Publications by authors named "Azeez Farooki"

42 Publications

Bone Mineral Density: Clinical Relevance and Quantitative Assessment.

J Nucl Med 2021 Apr 11;62(4):446-454. Epub 2020 Dec 11.

Endocrinology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York

Bone mineral density (BMD) measurement by dual-energy x-ray absorptiometry (DXA) is an internationally accepted standard-of-care screening tool used to assess fragility-fracture risk. Society guidelines have recommended which populations may benefit from DXA screening and the use of the fracture risk assessment tool (FRAX) to guide decisions regarding pharmacologic treatment for osteoporosis. According to the U.S. National Osteoporosis Foundation guidelines, postmenopausal women and men at least 50 y old with osteopenic BMD warrant pharmacologic treatment if they have a FRAX-calculated 10-y probability of at least 3% for hip fracture or at least 20% for major osteoporotic fracture. Patients with osteoporosis defined by a clinical event, namely a fragility fracture, or with an osteoporotic BMD should also be treated. Patients who are treated for osteoporosis should be monitored regularly to track expected gains in BMD by serial DXA scans. With some drug therapies, BMD targets can be reached whereby further improvements in BMD are not associated with further reductions in fracture risk. Although reaching this target might suggest a stopping point for therapy, the reversibility of most treatments for osteoporosis, except for the bisphosphonates, has dampened enthusiasm for this approach. In the case of denosumab, it is now apparent that stopping therapy at any point can lead to an increase in multiple-fracture risk. For patients who do not respond to antiosteoporosis pharmacologic therapy with an improvement in BMD, or who have an incident fragility fracture on therapy, secondary causes of osteoporosis or non-compliance with medical therapy should be considered.
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http://dx.doi.org/10.2967/jnumed.120.256180DOI Listing
April 2021

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.

Breast Cancer Res Treat 2020 Nov 14;184(1):53-62. Epub 2020 Aug 14.

Samuel Oschin Comprehensive Cancer Institute, 8700 Beverly Blvd, SCCT Mezzanine MS 35, Los Angeles, CA, 90048, USA.

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/m 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.
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http://dx.doi.org/10.1007/s10549-020-05817-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7572714PMC
November 2020

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

Cancer 2020 Oct 7;126(20):4532-4544. Epub 2020 Aug 7.

Genitourinary Oncology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

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.
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http://dx.doi.org/10.1002/cncr.33071DOI Listing
October 2020

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

Endocr Pract 2020 May;26(5):564-570

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). 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. 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. 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.
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http://dx.doi.org/10.4158/GL-2020-0524DOI Listing
May 2020

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

Endocr Pract 2020 May;26(Suppl 1):1-46

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). 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. 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. 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. = 25-hydroxyvitamin D; = American Association of Clinical Endocrinologists; = American College of Endocrinology; = atypical femoral fracture; = American Society for Bone and Mineral Research; = best evidence level; = bone mineral density; = bone turnover marker; = confidence interval; = clinical practice guideline; = C-terminal telopeptide type-I collagen; = dual-energy X-ray absorptiometry; = evidence level; = U.S. Food and Drug Administration; = Fracture Risk Assessment Tool; = gastrointestinal; = Health Outcomes and Reduced Incidence with Zoledronic acid ONce yearly Pivotal Fracture Trial (zoledronic acid and zoledronate are equivalent terms); = International Society for Clinical Densitometry; = international units; = intravenous; = least significant change; = National Osteoporosis Foundation; = osteonecrosis of the jaw; = serum amino-terminal propeptide of type-I collagen; = parathyroid hormone; = recommendation; = region of interest; = relative risk; = standard deviation; = trabecular bone score; = vertebral fracture assessment; = World Health Organization.
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http://dx.doi.org/10.4158/GL-2020-0524SUPPLDOI Listing
May 2020

Calcitriol Elevation Is Associated with a Higher Risk of Refractory Hypercalcemia of Malignancy in Solid Tumors.

J Clin Endocrinol Metab 2020 04;105(4)

Endocrinology Service, D epartment of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.

Background: Hypercalcemia of malignancy (HCM) is a common complication of advanced cancer. PTH-independent HCM may be mediated through different mechanisms: (1) humoral HCM, caused by the secretion of PTH-related peptide (PTHrP), (2) local osteolysis resulting from metastatic lesions, and (3) calcitriol-mediated hypercalcemia. Calcitriol-mediated HCM in patients with nonlymphomatous solid tumors is thought to be rare.

Methods: We performed a retrospective chart review from 2008 to 2017 to characterize further patients at our institution with solid tumors who had HCM with concomitant elevations in calcitriol. Patients with PTH-dependent hypercalcemia and patients with evidence of granulomatous disease were excluded, as were patients with hematologic malignancies. We hypothesized that patients with HCM and elevated calcitriol levels would respond less favorably to treatment with antiresorptive therapy compared with patients with HCM but without calcitriol elevation. We also aimed to assess mortality and determine if PTHrP and phosphorus levels correlate with calcitriol because both factors may alter calcitriol levels.

Results: Of 101 eligible patients, calcitriol was elevated in 45 (45%). PTHrP was elevated in 76% of patients with elevated calcitriol compared with 52% of patients without calcitriol elevation. The mean PTHrP value did not differ between patients with HCM and elevated calcitriol (36.3 ± 22 pg/mL) and those without calcitriol elevation (37.4 ± 19 pg/mL). Those with elevated calcitriol levels generally did not respond completely to antiresorptive treatment (80% incomplete response rate), whereas most patients without an elevation in calcitriol responded well to antiresorptive treatment (78% response rate: P < .001). There was no significant difference in the percentage of patients with metastatic bone disease among the 2 groups (49% vs. 55%, respectively). There was no difference in mortality between the 2 groups (P = .14). A weak but significant negative correlation was found between phosphorus and calcitriol (Pearson r = -0.261, P = .016). This correlation was only significant in patients without calcitriol elevation (Pearson r = -0.4, P = .0082). Also, a significant negative correlation was found between PTHrP and phosphorus, again only in patients without calcitriol elevation.

Discussion: In the setting of HCM, patients with calcitriol elevation are much less likely to respond to antiresorptive therapy than patients without calcitriol elevation. Because calcitriol elevation did not appear to be correlated with hypophosphatemia or elevated PTHrP, it would appear that calcitriol production under these conditions is autonomous, and not subject to normal physiological controls. These observations indicate that calcitriol elevations in patients with HCM have clinical significance.
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http://dx.doi.org/10.1210/clinem/dgz278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067545PMC
April 2020

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

Clin Diabetes 2019 Oct;37(4):316-337

Li Shing Knowledge Institute, St. Michael's Hospital, University of Toronto, Toronto, Ontario, Canada.

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.
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http://dx.doi.org/10.2337/cd19-0001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6794224PMC
October 2019

Impact of a Replacement Algorithm for Vitamin D Deficiency in Adult Hematopoietic Stem Cell Transplant Patients.

J Adv Pract Oncol 2019 Mar 1;10(2):109-118. Epub 2019 Mar 1.

Memorial Sloan Kettering Cancer Center, New York, New York.

Adults undergoing hematopoietic stem cell transplant (HSCT) are at risk for vitamin D deficiency. After HSCT, exposure to sunlight is restricted, and patients may experience poor nutrition and malabsorption from HSCT-related side effects. Vitamin D affects bone health and immunologic processes. The aim of this project is to establish a process for monitoring and treating vitamin D deficiency and to evaluate if therapeutic vitamin D levels are attainable posttransplant using an HSCT vitamin D replacement algorithm. A multidisciplinary group led by advanced practice providers established a workflow for monitoring and supplementing vitamin D and created an HSCT vitamin D replacement guideline. The medical records of 144 adult HSCT patients were reviewed, and the records of another 72 patients were reviewed a year later. Historical baseline data before the intervention found that 81% of patients were vitamin D deficient and 30% received supplementation. Postintervention and at 1-year follow-up, 76% and 65% of patients were vitamin D deficient before transplant and 97.1% and 100%, respectively, received supplementation for vitamin D deficiency. Post-HSCT compliance with monitoring demonstrated that approximately 91% of patients had a vitamin D level checked within 6 months of transplant. After implementation of the algorithm, there was a statistically significant difference ( < .001) between deficient vitamin D levels pretransplant (72.9%) and posttransplant (26.4%). Results demonstrate sustained compliance over a 2-year period with monitoring and supplementation of vitamin D pre- and peritransplant. Aggressive vitamin D repletion posttransplant decreased the incidence of vitamin D deficiency in HSCT patients. Further study is needed to investigate the long-term effects of vitamin D repletion on posttransplant complications.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6750922PMC
March 2019

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

Gynecol Oncol 2019 08 4;154(2):294-301. Epub 2019 Jun 4.

Memorial Sloan Kettering Cancer Center New York, NY and Weill Cornell Medical College, New York, NY, United States of America. Electronic address:

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/m). 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.
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http://dx.doi.org/10.1016/j.ygyno.2019.04.001DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7397408PMC
August 2019

Pituitary as a Source of HCG: Residual Levels After Bilateral Testicular Tumor Removal.

J Investig Med High Impact Case Rep 2019 Jan-Dec;7:2324709619841414

2 Memorial Sloan Kettering Cancer Center, Cornell-Weil School of Medicine, New York, NY, USA.

Context: Challenging clinical scenario in which elevated β-human chorionic gonadotropin (HCG, subsequently termed HCG) levels suggested occult tumor metastases after removal of bilateral testicular cancers and metastases from them and as well as after chemotherapy.

Case Report: A 22-year-old male, post excision of bilateral testicular tumors, who had no imaging or clinical evidence of residual tumor but an elevated HCG raising the question of the presence and location of occult tumor metastases. Clinical Questions. Does luteinizing hormone (LH) cross-react with HCG in current assays? What levels of testosterone and estradiol are necessary to suppress LH and follicle-stimulating hormone (FSH) in a male patient with bilateral orchiectomy, and therefore lacking inhibin? Does the pituitary secrete HCG and under what circumstances?

Assessment: Current HCG assays no longer cross-react with LH as did prior assays, but the presence of heterophile antibodies and other factors such as biotin can still cause false positive HCG levels. In the chronic post-orchiectomy state, the pituitary is relatively resistant to LH and FSH suppression by testosterone. The pituitary secretes HCG in very small amounts unless interruption of negative feedback results in high LH and FSH whereupon HCG levels become elevated. Clinical Conclusion. A GnRH antagonist suppressed both LH and HCG in this patient indicating that the elevated HCG was secreted by the pituitary and not by occult tumor metastases. Further credence for this conclusion resulted from the lack of a progressive increase in HCG levels over a 4-year period of follow-up and from no evidence of metastatic tumors on serial imaging.
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http://dx.doi.org/10.1177/2324709619841414DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6480980PMC
June 2020

Optimal Management of Adverse Events From Copanlisib in the Treatment of Patients With Non-Hodgkin Lymphomas.

Clin Lymphoma Myeloma Leuk 2019 03 29;19(3):135-141. Epub 2018 Nov 29.

Department of Internal Medicine, University of Munich, Munich, Germany.

Introduction: Copanlisib is a phosphoinositol 3-kinase (PI3K) inhibitor approved for the third-line treatment of follicular non-Hodgkin lymphoma. Although the drug is generally well-tolerated, it can be associated with several unique and potentially serious adverse effects (AEs). Two of the most common toxicities not seen with other PI3K inhibitors include hyperglycemia and hypertension, which primarily occur during infusion and resolve shortly thereafter, and likely relate to targeting the PI3K alpha isoform. Other toxicities less commonly observed with copanlisib than with other approved drugs in this class include non-infectious pneumonitis, infections, diarrhea and colitis, and hepatobiliary toxicity.

Materials And Methods: A panel composed of experts in lymphoma, diabetes, and hypertension convened to develop guidance pertaining to the administration of copanlisib and the management of the AEs associated with copanlisib treatment.

Results: Recommendations were formulated pertaining to the management of AEs associated with copanlisib treatment, particularly infusion-related hyperglycemia and hypertension, noninfectious pneumonitis, infections, diarrhea, and colitis. The recommendations herein reflect the consensus of the members of this panel, all of whom contributed to these suggested approaches to patient supportive care.

Conclusion: There are a number of challenges associated with the use of copanlisib. Infusion-related hypertension and hyperglycemia occur frequently, although they are transient, reversible, and rarely of clinical significance; this report provides guidance as to their management.
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http://dx.doi.org/10.1016/j.clml.2018.11.021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6642803PMC
March 2019

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

Br J Clin Pharmacol 2019 06 25;85(6):1125-1135. Epub 2019 Jan 25.

Endocrinology Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

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.
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http://dx.doi.org/10.1111/bcp.13834DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533425PMC
June 2019

The Current Understanding of the Endocrine Effects From Immune Checkpoint Inhibitors and Recommendations for Management.

JNCI Cancer Spectr 2018 Jul 19;2(3):pky021. Epub 2018 Jul 19.

The Emmes Corporation, Rockville, MD.

Clinical trials in the past decade have established the antitumor effects of immune checkpoint inhibition as a revolutionary treatment for cancer. Namely, blocking antibodies to cytotoxic T-lymphocyte antigen 4 and programmed death 1 or its ligand have reached routine clinical use. Manipulation of the immune system is not without side effects, and autoimmune toxicities often known as immune-related adverse events (IRAEs) are observed. Endocrine IRAEs, such as hypophysitis, thyroid dysfunction, and insulin-dependent diabetes mellitus, can present with unique profiles that are not seen with the use of traditional chemotherapeutics. In this Review, we discuss the current hypotheses regarding the mechanism of these endocrinopathies and their clinical presentations. Further, we suggest guidelines and algorithms for patient management and future clinical trials to optimize the detection and treatment of immune checkpoint-related endocrinopathies.
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http://dx.doi.org/10.1093/jncics/pky021DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6054022PMC
July 2018

Maintaining Bone Health During Hormonal Therapy for Prostate Cancer.

Ann Intern Med 2017 09 8;167(5):357-358. Epub 2017 Aug 8.

From Memorial Sloan Kettering Cancer Center and Weill Cornell Medical College, New York, New York.

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http://dx.doi.org/10.7326/M17-1800DOI Listing
September 2017

Assessing fracture risk in early stage breast cancer patients treated with aromatase-inhibitors: An enhanced screening approach incorporating trabecular bone score.

J Bone Oncol 2017 Jun 18;7:32-37. Epub 2016 Oct 18.

Memorial Sloan Kettering Cancer Center, Breast Medicine Service, Weil Cornell Medical College, New York, NY, United States.

Introduction: Aromatase-inhibitors (AIs) are commonly used for treatment of patients with hormone-receptor positive breast carcinoma, and are known to induce bone density loss and increase the risk of fractures. The current standard-of-care screening tool for fracture risk is bone mineral density (BMD) by dual-energy X-ray absorptiometry (DXA). The fracture risk assessment tool (FRAX®) may be used in conjunction with BMD to identify additional osteopenic patients at risk of fracture who may benefit from a bone-modifying agent (BMA). The trabecular bone score (TBS), a novel method of measuring bone microarchitecture by DXA, has been shown to be an independent indicator of increased fracture risk. We report how the addition of TBS and FRAX®, respectively, to BMD contribute to identification of elevated fracture risk (EFR) in postmenopausal breast cancer patients treated with AIs.

Methods: 100 patients with early stage hormone-positive breast cancer treated with AIs, no prior BMAs, and with serial DXAs were identified. BMD and TBS were measured from DXA images before and following initiation of AIs, and FRAX® scores were calculated from review of clinical records. EFR was defined as either: BMD ≤-2.5 or BMD between -2.5 and -1 plus either increased risk by FRAX® or degraded microstructure by TBS.

Results: At baseline, BMD alone identified 4% of patients with EFR. The addition of FRAX® increased detection to 13%, whereas the combination of BMD, FRAX® and TBS identified 20% of patients with EFR. Following AIs, changes in TBS were independent of changes in BMD. On follow-up DXA, BMD alone detected an additional 1 patient at EFR (1%), whereas BMD+ FRAX® identified 3 additional patients (3%), and BMD+FRAX®+TBS identified 7 additional patients (7%).

Conclusions: The combination of FRAX®, TBS, and BMD maximized the identification of patients with EFR. TBS is a novel assessment that enhances the detection of patients who may benefit from BMAs.
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http://dx.doi.org/10.1016/j.jbo.2016.10.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5469247PMC
June 2017

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

Oncologist 2017 04 8;22(4):438-444. Epub 2017 Mar 8.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York, USA.

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. 2017;22:438-444 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.
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http://dx.doi.org/10.1634/theoncologist.2016-0192DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5388375PMC
April 2017

Bone effects of canagliflozin, a sodium glucose co-transporter 2 inhibitor, in patients with type 2 diabetes mellitus.

Postgrad Med 2017 Jan 28;129(1):159-168. Epub 2016 Nov 28.

b Memorial Sloan Kettering Cancer Center , New York , NY , USA.

Canagliflozin, a sodium glucose co-transporter 2 (SGLT2) inhibitor approved for the treatment of type 2 diabetes mellitus (T2DM), lowers blood glucose by inhibiting renal glucose reabsorption and increasing urinary glucose excretion. It has been reported that SGLT2 inhibitors may have potential adverse effects on bone, including increased fracture risk and decreased bone mineral density (BMD). Across clinical studies, canagliflozin was not associated with meaningful changes in serum or urine calcium, vitamin D, or parathyroid hormone. Minimal increases in serum phosphate and magnesium that were within normal limits were seen with canagliflozin versus placebo. Canagliflozin was associated with increases in serum collagen type 1 beta-carboxy telopeptide (beta-CTX), a bone resorption marker, and osteocalcin, a bone formation marker. Decreases in total hip BMD were seen with canagliflozin 100 and 300 mg versus placebo after 2 years (-1.7%, -2.1%, -0.8%; differences of -0.9% and -1.2%), but not at other skeletal sites (normal age-related bone loss, ~0.5-1.0%/year). Changes in beta-CTX and total hip BMD were significantly associated with weight loss, which is known to increase bone resorption markers and decrease BMD. Canagliflozin was associated with a higher fracture incidence in an interim analysis of the CANagliflozin cardioVascular Assessment Study (CANVAS) in patients with a history or high risk of cardiovascular disease (incidence per 100 patient-years of 1.6, 1.6, and 1.1 with canagliflozin 100 and 300 mg and placebo), but not in other clinical studies of patients with T2DM. Fractures tended to occur as early as 12 weeks after initiating treatment and were primarily located in the distal parts of the upper and lower extremities. The reason for increased fracture risk with canagliflozin treatment is unknown, but is likely not related to a direct effect of canagliflozin on bone-related biomarkers. Data from ongoing canagliflozin studies, including CANVAS, will provide additional information on fracture risk in patients with T2DM.
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http://dx.doi.org/10.1080/00325481.2017.1256747DOI Listing
January 2017

Diabetes Management in Cancer Patients.

Oncology (Williston Park) 2016 Jun;30(6):565-70

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June 2016

Ga-68 DOTATOC PET/CT-Guided Biopsy and Cryoablation with Autoradiography of Biopsy Specimen for Treatment of Tumor-Induced Osteomalacia.

Cardiovasc Intervent Radiol 2016 Sep 5;39(9):1352-7. Epub 2016 May 5.

Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome caused by small benign tumors of mesenchymal origin also known as phosphaturic mesenchymal tumors mixed connective tissue variant. Excellent prognosis is expected with eradication of the culprit tumor. These small tumors are notoriously difficult to localize with conventional imaging studies; this often leads to an extensive work up and prolonged morbidity. We report a patient with clinical diagnosis of TIO whose culprit tumor was localized with Ga-68 DOTATOC PET/CT and MRI. Biopsy and cryoablation were performed under Ga-68 DOTATOC PET/CT guidance. Autoradiography of the biopsy specimen was performed and showed in situ correlation between Ga-68 DOTATOC uptake and histopathology with millimeter resolution.
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http://dx.doi.org/10.1007/s00270-016-1350-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5483397PMC
September 2016

Osteonecrosis of the jaw in patients treated with denosumab for metastatic tumors to the bone: A series of thirteen patients.

J Craniomaxillofac Surg 2016 Mar 20;44(3):265-70. Epub 2015 Dec 20.

Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA. Electronic address:

This case series describes the course of osteonecrosis of the jaw (ONJ) in thirteen patients with metastatic bone tumors treated solely with denosumab. Patients on denosumab may be more prone to developing ONJ even without a risk/precipitating factor and they may develop ONJ early in their denosumab therapy. The outcomes of ONJ in ten patients following a period of denosumab discontinuation after the onset of ONJ were: 3 had complete resolution of symptoms, 4 patients' ONJ progressed, 2 patients' ONJ was unchanged and in 1 patient there was partial ONJ resolution. The role of drug discontinuation prior to an invasive dental procedure or after the onset of ONJ still remains debatable.
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http://dx.doi.org/10.1016/j.jcms.2015.12.005DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4784099PMC
March 2016

Denosumab and fracture risk in women with breast cancer.

Lancet 2015 Nov 20;386(10008):2056-2057. Epub 2015 Nov 20.

Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.

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http://dx.doi.org/10.1016/S0140-6736(15)00973-3DOI Listing
November 2015

NCCN bone health task force: key recommendations.

Authors:
Azeez Farooki

J Natl Compr Canc Netw 2014 May;12(5 Suppl):813-6

Presented by Azeez Farooki, MD, from Memorial Sloan-Kettering Cancer Center, New York, New York.

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.
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http://dx.doi.org/10.6004/jnccn.2014.0196DOI Listing
May 2014

Effects of tyrosine kinase inhibition on bone metabolism: untargeted consequences of targeted therapies.

Endocr Relat Cancer 2014 Jun 8;21(3):R247-59. Epub 2014 May 8.

Endocrine Service, Department of Medicine, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, Weill Cornell Medical College, New York, New York 10065, USA.

Tyrosine kinase inhibitors (TKIs) are at the forefront of molecular-targeted therapies for cancer. With the advent of imatinib for the treatment of chronic myelogenous leukemia, a new wave of small-molecule therapeutics redefined the oncologic treatment to become chronically administered medications with tolerable side-effect profiles compared with cytotoxic agents. Effects on bone mineral metabolism were observed during early imatinib treatment, in the form of hypophosphatemia with increased urinary phosphorus excretion. This finding led to detailed investigations of off-target effects responsible for changes in bone cell maturation, activity, and impact on bone mass. Subsequently, another BCR-Abl inhibitor (dasatinib), vascular endothelial growth factor (VEGF) inhibitors (sorafenib and sunitinib) as well as rearranged during transfection (RET) inhibitors (vandetanib and cabozantinib) were developed. Inhibition of bone resorption appears to be a class effect and is likely contributed by TKI effects on the hematopoietic and mesenchymal stem cells. As long-term, prospective, clinical outcomes data accumulate on these targeted therapies, the full extent of off-target side effects on bone health will need to be considered along with the significant benefits of tyrosine kinase inhibition in oncologic treatment.
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http://dx.doi.org/10.1530/ERC-12-0400DOI Listing
June 2014

Natural history of small radioiodine-avid bone metastases that have no structural correlate on imaging studies.

Endocrine 2014 Sep 24;47(1):266-72. Epub 2013 Dec 24.

Endocrinology, Memorial Sloan Kettering Cancer Center, New York, 10021, USA,

Bone metastases from differentiated thyroid cancer are generally resistant to radioiodine (RAI) therapy and are associated with poor prognosis. However, in a recent study from our group we noted a small subgroup of patients with RAI-avid bone metastases who had no structural correlate on imaging studies, and had no skeletal complications during follow-up. The purpose of this study was to better define the natural history and outcome of these patients. In a retrospective review of medical records at Memorial Sloan-Kettering Cancer Center, 288 patients were identified with bone metastases from thyroid cancer between 1960 and 2011. Out of this group, 14 patients who had a RAI-avid bone metastasis without structural correlate on CT or MRI were included in the study. After a median follow-up period of 5 years (range 2-14 years) all patients were alive, none had evidence of structural bone metastases, and none had experienced skeletal-related events. The final disease status was: no evidence of disease in 6 patients (43 %), stable biochemical persistence in 2 patients (14 %), stable structural disease in 5 patients (36 %), and one patient with slowly progressive disease. To conclude, RAI-avid bone metastases with no structural correlate on high-resolution imaging studies often resolve following RAI treatment, do not cause skeletal-related complications, and do not have a major prognostic significance. Recognition of this unique type of bone metastases is important as it is not associated with the same poor prognosis and resistance to RAI therapy that is associated with structurally identifiable bone metastases.
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http://dx.doi.org/10.1007/s12020-013-0123-8DOI Listing
September 2014

NCCN Task Force Report: Bone Health In Cancer Care.

J Natl Compr Canc Netw 2013 Aug;11 Suppl 3:S1-50; quiz S51

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.
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http://dx.doi.org/10.6004/jnccn.2013.0215DOI Listing
August 2013

Effect of long term imatinib on bone in adults with chronic myelogenous leukemia and gastrointestinal stromal tumors.

Leuk Res 2013 Jul 6;37(7):790-4. Epub 2013 Mar 6.

Leukemia Service, Memorial Sloan Kettering Cancer Center and Weill Cornell Medical Center, New York, NY, USA.

Patients with chronic myelogenous leukemia (CML) or gastrointestinal stromal tumors (GIST) who take imatinib have abnormalities of bone metabolism. However, it is unclear what impact these changes have on bone mineral density (BMD). We prospectively analayzed levels of osteocalcin, a marker of bone formation secreted by osteoblasts, and serum N-telopeptide of type I collagen (NTX), a marker of bone resorption, as well as other minerals involved in bone metabolism in 19 patients with either CML or GIST We correlated these results with changes in bone mineral density as measured by serial dual energy X-ray absorptiometry (DEXA) scans over a two year period. Osteocalcin levels were low in 95% of patients and 37% had no measurable amount. Levels of NTX were less consistent. Nine patients (47%) had a decrease in BMD, four patients (2%) had an increase in BMD, and six patients (32%) had no change. There was no correlation between metabolic markers and change in BMD. We suggest that ongoing management of patients who take imatinib should include monitoring of bone health on a long term basis.
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http://dx.doi.org/10.1016/j.leukres.2013.02.005DOI Listing
July 2013

Management of metabolic effects associated with anticancer agents targeting the PI3K-Akt-mTOR pathway.

J Clin Oncol 2012 Aug 9;30(23):2919-28. Epub 2012 Jul 9.

Department of Endocrine Neoplasia and Hormonal Disorders, University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030, USA.

Agents inhibiting the phosphoinositide 3-kinase-Akt-mammalian target of rapamycin (PAM) pathway are currently in various stages of clinical development in oncology, ranging from some in early-phase evaluations to others that have already received regulatory approval for treatment in advanced cancers. The administration of PAM pathway inhibitors has been associated with metabolic toxicities of hyperlipidemia and hyperglycemia. The PAM Task Force of the National Cancer Institute Investigational Drug Steering Committee convened an interdisciplinary expert panel to review the pathophysiology of hyperlipidemia and hyperglycemia induced by PAM pathway inhibitors, summarize the incidence of these metabolic toxicities induced by such agents in the current literature, advise on clinical trial screening and monitoring criteria, and provide management guidance and therapeutic goals on occurrence of these toxicities. The overarching aim of this consensus report is to raise awareness of these metabolic adverse events to enable their early recognition, regular monitoring, and timely intervention in clinical trials. Hyperglycemia and hyperlipidemia are generally not acutely toxic and most often reversible with therapeutic intervention. Dose modifications or discontinuation of PAM pathway inhibitors should only be considered in situations of severe events or if progressive metabolic derangement persists after therapeutic interventions have been attempted for a sufficient duration. Specialty consultation should be sought to aid clinical trial planning and the management of these metabolic adverse events.
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http://dx.doi.org/10.1200/JCO.2011.39.7356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3410405PMC
August 2012

Skeletal-related events due to bone metastases from differentiated thyroid cancer.

J Clin Endocrinol Metab 2012 Jul 7;97(7):2433-9. Epub 2012 May 7.

Endocrinology Service, Department of Medicine, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA.

Background: In oncology, the clinical impact of metastatic bone disease is conveyed via a composite end point termed skeletal-related events (SRE), which encompasses spinal cord compression, pathological fracture, a need for external beam radiation or surgery to bone, and hypercalcemia of malignancy. An appreciation for the high incidence of SRE in other advanced cancers involving the bone has led to the approval of potent antiresorptive agents because they delay the time to the first SRE and decrease the incidence of SRE. The risk and rate of SRE after diagnosis of bone metastasis have not been described in thyroid cancer; antiresorptive agents are not routinely used.

Methods: This was a retrospective review of 245 differentiated thyroid cancer patients with bone metastases identified as part of routine clinical care at Memorial Sloan-Kettering Cancer Center between 1960 and 2011. The occurrence of SRE was recorded from the initial diagnosis of bone metastasis until final follow-up or death.

Results: Seventy-eight percent of patients (192 of 245) either presented with or developed at least one SRE after the diagnosis of metastatic bone disease. The median time from identification of bone metastasis to first SRE was 5 months (excluding the 97 patients in whom first SRE occurred at the time of the bone metastasis diagnosis). Of the patients who sustained an initial SRE, 65% (120 of 192) went on to sustain a second SRE at a median of 10.7 months after the first event. SRE were frequently multiple; 39% (74 of 192) sustained three or more discrete SRE.

Conclusion: Thyroid cancer bone metastases identified as part of routine clinical follow-up frequently cause significant and recurrent morbidity. The incidence of SRE and median time to first SRE in metastatic thyroid cancer to bone are similar to those reported in other solid tumors. Prospective clinical trials to assess the efficacy of antiresorptive agents in this population are needed.
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http://dx.doi.org/10.1210/jc.2012-1169DOI Listing
July 2012

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

J Oral Maxillofac Surg 2012 Dec 11;70(12):2768-75. Epub 2012 Feb 11.

Breast Cancer Medicine Service, Memorial Sloan-Kettering Cancer Center, New York, NY, USA.

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.
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http://dx.doi.org/10.1016/j.joms.2011.12.028DOI Listing
December 2012