76 days after denosumab discontinuation. The patients were followed for a median of 36.5 (IQR 28.2, 42.5) months after MVF. Two patients passed-away. Two patients suffered recurrent vertebral fractures. Following MVF, patients were treated inconsistently with denosumab, teriparatide, oral, and intravenous bisphosphonates, in various sequences. Two patients underwent vertebroplasty/kyphoplasty. This long-term follow-up of real-world patients with MVF following denosumab discontinuation reveals that management is inconsistent, and recurrent fractures are not uncommon. It calls for clear management guidelines for patients with MVF after denosumab discontinuation and for special attention to this high-risk group.

Thyroid dysfunction and survival in cancer patients treated with immune checkpoint inhibitors: analyses from a large single tertiary cancer center database.

PURPOSE: We aimed to assess the incidence, clinical and biochemical course of immunotherapy-induced thyroiditis and its implication on patients' survival, based on an extensive clinical experience from a tertiary cancer center. METHODS: Analyses were based on data from the electronic medical records of cancer patients treated with CPIs. Data included demographic characteristics, cancer type, Thyroid function tests (TFT), and survival. RESULTS: Thyroid function tests were available for 934 patients. After excluding patients with impaired baseline TFT or levothyroxine treatment, 754 euthyroid patients were included in the core analyses. Of those, 301 (39.9%) patients developed thyroid dysfunction ('thyroiditis'). Thyroiditis was more prevalent in patients with renal cell carcinoma than other types of cancer. Survival rates were comparable in patients who developed thyroiditis and in those who did not. during the 5 years follow-up period, there was a non-significant trend toward improved survival in patients who developed TD in four predefined groups: melanoma, lung cancer, renal cell carcinoma, and transitional cell carcinoma. Nevertheless, we observed a highly significant survival benefit for patients with renal cell carcinoma who developed TD (HR = 0.19, 95% CI 0.06-0.60; p = 0.005). CONCLUSIONS: Thyroiditis is common, often asymptomatic, and is more prevalent in patients treated with combinations of nivolumab and PD-L1 inhibitors, and in patients with renal cell carcinoma. Thyroiditis was associated with a trend for a survival benefit, particularly in patients with renal cell carcinoma.

INCREASED SERUM CALCIUM IS NOT COMMON IN HOSPITALIZED PATIENTS WITH PRIMARY HYPERPARATHYROIDISM: A RETROSPECTIVE, OBSERVATIONAL STUDY.

Objective: Serum calcium levels often decrease during acute illness in patients with an intact calcium-regulating system. However, the dynamics of serum calcium levels in hospitalized patients with primary hyperparathyroidism (PHPT) have not yet been described. Methods: Clinical and laboratory data were retrospectively retrieved from the electronic medical records of patients with PHPT before, during, and after hospitalization for various reasons (excluding parathyroid surgery). Results: There were 99 nonselected patients with asymptomatic, hypercalcemic PHPT, hospitalized for various reasons; 42% were admitted for apparent infectious or septic conditions, and 58% were admitted for noninfectious conditions. Total serum calcium increased >0.5 mg/dL in 7.4% of the patients: 10.9% and 2.5% of the patients with noninfectious and infectious conditions, respectively. In 65.7% of the patients, the mean total serum calcium (TsCa), but not albumin-corrected calcium (corrCa), decreased significantly during hospitalization, down to below the upper limit of the reference range. Although prehospitalization TsCa and corrCa were similar in patients with infectious and noninfectious conditions, during hospitalization, TsCa was lower in patients with infectious conditions (P = .02). Both TsCa and albumin returned to prehospitalization levels after recovery. Conclusion: TsCa increases in a minority of hospitalized PHPT patients. In the majority of hospitalized patients with PHPT, TsCa, but not corrCa, decreases to within the normal reference range, more so in patients with infectious conditions, obscuring the major characteristic of PHPT. Therefore, it is prudent to follow calcium and corrCa during hospitalization in patients with PHPT. Abbreviations: corrCa = albumin-corrected serum calcium; IQR = interquartile range; PHPT = primary hyperparathyroidism; PTH = parathyroid hormone; TsCa = total serum calcium.

CLOMIPHENE CITRATE IN THE TREATMENT OF IDIOPATHIC OR FUNCTIONAL HYPOGONADOTROPIC HYPOGONADISM IN MEN: A CASE SERIES AND REVIEW OF THE LITERATURE.

OBJECTIVE: Late-onset hypogonadotropic hypogonadism (LOH) is a complex, heterogeneous entity. Whenever treatment is indicated, the endocrine literature has recommend testosterone replacement. We present our experience with clomiphene citrate treatment in patients with LOH and a review of the literature. METHODS: This retrospective case series included 18 male patients with hypogonadotropic hypogonadism, roughly according to the European Male Aging Study criteria for LOH, attended at an academic hospital outpatient clinic. Data were retrieved from the patients' electronic medical records. RESULTS: The patients' mean age (±SD) was 44.3 ± 6.3 years (range 21-67 years) referred for evaluation of low testosterone together with decreased libido, erectile dysfunction, fatigue or tiredness, anxiety, and osteoporosis. Clomiphene was initially prescribed at doses between 25 mg 3 times a week and 50 mg/day. At 6 to 8 weeks following initiation of treatment, mean basal total-testosterone increased from 7.6 ± 2.6 to 19.3 ± 5.2 nmol/L (P<.0001). Mean basal luteinizing hormone (LH) increased from 2.7 ± 2.1 to 8.3 ± 3.5 nmol/L (P<.0001). Mean basal follicle-stimulating hormone (FSH) increased from 4.2 ± 3.6 to 8.6 ± 6.2 nmol/L (P = .007). Testosterone and LH responses were invariably observed, including 2 patients with history of nonpituitary cranial pathologies, 2 with somewhat elevated FSH, and 1 with an eating disorder. Twelve (67%) patients reported improvement in symptoms. Side effects included transient nipple tenderness in 1 patient. CONCLUSION: Available data suggest that clomiphene is an efficient and convenient alternative to testosterone replacement therapy in a substantial subset of patients with LOH. Additional long-term controlled studies should further establish the role of clomiphene in LOH. ABBREVIATIONS: FSH = follicle-stimulating hormone LH = luteinizing hormone LOH = late-onset hypogonadotropic hypogonadism.

BONE TURNOVER IN OSTEOPOROTIC WOMEN DURING LONG-TERM ORAL BISPHOSPHONATES TREATMENT: IMPLICATIONS FOR TREATMENT FAILURE AND "DRUG HOLIDAY" IN THE REAL WORLD.

OBJECTIVE: Little data exist to support concerns over bone turnover suppression during prolonged oral bisphosphonate treatment and on consequences of the recommended "drug holiday." This study was performed to assess bone resorption rates in postmenopausal osteoporotic women on prolonged oral bisphosphonate treatment and in response to switching to "drug holiday" intravenous bisphosphonate, or continuation of oral bisphosphonates. METHODS: The frequency distribution of the bone resorption marker urinary deoxypyridinoline crosslinks (uDPD), was obtained retrospectively from 211 osteoporotic women attended at an academic hospital endocrine clinic, treated for >2 years with oral bisphosphonates. In some patients, uDPD was re-assessed following modification or continuation of treatment. RESULTS: The mean duration of oral bisphosphonates treatment was 7.2 ± 3.1 years. uDPD was within reference range for premenopausal women in 61.6% of the patients, below in 7.6% of the patients, and above upper limit in 30.8%. uDPD decreased significantly following intravenous zoledronic acid, increased significantly during "drug holiday," and slightly decreased in those continued on oral bisphosphonate treatment. CONCLUSION: In this real-world study, the majority of women on prolonged oral bisphosphonates maintained bone resorption rates within the normal reference range for premenopausal women. The likelihood for inadequate suppression was considerably greater than that of over-suppression. Implementing a "drug holiday" resulted in a marked increase in bone resorption rates. Additional studies should explore the potential role of bone turnover markers in the evaluation of patients on prolonged oral bisphosphonates and during "drug holiday" in different settings and using additional markers. ABBREVIATIONS: BMD = bone mineral density; IQR = interquartile range; uDPD = urinary deoxypyridinoline crosslinks.

Capillary-leak syndrome: an unrecognized early immune adverse effect of checkpoint-inhibitors treatment.

Capillary-leak syndrome is strongly associated with cytokine activity states. It is an ill-recognized adverse effect of checkpoint inhibitors treatment, which are typically associated with cellular immune response. We describe two patients with capillary leak syndrome following immune checkpoint inhibitors treatment. We present linking mechanisms between checkpoint inhibitors, cellular immunity, cytokine action and endothelial damage. We suggest that capillary-leak syndrome is a unique adverse effect of immunotherapy, resulting from complex interactions between cellular and cytokine activation and that its expression is probably depending on inherent host immune variabilities.

Lay abstract Modern cancer treatment increasingly relies on means that encourage the patient's immune system to attack and destroy existing cancer cells. These means are very effective compared with standard treatments. However, the activation of the immune system is sometimes associated with untoward effects as a result of an attack of bystanding healthy tissues by the overactivated immune system and excessive inflammatory processes that accompany the immune response. We describe here two patients treated with immune checkpoint inhibiting drugs that developed transient extensive edema attributed to leakage of serum proteins and water from small blood vessels into the surrounding tissues (so-called 'capillary-leak syndrome'), after the drug-induced activation of the immune system. In both patients, the edema subsided following specific interventions.

Skin exposure to UVB light induces a skin-brain-gonad axis and sexual behavior.

Ultraviolet (UV) light affects endocrinological and behavioral aspects of sexuality via an unknown mechanism. Here we discover that ultraviolet B (UVB) exposure enhances the levels of sex-steroid hormones and sexual behavior, which are mediated by the skin. In female mice, UVB exposure increases hypothalamus-pituitary-gonadal axis hormone levels, resulting in larger ovaries; extends estrus days; and increases anti-Mullerian hormone (AMH) expression. UVB exposure also enhances the sexual responsiveness and attractiveness of females and male-female interactions. Conditional knockout of p53 specifically in skin keratinocytes abolishes the effects of UVB. Thus, UVB triggers a skin-brain-gonadal axis through skin p53 activation. In humans, solar exposure enhances romantic passion in both genders and aggressiveness in men, as seen in analysis of individual questionaries, and positively correlates with testosterone level. Our findings suggest opportunities for treatment of sex-steroid-related dysfunctions.

Long-term control of Paget's disease of bone with low-dose, once-weekly, oral bisphosphonate preparations, in a "real world" setting.

PURPOSE: Bisphosphonates are the mainstay of the treatment of Paget's disease of bone (PDB). Clinical practice guidelines recommend treatment with intravenous zoledronic acid or high-dose oral nitrogen bisphosphonates (N-BPs). We present our long-term experience treating PDB patients with lower than recommended oral doses of N-BPs, equivalent to once-weekly doses used for treating osteoporosis. METHODS: PDB patients were seen, between 1990 and 2015 at the endocrine clinic of an academic medical center. Diagnosis was established according to accepted criteria. Patients were initially treated with alendronate 70 mg/week or risedronate 35 mg/week. Whenever the initial dose failed to produce remission, the dosage was increased to twice a week the respective dose. RESULTS: Patients were followed for a mean of 11.9 years (range: 1.7-24.8). Out of 96 treatment courses with N-BPs, 89% were with alendronate and 11% with risedronate. Remission was achieved in 84% of the courses with alendronate 70 mg/week. 90% of those who did not achieve remission subsequently responded to 140 mg/week. Out of the 8 treatment courses with risedronate 35 mg/week, 87% achieved remission, and the 2 patients who did not achieve remission subsequently responded to 70 mg/week. The median duration of remissions following 3-4 months courses of alendronate 70 mg/week or risedronate 35 mg/week was 8.8 months (IQR: 5.5, 14.8). CONCLUSION: In a large proportion of "real world" PDB patients, remission can be achieved with once-weekly, "osteoporosis doses" of alendronate or risedronate.

A quantitative assessment of a methodology for collaborative specification and evaluation of clinical guidelines.

We introduce a three-phase, nine-step methodology for specification of clinical guidelines (GLs) by expert physicians, clinical editors, and knowledge engineers and for quantitative evaluation of the specification's quality. We applied this methodology to a particular framework for incremental GL structuring (mark-up) and to GLs in three clinical domains. A gold-standard mark-up was created, including 196 plans and subplans, and 326 instances of ontological knowledge roles (KRs). A completeness measure of the acquired knowledge revealed that 97% of the plans and 91% of the KR instances of the GLs were recreated by the clinical editors. A correctness measure often revealed high variability within clinical editor pairs structuring each GL, but for all GLs and clinical editors the specification quality was significantly higher than random (p<0.01). Procedural KRs were more difficult to mark-up than declarative KRs. We conclude that given an ontology-specific consensus, clinical editors with mark-up training can structure GL knowledge with high completeness, whereas the main demand for correct structuring is training in the ontology's semantics.

[Summary of the Israeli Endocrine Society's consensus statement on the diagnosis, treatment and follow-up of well-differentiated thyroid cancer].

Well differentiated epithelial cell thyroid cancer is not classified amongst the most aggressive diseases. Notwithstanding, it can potentially both impair quality of life and affect life expectancy. Appropriate treatment has been shown to be crucial in obtaining optimal outcomes on the course of the disease. Successful treatment rests upon strict adherence to confirmed principles of diagnosis, treatment and follow-up. The aim of the position paper is to present the Israeli medical community with a set of commonly accepted principles for the diagnosis, treatment and follow-up of patients with well differentiated epithelial thyroid cancer and in addition to highlight areas of legitimate differences in approach where those differences occur. We have attempted to provide a link between the various medical disciplines involved in care of these patients: family physicians, surgeons, nuclear medicine specialists, oncologists, pathologists, radiologists and endocrinologists; and have attempted to decrease to a minimum areas of uncertainty and to offer a common approach for the best possible care of thyroid cancer patients in Israel. In addition, we find it our duty to point out those areas and resources which, in our opinion, need to be upgraded in Israel and even included in the Israeli official "health basket".

Runtime application of Hybrid-Asbru clinical guidelines.

Clinical guidelines are a major tool in improving the quality of medical care. However, to support the automation of guideline-based care, several requirements must be filled, such as specification of the guidelines in a machine-interpretable format and a connection to an Electronic Patient Record (EPR). For several different reasons, it is beneficial to convert free-text guidelines gradually, through several intermediate representations, to a machine-interpretable format. It is also realistic to consider the case when an EPR is unavailable. We propose an innovative approach to the runtime application of intermediate-represented Hybrid-Asbru guidelines, with or without an available EPR. The new approach capitalizes on our extensive work on developing the Digital electronic Guideline Library (DeGeL) framework. The new approach was implemented as the Spock system. For evaluation, three guidelines were specified in an intermediate format and were applied to a set of simulated patient records designed to cover prototypical cases. In all cases, the Spock system produced the expected output, and did not produce an unexpected one. Thus, we have demonstrated the capability of the Spock system to apply guidelines encoded in the Hybrid-Asbru intermediate representation, when an EPR is not available.

Brief report: Use and misuse of thyroid ultrasound in the initial workup of patients with suspected thyroid problems referred by primary care physicians to an endocrine clinic.

BACKGROUND AND OBJECTIVES: Thyroid ultrasound (TUS) plays an important but limited role in the evaluation of some complaints related to the thyroid gland. This study was designed to examine how primary care physicians use TUS before referring patients to an endocrine clinic. DESIGN: We audited all charts of first-time referrals for appropriateness of TUS use. Recommendations in practice guidelines and current textbooks defined appropriate indications for TUS: (1) patients with a thyroid nodule and a history of head or neck irradiation; (2) follow-up of patients with nodules not surgically removed; and (3) evaluation of patients with amiodarone-induced thyrotoxicosis. SETTING: Endocrine referral clinic in a teaching hospital in Israel. RESULTS: Two hundred and eight unselected referrals were reviewed. Sixty-nine (33%) of the patients presented with a TUS. Documented reasons for TUS were suspected thyroid mass (n=35, 51%), thyroid dysfunction (n=21, 30%), neck pain (n=5, 7%), dyspnea (n=4, 6%), and dysphagia (n=2, 3%). Of the 69 TUS reviewed, 64 (93%) were not appropriate. CONCLUSIONS: Primary care clinicians obtain TUS studies in patients without recommended indications prior to referral to an endocrinologist.

Marked secular increase in the incidence rates of osteoporotic hip fractures in women and men in southern Israel.

BACKGROUND: For the last 35 years, our medical center has been the only referral center and provider of emergency medical services for a well-defined geographic area in southern Israel. OBJECTIVES: To evaluate trends in the incidence of hip fractures in this population. METHODS: The study was based on two surveys done approximately 20 years apart. It included women and men 50 years and older with radiographic evidence of a new hip fracture caused by low impact trauma. Only fractures that resulted from low or moderate trauma were considered for the current study. Incidence rates were calculated based on population data obtained from the official Central Bureau of Statistics. RESULTS: There was an overall twofold increase in the incidence rate of hip fractures. However, this increase occurred almost exclusively in the over-75 year old age groups (2.5-fold increase, both in women and men). The mean (and median) age of patients with hip fractures increased significantly over the study period, corresponding to the increase in longevity between the two periods. CONCLUSIONS: There was a marked secular increase in the incidence of proximal hip fractures in both genders, primarily because of an increase in the fracture rate in the very old. The increase in median age of fracture patients suggests that the observed increase in fracture rate can be attributed mainly to aging of the population rather than to deterioration in bone quality over the generations.

[Osteoporosis in men].

While many still consider osteoporosis a gender-specific condition of women, an increasing volume of data is accumulating on the epidemiology, pathophysiology and treatment of osteoporosis in men. The main conclusions arising from the available data indicate that the number of osteoporotic men is increasing, and is expected to continue rising due to the increase in life expectancy for men. Risk factors for osteoporotic fractures are similar in men and women. Despite some gender differences in the pathophysiology of osteoporosis, responses to available osteoporosis treatments seem to be the same. Based on available data, it is recommended to implement preventive measures (calcium and vitamin D supplementation) on aging men, similar to women, and to review the official policy on the management of osteoporosis to also include men at high risk.

[Incidence of osteoporotic fractures in southern Israel].

BACKGROUND: Very little is known about the epidemiology of osteoporotic fractures in Israel. AIM: We aimed to provide an estimate on the incidence of low-impact fractures in southern Israel. METHODS: The study included women and men 50 years and older with radiographic evidence of a new fracture. We screened and reviewed all the emergency room and hospital charts to identify all patients with low impact fractures who attended the Soroka Hospital during the corresponding months of January and February of 1998 through 2001. RESULTS: There were a total of 580 fracture patients (461 women and 119 men). The estimated incidence of all low-impact fractures in the entire population aged 50 and older was 1064:100,000 (95% C.I. 981: 1153) per year. The estimated incidence of low-impact fractures in women was three fold higher than in men [1526:100,000 (95% C.I. 1390: 1675) vs. 490/100,000 (95% C.I. 408: 580) per year, respectively]. Fractures of the distal forearm and proximal hip (26% each) were, by far, the most common in women, followed by fractures of the humerus (18%), ankle (12%) and pelvis (5%). In men, proximal hip fractures (39%) were the most common, followed by fractures of the humerus (18%), distal forearm (15%) and ankle (14%). Multiple concurrent fractures occurred in 2.5% of the patients. CONCLUSIONS: Our data provides a preliminary estimate of the incidence of osteoporotic fractures, not including most vertebral collapse fractures, among women and men in southern Israel. Further studies are warranted to characterize fracture risk in other regions of the country and population sub-groups.