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Original Studies |
Department of Molecular and Clinical Endocrinology and Oncology (R.P., A.F., C.D.S., M.F., G.L., A.C.) and CNR, Biomorphological and Functional Sciences (M.K., M.S.), Federico II University, 80131 Naples, Italy
Address all correspondence and requests for reprints to: Annamaria Colao M.D., Ph.D., Department of Molecular and Clinical Endocrinology and Oncology, Federico II University of Naples, Via Sergio Pansini 5, 80131, Naples, Italy. E-mail: colao{at}unina.it
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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At baseline, lumbar BMD values (0.86 ± 0.03 vs. 1.01 ± 0.02 g/cm2; P < 0.001) and serum OC levels (4.7 ± 0.3 vs. 7.9 ± 0.2 µg/L; P < 0.001) were significantly lower, whereas urinary Ntx levels were significantly higher [72.0 ± 1.9 vs. 64.6 ± 1.7 nmol bone collagen equivalents (BCE)/nmol creatinine (Cr); P < 0.01] in patients than in controls. After randomization, no difference in lumbar BMD, serum OC, or urinary Ntx was found between patients of group 1 and group 2. At the 6 month follow-up, no difference in serum OC levels was found compared to baseline evaluation in patients of both group 1 and group 2. By contrast, a significant decrease in urinary Ntx levels was found in patients of group 1 (70.3 ± 3.0 vs. 75.4 ± 2.1 nmol BCE/nmol Cr; P < 0.05), but not in patients of group 2 (68.8 ± 3.3 vs. 68.5 ± 3.0 nmol BCE/nmol Cr; P = NS). A significant increase in lumbar BMD values was found in patients of group 1 (0.88 ± 0.04 vs. 0.83 ± 0.04 g/cm2; P < 0.05), whereas a significant decrease in lumbar BMD values was found in patients of group 2 (0.86 ± 0.05 vs. 0.89 ± 0.05 g/cm2; P < 0.05). Lumbar BMD increased 7.0 ± 1.5% in patients of group 1 and decreased 4.2 ± 1.8% in patients of group 2 (P < 0.001).
In conclusion, this study demonstrated that a 6-month treatment with alendronate in patients with central diabetes insipidus was effective in significantly improving BMD at the lumbar spine, which was significantly worsened in untreated patients. Therefore, alendronate treatment could be used in patients with central diabetes insipidus with documented osteopenia or osteoporosis.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Alendronate is an aminobisphosphonate that has been successfully used in the treatment of postmenopausal osteoporosis (4). In recent years, treatment with alendronate for 6 months was also found to be effective in secondary osteoporosis of Cushing’s disease (5).
Taking into consideration that patients with postmenopausal osteoporosis are exposed to an increased risk of fractures and that a reduction in BMD of 1 SD from the mean is associated with a 2-fold increase in the fracture risk in these patients (6), this open prospective randomized study was designed to evaluate whether a short term treatment with alendronate was able to improve BMD in patients with central diabetes insipidus.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Eighteen patients with central diabetes insipidus (5 males and
13 females, 17–55 yr old) and 18 sex- and age-matched healthy subjects
entered this study after their informed consent had been obtained. Six
of the 18 patients did not receive any treatment with desmopressin.
Four of them had taken desmopressin for a short period, withdrawing it
spontaneously for allergy or bad compliance and had a disease history
of 3–25 yr. Two patients were new diagnosis of central diabetes
insipidus and received desmopressin replacement at study entry. Their
disease durations were 1 and 2 yr. The remaining 14 patients were
chronically treated with endonasal desmopressin at variable doses
ranging 5–20 µg/day since the diagnosis of diabetes insipidus
(1.5–29 yr before entering the study). The diagnosis of central
diabetes insipidus was established according to Thompson (7) and Baylis
(8). A dehydration test was performed with hourly evaluation of plasma
and urine osmolality until a steady state urinary osmolality was
achieved (variation in urinary osmolality of <30 mosmol/L in three
consecutive hourly urinary samples) or until a decrease in absolute
weight of more than 5% was observed. At the end of dehydration period,
the patients underwent im administration of 1 µg desmopressin with
evaluation of urinary osmolality every 30 min for 2 h. An increase
of 10% in this parameter in the presence of a urinary
osmolality/plasma osmolality ratio more than 1 was considered
diagnostic of central diabetes insipidus. The diagnosis of central
diabetes insipidus was confirmed by the normalization of water balance
without the onset of water intoxication in the patients after 2 days of
desmopressin replacement at standard doses (9). Normal dietary calcium
intake (1 g/day) was documented in all patients. The clinical
characteristics of the patients and controls are summarized in Table 1
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At study entry, all subjects underwent an evaluation of anterior
pituitary function, bone metabolism, and bone density. Thereafter, the
patients were randomized to receive alendronate treatment. Nine of the
18 patients were treated with alendronate at a dose of 10 mg, orally,
once daily (after fasting at 0800 h in the morning, at least
1 h before breakfast) for 6 months (group 1), whereas the
remaining 9 patients did not receive any treatment affecting bone
status during this period (group 2). After 6 months, in all patients
anterior pituitary function, bone metabolism, and bone density were
retested. After randomization, no significant difference was found in
sex, age, or body mass index among patients of group 1, patients of
group 2, and controls or in disease duration between the two groups of
patients (Table 1
).
Anterior pituitary function evaluation
At study entry and after 6 months, serum FSH, LH,
17
-estradiol (in females), testosterone (in males), TSH, free
T3 (fT3), free T4
(fT4), cortisol, and plasma ACTH levels were assayed twice
in a single sample, and urinary free cortisol levels were assayed in
the 24-h urinary collection. GH deficiency was excluded in all patients
by evaluating serum GH levels after a GH-releasing hormone plus
arginine test (10). Blood samples were collected in the morning at
fasting. All subjects had a body mass index within the normal range.
All female subjects had regular menses and were tested during the early
follicular phase.
Bone metabolism assessment
At study entry and after 6 months, circulating calcium, phosphorus, creatinine, alkaline phosphatase, intact PTH, and OC were assayed twice in a single sample, and urinary calcium, phosphorus, creatinine, and Ntx were assayed in the 24-h urinary collection. Blood samples were collected in the morning after a 12-h fast.
Bone density assessment
BMD was assessed by dual x-ray absorptiometry at study entry and after 6 months. Measurement of integral BMD in the lumbar spine (L1–L4) was made by Hologic QDR 1000 analyzer (Hologic, Inc., Waltham, MA). Data were expressed in grams per cm2 and t and z scores. All scans were analyzed by the same operator (M.K.), who was blind with respect to patients’ treatments.
Assays
Serum FSH, LH, 17ß-estradiol, testosterone, TSH, fT4, fT3, and cortisol; plasma ACTH; and urinary free cortisol were assayed using available commercial kits. Serum PTH was assayed by an immunoradiometric assay method using commercial kits; the normal range was 9–55 pg/mL. Serum OC levels were measured by RIA using a kit provided by Nichols Institute Diagnostics (San Juan Capistrano, CA); the normal range was 3.0–13.0 µg/L. Urinary Ntx levels were measured by enzyme-linked immunosorbent assay using a kit provided by Nichols Institute Diagnostics (San Juan Capistrano, CA); the normal range was 23–110 nmol bone collagen equivalents (BCE)/mmol creatinine (Cr) for males and 13–96 nmol BCE/mmol Cr for females. Urinary and serum calcium, phosphorus, and creatinine and circulating alkaline phosphatase were assayed using standard methods in our laboratory.
Statistical analysis
Statistical analysis was carried out using ANOVA, followed by the Newman-Keuls test and Student’s t test for unpaired or paired data where appropriate. Data were reported as the mean ± SEM. The significance was set at 5%.
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Results |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Serum FSH, LH, 17ß-estradiol or testosterone, TSH,
fT3, fT4, and plasma ACTH were within the
normal range in all patients, both at study entry and at the 6 month
follow-up, and in controls (data not shown). They were similar in
patients (without any difference between groups 1 and 2) and controls.
Serum and urinary cortisol levels were significantly higher in patients
(without any difference between groups 1 and 2) than in controls (Table 2).
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Serum and urinary calcium, phosphorus, and creatinine and
circulating alkaline phosphatase were within the normal range in all
patients, both at study entry and at 6 month follow-up, and in controls
(data not shown). Serum PTH levels were similar in patients at study
entry (30.5 ± 2.0 pg/mL) and in controls (25.5 ± 1.5 pg/mL)
without any change at the 6-month follow-up in the patient group
(28.6 ± 1.8 pg/mL). At baseline, serum OC levels were
significantly lower (4.7 ± 0.3 vs. 7.9 ± 0.2
µg/L; P < 0.001), whereas urinary Ntx levels were
significantly higher (72.0 ± 1.9 vs. 64.6 ± 1.7
nmol BCE/nmol Cr; P < 0.01) in patients than in
controls. After randomization, patients of both group 1 (4.6 ±
0.4 µg/L; P < 0.05) and group 2 (4.9 ± 0.4
µg/L; P < 0.05) had serum OC levels lower than
control values. By contrast, urinary Ntx levels were significantly
higher only in patients of group 1 (75.4 ± 2.1 nmol BCE/nmol Cr;
P < 0.05), but not in patients of group 2 (68.6
± 3.0 nmol BCE/nmol Cr), compared to control values. No difference in
serum OC or urinary Ntx was found between patients of group 1 and group
2. After 6 months, patients of both groups 1 and 2 had serum OC levels
similar to baseline evaluation (Table 3).
By contrast, serum Ntx levels were significantly decreased in
patients of group 1, but not in patients of group 2, compared to
baseline evaluation (Table 3).
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At baseline, BMD values at the lumbar spine were significantly
lower in patients than in controls (0.86 ± 0.03 vs.
1.01 ± 0.02; P < 0.001). After randomization,
patients of both group 1 (0.83 ± 0.04; P < 0.05)
and group 2 (0.89 ± 0.05; P < 0.05) had lumbar
BMD values significantly lower than controls. No difference in lumbar
BMD was found between the two groups of patients. After 6 months, a
significant increase in lumbar BMD was found in patients of group 1,
whereas a significant decrease in lumbar BMD was found in patients of
group 2 (Table 3). Lumbar BMD increased 7.0 ± 1.5% in patients
of group 1 and decreased 4.2 ± 1.8% in patients of group 2
(P < 0.001; Table 3).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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We recently reported that patients with central diabetes insipidus have an impairment of bone status and that standard replacement treatment with desmopressin cannot prevent or revert bone status abnormalities in these patients (2). A significant correlation was also found between bone loss severity and disease duration, suggesting a progressive development of bone impairment (2). In addition, a significant decrease in OC and a slight, but not significant, increase in Ntx were found in patients with central diabetes insipidus either treated or not treated with desmopressin, suggesting that a decrease in bone formation rather than an increase in bone resorption occurred in these patients (2).
In experimental models, AVP was shown to stimulate renal production of
PGs, mainly PGE2 and PGF2 (11, 12, 13). These
PGs are particularly involved in bone metabolism, acting in bone
formation more than in bone resorption (13, 14, 15, 16, 17). Moreover, a
reduced urinary excretion of PGs was reported in both animals and
humans with diabetes insipidus (18, 19). Thus, to explain the presence
of bone status abnormalities in patients with central diabetes
insipidus, AVP deficiency was hypothesized to cause a decrease in the
production of PGs (particularly PGE2 and
PGF2), thus inducing a reduced ratio between bone
formation and resorption and, therefore, a decrease in BMD.
This might not be the only explanation for the decrease in BMD in patients with central diabetes insipidus. Hyperactivation of the hypothalamus-pituitary-adrenal axis was described in patients with central diabetes insipidus (20, 21), and an increase in serum and urinary cortisol levels was found in the patients of this study. It is well known that the excess of glucocorticoids causes osteoporosis by decreasing bone formation, but mostly by increasing bone resorption (22, 23, 24). Glucocorticoid excess induces bone impairment, which is greater at the trabecular sites, such as the lumbar spine, than at the cortical sites, such as the femoral neck (24, 25). We reported that in patients with central diabetes insipidus a significant decrease in BMD occurred at both the lumbar spine and femoral neck, with the evidence of a clear-cut decrease in bone formation markers and a slight increase in bone resorption markers (2 and present study). However, bone impairment was more severe at the lumbar spine than at the femoral neck level (2). On the other hand, it is evident that patients with central diabetes insipidus do not present with symptoms or signs of hypercortisolism. Nevertheless, the possibility that a blunt, but chronic, glucocorticoid excess might induce bone loss as unique sign in these patients cannot be ruled out.
Aminobisphosphonates are effective compounds in the treatment of postmenopausal osteoporosis. They act by inhibiting bone resorption rather than by stimulating bone formation and have been successfully used (4). Alendronate is a new aminobisphosphonate that was demonstrated to be effective not only in postmenopausal osteoporosis (4, 26, 27), but also in secondary osteoporosis of hypercortisolism, particularly in Cushing’s disease (5). In particular, in Cushing’s disease, alendronate significantly improved BMD after only 6 months of treatment. Taking into consideration the beneficial effects of alendronate treatment in osteoporosis, this study was designed to investigate in an open prospective and randomized way whether a 6-month treatment with alendronate was effective in improving lumbar BMD in patients with central diabetes insipidus. The results of the study demonstrated that short term treatment with alendronate significantly increased (7.0 ± 1.5%) lumbar BMD in these patients. Interestingly, patients not receiving alendronate treatment had a significant reduction (4.2 ± 1.8%) in lumbar BMD during the same period.
Patients with postmenopausal osteoporosis are exposed to an increased risk of fractures (6). A 2-fold increase in the risk of fracture was associated with a reduction of 1 SD from the mean BMD in these patients (28, 29). This suggested that an increased risk of fractures might also be associated with the osteopenia/osteoporosis of patients with central diabetes insipidus. Therefore, alendronate treatment may be used in these patients to prevent this complication. In fact, a further bone loss at the lumbar spine was documented in patients with central diabetes insipidus not treated with alendronate, indicating that these patients might have a progressive increasing risk of fractures despite the standard replacement treatment with desmopressin.
Received November 9, 1998.
Revised March 12, 1999.
Accepted March 19, 1999.
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References |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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) on bone. Med Hypotheses. 38:125–131.[CrossRef][Medline]
on bone formation and
resorption in cultured neonatal mouse calvariae: role of prostaglandin
E2 production. Endocrinology. 126:1076–1079.[Abstract]
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