Markers of bone turnover in patients with differentiated thyroid cancer with and following withdrawal of thyroxine suppressive therapy

Abstract

Objective: To study whether levothyroxine (LT 4 ) suppressive therapy exposes patients with differentiated thyroid cancer (TC) to an increased risk of osteoporosis. Design and Methods: Markers of bone formation (serum alkaline phosphatase (ALP), osteocalcin (OC), type I procollagen carboxyterminal (PICP) and aminoterminal (PINP) propeptide) and resorption (serum type I collagen carboxyterminal telopeptide (ICTP) and urine hydroxyproline (HOP)), as well as serum intact parathyroid hormone (PTH), 25-hydroxyvitamin D, and 1,25-dihydroxyvitamin D (1,25(OH) 2 -D) were measured in 29 patients (25 women, 4 men) with a median age of 45 years, and in 38 age-and sexmatched controls. In a subgroup of 14 patients the measurements were repeated after 5 weeks' interruption of LT 4 therapy. Since the primary treatment of TC the patients had used TSH suppressive doses of LT 4 (a mean daily dose of 215 mg) for 9 to 11 years. The bone mineral density (BMD) of patients and controls was measured by dual energy X-ray absorptiometry. Results: When on T 4 therapy, patients had significantly higher mean levels of ALP (þ21%, P < 0.05), OC (þ35%, P < 0.01), PICP (þ10%, P < 0.05), PINP (þ46%, P < 0.001), ICTP (þ21%, P < 0.05), and HOP (þ37%, P < 0.001) compared with controls. After stopping treatment, OC (¹42%, P < 0.001), PINP (¹7%, P < 0.05), and ICTP (¹54%,P < 0.001) decreased, whereas PICP (þ24%, P < 0.001) and 1,25-(OH) 2 D (þ29%, P < 0.01) increased. BMD of the lumbar spine and the upper femur was similar in patients and controls. Conclusions: Patients with differentiated TC have high bone turnover when on LT 4 suppressive therapy. After withdrawing treatment both bone formation and resorption decrease acutely. During development of hypothyroidism, serum PICP and PINP, which form from the same type I procollagen molecule and should change similarly, behaved differently. This may be due to different effects of hypothyroidism on their removal through separate receptors in the liver.

The skeletal consequences of thyrotoxicosis

“…The bone formation phase is reduced to a greater extent than the resorption phase, leading to a 10% loss of bone per cycle (Mosekilde & Melsen 1978, Eriksen et al 1986). Furthermore, increases in biochemical markers of bone resorption (urinary cross-linked N-telopeptides pyridinoline of type I collagen, pyridinoline and deoxypyridinoline collagen crosslinks and hydroxyproline) and bone formation (carboxyterminal propeptide of type 1 collagen, serum alkaline phosphatase and osteocalcin) correlate with disease severity (Harvey et al 1991, Garnero et al 1994, Guo et al 1997, Toivonen et al 1998. By contrast, hypothyroidism results in reduced bone turnover with a prolongation of the bone remodelling cycle (Melsen & Mosekilde 1980, Eriksen et al 1986) but hypothyroidism is similarly associated with a two-to threefold increase in fracture risk (Vestergaard & Mosekilde 2002, Vestergaard et al 2005.…”

Bone turnover markers: understanding their value in clinical trials and clinical practice

“…The presence of PINP and PICP in serum can be determined with either RIA or ELISA, and electrochemiluminescence immunoassay analyzers [47], although PINP is preferred to PICP as a marker of bone formation. This is due in part to the fact that PICP, unlike PINP, is cleared by the mannose receptor, which in turn can be regulated by growth hormone and thyroid hormones, thus complicating interpretation in subjects with pituitary or thyroid dysfunction [46,48,49]. An automated method for measurement of serum PINP has recently become available, exhibiting very low (<3%) variability [12].…”

Efectos de la desnutrición sobre la colagenización de anastomosis intestinales: análisis de procolágeno y telopéptido carboxiterminal mediante radioinmunoanálisis

“…Su determinación mediante radioinmunoensayo o mediante enzimoinmunoensayo en estos pacientes, es una prueba de rutina desde hace años. Se han publicado además numerosos estudios de estas moléculas en patologías no asociadas al metabolismo óseo, como el cáncer esofágico (12) o el cáncer de mama (13), donde se proponen como marcador pronóstico en el cáncer de tiroides (14), donde pudiera ser marcador del efecto supresor de la levotiroxina, o asociado a tratamientos como la isotretinoina (15). También se han estudiado mediante radioinmunoensayo las modificaciones de colágeno tipo I y III en las placas de aterosclerosis de arterias carótida, femoral común y aorta (1), objetivándose en las mismas una escasa colagenización.…”