Long-term Pegvisomant Therapy of Acromegaly: Effects on Bone Density, Turnover and Microstructure Using HRpQCT.

Context: Fracture rate is increased in patients with active acromegaly and those in remission. Abnormalities of bone microstructure are present in patients with active disease and persist despite biochemical control after surgery. Effects of treatment with the GH receptor antagonist pegvisomant on bone microstructure were unknown. Methods: We studied 25 patients with acromegaly (15 men, 10 women). In 20, we evaluated areal bone mineral density (BMD) by dual-energy X-ray absorptiometry and bone turnover markers (BTMs) longitudinally, before and during pegvisomant treatment. After long-term pegvisomant in 17, we cross-sectionally assessed volumetric BMD, microarchitecture, stiffness, and failure load of the distal radius and tibia using high-resolution peripheral quantitative computed tomography (HRpQCT) and compared these results to those of healthy controls and 2 comparison groups of nonpegvisomant-treated acromegaly patients, remission, and active disease, matched for other therapies and characteristics. Results: In the longitudinal study, areal BMD improved at the lumbar spine but decreased at the hip in men after a median ∼7 years of pegvisomant. In the cross-sectional study, patients on a median ∼9 years of pegvisomant had significantly larger bones, lower trabecular and cortical volumetric density, and disrupted trabecular microarchitecture compared to healthy controls. Microstructure was similar in the pegvisomant and acromegaly comparison groups. BTMs were lowered, then stable over time. Conclusion: In this, the first study to examine bone microstructure in pegvisomant-treated acromegaly, we found deficits in volumetric BMD and microarchitecture of the peripheral skeleton. BTM levels remained stable with long-term therapy. Deficits in bone quality identified by HRpQCT may play a role in the pathogenesis of fragility in treated acromegaly.

Persistent Deficits in Bone Quality in Treated Acromegaly: Evidence From Assessments of Microstructure.

Purpose: Fractures are increased in patients with acromegaly, both before and after successful acromegaly treatment. Abnormalities of bone microstructure, which may underlie this fragility, are present in active acromegaly but to what extent these improve with acromegaly treatment or persist despite biochemical remission remains unclear. To examine these questions, we studied the effects of acromegaly treatment and remission on bone quality. Methods: Sixty-five women and men with acromegaly were studied. Subgroups underwent assessments of areal bone mineral density by dual x-ray absorptiometry, trabecular bone score (TBS), and volumetric bone mineral density, microarchitecture, stiffness and failure load of the distal radius and tibia by high-resolution peripheral quantitative tomography in a longitudinal study before and after acromegaly treatment and in a cross-sectional study in which patients were compared to sex-, age-, and body mass index-matched healthy controls. Results: In the longitudinal study, significant increases in total, cortical, and trabecular densities at the radius and tibia and increased stiffness and failure load of the tibia occurred with acromegaly treatment. In the cross-sectional study, patients in biochemical remission after surgery had larger bones, lower trabecular and cortical volumetric density, and disrupted trabecular microarchitecture compared to controls. TBS did not change with acromegaly treatment but correlated with some microstructural parameters. Conclusion: We show, for the first time, that volumetric bone mineral density and microarchitecture of the peripheral skeleton improve with acromegaly treatment but remain abnormal in patients in remission after surgery compared to controls. These abnormalities, known to be associated with fractures in other populations, may play a role in the pathogenesis of persistent fragility in treated acromegaly.

Long-term Outcome of Body Composition, Ectopic Lipid, and Insulin Resistance Changes With Surgical Treatment of Acromegaly.

Context: Acromegaly presents a unique pattern of lower adiposity and insulin resistance in active disease but reduction in insulin resistance despite a rise in adiposity after surgery. Depot-specific adipose tissue masses and ectopic lipid are important predictors of insulin resistance in other populations, but whether they are in acromegaly is unknown. Long-term persistence of body composition changes after surgery is unknown. Objective: To determine how depot-specific body composition and ectopic lipid relate to insulin resistance in active acromegaly and whether their changes with surgery are sustained long-term. Methods: Cross-sectional study in patients with active acromegaly and longitudinal study in newly diagnosed patients studied before and in long-term follow-up, 3 (1-8) years (median, range), after surgery. Seventy-one patients with active acromegaly studied cross-sectionally and 28 with newly diagnosed acromegaly studied longitudinally. Main outcome measures were visceral (VAT), subcutaneous (SAT), and intermuscular adipose tissue masses by whole-body magnetic resonance imaging; intrahepatic lipid (IHL) by proton magnetic resonance spectroscopy; insulin resistance measures derived from fasting; and oral glucose tolerance test insulin and glucose levels. Results: SAT and insulin-like growth factor 1 level, but not VAT or IHL, were independent predictors of insulin resistance in active acromegaly. VAT, SAT, and IHL gains were sustained long-term after surgery. VAT mass rise with surgery correlated inversely with rise in QUICKI while SAT rise correlated with fall in the Homeostatic Model Assessment score. Conclusion: SAT and disease activity are important predictors of insulin resistance in active acromegaly. Adiposity gains are sustained long-term after surgical treatment and impact on the accompanying improvement in insulin resistance.

Body Composition Changes with Long-term Pegvisomant Therapy of Acromegaly.

CONTEXT: In active acromegaly, the lipolytic and insulin antagonistic effects of growth hormone (GH) excess alter adipose tissue (AT) deposition, reduce body fat, and increase insulin resistance. This pattern reverses with surgical therapy. Pegvisomant treats acromegaly by blocking GH receptor (GHR) signal transduction and lowering insulin-like growth factor 1 (IGF-1) levels. The long-term effects of GHR antagonist treatment of acromegaly on body composition have not been studied. METHODS: We prospectively studied 21 patients with active acromegaly who were starting pegvisomant. Body composition was examined by whole body magnetic resonance imaging, proton magnetic resonance spectroscopy of liver and muscle and dual-energy x-ray absorptiometry, and endocrine and metabolic markers were measured before and serially during 1.0 to 13.4 years of pegvisomant therapy. The data of patients with acromegaly were compared with predicted and to matched controls. RESULTS: Mass of visceral AT (VAT) increased to a peak of 187% (1.56-229%) (P < .001) and subcutaneous AT (SAT) to 109% (-17% to 57%) (P = .04) of baseline. These remained persistently and stably increased, but did not differ from predicted during long-term pegvisomant therapy. Intrahepatic lipid rose from 1.75% to 3.04 % (P = .04). Although lean tissue mass decreased significantly, skeletal muscle (SM) did not change. IGF-1 levels normalized, and homeostasis model assessment insulin resistance and HbA1C were lowered. CONCLUSION: Long-term pegvisomant therapy is accompanied by increases in VAT and SAT mass that do not differ from predicted, stable SM mass and improvements in glucose metabolism. Long-term pegvisomant therapy does not produce a GH deficiency-like pattern of body composition change.

Langerhans Cell Histiocytosis: Diagnosis on Thyroid Aspirate and Review of the Literature.

Thyroid gland involvement by Langerhans cell histiocytosis is extremely rare. A 35-year-old woman with a history of a suprasellar mass previously diagnosed as a ganglioglioma and complicated by diabetes insipidus, hypogonadotropic hypogonadism, and central hypothyroidism presented with acute onset of neck enlargement. On ultrasound examination, almost the entire thyroid appeared replaced by abnormal lobulated hypoechoic tissue with increased vascularity. Fine needle aspiration (FNA) of the thyroid was performed and revealed singly scattered and loosely cohesive large cells with abundant cytoplasm, including some with irregular nuclear contours and nuclear grooves. No thyroid follicular cells were noted. Based on the cytomorphologic findings and ancillary studies (immunohistochemistry and flow cytometry analysis) a cytological diagnosis of "positive for neoplastic cells" with features suggestive of monocytic/histiocytic origin, possibly Langerhans cell histiocytosis (LCH) was rendered. Following FNA, the patient underwent an incisional thyroid biopsy that confirmed the cytological impression of LCH. In light of the new diagnosis of LCH, the prior suprasellar mass biopsy slides were re-reviewed and rare cells suspicious for LCH were observed. Appropriate treatment for systemic LCH was initiated successfully. This case demonstrates that the presence of enlarged and loosely cohesive cells, especially those with irregular nuclear contours, in thyroid FNA specimens should raise suspicion for LCH. The diagnosis of LCH in FNA specimens is challenging. Additional material should be allocated for ancillary studies to confirm the morphological impression. In our case, not only was the thyroid FNA crucial in diagnosing LCH, but instrumental in initiating a thorough diagnostic work-up for multisystem involvement and thus unmasking the true etiology of the patient's suprasellar mass and associated endocrinopathies.

Osteoporosis and Low Bone Mineral Density in Men with Testosterone Deficiency Syndrome.

INTRODUCTION: Testosterone deficiency syndrome (TDS) is a risk factor for low bone mineral density (BMD) and osteoporosis. Knowledge of the relationship between TDS and bone health, as well as the practical aspects of how to diagnose and treat low BMD, is therefore of practical importance to sexual medicine practitioners. AIM: The aim of this study was to review the physiologic basis and clinical evidence of the relationship between TDS and bone health; and to provide a practical, evidence-based algorithm for the diagnosis and management of low BMD in men with TDS. METHODS: Method used was a review of relevant publications in PubMed. MAIN OUTCOME MEASURES: Pathophysiology of low BMD in TDS, morbidity, and mortality of osteoporosis in men, association between TDS and osteoporosis, indications for dual X-ray absorptiometry (DXA) scanning in TDS, evidence for testosterone replacement therapy (TRT) in men with osteoporosis, treatment for osteoporosis in the setting of TDS. RESULTS: Sex hormones play a pleomorphic role in maintenance of BMD. TDS is associated with increased risk of osteoporosis and osteopenia, both of which contribute to morbidity and mortality in men. DXA scanning is indicated in men older than 50 years with TDS, and in younger men with longstanding TDS. Men with TDS and osteoporosis should be treated with anti-osteoporotic agents and TRT should be highly considered. Men with osteopenia should be stratified by fracture risk. Those at high risk should be treated with anti-osteoporotic agents with strong consideration of TRT; while those at low risk should be strongly considered for TRT, which has a beneficial effect on BMD. CONCLUSION: Low BMD is a prevalent and treatable cause of morbidity and mortality in men with TDS. Utilization of a practical, evidence-based approach to diagnosis and treatment of low BMD in men with TDS enables sexual medicine practitioners to make a meaningful impact on patient quality of life and longevity. Gaffney CD, Pagano MJ, Kuker AP, Stember DS, and Stahl PJ. Osteoporosis and low bone mineral density in men with testosterone deficiency syndrome.