The Journal of Clinical Endocrinology & Metabolism, 2023, 108, 59–84 https://doi.org/10.1210/clinem/dgac556 Advance access publication 23 September 2022 Clinical Research Article Bone Health in Adults With Prader–Willi Syndrome: Clinical Recommendations Based on a Multicenter Cohort Study Denise H. van Abswoude,1,2,3,4,* Karlijn Pellikaan,1,2,3,4,* Anna G. W. Rosenberg,1,2,3,4 Kirsten Davidse,1,2,3,4 Muriel Coupaye,5,6 Charlotte Høybye,6,7,8,9 Tania P. Markovic,6,10,11 Downloaded from https://academic.oup.com/jcem/article/108/1/59/6712600 by guest on 06 November 2023 Graziano Grugni,6,7,12 Antonino Crinò,6,13 Assumpta Caixàs,6,14,15 Christine Poitou,5,6,7 Helena Mosbah,5 Tessa Weir,16,17 Leo A. van Vlimmeren,18 Joost P. H. J. Rutges,19 Luuk W. L. De Klerk,20 M. Carola Zillikens,1,7,21,22 Aart J. van der Lely,1 and Laura C. G. de Graaff1,2,3,4,6,7 1 Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands 2 Center for Adults with Rare Genetic Syndromes, Department of Internal Medicine, Division of Endocrinology, Erasmus Medical Center, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands 3 Dutch Center of Reference for Prader-Willi Syndrome, 3015 GD Rotterdam, The Netherlands 4 Academic Center for Growth Disorders, Erasmus Medical Center, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands 5 Assistance Publique-Hôpitaux de Paris, Rare Diseases Center of reference ‘Prader-Willi Syndrome and obesity with eating disorders’ (PRADORT), Nutrition Department, Institute of Cardiometabolism and Nutrition, ICAN, Pitié-Salpêtrière Hospital, Sorbonne Université, INSERM, Nutriomics, F75013 Paris, France 6 International Network for Research, Management & Education on adults with Prader-Willi Syndrome (INfoRMEd-PWS) 7 ENDO-ERN (European Reference Network) 8 Department of Molecular Medicine and Surgery, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden 9 Department of Endocrinology, Karolinska Institute and Karolinska University Hospital, Stockholm, Sweden 10 Metabolism & Obesity Services, Royal Prince Alfred Hospital, Camperdown, Australia 11 Boden Initiative, Charles Perkins Centre, University of Sydney, Sydney Australia 12 Divison of Auxology, Istituto Auxologico Italiano, IRCCS, Piancavallo (VB), Italy 13 Reference Center for Prader-Willi syndrome, Bambino Gesù Hospital, Research Institute, Palidoro (Rome), Italy 14 Department of Endocrinology and Nutrition, Hospital Universitari Parc Taulí, Institut d’Investigació i Innovació Parc Taulí (I3PT), Universitat Autònoma de Barcelona, Sabadell, Spain 15 Department of Medicine, Universitat Autònoma de Barcelona, Sabadell, Spain 16 Department of Endocrinology, Nepean-Blue Mountains Hospital, Sydney, NSW, Australia 17 Northern Clinical School, Faculty of Medicine and Health, University of Sydney, Sydney, NSW, Australia 18 Department of Rehabilitation and Pediatric Physical Therapy, Radboud University Medical Centrum, 6525 GA Nijmegen, The Netherlands 19 Department of Orthopedic surgery, Erasmus Medical Center, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands 20 Department of Orthopedic surgery, Sint Maartensclinic, 6500 GM Nijmegen, The Netherlands 21 Academic Center for Rare Bone Disorders, Erasmus Medical Center, University Medical Center Rotterdam, 3015 GD Rotterdam, The Netherlands 22 European Reference Network for rare bone diseases (ERN BOND) Correspondence: Laura de Graaff, MD, PhD, Dept. of Internal Medicine, Erasmus MC, University Medical Center, Dr. Molewaterplein 40, 3015 GD Rotterdam, The Netherlands. Email: l.degraaff@erasmusmc.nl. *These authors contributed equally to this study. Abstract Context: Prader–Willi syndrome (PWS) is a rare complex genetic syndrome, characterized by delayed psychomotor development, hypotonia, and hyperphagia. Hormone deficiencies such as hypogonadism, hypothyroidism, and growth hormone deficiency are common. The combination of hypotonia, low physical activity, and hypogonadism might lead to a decrease in bone mass and increase in fracture risk. Moreover, one would expect an increased risk of scoliosis due to hypotonia and low physical activity. Objective: To study the prevalence and risk factors for skeletal problems (reduced bone mineral density, fractures, and scoliosis) in adults with PWS. Received: 12 July 2022. Editorial Decision: 19 September 2022. Corrected and Typeset: 25 October 2022 © The Author(s) 2022. Published by Oxford University Press on behalf of the Endocrine Society. This is an Open Access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs licence (https://creativecommons. org/licenses/by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any medium, provided the original work is not altered or transformed in any way, and that the work is properly cited. For commercial re-use, please contact journals.permissions@oup.com 60 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 1 Methods: We retrospectively collected patient characteristics, medical history, medication, biochemical measurements, dual-energy X-ray absorptiometry scans, and spinal X-rays and reviewed the current literature. Results: We included 354 adults with PWS (median age 31 years; 43% males), of whom 51 (14%) had osteoporosis (T-score below −2.5) and 143 (54%) had osteopenia (T-score −1 to −2.5). The most prevalent modifiable risk factors for osteoporosis were hypogonadism, insufficient dairy intake, sedentary lifestyle, and corticosteroid use. Male sex was associated with osteoporosis (P = .005). Growth hormone treatment was not associated with osteoporosis. A history of vertebral fractures was present in 10 (3%) and nonvertebral fractures in 59 (17%). Scoliosis was present in 263 (80%), but no modifiable risk factors were identified. Conclusion: Besides scoliosis, osteoporosis is common in adults with PWS. Based on the literature and the risk factors for osteoporosis found in our cohort, we provide practical clinical recommendations to avoid skeletal complications in these vulnerable patients. Key Words: Prader–Willi syndrome, osteoporosis, bone density, human growth hormone, hormone replacement therapy, scoliosis Abbreviations: 25(OH) vitamin D, 25-hydroxyvitamin D; BMD, bone mineral density; BMI, body mass index; DXA, dual-energy X-ray absorptiometry; GH, growth hormone; GHt, growth hormone treatment; ICD, imprinting center defect; IQR, interquartile range; mUPD, maternal uniparental disomy; OPG, osteoprotegerin; P1NP, propeptide of type I procollagen; PTH, parathyroid hormone; PWS, Prader–Willi syndrome; RANKL, Receptor activator of nuclear factor-κB Ligand; SHRT, sex hormone replacement therapy. Downloaded from https://academic.oup.com/jcem/article/108/1/59/6712600 by guest on 06 November 2023 Prader–Willi syndrome (PWS) is a rare, complex genetic syn­ prevention and treatment of skeletal problems in adults drome with an estimated prevalence of 1:10.000 to 30.000 with PWS. (1). It arises from a loss of expression of paternally expressed genes in the PWS region on chromosome 15q11.2-13, most often caused by a de novo paternal deletion (65-75%), a ma­ Materials and Methods ternal uniparental disomy (mUPD, 20-30%), an imprinting This study is a multicenter, retrospective cohort study. Ethical center defect (ICD, 1-3%), or a paternal chromosomal trans­ approval and/or individual informed consent was obtained by location (0.1%) (2, 3). Clinical features of PWS include in­ the participating centers according to local rules and regula­ fantile hypotonia, obesity due to hyperphagia (an insatiable tions. We included patients with genetically confirmed PWS, appetite), sleep disorders, disturbed temperature regulation, aged 18 years or older with available dual-energy X-ray ab­ disturbed pain perception, challenging behavior, and intel­ sorptiometry (DXA) scans who had been treated at one of lectual disability (4–6). Furthermore, hypothalamic dysfunc­ the participating PWS reference centers. A total of 354 pa­ tion in PWS can lead to multiple pituitary hormone tients were included from six countries: Australia (n = 51), deficiencies (1, 4–7). The Netherlands (n = 78), France (n = 64), Italy (n = 130), In patients with PWS, 29% to 44% have a history of bone Sweden (n = 4), and Spain (n = 27). fractures, which might be related to the high recorded Data on osteoporosis, risk factors for osteoporosis, growth prevalence of osteoporosis of up to 21% (8–12). Several hormone treatment (GHt), sex hormone replacement therapy risk factors contribute to this high prevalence. Firstly, there (SHRT), scoliosis, previous fractures, medication, and geno­ is a high prevalence of hypogonadism in adults with PWS type were collected from medical records. We studied demo­ (up to 100% in both males and females) (13–16), leading graphic (eg, ethnicity, sex), life style–related (eg, physical to increased bone turnover (17, 18). Secondly, adults with inactivity, smoking, alcohol intake, body mass index [BMI], PWS are considered (functionally) growth hormone (GH) and vitamin D and calcium intake), and comorbidity-related deficient, and GH deficiency has been linked to osteoporosis risk factors (eg, previous fractures, type 2 diabetes mellitus, (19–24). Other risk factors for osteoporosis that are preva­ hypogonadism, hyperparathyroidism, hyperthyroidism, lent in adults with PWS are reduced physical activity (25– chronic corticosteroid use, and malabsorption) (22, 46–49). 28) and low levels of fat-soluble vitamin D (29). A prevalent A BMI between 18.5 and 25 kg/m2 was considered lean, 25 risk factors for fractures without a low bone mineral density to 30 kg/m2 overweight, and more than 30 kg/m2 obesity, ac­ (BMD) is type 2 diabetes mellitus (30, 31), which is present cording to the 1997 World Health Organization criteria (50). in 11% to 24% of adults with PWS compared with 5% to Exercise of less than 30 minutes per day was considered insuf­ 7% in the general population (11, 32). The combination ficient for adults with PWS. of hypotonia, hypogonadism, and decreased physical activ­ Scoliosis was diagnosed when a gibbus deformity was ob­ ity can lead to decreased bone mass and an increased frac­ served during physical examination and/or if a Cobb angle ture risk, as has previously been reported in Down of ≥10 degrees was present on X-ray, according to the syndrome (33). Scoliosis Research Society criteria (51). If a patient had Another frequent bone-related health problem in both chil­ more than one spinal curvature, the largest Cobb angle was dren and adults with PWS is scoliosis. The reported prevalence used. If a patient had received surgery for scoliosis, the of scoliosis ranges between 38% and 86% (8, 10, 34–40). Cobb angle before surgery was used. Scoliosis is likely related to hypotonia of (paravertebral) The most recent 25-hydroxyvitamin D (25(OH) vitamin D) lev­ muscles, low physical activity, and obesity (35, 38, 41). els were collected in patients who did not receive vitamin D supple­ Additionally, late menarche and low estrogen levels might mentation. Vitamin D deficiency was defined as a 25(OH) vitamin be linked to scoliosis in females with PWS (42–45), although D level <50 nmol/L (52), and severe vitamin D deficiency was de­ results are inconclusive (40). fined as a 25(OH) vitamin D level of <20 nmol/L. Therefore, we studied the prevalence of osteoporosis, Bone mineral density was measured using DXA scans. osteopenia, fractures, and scoliosis and their risk factors Different DXA machines were used (Hologic DEXA systems® in a large cohort of adults with PWS. In addition, we per­ or GE Healthcare Lunar), depending on availability in partici­ formed a literature review. Based on both clinical and lit­ pating centers. In the absence of a spine phantom, we calcu­ erature data, we provide clinical recommendations for lated the standardized BMD (sBMD) in order to compare The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 1 61 the results from the different machines. sBMD in g/cm2 was Table 1. Baseline characteristics of 354 adults with PWS calculated using the following formulas (53, 54): Total sBMDspine Lunar = 0.9683 × (BMDspine-1.100) + 1.0436 n = 354 sBMDspine Hologic = 1.0550 × (BMDspine-0.972) + 1.0436 Age at baseline in years, median (IQR)a 31 (25-40) sBMDfemur neck Lunar = 0.939 × BMDfemur - 0.023 Age at first DXA (T-scores), median (IQR) 24 (21-33), n = 332 Male sex 152 (43) sBMDfemur neck Hologic = 1.087 × BMDfemur + 0.019 Height in m, median (IQR) 1.56 (1.49-1.64) Osteopenia was defined as a T-score between −1 and −2.5 Weight in kg, median (IQR) 81.3 (67.2-98.1) SD and osteoporosis was defined as a T-score below or equal BMI in kg/m2, median (IQR) 33.3 (26.8-41.4) to −2.5 SD, according to the World Health Organization criteria Obesity 219 (62) (55–58). T-scores are calculated based on a reference population, Ever received GHt 223 (64), n = 351 according to sex, ethnicity, skeletal site, and the bone densitom­ Genetic subtype Downloaded from https://academic.oup.com/jcem/article/108/1/59/6712600 by guest on 06 November 2023 eter used. When only Z-scores were available and not T-scores, Deletion 217 (61) osteopenia and osteoporosis were considered missing. Deletion type 1 24 When information on the day and month of biochemical Deletion type 2 43 and/or imaging data were missing while the year was known, Deletion, unspecified 141 we assigned the date of July 1 to calculate the age and other Atypical deletion 9 time intervals. mUPD 105 (30) ICD 7 (2) Literature Review Otherb 25 (7) In collaboration with the Medical Library of the Erasmus Country University Medical Center, a literature search was performed Australia 51 (14) in March 2021 and last updated on 21 June 2022. D.v.A. and France 64 (18) K.P. reviewed the medical literature on osteoporosis, frac­ Italy 130 (37) tures, scoliosis, and bone-related factors in adults with PWS Sweden 4 (1) in several databases (Embase, Medline All, Web of Science Spain 27 (8) Core Collection, Cochrane database, and Google Scholar). The Netherlands 78 (22) Search terms included “Prader-Willi Syndrome,” “osteopor­ Ethnicity osis,” “osteopenia,” “fracture,” “scoliosis,” “DEXA,” White/Caucasian 313 (88) “DXA,” “bone health,” and “bone mineral density”. The Black/African American 5 (1) full search strategy is available elsewhere (Table S1 (59)). Hispanic 2 (1) Additionally, the references of relevant articles were screened. Asian 6 (2) We included articles reporting on osteoporosis, scoliosis, or Arabic 6 (2) bone-related factors in adults with genetically confirmed PWS (≥16 years old). Nonoriginal research articles, confer­ African American 5 (1) ence abstracts, articles describing fewer than 10 patients, non­ Hispanic 2 (1) human research, non-English articles, and articles without Eurasian 1 (0) full-text availability were excluded. Articles about both chil­ Unknown 21 (6) dren and adults were only included if a subgroup analysis Osteoporosis for the age group of 16 years old or older was available. Currently diagnosed 51 (14) When articles reported on the same population, both articles Ever diagnosed 75 (21), n = 340 were combined. Current osteopeniac 143 (54), n = 263 History of vertebral fracture(s) 10 (3), n = 336 Data Analysis History of nonvertebral fracture(s) 59 (17), n = 326 Data were analyzed using IBM SPSS version 25.0. Continuous Scoliosis 263 (80), n = 329 variables were displayed as median (interquartile range Largest cobb angle in degrees, median (IQR) 23.0 (13.0-41.5) [IQR]), dichotomous variables as number and percentage of Data are presented as n (%), unless otherwise specified. patients, n (%). To investigate the relationship between the Abbreviations: BMI, body mass index; DXA, dual-energy X-ray determinants and osteoporosis or scoliosis, a chi-squared absorptiometry; GHt, growth hormone therapy; ICD, imprinting center defect; test was used for dichotomous variables, a Mann–Whitney IQR, interquartile range; mUPD, maternal uniparental disomy. a U test for continuous variables when we compared 2 groups, Current age or age of death for deceased patient. b Other genetic subtypes included nonspecified mUPD or ICD, nonspecified and a Kruskal–Wallis H test for continuous variables to com­ methylation positive, and rare genetic subtypes such as translocations. pare 3 or more groups. Ordinal and logistic regression mod­ c In patients not currently diagnosed with osteoporosis. els were used to correct for GHt, age, height, weight (and thereby indirectly for BMI), and/or sex. BMI was considered a possible confounder as high BMI is associated with an in­ Results creased BMD (60–62). Correction for GHt was performed because GHt improves body composition (63–65) and could Baseline Characteristics therefore influence BMD. P < .05 was considered to be stat­ We included 354 adults (152 males, 202 females) with PWS. istically significant. The median age was 31 years (IQR 25-40 years) and 43% 62 Table 2. Characteristics and risk factors of Patients with PWS with normal BMD, osteopenia and osteoporosis Number of Normal BMD Number of Osteopenia Number of Osteoporosis P-value Adjusted observations (n = 120) observations (n = 143) observations (n = 51) P-valuej Age in years, median (IQR)a 120 31.4 (24.8-38.5) 143 31.4 (26.3-39.8) 51 44.8 (32.4-52.2) <.001 <.001 Male sex 120 41 (31) 143 60 (46) 51 31 (61) .005 <.001 Height in m, median (IQR) 120 1.56 (1.48-1.65) 143 1.56 (1.49-1.63) 51 1.54 (1.44-1.61) .34 .045 Weight in kg, median (IQR) 120 87.4 (68.0-102.6) 143 80.6 (66.7-95.1) 51 74.0 (63.1-92.4) .010 <.001 BMI in kg/m2, median (IQR) 120 34.9 (27.2-42.9) 143 32.9 (27.0-40.6) 51 30.3 (26.5-38.9) .12 .58 Genotype 120 143 51 Deletion 73 (61) 87 (61) 36 (71) .13h .86h mUPD 38 (32) 43 (29) 8 (16) ICD 2 (2) 3 (2) 1 (2) Other 7 (6) 11 (8) 6 (12) Scoliosis 111 82 (74) 135 115 (85) 44 38 (86) .049 .061 Cobb angle, median (IQR) 48 19.5 (10.4-44.8) 63 24.0 (15.0-43.0) 18 25.0 (16.5-39.0) .66 .75 Fractures Vertebral 117 0 137 4 (3) 42 6 (14) <.001 .025 Nonvertebral 116 15 (13) 133 24 (18) 41 16 (39) .001 .010 Bisphosphonate treatment 120 0 (0) 142 5 (4) 47 19 (40) <.001 <.001 Alcohol usage 112 6 (5) 135 10 (7) 47 5 (10) .49 .68 Units/week median (IQR) 6 2.5 (1.0-6.5) 10 1.5 (1.0-3.3) 5 3.0 (0.5-4.0) .76 .72 Smoking 112 9 (8) 133 12 (9) 48 6 (13) .67 .69 Cigarettes/week median (IQR) 9 50 (15-85) 12 57 (26-70) 6 70 (70-98) .14 .20 Ever 120 78 (65) 140 93 (66) 51 23 (45) .020 .88 During childhoodb 109 67 (62) 117 70 (60) 38 10 (26) <.001 .45 During adulthoodc 91 49 (54) 95 48 (51) 42 14 (33) .080 .73 Current 119 40 (34) 136 40 (29) 47 11 (23) .42 .65 Hypogonadism males 41 37 (90) 59 57 (97) 30 28 (93) .42 .13 Ever received SHRT 40 30 (75) 60 41 (68) 30 22 (73) .75 .96 Untreated hypogonadism 37 7 (19) 57 17 (30) 28 6 (21) .44 .61 Hypogonadism females 78 66 (85) 82 71 (87) 20 16 (80) .76 .45 Ever received SHRT 75 55 (73) 79 56 (71) 19 15 (79) .77 .43 Untreated hypogonadism 66 13 (20) 71 16 (23) 16 2 (13) .66 .70 Hyperthyroidism 120 1 (0.8) 143 1 (0.7) 51 2 (4) .071 .088 Hyperparathyroidism 120 0 143 1 (0.7) 50 2 (4) NAi NAi Diabetes mellitus 120 143 48 Type 1 0 0 0 NAi NAi Type 2 27 (23) 37 (26) 10 (21) .69 .96 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 1 (continued) Downloaded from https://academic.oup.com/jcem/article/108/1/59/6712600 by guest on 06 November 2023 Table 2. Continued Number of Normal BMD Number of Osteopenia Number of Osteoporosis P-value Adjusted observations (n = 120) observations (n = 143) observations (n = 51) P-valuej Not specified 1 (0.8) 2 (1) 0 NAi NAi i IGT 10 (8) 6 (4) 1 (2) NA NAi Current corticosteroid use 119 16 (13) 140 11 (8) 47 3 (6) .22 .14 Exercise <30 minutes/day 109 38 (35) 131 55 (42) 40 16 (40) .52 .19 Dairy intake <3 units/day 82 69 (84) 105 95 (91) 37 29 (78) .15 .74 Calcium supplements 116 10 (9) 136 35 (26) 44 24 (55) <.001 <.001 Vit D supplements 116 83 (72) 138 112 (81) 46 40 (87) .055 .25 Vit D levels in nmol/L without supplements, 30 71.4 (58.4-85.5) 25 61.9 (40.4-86.4) 5 77.4 (50.5-129.1) .39 .93 median (IQR) Vit D deficiencyd 30 5 (17) 25 8 (32) 5 1 (20) .40 .18 Severe vit D deficiencye 30 1 (3) 25 2 (8) 5 0 NAi NAi Malabsorption Gastrointestinal surgeryf 116 9 (8) 138 8 (6) 48 7 (15) .15 .23 g Gastrointestinal comorbidities 117 4 (3) 137 8 (6) 47 6 (13) .74 .16 Data are presented as n (%), unless otherwise specified. P values are calculated using a chi-squared test for dichotomous variables and a Kruskal–Wallis H test for continuous variables. The adjusted P value was calculated using an ordinal regression analysis. Bold P values represent statistically significant differences. Forty patients were excluded from this analysis, as they were not diagnosed with osteoporosis but it was unknown whether they had osteopenia or a normal BMD. As not all variables were available for all included patients, we display the number of observations, representing the number of patients for whom that variable was known. Abbreviations: BMI, body mass index; BMD, bone mineral density; del, deletion; GHt, growth hormone treatment; IGT, impaired glucose tolerance; IQR, interquartile range; mUPD, maternal uniparental disomy; NA, not applicable; SHRT, sex hormone replacement therapy; vit, vitamin.aCurrent age or age of death for deceased patients. b During childhood includes all patients who received GHt at some point during childhood, independent of whether the patient received GHt during adulthood compared with patients who never received GHt. The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 1 c During adulthood includes all patients who received GHt at some point during adulthood, independent of GHt during childhood compared with patients who never received GHt. d Vitamin D deficiency was defined as a vitamin D level <50 nmol/L without the use of vitamin D supplements. e Severe vitamin D deficiency was defined as a vitamin D level <20 nmol/L without the use of vitamin D supplements. f In the normal BMD group, operations included sleeve gastrectomy and/or gastric bypass (n = 4), cholecystectomy (n = 3), appendectomy (n = 1), and bioenteric intragastric balloon (n = 1). In the osteopenia group, operations included sleeve gastrectomy, gastric bypasss or biliopancreatic diversion (n = 6), and cholecystectomy (n = 3). In the osteoporosis group, operations performed were biliopancreatic diversion (n = 4), and cholecystectomy (n = 2), which was combined with ileal resection for ileus in 1 patient (n = 1). g In the normal BMD group, gastrointestinal comorbidities included malabsorption after previous sleeve gastrectomy (n = 4), dysbiosis (n = 1), acute alithiasic cholecystitis (n = 1). In patients with osteopenia, the most common causes of malabsorption were postoperative (n = 3), inflammatory bowel disease (n = 2), and hepatic disease (n = 2). In the patients with osteoporosis, 3 patients had malabsorption due to biliopancreatic diversion. h P value calculated for deletion vs mUPD only, other genotypes were excluded from this analysis. i P value not calculated because of small numbers. j P values were adjusted for age, sex, height, and weight except for hypogonadism. For hypogonadism the P value was adjusted for age, height, and weight only. 63 Downloaded from https://academic.oup.com/jcem/article/108/1/59/6712600 by guest on 06 November 2023 64 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 1 Table 3. Comparison of adults with PWS with and without fractures Number of No fracture Number of Vertebral P value Number of Nonvertebral P value observations observations fracture observations fracture Age, median (IQR)a 326 31.3 (25.2-40.0) 10 54.5 (45.2-56.3) <.001 59 36.3 (30.5-45.3) .001 Male sex 326 134 (41) 10 7 (70) .068 59 34 (58) .005 Height in m, median 326 1.56 (1.49-1.64) 10 1.56 (1.50-1.65) .92 59 1.59 (1.49-1.68) .13 (IQR) Weight in kg, median 326 82.0 (67.1-98.5) 10 71.4 (55.3-80.4) .069 59 82.1 (72.2-104.1) .14 (IQR) BMI in kg/m2, 326 33.4 (26.8-41.6) 10 28.4 (24.4-31.4) .056 59 34.3 (26.9-40.5) .48 median (IQR) Current osteoporosis 153 36 (24) 6 6 (100) <.001b 31 16 (52) <.001c Downloaded from https://academic.oup.com/jcem/article/108/1/59/6712600 by guest on 06 November 2023 Current osteopenia 250 133 (53) 4 4 (100) .062 39 24 (62) .27 Scoliosis Cobb angle, 313 251 (80) 8 5 (63) .22 53 42 (79) .77 median (IQR) 144 22.5 (13.0-41.0) 1 51.0 .23 20 23.5 (13.5-37.75) .95 GHt Ever 326 217 (67) 10 2 (20) .002d 58 35 (60) .36 e During childhood 278 169 (61) 10 2 (20) .010 50 27 (54) .33 During adulthood 237 128 (54) 8 0 (0) .003f 41 18 (44) .22 Hypogonadism 133 123 (93) 6 6 (100) .49 33 32 (97) .26 males Ever received 131 93 (71) 7 5 (71) .98 33 24 (73) .59 SHRT Hypogonadism 188 162 (86) 3 2 (67) .34 24 22 (92) .40 females Ever received 184 133 (72) 2 2 (100) .38 24 18 (75) .77 SHRT Data are presented as n (%), unless otherwise specified. P values are calculated using a chi-squared test for dichotomous variables and a Mann–Whitney U test for continuous variables. P values are calculated for patients with vertebral fractures vs no fractures and for patients with nonvertebral fractures vs no fractures. Bold P values represent statistically significant differences. Abbreviations: BMI, body mass index; GHt, growth hormone treatment; IQR, interquartile range; SHRT, sex hormone replacement therapy. a Current age or age of death for deceased patients. b P = .996 after adjusting for age, sex, weight, and GHt (ever received) for patients with osteoporosis compared to normal BMD. c P = .003 after adjusting for age, sex, weight, and GHt (ever received) for patients with osteoporosis compared with normal BMD. d P = .117 after adjusting for age, sex, height, and weight. e P = .867 after adjusting for age, sex, height, and weight. f P = .995 after adjusting for age, sex, height, and weight. were male. Median BMI was 33 kg/m2(IQR 27-41 kg/m2); normal BMD and 31 (26-40) in osteopenia (P < .001 after ad­ 62% had obesity. Paternal deletion was the most common justing for sex, height, and weight) (Table 2). There was a genotype (61%), followed by mUPD (30%). ICD (2%) was male predominance in the osteoporosis group, but not in the less common. One percent of subjects were methylation posi­ normal BMD group (61% vs 31% P < .001); males had a sig­ tive, but the underlying genetic defect was unknown. In the re­ nificantly lower BMI than females (31 [IQR 27-38] kg/m2 vs maining 6%, the genotype was either mUPD or ICD (not 35 [IQR 27-42] kg/m2, P = .013). After adjusting for age, specified) or a rare genetic defect. Sixty-four percent (223 of height, and weight, sex remained significantly associated 351) had ever received GHt. The median (IQR) duration of with current osteoporosis (P < .001). Both height and weight GHt during childhood was 6.0 (3.3-9.5) years. Baseline char­ were significantly associated with osteopenia or osteoporosis acteristics are displayed in Table 1. (adjusted P = .045 and P < .001 respectively). We corrected for BMI indirectly by correcting for height and weight. Genotype (deletion vs mUPD) was not significantly related Osteoporosis to osteoporosis or osteopenia (adjusted P = .86). Fifty-one of 354 patients (14%) had osteoporosis based on a T-score below or equal to −2.5 SD at the time of data collec­ tion (“current osteoporosis”); 143 of 263 (54%) had current Risk Factors for Osteoporosis osteopenia based on a T-score between −1 and −2.5 SD. Use of alcohol (7%) and tobacco (9%) was not significantly re­ Seventy-five patients (21%) had ever been diagnosed with lated to osteoporosis or osteopenia (Table 2). Hypogonadism, osteoporosis, either at the time of data-collection or at some irrespective of treatment with SHRT, was the most prevalent point in their medical history. The median T-scores and risk factor (with a prevalence of 93% in males and 80% in fe­ sBMD values of the most recent DXA scans are shown else­ males), followed by insufficient physical exercise (present in where (Table S2 (59)). The median age of patients currently 40%). No significant association was found between (un)treated diagnosed with osteoporosis was 45 years (IQR 32-52 years) hypogonadism and normal BMD, osteopenia, or osteoporosis. compared with 31 years (IQR 25-39 years) for patients with a Use of GHt at some point in life (ie, either current use or use in The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 1 65 Table 4. Comparison of individuals with PWS with and without scoliosis Number of No scoliosis Number of Scoliosis P value observations (n = 66) observations (n = 263) Age in years, median (IQR)a 66 30.1 (24.8-36.8) 263 31.4 (25.4-40.2) .33 Male sex 66 34 (52) 263 106 (40) .10 Height in m, median (IQR) 66 1.58 (1.51-1.69) 263 1.56 (1.48-1.64) .007b Weight in kg, median (IQR) 66 85.2 (71.4-104.8) 263 79.7 (66.2-95.3) .006c 2 BMI in kg/m , median (IQR) 66 33.7 (28.6-42.5) 263 32.6 (26.5-40.1) .21 Deletion vs mUPD 59 39 (66) del/20 (34) mUPD 243 166 (68) del/77 (32) mUPD .74 GHt Ever 66 42 (64) 263 179 (68) .49 During childhoodd Downloaded from https://academic.oup.com/jcem/article/108/1/59/6712600 by guest on 06 November 2023 57 33 (58) 222 138 (62) .56 During adulthoode 52 28 (54) 183 99 (54) .97 Current 66 23 (35) 252 82 (33) .72 Hypogonadism males 34 31 (91) 104 98 (94) .53 Ever received SHRT 32 25 (78) 105 72 (69) .30 Hypogonadism females 30 23 (77) 155 136 (88) .11 Ever received SHRT 29 22 (76) 151 108 (72) .63 Data are presented as n (%), unless otherwise specified. P values are calculated using a chi-squared test for dichotomous variables and a Mann–Whitney U test for continuous variables. Bold P values represent statistically significant differences. As not all variables were available for all included patients, we display the number of observations, representing the number of patients for whom that variable was known. Abbreviations: BMI, body mass index; del, deletion; GHt, growth hormone treatment; IQR, interquartile range; mUPD, maternal uniparental disomy; SHRT, sex hormonal replacement therapy. a Current age or age of death for deceased patients. b P < .001 after adjusting for GHt (ever received). c P = .004 after adjusting for GHt (ever received). d During childhood includes all patients who had received GHt at some point during childhood, independent of whether the patient received GHt as an adult compared with patients who never received GHt. e During adulthood includes all patients who had received GHt at some point when they were 18 years old, or older, independent of GHt during childhood compared with patients who never received GHt. the past) was lower in patients with osteoporosis than in patients SHRT for hypogonadism. Four patients, all previously diag­ with normal bone density (45% vs 65%, P = .020). However, nosed with osteoporosis, had suffered from both vertebral after adjusting for age, height, weight, and sex, this difference and at least one nonvertebral fracture. Fractures (both verte­ was no longer statistically significant (P = .88). GHt during child­ bral and nonvertebral) were more frequent in patients with hood was not significantly related to osteoporosis after correc­ a current diagnosis of osteoporosis. However, after correcting tion for age, sex, weight, and height either (P = .45). Only 4 for age, sex, weight, and GHt, only nonvertebral fractures re­ patients had hyperthyroidism and 3 had hyperparathyroidism. mained significantly associated with osteoporosis (P = .003). Scoliosis was not significantly more prevalent in adults with os­ Patients with (vertebral or nonvertebral) fractures were sig­ teopenia (85%) or osteoporosis (86%) than in those with normal nificantly older than adults without fractures (P < .001 and bone density (74%, adjusted P = .061). Eleven percent of the co­ P = .001 respectively, Table 3). GHt was not associated with hort used corticosteroids, either daily or only during physical or either vertebral or nonvertebral fractures after correcting for psychological stress. Corticosteroid use was not significantly re­ age, sex, height, and weight. We did not find any association lated to osteoporosis or osteopenia (adjusted P = .14). between (vertebral or nonvertebral) fractures and hypogonad­ Osteoporosis showed no correlation with gastrointestinal co­ ism or SHRT in either of the sexes. morbidities or surgery either (adjusted P = .16 and P = .23 respectively). Scoliosis Scoliosis was present in the majority of patients (80%, 263 out Fractures of 329 patients) with a median Cobb angle of 23.0 (IQR Ten of 326 (3%) patients had previously suffered at least one 13.0-41.5) degrees. Table 4 shows the clinical characteristics vertebral fracture. In six patients, the fractures were spontan­ of adults with PWS with and without scoliosis. No significant eous, in other words, not caused by any (observed or reported) difference was found for age, sex, BMI, genotype (deletion vs mechanical trauma. Fifty-nine (17%) of all patients had suf­ mUPD), GHt at any point in life, GHt during childhood, hypo­ fered from a nonvertebral fracture at any point in life. In eight gonadism, or SHRT between patients with and without scoli­ patients (14%), this was a spontaneous fracture without pre­ osis. Scoliosis was not related to osteoporosis or fractures. vious (observed or reported) adequate trauma. Forty-five pa­ tients had had a single fracture; the remaining 14 patients suffered from multiple fractures, either at different time points Results of the Literature Review or simultaneously. The maximum number of fractures in one Our search resulted in 1464 articles. A total of 1289 articles patient was six. This patient had osteoporosis and received were excluded based on title and abstract. The remaining Table 5. Results of studies reporting on osteoporosis and bone mineral density in adults with Prade–Willi syndrome 66 Author (year) Country Patient characteristics Methods Outcome Influencing factors Remarks Butler et al UK N: 58 Cross-sectional study. Osteoporosis: 1/58 (2%) — Not all cases with (2002) (11) Age range: 18-46 years Semistructured History of any fractures: 25/58 PWS were Sex: 32M, 26F interviews with family (43%) genetically Mean BMI: 35 kg/m2 or caregivers History of >1 fractures: 13/58 confirmed. No Genotype: NA (22%) systematic GHt: NA BMD SHRT: 13% assessment Sinnema et al NL N: 102 Cross-sectional study. Osteoporosis: 16/102 (16%) Osteoporosis more prevalent in del (13/ No systematic (2011) (10)a Mean age: 36 years (range 18-66) Semistructured 55, 24%) compared with mUPD (2/44, BMD Sex: 49M, 53F interviews with 5%, P = .02) assessment Mean BMI: 32 kg/m2 (range caregivers and review No significant different was found in the 17-52 kg/m2) of medical files prevalence of osteoporosis for different Genotype: 55 del, 44 mUPD, 3 ICD age groups or sex GHt: 5%, past 8% SHRT: males: current 16%, past 14% females: current 17%, past 9% Butler et al USA N: 11 Cohort study. 12 Osteoporosis: NA — — (2013) (65) Mean age: 32 years (range 23-50) months GHt followed Total body BMD (mean ± SE) at Sex: 5M, 6F by 12 months no GHt. baseline: 1.14 ± 0.05 g/cm2 BMI: 34.5 kg/m2 BMD assessment by Genotype: 9 del, 1 mUPD, 1 ICD DXA at baseline and GHt: no prior GHt 12 and 24 months SHRT: NA, but evidence of hypogonadism and low sex steroid levels were present Jørgensen et al Scandinavia N: 42 Double blind RCT for Osteoporosis: NA Z-scores of men at lumbar spine and total — (2013) (67)a Mean age: 28.5 years GHt vs placebo for 12 BMD lumbar spine: 1.038 ± body were significantly lower than Sex: 21M, 21F months, open label, 0.138 g/cm2 Z-scores of women (lumbar spine, mean Mean BMI: 28.1 kg/m2 GHt for additional 24 BMD total hip: 0.864 ± 0.120 g/ (95% CI): −1.9 (−2.5 to −1.3) vs −1.0 Genotype: NA months cm2 (−1.5 to −0.5), P < .05, total body, GHt: no GHt at least 12 months Controls were 15 Z-score lumbar spine, mean (95% mean (95% CI): −1.5 (−2.0 to −1.0) vs before study, none during healthy age-, weight-, CI): −1.4 (−1.8 to −1.0) −0.5 (−0.9 to 0.0), P < .01). No adulthood and sex matched Z-score total hip, mean (95% CI): significant difference was found for SHRT: not started at least 12 Norwegian subjects −1.5 (−1.8 to −1.3) total hip months before study 43%M, Bone density assessment Z-score total body, mean (95% BMD Z-score of eugonadal women at 29%F by DXA at baseline, CI): −1.0 (−1.4 to −0.6) baseline were normal and higher than 12, 24, and 36 months Compared with healthy controls, hypogonadal women (mean (95% CI): BMD of lumbar spine and BMD 0.0 (−0.6 to 0.6) vs −1.0 (−1.7 to −0.4), Z-score were significantly lower P < .05) in adults with PWS; however, A BMI >30 kg/m2 was associated with BMD was not significantly higher baseline BMD of the lumbar different after correction for spine (P < .01), total hip (P < .01) and height total body (P < .05) Regression analysis showed baseline BMD as a predictor of total hip BMD (P = (continued) The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 1 Downloaded from https://academic.oup.com/jcem/article/108/1/59/6712600 by guest on 06 November 2023 Table 5. Continued Author (year) Country Patient characteristics Methods Outcome Influencing factors Remarks .028). Lumbar spine BMD predictors were BMI (P = .010) and sex (P = .026) Kido et al (2013) Japan N: 22 Observational cohort Osteoporosis: NA 2 years of monthly intramuscular — (69) Age range: 16-48 years study. BMD At baseline (before start of SHRT): testosterone injections of 125 mg Sex: 22M assessment by DXA Lumbar spine BMD: 0.8505 ± significantly increased lumbar spine Mean BMI: 33.6 kg/m2 0.0426 g/cm2 (n = 18) BMD (to 0.9035 ± 0.0465 g/cm2, P = Genotype: 21 del, 1 mUPD Lumbar spine T-score: −1.547 ± .036), lumbar spine T-scores (to −1.092 GHt: 9% 1.871 ± 1.333, P = .036) and lumbar spine Hypogonadism: 100% Lumbar spine Z-score: −1.510 ± Z-scores (to −0.934 ± 1.333, P = .036) SHRT: 0% at baseline, then SHRT 1.871 was initiated in 100% Longhi et al Italy N: 41 Cross-sectional study. Osteoporosis: NA No significant differences found between Control group (2015) (70)a Mean age: 29.4 years Controls matched for No significant difference between BMD total body, L2-L4 or femur neck had a lower Sex: 17M, 24F age and sex. BMD PWS and controls for patients with and without SHRT BMI (mean Mean BMI: males 41.6 kg/m2, assessment by DXA In total body BMD (1.13 ± 0.01 vs BMI 24.5 kg/ females 41.2 kg/m2 scan 1.07 ± 0.16 g/cm2), L2-L4 (1.04 m2 in males Genotype: 33 del, 8 mUPD ± 0.14 vs 1.21 ± 0.13 g/cm2) or and 21.1 kg/ GHt: current 34%, 22% past femur neck (0.89 ± 0.14 vs 1.02 m2 in females) SHRT: 6%M, 54%F ± 0.17 g/cm2) after correcting than patients for height with PWS Donze et al NL N: 27 Baseline characteristics Osteoporosis: NA There was no significant difference in total All patients had (2018) (71)a Mean age: 17.2 years of a crossover GHt At adult height, total body BMD body BMD SDS between hypogonadal received GHt Sex: 8M, 19F RCT SD (Z-score) was −0.7 ± 1.1, adults with and without SHRT (P = .49 during Mean BMI SDS: 0.9 BMD assessment by which was significantly lower and P = .39 respectively) childhood Genotype: 9 del, 15 mUPD, 2 ICD, DXA scan. Compared than in healthy peers (P < .01) Not clear if all The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 1 1 translocation with age- and 4/27 (15%) had total body BMD patients were GHt: 100% at time of inclusion sex-matched SD of <−2.0 aged >15 years Hypogonadism: 88%M and 84%F references SHRT: 38%M, 42%F van Nieuwpoort NL N: 15 Cross-sectional study. Osteoporosis: Lumbar spine and total hip T-scores were Criteria for et al (2018) Median age: 22.0 years (range BMD assessment by Lumbar spine: 2 (13%) significantly lower in men (median osteoporosis (68) 19.2-42.9) DXA scan Total hip: 2 (13%) T-scores −2.6 and −2.0 respectively) not specified Sex: 4M, 11F Osteopenia: than in women (median T-scores −0.9 DXA scans only Median BMI: 27.5 kg/m2 Lumbar spine: 6 (40%) and −1.2 respectively, P < .05). BMD performed in Genotype: 93.3% del, 6.7% mUPD Total hip: 10 (67%) for lumbar spine, hip, and total body 11 patients GHt: current 0%, past 27% Median lumbar spine BMD: 0.91 and Z-scores were not significantly Hypogonadism: 87% (IQR 0.17) g/m2 different SHRT: 54% Median T-score lumbar spine: −1.4 (IQR 2.0) Median Z-score lumbar spine: −1.7 (IQR 1.4) Median total hip BMD: 0.76 (IQR 0.10) g/m2 Median T-score total hip: −1.6 (IQR 0.9) Median Z-score total hip: −1.5 (IQR 1.1) (continued) 67 Downloaded from https://academic.oup.com/jcem/article/108/1/59/6712600 by guest on 06 November 2023 Table 5. Continued 68 Author (year) Country Patient characteristics Methods Outcome Influencing factors Remarks Median total body BMD: 0.99 (IQR 0.13) g/cm2 Viardot et al Australia N: 11 Cross-sectional study. Osteoporosis: NA Multiple linear regression in all (PWS and No DXA results (2018) (72) Mean age: 27.6 years BMD assessment by Total body BMD (mean ± SE): non-PWS) included individuals showed for lumbar Sex: 7M, 4F DXA scan PWS: 1.21 ± 0.07 g/cm2 that total lean mass was a significant spine or hip. Mean BMI: 37.4 kg/m2 2 control groups: 1 Obese controls: 1.25 ± 0.07 g/cm2 predictor of BMD (coefficient 0.005, P SHRT no Genotype: NA obese (n = 12) and 1 Lean controls: 1.13 ± 0.06 g/cm2 = .024), while having obesity, having included in GHt: 0% lean (n = 10) group No significant differences between PWS, fat mass, height, and age were not multiple SHRT: 71%M, 25%F PWS and the control groups in regression total body BMD model Matching was performed by recruiting control groups with similar baseline characteristics to the PWS group rather than case to case matching. Unknown how patients with similar characteristics were selected Baraghithy et al Israel N: 30 Cross-sectional study. Osteoporosis: NA — — (2019) (73) Mean age: 29.9 years BMD assessment by Z-scores of Patients with PWS Sex: 60% M DXA scan. Compared significantly lower than controls Mean BMI: 28.4 kg/m2 with 28 age- and (femoral neck: −1.6 ± 1.0 vs 0.2 Genotype: 16 del, 13 mUPD, 1 ICD BMI-matched ± 1.2, P < .001, total hip −1.3 ± GHt: NA controls 1.4 vs 0.4 ± 1.1, P < .001, SHRT: NA lumbar spine −1.6 ± 1.3 vs −0.4 ± 1.3, P = .001 and forearm −2.4 ± 1.2 vs −0.4 ± 0.7 P < .001) Damen et al NL N: 43 Baseline characteristics Osteoporosis: NA — All patients had (2021) (74)a Mean age (range): 19.5 years of a prospective Total body BMD (median [IQR]) received GHt (18.7-20.7) for males and 18.4 cohort study on GHt. was 1.15 (1.08 to 1.19) g/cm2, for at least 5 years (15.8-23.8) for females BMD assessment with total body SDS −0.78 (−1.31 to years during Sex: 18M, 25F DXA scans, compared 0.11), which was significantly childhood Mean BMI: 24.5 kg/m2 with age- and lower than in the reference group No baseline Genotype: 18 del, 20 mUPD, 4 sex-matched (P < .01) characteristics ICD, 1 translocation references 9/43 (21%) patients total body SD of controls GHt: 100% <−2.0 Hypogonadism: 93% Lumbar spine BMD (median SHRT: 83% [IQR]): 1.19 (1.09 to 1.26) g/ Hypogonadal without SHRT: 16% (continued) The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 1 Downloaded from https://academic.oup.com/jcem/article/108/1/59/6712600 by guest on 06 November 2023 Table 5. Continued Author (year) Country Patient characteristics Methods Outcome Influencing factors Remarks cm2, lumbar spine SDS −0.62 (−1.16 to −0.09) 1 patient (2%) had a fracture during the study Faienza et al Italy N: 52 Cross-sectional study. Osteoporosis: NA No significant difference between del and Controls are (2021) (66)a Mean age: 30.6 years (SD 10.7 Biochemical T-score BMD of lumbar spine mUPD. normal weight years) measurement from (median [IQR]): −1.10 [0.20]) adults, while Sex: 22M, 30F blood samples and Lumbar spine BMD: 1.05 (0.06) g/ irisin is also Median BMI: 35.3 kg/m2 DXA scans to asses cm2 released from Genotype: 32 del, 20 mUPD BMD Total body less head BMD: 1.18 adipose tissue GHt: 6 Compared with 54 (0.08) g/cm2 Exclusion SHRT: 5%M, 33%F normal weight adult No significant difference between criteria: use of Vitamin D: 50% supplementation controls del and mUPD genotype mineral or 5 (10%) adults had a history of vitamin post-traumatic fractures supplements (except for vitamin D), presence of chronic diseases with possible impact on bone metabolism, use of The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 1 medication affecting bone turnover and fractures in the 6 months preceding the study Noh et al (2022) Korea N: 68 Cross-sectional study. Decreased bone density: 18/68 Decreased bone density according to GHt: — (75) Age range: 19-34 years Data collection from (26%) in Adults with PWS Without GHt: 2/10 (20%) Sex: 39M, 29F patient records compared with 2/204 (1%) in Previous GHt: 14/48 (29%) Mean BMI: 35 kg/m2 Compared with 204 age, controls (P < .001) Current GHt: 2/10: (20%) Genotype: 44 del, 24 other sex and BMI-matched P > .05 for all comparisons GHt: 48 previous, 10 current controls SHRT: NA BMD assessment by DXA scan Data are presented as mean ± SD, unless otherwise specified. When articles reported subgroup analysis for adults and children or patients >16 years old and patients <16 years old, only information for the adults or patients >16 years old are reported here whenever possible. Abbreviations: BMI, body mass index; BMD, bone mineral density; del, deletion; DXA, dual-energy X-ray absorptiometry; F, females; GHt, growth hormone treatment; ICD, imprinting center defect; IQR, interquartile range; M, males; mUPD, maternal uniparental disomy; NA, not available; N, number of patients; RCT, randomized controlled trial; SHRT, sex hormone replacement therapy with estrogen or testosterone; SD, standard deviation; SDS, standard deviation score; SE, standard error; NL, The Netherlands;; WHO, World Health Organization. a Partly overlapping study population as current study. 69 Downloaded from https://academic.oup.com/jcem/article/108/1/59/6712600 by guest on 06 November 2023 70 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 1 Table 6. Results of studies reporting on growth hormone treatment in relation to bone mineral density in adults with Prader–Willi syndrome Author Country Patient Methods Outcome Influencing factors Remarks (year) characteristics Butler et al USA N: 11 Cohort study. 12 Total BMD (mean ± SE) — All low plasma (2013) Mean age: 32 years months GHt, At baseline: 1.14 ± IGF-1 level at (65) (range 23-50) followed by 12 0.05 g/cm2 baseline Sex: 5M, 6F months without At 12 months: 1.12 ± BMI: 34.5 kg/m2 GHt 0.05 g/cm2 Genotype: 9 del, 1 BMD assessment by At 24 months: 1.15 ± mUPD, 1 ICD DXA at baseline 0.05 g/cm2 GHt: no prior GHt and 12 and 24 No significant change in SHRT: NA, but months BMD was found evidence of during follow-up hypogonadism and Downloaded from https://academic.oup.com/jcem/article/108/1/59/6712600 by guest on 06 November 2023 low sex steroid levels were present Jørgensen Scandinavia N: 42 Double-blind RCT 12 months of GHt After 24 months of GHt, Patients lost to et al Mean age: 28.5 years for GHt vs placebo significantly decreased Z-score of men follow-up were (2013) Sex: 21M, 21F for 12 months, Z-score of lumbar remained significantly excluded from (67)a BMI: 28.1 kg/m2 open-label GHt for spine (−2.1%±3.4%) lower than women. analysis Genotype: additional 24 compared with Lumbar spine, mean GHt: no GHt at least months placebo (+1.9% (95% CI): −2.2 (−2.8 12 months before Controls were 15 ±3.4%, P < .01). No to −1.6) vs −1.1 (−1.6 study, none during healthy age, other changes in BMD to −0.5), P < .05. Total adulthood weight, and sex at other sides or any body, mean (95% CI): SHRT: 43% M, 29% matched significant changes −1.7 (−2.2 to −1.1) vs F, not started at Norwegian after 24 months of −0.5 (−0.9 to 0.0), P < least 12 months subjects GHt were found .01) before study Bone density assessment by DXA at baseline, 12, 24, and 36 months Khare et al USA N: 18 Cross-sectional BMD Z-score of the There was no statistically — (2014) Mean age: >15 years study; 7 subjects spine was significantly significant difference (77) old received GHt and higher in the GHt in BMD Z-score of the Sex: NA 11 subjects had group than in the no spine between patients BMI: NA never received GHt GHt group (P = .021) with a del or mUPD Genotype: 9 del, 8 Assessment of BMD mUPD, 1 unknown by DXA scan GHt: 0% prior to study SHRT: NA Longhi et al Italy N: 41 Cross-sectional study No significant difference — No distinction (2015) Mean age 29.4 years comparing between GHt and no between (70)a Sex: 17M, 24F previous or current GHt Patients with current and BMI: males 41.6 kg/ GHt (n = 23) vs no PWS in BMD (g/cm2) past GHt m2, females GHt (n = 18) of total body (1.11 ± 41.2 kg/m2 BMD assessment by 0.09 vs 1.15 ± 0.12), Genotype: 33 del, 8 DXA scan lumbar spine (1.02 ± mUPD 0.12 vs 1.05 ± 0.16) or GHt: current 34%, femur neck (0.86 ± 22% past 0.13 vs 0.91 ± 0.16) SHRT: 6%M, 54%F Donze et al NL N: 27 Double blind RCT 1 GHt did not affect BMD SHRT did influence All patients had (2018) Mean age: 17.2 years year GHt vs measurements BMD measurements received GHt (71)a Sex: 8M, 19F placebo followed No significant difference Independent of GHt or during Mean BMI SDS: 0.9 by crossover to the was found in total placebo, total body childhood Genotype: 9 del, 15 alternative body and lumbar spine BMD SDS did not Not clear if all mUPD, 2 ICD, 1 treatment for 1 BMD SDS after 12 change significantly in patients were translocation year months of GHt hypogonadal patients aged >15 years GHt: 100% at time of BMD assessment by compared with without SHRT (−0.8 inclusion DXA scan at placebo (P = .51 and P to −0.9, P = .11), while Hypogonadism: 88% baseline, 6, 12, 18, = .37 respectively). there was a significant M and 84%F and 24 months After 2 years, BMD of increase in total body SHRT: 38%M, 42% total body SDS did not BMD SDS from −1.1 F change significantly to −0.7 (P < .01) in (P = .20), but BMD patients with SHRT SDS of the lumbar after 2 years. SDS of spine corrected for the BMD of the lumbar (continued) The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 1 71 Table 6. Continued Author Country Patient Methods Outcome Influencing factors Remarks (year) characteristics bone size declined spine corrected for significantly, bone size decreased independent of GHt (P from −0.2 to −0.6 in < .01). There was no hypogonadal patients significant difference without SHRT in change in BMD SDS (P = .01), while it for total body and remained similar in BMD SWS for lumbar patients with SHRT spine corrected for (−0.5 at baseline and bone size between GH after 2 years, P = 0.79) and placebo There were no bone Downloaded from https://academic.oup.com/jcem/article/108/1/59/6712600 by guest on 06 November 2023 fractures during the study period Damen NL N: 43 Open-label No significant difference In men, a significant All patients had et al Mean age (range): prospective cohort were found for BMD decrease in SDS BMD received GHt (2021) 19.5 years study, patients of total body at start of total body after 3 for at least 5 (74)a (18.7-20.7) for received GHt and after 3 years (SDS years was found years during males and 18.4 during 3 years −0.76 (−1.11 to (−1.10 (−1.70 to childhood years (15.8-23.8) BMD assessment −0.41) vs −0.90 −0.49) vs −1.46 No baseline for females with DXA scans (−1.27 to −0.54), (−1.94 to −0.98), P = characteristics Sex: 18M, 25F P = .11) .008). In women, no of controls Mean BMI: 24.5 kg/ significant different m2 was found in total Genotype: 18 del, 20 body BMD SDS mUPD, 4 ICD, 1 (P = .78) translocation No significant different Hypogonadism: 93% was found in total SHRT: 83% body BMD of 33 male Hypogonadal and female subjects without SHRT: with SHRT after 3 16% years (P = .37). In men receiving SHRT, a significant decrease in total body BMD was found during 3 years from −1.33 (−1.96 to −0.69) to −1.59 (−2.15 to −1.01), P = .014. In women, no difference was found (P = .72) Regression analysis showed and association between female sex and higher BMD total body at baseline (β = 1.956, P < .001) and after 3 years (β = 2.100, P < .001) No associated was found between age and genetic subtypes Data are presented as mean ± SD, unless otherwise specified. Abbreviations: BMI, body mass index; BMD, bone mineral density; del, deletion; DXA, dual-energy X-ray absorptiometry; ICD, imprinting center defect; F, females; GHt, growth hormone treatment; M, males; mUPD, maternal uniparental disomy; NA, not available; N, number of patients; SHRT, sex hormone replacement therapy; SDS, standard deviation score; SE, standard error; NL, The Netherlands. a Partly overlapping study population as current study. 175 articles underwent full-text screening. One article was ex­ Osteoporosis and Bone Mineral Density cluded because the full-text was unavailable. Another 149 ar­ Table 5 shows the results of the literature review of articles re­ ticles were excluded when, after reading the full-text, it turned porting on osteoporosis and BMD in adults with PWS. out they did not meet the inclusion criteria. Twenty-six ar­ Osteoporosis was present in 2% to 26% of adults with ticles were included in the review. PWS. Sinnema et al (10) reported that osteoporosis was 72 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 1 Table 7. Results of studies reporting on vitamin D and bone related factors in adults with Prader–Willi syndrome Author (year) Country Patient characteristics Methods Outcome Influencing factors Remarks Jørgensen et al Scandinavia N: 42 Randomized controlled At baseline: GHt for 12 months increased Patients lost-to-follow-up were (2013) Mean age: 28.5 years double blind for GHt vs P1NP was at the high end of P1NP levels (P < .001) and excluded from analysis a (67) Sex: 21M, 21F placebo for 12 months, normal (73.8 ± 36.6 µg/L), normalized osteocalcin 2 BMI: 28.1 kg/m open label GHt for osteocalcin was low levels Genotype: NA additional 24 months (4.1 ± 2.8 µg/L), (P < .05). Cross-linked GHt: no GHt at least Blood samples were collected cross-linked N-telopeptides N-telopeptides of type I 12 months before for biochemical essay of type I collagen was in the collagen did not change study, none during upper range of expected significantly adulthood (20.7 ± 6.2 nM) SHRT: 43%M, 29%F, not started at least 12 months before study Longhi et al Italy N: 41 Cross-sectional study. Vitamin D levels of Patients — Control group had a lower Downloaded from https://academic.oup.com/jcem/article/108/1/59/6712600 by guest on 06 November 2023 (2015) Mean age: 29.4 years Controls matched for age with PWS were significantly BMI (mean BMI 24.5 kg/m2 (70)a Sex: 17M, 24F and sex. Blood samples lower than controls (19.8 ± in males and 21.1 kg/m2 in BMI: males 41.6 kg/ were taken for 25(OH) 9.7 vs 36.2 ± 16.7 µg/L, P < females) than patients with m2, females vitamin D, intact PTH and .01) PWS 41.2 kg/m2 BAP measurements patients with PWS showed Use of vitamin D supplements Genotype: 33 del, 8 significantly higher value of unknown mUPD BAP (15.1 ± 7.7 vs 12.2 ± GHt: 34% current, 3.8 μg/L, P < .05) than 22% past controls SHRT: 6%M, 54%F Purtell et al Australia N: 10 Cross-sectional study. Blood No significant differences — Unknown if any individuals (2016) (29) Mean age: 27.9 years samples were taken for between 25(OH) vitamin D used vitamin D supplements Sex: NA analysis levels between the lean (23.4 Mean BMI: 37.0 kg/ 2 control groups: 1 obese (n ± 4.4 ng/mL), obese (18.6 ± m2 = 12) and 1 lean (n = 10) 3.1 ng/mL) and PWS group Genotype: NA group (12.7 ± 1.5 ng/mL). The GHt: 0% mean vitamin D level in PWS was in the range of mild to moderate vitamin D deficiency Brunetti et al Italy N: 14 Cross-sectional study. 25(OH) vitamin D (ng/mL), Multivariate analysis showed Patients and controls who used (2018) (78) Mean age: 29.5 years Venous blood samples osteocalcin (ng/mL), OPG no correlation between vitamin D or mineral (SD 7.2 years) were collected to assess (pg/mL) and sclerostin RANKL and T-score of supplements, had chronic Sex: 5M, 9F blood values (pg/mL) levels significantly lumbar spine BMD (β = diseases impacting bone Mean BMI: 44.6 kg/ BMD assessed by DXA scan lower in adults with PWS −0.033, P = .134) but a metabolism, used m2 15 normal weight controls than in controls (25.17 ± positive correlation between medications affecting bone Genotype: 12 del, 2 matched for sex and age 11.83 vs 35.2 ± 5.8, P < OPG and T-score of lumbar turnover, or had a fracture mUPD .001, 7.91 ± 7.94 vs 21.3 ± spine BMD (β = 1.521, P = in the 6 months preceding GHt: 43% 3.21, P < .01, 317.2 ± 77.5 .0001) and sclerostin and the study were excluded SHRT: 0%M, 43%F vs 443.5 ± 116, T-score of lumbar spine P < .006 and 1298 ± 318 vs BMD 1906 ± 698, P < .01 (β = 0.331, P = .0001) respectively) RANKL (pg/mL) significantly higher in adults with PWS than controls (77.5 ± 42.2 vs 51.8 ± 20.9, P < .004). However, this was no longer significant after correction for GHt and SHRT CTX and DKK-1 were not significantly different between PWS and controls Baraghithy Israel N: 30 Cross-sectional study. Vitamin D levels in PWS were N-oleoyl serine was positively Use of vitamin D supplements et al (2019) Mean age: 29.9 years Measurement of N-oleoyl 74.5 ± 79.3 ng/mL associated with Z-scores of unknown. (73) Sex: 18M, 12F serine, 25(OH) vitamin D, N-oleoyl serine was femoral neck (r = 0.405, Mean BMI: 28.4 kg/ calcium, alkaline significantly lower in PWS P = .0018), total hip (r = m2 phosphatase and than in controls (1.4 ± 0.439, P = .0007), lumbar Genotype: 16 del, 13 phosphatase in venous 0.7 pmol/mL vs 2.4 ± spine mUPD, 1 ICD blood. Assessment of 0.95 pmol/mL, P < .001) (r = 0.296, P = .0251) and GHt: NA Z-scores by DXA scan No significant differences in forearm (r = 0.349, P = SHRT: NA 25(OH) vitamin D, calcium, .0186) alkaline phosphatase, and phosphatase between patients with and without PWS Barrea et al Italy N: 15 Cross-sectional study. Data Vitamin D deficiency: 15/15 25(OH) vitamin D levels were Many exclusion criteria, (2020) (79) Mean age: 28 years collected by interview, (100%) significantly associated with including current therapy (range 19-41 years) physical examination and Dietary vitamin D intake was BMI (r = −0.52, P = .04), with calcium, osteoporosis Sex: 6M, 9F biochemical essays significantly lower in adults waist circumference (r = therapies, and medications Mean BMI: 44 kg/m2 Compared with 15 age-, sex-, with PWS than controls (4 ± −0.56, P = .03), fat mass (r = that may affect vitamin Genotype: NA and BMI-matched 1 µg/1.000 kcal vs 5 ± 1 µg/ −0.52, P = .04), and dietary absorption of metabolism GHt: none current, controls 1.000 kcal, P = .01). 25(OH) vitamin D intake (r = 0.91, P like SHRT 100% past vitamin D in adults with < .001) (continued) The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 1 73 Table 7. Continued Author (year) Country Patient characteristics Methods Outcome Influencing factors Remarks PWS significantly lower than Inclusion period October to controls (22 ± 7 vs 35 ± 10, March P = .001), regardless of BMI or fat mass category Damen et al NL N: 43 Open-label, prospective 25(OH) vitamin D levels at No significant difference was All patients had received GHt (2021) Mean age (range): cohort study, patients baseline (mean [range]): found in 25(OH) vitamin D for at least 5 years during (74)a 19.5 years received GHt during 3 66.0 (55.3-88.8) nmol/L levels after 3 years of GHt childhood (18.7-20.7) for years males and 18.4 Biochemical measurement years (15.8-23.8) from blood samples for females Sex: 18M, 25F Mean BMI: 24.5 kg/ m2 Downloaded from https://academic.oup.com/jcem/article/108/1/59/6712600 by guest on 06 November 2023 Genotype: 18 del, 20 mUPD, 4 ICD, 1 translocation Hypogonadism: 93% SHRT: 83% Hypogonadal without SHRT: 16% Faienza et al Italy N: 52 Cross-sectional study. 25(OH) vitamin D: After adjusting for age, irisin in Controls are normal weight (2021) Mean age: 30.6 years Biochemical measurement Median (IQR) vitamin D level adults with PWS the best adults, while irisin is also (66)a (SD 10.7 years) from blood samples and in adults with PWS was 28.8 predictors for irisin levels released from adipose tissue Sex: 22M, 30F DXA scans to asses BMD (9.2) ng/mL were the genetic background Exclusion criteria: use of Median BMI: 35.3 kg/ Compared with 54 normal Irisin: (β = −0.365, P = .0001), mineral or vitamin m2 weight adult controls No significant difference 25(OH) vitamin D levels supplements (except for Genotype: 32 del, 20 between Adults with PWS (β = 0.346, P = .0001), GHt vitamin D), presence of mUPD and controls (6.65 ± (β = −0.139, P = .0001), age chronic diseases with GHt: 6 4.49 μg/mL vs 7.24 ± at start (β = −0.317, P = possible impact on bone SHRT: 5%M, 33%F 5.20 μg/mL) .0001) and duration of GHt metabolism, use of Vitamin D: 50% (β = −0.139, P = .0001 age medication affecting bone supplementation at start of SHRT (β = turnover and fractures in −0.324, the 6 months preceding the P = .0001), IQ (β = 0.910, study P = .0001) and total body Study population might BMD adjusted for height (β overlap with Brunetti et al = 0.412, (78) P = .0001) 25(OH) vitamin D: No significant difference between 25(OH) vitamin D levels of adults with deletion and mUPD genotype (31.6 ± 9.2 vs 28.7 ± 10.5 ng/mL) Irisin: Significantly reduced in del compared with controls (P < .04), but not in mUPD compared with controls Patients with PWS without vitamin D supplementation had a significant reduction in irisin compared with controls (P < .001) and patients with supplementation (P < .02), for both the del (P < .004) and mUPD (P < .001) genotype Casamitjana Spain N: 27 Cohort study with GHt for At baseline: After 12 months of GHt the — et al (2022) Median age: 26 years 12 months in the adults Median (IQR): median (IQR) irisin level (80) (all >18 years) with PWS Irisin was 982.3 was 906.8 (583.5-1770.4) Sex: 12M, 15F Fasting blood samples were (519.4-1789.6) ng/mL in ng/mL (P = .76 compared to Median BMI: 34.5 kg/ collected for biochemical adults with PWS compared baseline) m2 essay with 89.8 (41.8-219.4) ng/ No significant change was Genotype: 18 del, 6 Control group: 22 volunteers mL in controls (P < .0001) observed for myostatin and mUPD, 3 ICD from hospital staff or Myostatin and IL-6 did not IL-6 GHt: 0% at baseline acquaintances, median differ significantly between (P > .05 for both) SHRT: 8 M, 7F age 27.5 years, 13 women Adults with PWS and controls (P > .05) Data are presented as mean ± SD, unless otherwise specified. When articles reported subgroup analysis for adults and children or patients >16 years old and patients <16 years old, only information for the adults or patients >16 years old are reported here whenever possible. Abbreviations: BMI, body mass index; BAP, bone alkaline phosphatase; BMD, bone mineral density; CTX-1, C-terminal telopeptide of type I collagen; del, deletion; DKK-1, Dickkopf-1; DXA, dual-energy X-ray absorptiometry; F, females; GHt, growth hormone treatment; M, males; mUPD, maternal uniparental disomy; N, number of patients; NA, not available; P1NP, N-terminal propeptide of type I procollagen; OPG, osteoprotegerin; RANKL, receptor activator of nuclear factor-κB ligand; SHRT, sex hormone replacement therapy; 25(OH) vitamin D, 25-hydroxy vitamin D. a Partly overlapping study population as current study. 74 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 1 Table 8. Results of studies reporting on scoliosis and other orthopedic conditions in adults with Prader–Willi syndrome Author (year) Country Patient Methods Prevalence scoliosis Influencing factors Remarks characteristics and orthopedic conditions Holm et al (1981) USA N: 10 Cross-sectional study. Cobb Scoliosis: 10/10 — Diagnosis PWS (35) Mean age: 28 years angle of ≥10° on spinal (100%). Average based on (range 20-41 X-ray Cobb angle: 22.5° clinical criteria years) Kyphosis: 5/10 (50%) instead of Sex: 6M, 4F Mean curve genetic tests BMI: NA kyphosis: 61° Genotype: NA GHt: NA Partsch et al Germany N: 19 Cross-sectional study. Data Scoliosis: 7/19 (37%) — Unknown (2000) (81) Mean age: 23 years collection from patient Kyphosis: 19/19 whether spinal (range 18-34 records (100%) X-ray was Downloaded from https://academic.oup.com/jcem/article/108/1/59/6712600 by guest on 06 November 2023 years) Gonarthrosis: 1/19 performed Sex: 7M, 12F (5%) Mean BMI 46 kg/ m2, range 31-74 kg/m2 Genotype: All deletion or mUPD GHt: 0% Butler et al UK N: 58 (information Cross-sectional study. Suspected scoliosis/ Scoliosis more prevalent Not all cases with (2002) (11) about scoliosis Semistructured interview kyphosis: 23/56 in females than in PWS were known for 56) with family or carers (41%) males (1.23:1 and 2.3:1 genetically Age range: 18-46 Scoliosis observed by for severe deformity). confirmed. No years a professional: 19/ BMI not significantly spinal X-ray Sex: 32M, 26F 56 (34%) associated with Mean BMI: 35 kg/ Serious scoliosis or scoliosis m2 intervention for Genotype: NA scoliosis: 7/56 GHt: NA (13%) Nakamura et al Japan N: 34 Retrospective cohort study. Scoliosis: 16/34 Genotype and GHt were — (2009) (39) Age range: 16-50 Cobb angle of ≥10° on (47%). Mean Cobb not significantly years spinal X-ray angle: 27° associated (analysis in Sex: 67M, 34Fb Severe scoliosis: 3/34 entire group of children BMI: NA (9%) and adults) Genotype: 80 del, 21 Surgery for scoliosis: no delb 1/34 (3%) GHt: 57%b Sode-Carlsen Scandinavia N: 43 Multicenter international Scoliosis: 23/38 (61%) After 2 years of GHt, 6 Unknown GHt et al (2011) Mean age: 29.5 RCT. GHt vs placebo for Median Cobb patients (16%) showed prior to study, (64)a years (range 1 year, followed by angle: 13° progression of scoliosis but none was 16-42) open-label GHt for all Operation for and 3 (8%) showed a treated for at Sex: 19M, 24F patients for 1 year (GHt scoliosis: 2/38 (5%) decrease of Cobb angle least 1 year Mean (SD) BMI at group) or 2 years (placebo >5° preceding the baseline 28.9 group), until all patients study (19.4-44.8) kg/m2 had received GHt for 2 4 patients did not Genotype: NA years in total complete the SHRT: 47%M, Scoliosis evaluated by spinal study 25%F X-ray and defined as Cobb angle >10° and progression as a change of ≥+5° change in Cobb angle Sinnema et al NL N: 102 Cross-sectional study. Scoliosis: 57/102 Patients with a deletion Unknown if (2011) (10) Mean age: 36 years Semistructured interviews (56%) had more knee scoliosis was and Sinnema (range 18-66 with caregivers and review Foot problems: 81/ problems than other confirmed by et al (2013) years) of medical files 102 (79%) genotypes (11% vs spinal X-ray in (82)a Sex: 49M, 53F Knee problems: 6/102 0%, P = .02), there was all cases Mean BMI: 32 kg/ (6%) no difference in m2 (range Hip problems: 9/102 scoliosis, foot 17-52 kg/m2) (9%) problems or hip Genotype: 55 del, 44 Surgery for problems mUPD, 3 ICD musculoskeletal BMI and age were not GHt: 5% current, conditions: 28/102 associated to any 8% past (27%) orthopedic conditions Of which: Surgery for scoliosis: 11/102 (11%) Hip surgery: 4/102 (4%) (continued) The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 1 75 Table 8. Continued Author (year) Country Patient Methods Prevalence scoliosis Influencing factors Remarks characteristics and orthopedic conditions Arthroscopy: 4/102 (4%) Knee surgery: 3/102 (3%) Osteosynthesis: 3/102 (3%) Foot surgery: 3/102 (3%) Laurier et al France N: 154 Cross-sectional study. Spinal Scoliosis: 95/126 No association with — (2015) (37)a Mean age: 28 years X-ray (75%) genotype (del vs (range 16-54 mUPD) or age Downloaded from https://academic.oup.com/jcem/article/108/1/59/6712600 by guest on 06 November 2023 years) Sex: 68M, 86F Mean BMI ± SD: 42 ± 11 kg/m2 Genotype: 101 del, 24 mUPD, 3 ICD, 3 translocation, 18 AMP non del, 5 AMP GHt 14% current, 24% past Coupaye et al France N: 73 Cross-sectional study. Scoliosis: 57/73 (78%) No association between Unknown if spinal (2016) (84)a Mean age: 25 years Systematic examination at Severe/operated scoliosis and genotype, X-rays were (range 16-58 outpatient clinic scoliosis: 16/73 but severe/operated performed years) (22%) scoliosis was more Sex: 35M, 38F prevalent in mUPD (9/ Mean BMI ± SD: 26, 35%) than del (7/ del-group: 41 ± 47, 15%, P = .047) 11 kg/m2 mUPD-group: 35 ± 10 kg/m2 Genotype: 47 del, 26 mUPD GHt: 15% current, 36% past Woods et al USA N: 19 Cross-sectional study. Scoliosis: 1/19 (5%) — Unknown if PWS (2018) (83) Mean age: 34.5 Questionnaires filled in by was genetically (range 18-62 guardians or caregivers confirmed years) Sex: 11M, 8F Mean BMI: 27 kg/ m2 (range 19.5-35.0 kg/m2) Genotype: NA GHt: NA Pellikaan et al NL N: 115 Cross-sectional study Scoliosis after Scoliosis was more — (2020) (8)a Median age: 29 Spinal X-ray if gibbus systematic frequent in patients years (range deformity present during screening: 83/112c with an mUPD (59%) 18-72 years) physical examination (74%) than with a deletion Sex: 56M, 59F Scoliosis was (81%, P = .02). Median BMI: 29 kg/ undiagnosed before Scoliosis was not m2 (IQR systematic health associated with BMI, 26-35 kg/m2) screening in 22 age, sex, or living Genotype: 64 del, 41 (20%) patients situation mUPD, 3 ICD, 7 unknown GHt: 36% current Crinò et al (2022) N: 74 Cross-sectional study Scoliosis: 87.8% — — (40) Age range: 18-50 Observation of the standing years and sitting posture, Sex: 34M, 40F Adam’s forward bend test, Mean BMI ± SD: 36 and spinal X-ray ± 9 kg/m2 Genotype: 46 del, 28 mUPD GHt: 53 current or past (continued) 76 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 1 Table 8. Continued Author (year) Country Patient Methods Prevalence scoliosis Influencing factors Remarks characteristics and orthopedic conditions Noh et al Korea N: 68 Cross-sectional study. Scoliosis: 41/68 — Unknown (2022) (75) Age range: 19-34 Data collection from (60%) whether years patient records spinal X-ray Sex: 39M, 29F was Mean BMI: 35 kg/ performed m2 Genotype: 44 del, 24 other GHt: 48 previous, 10 current Downloaded from https://academic.oup.com/jcem/article/108/1/59/6712600 by guest on 06 November 2023 Data are presented as mean ± SD, unless otherwise specified. When articles reported subgroup analysis for adults and children or patients >16 years old and patients <16 years old, only information for the adults or patients >16 years old are reported here whenever possible. Abbreviations: AMP, abnormal methylation profile; BMI, body mass index; del, deletion; F, females; GHt, growth hormone treatment; IQR, interquartile range; M, males; mUPD, maternal uniparental disomy; N, number of patients; NA, not available. a Study population partly overlapping with current study. b Data for the entire cohort of 101 patients, which also included patients <16 years old. c Scoliosis was missing for three patients. more prevalent in adults with PWS with a deletion. However, Scoliosis Faienza et al (66) did not find a significant association between According to our literature review, the prevalence of scoliosis genotype and osteoporosis. Jørgensen et al (67) reported that in adults with PWS is 5% to 100% Table 8. The large vari­ Z-scores of men were significantly lower than those in women ation in this prevalence could be explained by underestima­ with PWS and that a BMI > 30 kg/m2 was associated with a tion of the prevalence due to the use of interviews and/or higher BMD. Van Nieuwpoort et al (68) reported that male questionnaires (without physical examination or X-ray) to sex was associated with lower lumbar spine T-scores. In this diagnose scoliosis in some studies (10, 11, 81–83). Studies study, 87% of patients (both male and female) had hypo­ that systematically screened for scoliosis by physical examin­ gonadism, of whom 54% were treated with SHRT. ation and/or spinal X-ray reported a prevalence between 47% Information on (the treatment of) hypogonadism was not giv­ and 100%. Some studies reported a significantly higher preva­ en for males and females separately. lence of scoliosis in females (10, 11, 82) and patients with an A prospective cohort study by Kido et al (69) found that tes­ mUPD (8). However, not all studies replicated these findings tosterone replacement therapy increased BMD after 2 years. (10, 37, 39, 82, 84). Sode-Carlsen et al (64) found that 16% Donze et al (71) found a significant increase in SDS of total of patients receiving GHt had progression of scoliosis (ie, in­ body BMD after 2 years of SHRT. However, Longhi et al crease in the Cobb angle) and 8% had a decrease in the (70) did not find an association between SHRT and BMD. Cobb angle after 2 years of GHt. Growth Hormone Treatment in Relation to Bone Health Discussion Table 6 shows the studies reporting on the effect of GHt on In this study, we showed that osteoporosis, osteopenia, skeletal problems (osteoporosis and/or scoliosis). Previous lit­ and scoliosis are common skeletal problems in adults with erature remains controversial regarding the effects of GHt. PWS. Modifiable risk factors for osteoporosis such as hypo­ Several studies (65, 71–76) did not find any significant effect gonadism, insufficient dairy intake, sedentary lifestyle, and of GHt on BMD. Other studies showed conflicting results corticosteroid use were often present, but we did not find (67, 77). modifiable risk factors for scoliosis. The prevalence of osteoporosis found in this study is in line with previous studies in adults with PWS that showed Vitamin D Levels and Bone Markers and a prevalence of 2% to 26% (8, 10–12, 75). However, not Bone-related Factors all studies performed a systematic screening for osteopor­ Table 7 summarizes the results of the studies that investigated osis using DXA scans, likely leading to an underestimation 25(OH) vitamin D and the bone related factors irisin, of the true prevalence in these studies. Osteoporosis was N-terminal propeptide of type I procollagen (P1NP), osteocal­ more prevalent in males than in females, and this remained cin, Receptor activator of nuclear factor-κB Ligand (RANKL), significant even after correction for age, height, weight, and osteoprotegerin (OPG), and N-oleoyl serine in patients with genotype. In a previous study, males and females differed PWS (66, 67, 73, 78). with regard to the use of psychotropic medication, which Longhi et al (70) and Brunetti et al (78) found lower levels was slightly increased in males (85). As the use of some of vitamin D in adults with PWS than in controls. However, types of psychotropic medication is related to decreased Purtell et al (29) did not find any association. According to BMD (86, 87), this might partly explain this difference. Faienza et al (66) vitamin D levels were not related to Fractures were more prevalent in males. Behavioral chal­ genotype. lenges are comparable between males and females, which The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 1 77 Downloaded from https://academic.oup.com/jcem/article/108/1/59/6712600 by guest on 06 November 2023 Figure 1. Recommendations for the prevention, detection, and treatment of osteoporosis in adults with PWS (49, 95, 96). Abbreviations: DXA, dual-energy X-ray absorptiometry; PWS, Prader–Willi syndrome; VFA, vertebral fracture assessment. suggests that the increased risk of fractures in males is not treatment of risk factors such as hypogonadism or hyperthy­ due to temper outburst (88, 89). roidism, leading to small numbers of untreated patients. GHt may increase BMD and decrease the risk of osteoporosis Additionally, some risk factors were rare, also resulting in in patients with PWS (77), although results are inconclusive low statistical power. (65, 67, 70, 76, 82). In our study, GHt was not associated In our cohort, vertebral fractures were found in 3%, which with a decreased risk of osteoporosis. However, Longhi et al is similar to the prevalence found by Waterloo et al (90) for showed that adults with PWS have unfavorable bone geometry vertebral fractures in the general population before the age and reduced bone strength, leading to an increased risk of frac­ of 60. However, the patients in our cohort were relatively tures independent of BMD. GHt improves bone geometry, pos­ young with a median age of only 31 years (IQR 25-40), sibly reducing fracture risk without increasing BMD (70). with only a few patients who were above 50 years old. Risk factors for osteoporosis were prevalent. However, in Therefore, we were not able to investigate the prevalence of our cohort many well-known risk factors for osteoporosis fractures in older adults. Moreover, data on vertebral fracture were not significantly related to osteoporosis or osteopenia. assessments were not available for all patients, possibly lead­ This is could be caused by lack of statistical power due to early ing to an underestimation. 78 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 1 Downloaded from https://academic.oup.com/jcem/article/108/1/59/6712600 by guest on 06 November 2023 Figure 2. Recommendations for the detection, monitoring of progression, and treatment of scoliosis in adults with PWS (97–9997–99). Abbreviation: GHt, growth hormone therapy. The prevalence of scoliosis found in this study was 80%. available (64). However, in our study, childhood GHt was not as­ Previous research reported a prevalence of scoliosis between sociated with scoliosis. This is in line with previous pediatric stud­ 5% and 100% (Table 8). Scoliosis is thought to be related to ies that reported no effect of GHt on onset of scoliosis, curve obesity and hypotonia of (paravertebral) muscles (35, 38). progression or need for surgery in patients with PWS (38, 92, 93). However, in our cohort, scoliosis was not significantly related Although the median age of our cohort was only 31 years, to BMI and hypotonia was not assessed. According to Burwell we already found a high prevalence of osteoporosis (14%) et al, childhood GHt could be related to an increased risk of scoli­ and osteopenia (54%). Due to improved health care, life ex­ osis due to increased growth velocity (91). Sode-Carlson et al pectancy of patients with PWS has drastically increased found a progression of the Cobb angle of >5° in 16% of patients (94). Therefore, early prevention and detection is crucial to with PWS after 2 years of GHt, although no control group was prevent complications later in life. The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 1 79 Clinical Recommendations trials. However, beside the (expected) possible positive effects Due to the complexity of the syndrome, patients with PWS are on BMD, regular exercise is also important in patients with preferably treated in a PWS reference center. However, refer­ PWS to decrease body fat mass, increase lean body mass, ence centers are not always available. Therefore, we have de­ and improve coordination to decrease fall risk (25). fined practical clinical recommendations for the optimization Therefore, we recommend regular physical activity of at least of skeletal health in adults with PWS (Figs. 1 and 2) that can be 30 minutes, but ideally at least 1 hour daily, preferably used in any clinical setting. weight-bearing in order to maintain and possibly improve We recommend screening for osteoporosis and scoliosis in BMD and body composition. We also recommend aerobic all adults with PWS and assessing risk factors for osteoporosis. and muscle strengthening exercises, but we realize this might The screening should consist of a DXA scan (if possible, with be difficult due to hypotonia and challenging behavior. vertebral fracture assessment) every 5 years in patients with normal BMD on the previous DXA scan and every 2 years in Recommendation 3: Avoidance of Unnecessary patients with osteopenia or osteoporosis. For scoliosis, yearly Corticosteroid use in Central Adrenal Insufficiency evaluation should be performed. We want to stress the fact that One in 10 adults in our cohort used corticosteroid replace­ Downloaded from https://academic.oup.com/jcem/article/108/1/59/6712600 by guest on 06 November 2023 osteoporotic fractures can be easily missed due to the high pain ment, mostly only during physical or psychological stress. threshold and intellectual disability often present in patients Few patients had proven central adrenal insufficiency; most with PWS. Preventive measures to avoid the development of patients received corticosteroids as part of local guidelines osteoporosis in adults with PWS include (1) optimizing cal­ for the treatment of PWS. cium and vitamin D intake, (2) optimizing physical activity, Corticosteroid-induced osteoporosis is the most common (3) avoidance of unnecessary use of corticosteroids, (4) yearly cause of secondary osteoporosis in the general population screening for (and treatment of) hypogonadism, (5) yearly (107, 108). Glucocorticoid use increases the risk of fractures screening for hyperthyroidism and hyperparathyroidism, (6) (109, 110), which can occur as early as 3 months after start extra caution in patients using psychotropic medication, and of corticosteroids and even with low doses of steroids (eg, (7) cessation of smoking and alcohol use. 2.5-7.5 mg of prednisone daily) (111). In our clinical experi­ ence, when adults with PWS are prescribed corticosteroid Recommendation 1: Optimizing Calcium and Vitamin D stress doses, these stress doses are sometimes frequently ad­ Intake ministered due to recurrent episodes of psychological stress. In our study, we showed that 78% of participants used vita­ As we previously showed that central adrenal insufficiency is min D supplements and 14% had a dairy intake of ≥3 units/ rare in adults with PWS (1.2%) (112), we strongly recom­ day. Vitamin D has a direct effect on osteocytes, osteoblasts, mend refraining from routine corticosteroid “stress-doses” and osteoclasts and regulates calcium and phosphate metabol­ in adults with PWS. In order to prevent secondary osteopor­ ism (100, 101). In the general population, vitamin D defi­ osis due to corticosteroid use, we advise only prescribing cor­ ciency increases the risk of osteoporosis and studies with ticosteroids when central adrenal insufficiency is proven. vitamin D supplementation show a reduced fracture risk and increased BMD (102, 103). We did not find a difference Recommendation 4: Yearly Screening for (and Treatment of) in 25(OH) vitamin D levels or vitamin D supplementation be­ Hypogonadism tween patients with and without osteoporosis, probably due Hypogonadism was prevalent in both males (93%) and fe­ to lack of power as few patients had low vitamin D levels males (86%). Hypogonadism is a well-known risk factor for and many patients already received vitamin D supplementa­ osteoporosis and timely treatment with hormone replacement tion. However, previous studies reported reduced vitamin D therapy can reduce this risk (113–115). In this study we did not levels in adults with PWS, especially in those with obesity find an association between hypogonadism or SHRT and (70, 78, 79). The reduced 25(OH) vitamin D levels could be osteoporosis. However, as all patients were treated in a PWS related to reduced exposure to sunshine and an increased vol­ reference center, untreated hypogonadism was rare, resulting ume of distribution in adipose patients as vitamin D is fat sol­ in low statistical power. Previous research has shown a signifi­ uble (104). We recommend yearly measurement of 25(OH) cant improvement in BMD in men (69) and women (71) with vitamin D levels in all adults with PWS not receiving vitamin PWS after the start of SHRT. Therefore, we recommend yearly D supplementation. We recommend starting vitamin D screening for hypogonadism. If hypogonadism is present, ad­ supplementation in patients with PWS with a vitamin D level equate SHRT should be started as soon as possible to avoid below the reference, irrespective of DXA scan results. Addition­ the negative effects of hypogonadism on BMD (69, 70). As ally, we recommend a dairy intake of ≥3 units a day or calcium starting and maintaining SHRT can be challenging, we have supplementation to ensure adequate calcium intake. previously defined practical recommendations for hormone re­ placement therapy in males (15) and females (16). Recommendation 2: Optimizing Physical Activity Many patients (39%) in our cohort exercised less than 30 mi­ Recommendation 5: Yearly Screening for Hyperthyroidism nutes a day. In nonsyndromic pre- and postmenopausal wom­ and Primary Hyperparathyroidism en with osteoporosis, physical activity is known to improve The prevalence of hyperthyroidism in this study was 1.1%, bone mineral content and BMD, provided enough nutrients, which is similar to the prevalence in the general population calcium, and vitamin D are available (105). In children with in Europe (<1%) and the United States (1.3%) (116, 117). PWS, Duran et al (26, 106) showed a positive association be­ The prevalence of primary hyperparathyroidism found in tween moderate weight-bearing physical activity and hip the current study was 0.8%, which is in line with prevalence BMD. The effect of physical activity on BMD in adults with in the general adult population (0.1-0.7%) (118–121). PWS has, to our knowledge, not yet been studied in clinical Patients with PWS are already at risk of developing 80 The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 1 osteoporosis and they might be unable to express the subtle that patients with PWS may have an atypical presentation complaints of hyperthyroidism and hyperparathyroidism of fractures. Thorough physical examination should be per­ due to intellectual disability. Therefore, we recommend yearly formed in case of unexplained behavioral changes or refusal screening for hyperthyroidism and hyperparathyroidism by of physical activities to exclude underlying physical prob­ measuring thyroid-stimulating hormone, free thyroxine, and lems such as undiagnosed fractures. Additionally, when a serum calcium levels. In case of hypercalcemia, parathyroid DXA scan is performed, preferably a vertebral fracture as­ hormone (PTH) should also be measured. Depending on local sessment should also be performed to exclude undiagnosed hospital policy and the costs of PTH measurement, yearly vertebral fractures. (simultaneous) screening for both calcium and PTH could also be performed. Yearly Screening for Scoliosis and Other Orthopedic Conditions Recommendation 6: Extra Caution in Patients Using We recommend clinical assessment of scoliosis in all patients Psychotropic Medication with PWS during yearly physical examination. Furthermore, Psychiatric disorders, such as manic or depressive episodes Downloaded from https://academic.oup.com/jcem/article/108/1/59/6712600 by guest on 06 November 2023 we recommend that a standing full spine posterior-anterior with psychotic features are common in PWS, with an esti­ X-ray is performed in case of doubt, progression, or when mated prevalence of 16% to 28% (122–125). Psychotic fea­ spine deformity surgery is considered (see Fig. 2). When scoli­ tures are most common in patients with an mUPD (122– osis and low BMD are both present, complications of surgery 125). Most psychotropic medications, such as selective sero­ such as iatrogenic instability and postoperative fractures are tonin reuptake inhibitors, benzodiazepines, tricyclic antide­ more prevalent (144, 145). Therefore, surgical correction of pressants, and conventional antipsychotics (eg, haloperidol) scoliosis is more challenging in patients with low BMD. have been associated with an increased (osteoporotic) fracture Besides scoliosis, patients with PWS also have an increased risk in the general population (126–131). Furthermore, select­ risk of other orthopedic conditions, such as hip dysplasia, ive serotonin reuptake inhibitors, benzodiazepines, and atyp­ genu valgum, and kyphosis (146). In case of suspect kyphosis, ical antipsychotics (eg, risperidone, clozapine) have been a lateral view total spine X-ray should be performed. These associated with a higher osteoporosis risk, though tricyclic conditions were not systematically documented in the medical antidepressants might reduce the risk for osteoporosis (86). records and could not be investigated in this retrospective It has been suggested that use of conventional antipsychotics study. may cause higher prolactin levels, possibly leading to hypo­ gonadism and osteoporosis (131). There is conflicting evi­ Strengths and Limitations dence regarding the effect on BMD of antipsychotics that do not raise prolactin levels (132). The relationship between The current study is, to our knowledge, the first multicenter osteoporosis and the use of psychotropic medication in adults study on osteoporosis including more than 300 adults with with PWS is still unknown. As current evidence is scarce, we PWS. We were able to assess not only the prevalence of suggest performing a DXA scan every 5 years in adults with scoliosis and osteoporosis, but also the risk factors for osteo­ PWS who are taking psychotropic medication, just like in porosis in this rare genetic syndrome. Additionally, we per­ adults who do not use psychotropic medication. We advise formed an extensive literature review on both osteoporosis continuing psychotropic treatment as long as it is indicated, and scoliosis in adults with PWS. However, our study also regardless of the BMD. has some limitations. First, as data were collected retrospect­ ively from patient records in different centers, screening and treatment protocols varied between centers. In particular, Recommendation 7: Cessation of Smoking and Alcohol use the assessment of vertebral fractures varied between centers, In our cohort, there was no relation between alcohol usage possibly leading to underdiagnosis of asymptomatic vertebral and osteoporosis. However, adults with osteoporosis fractures in some centers. In some centers, DXA scans were smoked significantly more cigarettes per week than those only performed when risk factors for osteoporosis were pre­ without osteoporosis. In the general population, smoking sent. As we only included patients for whom DXA scans re­ has been associated with low BMD (133–135) and increased sults were available, the prevalence of osteoporosis and fracture risk (133, 136). Cessation of smoking has been osteopenia we report might be an overestimation. Second, shown to increase BMD (137–139). Furthermore, chronic scoliosis was not systematically assessed using standing full heavy alcohol usage has been associated with decreased spine X-rays in all patients, possibly leading to an underesti­ BMD (140, 141). In contrast, light to moderate alcohol con­ mation of scoliosis prevalence. Third, as this was an inter­ sumption might increase BMD in females (141, 142). We rec­ national study, different DXA machines were used. To ommend that smoking and heavy alcohol usage is compare the results of different machines, the sBMD discouraged in all adults with PWS. was calculated for all DXA scan results. However, earlier re­ search has shown that a small bias might remain (147). Awareness of High Pain Threshold and Intellectual Disability Furthermore, the results could have been influenced by obes­ Patients with PWS seldomly report pain. This can be due to ity, which might lead to an overestimation of BMD their high pain threshold and intellectual disability (12, 148). Moreover, previous research has shown that the (6, 143), which may impair their ability to express physical true BMD might be underestimated in subjects with short stat­ complaints. This may lead to delay in the diagnosis of (osteo­ ure (12, 149). As the median height in our cohort was 1.56 porotic) fractures. In our cohort, several fractures had re­ (IQR 1.49-1.64) meters, our reported prevalence of osteopor­ mained unnoticed for weeks, as the only symptoms had osis and osteopenia might be an overestimation. Uniform pro­ been change of behavior or walking pattern (personal com­ spective studies are needed to overcome these limitations and munications). Therefore, it is important to keep in mind to prospectively assess the fracture incidence. The Journal of Clinical Endocrinology & Metabolism, 2023, Vol. 108, No. 1 81 Conclusion Prader-Willi syndrome: recommendations for screening and treat­ ment. J Clin Endocrinol Metab. 2020;105(12):e4671-e4687. In conclusion, osteoporosis, fractures, and scoliosis are com­ 9. Proffitt J, Osann K, McManus B, et al. Contributing factors of mon skeletal problems in adults with PWS. Male sex was asso­ mortality in Prader–Willi syndrome. Am J Med Genet Part A. ciated with a higher prevalence of osteoporosis. In our cohort, 2019;179(2):196-205. the most prevalent modifiable risk factors for osteoporosis were 10. Sinnema M, Maaskant MA, van Schrojenstein Lantman-de Valk (male and female) hypogonadism, insufficient dairy intake, sed­ HM, et al. Physical health problems in adults with Prader-Willi entary lifestyle, and corticosteroid treatment. We did not iden­ syndrome. Am J Med Genet Part A. 2011;155(9):2112-2124. tify any risk factors for scoliosis. In particular, GHt was not 11. Butler JV, Whittington JE, Holland AJ, Boer H, Clarke D, Webb associated with scoliosis. Based on the cohort study and litera­ T. Prevalence of, and risk factors for, physical ill-health in people ture review, we provide practical clinical recommendations to with Prader-Willi syndrome: a population-based study. Dev Med prevent complications in this vulnerable patient population. Child Neurol. 2002;44(4):248-255. 12. Höybye C, Hilding A, Jacobsson H, Thorén M. Metabolic profile and body composition in adults with Prader-Willi syndrome and Acknowledgments severe obesity. J Clin Endocrinol Metab. 2002;87(8):3590-3597. Downloaded from https://academic.oup.com/jcem/article/108/1/59/6712600 by guest on 06 November 2023 13. Crino A, Schiaffini R, Ciampalini P, et al. Hypogonadism and pu­ The authors would like to thank Elise Krabbendam and bertal development in Prader-Willi syndrome. Eur J Pediatr. Marjolein Udo from the Erasmus Medical University 2003;162(5):327-333. Library for developing and updating the search strategy for 14. Greenswag LR. Adults with Prader-Willi syndrome: a survey of the literature review. 232 cases. Dev Med Child Neurol. 1987;29(2):145-152. 15. Pellikaan K, Brahim YB, Rosenberg AGW, et al. Hypogonadism in adult males with Prader-Willi syndrome-clinical recommenda­ Author Contributions tions based on a Dutch cohort study, review of the literature Conceptualization, K.P. and L.C.G.d.G.; methodology, and an international expert panel discussion. J Clin Med. D.v.A., K.P., and L.C.G.d.G.; formal analysis, D.v.A; investi­ 2021;10(19):4361. gation, D.v.A, K.P., M.C., C.H., T.M., G.G., A.C. (Antonino 16. Pellikaan K, Ben Brahim Y, Rosenberg AGW, et al. Crinò), A.C. (Assumpta Caixàs), C.P., H.M., T.W., and Hypogonadism in women with Prader-Willi syndrome—clinical L.C.G.d.G.; resources, M.C., C.H., T.M., G.G., A.C. recommendations based on a Dutch cohort study, review of the lit­ (Antonino Crinò), A.C. (Assumpta Caixàs), C.P., H.M., erature and an international expert panel discussion. J Clin Med. 2021;10(24):5781. T.W., and L.C.G.d.G.; data curation D.v.A; writing—original 17. Vestergaard P, Kristensen K, Bruun JM, et al. Reduced bone min­ draft preparation, D.v.A. and K.P.; writing—review and edit­ eral density and increased bone turnover in Prader-Willi syndrome ing, all authors; visualization: D.v.A.; supervision, L.C.G.d.G. compared with controls matched for sex and body mass index – a and A.J.v.d.L.; project administration, D.v.A., K.P., and cross-sectional study. J Pediatr. 2004;144(5):614-619. L.C.G.d.G. All authors have read and agreed to the published 18. Butler MG, Haber L, Mernaugh R, Carlson MG, Price R, Feurer version of the manuscript. ID. Decreased bone mineral density in Prader-Willi syndrome: comparison with obese subjects. Am J Med Genet. 2001;103(3): 216-222. Conflict of Interest 19. Degerblad M, Bengtsson B-A, Bramnert M, et al. Reduced bone The authors have no conflict of interest to disclose. mineral density in adults with growth hormone (GH) deficiency: increased bone turnover during 12 months of GH substitution therapy. Eur J Endocrinol. 1995;133(2):180-188. 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