A risk analysis of alpelisib-induced hyperglycemia in patients with advanced solid tumors and breast cancer.

BACKGROUND: Hyperglycemia is an on-target effect of PI3Kα inhibitors. Early identification and intervention of treatment-induced hyperglycemia is important for improving management of patients receiving a PI3Kα inhibitor like alpelisib. Here, we characterize incidence of grade 3/4 alpelisib-related hyperglycemia, along with time to event, management, and outcomes using a machine learning model. METHODS: Data for the risk model were pooled from patients receiving alpelisib ± fulvestrant in the open-label, phase 1 X2101 trial and the randomized, double-blind, phase 3 SOLAR-1 trial. The pooled population (n = 505) included patients with advanced solid tumors (X2101, n = 221) or HR+/HER2- advanced breast cancer (SOLAR-1, n = 284). External validation was performed using BYLieve trial patient data (n = 340). Hyperglycemia incidence and management were analyzed for SOLAR-1. RESULTS: A random forest model identified 5 baseline characteristics most associated with risk of developing grade 3/4 hyperglycemia (fasting plasma glucose, body mass index, HbA1c, monocytes, age). This model was used to derive a score to classify patients as high or low risk for developing grade 3/4 hyperglycemia. Applying the model to patients treated with alpelisib and fulvestrant in SOLAR-1 showed higher incidence of hyperglycemia (all grade and grade 3/4), increased use of antihyperglycemic medications, and more discontinuations due to hyperglycemia (16.7% vs. 2.6% of discontinuations) in the high- versus low-risk group. Among patients in SOLAR-1 (alpelisib + fulvestrant arm) with PIK3CA mutations, median progression-free survival was similar between the high- and low-risk groups (11.0 vs. 10.9 months). For external validation, the model was applied to the BYLieve trial, for which successful classification into high- and low-risk groups with shorter time to grade 3/4 hyperglycemia in the high-risk group was observed. CONCLUSIONS: A risk model using 5 clinically relevant baseline characteristics was able to identify patients at higher or lower probability for developing alpelisib-induced hyperglycemia. Early identification of patients who may be at higher risk for hyperglycemia may improve management (including monitoring and early intervention) and potentially lead to improved outcomes. REGISTRATION: ClinicalTrials.gov: NCT01219699 (registration date: October 13, 2010; retrospectively registered), ClinicalTrials.gov: NCT02437318 (registration date: May 7, 2015); ClinicalTrials.gov: NCT03056755 (registration date: February 17, 2017).

Physician knowledge, practice patterns, and barriers encountered regarding guideline-concordant use of bone modifying agents for prostate cancer.

BACKGROUND: Guidelines recommend bone-modifying agents (BMAs) for patients with castrate-resistant prostate cancer (CRPC) and bone metastasis, but not for castrate-sensitive prostate cancer (CSPC). Physicians beliefs and practices regarding BMA therapy are poorly understood. METHODS: This was a qualitative interview study with embedded Likert-scale elements. Study participants were physicians who treat prostate cancer, located within an academic cancer center or an affiliated community-based network. Participants were asked about their experiences and practice patterns regarding BMA therapy. Participants used Likert-scale items to identify the most common barriers to guideline-concordant BMA use and the most effective potential interventions. Participants were subsequently asked to rank the three most common barriers and the three most effective interventions to reduce underuse (for CRPC) and overuse (for CSPC). RESULTS: Nineteen physicians were invited and 15 participated; one physician did not answer some questions as outside of their practice scope. All were aware of the recommendation for BMAs in CRPC. 14% (2/14) were unaware of the recommendation against BMA use for CSPC; an additional 29% (4/14) believed that BMA use could be appropriate for CSPC depending on the metastatic disease burden. 36% (5/14) were unaware of recommendations for screening and treatment of low bone mineral density. The most common barriers (occurring "often" or "sometimes") were obtaining dental clearance (11/15) and insufficient clinic time (6/15). The interventions identified as most effective to reduce underuse were dental navigation (11/15) and electronic medical record (EMR)-based guidance (9/15). The interventions identified as most effective to reduce overuse were peer-to-peer education (14/15) and EMR-based guidance (13/15). CONCLUSIONS: Awareness of guideline recommendations for screening and treatment of low bone mineral density and against BMA use for CSPC was good, but not complete. Dental navigation, peer-to-peer education, and EMR-based guidance were preferred intervention strategies to improve guideline-concordant use.

Proceedings of the 2023 Santa Fe Bone Symposium: Progress and Controversies in the Management of Patients with Skeletal Diseases.

The Santa Fe Bone Symposium (SFBS) held its 23rd annual event on August 5-6, 2023, in Santa Fe, New Mexico, USA. Attendees participated in-person and remotely, representing many states and countries. The program included plenary presentations, panel discussions, satellite symposia, a Project ECHO workshop, and a session on healthcare policy and reimbursement for fracture liaison programs. A broad range of topics were addressed, including transitions of osteoporosis treatments over a lifetime; controversies in vitamin D; update on Official Positions of the International Society for Clinical Densitometry; spine surgery and bone health; clinical applications of bone turnover markers; basic bone biology for clinicians; premenopausal-, pregnancy-, and lactation-associated osteoporosis; cancer treatment induced bone loss in patients with breast cancer and prostate cancer; genetic testing for skeletal diseases; and an update on nutrition and bone health. There were also sessions on rare bone diseases, including managing patients with hypophosphatasia; treatment of X-linked hypophosphatemia; and assessment and treatment of patients with hypoparathyroidism. There were oral presentations of abstracts by endocrinology fellows selected from those who participated in the Santa Fe Fellows Workshop on Metabolic Bone Diseases, held the 2 days prior to the SFBS. These proceedings of the 2023 SFBS present the clinical highlights and insights generated from many formal and informal discussions in Santa Fe.

A phase 2 trial of buparlisib in patients with platinum-resistant metastatic urothelial carcinoma.

BACKGROUND: The phosphatidyl 3-inositol kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) pathway frequently is activated in patients with urothelial carcinoma (UC). In the current study, the authors performed a phase 2 study evaluating the efficacy of the pan-isoform class I PI3K inhibitor buparlisib in patients with platinum-refractory metastatic UC. METHODS: Two cohorts were recruited: an initial genetically unselected cohort and a subsequent expansion cohort of patients with PI3K/Akt/mTOR pathway-altered tumors. The primary endpoint was the 2-month progression-free survival rate. A rate of ≥80% was considered promising using a Simon 2-stage minimax design. Secondary endpoints included safety and correlation of markers of PI3K pathway activation with outcome. RESULTS: Six of 13 evaluable patients within the initial cohort demonstrated stable disease and 1 demonstrated a partial response, which was below the cutoff of 9 patients required to proceed to stage 2. Three of the patients with stable disease and the patient with a partial response harbored somatic TSC1 alterations. Four patients subsequently were recruited onto an expansion cohort: 3 patients with TSC1 alterations and 1 patient with a PIK3CA-activating mutation. No patient achieved disease control at 8 weeks and accrual was halted. Of the 19 patients evaluable for toxicity, 17 demonstrated treatment-related toxicities, 2 of whom had to discontinue therapy. CONCLUSIONS: Buparlisib was found to demonstrate modest activity in patients with metastatic UC whose tumors harbored TSC1 loss of function alterations; however, this was not a robust predictor of response to buparlisib. The pattern of genetic coalterations likely influences drug sensitivity. Given the modest clinical activity and substantial toxicity of buparlisib, future trials of PI3K inhibitors in patients with UC should focus on isoform-selective PI3K inhibitors in genomically selected patients. LAY SUMMARY: The phosphatidyl 3-inositol kinase (PI3K)/Akt/mechanistic target of rapamycin (mTOR) signaling pathway frequently is upregulated in patients with metastatic urothelial carcinoma (UC). This trial explored buparlisib, an inhibitor of the pathway, in patients with heavily pretreated metastatic UC. Although the drug was found to have modest efficacy, with 6 patients experiencing stable disease and 1 patient achieving a partial response at 8 weeks on therapy, significant side effects also were observed. Patients with specific genetic alterations responded to treatment. Further studies of PI3K pathway inhibition are warranted using newer agents that have superior toxicity profiles and are more selective inhibitors of the pathway.

Phase Ib clinical trial of the anti-frizzled antibody vantictumab (OMP-18R5) plus paclitaxel in patients with locally advanced or metastatic HER2-negative breast cancer.

PURPOSE: Vantictumab is a monoclonal antibody that binds to frizzled (FZD) receptors and inhibits canonical WNT signaling. This phase Ib dose escalation study enrolled patients with locally recurrent or metastatic HER2-negative breast cancer who were treated with weekly paclitaxel in combination with escalating doses of vantictumab. METHODS: Patients were enrolled in dose escalation cohorts treated with weekly paclitaxel 90 mg/m2 on days 1, 8 and 15 in combination with vantictumab 3.5-14 mg/kg days 1 and 15 or 3-8 mg/kg day 1 of every 28-day cycle. Primary endpoints were safety, dose-limiting toxicities (DLTs). Secondary endpoints included pharmacokinetics, efficacy and an exploratory biomarker analysis. RESULTS: Forty-eight female patients with a mean age of 54 were enrolled. The majority (66.6%) received prior chemotherapy for recurrent or metastatic disease; 45.8% were hormone receptor (HR)-positive, HER2-negative and 54.2% triple-negative. The most frequent adverse events related to any study treatment were nausea (54.2%), alopecia (52.1%), fatigue (47.9%), and peripheral neuropathy (43.8%). No DLTs occurred; however, 6 patients experienced fractures outside of the DLT window. The overall response rate was 31.3% and the clinical benefit rate was 68.8%. A 6-gene WNT pathway signature showed significant association with progression-free survival (PFS) and overall survival (OS) for the biomarker high versus biomarker low groups (PFS: p = 0.029 and OS: p = 0.00045, respectively). CONCLUSIONS: The combination of vantictumab and weekly paclitaxel was generally well tolerated with promising efficacy; however, the incidence of fractures limits future clinical development of this particular WNT inhibitor in metastatic breast cancer. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov registration: NCT01973309.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS/AMERICAN COLLEGE OF ENDOCRINOLOGY CLINICAL PRACTICE GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS-2020 UPDATE.

Objective: The development of these guidelines is sponsored by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPGs). Methods: Recommendations are based on diligent reviews of the clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols. Results: The Executive Summary of this 2020 updated guideline contains 52 recommendations: 21 Grade A (40%), 24 Grade B (46%), 7 Grade C (14%), and no Grade D (0%). These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world care of patients. The evidence base presented in the subsequent Appendix provides relevant supporting information for the Executive Summary recommendations. This update contains 368 citations: 123 (33.5%) evidence level (EL) 1 (highest), 132 (36%) EL 2 (intermediate), 20 (5.5%) EL 3 (weak), and 93 (25%) EL 4 (lowest). New or updated topics in this CPG include: clarification of the diagnosis of osteoporosis, stratification of the patient according to high-risk and very-high-risk features, a new dual-action therapy option, and transitions from therapeutic options. Conclusion: This guideline is a practical tool for endocrinologists, physicians in general, regulatory bodies, health-related organizations, and interested laypersons regarding the diagnosis, evaluation, and treatment of post-menopausal osteoporosis. Abbreviations: 25(OH)D = 25-hydroxyvitamin D; AACE = American Association of Clinical Endocrinologists; ACE = American College of Endocrinology; AFF = atypical femoral fracture; ASBMR = American Society for Bone and Mineral Research; BEL = best evidence level; BMD = bone mineral density; BTM = bone turnover marker; CI = confidence interval; CPG = clinical practice guideline; CTX = C-terminal telopeptide type-I collagen; DXA = dual-energy X-ray absorptiometry; EL = evidence level; FDA = U.S. Food and Drug Administration; FRAX® = Fracture Risk Assessment Tool; GI = gastrointestinal; HORIZON = Health Outcomes and Reduced Incidence with Zoledronic acid ONce yearly Pivotal Fracture Trial (zoledronic acid and zoledronate are equivalent terms); ISCD = International Society for Clinical Densitometry; IU = international units; IV = intravenous; LSC = least significant change; NOF = National Osteoporosis Foundation; ONJ = osteonecrosis of the jaw; PINP = serum amino-terminal propeptide of type-I collagen; PTH = parathyroid hormone; R = recommendation; ROI = region of interest; RR = relative risk; SD = standard deviation; TBS = trabecular bone score; VFA = vertebral fracture assessment; WHO = World Health Organization.

AMERICAN ASSOCIATION OF CLINICAL ENDOCRINOLOGISTS/AMERICAN COLLEGE OF ENDOCRINOLOGY CLINICAL PRACTICE GUIDELINES FOR THE DIAGNOSIS AND TREATMENT OF POSTMENOPAUSAL OSTEOPOROSIS- 2020 UPDATE EXECUTIVE SUMMARY.

Objective: The development of these guidelines is sponsored by the American Association of Clinical Endocrinologists (AACE) Board of Directors and American College of Endocrinology (ACE) Board of Trustees and adheres with published AACE protocols for the standardized production of clinical practice guidelines (CPGs). Methods: Recommendations are based on diligent reviews of the clinical evidence with transparent incorporation of subjective factors, according to established AACE/ACE guidelines for guidelines protocols. Results: The Executive Summary of this 2020 updated guideline contains 52 recommendations: 21 Grade A (40%), 24 Grade B (46%), 7 Grade C (14%), and no Grade D (0%). These detailed, evidence-based recommendations allow for nuance-based clinical decision-making that addresses multiple aspects of real-world care of patients. The evidence base presented in the subsequent Appendix provides relevant supporting information for the Executive Summary recommendations. This update contains 368 citations: 123 (33.5%) evidence level (EL) 1 (highest), 132 (36%) EL 2 (intermediate), 20 (5.5%) EL 3 (weak), and 93 (25%) EL 4 (lowest). New or updated topics in this CPG include: clarification of the diagnosis of osteoporosis, stratification of the patient according to high-risk and very-high-risk features, a new dual-action therapy option, and transitions from therapeutic options. Conclusion: This guideline is a practical tool for endocrinologists, physicians in general, regulatory bodies, health-related organizations, and interested laypersons regarding the diagnosis, evaluation, and treatment of post-menopausal osteoporosis.

A phase 1b dose escalation study of ipafricept (OMP54F28) in combination with paclitaxel and carboplatin in patients with recurrent platinum-sensitive ovarian cancer.

OBJECTIVES: The WNT pathway is an important oncologic driver of epithelial ovarian cancer (EOC). The first-in-class recombinant fusion protein ipafricept (IPA) blocks Wnt signaling through binding of Wnt ligands. This phase Ib trial was designed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RPh2) for IPA in combination with taxane and platinum therapy (C/P). METHODS: Dose escalation started with a standard 3 + 3 design for IPA/C/P with q3w intravenous IPA on Day 1, in cycles 1 to 6 with C (AUC = 5 mg/ml·min) and P (175 mg/m2). For enhanced bone safety the trial was revised to 6-patient cohorts with a q3w regimen of IPA on Day 1 and C/P on Day 3 (IPA → C/P). RESULTS: 37 patients have been treated; 30 of whom were treated following protocol revision to q3w IPA(D1) → C/P(D3) (2 & 4 mg/kg). IPA-related TEAEs that occurred in ≥15% included: fatigue (40%); nausea (35%); diarrhea and decreased appetite (22%) each; dysgeusia (19%); and vomiting (16.2%). 22% reported ≥1 IPA related TEAE Grade ≥3 the most common of which was neutropenia at 16%. There were no DLTs; the MTD was not reached. The maximum administered dose based on bone safety was 6 mg/kg. The overall response rate (ORR) was 75.7%. Median PFS was 10.3 months (95% CI 8.5-14.2) and OS 33 months (95% CI 23.4-NR). CONCLUSIONS: IPA is well tolerated in combination with sequential C/P. ORR, PFS and OS are comparable to historical data but bone toxicity at efficacy doses of this particular Wnt inhibitor limit further development in EOC.

Antiresorptive agents' bone-protective and adjuvant effects in postmenopausal women with early breast cancer.

Potent antiresorptive drugs (bisphosphonate and denosumab) are often used to protect bone health in postmenopausal breast cancer patients. In addition, clinical trials have shown that these drugs increase disease-free survival, though the mechanism of adjuvant benefit is largely unknown. Here we review the bone health and adjuvant data for both classes of antiresorptive drugs and highlight differences in their pharmacology. Inhibition of bone resorption is vitally important to protect against osteoporotic fractures, and may also contribute to adjuvant survival benefits by making the bone microenvironment less amenable to breast cancer metastasis. After a course of therapy, stoppage of bisphosphonates yields a persistent antiresorptive effect, whereas discontinuation of denosumab causes a rebound increase in bone resorption markers and a loss of bone mineral density to baseline levels. Whether the potential adjuvant benefits of denosumab are also rapidly lost after drug discontinuation deserves further investigation.

Cardiovascular Outcome Trials in Type 2 Diabetes: What Do They Mean for Clinical Practice?

IN BRIEF Cardiovascular disease is the leading cause of morbidity and mortality in people with diabetes, and deaths from heart disease are two to four times higher among adults with type 2 diabetes. Trials such as the U.K. Prospective Diabetes Study, ACCORD (Action to Control Cardiovascular Risk in Diabetes), ADVANCE (Action in Diabetes and Vascular Disease: Preterax and Diamicron MR Controlled Evaluation), and VADT (Veteran's Affairs Diabetes Trial) produced mixed findings regarding whether intensive glycemic control results in improved cardiovascular (CV) outcomes for patients with diabetes. In response to concerns, including the CV safety of the thiazolidinedione rosiglitazone, the U.S. Food and Drug Administration and subsequently the European Medicines Agency issued guidance that trials should be conducted to prove that antihyperglycemic agents have acceptable CV risk profiles. In this article, the authors review the study designs and results of CV outcomes trials conducted with sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide 1 receptor agonists and discuss how these may affect clinical practice.

Retrospective Review of Atypical Femoral Fracture in Metastatic Bone Disease Patients Receiving Denosumab Therapy.

BACKGROUND: Denosumab therapy is used to reduce skeletal-related events in metastatic bone disease (MBD). There have been reports of atypical femoral fracture (AFF) in osteoporotic patients treated with denosumab but none in the context of higher dose and more frequent denosumab therapy for MBD. The goal of this study was to assess the incidence of AFF in MBD. PATIENTS AND METHODS: We conducted a retrospective review of 253 patients who received a minimum of 12 doses of denosumab at 120 mg each for MBD. To identify patients with asymptomatic atypical stress reactions in the lateral subtrochanteric femur (which precede fractures), we reviewed the skeletal images of 66 patients who had received at least 21 doses of denosumab for AFF features. RESULTS: These patients received a median of 17 doses, with a median treatment duration of 23 months. There was 1 case of undiagnosed clinical AFF detected after chart review and 2 cases of subclinical atypical femoral stress reaction observed on imaging review after 23 doses of denosumab over 33 months, 28 doses over 27 months, and 21 doses over 21 months, respectively. Scout computed tomography films showed diffuse cortical thickening of diaphysis with localized periosteal reaction of lateral femoral cortex. Bone scan and magnetic resonance imaging scan of 2 patients with stress reactions confirmed the diagnosis. CONCLUSION: The incidence of clinical AFF in this context is 0.4% (1/253; 95% confidence interval [CI] 0.1%-2.2%), and the incidence of atypical femoral stress reaction based on imaging review is 4.5% (3/66; 95% CI 1.6%-12.5%). Clinicians should be aware of the clinical prodrome (which may or may not be present) and antecedent imaging changes associated with AFF. The Oncologist 2017;22:438-444Implications for Practice: Among patients with metastatic bone disease treated with denosumab, cases of clinical and subclinical atypical femoral fracture (AFF) are rare. The one detected case of clinical fracture went unrecognized despite prodromic symptoms. Clinicians should be aware of (a) the potential prodrome of anterior thigh/groin pain and (b) subclinical imaging changes in the lateral femur, both of which may precede clinical AFF.

NCCN bone health task force: key recommendations.

For patients with advanced cancers involving bone, the standard of care for maintaining bone health is the use of antiresorptive therapies such as bisphosphonates, selective estrogen-receptor modulators, and denosumab. However, although long-term adverse events are rare and the risk-benefit ratio of these agents is usually markedly in favor of treatment, clinicians should be aware that they can occur. At the NCCN 19th Annual Conference, Dr. Azeez Farooki presented the key findings of the NCCN Bone Health Task Force, focusing on such topics as screening for osteoporosis; the controversial use of drug holidays from chronic bisphosphonate therapy; the provocative yet unclear story surrounding the potential anticancer benefits of antiresorptive agents; imaging for metastatic bone disease; and safety considerations linked to calcium supplements, vitamin D, and bone-strengthening agents.

Costs to Medicare of Nonrecommended Bone-Modifying Agent Use for Castration-Sensitive Prostate Cancer.

PURPOSE: Bone-modifying agents (BMAs) do not prevent skeletal-related events among patients with castration-sensitive prostate cancer (CSPC), but many patients receive BMAs unnecessarily. The costs to Medicare from overuse have not been assessed. METHODS: We used linked SEER-Medicare data 2011-2015 to measure the frequency and number of doses of zoledronic acid (ZA) and denosumab received during CSPC (between diagnosis and initiation of metastatic, castration resistant prostate cancer therapy). We estimated excess BMA among patients who received BMA therapy for CSPC and did not have an indication for osteoporosis fracture prevention. We used the Medicare fee schedule for drug prices and peer-reviewed sources to estimate adverse event frequencies and costs. RESULTS: Median CSPC duration was 387 days (IQR, 253-573), during which time 42% of patients received ≥one dose of denosumab (mean doses, 7) and 18% received ≥one dose of ZA (mean doses, 7). Thirty-eight percent of those receiving denosumab and 47% of those receiving ZA had a history of osteoporosis, osteopenia, spine or hip fracture, or hypercalcemia. The estimated, annual excess BMA cost to Medicare was $44,105,041 in US dollars (USD), composed of $43,303,078 USD and $45,512 USD in drug costs for denosumab and ZA, respectively, and $682,865 USD and $75,585 USD in adverse event costs, respectively. In one-way sensitivity analysis, the estimate was most sensitive to denosumab dosing frequency (estimate range, $28,469,237 USD-$98,830,351 USD) and duration of CSPC (estimate range, $36,823,311 USD-$99,015,908 USD). CONCLUSION: BMA overuse in CSPC incurs substantial cost to Medicare, largely because of denosumab drug costs. Excess costs may be reduced by greater adherence to guideline-concordant BMA use.

Managing hyperglycemia and rash associated with alpelisib: expert consensus recommendations using the Delphi technique.

Hyperglycemia and rash are expected but challenging adverse events of phosphatidylinositol-3-kinase inhibition (such as with alpelisib). Two modified Delphi panels were conducted to provide consensus recommendations for managing hyperglycemia and rash in patients taking alpelisib. Experts rated the appropriateness of interventions on a 1-to-9 scale; median scores and dispersion were used to classify the levels of agreement. Per the hyperglycemia panel, it is appropriate to start alpelisib in patients with HbA1c 6.5% (diabetes) to <8%, or at highest risk for developing hyperglycemia, if they have a pre-treatment endocrinology consult. Recommend prophylactic metformin in patients with baseline HbA1c 5.7% to 6.4%. Metformin is the preferred first-line anti-hyperglycemic agent. Per the rash panel, initiate prophylactic nonsedating H1 antihistamines in patients starting alpelisib. Nonsedating H1 antihistamines and topical steroids are the preferred initial management for rash. In addition to clinical trial evidence, these recommendations will help address gaps encountered in clinical practice.

NCCN Task Force Report: Bone Health In Cancer Care.

Bone health and maintenance of bone integrity are important components of comprehensive cancer care. Many patients with cancer are at risk for therapy-induced bone loss, with resultant osteoporotic fractures, or skeletal metastases, which may result in pathologic fractures, hypercalcemia, bone pain, and decline in motility and performance status. Effective screening and timely interventions are essential for reducing bone-related morbidity. Management of long-term bone health requires a broad knowledge base. A multidisciplinary health care team may be needed for optimal assessment and treatment of bone-related issues in patients with cancer. Since publication of the previous NCCN Task Force Report: Bone Health in Cancer Care in 2009, new data have emerged on bone health and treatment, prompting NCCN to convene this multidisciplinary task force to discuss the progress made in optimizing bone health in patients with cancer. In December 2012, the panel members provided didactic presentations on various topics, integrating expert judgment with a review of the key literature. This report summarizes issues surrounding bone health in cancer care presented and discussed during this NCCN Bone Health in Cancer Care Task Force meeting.

Refractory hypercalcemia of malignancy: a problem with many potential roots.

Hypercalcemia of malignancy (HCM) is a common clinical problem that is associated with considerable morbidity and negative effects on quality of life. Despite the availability of effective medical treatments for HCM, options are needed for cases that are refractory to conventional therapies. In this context, "refractory" refers to reasonable control of calcium in the setting of inpatient hospitalization (after receipt of standard of care therapies, such as continuous intravenous fluids, calcitonin, and intravenous bisphosphonates) with relapse into severe hypercalcemia within days or weeks of discharge from the hospital. Here we discuss drivers of hypercalcemia of malignancy and the physiologic mechanisms whereby they operate to increase serum calcium. Additionally, we discuss multiple available treatments targeted to a given contributory mechanism and also briefly discuss potential future treatments in need of further study.

Real-world use of bone modifying agents in metastatic, castration-resistant prostate cancer.

BACKGROUND: Bone modifying agents (BMAs) prevent skeletal related events among patients with metastatic, castration-resistant prostate cancer (mCRPC) involving bone and prevent osteoporotic fractures among patients at high risk. BMA utilization for patients with mCRPC has not been well quantified. METHODS: We used linked SEER registry and Medicare claims data. We included men diagnosed with stage IV prostate adenocarcinoma during 2007-2015, aged > = 66 at diagnosis, with sufficient continuous enrollment in Medicare Parts A, B, and D, who received androgen deprivation therapy. We limited to those who subsequently received a CRPC-defining treatment (CDT). We identified patients with evidence of bone metastasis using claims. Our primary outcome was receipt of a BMA (zoledronic acid or denosumab) within 180 days of initiating CDT. RESULTS: Among 1292 included patients, 1034 (80%) had bone metastasis. BMA use within 180 days of initiating CDT was higher among patients with bone metastases than those without (705/1034 [68%] vs 56/258 [22%]). Among patients without bone metastasis, those with high osteoporotic fracture risk were more likely than those without to receive a BMA (OR = 2.48, 95% CI: 1.17, 5.29); however, only 26% of patients with high fracture risk received a BMA. Among patients who received BMAs, most (62%) first initiated them >90 days before initiating CDT. CONCLUSIONS: Two-thirds of patients with mCRPC and bone metastases received BMAs within 180 days after initiating CDT. A greater proportion of patients without bone metastasis may warrant BMA therapy for osteoporotic fracture prevention. Some patients with bone metastasis may be able to delay BMA initiation until CRPC.

Serum N-telopeptide and bone-specific alkaline phosphatase levels in patients with osteonecrosis of the jaw receiving bisphosphonates for bone metastases.

PURPOSE: Oversuppression of bone turnover can be a critical factor in the pathogenesis of osteonecrosis of the jaw (ONJ). We investigated N-telopeptide of type I collagen (NTX) and bone-specific alkaline phosphatase (BAP) as potential predictors of ONJ onset. PATIENTS AND METHODS: Patients with ONJ and available stored serum were identified retrospectively from the institutional databases. Four approximate points were examined: point of ONJ diagnosis and 12, 6, and 1 month before the diagnosis. NTX and BAP were measured using enzyme-linked immunosorbent assays and examined as possible predictors of ONJ. RESULTS: From March 1998 to September 2009, we identified 122 patients with ONJ. Of these, 56 (46%) had one or more serum samples available. Overall, 55 patients (98%) received bisphosphonates. Using the exact dates, no obvious patterns in either NTX or BAP were noted. Similarly, using the ordinal points, no evidence of suppression of NTX or BAP over time was seen. The consecutive median values were as follows: The median NTX values were 8.0 nmol/L (range 3.8 to 32.9) at 12 months before ONJ; 9.5 nmol/L (range 4.7 to 42.7) at 6 months; 9.5 nmol/L (range 4.5 to 24.6) at 1 month, and 10.4 nmol/L (range 4.4 to 32.5) at the ONJ diagnosis. The median BAP values were BAP 18.0 U/L (range 7.0 to 74) at 12 months before ONJ; 18.0 U/L (range 4.0 to 134) at 6 months; 14.0 U/L (range 4.0 to 132) at 1 month, and 18.0 U/L (range 0.7 to 375) at the ONJ diagnosis. Only 2 patients (4%) had NTX and 17 (30%) had BAP below the normal range at the ONJ diagnosis. CONCLUSIONS: In the present large retrospective study, no trends were seen in the NTX and BAP levels before the ONJ diagnosis.

Management of Phosphatidylinositol-3-Kinase Inhibitor-Associated Hyperglycemia.

Phosphatidylinositol-3-kinase (PI3K) pathway hyperactivation has been associated with the development of cancer and treatment resistance. PI3K inhibitors are now used to treat hormone receptor-positive (HR+), human epidermal growth factor receptor-2-negative (HER2-), PIK3CA-mutated advanced breast cancer. Hyperglycemia, a frequently observed adverse event with PI3K inhibitors (PI3Ki), is regarded as an on-target effect because inhibition of the PI3K pathway has been shown to decrease glucose transport and increase glycogenolysis and gluconeogenesis. PI3Ki-induced hyperglycemia results in a compensatory increase in insulin release, which has been shown to reduce the efficacy of treatment by reactivating the PI3K pathway in preclinical models. Patients with an absolute or relative deficiency in insulin, and those with insulin resistance or pancreatic dysfunction, may experience exacerbated or prolonged hyperglycemia. Therefore, the effective management of PI3Ki-associated hyperglycemia depends on early identification of patients at risk, frequent monitoring to allow prompt recognition of hyperglycemia and its sequelae, and initiating appropriate management strategies. Risk factors for the development of hyperglycemia include older age (≥75 years), overweight/obese at baseline, and family history of diabetes. Consultation with an endocrinologist is recommended for patients considered high risk. The management of PI3Ki-induced hyperglycemia requires an integrative approach that combines diets low in carbohydrates and glucose-lowering medications. Medications that do not affect the PI3K pathway are preferred as the primary and secondary agents for the management of hyperglycemia. These include metformin, sodium-glucose co-transporter 2 inhibitors, thiazolidinediones, and α-glucosidase inhibitors. Insulin should only be considered as a last-line agent for PI3Ki-associated hyperglycemia due to its stimulatory effect of PI3K signaling. Clinical studies show that alpelisib-associated hyperglycemia is reversible and manageable, rarely leading to treatment discontinuation. Management of PI3Ki-associated hyperglycemia in patients with breast cancer should focus on the prevention of acute and subacute complications of hyperglycemia, allowing patients to remain on anticancer treatment longer.