JBMR

ORIGINAL ARTICLE

Early-Onset, Progressive, Frequent, Extensive, and Severe Bone Mineral and Renal Complications in Multiple Endocrine Neoplasia Type 1–Associated Primary Hyperparathyroidism Delmar M Lourenc¸o Jr , 1* Flavia L Coutinho , 1* Rodrigo A Toledo , 1* Fabio LM Montenegro , 2 Joya EM Correia-Deur , 1 and Sergio PA Toledo 1 1 2

Endocrine Genetics Unit (LIM-25), Division of Endocrinology, University of Sa˜o Paulo School of Medicine, Sa˜o Paulo, Brazil Division of Head and Neck Surgery, Hospital das Clı´nicas, University of Sa˜o Paulo School of Medicine, Sa˜o Paulo, Brazil

ABSTRACT Differences in bone mineral density (BMD) patterns have been recently reported between multiple endocrine neoplasia type 1–related primary hyperparathyroidism (HPT/MEN1) and sporadic primary HPT. However, studies on the early and later outcomes of bone/renal complications in HPT/MEN1 are lacking. In this cross-sectional study, performed in a tertiary academic hospital, 36 patients cases with uncontrolled HPT from 8 unrelated MEN1 families underwent dual-energy X-ray absorptiometry (DXA) scanning of the proximal one-third of the distal radius (1/3DR), femoral neck, total hip, and lumbar spine (LS). The mean age of the patients was 38.9
14.5 years. Parathyroid hormone (PTH)/calcium values were mildly elevated despite an overall high percentage of bone demineralization (77.8%). In the younger group (50 years of age) had a higher frequency of bone demineralization at all sites ( p < .005) and a larger number of affected bone sites ( p < .0001), and BMD was more severely compromised in the 1/3DR ( p ¼ .007) and LS ( p ¼ .002). BMD values were lower in symptomatic (88.9%) than in asymptomatic HPT patients ( p < .006). Patients with long-standing HPT (>10 years) and gastrinoma/HPT presented significantly lower 1/3DR BMD values. Urolithiasis occurred earlier (40%) and more severe degrees of lumbar spine (LS) demineralization have been reported in patients with HPT/MEN1.(14–16) Even though basal proximal onethird of the distal radius (1/3DR) bone mineral density (BMD) profiles are similar in both diseases, short-term bone recovery after PTX may differ.(1–3,15,17,20,21) In addition, the early and late natural history of the bone disease in SPHPT has been underscored in prospective studies of untreated patients with follow-ups of up to 15 years.(22–24) In contrast, the outcomes of the bone mineral complications in asymptomatic and symptomatic patients with HPT/MEN1 have not been reported. Also, high frequencies of urolithiasis (>30% to 75%) have been reported systematically in HPT/MEN1, unlike what has been observed in modern SPHPT series (290 mg/vol per 24 hours, females > 320 mg/vol per 24 hours), uricosuria (n.v., 0.2 to 1.0 g/ vol per 24 hours), and oxaluria (n.v., males 0.08 to 0.49 mmol/ 24 h, females 0.04 to 0.34 mmol/24 h) also were investigated. Journal of Bone and Mineral Research

2383

Bone mineral density BMD values were measured by dual-energy X-ray absorptiometry (DXA; Hologic QDR-4500A S/N 45130, Waltham, MA. USA) at the four classic bone sites: the lumbar spine (L1–L4, LS); the proximal femur, including the femoral neck (FN) and total hip (TH); and the proximal third of the distal radius (1/3DR).(30,31) Values were expressed as grams per square centimeter and T- and Z-scores. BMD values were analyzed by the criteria recently adopted by the International Society for Clinic Densitometry (ISCD) and accepted by the HPT Consensus.(30,31) Based on these criteria, Zscores were used for patients younger than 50 years of age, and Zscores of less than 2.0 indicate reduced BMD. T-scores were used for patients older than 50 years of age. T-scores of less than 1.0 indicate reduced BMD, values between 1.0 and 2.5 indicate osteopenia, and values less than 2.5 indicate osteoporosis.(30,31) Following the ISCD recommendations, two groups were established at the time of the BMD analysis: group A, with 21 HPT/MEN1 patients (50 years). This division point also coincides with the age at which penetrance of HPT in MEN1 is almost complete.(4–8,15) Some definitions were used in this study. The term severe demineralization was applied to patients with at least one of the four analyzed bone sites with Z-scores of less than 3.0 (group A) or T-scores of less than 3.0 (group B). Frequent demineralization indicated that at least half the analyzed patients presented one

or more compromised bone sites. Early-onset demineralization indicated that reduced BMD occurred either before 30 years of age or in asymptomatic HPT patients. Extensive demineralization indicated patients presenting with at least three affected bone sites. Progressive demineralization was applied based on the following parameters: frequency of reduced BMD, number of affected bone sites, degree of bone loss, and duration of HPT disease.

Statistics Data are expressed as the mean
SD for each index unless otherwise mentioned. Mean
SE is used to express the BMD data. Correlations between the variables were tested by the Pearson test. Several clinical, biochemical, and densitometric parameters between different groups were analyzed using an unpaired t test, chi-square test, or Fisher exact test when applicable. P values of less than .05 were considered significant. Statistical analyses were performed using the Stata 8.0 software program (Stata, College Station, TX, USA).

Results Groups A (50 years) Baseline parameters of the 36 HPT/MEN1 patients are shown in Table 1. The mean age at the HPT diagnosis was 38.9
14.5 years (range 17 to 73 years). At the time of HPT diagnosis, the mean

Table 1. Baseline Clinical and Biochemical Data in the 36 HPT/MEN1 Patients Feature Age at HPT diagnosis (years) Age at the time of BMD analysis (years) Sex (M/F) First renal crisis (years) Duration of HPT diseasea (years) Intact PTHc Serum total calciumd Serum phosphoruse Serum magnesiumf 24-h urinary calciumg 25-OHDh OC CTX ALP

N

Mean
SD

Range

Reference values

36 36 18/18 29 36 36 36 35 35 27 21 12 (M) 9 (F) 10 (M) 7 (F) 17 (M) 17 (F)

38.9
14.5 41.6
15.2 — 26.1
8.6 15.4
12.8 114.9
90.6 11.0
0.53 2.7
0.57 1.9
0.37 319.1
138.6 24.8
11.5 35.9
21.0 71.8
88.5 0.86
0.56 0.96
0.78 114.5
27.9 111.7
52.5

17–73 20–74 — 16–55 0–38 52–592 10.1–12.2 1.5–4.5 1.24–2.54 139.5–648 11–46 13.7–85.6 17.5–296.6 0.27–2.07 0.26–2.6 83–188 58–246

— — — — — 11–62 (pg/mL) 8.6–10.2 (mg/dL) 2.7–4.5 (mg/dL) 1.58–2.55 (mg/dL) 100–320 (mg/vol) 9–37.6 (ng/mL) M: 14–46 (ng/mL) F: 11–43 (ng/mL) M: