Bone loss in diabetes: Effects of metabolic state

Diabetologia, Nov 1979

P. McNair, S. Madsbad, C. Christiansen, M. S. Christensen, O. K. Faber, C. Binder, I. Transbøl

A PDF file should load here. If you do not see its contents the file may be temporarily unavailable at the journal website or you do not have a PDF plug-in installed and enabled in your browser.

Alternatively, you can download the file locally and open with any standalone PDF reader:

https://link.springer.com/content/pdf/10.1007%2FBF01235883.pdf

Bone loss in diabetes: Effects of metabolic state

B o n e Loss in Diabetes: Effects of Metabolic State P. M c N a i r 0 S. M a d s b a d 0 C. Christiansen 0 M. S. C h r i s t e n s e n 0 O. K. F a b e r : 0 C. B i n d e r : 0 a n d I. T r a n s b o l 0 0 ~Department of Clinical Chemistry, Glostrup Hospital , Glostrnp , aHvidore Hospital, Klampenborg, 3Department of Clinical Chemistry, and 4Division of Endocrinology, Department of Internal Medicine, Hvidovre Hospital, University Hospital of Copenhagen , Hvidovre , Denmark Summary. T h e significance of different risk factors f o r the d e v e l o p m e n t o f b o n e loss in d i a b e t e s mellitus was e v a l u a t e d in a cross sectional s t u d y of 215 insulin t r e a t e d diabetic outpatients. B o n e m i n e r a l c o n t e n t in fasting b l o o d glucose. 0 0 1 2 - 1 8 6 X / 7 9 / 0 0 1 7 / 0 2 8 3 / $ 0 1 . 0 0 B o n e m i n e r a l c o n t e n t; diabetes mellitus - the f o r e a r m s was m e a s u r e d b y p h o t o n a b s o r p t i o m e t r y a n d the m e t a b o l i c status was e v a l u a t e d b y t h r e e indices: residual B-cell function, insulin d o s a g e a n d fasting b l o o d glucose. T h e m e a n b o n e m i n e r a l c o n t e n t was r e d u c e d t o 9 0 . 2 % of sex- a n d agem a t c h e d n o r m a l m e a n values (P < 0 . 0 0 1 ) . Stratificat i o n of the p a t i e n t s s h o w e d t h a t b o n e m i n e r a l c o n t e n t was 9 9 . 3 % of t h a t f o u n d in sex- a n d age m a t c h e d n o r m a l subjects in the g r o u p with residual B-cell function, low insulin d o s a g e a n d low fasting b l o o d glucose; it was o n l y 7 9 . 3 % of n o r m a l in the g r o u p with n o d e t e c t a b l e insulin secretion, h i g h insulin dosage a n d m o r e severe h y p e r g l y c a e m i a . T h u s , residual insulin s e c r e t i o n a n d t h e quality of m e t a b o l i c c o n t r o l are m a j o r factors in d e t e r m i n i n g b o n e m i n e r a l c o n tent in insulin t r e a t e d diabetic patients. R e c e n t e v i d e n c e suggests t h a t b o n e loss s h o u l d b e i n c l u d e d a m o n g t h e c o m p l i c a t i o n s of insulin t r e a t e d d i a b e t e s mellitus [1--4]. T h e r e d u c t i o n in b o n e m i n eral c o n t e n t ( B M C ) b e c o m e s d e t e c t a b l e 2 - 3 y e a r s after o n s e t of clinical diabetes, attaining a stable level of a b o u t 9 0 % of n o r m a l B M C after a b o u t 5 years of d i a b e t e s [ 5 ]. L o w B M C has b e e n r e l a t e d to early diabetes o n s e t ( b e f o r e the age of 2 0 - 2 5 years) [ 5 ], t o a high daily t o b a c c o c o n s u m p t i o n [ 6 ] a n d to the f o p lowing indices of diabetes c o n t r o l : low o r absent insulin secretion, high daily insulin d o s a g e a n d h y p e r g l y c a e m i a [ 7 ]. T h e p r e s e n t s t u d y was d e s i g n e d to e v a l u a t e the additive effects of these i n t e r r e l a t e d indices of diabetic c o n t r o l o n diabetic b o n e loss. Patients The investigation was carried out as a cross-sectional study of 215 insulin treated diabetics with varying length of clinical diabetes (between 0-29 years, mean duration 10 years). All patients gave informed consent to the study. The patients' ages were 7-70 years and all had a normal serum creatinine level (<115 gmol/1). None of the patients had other diseases or received drugs known to interfere with mineral metabolism [ 5 ]. The patients were invited to participate in a study of calcium metabolism outside the diabetes clinic (see discussion). Blood samples were drawn in the morning after an overnight fast before administration of insulin. Methods Bone mineral content (BMC) was measured in both forearms by photon absorptiometric scanning at 6 positions on the distal part of each forearm, as described in detail previously [ 5, 8 ]. In each patient the mean value of these scans was calculated as % mean BMC value of sex- and age matched controls (2 year age groups for children and adolescents and 10 year age groups for adults). The influence of sex and age was thus minimized and this value for bone mineral content was suitable for evaluation. The method has a high precision (coefficient of variation: 1.2%) [9], but the interindividual variation is considerable (SD = 16%) in normal subjects [ 10 ]. Endogenous insulin secretion was estimated by measuring the serum concentration of immunoreactive C-peptide 6 rain after 1V injection of 1 mg glucagon. Patients with a serum C-peptide level exceeding the upper limit of C-peptide levels measured in 10 pancreatectomized patients (0.05 nmol/1) were considered to have residual insulin secretion and were designated secretors [ 11 ]. The insulin dose was calculated for each patient as insulin IU/kg body weight/day at the time of the investigation. Selection according to high risk Analyses of variance (concerning groups D + De + Ce + Be + A~): P <0.005 Glucose was measured in blood by an enzymatic analysis [ 12 ] and serum creatinine by the Jaff6 reaction modified for the SMA 6/60 autoanalyzer. 14 patients had a blood glucose value below the median for the 28 (11.1 mmol/1). The right part of both tables gives the results for the patients excluded at each selection. Stratification of the patients. We have previously found that low BMC is correlated with early onset of diabetes [ 5 ] and to the following indices of diabetes: low serum C-peptide concentration, high insulin dosage, high fasting blood glucose and glycosuria [ 7 ]. In order to elucidate this multifactorial relationship the patients were stratified according to high/low risk of BMC reduction (Tables 1 and 2, left part). Table 1 gives the results after stratification for high risk of bone loss: 86 of 215 patients had an onset of diabetes before the age of 21 years and 70 of the 86 were non-secretors. Thirty-five of the 70 patients were treated with more than 0.7 IU/kg/day, which was the median daily insulin dose in the 70 non-secretors. Finally the 18 patients with the highest blood glucose level were selected from the group of 35 patients. Table 2 gives the results after stratification for low risk of bone loss: 129 patients had onset of diabetes after 25 years of age, 54 of these were secretors, and in 28 diabetics the daily insulin dose was below 0.371U/kg/day (median value of the 54 patients). Of these, Statistical evaluation. Analysis of variance and Spearman Rank correlation analysis were used for statistical evaluation of results. R e s u l t s T h e m e a n B M C o f a l l d i a b e t i c s w a s r e d u c e d t o 9 0 . 2 % o f t h e m e a n n o r m a l v a l u e ( P < 0 . 0 0 1 ) . T h e i n f l u e n c e o f t h e d i a b e t i c " r i s k f a c t o r s " a p p e a r s f r o m T a b l e s 1 a n d 2. T a b l e 1 d e m o n s t r a t e s t h e g r a d u a l d e c r e a s e i n B M C w i t h s u c c e s s i v e s e l e c t i o n o f t h e p a t i e n t s w i t h t h e h i g h e s t r i s k o f b o n e loss. A s t e p w i s e r e d u c t i o n i n B M C is s e e n t o a m i n i m u m m e a n v a l u e o f 7 9 . 3 % n o r m a l i n t h e p a t i e n t s w i t h t h e p o o r e s t m e t a b o l i c c o n t r o l . Group ae be % d e Group A~ Be Ce D e n 129 16 35 17 n 86 75 26 14 BMC (% of normal) Mean + SEM 92.9 _+ 1.3 91.8 + 4.1 87.2 _+ 1.9 85.4 + 2.3 BMC (% of normal) Mean + SEM 86.1 _+ 1.3 92.3 _+ 1.8 90.2 _+ 2.2 95.2 _+ 4.4 T a b l e 2 shows the opposite, i.e. the gradual increase in m e a n B M C with successive selection of the patients with the lowest risk of b o n e loss. In this way m e a n B M C is seen to rise stepwise to a m a x i m u m of 9 9 . 3 % of n o r m a l in the patients with the best m e t a b o l i c status. If glycosuria was used for the last stratification instead of the fasting b l o o d glucose level, the results w e r e similar. Stratification according to risk factors subdivided the patients into groups with strictly c o m p a r a b l e duration of diabetes. In the entire series B M C was inversely correlated with the fasting b l o o d glucose level ( R = - 0 . 1 7 , P < 0 . 0 2 ) and dally insulin dose ( R = --0.22, P < 0 . 0 0 2 ) , and positively with the Cp e p t i d e level ( R = 0.19, P < 0 . 0 0 5 ) . Discussion N o n e of the indices of m e t a b o l i c control used in the p r e s e n t study estimates accurately the overall m e t a b o l i c state of the patient. T h e c o m b i n a t i o n of these indices m a y , however, p r o v i d e a sufficient estim a t e of the severity of the disturbances in glucose homeostasis. In fact, a b o n e loss of 2 0 . 7 % was found in the patients selected to h a v e the p o o r e s t m e t a b o l i c state on the day of study, w h e r e a s no b o n e loss was f o u n d in patients with the mildest disturbances. It m a y s e e m surprising that the d e p e n d e n c y of b o n e mineral content on m e t a b o l i c status was so readily d o c u m e n t e d in view of the controversies a b o u t the role of m e t a b o l i c control for the vascular complications, still present after 50 years of insulin t r e a t m e n t [ 13, 14 ]. T h e large n u m b e r of patients studied as well as the high precision and accuracy of the m e a s u r e m e n t of B M C are b o t h i m p o r t a n t factors. F u r t h e r m o r e , the patients w e r e studied outside the diabetic clinic, and had 1.8 times higher 24 h-glycosuria c o m p a r e d with the m o s t recent visits at the diabetes clinic [15]. T h e higher glycosuria m a y indeed give a b e t t e r estimate of the " e v e r y d a y " m e t a b o l i c state. O u r indices of m e t a b o l i c status are certainly interrelated, but characterize the state of control in different ways [ 16-19 ]. Residual B-cell function is k n o w n to contribute to g o o d m e t a b o l i c control, m o s t easily shown by the smaller insulin r e q u i r e m e n t of patients with p r e s e r v e d insulin secretion [16]. T h e dosage of insulin reflects a n u m b e r of variables, affecting b l o o d and urine glucose levels at the preceding visits to the clinic. Residual B-cell function and insulin dosage m a y b o t h b e relatively g o o d indices of l o n g - t e r m m e t a b o l i c control. O u r data p r o v i d e an explanation for the r e p o r t e d n o r m a l b o n e mineral content in well-controlled diabetics t r e a t e d exclusively with diet a n d / o r oral antidiabetics [ 20 ]. L e v i n et al. [ 1 ] found a m i n o r reduction of B M C in their diabetics t r e a t e d with diet a n d / o r sulphonylureas, but c o n t r a r y to the patients studied by D e L e e u w and A b s [ 20 ] they had not selected their patients to be especially well-controlled. T h e increased f r e q u e n c y of b o n e fractures previously r e p o r t e d in diabetics [ 21, 22 ] is c o m p r e h e n s i b l e in view of the 2 0 % loss of b o n e minerals f o u n d in the poorly controlled patients. Acknowledgements. This work was supported by grants from the Danish Hospital Foundation for Medical Research, Region of Copenhagen, Faroe Islands, and Greenland; the Danish Diabetic Association; the Danish Medical Research Council; and Dr. Erik Garde and Elisabeth Garde's Fund. Dr. Peter McNair Department of Clinical Chemistry Glostrup Hospital DK-2600 Glostrup Denmark 1. Levin , M. E. , Boisseau , V. C. , Avioli , L. V.: Effects of diabetes mellitus on bone mass in juvenile and adult-onset diabetes . N. Engl. J. Med . 294 , 241 - 245 ( 1976 ) 2. Ringe , J.-D. , Kuhlencordt , F. , Kiihnau , Jr. J.: Mineralgehalt des Skeletts bei Langzeitdiabetikern. Densitometrischer Beitrag zur "Osteopathia diabetica" . Dtsch. Med . Wochenschr. 101 , 280 - 282 ( 1976 ) 3. McNair , p., Madsbad , S. , Christiansen , C. , Transbol , I. , Faber , O. K. , Binder , C. : Bone mineral loss in diabetes meltitus . Acta Endocrinol. [Suppl . 209] (Kbh.) 85 , 45 ( 1977 ) 4. Rosenbloom , A.L. , Lezotte , D.C. , Weber , F.T. , Gudat , J. , Heller , D.R. , Weber , M.L. , Klein , S. , Kennedy , B.B. : Diminution of bone mass in childhood diabetes . Diabetes 26 , 1052 - 1055 ( 1977 ) 5. McNair , P. , Madsbad , S. , Christiansen , C. , Faber , O.K. , Transbol , I. , Binder , C. : Osteopenia in insulin treated diabetes mellitus: Its relation to age at onset, sex and duration of disease . Diabetologia 15 , 87 - 90 ( 1978 ) 6. McNair , P. , Christensen , M. S. , Madsbad , S. , Christiansen , C. , Binder , C. , Transbol , I. : Bone loss in patients with diabetes mellitus: Effects of smoking. Mineral and electrolyte metabolism (In press) 7. McNair , P. , Madsbad , S. , Christensen , M. S. , Christiansen , C. , Faber , O.K. , Binder , C. , Transbol , I. : Bone mineral loss in insulin-treated diabetes mellitus: Studies on pathogenesis . Acta Endocrinol . (Kbh.) 90 , 463 - 472 ( 1979 ) 8. Christiansen , C. , Rodbro , P. , Jensen , H.: Bone mineral content in the forearm measured by photon absorptiometry. Principles and reliability . Scand. J. Clin. Lab. Invest . 35 , 323 - 330 ( 1975 ) 9. Christiansen , C. , Rodbro , P. : Long-term reproducibility of bone mineral content measurements . Scand. J. Clin. Lab. Invest . 37 , 321 - 323 ( 1977 ) 10. Christiansen , C. , Rodbro , P. : Bone mineral content and estimated total body calciumin normal adults . Scand. J. Clin. Lab. Invest . 35 , 433 - 439 ( 1975 ) 11. Hendriksen , C. , Faber , O.K. , Drejer , J. , Binder , C. : Prevalence of residual B-cell function in insulin-treated diabetics evaluated by the plasma C-peptide response to intravenous glucagon . Diabetologia 13 , 615 - 619 ( 1977 ) 12. Holm , H. , Pianezzi , A. , Scholer , A. : Mikrometode zur Bestimmung der Glucosekonzentration aus 20 ul Probe auf dem Auto-Analyzer . Z. Klin . Chem. Klin. Biochem . 13 , 541 - 543 ( 1975 ) 13. Cahill , Jr. G. F. , Etzwiler , D. D. , Freinkel , N.: "Control" and diabetes . N. Engl. J. Med . 294 , 1004 - 1005 ( 1976 ) 14. Siperstein , M. D. , Foster , D.W. , Knowles , Jr., H. C. , Levine , R. , Madison , L.L. , Roth , J.: Control of blood glucose and diabetic vascular disease . N. Engl. J. Med . 296 , 1060 - 1063 ( 1977 ) 15. Madsbad , S. , McNalr , P. , Faber , O. K. , Binder , C. , Christiansen , C. , Transbol , I. : Beta-cell function and metabolic control in insulin treated diabetics . Acta Endocrinol. (Kbh.) (In press) 16. Faber , O.K. , Binder , C. : B-cell function and blood glucose control in insulin dependent diabetics within the first month of insulin treatment . Diabetologia 13 , 263 - 268 ( 1977 ) 17. Enk , B. : Insulin secretion in insulin-requiring diabetics before and during insulin treatment . Acta Endocrinol . (Kbh.) 85 , 559 - 570 ( 1977 ) 18. Yue , D.K. , Baxter , R. C. , Turtle , J.R.: C-peptide secretion and insulin antibodies as determinants of stability in diabetes mellitus . Metabolism 27 , 35 - 44 ( 1978 ) 19. Shima , K. , Tanaka , R. , Morishita , S. , Tarvi , S. , Kumahara , Y. , Nishikawa , M. : Studies on the etiology of "brittle diabetes". Relationship between diabetic instability and insulinogenic reserve . Diabetes 26 , 717 - 725 ( 1977 ) 20. D e Leeuw, I. , Abs. , R. : Bone mass and bone density in maturity type diabetics measured by the 125I photon absorption technique . Diabetes 26 , 1130 - 1135 ( 1977 ) 21. Alfram , P. A. : A n epidemiologic study of cervical and trochanteric fractures of the femur in an urban population . Acta Orthop. Scand . 65 [Suppl.] ( 1964 ) 22. Menczel , J. , Makin , M. , Robin , G. , Joge , I. , Naor , E.: Prevalence of diabetes mellitus in Jerusalem. Its association with presenile osteoporosis . Isr. J. Med. Sci. 8 , 918 - 919 ( 1972 )


This is a preview of a remote PDF: https://link.springer.com/content/pdf/10.1007%2FBF01235883.pdf

P. McNair, S. Madsbad, C. Christiansen, M. S. Christensen, O. K. Faber, C. Binder, I. Transbøl. Bone loss in diabetes: Effects of metabolic state, Diabetologia, 1979, 283-286, DOI: 10.1007/BF01235883