Treatment of Obesity with Thyroid hormones in Europe. Data from the THESIS* Collaboration.

PURPOSE: The use of thyroid hormones (TH) to treat obesity is unsupported by evidence as reflected in international guidelines. We explored views about this practice, and associations with respondent characteristics among European thyroid specialists. METHODS: Specialists from 28 countries were invited to a survey via professional organisations. The relevant question was whether "Thyroid hormones may be indicated in biochemically euthyroid patients with obesity resistant to lifestyle interventions". RESULTS: Of 17,232 invitations 5695 responses were received (33% valid response rate; 65% women; 90% endocrinologists). Of these, 290 (5.1%) stated that TH may be indicated as treatment for obesity in euthyroid patients. This view was commoner among non-endocrinologists (8.7% vs. 4.7%, p < 0.01), private practice (6.5% vs. 4.5%, p < 0.01), and varied geographically (Eastern Europe, 7.3%; Southern Europe, 4.8%; Western Europe, 2.7%; and Northern Europe, 2.5%). Respondents from Northern and Western Europe were less likely to use TH than those from Eastern Europe (p < 0.01). Gross national income (GNI) correlated inversely with this view (OR 0.97, CI: 0.96-0.97; p < 0.001). Having national guidelines on hypothyroidism correlated negatively with treating obesity with TH (OR 0.71, CI: 0.55-0.91). CONCLUSIONS: Despite the lack of evidence, and contrary to guidelines' recommendations, about 5% of respondents stated that TH may be indicated as a treatment for obesity in euthyroid patients resistant to life-style interventions. This opinion was associated with (i) respondent characteristics: being non-endocrinologist, working in private practice, treating a small number of hypothyroid patients annually and (ii) national characteristics: prevalence of obesity, Eastern Europe, low GNI and lack of national hypothyroidism guidelines.

Effect of vitamin D3 on bone turnover markers in critical illness: post hoc analysis from the VITdAL-ICU study.

In this post hoc analysis of the VITdAL-ICU study, an RCT in critically ill adults with 25-hydroxyvitamin D levels ≤20 ng/ml, vitamin D3 did not have a significant effect on ß-Crosslaps and osteocalcin. INTRODUCTION: Observational studies have shown accelerated bone loss in ICU survivors. A reversible contributor is vitamin D deficiency. In a post hoc analysis of the VITdAL-ICU study, we evaluated the effect of high-dose vitamin D3 on the bone turnover markers (BTM) ß-Crosslaps (CTX) and osteocalcin (OC). METHODS: The VITdAL-ICU study was a randomized, double-blind, placebo-controlled trial in critically ill adults with 25-hydroxyvitamin D levels ≤20 ng/ml who received placebo or high-dose vitamin D3 (a loading dose of 540,000 IU and starting 1 month after the loading dose five monthly maintenance doses of 90,000 IU). In this analysis on 289 survivors (209 telephone, 80 personal follow-up visits), BTM were analyzed on days 0, 3, 7, 28, and 180; self-reported falls and fractures were assessed. Bone mineral density (BMD) was measured after 6 months. RESULTS: At baseline, CTX was elevated; OC was low in both groups-after 6 months, both had returned to normal. There were no differences between groups concerning BTM, BMD, falls, or fractures. In linear mixed effects models, CTX and OC showed a significant change over time (p < 0.001, respectively), but there was no difference between the vitamin D and placebo group (p = 0.688 and p = 0.972, respectively). CONCLUSIONS: Vitamin D supplementation did not have a significant effect on BTM. Further studies should assess the effectiveness of vitamin D on musculoskeletal outcomes in ICU survivors.

Vitamin D and calcium supplementation for three years in postmenopausal osteoporosis significantly alters bone mineral and organic matrix quality.

Prospective, controlled clinical trials in postmenopausal osteoporosis typically compare effects of an active drug with placebo in addition to vitamin D and calcium supplementation in both treatment arms. While clinical benefits are documented, the effect of this supplementation in the placebo arm and in clinical practice on bone material composition properties is unknown. The purpose of the present study was to evaluate these bone quality indices (specifically mineral/matrix, nanoporosity, glycosaminoglycan content, mineral maturity/crystallinity, and pyridinoline content) in patients that either received long-term vitamin D (400-1200IU) and calcium (1.0-1.5g) supplementation, or did not. We have analyzed by Raman microspectroscopy the bone forming trabecular surfaces of iliac crest in pre-treatment samples of a teriparatide study and the endpoint biopsies of the control arm obtained from the HORIZON trial. In general, the mineral/matrix ratio and the glycosaminoglycan (GAG) content was higher while nanoporosity, (a surrogate for tissue water content), the mineral maturity/crystallinity (MMC) and the pyridinoline (Pyd) content was lower in patients without long-term supplementation. Moreover, all indices were significantly dependent on tissue age. In conclusion, vitamin D and calcium supplementation is associated with altered mineral and organic matrix properties.

Bone quality of the newest bone formed after two years of teriparatide therapy in patients who were previously treatment-naïve or on long-term alendronate therapy.

UNLABELLED: The results of the present study, involving analysis of biopsies from patients who received teriparatide for 2 years and were previously either treatment-naïve or on long-term alendronate therapy, suggest that prior alendronate use does not blunt the favorable effects of teriparatide on bone quality. INTRODUCTION: Examine the effect of 2 years of teriparatide (TPTD) treatment on mineral and organic matrix properties of the newest formed bone in patients who were previously treatment-naïve (TN) or on long-term alendronate (ALN) therapy. METHODS: Raman and Fourier transform infrared microspectroscopic analyses were used to determine the mineral/matrix (M/M) ratio, the relative proteoglycan (PG) content, and the mineral maturity/crystallinity (MMC; determined by three methods: carbonate content, full width at half height of the v 1 PO4 band [FWHH], and wavelength at maxima of the v 1 PO4 band), as well as collagen maturity (ratio of pyridinoline/divalent cross-links), in paired iliac crest biopsies at trabecular, endosteal, and osteonal surfaces of newly formed bone in postmenopausal osteoporotic women who were previously either TN (n = 16) or receiving long-term ALN treatment (n = 24). RESULTS: Trabecular M/M ratio increased and matrix content decreased significantly in the ALN pretreated group. Collagen maturity decreased in both patient groups. Endosteal M/M ratio increased significantly in the TN group. Trabecular M/M ratio was higher at endpoint in the ALN pretreated group than in the TN group. Overall, no changes from baseline were observed in PG content, except that PG content was higher in the ALN pretreated group than in the TN group at endosteal surfaces at endpoint. The ability of TPTD treatment to reduce MMC in both patient groups and at the different bone surfaces depended on the measurement tool (relative carbonate content or wavelength at maxima of the v 1 PO4 band). None of the changes in MMC were different between the two patient groups. CONCLUSIONS: The results suggest some favorable impact of TPTD on bone mineral and organic matrix properties of in situ forming bone in terms of increased initial mineralization and decreased MMC and collagen maturity. Moreover, prior long-term ALN administration may have only limited influence on these properties in bone newly formed after 2 years of TPTD treatment.

Current controversies in clinical management of postmenopausal osteoporosis.

Osteoporosis is a frequent disease in postmenopausal women. Despite the fact that fragility fractures cause many problems - a bio-psycho-social burden for the individual and an economic burden for the society - osteoporosis is still underdiagnosed and undertreated. Controversies exist concerning assessment with different tools for initiating a disease-specific treatment, patient monitoring with bone turnover markers, and treatment duration due to potential side effects in long-term treatment. This manuscript outlines and discusses these controversies and the presented cases, representatives for frequent clinical problems, may give guidance for the clinician in deciding how and how long to treat his/her patient. Re-evaluations of the patients on a regular basis are essential to warrant the necessity of treatment continuation and may improve patients' compliance.

How long should women with postmenopausal osteoporosis be treated with a bisphosphonate?

Bisphosphonates are very frequently prescribed to women suffering from postmenopausal osteoporosis with or without fragility fractures. The present review was aimed to update the available information on the most efficient treatment duration. Studies on bisphosphonate treatment duration were identified by Medline up to January 2013. Bisphosphonates are very effective in the short as well as in the medium-term. However, the optimal duration of use has not been determined yet. Therefore, this review summarizes the long-term effects of bisphosphonates on surrogate parameters of fracture prevention, bone mineral density measurements, and bone turnover markers. An initial treatment period of 3-5 years is recommended. Then, the patient has to be re-evaluated for fracture risk, which depends on fracture status as well as on other health issues. Beyond that, life style factors such as regular physical activity as well as a sufficient intake of calcium and vitamin D or, if necessary supplementation of calcium and/or vitamin D play an essential part in fracture prevention.

Associations of homoarginine with bone metabolism and density, muscle strength and mortality: cross-sectional and prospective data from 506 female nursing home patients.

UNLABELLED: In female nursing home patients, homoarginine was associated with lower bone turnover, higher bone density, lower mortality and, by trend, with muscle strength. INTRODUCTION: Homoarginine, a cationic amino acid, may be relevant for muscusloskeletal health because it inhibits alkaline phosphatases (AP) and is involved in nitric oxide and energy metabolism. We aimed to evaluate whether homoarginine serum concentrations are associated with bone density and metabolism, muscle strength, fractures and mortality. METHODS: We examined a cohort of female nursing home patients that underwent quantitative bone ultrasound (QUS) measurements and assessments of knee extensor strength. Measurements of serum homoarginine, C-terminal telopeptide cross-links (ß-CTxs) and osteocalcin were also performed at baseline. Thereafter, patients were followed-up with respect to fractures and mortality. RESULTS: Serum homoarginine concentrations were determined in 506 female study participants (mean age: 83.9 ± 6.0 years). Homoarginine was inversely correlated with ß-CTxs (r = -0.26; p < 0.001) and osteocalcin (r = -0.21; p < 0.001), and these associations remained significant in multiple regression analyses. Multivariate regression analyses showed that homoarginine is significantly associated with calcaneus stiffness (beta coefficient = 0.11; p = 0.020) and by trend with knee extensor strength (beta coefficient = 0.09; p = 0.065). During a mean follow-up time of 27 ± 8 months, we recorded 119 deaths (23.5%) and 63 fractures (12.5%). In multivariate analyses, homoarginine was associated with significantly reduced risk of mortality and the combined endpoint of fractures and mortality. CONCLUSIONS: Whether homoarginine metabolism is critically involved into the pathogenesis of musculoskeletal diseases and fatal events warrants further studies.

Low bone turnover and increase of bone mineral density in a premenopausal woman with postoperative hypoparathyroidism and thyroxine suppressive therapy.

We report the case of a 36-year-old woman who developed permanent hypoparathyroidism after thyroidectomy for differentiated thyroid carcinoma. A 6-year follow-up showed an increase of 11% in absolute bone mineral density at the spine and 6% at the hip accompanied by low bone turnover despite thyroid-stimulating hormone suppressive thyroxine therapy.

Histomorphometric changes by teriparatide in alendronate-pretreated women with osteoporosis.

SUMMARY: The level of increased bone formation after 24 months of treatment with teriparatide (rhPTH (1-34), TPTD) is similar in patients who were either treatment-naïve (TN) or had lower bone turnover initially due to previous alendronate (ALN) therapy. INTRODUCTION: Bone anabolic effects of TPTD in postmenopausal women with osteoporosis may be blunted during the initial phase after switching from ALN to TPTD. To explore the long-term implications, we examined histomorphometric and biochemical markers of bone turnover of patients on TPTD therapy after long-term ALN treatment. METHODS: Paired biopsies were obtained after tetracycline double labeling at baseline and after 24 months of TPTD treatment from 29 ALN-pretreated (64.5 ± 16.4 months) and 16 TN patients. Biochemical markers were measured at baseline, during the treatment, or at study end. RESULTS: Compared with the baseline, after 24-month TPTD, activation frequency (Ac.F.) and osteoid surface (OS) increased in both groups: 0.11-0.34 cycles per year, 3.96-9.8% in the ALN-pretreated group and 0.19-0.33 cycles per year, 6.2-11.3% (p < 0.05) in the TN group, respectively. Biochemical and histomorphometric markers correlated positively both at baseline and endpoint. Serum amino terminal propeptide of type I procollagen (PINP) correlated with Ac.F. (r = 0.57, p < 0.001 and r = 0.48, p < 0.01) and OS (r = 0.51, p < 0.01 and r = 0.56, p < 0.01) at baseline and endpoint, respectively. Following 3 months of treatment, increases in biochemical markers like PINP predicted the increase in Ac.F. (r = 0.52, p < 0.01) and OS (r = 0.54, p < 0.01) after 24 months. CONCLUSIONS: The increased level of formation is similar in patients who were either TN or had lower bone turnover initially due to previous ALN therapy. Elevated bone formation in postmenopausal women with osteoporosis was sustained over a 24-month period by TPTD. Biochemical markers of bone formation are a good surrogate for the assessment of TPTD effects.

The effect of RANKL and OPG on bone mineral density in pre-dialysis chronic renal failure.

AIMS: The influence of pre-dialysis chronic kidney disease (CKD) on bone is ill defined. Isolation of specific pathogenic mechanisms would improve the understanding and therapeutic options. We therefore investigated whether parathyroid dysfunction, altered vitamin D and hormonal status, or RANKL and OPG have an influence on bone mineral density (BMD) in patients with pre-dialysis renal failure. MATERIAL: 132 patients with chronic renal failure stage 1 - 5 (not yet on dialysis) were investigated in a cross sectional study. Osteoprotegerin (OPG), receptor activator of nuclear factor kB ligand (RANKL), parathyroid hormone (whole, intact and 7-84 fragment), bone markers, sex hormones, and vitamin D status were assessed together with femoral neck and trochanter z-score. Correlation and multivariate analyses were performed between the different parameters and BMD. RESULTS: In the multivariate analysis a significant association was found between the femoral neck z-score and sRANKL (B = -0.45; p < 0.001), and OPG (B = 0.20; p < 0.05). A significant negative association was also found between the trochanter z-score and sRANKL (B = -0.32; p < 0.001). No associations were found between the trochanter z-score and OPG or the sRANKL/OPG ratio. The body mass index was the only additional marker associated with both FN z-score (B = 0.20, p < 0.05) and TR z-score (B = 0.20, p < 0.05). Neither markers of osteoblast nor osteoclast activity, or intact PTH, whole PTH, the PTH 7-84 fragment or vitamin D status were related to bone mineral density. CONCLUSION: Our results demonstrate that the RANKL/RANK/OPG system is associated with bone mineral density in pre-dialysis chronic renal failure.

Teriparatide versus alendronate for treating glucocorticoid-induced osteoporosis: an analysis by gender and menopausal status.

SUMMARY: The effects of teriparatide versus alendronate were compared by gender and menopausal status in patients with glucocorticoid-induced osteoporosis. At 18 months, increases in lumbar spine BMD were significantly greater in the teriparatide versus alendronate group in postmenopausal women (7.8% versus 3.7%, p < 0.001), premenopausal women (7.0% versus 0.7%, p < 0.001), and men (7.3% versus 3.7%, p = 0.03). INTRODUCTION: In patients with glucocorticoid-induced osteoporosis (GIO), teriparatide significantly increased bone mineral density (BMD) and decreased vertebral fractures compared with alendronate. We examined effects of teriparatide versus alendronate by gender and menopausal status. METHODS: This was a multicenter, randomized, double-blind study of teriparatide 20 microg/day versus alendronate 10 mg/day in patients with GIO (277 postmenopausal women, 67 premenopausal women, 83 men). Primary outcome was change in lumbar spine BMD. Secondary outcomes included change in hip BMD, change in bone biomarkers, fracture incidence, and safety. RESULTS: At 18 months, mean percent increases from baseline in lumbar spine BMD were significantly greater in the teriparatide versus alendronate group in postmenopausal women (7.8% versus 3.7%, p < 0.001), premenopausal women (7.0% versus 0.7%, p < 0.001), and men (7.3% versus 3.7%, p = 0.03). Radiographic vertebral fractures occurred in one teriparatide (one postmenopausal) and ten alendronate patients (six postmenopausal, four men), and nonvertebral fractures occurred in 12 teriparatide (nine postmenopausal, two premenopausal, one man) and eight alendronate patients (six postmenopausal, two men). The proportion of patients reporting adverse events in teriparatide versus alendronate groups was consistent across subgroups. CONCLUSION: Among men and pre- and postmenopausal women with GIO, lumbar spine BMD increased more in patients receiving teriparatide compared with alendronate.

Effects of a long-term vitamin D and calcium supplementation on falls and parameters of muscle function in community-dwelling older individuals.

UNLABELLED: In 242 community-dwelling seniors, supplementation with either 1000 mg of calcium or 1000 mg of calcium plus vitamin D resulted in a decrease in the number of subjects with first falls of 27% at month 12 and 39% at month 20. Additionally, parameters of muscle function improved significantly. INTRODUCTION: The efficacy of vitamin D and calcium supplementation on risk of falling in the elderly is discussed controversially. Randomized controlled trials using falls as primary outcome are needed. We investigated long-term effects of calcium and vitamin D on falls and parameters of muscle function in community-dwelling elderly women and men. METHODS: Our study population consisted of 242 individuals recruited by advertisements and mailing lists (mean [ +/- SD] age, 77 +/- 4 years). All serum 25-hydroxyvitamin D (25[OH]D) levels were below 78 nmol/l. Individuals received in a double blinded fashion either 1000 mg of calcium or 1000 mg of calcium plus 800 IU of vitamin D per day over a treatment period of 12 months, which was followed by a treatment-free but still blinded observation period of 8 months. Falls were documented using diaries. The study took place in Bad Pyrmont, Germany (latitude 52 degrees ) and Graz, Austria (latitude 46 degrees ). RESULTS: Compared to calcium mono, supplementation with calcium plus vitamin D resulted in a significant decrease in the number of subjects with first falls of 27% at month 12 (RR = 0.73; CI = 0.54-0.96) and 39% at month 20 (RR = 0.61; CI = 0.34-0.76). Concerning secondary endpoints, we observed significant improvements in quadriceps strength of 8%, a decrease in body sway of 28%, and a decrease in time needed to perform the TUG test of 11%. DISCUSSION: Combined calcium and vitamin D supplementation proved superior to calcium alone in reducing the number of falls and improving muscle function in community-dwelling older individuals.

Calcium supply, bone mineral density and genetically defined lactose maldigestion in a cohort of elderly men.

OBJECTIVE: To examine a relationship of molecularly defined lactose malabsorption (LM; by LCT-polymorphism) to calcium supply, bone mineral density (BMD) and parameters of bone metabolism in an elderly male cohort. Furthermore, to reveal gender differences in BMD, calcium consumption rates and parameters of bone metabolism according to LCT polymorphism in an existing female cohort. SETTING AND SUBJECTS: A total of 239 men, aged 61+/-9 yr, were available from a former population based study cohort. All men were of Caucasian origin and came from the same region. Blood was sampled for genotyping of the LCT polymorphism and determination of markers of bone metabolism. All participants underwent physical examination, measurement of bone density and completed a standardized calcium questionnaire. Identical procedures had been carried out in a female cohort before (no. 350). RESULTS: Distribution of the LCT genotype in the study cohort was 27% CC (associated with LM; adult-type hypolactasia), 55% TC and 18% TT (lactase persistence). Amounts of total ingested calcium were similar among the three genotype groups. Amounts of consumed milk were generally low in men, LCT polymorphism did not influence rates of milk consumption for men preferred other sources of calcium. BMD, markers of bone metabolism and fracture rates did not differ. General anthropometric characteristics did not differ between the LCT groups either. CONCLUSIONS: Under conditions of low milk intake LCT polymorphism does not alter bone density, markers of bone metabolism and fractures in this cohort of elderly Caucasian men.

Adult-type hypolactasia and calcium availability: decreased calcium intake or impaired calcium absorption?

UNLABELLED: Adult-type hypolactasia, as mediated by a widespread genetic predisposition, not only reduces calcium intake but also calcium absorption in the presence of high amounts of lactose and may, therefore, promote osteoporosis. A lactose-reduced diet and lactose-free calcium supplements may reverse this imbalance. INTRODUCTION AND HYPOTHESIS: Adult-type hypolactasia (HL) defined by the LCT(-13910) polymorphism may reduce calcium intake by reducing dairy consumption and, therefore, promote osteoporosis. This study aimed to evaluate whether lactose also decreases intestinal calcium absorption in subjects with HL and whether lactose-reduced diet and lactose-free calcium supplementation as recommended could maintain bone mineral density (BMD). METHODS: Based on LCT genotyping, 73 postmenopausal women with and without HL underwent a conventional H(2) breath test with a concomitant oral strontium absorption test lasting 150 minutes, which closely reflects intestinal calcium absorption. In addition, we compared bone-specific laboratory parameters, lumbar and femoral BMD, and spinal radiographs to a similar bone assessment 5 years earlier. RESULTS: LCT genotyping and functional lactose malabsorption tests were highly correlated. Dairy product consumption was reduced by 80% in HL individuals. During concomitant lactose application, mean strontium absorption was blunted by 54% in HL subjects after 150 minutes (1272 +/- 629 microg/L vs. 2020 +/- 1130 microg/L in lactose tolerant subjects, p=0.001). Nevertheless, BMD in HL subjects remained stable with lactose-free calcium supplements during the observation period. CONCLUSION: Both decreased calcium intake as well as lactose-associated impaired calcium absorption may predispose subjects with HL to osteoporosis. Lactose-free calcium supplementation may help to maintain BMD in HL subjects.

Vascular calcification and osteoporosis--from clinical observation towards molecular understanding.

Patients with osteoporosis frequently suffer from vascular calcification, which was shown to predict both cardiovascular morbidity/mortality and osteoporotic fractures. Various common risk factors and mechanisms have been suggested to cause both bone loss and vascular calcification, including aging, estrogen deficiency, vitamin D and K abnormalities, chronic inflammation and oxidative stress. Major breakthroughs in molecular and cellular biology of bone metabolism and the characterization of knockout animals with deletion of bone-related genes have led to the concept that common signaling pathways, transcription factors and extracellular matrix interactions may account for both skeletal and vascular abnormalities. For example, mice that lack the cytokine decoy receptor osteoprotegerin or the hormone Klotho display a combined osteoporosis-arterial calcification phenotype. In this review, we summarize the current data and evaluate potential mechanisms of the osteoporosis-arterial calcification syndrome. We propose a unifying hypothesis of vascular calcification that combines both active and passive mechanisms of vascular mineralization with aspects of bone resorption and age-related changes.

Changes in total parathyroid hormone (PTH), PTH-(1-84) and large C-PTH fragments in different stages of chronic kidney disease.

INTRODUCTION: Loss of renal function is accompanied by progressive increase in serum levels of intact parathyroid hormone (iPTH) in patients with end-stage renal disease (ESRD). There is a paucity of data regarding levels of PTH-(1-84) and its large carboxyl-terminal fragments (large C-PTH fragments) and progressive loss of kidney function in patients with chronic kidney disease (CKD). The current study was undertaken to describe the glomerular filtration rate (GFR)-dependent plasma concentrations of PTH-(1-84) and related large C-PTH fragments in adult patients with CKD by using different commercially available PTH assays. METHODS: We studied 80 Caucasian patients with CKD stages 1-5 without renal replacement therapy. Creatinine clearance was calculated by the Modification of Diet in Renal Disease (MDRD) formula. Levels of iPTH were determined by second-generation assays (iPTH Elecsys system, Roche Diagnostics; DUO total iPTH, Scantibodies Laboratory, Inc.; iPTH, Nichols Institute Diagnostics). Third-generation assays were used to measure PTH-(1-84) (CAP (cyclase activating PTH), Scantibodies; Bio-Intact PTH, Nichols). Levels of large C-PTH fragments and ratios of PTH-(1-84)/large C-PTH fragments were calculated and statistical analyses performed. RESULTS: Levels of iPTH and PTH-(1-84) showed CKD stage-dependent increases. Variations among the assays increased with progressive loss of kidney function. The assay from Scantibodies showed a GFR-dependent decrease of the ratio 1-84 PTH / large C-PTH fragment that was not observed with the Nichols assay. CONCLUSION: Increasing variations among the assays with progression of CKD emphasize the fact that the interpretation of measurements must take into consideration the specific assay. We found evidence for a possible preferential increase of the level of large C-PTH fragments over 1-84 PTH in a CKD stage-dependent manner (Scantibodies). The clinical implications of this finding have to be further evaluated by bone biopsy studies.

Changes in the RANK ligand/osteoprotegerin system are correlated to changes in bone mineral density in bisphosphonate-treated osteoporotic patients.

INTRODUCTION: Since the soluble receptor activator of the NF-kappaB ligand (sRANKL) as well as the endogenous anti-resorptive cytokine osteoprotegerin (OPG) are produced by osteoblasts and given that these cells undergo significant changes during antiresorptive treatment, we hypothesized that treatment with bisphosphonates (BP) would be accompanied by changes in serum OPG and sRANKL levels. METHODS: In a prospective, randomized controlled trial of previously untreated postmenopausal women with osteoporosis, oral BP therapy (daily doses of either 10 mg alendronate or 5 mg risedronate) in combination with calcium/vitamin D was compared to calcium/vitamin D treatment alone (control group). Follow-up at 2, 6 and 12 months was completed for 56 patients. Standardized spinal X-rays were performed at baseline, and DEXA measurements at the femoral neck and trochanter were made at baseline and after 1 year. Serum OPG and sRANKL levels were measured with a polyclonal antibody-based ELISA system. RESULTS: After 1 year, there was a non-significant loss in neck and trochanteric bone mineral density (BMD) in the CTR group and a mean increase of 3.3% and 4.6% in the combined BP group (both p<0.0001), respectively. Serum levels of C-terminal telopeptides of type I collagen (sCTX) and osteocalcin decreased by 12% and 10% at 12 months in the CTR group and by 43% and 23% in the combined BP group, respectively (all significant). OPG serum levels in the CTR group decreased significantly by 9% at 2 months (p<0.005) and remained below pre-treatment levels at later time points. Both the alendronate- and risedronate-treated patient groups showed unaltered OPG levels after 2 months, but they had significantly increased serum levels at 6 and 12 months. Levels of sRANKL were unchanged throughout the treatment period. Univariate regression analysis demonstrated that changes in serum OPG levels after 12 months of BP treatment were positively and better correlated to BMD changes (trochanter: r=0.59, p<0.0001; neck: r=0.50, p<0.001) than those of sCTX, which showed the expected negative correlation to BMD change (trochanter: r=-0.35, p=0.03; neck: r=-0.23, p=0.16). With multiple regression analyses at 12 months, R2 values for 1-year changes in trochanteric BMD of 0.33 (OPG alone) and 0.23 (sCTX alone) were significantly improved to the 0.57 when OPG and sCTX changes were combined (p<0.001). Results for the femoral neck were also statistically significant R2=0.35, p<0.001). BMD and OPG changes in the CTR group were not correlated with each other. CONCLUSIONS: We conclude that with BP treatment, changes in serum OPG levels, unlike changes in sCTX levels, are positively correlated to changes in BMD response. The BP-related changes in serum OPG levels during treatment could result from effects on osteoclastogenesis and osteoclast apoptosis as well as from a direct stimulatory effect on osteoblastic OPG production. These changes in OPG levels may be used to predict the individual response of patients to BP treatment.

Molecularly-defined lactose malabsorption, milk consumption and anthropometric differences in adult males.

BACKGROUND: Lactose malabsorption (LM) may be associated with reduced skeletal calcium content. Diagnosis to date has been based on indirect methods, with a high false-negative rate. Identification of the LCT polymorphism led to development of a PCR-based test. AIM: To evaluate the PCR-based test compared to a combination the hydrogen breath test and the lactose tolerance test, and investigate anthropometrical differences, changes in bone mineral density and oral calcium intake according to LCT polymorphism and milk-drinking habits. METHODS: All participants (n = 278) underwent clinical examination, with measurement of height, weight and bone density (DXA), and were genotyped for LCT polymorphism (LCT CC or LCT TT: CC is associated with LM). A subgroup (n = 51) had a hydrogen breath test and a lactose tolerance test, in addition to genotyping. RESULTS: Detection of LM by LCT polymorphism was highly significant (p = 0.001). The correlation between LCT genotype and self-reported milk-intolerance or dislike of milk with was slight, but the correlation with functional tests was highly significant. Non-milk-drinkers were lighter (-5 kg) and significantly shorter (-4 cm) than milk-drinkers (p = 0.07 and 0.04, respectively). Total calcium consumption was lower among non-milk-drinkers by about 18% (p = 0.03). DISCUSSION: Genotyping is an economic, quick and convenient method for diagnosing lactose malabsorption, with results comparable to existing tests. Sufficient calcium consumption may be relevant to body growth, as milk-drinkers were taller. Negative calcium bone balance may be prevented when provision is made for adequate calcium intake.

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.