Erik Lindh

Increased fracture rate in diabetes mellitus and females after renal transplantation.

BACKGROUND Bone disease and fractures after organ transplantation pose severe clinical problems. About 20% of renal transplant patients have type 1 diabetes (IDDM). However, data are scarce in the literature about the occurrence of spontaneous fractures in IDDM patients posttransplantation. METHODS In this cross-sectional study using a questionnaire and hospital records the prevalence of symptomatic bone disease was investigated in 193 renal transplanted patients with functioning renal grafts 6 months to 23 years after the transplantation. RESULTS The frequency of IDDM was 18%. In the total group the rate of osteoporotic fractures posttransplantation was 17%, and the majority of fractures occurred within the first 3 years after the transplantation. A high rate of fractures, 40%, was noted in the diabetes group (P<0.001), compared with 11% in the nondiabetes group. Fractures seen in IDDM were often multiple and located mostly in the appendicular skeleton, i.e., in ankles and feet. Female gender was also associated with an elevated fracture rate, 23% (P<0.05). CONCLUSION An increased incidence of osteoporotic fractures after renal transplantation was found in diabetic and female patients. The mechanism behind bone fragility in IDDM is multifactorial and despite a restored renal function bone disease may progress, and is probably enhanced by the immunosuppressive treatment.

The risk of hip fractures in patients with primary hyperparathyroidism: A population-based cohort study with a follow-up of 19 years

Abstract. Objective. To evaluate primary hyperparathyroidism (HPT) as a risk factor for hip fractures.

Screening for antibodies against gliadin in patients with osteoporosis

Abstract. Intestinal disease might contribute to osteopenia. Measurements of IgA antibodies to gliadin have been established as an accepted screening procedure for detection of coeliac disease. When we applied these measurements to 92 patients with verified osteoporosis, 11 subjects (12%) were found to have elevated levels. This is markedly higher than the incidence in healthy subjects (3%). However, the patients with raised levels of IgA antibodies displayed no clinical symptoms and no laboratory evidence of calcium malabsorption. Thus their values for serum calcium, phosphate, parathyroid hormone (PTH), alkaline phosphatase and osteocalcin, as well as the fasting urinary excretion of hydroxyproline and calcium, were similar to those found in other patients with osteoporosis. Intestinal biopsy verified coeliac disease in three patients and was normal in another three. This gives an incidence of verified coeliac disease in this patient group that is approximately tenfold higher than that in the healthy population. Subclinical coeliac disease appears to be unusually over‐represented among patients with idiopathic osteoporosis, and screening for gliadin antibodies might therefore be a valuable addition to the routine assessment of the osteopenic patient. The mechanisms underlying the relationship are not clear, but calcium malabsorption is not evident.

Increased fracture risk in hypercalcemia: bone mineral content measured in hyperparathyroidism

In the present study, 39 women with mild hypercalcemia, which had been detected 18 years earlier during a health survey, and presumably caused by primary hyperparathyroidism (HPT), were investigated together with 34 age-matched controls. The bone mineral content (BMC) of the nondominant distal forearm was measured by single-photon absorptiometry, and the occurrence of fractures was recorded. Among women up to the age of 70 years, those with hypercalcemia had lower BMC than the controls (P less than 0.05), whereas among the older women, there was no difference. Twelve of the women with probable primary HPT had suffered a distal radius fracture as compared with 3 of the controls (P less than 0.05). Thus, also mild hypercalcemia is a risk factor for bone loss and distal forearm fractures. The findings constitute arguments in favor of early detection and treatment of primary HPT.

Circulating levels of insulin-like growth factor-I and -II, and IGF-binding protein-3 in inflammation and after parathyroid hormone infusion

In order to assess if the anabolic action of PTH is related to changes in circulating levels of insulin-like growth factor-I and -II (IGF-I and -II), and IGF binding protein 3 (IGFBP-3), 24 h of PTH infusion was performed in healthy women and in patients with rheumatoid arthritis (RA), a state where both bone metabolism and PTH secretion is influenced by the inflammatory activity. The patients with RA had lower basal levels of both IGF-I and -II than the healthy controls (P < 0.05). In neither group did the IGFs change after 24 h of PTH administration, while IGFBP-3 was significantly increased in the healthy controls (4600 +/- 1200 to 5750 +/- 2200 micrograms/l, P < 0.05). IGFBP-3 was not affected by PTH infusion in patients with RA when the disease had high activity, but when inflammation had subsided they responded with a similar increase in IGFBP-3 as the control group and basal IGF-I and -II levels were normalised. Since IGFBP-3 can enhance the anabolic action of IGF-I, increased IGFBP-3 levels after PTH infusion may reflect a mechanism by which PTH is anabolic for bone. Inflammation may inhibit bone formation via decreased serum levels of IGFs and blocked IGFBP-3 response to PTH.

Synthetic human calcitonin in postmenopausal osteoporosis: a placebo-controlled, double-blind study.

SummaryA placebo-controlled, double-blind study was carried out over 4 months to evaluate two doses of synthetic human calcitonin (0.25 and 0.125 mg) given s.c. three times per week. Enrolled were 60 women, aged 56–82 years, who had experienced a vertebral fracture due to low-energy trauma within the preceding year. During active treatment there was within the first month a dose-dependent decrease of the indices of bone resorption (fasting urinary calcium and hydroxyproline excretions), whereas only the higher dose and a treatment period of 4 months produced a reduction of bone formation (serum osteocalcin). The bone mineral content (BMC) of the nondominant forearm was unchanged. Treatment with calcitonin also had significant, dosedependent, analgetic effects. The amelioration of pain was, in multivariate analyses, related to a reduction in parameters felt to be markers for bone resorption. In the placebo group there was a significant reduction of the BMC of the forearm but no changes of any of the biochemical markers for bone turnover and no improvement of pain. In conclusion, treatment with two low doses of calcitonin induced changes of the biochemical markers of bone turnover in a dosedependent manner. The analgetic properties of calcitonin were also of salient clinical importance. The knowledge derived from this study could be adapted to the dosage schedule in long-term trials in osteoporosis.

Regulation of Interleukin‐6 Secretion from Mononuclear Blood Cells by Extracellular Calcium

Interleukin‐6 (IL‐6) is known to enhance osteoclast recruitment, and thereby bone resorption. Thus, IL‐6 has been proposed to mediate hypercalcemia in multiple myeloma and the enhanced osteoclastic activity seen in postmenopausal osteoporosis. We recently reported that the calcium concentration in plasma affects IL‐6 secretion from mononuclear blood cells. To investigate the underlying mechanism, we have studied the effect of calcium on IL‐6 formation in mononuclear blood cells ex vivo and in vitro. Thirteen healthy volunteers were given 1 g of calcium orally after overnight fasting. Plasma levels of ionized calcium (pCa2+) and serum levels of parathyroid hormone (sPTH) were measured after 2 and 4 h, with all subjects still fasting. After 2 h, pCa2+ was increased and sPTH decreased in all 13 persons. IL‐6 secretion ex vivo from mononuclear blood cells drawn 4 h after calcium intake was increased 185% as compared with IL‐6 secretion from cells drawn just before calcium intake. In control experiments without calcium intake, there was no alteration in pCa2+ and no effect on IL‐6 secretion from mononuclear blood cells. In vitro studies revealed that stimulation of isolated mononuclear blood cells with physiological concentrations of calcium dose‐dependently increased IL‐6 secretion with an estimated EC50 at 1.2 mM Ca2+. No effect on the IL‐6 secretion was seen following treatment of the isolated mononuclear blood cells with PTH or calcitonin. These observations demonstrate that the plasma calcium concentration affects IL‐6 secretion from mononuclear blood cells. The in vitro data indicate the involvement of a direct calcium sensing mechanism. These findings might have implications in hypercalcemia and should also be borne in mind when considering the role of cytokines in osteoporosis.

IGFs: function and clinical importance 4 Growth hormone, insulin-like growth factor I, and bone: a clinical review

During the last few years, growth hormone (GH) and insulin-like growth factor I (IGF-I) have received much attention as possible anabolic agents for the treatment of osteoporosis as well as other age-related phenomena such as loss of muscle mass, decreased physical capacity, and increased body fat content [l-31. An age-related decline in GH secretion and serum IGF-I levels has been observed [4-121, and, in addition, IGF-I is even further lowered after menopause. Based mostly on results from in-vitro studies, IGF-I is assumed to be an ‘oestromedin’ for osteoblasts, i.e. IGF-I may mediate some of the effects of oestrogen on bone cells [6, 7, 10, 13-15]. Both hormones are now available in pure form for clinical studies thanks to recombinant technology. Growth hormone exerts. direct effects on several tissues and increases the synthesis of IGF-I which acts as an endocrine or paracrine/autocrine somatomedin [ 16, 171. IGF-I production is also regulated by many other hormones, cytokines, nutritional status, and may be altered in disease states [18]. Another regulatory mechanism of the bioactivity is achieved by binding of IGF-I and -11 to specific binding proteins (BPs) in serum and the interstitial fluid. At present, six BPs have been cloned and numbered IGFBP-1 to -6 [19, 201. IGFBPs are regulated by both systemic hormones and local factors, and are expressed in a tissue-specific manner.

Effects of infusion of parathyroid hormone and primary hyperparathyroidism on formation and breakdown of type I collagen

The influence of chronic and acute exposure to parathyroid hormone (PTH) on formation and breakdown of type I collagen, using two recently developed radioimmunoassays for serum PICP (the carboxyterminal propeptide of type I procollagen) and serum ICTP (the carboxyterminal telopeptide of type I collagen), have been evaluated. Fasting morning values were obtained from 18 women with primary hyperparathyroidism (HPT) and an equal number of age-matched, healthy controls. A 24-hour infusion of synthetic human parathyroid hormone (PTH 1-38) was performed in 14 healthy females. The patients with HPT had higher values for serum ICTP than the controls (6.0±3.0 and 4.1±2.1 μg/liter; P<0.05), whereas the serum PICP concentrations were not different (170±72 and 151±65 μg/liter; n.s.). During infusion of PTH in healthy subjects, there was an increase of the serum ICTP concentrations (from 3.6±1.3 to 4.4±1.8 μg/liter; P<0.001) whereas those of serum PICP decreased (from 185±78 to 118±42 μg/liter; P≤0.0001). The increase of serum ICTP during infusion of PTH was positively related to the increase of serum calcium and other indices of bone resorption, i.e., fasting urinary excretions of hydroxyproline and calcium. The decrease of serum PICP was also related to the changes of serum ICTP and hydroxyproline in urine, serum calcium, and alkaline phosphatase but not to osteocalcin, an established marker of osteoblastic activity. The findings support the fact that serum ICTP is a valuable method for evaluating bone resorption and is also easy to perform. Furthermore, the discordant results for the different markers of osteoblastic activity indicat that they reflect different functions of the cell.

Assessment of bone turnover with biochemical markers

There is an obvious need for a convenient and accurate means of evaluating bone turnover both for diagnostic purposes and for monitoring of therapy. During recent years there have been considerable advances with respect to radiological and densitomctric monitoring as well as for bone biopsy examination. Measurements of bone specific biochemical markers have also been developed. The proteins of bone tissue range from collagen, which is found in all connective tissues, to the quantitatively minor, but more specific proteins located mainly, if not exclusively, in bone as a result of synthesis by the bone-forming cell, the osteoblast [l]. All currently used markers for bone formation are produced by osteoblasts, whereas markers for bone resorption either directly reflect the activity of the bone resorbing cell, the osteoclast, or provide indices of bone matrix degradation. Bone formation in clinical practice is most commonly evaluated by measurement of serum alkaline phosphatase activity (ALP). Skeletal ALP is localized in the osteoblasts but the mechanisms of its release remain unclear and its actual function in bone formation has not been clarified. Alkaline phosphatase activity is also present in a number of tissues other than bone [ 2 ] . Because of the difficulties involved in the measurement of the specific isoenzymes of ALP, most studies usually only include determinations of the total ALP activity, which is generally considered to be a useful, although rather insensitive, marker for the rate of bone formation. There are as yet only a few reports on the value of skeletal ALP in the evaluation of metabolic bone disease. Osteocalcin is a small protein with a molecular weight of about 5800Da which makes up 20% of the non-collagenous proteins in bones. Its biological function has not yet been precisely determined, but it appears to be unique to bone and synthesized by osteoblasts. A small fraction of the synthesized protein does not accumulate in bone but is secreted directly into the circulation. Furthermore, upon catabolism of osteocalcin, its characteristic amino-acid. gammacarboxyglutamic acid (Gla), is excreted into the urine. Both serum osteocalcin and urine Gla are currently being widely used for the assessment of bone disease. The serum level is modulated by numerous factors that affect osteoblast numbers and activity, but several studies monitoring serum osteocalcin in normal individuals and patients with metabolic bone disease indicate that it is a useful specific marker of bone formation [3]. In a recent study where concurrent assays were made of serum osteocalcin and bone alkaline phosphatase it was found that these measurements gave concordant results in, e.g. osteoporosis and primary hyperparathyroidism, but discordant results in patients with glucocorticoid excess, chronic renal failure, Paget’s disease and osteolytic metastases, suggesting that the discrepancies occurred because the two biochemical markers reflected different aspects of osteoblast function [4]. A third index of bone formation is the level of the terminal extensions of procollagen, the precursor molecules for collagen. Several types of collagen have been identified and classified according to their polypeptide chains. Among the most abundant are type I, predominantly formed in bone, and type 111, which constitutes the major structural protein in reticular fibres and is present in smooth muscle and skin. Elevated serum levels of type I procollagen corboxyterminal peptide is presumably derived from synthesis of mineralized bone collagen [5]. The serum levels of procollagen-I11 peptide are elevated in, e.g. Paget’s disease of bone, however the most probable source is not the Pagetic bone per se, but the vascular fibrous connective tissue which replaces normal bone marrow. Since there is a direct relationship between procollagen peptide synthesis and new bone specific collagen formation, it seems probable that assay of the peptides, in particular type I, could be valuable for diagnosis and monitoring of metabolic bone diseases. The most commonly used marker for bone resorption is urinary hydroxyproline. The biochemical background for this variable is that the skeleton is the organ with the highest collagen content and that collagen is the only protein containing. this amino-