Cost-effectiveness analysis of hip fracture prevention with vitamin D supplementation: a Markov micro-simulation model applied to the French population over 65 years old without previous hip fracture.

UNLABELLED: We performed a cost-effectiveness analysis of four vitamin D supplementation strategies for primary prevention of hip fracture among the elderly population and found that the most cost-effective strategy was screening for vitamin D insufficiency followed by adequate treatment to attain a minimum 25(OH) serum level. INTRODUCTION: Vitamin D supplementation has a demonstrated ability to reduce the incidence of hip fractures. The efficiency of lifetime supplementation has not yet been assessed in the population over 65 years without previous hip fracture. The objective was to analyze the efficiency of various vitamin D supplementation strategies for that population. METHODS: A Markov micro-simulation model was built with data extracted from published studies and from the French reimbursement schedule. Four vitamin D supplementation strategies were evaluated on our study population: (1) no treatment, (2) supplementation without any serum level check; (3) supplementation with a serum level check 3 months after initiation and subsequent treatment adaptation; (4) population screening for vitamin D insufficiency followed by treatment based on the vitamin D serum level. RESULTS: "Treat, then check" and "screen and treat" were two cost-effective strategies and dominated "treat without check" with incremental cost-effectiveness ratios of €5,219/quality-adjusted life-years (QALY) and €9,104/QALY, respectively. The acceptability curves showed that over €6,000/QALY, the "screen and treat" strategy had the greatest probability of being cost-effective, and the "no treatment" strategy would never be cost-effective if society were willing to spend over €8,000/QALY. The sensitivity analysis showed that among all parameters varying within realistic ranges, the cost of vitamin D treatment had the greatest effect and yet remained below the WHO cost-effectiveness thresholds. CONCLUSIONS: Population screening for vitamin D insufficiency followed by treatment based on the vitamin D serum level is the most cost-effective strategy for preventing hip fracture occurrence in the population over 65 years old.

A Double-Blind, Placebo Controlled, Randomized Trial to Assess the Impact of a Monthly Administration of 50,000 IU of Vitamin D3 for 6 Months on Serum Levels of 25-Hydroxyvitamin D in Healthy Young Adults.

In this double blind, unicentre, randomized, placebo controlled study, we evaluated the changes in 25-hydroxyvitamin D (25(OH)D) serum levels in 150 young Belgian adults (18-30 years), monthly supplemented with 50,000 IU of vitamin D (VTD) or placebo for 6 months, from November 2010 to May 2011. At T0, 30% of the population presented 25(OH)D serum levels below 20 ng/mL. In the VTD-treated group, mean serum levels increased from 21.2 ± 8.2 to 30.6 ± 8.8 ng/mL (P < 0.001) at T3mo and to 36.0 ± 9.2 ng/mL (P < 0.001) at T6mo. Despite documented VTD intake, no changes in serum levels were, however, observed in 10% of the treated group. In the placebo group, mean 25(OH)D serum levels decreased from 22.8 ± 8.5 to 14.0 ± 6.9 ng/mL at T3mo (P < 0.001) but returned to values not significantly different from those observed at T0 (23.5 ± 8.6 ng/mL) at T6mo. No difference between serum calcium levels was observed between the groups throughout the study. In conclusion, monthly supplementation with 50,000 UI of VTD in winter can warrant serum 25(OH)D levels above 20 ng/mL in 96.2% of those healthy young adults without inducing unacceptably high 25(OH)D concentration. This supplementation is safe and may be proposed without 25(OH)D testing.

Vitamin D supplementation in a healthy, middle-aged population: actual practices based on data from a French comprehensive regional health-care database.

BACKGROUND/OBJECTIVES: The debate surrounding recommendations for vitamin D supplementation in middle-aged patients (that is, 20-60 years of age) with low serum concentrations of 25-hydroxyvitamin D (25(OH)D) is growing. Our aim was to describe practices regarding vitamin D supplementation in this age group, which are basically unknown. SUBJECTS/METHODS: We performed an analysis using exhaustive reimbursement data from the individuals in Rhône-Alpes area, a French region regrouping more than 6 million of inhabitants. The data were collected from the French Insurance Health-care System. Patients who were 20-60 years of age, had no severe comorbidities, had a 25(OH)D assay between 1 December 2008 and 31 January 2009 were identified. Those who received a subsequent prescription for vitamin D were included in this analysis. We described patterns of vitamin D supplementation by frequency and daily dose. RESULTS: The sample in this study included 1311 patients. The mean age was 47.7 years (s.d.: 9.5) and the median age was 50.2 years. Most of the participants (that is, 85.9%) were women. A total of 372 distinct prescription patterns for vitamin D supplementation were observed. The two most frequent (that is, 32.6% in total) involved a unique dispensation of a high dose of either 200,000 (17.5%) or 100,000 IU (15.1%). Most prescribed supplements were based on vitamin D3 (65%), and the most prescribed forms were high dose ampoules (81.6%). Only 48.9% of the participants were given a maintenance prescription after the initial loading phase. CONCLUSIONS: Our results reveal a significant variability in the prescriptions for vitamin D supplementation from physicians in the French population. Moreover, less than half of the patients receive maintenance therapy after the initial loading phase of supplementation.

Vitamin D supplementation in older adults: searching for specific guidelines in nursing homes.

BACKGROUND: The prevalence of vitamin D insufficiency is very high in the nursing home (NH) population. Paradoxically, vitamin D insufficiency is rarely treated despite of strong clinical evidence and recommendations for supplementation. This review aims at reporting the current knowledge of vitamin D supplementation in NH and proposing recommendations adapted to the specificities of this institutional setting. DESIGN: Current literature on vitamin D supplementation for NH residents was narratively presented and discussed by the French Group of Geriatrics and Nutrition. RESULT: Vitamin D supplementation is a safe and well-tolerated treatment. Most residents in NH have vitamin D insufficiency, and would benefit from vitamin D supplement. However, only few residents are actually treated. Current specific and personalized protocols for vitamin D supplementation may not be practical for use in NH settings (e.g., assessment of serum vitamin D concentrations before and after supplementation). Therefore, our group proposes a model of intervention based on the systematic supplementation of vitamin D (1,000 IU/day) since the patient's admission to the NH and throughout his/her stay without the need of a preliminary evaluation of the baseline levels. Calcium should be prescribed only in case of poor dietary calcium intake. CONCLUSION: A population-based rather than individual-based approach may probably improve the management of vitamin D insufficiency in the older population living in NH, without increasing the risks of adverse health problems. The clinical relevance and cost effectiveness of this proposal should be assessed under NH real-world conditions to establish its feasibility.

Nutritional approach for inhibiting bone resorption in institutionalized elderly women with vitamin D insufficiency and high prevalence of fracture.

BACKGROUND: Nutritional approach to the deterioration of bone integrity and increased fracture risk appears to be particularly appropriate in elderly women living in nursing homes. OBJECTIVE: To investigate the beneficial effect of the consumption of soft plain cheese on bone resorption markers in institutionalized elderly women. DESIGN: Prospective, randomized crossover controlled study. SETTING: Six French nursing homes or other institutions for elderly. PARTICIPANTS: Institutionalized women ≥ 65 years old with low vitamin D status and calcium intake below 700 mg/day. INTERVENTION: Consumption of soft plain cheese made of semi-skimmed milk which was fortified by both vitamin D3 (+1.25 µg/100g) and milk extracted Ca, thus achieving a total Ca content of 151 mg/100g as compared to about 118 mg/100g for standard fresh cheese. Two servings were taken every day during the 6 weeks that preceded or followed a period of 6 weeks without soft plain cheese consumption. MEASUREMENTS: The primary end point was the change in serum carboxy terminal cross-linked telopeptide of type I collagen (CTX) selected as a marker of bone resorption. RESULTS: 29 women aged 73-94 yr were selected, 21 of them with mean age 87.2±6.1 years remained compliant. The intervention increased calcium and protein intakes by 51% (904±228 vs. 599±122 mg/d) and 33 % (74.2±17.1 vs. 55.6±12.7 g/d, mean±SD), respectively. The dietary intervention was associated with a statistically significant increase in serum levels of both 25OHD and IGF-I, while those of [corrected] CTX and TRAP5b were significantly reduced. Compliance was 93,4 %. The daily consumption of two servings of soft plain cheese was well accepted in terms of tastiness and appetite suited portion size. CONCLUSION: This randomized crossover controlled trial demonstrates that in elderly women living in nursing homes, the consumption of soft plain cheese increasing the supply of vitamin D, calcium and proteins, could reduce bone resorption and thereby reduce the risk of incidental fragility fractures in the long term.

[Update on vitamin D and evaluation of vitamin D status]. / Actualité sur les effets de la vitamine D et l'évaluation du statut vitaminique D.

Knowledge about vitamin D has greatly improved during the last few years. Vitamin D cannot any more be considered as exclusively necessary to prevent ricket/osteomalacia. Its role in the prevention of some osteoporotic fractures in the elderly (in association with calcium nutrition) is now well demonstrated and many epidemiologic and laboratory data argue for a role in the prevention of several diseases or anomalies (cancer, auto-immune diseases, cardiovascular events, sarcopenia...). A few intervention studies confirming some of these effects also exist. Vitamin D status can easily be assessed by measuring serum 25 hydroxy vitamin D (25OHD) level. However, many experts have claimed that the population-based reference values for 25OHD are too low and that the cut-off value below which vitamin D insufficiency can be present is somewhere between 20 and 40 ng/mL with a clear tendency to target values above 30 ng/mL (75 nmol/L). The main consequences are that vitamin D insufficiency is highly frequent whereas the currently recommended supplementation doses are not sufficient.

[Vitamin D2 or vitamin D3?]. / Vitamine D2 ou vitamine D3?

PURPOSE: Nearly one billion people around the world are deficient in vitamin D and need to be supplemented. Vitamin D is available in medicines and fortified foods. It is available in two forms: vitamin D2 (ergocalciferol) and vitamin D3 (cholecalciferol). KEY POINTS: The pharmacopeiae consider these steroid hormones as equivalent and interchangeable. However, several studies have showed that serum level of 25(OH)D is increased more effectively with vitamin D3 than vitamin D2. Vitamin D2 has shorter plasma half-life and a lower affinity for the vitamin D binding protein, the hepatic vitamin D hydroxylase and the vitamin D receptor. CONCLUSION: Vitamin D2 should not be regarded anymore as suitable for supplementation or fortification. Currently though, it is still the most used in some countries such as Portugal and Australia.

[Recommendations for the management of bone demineralization in cystic fibrosis]. / Recommandations pour la prise en charge de la déminéralisation osseuse dans la mucoviscidose.

A high prevalence of low bone mineralization is documented in adult patients with cystic fibrosis (CF). Osteopenia is present in as much as 85% of adult patients and osteoporosis in 13 to 57% of them. In children, studies are discordant probably because of different control database. Denutrition, inflammation, vitamin D and vitamin K deficiency, altered sex hormone production, glucocorticoid therapy, and physical inactivity are well known risk factors for poor bone health. Puberty is a critical period and requires a careful follow-up for an optimal bone peak mass. This review is a consensus statement established by the national working group of the French Federation of CF Centers to develop practice guidelines for optimizing bone health in patients with CF. Recommendations for screening and for calcium, vitamin D and K supplementation are given. Further work is needed to define indications for treatment with biphosphonates and anabolic agents.

Evidence of a marked 25-hydroxyvitamin D deficiency in patients with congenital ichthyosis.

BACKGROUND: Vitamin D is essential for bone mineralization, and its deficiency may be the cause of skeletal fractures and osteomalacia. Geographical or ethnic factors may modulate the cutaneous synthesis of vitamin D. We hypothesized that major changes in keratinization may similarly alter the cutaneous synthesis of vitamin D. OBJECTIVES: To explore calciotrophic hormones, parameters of bone remodelling and bone mineral density (BMD) in nine patients with non-bullous congenital ichthyosis. PATIENTS AND METHODS: Six patients were European, three were North African. Four had received acitretin over a long period of time. A complete biological investigation, including serum and urinary calcium and phosphorus, calciotrophic hormones [intact parathyroid hormone (iPTH), 25-hydroxyvitamin D (25-(OH)D) and 1,25-dihydroxyvitamin D (1,25-(OH)2D)], bone formation and resorption markers, was performed on all patients during the winter season and repeated among four patients after summer. BMD was measured in all patients. RESULTS: All patients had a marked 25-(OH)D deficiency, clearly below the deficiency threshold of 25 nmol/L. Patients from North Africa had a greater deficiency than European patients, perhaps because of the difference in skin pigmentation. iPTH remained normal in European patients but was elevated among the North Africans. After sun exposure, an improvement in vitamin status was visible in only one patient. Bone formation and resorption markers remained normal. Femoral neck osteodensitometry indicated values near the osteopaenic threshold in two young North African females. No deleterious effect of retinoids on vitamin D metabolism was observed. CONCLUSION: Patients, and in particular pigmented patients, with congenital ichthyosis present a severe deficiency in vitamin D. Care provided to protect the skeletal future of these patients involves measuring BMD and prescribing supplementation.

Methylmalonic and propionic acidurias: management without or with a few supplements of specific amino acid mixture.

In a series of 137 patients with methylmalonic acidaemia (MMA) and propionic acidaemia (PA) diagnosed since the early 1970s, we report in more detail 81 patients (51 MMA and 30 PA) diagnosed between 1988 and 2005. In this series, 14% of patients died at initial access revealing the disease before or despite treatment, 18% died later, and the remainder (68%) are still alive. All patients were treated with the same protocol of enteral feeds with a low-protein diet adjusted to individual tolerance, carnitine, antibiotics, and only occasional use of an amino acid (AA) mixture. There was intensive follow-up and monitoring using measurements of urinary urea. Thirty-nine patients with severe forms, followed for more than 3 years, are analysed in particular detail. Of the 17 PA patients, 6 had moderate disability (all neonatal-onset forms), whereas 11 were normal or slightly delayed in their mental development. Four presented with cardiomyopathy, of whom 2 died. Of the 22 MMA patients, 13 presented in the neonatal period, of whom 3 died later, 2 are in renal failure and only 5 are still alive and have a normal or slightly delayed mental development. In the 9 patients with late-onset forms, there were no deaths and all patients but one have normal mental development. Among the 39 patients, only 40% were given an AA supplement at 3 years, and 50% between 6 and 11 years. The actual intake of natural protein was 0.92, 0.78 and 0.77 g/kg per day at 3, 6 and 11 years, respectively, in patients without AA supplementation, whereas it was 0.75, 0.74 and 0.54 g/kg per day in the group who received small quantities of AA (0.4-0.6 g/kg per day). In both groups, feeding disorders were frequent: 55% at 3 years, 35% at 6 years and 12% at 11 years. Many patients were given a food supplement by tube overnight or were even exclusively tube fed: 60% at 3 years, 48% at 6 years and still 27% at 11 years. Growth velocity was near the normal values. Plasma valine and isoleucine were low to very low, as were leucine and phenylalanine but to a lesser extent. Albumin, vitamins, trace elements and markers of bone metabolism were within the normal values. IGF1, 24-hour urine calcium and body mass density were low. Body composition showed a normal to low lean mass and a normal to high fat mass.

[New definition of optimal vitamin D status and redefening serum parathyroid hormone reference range]. / Nouvelles définitions de l'insuffisance vitaminique D, retentissement sur les normes de PTH.

SCOPE: Knowledge concerning vitamin D has greatly improved during the past few years. Vitamin D can no longer be considered only as a preventive therapy for rickets-osteomalacia. Indeed, beside its role in the prevention of osteoporotic fractures in the elderly, many data suggest that it may be involved in the prevention of various diseases including cancers and auto-immune diseases. CURRENT SITUATION AND SALIENT POINTS: Vitamin D status may be easily assessed by the measurement of 25OHD serum concentration. However, many specialists in the field regard most 25OHD reference values as being too low, and believe that the 25OHD threshold below which vitamin D status can be considered as insufficient is somewhere between 50 and 100 nmol/L (20 to 40 ng/mL). It then appears that usually recommended amounts of supplemental vitamin D may be too low to reach these 25OHD concentrations, and thus need to be revised. We have proposed that PTH reference values should be established in healthy subjects with a normal vitamin D status. This supposes that 25OHD is measured in the reference population beforehand, and that the subjects with vitamin D insufficiency are eliminated from the reference group. PERSPECTIVES: Although more complicated than the usual way to establish normative data, we have shown that it decreases the upper limit of normal by 25-35%, enhancing thus the diagnostic sensitivity for hyperparathyroidism without a decrease in specificity.

Factors influencing the growth hormone response to growth hormone-releasing hormone in children with idiopathic growth hormone deficiency.

OBJECTIVE: To evaluate the factors influencing the growth hormone (GH) response to GH-releasing hormone (GHRH) test in idiopathic GH deficiency. METHODS: 28 patients aged 4.9 +/- 0.7 years with certain GH deficiency were given GHRH (2 microg/kg). RESULTS: The GH peak after GHRH was correlated negatively with age at evaluation (r = -0.37, p < 0.05) and body mass index (r = -0.44, p = 0.02), and positively with anterior pituitary height (r = 0.47, p = 0.02), GH peak after non-GHRH stimulation (r = 0.78, p < 0.0001) and spontaneous GH peak (r = 0.82, p = 0.007). It was lower in the patients aged >5 years than in the youngest (p = 0.04), but it was similar in the patients with and without features suggesting a hypothalamic origin. CONCLUSION: The GH response to GHRH test cannot be used to differentiate between hypothalamic and pituitary forms of idiopathic GH deficiency, probably because the GH response decreases after the first 5 years of life, whatever the origin of the deficiency.

Effect of type of dialysis membrane on bone in haemodialysis patients.

BACKGROUND: Uraemic bone disease is the result of a number of factors modulating bone formation and resorption in a complex manner. In the present study, the hypothesis tested was that the type of haemodialysis membrane used for renal replacement therapy might also play a role. METHODS: We conducted a prospective, open study in 24 chronic haemodialysis patients who were randomized to dialysis treatment with either cellulosic (CELL group, n=11) or polyacrylonitrile (AN-69 group, n=13) membrane for 9 months. Repeated determinations of plasma parameters reflecting bone turnover were done in all patients, and a bone biopsy in a subgroup at the start and end of study. RESULTS: At the start, mean plasma intact parathyroid hormone levels were comparable between the two groups and they did not vary significantly at 9 months of treatment. Similarly, plasma bone-specific alkaline phosphatase and osteocalcin (markers of bone formation), and cross-laps (marker of bone resorption) remained unchanged. However, plasma insulin-like growth factor-I (IGF-I) progressively decreased from 169 to 119 ng/ml in AN-69 group (P<0.01), whereas it remained unchanged in CELL group. In addition, the levels of IGF binding protein (IGFBP)-1 and IGFBP-2 were increased while the levels of IGFBP-5 were decreased in AN-69 group. In the five patients of each group who had repeat bone biopsies, histomorphometric analysis showed a decrease in osteoblast surface, osteoclast surface and osteoclast number in AN-69 group at 9 months, compared with baseline values measured at the start of the study. In contrast, all three parameters significantly increased in the CELL group at 9 months (P<0.001 for the difference between each of the three parameters). Bone formation rate decreased by 31% in the AN-69 group, but increased by 50% in CELL group. However, this latter difference was not statistically significant. Plasma interleukin (IL)-6 and soluble IL-6 receptor levels did not change in the two groups of patients who had undergone bone biopsy. CONCLUSION: Dialysis with CELL membrane was associated with increased bone turnover whereas the use of AN-69 membrane was associated with decreased bone turnover, suggesting a beneficial effect of the latter on high-turnover uraemic bone disease. However, as the number of patients with repeat bone biopsies was small, these findings need to be confirmed in a larger study. Further studies are also needed to evaluate whether or not the changes in IGF system components play a role in decreased bone cell activity in patients on dialysis using the AN-69 polyacrylonitrile membrane.

Space flight is associated with rapid decreases of undercarboxylated osteocalcin and increases of markers of bone resorption without changes in their circadian variation: observations in two cosmonauts.

BACKGROUND: Microgravity induces bone loss by mechanism(s) that remain largely unknown. METHODS: We measured biochemical markers related to bone remodeling in two cosmonauts before, during, and after 21- and 180-day space flights, respectively. RESULTS: During both flights, type I procollagen propeptide and bone alkaline phosphatase decreased as early as 8 days after launch. Undercarboxylated osteocalcin percentage increased early and remained high during both flights. Vitamin K supplementation restored carboxylation of osteocalcin during the long-term flight. Urinary and serum C-telopeptide of type I collagen (CTX) increased as early as day 8 of the flights; the increase was greater in serum than in urine. Pyridinoline, free deoxypyridinoline, and N-telopeptide increased less than CTX during the short-term space flight. The circadian rhythm of bone resorption assessed by urine CTX and free deoxypyridinoline was not altered by microgravity. CONCLUSION: Vitamin K metabolism or action and bone remodeling may be altered in cosmonauts.

Persistence of Ca2+-sensing receptor expression in functionally active, long-term human parathyroid cell cultures.

An original human parathyroid cell culture model from uremic patients with IIo hyperparathyroidism has been developed, with its main feature being long-term functionally active viability up to 5 months, as assessed by persistent responsiveness to changes of extracellular Ca2+ concentrations ([Ca2+]e). In addition to the inhibitory effect of increasing [Ca2+]e, increasing extracellular phosphate exerted a biphasic effect on parathyroid hormone (PTH) secretion. The presence of the Ca2+-sensing receptor (CaR), on which depends the response to [Ca2+]e and its persistence, has been demonstrated in our culture system both by direct detection and by inhibition of its activity. CaR protein was detected by Western blot analysis with a specific anti-CaR antibody. CaR gene transcripts have been identified by reverse transcription-polymerase chain reaction analysis. mRNA (by in situ hybridization) and protein (by immunocytochemistry) expression were detected for both CaR and PTH. Adding a specific anti-CaR antibody to the medium induced a marked reduction of low [Ca2+]e-stimulated PTH release, which decreased to levels equivalent to those obtained in high [Ca2+]e medium. The described long-term functionality could be due to several factors, including the clustered cell type of culture yielded by our preparation procedure, the growth characteristics of hyperplastic uremic tissue, and the use of a phosphate-rich medium. The present model, because of its long-term functionality, is a unique tool for the exploration of PTH synthesis and secretion and for studies of parathyroid cell growth in vitro.

[Neonatal cardiac failure secondary to hypocalcemia caused by maternal vitamin D deficiency]. / Insuffisance cardiaque néonatale secondaire à une hypocalcémie par carence maternelle en vitamine D.

BACKGROUND: Heart failure is a rare manifestation of neonatal hypocalcemia. This paper describes such a case resulting from maternal vitamin D deficiency. CASE REPORT: A full-term boy, born in December after a normal pregnancy, was admitted at the age of 6 weeks because of dyspnea that appeared during suckling. Examination showed heart failure. Electrocardiogram showed that the corrected QT-interval was lengthened (0.54 s, normal < 0.45 s). Echocardiogram showed dilated, hypokinetic myocardiopathy. His serum calcium concentration was low (1.40 mmol/l) and phosphate was high (2.8 mmol/l); his alkaline phosphatase was 513 Ul/l. His blood PTH concentration was high (120 pg/ml) and his 25 (OH) D was low (5 ng/ml). The patient was given calcium (1 g/m2/day) and 1.25 (OH)2 D (2 micrograms/day orally). His serum calcium returned to normal within 4 days, and his cardiac abnormality was resolved within 3 months. His mother's blood 25 (OH) D concentration was very low (3 ng/ml), 6 weeks after birth. CONCLUSION: Neonatal hypocalcemia appears to have been compounded in this case by a maternal vitamin D deficiency. Hence, all pregnant women at risk of deficiency should be given vitamin D.

[Growth and endocrine function in major thalassemia]. / Croissance et fonction endocrine dans la thalassémie majeure.

BACKGROUND: The risk of secondary endocrine dysfunction in patients with thalassemia major remains high, despite improvements in the care of hematologic problems. POPULATION AND METHODS: 31 patients (15 males, 16 females) with thalassemia major were studied. 28 of them had been regularly given blood transfusions since the age of 3.7 +/- 3.6 years. Iron chelation therapy had started before the age of 10 years in 9 patients, after this age in 15 patients; it was not performed or the time not specified in the 7 others. The mean dosage of deferoxamine was 20 +/- 6 mg/kg/day (9.6-34 mg/kg/day). Endocrine functions were evaluated at a mean age of 11.8 +/- 4.9 years and were monitored for 6.1 +/- 4.6 years (0 to 19 years). The hormones assay were: growth hormone (GH), thyroid, adrenal cortex, parathyroid and gonadal functions. RESULTS: The GH peak after stimulation was normal, but plasma somatomedin CIGFI was low and did not increase at puberty. 6 patients had peripheral hypothyroidism. Plasma cortisol was normal in the 16 patients examined, but plasma dehydroepiandrosterone sulfate was low in 24; this might be partly responsible for the delayed development of pubic hair. 2 patients aged 20 and 27 years was suffered from diabetes mellitus. Hypoparathyroidism occurred in 7 patients and 12 of the 24 patients with impuberism had a gonadotropin deficiency. The mean final height was -1.3 +/- 1.0 SD in boys (n = 7, mean age: 20 +/- 1 yr) and -1.3 +/- 0.9 SD in girls (n = 7; mean age: 19 +/- 1 yr), whether puberty was spontaneous or induced. CONCLUSIONS: The most frequent endocrine complications in these patients are delayed puberty because of gonadotropin deficiency, hypoparathyroidism and peripheral hypothyroidism. Substitution therapy, using sex steroids at an appropriate age, can induce the pubertal growth spurt.