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Case report

Low bone mineral density in a growth hormone deficient (GHD) adolescent

Anna Capozzi Silvia Della Casa Barbara Altieri Alfredo Pontecorvi

Address for correspondence: Anna Capozzi, MD Department of Endocrinology Catholic University Largo F. Vito 1 00168 Rome, Italy Phone: +39 06 30154165-7094 Fax: +39 06 30157232 E-mail: [email protected]

pogonadism, hypopituitarism) (1). A BMD reduction in hypopituitarism, especially in growth hormone deficient patients, is well established and points out to the key role of GH in bone mass and bone density outcomes (2, 3). It is known the Growth Hormone/Insulin-like Growth Factor 1 (GH/IGF1) axis is mainly involved in the achievement of final height in childhood and GH plays a key role in the attainment and maintenance of peak bone mass in young people even if growth has already been completed (4). Peak bone mass is generally defined as the highest level of bone mass achieved at the end of skeletal maturation. It is considered one of the most significant predictors of osteoporotic fracture risk in adulthood and is influenced by diet, physical activity, weight and hormonal status. We describe the case of a young male presenting low BMD. Though initially unsuspected, GHD was finally determined to be the cause of his precocious bone loss.

Summary

Case report

It is largely recognized that Growth Hormone (GH) plays an important role in linear growth during childhood and subsequent completion of appropriate height in early adulthood. It has also significant influence on a variety of metabolic activities, as well as the cardiovascular system and quality of life (QoL) in adults. GH is involved in the attainment of optimal Bone Mineral Density (BMD), the most important predictor of osteoporotic fractures, during the transition from paediatric to adult age. The time interval between paediatric and adult age is a critical period of life to clinically assess persistence of GHD in patients affected by childhood onset GHD (COGHD) and determine the need for continuing treatment with recombinant human Growth Hormone (rhGH) even in the face of closure of epiphyseal growth plates. It has been reported GHD is associated with higher fracture’s risk in COGHD patients and GH therapy should minimize, if not prevent, osteoporosis in adulthood. We report the case of a COGHD young man, rhGH treated until final height completion, presenting a wrist fracture and precocious bone density loss.

A 18-year-old boy (BMI 31,2 kg/m2 height 174 cm WHR 0.98) was admitted for arm fracture following a minor trauma. X-ray showed evidence of fracture and significant unexpected decalcification at his age. He had no specific symptoms and no medical history for other causes of secondary osteoporosis. On physical examination, he seemed to be a healthy, obese man, without relevant clinical signs. He denied the use of any specific medications. He reported that he had isolated idiopathic GHD as a child that had been treated with rhGH until longitudinal growth completion. RhGH therapy was withdrawn as per closure of epiphyseal growth plates, which was ascertained 9 months before his admission into our Unit. Laboratory tests were normal and hormonal tests, including cortisol, sex hormone binding globulin (SHBG), follicle stimulating hormone (FSH), luteinizing hormone (LH), parathyroid hormone (PTH), free (FT) and total testosterone (TT), Insulin like Growth Factor (IGF1) and Thyroid-stimulating hormone (TSH), prolactin (PRL), Adrenocorticotropin (ACTH) and serum and urine calcium and phosphate were within the normal range. Malabsorption tests were negative. IGF-1 levels, instead, were low: 130 ng/ml (v.n 240-540 ng/ml). In order to better investigate his unusual bone decalcification, we performed bone densitometry, which revealed low bone mineral density (BMD) (0.781g/cm3) at lumbar spine (Figure 1) and low BMD (0.821g/cm3) at femoral neck (Figure 2) (Zscore:-2,1). In addition, we tested serum bone alkaline phosphatase (ALP) 167 UI/l (normal range 98-279), osteocalcin (OCN) 24.4 ng/ml (10-45), beta-cross-laps (beta-CTx’s) 1 ng/ml (0.2-0.7). According to the 2007 Consensus guidelines for diagnosis and management of COGHD, we retested our patient for GHD using stimulus with arginine plus Growth Hormone-Releasing Hormone (GHRH) and our results confirmed persistence of GHD. GH peak level was 2,9 ng/ml (normal value >

Department of Endocrinology, Catholic University, Rome, Italy

KEY WORDS: growth hormone deficiency; osteoporosis; adolescence.

Introduction Osteoporosis usually presents as a primary condition in postmenopausal women or in people 65 years of age and older. Secondary osteoporosis is more frequent in young people and is generally due to an underlying cause, like lifestyle factors (smoking, alcohol abuse), nutritional deficiencies, longterm glucocorticoid or immunosuppressive therapy, systemic affections (myeloma, mastocytosis), or endocrinopathy (Thyroid or Parathyroid hormone excess, hyperprolactinemia, hyClinical Cases in Mineral and Bone Metabolism 2013; 10(3): 203-205

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Figure 1 - BMD at lumbar spine.

Figure 2 - BMD at femoral neck.

10 ng/ml). To exclude the possibility of brain lesions underlying GH deficit we performed Magnetic Resonance Imaging (MRI). We restarted treatment with rhGH at 0.25 mg/kg/die (according to National Note AIFA 39/2010) and recommended having an appropriate diet with right intake of calcium and vitamin D- in combination with regular physical activity to lose weight. The follow-up consisted in a) testing levels of IGF1, blood sugar and blood count every 6 months and b) retesting those parameters after one-year treatment with Dual X-ray absorptiometry (DEXA). After 1 year of therapy, we observed a significant increase of BMD at lumbar spine (0.920 g/cm3) and femoral neck (0.890 g/cm3), as well as an increase in bone turnover markers (ALP 204 UI/l; OCN 42 ng/ml; beta-CTx’s) 1.1 ng/ml (0.2-0.7).

It is well known that children with GH deficiency show reduced longitudinal bone growth and are shorter than healthy subjects of the same age. In GHD deficient people, there is not only a delay in skeletal maturation but also low BMD. This is most likely due to a reduction in bone formation rather than an increase in bone resorption (8). In adult-onset GHD, bone density is usually decreased resulting in a mild deficit of bone mineral content and BMD (generally between -0,5 and -1 Zscore) at lumbar spine, femoral neck and radius. This mild deficit is more evident in GHD young adults than in elderly GHD patients and is probably due to the greater age-related bone demineralization, hiding the effect of GH deficiency in the old age (9, 10). However, many authors have demonstrated an increased prevalence of osteoporosis in all patients with adult-onset GHD (2, 9, 11) and GHD is associated with an increased fracture rate, as calculated from different cross-sectional studies (12). Johansson studied 17 adult GHD men and found that total BMD, measured with DEXA, was lower in the patients group than in the control healthy group (13). Several studies show low bone mass in adults with COGHD (9-11). In a cross-sectional study of 30 COGHD adult males, Kaufman observed decreased bone mineral content of the lumbar spine and forearm when patients values were compared with height and age matched controls. BMD in the lumbar spine was between 9% and 19% lower 20% and 30% lower values were found in the forearm compared with control subjects (14). The similar significant reduction of BMD found in patients with multiple pituitary deficiencies and isolated GHD, suggests that deficiency of GH might be the most important factor producing the observed bone loss in COGHD. GH treatment has positive effects in that it increases bone turnover in COGHD patients and adult-onset GHD. The effects are seen in a) significant increase of biochemical bone markers in serum accounting for between 50 and 100 %; b) higher bone mineral mass content and c) accelerating linear growth (15,16). Boot et al. studied BMD and bone metabolism in 40 GHD children before and during 2-3 years of rhGH treatment. At baseline, lumbar spine and total BMD were sig-

Discussion The most important role of GH is promoting growth and attainment of linear bone growth during childhood and adolescence. GH increases bone formation by direct interaction with GH receptors on osteoblasts, as well as by locally produced IGF 1 (2-5). GH/IGF1 axis has also important metabolic functions in adult life, producing different effects on a variety of target tissues such as liver, muscle, adipocytes and bone cells. GH deficiency in adults has significant negative effects on cardiovascular risk factors (decreased fibrinolysis, increased atherosclerosis, hyperlipidemia) and causes some important alterations in body composition and bone density (6, 7). The overweight of our patient may be partly explained by the lack of GH effects on body composition. It is largely recognized that GH has important lipolytic effects. Whether these lipolytic effects are the direct result of GH’s action or more indirectly or GH’s potential inhibitory activities on antilipolytic compounds (e.g. adenosine, prostaglandins and insulin) is presently unknown. However, it has been demonstrated that GH reduces adipose tissue mass by inhibiting adipocyte differentiation, reducing triglyceride accumulation and increasing lipolysis.

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Low bone mineral density in a growth hormone deficient (GHD) adolescent nificantly lower than normal but they increase together with height and lean tissue mass during GH therapy (17). Many studies showed that COGHD, if untreated with rhGH, causes smaller bone size and volume, as well as less bone mass (15, 16). These observations may explain the higher fracture prevalence of adults with untreated COGHD. Because approximately one quarter of children confirm GHD at the end of longitudinal growth, it is critical to retest COGHD at the age of transition to determine the need for continuing therapy with an appropriate age-dependent dosage. The aim would be to reduce the effects in bones of hormone deficiency in adulthood. There is evidence indicating that peak bone mass is mainly achieved at the age of transition, although small increases in BMD continue throughout late adolescence. And there are data supporting the concept that GHD young adults, who have not reached lumbar peak bone mass at the time of rhGH discontinuation, might present lower BMD than their genetic potential if they are no treated during the transition to young adulthood (17, 18). An appropriate GH therapy replacement can largely correct impairment of bone mass and strength in adult-onset and COGHD patients confirmed at retesting. It seems to produce mild but continuous beneficial effect on bone balance, if given over a prolonged period (19, 20). This case shows that this GHD patient achieved a significant increase in BMD after restoration of rhGH treatment and suggests that GH replacement benefits bone density when linear growth had just been completed. At the age of transition to young adulthood, rhGH treatment of COGHD might be crucial for the achievement of peak bone mass, one of the most important predictor of osteoporosis.

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Low bone mineral density in a growth hormone deficient (GHD) adolescent.

It is largely recognized that Growth Hormone (GH) plays an important role in linear growth during childhood and subsequent completion of appropriate h...
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