Georg Leb

Genetic predisposition for adult lactose intolerance and relation to diet, bone density, and bone fractures

Evidence that genetic disposition for adult lactose intolerance significantly affects calcium intake, bone density, and fractures in postmenopausal women is presented. PCR‐based genotyping of lactase gene polymorphisms may complement diagnostic procedures to identify persons at risk for both lactose malabsorption and osteoporosis.

Vitamin D deficiency and secondary hyperparathyroidism are common complications in patients with peripheral arterial disease

OBJECTIVE: To investigate via the vitamin D status whether patients with peripheral arterial disease (PAD) tend to develop vitamin D deficiency that in turn influences their clinical symptoms.DESIGN: Cross-sectional.SETTING: University hospital.PATIENTS AND PARTICIPANTS: Three hundred twenty-seven patients were evaluated; subjects with secondary causes of bone disease or bone active medication were excluded. One hundred sixty-one patients with either PAD stage II (n = 84) or stage IV (n=77) were enrolled and compared to 45 age- and sex-matched healthy controls.MEASUREMENTS AND MAIN RESULTS: All patients underwent determinations of serum chemistry, 25-hydroxyvitamin D (vitamin D3) intact parathyroid hormone (iPTH), alkaline phosphatase (ALP), and osteocalcin and were further stratified according to an individual restriction score into 3 groups: mildly, moderately, or severely restricted in daily life due to the underlying disease. Patients with PAD IV showed significantly lower vitamin D3 (P=.0001), and calcium (P=.0001) values and significantly higher iPTH (P=.0001), osteocalcin (P=.0001) and ALP (P=.02) levels as compared to patients with PAD II. Patients considering themselves as severely restricted due to the underlying disease showed lower vitamin D3 and higher iPTH levels than those who described only a moderate (vitamin D3: P<.001; iPTH: P<.01) or mild (vitamin D3: P<.001; iPTH: P<.001) restriction in daily life.CONCLUSION: Patients with PAD IV, especially those who feel severely restricted due to the disease, are at high risk of developing vitamin D deficiency, secondary hyperparathyroidism, and ultimately osteomalacia due to immobilization and subsequent lack of exposure to sunlight, all of which in turn lead to further deterioration. Monitoring of vitamin D metabolism and vitamin D replacement therapy could be a simple, inexpensive approach to mitigating clinical symptoms and improving quality of life in patients with advanced PAD.

Serum osteoprotegerin is a major determinant of bone density development and prevalent vertebral fracture status following cardiac transplantation

Osteoprotegerin (OPG) is an antiresorptive cytokine and a key regulator of osteoclastogenesis and activity. Since OPG is downregulated by glucocorticoids and cyclosporine A in vitro we examined whether immunosuppressive therapy would play a role in the development of transplantation osteoporosis. We enrolled 57 cardiac transplant recipients (median time since transplantation, 3.2 years (1.1-11.5 years)) in this cross-sectional study. Standardized spinal X-rays as well as hip bone density measurements were performed in all patients. Serum OPG was determined using a commercially available ELISA. Vertebral fractures were present in 56% of the patients. Bone densities of all femoral neck subregions were correlated to serum OPG concentrations (r values between 0.40 and 0.48, all P < 0.005). Multiple regression analysis revealed OPG levels to be independently correlated to femoral neck Z scores (r = 0.49, P = 0.002). After adjustment for age, BMI, neck Z score, renal function, and months since transplantation, serum OPG was the only significant predictor of prevalent vertebral fractures (P = 0.001). In a separate 6-month prospective study of 14 heart transplant recipients receiving calcium and vitamin D serum OPG levels fell by 41% (P = 0.0004) after 3 months and 47% (P = 0.0001) after 6 months following cardiac transplantation. Bone loss at the lumbar spine and femoral neck after 6 months was correlated to the decrease in serum OPG at 6 months (r = 0.82, P < 0.0001, and r = 0.60, P = 0.02, respectively) as well as 3 months after cardiac transplantation (r = 0.65, P = 0.01, and r = 0.69, P = 0.006, respectively). Serum OPG alone accounted for 67% of the variance of lumbar spine bone density changes over the first 6 months posttransplantation. We conclude that serum OPG levels decline consistently in all patients following initiation of immunosuppressive therapy and are independently correlated with changes in bone density. We hypothesize that OPG plays a major role in the development of transplantation osteoporosis.

Bone Loss in Patients with Untreated Chronic Obstructive Pulmonary Disease Is Mediated by an Increase in Bone Resorption Associated with Hypercapnia

This study sought to determine whether the bone loss in untreated chronic obstructive pulmonary disease (COPD) is associated with hypercapnia and/or respiratory acidosis. Bone mineral density (BMD) measured at the distal forearm of the nondominant arm (with peripheral quantitative computed tomography [pQCT]) and serum markers of bone turnover were determined in 71 male patients with untreated COPD and 40 healthy male subjects who matched the patients in age, weight, and body mass index (BMI). The COPD patients, compared with controls, had reduced pulmonary functions, lower arterial pH, and elevated arterial partial pressure of CO2 (P  CO 2 ). The BMD (in T score) was significantly lower in COPD patients than that in control subjects (−1.628 ± 0.168 vs. −0.058 ± 0.157; p < 0.001). The BMD of COPD patients correlated positively with arterial pH (r = 0.582; p < 0.001), negatively with P  CO 2 (r = −0.442; p < 0.001), and negatively with serum cross‐linked telopeptide of type I collagen (ICTP), a bone resorption marker (r = −0.444; p < 0.001) but not with serum osteocalcin, a bone formation marker. Serum ICTP, but not osteocalcin, correlated with P  CO 2 (r = 0.593; p < 0.001) and arterial pH (r = −0.415; p < 0.001). To assess the role of hypercapnia, COPD patients were divided into the hypercapnic (P  CO 2 > 45 mm Hg; n = 35) and eucapnic (P  CO 2 = 35–45 mm Hg) group (n = 36). Patients with hypercapnia had lower BMD, lower arterial pH, and higher serum ICTP than did patients with eucapnia. Arterial pH and serum ICTP of eucapnic patients were not different from those of controls. To evaluate the role of uncompensated respiratory acidosis, COPD patients with hypercapnia were subdivided into those with compensatory respiratory acidosis (pH ≥ 7.35; n = 20) and those with uncompensated respiratory acidosis (pH < 7.35; n = 15). The BMD and serum ICTP were not different among the two subgroups. In conclusion, this study presents the first associative evidence that the bone loss in COPD is at least in part attributed to an increased bone resorption that is associated primarily with hypercapnia rather than uncompensated respiratory acidosis.

Osteoprotegerin serum levels in women: Correlation with age, bone mass, bone turnover and fracture status

ZusammenfassungIn präklinischen Studien wurde gezeigt, dass Osteoprotegerin (OPG) einen hemmenden Einfluss auf die Osteoklasten ausübt und daher eine wesentliche Rolle im Knochenstoffwechsel spielt. Ziel dieser Studie war es denklinischen Stellenwert von OPG zu evaluieren. Ist auch bei Menschen ein hoher Serum-OPG Spiegel mit niedriger Knochenresorption und konsekutiv höherer Knochendichte verbunden?Bei 177 gesunden Frauen (17–85 Jahre) und bei 48 unbehandelten Patientinnen (71±5 Jahre) mit primärer postmenopausaler Osteoporose wurde OPG im Serum gemessen und in Relation zu Alter, Knochendichte, Knochenstoffwechselparametern un — im Fall der Patientinnen mit Osteoporose — zu prävalenten Wirbelkörperfrakturen gestellt.Bei den gesunden Probanden korrelierte OPG positiv mit dem Alter (r=0,25, p<0,001), während kein Zusammenhang mit der Knochendichte oder den Knochenumbauparametern gefunden wurde. Bei den Osteoporose-Patientinnen hingegen zeigte sich eine klare Korrelation mit den Knochenmarkern: Serum-Crosslaps r=+0.82, p<0.0001; Osteokalzin r=+0,69; p<0,0001.Nach Normalisierung der Serum-OPG Werte für die Knochendichte und Umbaumarker zeigten Patientinnen mit prävalenten Wirbelkörperfrakturen deutlich niedrigere Werte im Vergleich zu den Patientinnen ohne Frakturen (57±8 vs. 97±10 pg/ml; p<0,01).Der altersabhängige Anstieg von OPG als antiresorptiver Faktor könnte einen insuffizienten parakrinen Kompensationsversuch der Osteoblasten auf den Knochenverlust im Alter darstellen. Der klare Zusammenhang von OPG mit den Knochenumbaumarkern bei Patientinnen mit Osteoporose ist wahrscheinlich als Ausdruck einer erhöhten RANKL/OPG Expression zu werten.Niedrige OPG-Spiegel scheinen mit einem erhöhten Frakturrisiko assoziiert zu sein. Der individuelle Serum OPG Wert könnte unter Berücksichtigung des Knochenstoffwechsels ein prädiktiver Faktor für das Frakturrisiko bei Frauen mit primärer postmenopausaler Osteoporose sein.SummaryPre-clinical data have shown that osteoprotegerin (OPG) inhibits osteoclast function and therefore plays an important role in bone remodelling. This study aimed to evaluate theclinical value of serum OPG. Do higher OPG serum levels reflect decreased bone resorption and perhaps higher bone mass in women?Serum OPG levels were measured in 177 healthy women (aged 17–85 years) and in 48 untreated patients (mean age 71±5) with established osteoporosis, and related to age, bone mass, markers of bone turnover and, in the case of patients with osteoporosis, to pre-existing vertebral fractures.In healthy women OPG levels showed a positive correlation with age (r=0.25, p<0.001) but not to bone mass or markers of bone turnover. In women with osteoporosis, however, there was a strong relationship between serum OPG and markers of bone turnover (serum c-terminal crosslinked telopeptides of type I collagen (sCTX): r=+0.82, p<0.0001; osteocalcin (OC): r=+0.69, p<0.0001), with patients who had higher levels of bone-turnover markers showing higher serum levels of OPG. After adjustment for bone mass and bone markers, patients with pre-existing vertebral fractures had significantly lower serum OPG levels than patients without fractures (57±8 vs. 97±10 pg/ml, [mean±SE], p<0.01).The age-dependent increase of OPG as an antiresorptive factor may reflect an insufficient paracrine mechanism of bone cells to compensate for bone loss in older age. In patients with osteoporosis, however, OPG correlated strongly with markers of bone turnover; this may point toward a higher level of RANKL/OPG expression in these patients.Finally, low OPG serum levels seem to be associated with vertebral fractures. We hypothesise that low OPG levels in preset conditions of bone turnover may indicate a higher risk of fracture in patients with osteoporosis.

Bone Metabolism in Patients with Differentiated Thyroid Carcinoma Receiving Suppressive Levothyroxine Treatment

AIM Patients with differentiated thyroid carcinoma (DTC) must receive suppressive levothyroxine (LT(4)) therapy for the rest of their lives. The literature, however, presents conflicting results on how this affects bone metabolism. The aim of this study was to assess the influence of the estrogen status and LT(4) therapy, in particular LT(4) dosage in micrograms per kilograms (microg/kg), on bone metabolism in female patients with DTC. MATERIAL AND METHODS Three markers of bone metabolism (C-terminal telopeptide of type I collagen in serum [SCTx]; N-terminal telopeptide of type I collagen in urine [U-NTx]; and osteocalcin [OC]) were investigated in four groups: group REF (healthy premenopausal female controls), group DTC-ES (premenopausal women with DTC and normal estrogen levels), group DTC-ED (postmenopausal women with DTC and estrogen deficiency), and group DTC-HRT (postmenopausal women with DTC undergoing hormone replacement therapy [HRT]). All patients with DTC were on a well-adjusted suppressive LT(4) therapy with TSH levels 0.1 mU/L or less. RESULTS In group DTC-ES bone turnover was comparable to group REF, whereas in group DTC-ED, all three markers were significantly increased as compared to groups REF and DTC-ES. In group DTC-HRT, the HRT normalized U-NTx and OC. However, in this group S-CTx was not completely normalized by HRT in all patients, although also significantly lowered compared to group DTC-ED. The analysis of LT(4 )dosage per kilogram showed that premenopausal DTC-patients had increased markers of bone metabolism if LT(4) dosage exceeded 2.6 microg/kg. Estrogen-deficient patients with DTC, however, had a much lower critical LT(4) dosage, above which increased markers of bone metabolism were seen. CONCLUSION A well-adjusted suppressive LT(4) therapy of less than 2.6 microg/kg and normal estrogen levels do not seem to increase bone metabolism in estrogen-sufficient patients with DTC. The normalization of an estrogen deficiency by HRT or other antiresorptive therapies and minimal suppressive dosages of LT(4) are attempts to optimize the care of patients with DTC. In postmenopausal patients with DTC and patients with DTC who require LT(4) dosages in excess of 2.6 microg/kg, the information provided by markers of bone metabolism may help to prevent bone damage.

Thyroid hormones and thyroid antibodies in infertile males

OBJECTIVE To investigate the incidence of thyroid dysfunction, thyroid antibodies, and the correlation with semen and hormonal parameters in infertile men. DESIGN Prospective study. SETTING University-based andrology laboratory. PATIENT(S) Three hundred five infertile men with idiopathic infertility. INTERVENTION(S) Medical history, clinical examination, semen analysis, measurement of free thyroxin (fT4), free triiodothyronine (fT3), basal thyroid-stimulating hormone (bTSH), LH, FSH, T, free testosterone (fT), PRL, E2, sex hormone-binding globulin (SHBG), DHEAS, and the thyroid antibodies thyreoglobulin antibody (TGA), thyroid peroxidase antibody (TPO-Ab), and thyroid receptor antibody (TRAK). MAIN OUTCOME MEASURE(S) Incidence of thyroid dysfunction and thyroid antibodies, as well as the correlation with hormones and the results of semen analyses. RESULT(S) No manifest thyroid dysfunction was observed. Latent thyroid dysfunction and latent hypothyroidism were diagnosed in 11.5% and 3% of infertile men, respectively. No correlation between thyroid dysfunction and semen parameters was detected. bTSH correlated significantly with PRL (P<.001). Thyroid antibodies were elevated in 7.5%. Elevated TPO-Ab were significantly correlated with pathozoospermia (P=.036) and asthenozoospermia (P=.049). CONCLUSION(S) Latent thyroid dysfunction had no impact on semen parameters. In patients with elevated TPO-Ab levels, pathozoospermia or asthenozoospermia should be considered.

Effects of postprandial walking on delayed gastric emptying and intragastric meal distribution in longstanding diabetics

OBJECTIVE:We investigated the influence of standardized postprandial walking on the rates of gastric emptying and of intragastric meal distribution in 50 consecutive patients with longstanding insulin-dependent diabetes mellitus.METHODS:Gastric emptying of a semisolid meal labeled with 99mTc was continuously recorded with a dual-head gamma camera with patients in the supine position for 90 min before and 20 min after a 30-min postprandial walk. Regions of interest enclosing total stomach, and proximal and distal gastric compartments were calculated to determine gastric emptying rates and intragastric meal distribution.RESULTS:The evaluation of gastric emptying rates before and after postprandial walking demonstrated two variants of delayed gastric emptying: one variant that was counteracted by postprandial walking in seven patients (14%, Group I) and another variant that was not influenced by postprandial walking in 11 patients (22%, Group II). In addition, the emptying rates of 28 patients (56%) were within the range of controls and in four patients the emptying was accelerated (8%). The filling of the proximal gastric compartment was predominant and remained dominant after walking in Groups I and II. In controls and in diabetics with normal gastric emptying, the preliminary predominant filling of the proximal compartment was equalized after walking and the proximal compartment regained predominance thereafter. The changes in gastric emptying characteristics from delayed to accelerated gastric emptying may be related to the duration of diabetes (r =−0.47, p < 0.03) and were not indicated by symptoms of upper GI discomfort or by secondary diabetic manifestations.CONCLUSION:Postprandial walking may improve gastric emptying in 14% of patients with longstanding insulin-dependent diabetes mellitus.

Variable bone mass recovery in hyperthyroid bone disease after radioiodine therapy in postmenopausal patients.

OBJECTIVES Long-term follow-up of postmenopausal hyperthyroid females after radioiodine therapy, since hyperthyroidism is known to cause impressive bone loss which may increase the risk of bone fractures. METHODS Bone mineral density (BMD) and biochemical parameters of bone metabolism in hyperthyroid postmenopausal patients were investigated before and 2 years after radioiodine therapy and compared with euthyroid age-matched controls. RESULTS At baseline, the incidence of low BMD with t-scores more than 2.5 S.D. below normal was significantly higher in hyperthyroid patients (54%) than in controls (20%, P<0.001). Regardless of initial BMD values, osteocalcin (OC) was also higher in all hyperthyroid patients (P<0.0001). After 2 years, all treated patients were euthyroid and OC levels were in the upper normal range. In hyperthyroid patients with initially low BMD, bone density values had increased significantly by +6.5% (P<0.008) as compared with baseline values. In contrast, hyperthyroid patients with initially normal BMD showed a further decrease in lumbar BMD values of -4.3% despite radioiodine treatment. BMD in euthyroid controls decreased by -6.5% within 2 years. CONCLUSIONS We conclude that hyperthyroid postmenopausal patients with generally increased bone turnover may show individual differences in bone loss and BMD recovery after radioiodine treatment. The mechanisms for this variable manifestation of osteoporosis have still to be elucidated, since this has implications for prophylactic and therapeutic strategies in these elderly patients.

Recovery from severe osteoporosis following cure from ectopic ACTH syndrome caused by an appendix carcinoid

Dobnig H et al. (Department of Internal Medicine, Karl Franzens University, Graz, Austria). Recovery from severe osteoporosis following cure from ectopic ACTH syndrome caused by an appendix carcinoid (Case report). J Intern Med 1996; 239: 365–9.