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Original Studies |
Department of Molecular and Clinical Endocrinology and Oncology, "Federico II" University (R.P., A.C., C.D.S., G.F., A.F., G.L.); and CNR, Biomorphological and Functional Sciences (M.K., M.S.), 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, via Sergio Pansini, 5, 80131, Naples, Italy. E-mail: rpivone{at}tin.it
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Abstract |
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 Top Abstract IntroductionSubjects and MethodsResultsDiscussionReferences |
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Eighteen patients with central diabetes insipidus and 18 sex- and age-matched healthy subjects entered the study. The patients were divided into 2 groups: patients who did not receive treatment with desmopressin for at least 1 yr (group 1), and patients chronically treated with desmopressin since the diagnosis of diabetes insipidus (group 2). Serum osteocalcin and urinary cross-linked N-telopeptide of type I collagen levels were measured in all patients and controls using RIA and enzyme-linked immunosorbent assay kits, respectively. BMD was measured at the lumbar spine (L1-L4) and at the femoral neck in all subjects, using a Hologic QDR 1000 analyzer (Hologic Inc., Waltham, MA).
Serum osteocalcin concentrations were significantly lower, both in patients of group 1 and group 2, compared with healthy subjects (5.1 ± 0.6 and 4.5 ± 0.3 vs. 7.9 ± 0.2 µg/L, P < 0.05), whereas urinary cross-linked N-telopeptide of type I collagen concentrations were similar in the three groups of subjects (72.8 ± 2.2, 71.6 ± 2.7, and 64.6 ± 1.7 nmol bone collagen equivalent/mmol creatinine). BMD was significantly decreased in patients of groups 1 and 2, compared with controls, both at lumbar spine (0.84 ± 0.06 and 0.87 ± 0.04 vs. 1.01 ± 0.02 g/cm2, P < 0.05) and femoral neck (0.78 ± 0.06 and 0.80 ± 0.04 vs. 0.93 ± 0.02 g/cm2, P < 0.05). A significant inverse correlation was found between disease duration and BMD values, evaluated as T scores, both at lumbar spine (group 1: r = -0.952, P < 0.005; group 2: r = -0.921, P < 0.001) and at femoral neck (group 1: r = -0.914, P < 0.05; group 2: r = -0.683, P < 0.05).
In conclusion, patients with central diabetes insipidus had a significant bone impairment, compared with healthy subjects. Replacement with endonasal desmopressin at standard doses was not able to prevent or reverse the bone impairment. These findings suggest that, in patients with central diabetes insipidus, bone status analysis is mandatory; and a bone-loss preventing treatment might be beneficial.
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Introduction |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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The aim of the current study was to evaluate the bone metabolism, by measuring serum osteocalcin (OC) and urinary cross-linked N-telopeptide of type I collagen (Ntx) levels, markers of bone formation and resorption, respectively, and bone mineral density (BMD) at the level of lumbar spine and femoral neck in patients with central diabetes insipidus, either treated or not treated with endonasal desmopressin.
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Subjects and Methods |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Eighteen patients with central diabetes insipidus (6 males, 12
females, 17–55 yr old) and 18 sex- and age-matched healthy subjects
entered the study after their informed consent had been obtained. Six
of the 18 patients (group 1) had not received any treatment with
desmopressin for at least 1 yr. Two of them were newly diagnosed with a
history of the disease spanning 1–2 yr, whereas the remaining 4 had a
disease history of 3–25 yr and had taken desmopressin for a short
period, withdrawing from it spontaneously because of allergy or bad
compliance (Table 1
). The remaining 12
patients (group 2) were chronically treated with endonasal desmopressin
at variable doses ranging from 5–20 µg/day since the time of
diagnosis of diabetes insipidus, 3–29 yr before entering the study
(Table 1). The diagnosis of central diabetes insipidus was established
according to Thompson (4) and Baylis (5): 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 less than 30 mosmol/L in 3 consecutive hourly urinary
samples) or until a decrease in absolute weight of more than 5% was
observed. At the end of the 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 to be diagnostic for central diabetes
insipidus. The diagnosis of central diabetes insipidus was confirmed by
normalization of water balance without onset of water intoxication in
the patients after 2 days of desmopressin replacement at the standard
doses (6). Normal dietary calcium intake (1 g/day) was documented in
all patients. The patients’ profile at study entry is shown in Table 1.
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Serum FSH, LH, 17ß-estradiol or testosterone, TSH, fT3, fT4, cortisol, and plasma ACTH levels were assayed twice in a single sample, whereas urinary free cortisol levels were assayed in the 24-h urinary collection in all patients and controls during the day of the study. Blood samples were collected in the morning. 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
Serum calcium, phosphorus and creatinine (Cr), circulating alkaline phosphatase, intact PTH, and OC were assayed twice in a single sample, whereas urinary calcium, phosphorus and Cr, and Ntx were assayed in the 24-h urinary collection in all patients and controls during the day of the study. Blood samples were collected in the morning after an overnight fasting.
Bone density assessment
In all patients and controls, BMD was assessed by dual x-ray absorptiometry. The measurement of the integral bone density in lumbar spine (L1-L4) and in femoral neck was made by Hologic QDR 1000 analyzer. Data were expressed in g/cm2 and T score. In line with literature, patients were considered osteopenic when T score was between -1 and -2.5, and they were considered osteoporotic when T score was lower than -2.5. All scans were analyzed by the same operator (M.K.), who was blind, with respect to patients treatment.
Assays
Serum FSH, LH, 17ß-estradiol, testosterone, TSH, free(f)T4, fT3, cortisol, plasma ACTH, and urinary free cortisol were assayed using routinely available commercial kits. Serum PTH was assayed by immunoradiometric assay using a kit provided by Radim (Pomezia, Italy); the normal range was 9–55 pg/mL. Serum OC levels were measured by RIA using a kit provided by Nichols Institute (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; the normal range was 23–110 nmol bone collagen equivalent (BCE)/mmol Cr for males and 13–96 nmol BCE/mmol Cr for females. Urinary and serum calcium, phosphorus and Cr, and circulating alkaline phosphatase were assayed using standard methods in our laboratory.
Statistical analysis
The statistical analysis was carried out by ANOVA. Linear regression analysis was carried out by calculating the Pearson’s correlation coefficient. Data were reported as 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 (Table 2)
and controls (data not shown). Conversely, mildly elevated serum and
urinary cortisol levels were found in the patients with central
diabetes insipidus (Table 2).
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Serum calcium, phosphorus and Cr, circulating alkaline
phosphatase, urinary calcium, phosphorus, and Cr were in the normal
range in the two groups of patients with diabetes insipidus and normal
subjects (data not shown). Serum PTH levels were similar in patients
and controls (data not shown). Both patients of group 1 and those of
group 2 had serum OC levels significantly lower than those of healthy
subjects, whereas serum OC levels were similar in the two groups of
patients (Table 3). Conversely, similar
urinary Ntx levels were found in all three groups (Table 3).
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Both at lumbar spine and femoral neck levels, BMD values
were significantly reduced in patients of groups 1 and 2 (without any
difference between them), compared with healthy subjects (Table 3
). As
far as lumbar spine examination was concerned, among the 6 patients of
group 1, 2 patients (33.3%) were considered osteoporotic, 3 (50%)
were osteopenic, and 1 (16.7%) had BMD values within the normal range.
Conversely, among the 12 patients of group 2, 2 patients (16.7%) were
considered osteoporotic, 7 (58.3%) were osteopenic, and 3 (25%) had
BMD values within the normal range (Table 3). As far as femoral neck
examination was concerned, among the 6 patients of group 1, 1 (16.7%)
were considered osteoporotic, 3 (50%) were osteopenic, and 2 (33.3%)
had BMD values within the normal range. Conversely, among the 12
patients of group 2, 3 (25%) were considered osteoporotic, 3 (25%)
were osteopenic, and 6 (50%) had BMD values within the normal range
(Table 3). Among the 18 controls, only 3 patients (16.7%) at lumbar
spine and 1 patient (5.5%) at femoral neck were considered osteopenic,
whereas all the remaining patients (83.3% at lumbar spine and 94.5%
at femoral neck) had BMD values within the normal range. Osteoporosis
was never found in the healthy controls (Table 3).
A significant inverse correlation was found between disease duration
and both lumbar spine (r = -0.952, P < 0.005;
r = -0.921, P < 0.001) and femoral neck (r
= -0.914, P < 0.05; r = -0.683,
P < 0.05) BMD, evaluated as T score, respectively, in
patients of groups 1 and 2 (Figure 1).
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Discussion |
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TopAbstractIntroductionSubjects and MethodsResultsDiscussionReferences |
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Why patients with diabetes insipidus have bone metabolism and bone
density deficiency is still unknown. However, AVP was hypothesized to
prevent osteoporosis, because it was demonstrated to induce production
of PGs, especially PG E2 and F2
(3, 7, 8).
These PGs were found to be involved in bone metabolism, stimulating
overall bone formation (9, 10). Therefore, it is likely that AVP
deficiency causes a decrease of PG production, with a consequent
reduced bone formation and, therefore, osteopenia. This hypothesis
might explain the presence of bone impairment in patients with central
diabetes insipidus. In addition, several observations supported the
hypothesis of a role for AVP in maintaining bone status. AVP release is
known to occur during physical exercise (11) and, therefore, it was
suggested to be responsible for the beneficial effect of physical
exercise on the prevention of osteoporosis (12). Moreover, AVP release
is stimulated in warmer, and depressed in colder, climates (13). This
evidence may explain the higher incidence of bone fractures in the
populations who lived in countries north, compared with those living
south, of Barcelona (14). Finally, AVP release was demonstrated to be
inhibited by alcohol consumption (15), and this was claimed to explain
the osteoporosis associated with alcohol abuse (16). Anyhow, these
evidences seemed to confirm the possible role of AVP deficiency in
inducing bone loss.
It is noteworthy, however, that not only the patients not treated, but also those chronically treated, with endonasal desmopressin had impairment of bone status. In fact, it was expected that the patients with replaced desmopressin normally would not have problems related to AVP deficiency. However, it is known that desmopressin, though it is an analogue of AVP, possesses different pharmacological properties, as compared with AVP. In fact, it was demonstrated that desmopressin has a greater antidiuretic activity, a lesser vasoconstructing action, and a longer-lasting effect than AVP (2). In fact, under normal conditions, AVP exerts its action by binding two types of receptors: type V1, which mediates pressor effects trough vasoconstriction; and type V2, which mediates antidiuretic effect (17). Type V1 receptors are widely distributed, whereas type V2 receptors are localized only in the renal medulla. Because desmopressin acts mainly through V2 receptors (18), it is likely that it does not affect or scarcely affects PGs production and bone status. Alternatively, it may be hypothesized that chronic treatment with endonasal desmopressin, at the dose sufficient to normalize water intake and excretion, was not sufficient to maintain a normal bone formation and to ideally prevent bone impairment. The possibility that a chronic treatment with desmopressin itself could have induced the pathologic reduction of bone formation and density cannot be ruled out.
A further hypothesis may be raised to explain the bone impairment of patients with central diabetes insipidus. In fact, a hyperactivation of hypothalamus-pituitary-adrenal axis has been described in these patients (19, 20). In line with these studies, the results of the current one showed the presence of a mild increase of serum and urinary cortisol levels in patients with central diabetes insipidus. Therefore, a blunt but chronic glucocorticoid excess may have also contributed to the bone impairment of these patients.
Anyhow, the observation of a significant inverse correlation between disease duration and both lumbar spine and femoral neck BMD, evaluated as T score, strongly agreed with the possibility of a cause-effect relationship between diabetes insipidus and bone impairment.
In conclusion, patients with central diabetes insipidus had a significant bone impairment, compared with healthy subjects, and the treatment with endonasal desmopressin at standard doses was not able to prevent or reverse this bone loss. These findings suggest that, in patients with central diabetes insipidus, the examination of bone status is mandatory and that a bone loss-preventing treatment might be beneficial.
Received February 23, 1998.
Accepted April 15, 1998.
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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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