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Alterations of bone and mineral metabolism in diabetes mellitus : Part II. Clinical studies in 206 patients with type I diabetes mellitus

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120 SAMJ VOL72 18JULY1987

Alterations

metabolism

·of

bone and

in diabetes

mineral

mellitus

Part 11. Clinical studies in 206 patients with type I diabetes mellitus

F. S. HOUGH

Summary

This study reports a 22% prevalence of significant cortical osteopenia in 206 patients, aged 7 - 20 years, with established insulin-dependent diabetes mellitus (lOOM). A parallel decrease in trabecular bone mass was also noted. Bone loss was more evident in males (16%) than in females (6%) and was rare before 10 years of age (3%). No relationship between bone loss and the. duration of diabetes, degree of metabolic control or diabetic complications was apparent. Delayed skeletal maturation did not account for cortical thinning, and the mean bone age of osteopenic diabetics was similar to that of non-osteopenic diabetics.

There was no significant correlation between HLA-antigen frequency and the predisposition to diabetic osteopenia. Metabolic alterations comparable with previous findings in the chronically diabetic rat were documented in lOOM. The data documented are consistent with the conclusion that lOOM results in intestinal hyperabsorption of calcium, absorptive hypercalciuria, phosphaturia, hypomagnesaemia, hyperphosphatasaemia, and decreased circulating parathyroid hormone levels. These alterations in mineral metabolism may relate to the decrease in cortical and trabecular bone mass observed in patients with lOOM.

SAlr MedJ1987; 72: 120-126.

The effect of diabetes mellitus on the metabolism of minerals and the integrity of bone is poorly understood. Clinical studies on heterogeneous patient populations have yielded conflicting data on the type, extent and severity of disordered bone and mineral homeostasis in diabetes.I-l2Most studies employing a

more homogeneous population of juvenile insulin-dependent (type I) diabetics have, however, demonstrated a decrease in bone mass (osteopenia) in up to 50% of subjects.I-4 Although

the decreased bone mass appears to be unrelated to the duration of diabetes, it seems to be most pronounced during the first 5 years of disease;1,3,5 thereafter, the bone mineral content remains relatively constant, albeit less than normal.5,6

The true prevalence, pathogenesis and clinical significance of diabetic osteopenia remains ill defined. Earlier clinical

Endocrine Unit, Department of Internal Medicine, Univer-sity of Stellenbosch and Tygerberg Hospital, Parowvaliei,

CP

F.S. HOUGH, B.sc.HONS, F.C.P. (S.A.), M.MED. (INT.), M.D.

Reprint requests[0: Professor F. S.Hough.Endocrine Unit, Dept of Internal Medicine,

Tygerberg Hospital, Tygetberg,7505RSA.

studies implicated poor metabolic control, keto-acidosis and nutritional deprivation.12Recent repons propose that skeletal

derangements are not related to the severity of the diabetes, hyperglycaemia, or insulin deficiency, bur rather reflect the underlying basic disease.l Accumulated evidence obtained in

studies on human insulinopenic diabetes and in animals exposed tothe effects· of insulin deficiency do, however, reveal metabolic and hormonal derangements which must be considered poten-tially harmful to skeletal homeostasis, notably alterations in parathyroid hormone (PTH),vitamin D, calcitonin, and adreno-conical metabolism.13-25 It was therefore decided to evaluate

aspects of bone and mineral metabolism in a large group of juvenile insulinopenic diabetic subjects.

Subjects and methods

Patients aged 7 - 20 years with established insulin-dependent (type I) diabetes mellitus (IDDM) were studied: In protocol A 206 diabetic subjects were screenedtodetermine the prevalence of diabetic osteopenia (as evidenced from radiogrammetry of meta-carpal conical widths), and to assess the relationship between alterations in bone mass and a limited number of clinical and biochemical parameters. HLA-antigen distribution in these subjects was also analysed to determine whether miJIker HLA antigens exist for insulin-dependent diabetics with bone disease.

From the group of patients studied in protocol A, 41 subjects were adrninedtoa clinical research unit for protocol B, a more detailed evaluation of bone mass as well as clinical, metabolic and endocrine status. Although they were randomly selected in all other respects, an anempt was made, based on protocol A's radiogrammetric data, to admit an approximately equal number of subjects with and without decreased bone mass. Once adrnined to the protocol,allpatients were studied: 16 subjects with osteopenia (conical bone mass (CBM) more than 2 standard deviations below the mean value for age- and sex-matched controls) and 25 subjects without osteopenia. None of these subjects had had any known episodes of diabetic keto-acidosis for the 3-month period immediately preceding the study. Patients with known endocrino-pathies, hepatic, renal. or gastro-intestinal diseases, and those receiving anticonvulsant or glucocorticoid therapy were not included in the study; no patient had been subjectedtotherapeutic amounts of vitamin D, excessive exposuretosunlight or prolonged immobilisation and no patient had sustained a fracture during the 6-month period priortothe study.

On admission a thorough general and dietary history was obtained, and a full clinical examination was performed on each of the 41 subjects. In addition to their individual diabetic diets,all parricipants followed a strict metabolic diet (400 mg calcium, 1000 mg phosphorus and 100 mmol sodium per day) during their entire hospital stay, and a gelatin-free diet for 1 day before the determination of urinary hydroxyproline levels.

Determination of bone mass and skeletal

maturation

In both study populations, metacarpal conical thickness (MCT) was measured by the method of Garn er al.26at the mid-shaft of the second metacarpal bone, and expressed as the number of standard deviations from age- and sex-matched standards.

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In those patients studied under protocol B, bone mass was determined also by single photon absorptiometry with the Norland Cameron Bone Mineral Analyzer. The physical and mathematical principles involved in photon absorptiomerry have been amply detailed elsewhere.2' Mter calibration of the instrument, bone mineral content (BMC) and bone width (BW) were determined; bone mass (g/cm2) was calculated by dividing BMC by BW. This value has proved to be a more useful comparative index than BMCper sewhen comparing groups of individuals with varying bone dimensions. 2B The radial bone of the lesser-used arm was measured at two locations in. each subject: a metaphyseal site approximately 2 cm from the distal end of the radius (a site composed primarily of trabecular bone); and a diaphyseal site one-third the distance from the distal to the proximal end of the radius (composed mainly of cortical bone). Bone maturation, expressed as bone age, was estimated from hand films by the method of Greulich and Pyle. 29

Biochemical determinations

Peripheral venous blood samples were obtained at 08hOO with patients still in the fasting state, on 4 consecutive mornings. Urine specimens were collected during each 24-hour period and equally divided into:(a)clean refrigerated containers (for glucose, cortisol and creatinine); and(b) borues containing 6N HCI (for calcium, phosphate, hydroxyproline, sodium and creatinine).

Serum glucose was measured by the glucose oxidase method, using a Beckman glucose analyser. Serum calcium (total), phos-phate, alkaline phosphatase (total), magnesium, creatinine, urea and electrolyte levels and liver function profiles were determined by routine Technicon auto-analytical techniques. Ionised (free) calcium was measured with an Orion calcium electrode. The percentage circulating heat-stable alkaline phosphatase was deter-mined by heat inactivation of serum samples at 57°C for 10 minutes. Haemoglobin Al (Rh At) was quantitated by the method of Davis el apo and urinary total hydroxyproline according to Kivirikko el al. 3t Serum cortisol was measured with a competitive protein-binding assay32 and immunoreactive PTH with a carboxy-terminal antibody.33

Oral calcium tolerance test

The differentiation between absorptive (intestinal), resorptive (bone) and tubular (renal) hypercalciurias can 'Iargely be accomplished by oral calcium tolerance tests as outlined previously by Pak el al.34and more recently by Broadus el al. 35

While renal and resorptive hypercalciurias are not sigriificantly influenced by dietary calcium intake, urinary calcium excretion in hyperabsorptive states is higWy dependent on diet - calciuria being normal at low intakes (400 mg calcium per day) but increased at normal or high intakes. The basic protocol consists of 3 sequential 2-hour urine collection periods (referred to as the first, second and third periods) in a fasting hydrated patient, with the oral administration of I 000 mg calcium immediately after completion of the first 2-hour collection period, and midpoint blood samples drawn during the first and third collection periods. Patients are limited to bed during the entire test and remain supine for 30 minutes before blood sampling. The calciuric response in the second and third periods, when expressed as changes from individual baseline values of creatinine or unit of glomerular fJ.1tration, provides a useful index of intestinal absorptive

capaciry for calcium. .

All subjects were maintained on a calcium-restricted metabolIc diet for 3 days before the test. The average daily intake of calcium, phosphorus and sodium in the non-osteopenic and the osteoperuc groups were 417 mg, 1168 mg, 120 mmol and 462 mg, 1137~g, 124 mmol respectively. Patients fasted from 20hOO on the preceding evening except for 300 ml distilled water at 21hOO and 24hOO. Plasma glucose levels were monitored periodically and short-acting insulin was administered to maintain euglycaemia. At 06hOO on the morning of the test the patient was given distilled water (350 mllm2 body surface areayand the first urine collecti0D: was started. At 07hOO the first midpoint blood sample was obtamed, without stasis, for the measurement of calcium, phosphate and creatinine levels. At 08hOO the first urine collection was completed

and 1000 mg oral calcium (44mlgluconogalactogluconate dissolved in 300mldistilled warer) was administered. Ar 10hOO the second urine collecrion was completed and the patient was given more disrilled warer (175 ml/m2). The second midpoint blood sample was obrained at IlhOO, and the third urine collection was completed at 12hOO. Calcium, phosphare, glucose and creatinine levels were measured in all urine specimens.

Serological tests

HLA typing was performed by the microlymphocyrotoxicity method of Terasaki elal.36

Statistical analyses

Results are presented as the mean

±

SEM, and srarisrical analysis for significance of differences 'benveen diabetic parients and normal controls and between osreopenic and non-osreopenic diabetic subjects was calculated by means of Studenr's I-test.

In the statisrical analysis of the HLA-anrigen distribution, due cognisance was taken of rhe relatively small sample size (82 diaberics without and 31 diabetics wirh osreo~enia). This con-sideration has been amply detailed elsewhere.37, B. Thus, for each antigen, given that patiems carry aand patienrs lack band thar controls carry c and lackd, where a, b,c anddare rhe entries of the appropriate 2 x 2 £able, the formula of Haldane37 was used:

the relative riskx

=

(2a+ I) (2d+ I)

(2b

+

I) (2c

+

I)

The narurallogarithmy = Inx,with a variance given by

v= __1_ + __1_ + __1_ + _ _1 _

a+1 b+1 c+1 d+1

and weight, w = l/v, were computed. The significance of the divergence of y from zero was measured byX2

=

wy2for I degree of freedom. In addition, Fisher's test was used to determine the exact probabiliry(P)of finding differences of extreme between rhe antigen frequencies in patients and controls by chance alone, if there was no true difference.

Results

Protocol A

Metacarpal radiograrnmerry (MCT) measuremenrs in this group of 206 juvenile diabetic parients revealed that 85% were below rhe mean for age- and sex-matched controls. Forry-five subjecrs (22%) had MCT values more than 2 standard deviations below the mean for their respective ages and could thus be classified as osreopenic (Table I). Significant bone loss was more evident in males (16%) than in females (6%) and was rare before 10 years of age (3%).

TABLEI. MCT DATA FOR DIABETIC SUBJECTS Non-osteopenic Osteopenic No. of patients 161 (78%) 45 (22%) Sex distribution Male 72 (35%) 33 (16%) Female 89 (43%) 12 (6%) Age distribution

<

10 yrs Male (%) 13 (6%) 5 (2%) Female 12 (6%) 2 (1 %) 10 -15 yrs Male 30 (15%) 12 (6%) Female 43 (21%) 6 (3%)

>

15 yrs Male 29 (14%) 16 (8%) Female 34 (16%) 4 (2%)

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122 SAMJ VOL.72 18JULY1987

Cortical bone loss did not correlate with the duration of clinical diabetes (Table II): Although fasting blood glucose levels were significantly higher in the osteopenic than in the non-osteopenic subjects, other parameters of metabolic control such as body weight, insulin dose, and Hb Al levels were similar in both groups (Table II). Bone age was similar in the osteopenic and the non-osteopenic patients and did not differ significantly from chrono-logical age. Delayed skeletal maruration can therefore not account for the cortical thinning and osteopenia observed in these patients.

TABLE 11. PROTOCOL A

Non-osteopenic Osteopenic

No. of patients 161 45

Chronological age (yrs) 14,OO±0,20 14,50±O,40 Duration of diabetes (yrs) 5,60±0,30 5,50±0,50 Weight (kg) 51,80± 1,20 47,60±1,90 Height (cm) 156,20 ± 1,20 154,20 ± 2,30 Total daily insulin(U/d) 47,OO±1,60 47,40±3,70 Fasting blood glucose·

(mmolll) 12,90±0,40 14,10±0,60*

A, (%) (normal Hb

<

8,4%) 11,90 ± 0,20 12,40±O,50 Total calcium (mmolll) 2,45±0,01 2,48±O,02 Phosphate (mmolll) 1,12±0,01 1,15±0,02 Alkaline phosphatase

(lUll) 214,00 ± 10,00 263,00 ± 16,00* Bone mass (mm) 4,28 ± 0,07 3,22 ± 0,09** Bone age (yrs) 13,80±0,30 12,90±0,50 'Significantly different(P<0.02) compared with non-osteopenic subjects. **Significantty different(P<O,001) compared with non-osteopenic subjects.

Serum total calcium and phosphate levels and renal and liver function proftles were normal and comparable and serum alkaline phosphatase levels were increased in both groups (Tables II and Ill). Moreover, significantly higher alkaline phosphatase levels were observed in the older (15 - 20-year) osteopenic patients than in the non-osteopenic patients (Table Ill). The HLA-antigen distribution (Table IV) for the entire diabetic population revealed a highly significant increased frequency of A2, B8, BlS and BW44 and a reduced frequency of A9, B7, Bl2 and BW3S, compared with non-diabetic controls. In comparing the HLA-antigen distri-bution of the osteopenic with that of the non-osteopenic diabetics a 2 - 3-fold increased relative risk of A9, AIO, AW23, B17, B2l, B38 and B44, and a decreased relative risk of A29, AW30 and BW3S were noted in the osteopenic subjects. However, only the decreased BW3S reached statistical significance.

TABLE IV. HLA-ANTIGEN DISTRIBUTION IN NON-OSTEOPENIC AND NON-OSTEOPENIC DIABETICS HLA Non-osteopenic Osteopenic Relative

antigen (%) (%) risk Pvalue

A2 63 65 1,04 0,20 A9 6 16 2,93 . 0,09 Al0 2 10 3,95 0,12 AW23 1 3 2,67 0,48 A29 6 0 0,22 0,19 AW30 9 0 0,16 0,09 AW32 5 0 0,28 0,27 B7 12 6 0,59 0,22 B8 35 26 0,66 0,12 B12 17 19 1,20 0,24 B13 4 0 0,36 0,38 B15 23 23 1,00 0,23 B17 1 3 2,67 0,48 BW21 6 13 2,31 0,18 BW35 16 3 0,25 0,05 BW38 1 3 2,67 0,47 BW44 9 16 2,09 0,16

Protocol B

Bone mass measurements in the 41 diabetic patients studied under this protocol are depicted in Table V. Patients with a cortical bone mass (CBM), as determined by either osteodensi-tometry or MCT of 2 SDs below the normal for age- and sex-matched controls were regarded as osteopenic. A good correlation

(r

=

0,84;P

<

0,001) existed between SPA and MCT values for CBM. Normal reference values for trabecular bone mass (TBM) in children are not available. However, a comparable decrease in TBM was documented in subjects with cortical thinning and the ratio of CBM to TBM was similar in both groups (Table V).

Bone loss was found to be unrelated to the duration of diabetes, or to the daily insulin dose, energy intake, body weight or height (Table VI). Osteopenic diabetics did, however, reveal a significantly increased growth velocity compared with their non-osteopenic peers. Diabetic complications, specifically peripheral neuropathy and vasculopathy, did not appear to be more prevalent among osteopenic diabetics.

Serum glucose, Hb AI' total and ionised serum calcium, phos-phate and magnesium levels were similar in both diabetic popula-tions (Table VII). Magnesium levelsin both groups were, however, clearly decreased. The general increase in alkaline phosphatase in diabetic patients, as well as the higher values in osteopenic diabetics (Tables II and Ill), were confirmed in protocol B (Table VII). Heat fractionation srudies revealed a decreased percentage of

heat-TABLE Ill. SERUM TOTAL ALKALINE PHOSPHATASE ACTIVITY (lUll)

Non-osteopenic diabetics Osteopenic diabetics Normal values No. Mean±SEM No. Mean±SEM Mean Range

7 - 10 yrs, males and 21 288 ± 10 4 300 ± 21 145 45 - 240 females 10-15yrs Males 32 308±24 10 309±26 190 Females 31 241 ±20 5 304±34 175 15 - 20 yrs Males 26 167±17 14 262±22* 110 Females 36 105±5 5 158± 12* 60

'Significantly different(P<0.001) compared with non-osteopenic subjects.

119-310 71 - 320 58 - 252 36 - 125

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TABLE V. BONE MASS AND AGE IN SOME DIABETIC SUBJECTS Chronological age Bone age Osteodensitometry

No. (yrs) (yrs) CBM (g/cm2) TBM (g/cm2) CfT MCT(mm)

Non-osteopenic 25 13,2±O,6 13,3±O,6 0,63±O,02 O,40±O,02 1,60±O,04 4,2±O,16 Osteopenic 16 13,2±O,8 12,5±O,7 O,54±O,02* O,33±O,01* 1,68±O,05 3,33±0,15** "Significantly different from non-osteopenic subjects:P<0,005.

*"Significantly different from non-osteopenic SUbjects:P<0,001.

The mean(±SO) reference value for CBM in both patient groups is 0.67±0,06 gl cm', and far MCT 4,6±0,05 mm.

CIT=ratio of cortical to trabecular bone mass.

Data are presented as the mean±SEM of 24 non-osteopenic and 16 osteopenic diabetic subjects.

·Significantly different(P<0,025) compared with nan-osteopenic subjects. TABLE VI. PROTOCOL B

Non-osteopenic

Age (yrs) 13,20±O,60

Duration of diabetes (yrs) 4,50 ± 0,60 Diet (kJ/d) 9169,OO±454,00 Total daily insulin (U/d) 47,00 ± 4,00 Weight (kg) 49,90 ± 2,90 ~kg/6 moo 2,00 ± 0,31 Height (cm) 153,80 ± 3,10 ~cm/6 moo 1,34 ± 0,29 Surface area (m2) 1,46 ± 0,06 Diabetic complication(%) Total 52 Retinopathy 8 Hyperlipidaemia 28 Peripheral neuropathy 36 Osteopenic 13,20±O,80 5,90±O,90 8665,00 ± 407,00 45,00±8,OO 45,20±3,80 3,02±O,48 149,50 ± 3,90 2,56 ± 0,42* 1,37±O,07 25 13 13 6

stable enzyme activity in the circulation of both osteopenic and non-osteopenic subjects. Circulating PTH levels were similar but clearly decreased in both groups. Parameters of acid-base balance, blood and urine cortisol, and circulating thyroid hormone levels were unremarkable.

Glomerular function was normal in all patients (Table VIII). Twenty-four-hour urinary calcium excretion was normal despite significant glycosuria, and was identical in both groups (Table VIII). Moreover, no correlation existed between urinary glucose and calcium values. Urinary phosphate excretion was higher in osteopenic than in non-osteopenic subjects (Table VIII). Since urinary phosphate levels in 24-hour urine collections tend to be variable, the mbular reabsorption of phosphate (TRP) during the first 2 hours (preload period) of the calcium-tolerance test was calculated. A mean TRP value of 85, I

±

2, I%was obtained for osteopenic subjects, which did not differ significantly from the 83,6

±

1,1%calculated for non-osteopenic patients. TRP values on an 800 mg phosphorus diet are reported to range from 87% to 99%.38b Moreover, in the presence oflow-normal serum phosphate and markedly decreased serum PTH levels, both these values are clearly decreased. Urinary sodium and hydroxyproline excretion were normal and comparableinboth groups (Table VIII).

Pertinent features of the oral calcium tolerance test are summarised in Table IX. Urinary calcium excretion after an overnight fast (first period) was similarinboth diabetic populations,

TABLE VII. SERUM BIOCHEMISTRY IN OSTEOPENIC AND NON-OSTEOPENIC DIABETICS Normal values Non-osteopenic Osteopenic (range) Glucose (mmolll)

Fasting 12,OO±O,60 13,20±O,80 < 6,00

16hOO 13,10±1,00 13,90±O,90 < 11,00

HbA, (%) 12,20±O,40 12,80±O,40 <8,40

Calcium (mmolll)

Total 2,38±O,02 2,38±O,03 2,10 - 2,60

Free 1,18 ± 0,02 1,18±O,02 1,13-1,30

Phosphate (mmolll) 1,08±O,02 1,10±O,02 1,00 -1,50 Magnesium (mmolll) 0,57±O,01 O,57±0,02 0,60-1,20 Alkaline phosphatase (lUll)

Total 219,00 ± 18,00 277,OO±21,OO* 25,00 -150,00 %heat-stable 11,60 ± 1,30 10,10±1,20 20,00 - 28,00 pH 7,37±0,01 7,37±O,01 7,36-7,44 HC03(mmol/I) 26,10±0,40 26,OO±O,60 25,00 - 29,00 pC02(mmHg) 45,20±0,90 45,70±1,40 36,00 - 46,00 PTH (j.LIEq/ml) 3,OO±0,10 3,00±0,20 3,00 -11,00 Cortisol (j.Lmol) Blood 431,00 ± 19,00 505,00 ± 64,00 165,00 - 635,00 Urine 160,00 ± 22,00 149,00 ± 19,00 44,00 - 276,00 Thyroxine (nmol/I) 97,00±2,60 102,00 ± 2,80 50,00 -150,00 TSH (mUll) 5,00±O,40 4,40±0,60 <7,00

Patient data are presented as the mean±SEM of two or more determinations per subject, in 25 non-osteopenic and 16 osteopenic subjects.

·Significantly different(P<0,05) compared with nan-osteopenic subiects. TSH=thyroid-stimulating hormone.

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124 SAMJ VOL72 18JULY1987

Discussion

Data are expressed as the mean±SEM of two or more determinations per subject, in 25 non-osteopenic and 16 osteopenic diabetics.

'Significantly different(P<0,02) compared with the non-osteopenic subjects.

TABLE VIII. TWENTY-FOUR HOUR URINARY DATA IN OSTEOPENIC AND NON-OSTEOPENIC DIABETICS

Non-osteopenic Osteopenic

A number of investigations have documented a 15 - 20% prevalence of bone loss in diabetic children. These studies demonstrate clearly that IDDM affects skeletal growth and/or remodelling in children, resulting in reduced bone density and cortical thinning. The present study also reveals a significant and parallel decrease in TBM in juvenile diabetic subjects. The osteopenia could not be accounted for by delayed skeletal maturation; a fmding that is to be contrasted with that of Nielsen et al.,39 who noted that delayed skeletal maturation contributed significantly to the decreased BMC observed in juvenile diabetic patients. In contrasttothe findings of Ringe

et al.2 and McNair et al.,6 but in accord with othersl3,4 no

significant correlation was observed between bone loss and the duration of diabetes or the degree of metabolic control. In

addition, no correlation was apparent between bone loss and other complications of diabetes, specifically peripheral neuro-pathy or vascular involvement.

The pathogenesis of diabetic osteopenia is unknown, although various metabolic, hormonal and/or genetic influences may be involved. 40 In the present study an anempt was made to gain some insight into mechanisms which may underlie the develop-ment of diabetic bone disease. This study and other studies41,42 of the genetic predisposition to diabetes have confirmed an association of IDDM with cenain HLA antigens, most notably B8 and B15. In comparing the HLA-antigen distribution in osteopenic with that in non-osteopenic diabetic patients, an altered frequency of certain antigens was noted in the osteo-penic patients. However, this association only rarely reached statistical significance and it would appear that, if genetic factors are involved in the predisposition of diabetic patients tothe development of osteopenia, considerable genetic hetero-geneity must exist. Since HLA-D antigens were not determined in the present study further work is required to confirm any possible association between HLA-antigen distribution and diabetic osteopenia.

Serum calcium levels in diabetic subjects have generally been found to be within normal limits. 6,8-11 Diabetes is, however, anended by hypercalciuria, ascribed to the osmotic diuresis caused by glycosuria. 6,43 Intestinal absorption of calcium has been shownto be increased44or normal8in adult

diabetic subjects. In the present study serum total and ionised calcium levels were normal in diabetic patients. Twenty-four-hour urinary calcium excretion in these individuals who were maintained on a low calcium intake, was not increased despite severe glycosuria (> 3,5 g/24 h), suggesting an intestinal origin of the calciuria previously reported. The correlation purported to exist between urinary glucose and calcium levels,6,43 could not be confirmed. Furthermore, fasting urinary calcium values in these subjects were normal and did not support a diagnosis of renal or resorptive (skeletal) hyper-calciuria. Finally, circulating PTH was clearly decreased in diabetic patients. The accumulated data strongly suggest that the hypercalciuria reported in IDDM is secondary to intestinal hyperabsorption of calcium. This was supported by the results of oral calcium tolerance tests.

Poorly controlled diabetes results in marked urinary losses of phosphorus and magnesium.IO

,43 Phosphorus metabolism is important in bone mineralisation and matrix synthesis45 and also influences calcium and vitamin D metabolism46 while· magnesium deficiency results in a decreased secretion47 of and skeletal responsiveness48 to PTH. In this study urinary phos-phate excretion was increased in both groups. Moreover, hyperphosphaturia occurred in both groups, despite markedly decreased circulating PTH levels, which would tendtodecrease urinary phosphate wasting. Phosphaturia was, however, not convincingly more severe in the osteopenic subjects.

3,29 ± 0,20* 9,05±O,68 95,20 ± 10,60 127,OO±7,OO 258,00 ± 46,00 O,35±O,08 2,70±O,10 8,48±O,45 .89,10± 11,00 130,00 ± 6,00 303,00 ± 44,00 O,35±O,06 Creatinine clearance (m/lmin/1,732 )

Glucose (mmol/mmol creat.) Calcium (mmo/lmmol creat.) Phosphate (mmol/mmol creat.)

Sodium (mmol/mmol creat.) Total hydroxyproline

(mg/24 h)

did not differ significantly from the values reported by Pak et al. 34 and Broadus et al. 35 for normal subjects or subjects with absorptive hypercalciuria, and did not exceed the value of 0,31 mm01lmmol creatinine regarded as indicative of renal or resorptive hyper-calciuria.34 After an oral calcium load, the urinary calcium level increased during the second collection period. In osteopenic subjects it approximated the value reported by Broadus et al. 35 for patients with absorptive hypercalciuria(=6,75 ± 2,0 J.lm01ll00

ml glomerular filtrate) and also differed significantly from that observed in the non-osteopenic population (Table IX). Although a tendency toward a higher urinary calcium level in osteopenic patients was maintained during the third collection period, this difference was not statistically significant. The calcaemic response

toan oral calcium load in osteopenic and non-osteopenic subjects did not differ significantly (2,23 v. 2,43= 0,2 mm01ll and 2,25 v. 2,41= 0,16 mm01ll respectively). 4,25±O,75 7,50± 1,25 3,50±O,50 6,00 ± 0,75 3,O±O,5t 6,25±1,Ot l,50±O,50 4,OO±0,75 3,25±O,50 2,50±O,50

TABLEIX.URINARY CALCIUM EXCRETION DURING A FAST AND A1 000mg CALCIUM TOLERANCE TEST 1st period 2nd period 3rd period

Non-osteopenic Osteopenic Non-osteopenic Osteopenic Non-osteopenic Osteopenic

O,26±O,06 O,28±O,06 O,43±0,06 O,60±O,12 O,54±O,06 O,74±O,14 0,17 ± 0,03 0,32 ± 0,09 0,28±0,06 0,46 ± 0,12 Ca mmol/mmol creat. D.mmol/mmol creat.* Ca~mo1/100ml glomerular filtrate D.~mo1/100 ml glomerular filtrate*

Data are expressed as the mean±SEM of 21 non-osteopenic and 13 osteopenic diabetics. *Expressed as change from individual fasting values.

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Shon-term animal studies have advanced the hypothesis that secondary hyperparathyroidism may be involved in main-taining phosphocalcium homeostasis in the diabetic ral.40 In human diabetes, circulating PTH levels ·have generally been found to be normal/,II however, Cruikshanker al.49noted that

pregnant diabetics had significantly decreased serum PTH and ascribed this to the associated hypomagnesaemia observed in these individuals. In this study decreased serum magnesium and PTH levels were also documented in juvenile-onset diabetic patients. Other factors may, however, be involved in the genesis of the decreased circulating PTH observed in diabetes, including intestinal hyperabsorption of calcium, phosphate depletion and altered vitamin D metabolism.

Elevated levels of serum alkaline phosphatase occur in 7 -44% of patients with diabetes. 50· Diabetes-induced hyper-phospharasaemia was confirmed in the present study. Moreover, in those subjects older than 15 years, significantly higher levels were documented in the osteopenic than in the non-osteopenic patients. The source of circulating alkaline phosphatase in diabetic subjects has not been established. Heat fractionation studies revealed a decreased percentage of heat-stable enzyme activity in the circulation of both diabetic groups, suggesting that the increased enzyme activity was of skeletal origin. Itis also of interest to note that osteopenic patients, when compared with their 'non-osteopenic peers, were characterised by a significantly greater longitudinal· growth rate. The present study, and others5l have, however, found urinary hydroxypro-line levels to be normal in diabetic patients, an observation that argues against a significant increase in bone resorption/ turnover in these individuals. The exact relationship between alkaline phosphatase activity, growth velocity and bone mass in diabetic children therefore remains speculative.

The decreased bone mass documented in rats with experi-mentally induced diabetes mellitus has been ascribed, in pan, to acquired alterations in vitamin D metabolism.4o Preliminary studies in humans have however, been contradictory. Heather al.8 found normal circulating 25-0H vitamin D and 1,25-(OH)z vitamin D levels in adult diabetics. Genner er al.10 documented decreased serum 1,25-(OH)z D levels in young, growing diabetics - observations similar to those previously reponed byUS12 and analogous to findings in the growing rat

with experimental insulin deficiency.40 The genesis of the deranged vitamin D metabolism in IDDM remains obscure but could relate to the intestinal hyperabsorption of calcium and the decreased circulating PTH levels observed in these patients. Although hypercortisolaemia25 and systemic acidosis are occasionally found in poorly controlled diabetics and may impair renal la-hydroxylase activity,52,53 a direct effect of insulin on renal hydroxylation of vitamin D seems more likely.

The author wishes to thank Professors L. V. Avioli, S. L. Teitelbaum and

J.

Santiago for valuable advice, Mrs S. C. Stipp for the efficient typing of the manuscript, and the South African Medical Research Council for assistance.

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Alterations in circulating vitamin 0 merabolires in [he young insulin

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Important problems identified by

patients with chronic arthritis

G. M. M. BROWN,

C. M. DARE,

P.

R.

SMITH,

O.

L.

MEYERS

Summary

To assess the impact of their illness on their whole life experience 345 patients with chronic arthritis were interviewed and completed a questionnaire. Four major sub-groups were identified - rheumatoid arthritis, gout, ankylosing spondylitis and osteo-arthritis. Taking into account definite inter-group dif-ferences, the commonest problems were pain (65%), stiffness (61 %), inability to do everyday tasks (43%) and sexual difficulties (31%).The implications these problems raise in clinical practice are discussed and some suggestions for a rehabilitation programme made.

S Air MedJ1987; 72: 126-128.

'Because of the tendency to disable and even perma-nently cripple without killing, anhritis and rheuma-tism belong at the top of the list of chronic diseases from the standpoint of social and economic impor-tance.'

- J.

L. Hollander.1

Rheumatic Diseases Unit, Department of Medicine, Univer-sity of Cape Town and Groote Schuur and Princess Alice Orthopaedic Hospitals, Cape Town

G. M. M.BROWN,R.N. C. M. DARE,M.B. CH.B.

P.R. SMITH,M.B. CH.B.

O. L. MEYERS,M.D., F.C.P. (S.A.)

Successful rehabilitation requires that the goals of both patient and staff should be clear and preferably identical. The lot of the chronic arthritic is often described as being a difficult one. However, it is only when one studies these difficulties objec-tively and in a large patient sample, that the enormity and depth of the problem is revealed.

According to figures published by the Arthritis Foundation of America2in 1982 there wereinexcess of 36 million people suffering from some form of arthritis or related disease inthe USA. No comparative information exists in South Africa, but two studies have shown that from 8% to 10% ofall general practice visits are for rheumatic complaints and that chronic arthritis ranks first as a cause for disabilityinthe metropolitan area of Cape Town.3,4

In an outpatient department setting, the medical and physical aspects of the patient's illness tend to receive most attention. However, it is important to be aware of the effect of the disease on every aspect of the patient's existence because chronic arthritis has emotional as well as physical effects.

This study was conducted to assess the problems experienced by a large group of patients with chronic arthritis. It was hoped that the information obtained would prove useful in planning more effective approaches to their health care.

Patients and methods

Questionnaire

A 46-item questionnaire divided into 5 sections was designed to determine the difficulties encountered by the patients in the following areas - sociodemographic, medical, emotional and phy-sical. Each section contained 3 - 17 items and, depending on the phrasing of the question, the patient had the choice of either a single response· or several responses. The patients' evaluation of their ability to perform certain tasks (eating, hand activities, personal hygiene, home and work activities) was used to assess' their functional activity.

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