Once-weekly semaglutide versus placebo in adults with increased fracture risk: a randomised, double-blinded, two-centre, phase 2 trial.

Background: Previous studies have indicated that glucagon-like peptide-1 (GLP-1) receptor agonists (GLP-1RAs) may enhance bone formation and have neutral or beneficial effects on fracture risk. We evaluated the effect of the GLP-1RA semaglutide on the bone formation marker Procollagen type I N-terminal propeptide (PINP) in adults with increased fracture risk. Methods: This randomised, placebo-controlled, double-blinded, phase 2 clinical trial was conducted at two public hospitals in Denmark. We enrolled 64 men and women with increased fracture risk based on a T-score < -1.0 at the total hip or lumbar spine and/or low-energy fracture within three years of recruitment. Participants were randomised (1:1) to receive once-weekly subcutaneous semaglutide 1.0 mg or placebo. The primary outcome was changes in plasma (P)-PINP from baseline to week 52. Primary and safety outcomes were assessed and evaluated for all participants. This trial is complete and registered with ClinicalTrials.gov, NCT04702516. Findings: Between March 24 and December 8, 2021, 55 (86%) postmenopausal women and nine men with a mean age of 63 years (SD 5.5) and BMI of 27.5 kg/m2 (SD 4.5) were enrolled. There was no effect on changes in P-PINP from baseline to week 52 between the two groups (estimated treatment difference (ETD) semaglutide versus placebo 3.8 µg/L [95% CI -5.6 to 13.3]; p = 0.418), and no difference in P-PINP levels between groups at week 52 (semaglutide 64.3 µg/L versus placebo 62.3 µg/L [95% CI -10.8 to 15.0]; p = 0.749). The secondary outcomes showed higher plasma levels of bone resorption marker Collagen type I cross-linked C-terminal telopeptide (P-CTX) in the semaglutide group than in the placebo group (ETD 166.4 ng/L [95% CI 25.5-307.3]; p = 0.021). Compared to placebo, lumbar spine and total hip areal bone mineral densities (aBMD) were lower in the semaglutide group after 52 weeks ((ETD lumbar spine -0.018 g/cm3 [95% CI -0.031 to -0.005]; p = 0.007); ETD total hip -0.020 g/cm2 ([95% CI -0.032 to -0.008]; p = 0.001). Treatment differences in femoral neck aBMD were not observed ([95% CI [-0.017 to 0.006]; p = 0.328). Further, body weight was lower in the semaglutide group than in the placebo group after 52 weeks (ETD -6.8 kg [95% CI -8.8 to -4.7]; p < 0.001). Thirty-one [97%] in the semaglutide group and 18 [56%] in the placebo group experienced at least one adverse event, including four serious events (two in each group). No episodes of hypoglycaemia or deaths were reported. Interpretation: In adults with increased fracture risk, semaglutide once weekly did not increase bone formation based on the bone formation marker P-PINP. The observed increase in bone resorption in the semaglutide group may be explained by the accompanying weight loss. Funding: Region of Southern Denmark, Novo Nordisk Foundation, and Gangsted Foundation. Novo Nordisk provided the investigational drug and placebo.

Microvascular Disease Associates with Larger Osteocyte Lacunae in Cortical Bone in Type 2 Diabetes Mellitus.

Clinical studies indicate that microvascular disease (MVD) affects bone microstructure and decreases bone strength in type 2 diabetes mellitus (T2D). Osteocytes are housed in small voids within the bone matrix and lacunae and act as sensors of mechanical forces in bone. These cells regulate osteoclastic bone resorption and osteoblastic bone formation as well as osteocytic perilacunar remodeling. We hypothesized that MVD changes morphometric osteocyte lacunar parameters in individuals with T2D. We collected iliac crest bone biopsies from 35 individuals (10 female, 25 male) with T2D with MVD (15%) or without MVD (21%) with a median age of 67 years (interquartile range [IQR] 62-72 years). The participants were included based on c-peptide levels >700 pmol L-1, absence of anti-GAD65 antibodies, and glycated hemoglobin (HbA1c) levels between 40 and 82 mmol mol-1 or 5.8% and 9.7%, respectively. We assessed osteocyte lacunar morphometric parameters in trabecular and cortical bone regions using micro-computed tomography (micro-CT) at a nominal resolution of 1.2 µm voxel size. The cortical osteocyte lacunar volume (Lc.V) was 7.7% larger (p = 0.05) and more spherical (Lc.Sr, p < 0.01) in the T2D + MVD group. Using linear regression, we found that lacunar density (Lc.N/BV) in trabecular but not cortical bone was associated with HbA1c (p < 0.05, R 2 = 0.067) independently of MVD. Furthermore, Lc.V was larger and Lc.Sr higher in the center than in the periphery of the trabecular and cortical bone regions (p < 0.05). In conclusion, these data imply that MVD may impair skeletal integrity, possibly contributing to increased skeletal fragility in T2D complicated by MVD. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Trabecular bone deterioration in a postmenopausal female suffering multiple spontaneous vertebral fractures due to a delayed denosumab injection - A post-treatment re-initiation bone biopsy-based case study.

Background: Denosumab, is a potent anti-resorptive that, increases bone mineral density, and reduces fracture risk in osteoporotic patients. However, several case studies have reported multiple vertebral fractures in patients discontinuing denosumab. Case presentation: This case report describes a 64-year-old female with postmenopausal osteoporosis treated with denosumab, who had her 11th injection delayed by 4 months. The patient suffered eight spontaneous vertebral fractures. After consent, an iliac crest bone biopsy was obtained following re-initiation of the denosumab treatment and analyzed by micro-computed tomography and histomorphometry. Results: micro-computed tomography analysis revealed a low trabecular bone volume of 10 %, a low trabecular thickness of 97 µm, a low trabecular spacing of 546 µm, a high trabecular number of 1.8/mm, and a high structure model index of 2.2, suggesting trabecular thinning and loss of trabecular plates. Histomorphometric trabecular bone analysis revealed an eroded perimeter per bone perimeter of 33 % and an osteoid perimeter per bone perimeter of 62 %. Importantly, 88 % of the osteoid perimeter was immediately above an eroded-scalloped cement line with no sign of mineralization, and often with no clear bone-forming osteoblasts on the surface. Moreover, only 5 % of the bone perimeter was mineralizing, reflecting that only 8 % of the osteoid perimeter underwent mineralization, resulting in a mineralization lag time of 545 days. Taken together, this indicates limited bone formation and delayed mineralization. Conclusion: We present a case report of multiple vertebral fractures after denosumab discontinuation with histomorphometric evidence that denosumab discontinuation leads to extensive trabecular bone resorption followed by a limited bone formation and delayed mineralization if the denosumab treatment is reinitiated. This highlights the importance of developing optimal discontinuation strategies for patients that are to discontinue treatment.

A Critical Role of the Bone Marrow Envelope in Human Bone Remodeling.

Proper bone remodeling depends not only on a team of bone-resorbing osteoclasts and bone-forming osteoblasts. It also depends on the site-specific delivery of a large amount of osteoblast lineage cells to the bone remodeling site. How this delivery occurs is poorly known. Here, we gained insight into this mechanism by analyzing the distribution of markers of osteoblastogenesis on bone surfaces and in their bone marrow neighborhood in human cancellous bone. We found a CD271-positive/PDGFß-R-positive cell layer surrounding the bone marrow that provides osteoblastogenic potential along all bone surfaces, whether quiescent or remodeling. This bone marrow envelope cell layer takes the appearance of a canopy above remodeling sites, where it then also shows an upregulation of the proliferation marker Ki67, smooth muscle actin (SMA), tenascin C, fibronectin, and MMP13. This indicates that the canopy is a region of the bone marrow envelope where early markers of osteoblastogenesis are activated concurrently with initiation of bone remodeling. Importantly, the high proliferation index in the canopy is not associated with increasing cell densities at the canopy level, but it is at the bone surface level, thereby supporting delivery of cells from the canopy to the bone surface. This delivery route explains why lack of canopies was previously found to coincide with lack of bone formation, and fits current knowledge on the canopies as a target for regulators of bone remodeling. We conclude that the coordination of bone marrow envelope activities and bone surface activities allows integrating osteoblastogenesis and bone remodeling into the same functional unit, and propose that the bone marrow envelope is critical for preserving bone health. © 2023 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).

Head-to-Head Comparison of Tc-99m-sestamibi SPECT/CT and C-11-L-Methionin PET/CT in Parathyroid Scanning Before Operation for Primary Hyperparathyroidism.

PURPOSE: The preferred nuclear medicine method for identification of hyperfunctioning parathyroid glands in hyperparathyroidism (HPT) develops continuously in relation to the technological progress. Diagnostic methods based on PET/CT have during recent years evolved with new tracer possibilities competing with traditional scintigraphic methods. This investigation is a head-to-head comparison of Tc-99m-sestamibi SPECT/CT gamma camera scintigraphy (sestamibi SPECT/CT) and C-11-L-methionin PET/CT imaging (methionine PET/CT) for preoperative identification of hyperfunctioning parathyroid glands. PROCEDURES: The study is a prospective cohort study including 27 patients diagnosed with primary hyperparathyroidism (PHPT). Two nuclear medicine physicians assessed all examinations independently and blinded. All scanning assessments were matched to the final surgical diagnosis as confirmed by histopathology. Biochemical monitoring of the therapeutical effects was performed preoperatively by PTH-measurements and followed postoperatively for up to 12 months. Comparisons were made for differences in sensitivity and positive predictive value (PPV). RESULTS: Twenty-seven patients (18 females, 9 males; mean age (range): 58.9 years (34.1-79)) were enrolled into the study. The 27 patients had a total of 33 identified sites of lesions of which 28 (85%) turned out to be histopathological verified hyperfunctioning parathyroid glands. The sensitivity and PPV for sestamibi SPECT/CT were 0.71 and 0.95; that of methionine PET/CT was 0.82 and 1, respectively. Both sensitivity and PPV were slightly lower for sestamibi SPECT/CT than for methionine PET PET/CT (-0.11, 95% confidence interval (95% CI): -0.29 to 0.08; -0.05, 95% CI: -0.14 to 0.04, respectively), but not to a statistically significant extent (p=0.38 and p=0.31). The sensitivity and PPV for diagnostic CT were 0.64 (95% CI: 0.44 to 0.81) and 1 (95% CI: 0.81 to 1). CONCLUSIONS: Methionine PET/CT performed comparable to sestamibi SPECT/CT with respect to identification and localization of hyperfunctioning parathyroid glands prior to surgery.

Profiles of GPs with high and low self-reported physician empathy-personal, professional, and antibiotic prescribing characteristics.

BACKGROUND: General Practitioners' (GPs) professional empathy has been hypothesized to have substantial impact on their healthcare delivery and medication prescribing patterns. This study compares profiles of personal, professional, and antibiotic prescribing characteristics of GPs with high and low empathy. METHODS: We apply an extreme group approach to a unique combined set of survey and drug register data. The survey included questions about demographic, professional, and antibiotic prescribing characteristics, as well as the Jefferson Scale of Empathy for Health Professionals (JSE-HP) to assess self-reported physician empathy. It was sent to a stratified sample of 1,196 GPs comprising 30% of the Danish GP population of whom 464 (38.8%) GPs responded. GPs in the top and bottom decile of empathy levels were identified. All intra- and inter-profile descriptive statistics and differences were bootstrapped to estimate the variability and related confidence intervals.  RESULTS: 61% of GPs in the top decile of the empathy score were female. GPs in this decile reported the following person-centered factors as more important for their job satisfaction than the bottom decile: The Patient-physician relationship, interaction with colleagues, and intellectual stimulation. High-empathy scoring GPs prescribed significantly less penicillin than the low-empathy GPs. This was true for most penicillin subcategories. There were no significant differences in age, practice setting (urban vs. rural), practice type (partnership vs. single-handed), overall job satisfaction, or GP's value of prestige and economic profit for their job satisfaction. The intra profile variation index and confidence intervals show less prescribing uncertainty among GPs with high empathy. CONCLUSIONS: This study reveals that high empathy GPs may have different personal, professional, and antibiotic prescribing characteristics than low empathy GPs and have less variable empathy levels as a group. Furthermore, person-centered high empathy GPs on average seem to prescribe less penicillins than low empathy GPs.

Neuronal Sprouting and Reorganization in Bone Tissue Infiltrated by Human Breast Cancer Cells.

Background: Pain is a common complication for patients with metastatic bone disease. Animal models suggest that the pain, in part, is driven by pathological sprouting and reorganization of the nerve fibers innervating the bone. Here, we investigate how these findings translate to humans. Methods: Bone biopsies were collected from healthy volunteers (n = 7) and patients with breast cancer and metastatic bone disease (permissions H-15000679, S-20180057 and S-20110112). Cancer-infiltrated biopsies were from patients without recent anticancer treatment (n = 10), patients with recent anticancer treatment (n = 10), and patients with joint replacement surgery (n = 9). Adjacent bone sections were stained for (1) protein gene product 9.5 and CD34, and (2) cytokeratin 7 and 19. Histomorphometry was used to estimate the area of bone marrow and tumor burden. Nerve profiles were counted, and the nerve profile density calculated. The location of each nerve profile within 25 µm of a vascular structure and/or cancer cells was determined. Results: Cancer-infiltrated bone tissue demonstrated a significantly higher nerve profile density compared to healthy bone tissue. The percentage of nerve profiles found close to vascular structures was significantly lower in cancer-infiltrated bone tissue. No difference was found in the percentage of nerve profiles located close to cancer between the subgroups of cancer-infiltrated bone tissue. Interestingly, no correlation was found between nerve profile density and tumor burden. Conclusions: Together, the increased nerve profile density and the decreased association of nerve profiles to vasculature strongly suggests that neuronal sprouting and reorganization occurs in human cancer-infiltrated bone tissue.

RSPO3 is important for trabecular bone and fracture risk in mice and humans.

With increasing age of the population, countries across the globe are facing a substantial increase in osteoporotic fractures. Genetic association signals for fractures have been reported at the RSPO3 locus, but the causal gene and the underlying mechanism are unknown. Here we show that the fracture reducing allele at the RSPO3 locus associate with increased RSPO3 expression both at the mRNA and protein levels, increased trabecular bone mineral density and reduced risk mainly of distal forearm fractures in humans. We also demonstrate that RSPO3 is expressed in osteoprogenitor cells and osteoblasts and that osteoblast-derived RSPO3 is the principal source of RSPO3 in bone and an important regulator of vertebral trabecular bone mass and bone strength in adult mice. Mechanistic studies revealed that RSPO3 in a cell-autonomous manner increases osteoblast proliferation and differentiation. In conclusion, RSPO3 regulates vertebral trabecular bone mass and bone strength in mice and fracture risk in humans.

Human hematopoietic microenvironments.

Dormancy of hematopoietic stem cells and formation of progenitors are directed by signals that come from the bone marrow microenvironment. Considerable knowledge has been gained on the murine hematopoietic stem cell microenvironment, while less so on the murine progenitor microenvironment and even less so on these microenvironments in humans. Characterization of these microenvironments is decisive for understanding hematopoiesis and finding new treatment modalities against bone marrow malignancies in the clinic. However, it is equally challenging, because hematopoietic stem cells are difficult to detect in the complex bone marrow landscape. In the present study we are characterizing the human hematopoietic stem cell and progenitor microenvironment. We obtained three adjacent bone marrow sections from ten healthy volunteers. One was used to identify a population of CD34+/CD38- "hematopoietic stem cells and multipotent progenitors" and a population of CD34+/CD38+ "progenitors" based on immunofluorescence pattern/intensity and cellular morphology. The other two were immunostained respectively for CD34/CD56 and for CD34/SMA. Using the combined information we performed a non-computer-assisted quantification of nine bone marrow components (adipocytes, megakaryocytes, bone surfaces, four different vessel types (arteries, capillaries, sinusoids and collecting sinuses), other "hematopoietic stem cells and multipotent progenitors" and other "progenitors") within 30 µm of "hematopoietic stem cells and multipotent progenitors", "progenitors", and "random cell profiles". We show that the microenvironment of the "hematopoietic stem cells and multipotent progenitors" is significantly enriched in sinusoids and megakaryocytes, while the microenvironment of the "progenitors" is significantly enriched in capillaries, other "progenitors", bone surfaces and arteries.

Adipocyte-induced transdifferentiation of osteoblasts and its potential role in age-related bone loss.

Our preliminary findings have lead us to propose bone marrow adipocyte secretions as new contributors to bone loss. Indeed, using a coculture model based on human bone marrow stromal cells, we previously showed that soluble factors secreted by adipocytes induced the conversion of osteoblasts towards an adipocyte-like phenotype. In this study, microarray gene expression profiling showed profound transcriptomic changes in osteoblasts following coculture and confirmed the enrichment of the adipocyte gene signature. Double immunofluorescence microscopic analyses demonstrated the coexpression of adipogenic and osteoblastic specific markers in individual cells, providing evidence for a transdifferentiation event. At the molecular level, this conversion was associated with upregulated expression levels of reprogramming genes and a decrease in the DNA methylation level. In line with these in vitro results, preliminary immunohistochemical analysis of bone sections revealed adipogenic marker expression in osteoblasts from elderly subjects. Altogether, these data suggest that osteoblast transdifferentiation could contribute to decreased bone mass upon ageing.

PDGF Receptor Signaling in Osteoblast Lineage Cells Controls Bone Resorption Through Upregulation of Csf1 Expression.

The physiological functions of platelet-derived growth factor receptors (PDGFRs) α and ß in osteoblast biology and bone metabolism remain to be established. Here, we show that PDGFRA and PDGFRB genes are expressed by osteoblast-lineage canopy and reversal cells in close proximity to PDGFB-expressing osteoclasts within human trabecular bone remodeling units. We also report that, although removal of only one of the two PDGFRs in Osterix-positive cells does not affect bone phenotype, suppression of both PDGFRs in those osteoblast lineage cells increases trabecular bone volume in male mice as well as in female gonad-intact and ovariectomized mice. Furthermore, osteoblast lineage-specific suppression of PDGFRs reduces Csf1 expression, bone marrow level of macrophage colony-stimulating factor (M-CSF), number of osteoclasts, and, therefore, bone resorption, but does not change bone formation. Finally, abrogation of PDGFR signaling in osteoblasts blocks PDGF-induced ERK1/2-mediated Csf1 expression and M-CSF secretion in osteoblast cultures and calcitriol-mediated osteoclastogenesis in co-cultures. In conclusion, our results indicate that PDGFR signaling in osteoblast lineage cells controls bone resorption through ERK1/2-mediated Csf1 expression. © 2020 American Society for Bone and Mineral Research (ASBMR).

Obesity-Associated Hypermetabolism and Accelerated Senescence of Bone Marrow Stromal Stem Cells Suggest a Potential Mechanism for Bone Fragility.

Obesity is associated with increased risk for fragility fractures. However, the cellular mechanisms are unknown. Using a translational approach combining RNA sequencing and cellular analyses, we investigated bone marrow stromal stem cells (BM-MSCs) of 54 men divided into lean, overweight, and obese groups on the basis of BMI. Compared with BM-MSCs obtained from lean, obese BM-MSCs exhibited a shift of molecular phenotype toward committed adipocytic progenitors and increased expression of metabolic genes involved in glycolytic and oxidoreductase activity. Interestingly, compared with paired samples of peripheral adipose tissue-derived stromal cells (AT-MSCs), insulin signaling of obese BM-MSCs was enhanced and accompanied by increased abundance of insulin receptor positive (IR+) and leptin receptor positive (LEPR+) cells in BM-MSC cultures. Their hyper-activated metabolic state was accompanied by an accelerated senescence phenotype. Our data provide a plausible explanation for the bone fragility in obesity caused by enhanced insulin signaling leading to accelerated metabolic senescence of BM-MSCs.

Clinical Features of Multiple Endocrine Neoplasia Type 4: Novel Pathogenic Variant and Review of Published Cases.

CONTEXT: The clinical phenotype of multiple endocrine neoplasia type 4 (MEN4) is undefined due to a limited number of published cases. Knowledge on disease manifestation in MEN4 is essential for developing prevention programs and treatment. OBJECTIVE: To expand current knowledge of the MEN4 phenotype including assessment of penetrance. DESIGN: This is a case report and a brief review of previously published MEN4 cases. PATIENTS: We report a large Danish family with multiple cases of endocrine tumors that segregated with a pathogenic variant in the CDKN1B gene. MAIN OUTCOME/RESULT: The medical history of the proband included primary hyperparathyroidism and Cushing disease. Genetic analysis identified a pathogenic variant in CDKN1B (c.121_122delTT, p.Leu41Asnfs*83). Among the family members, another 12 individuals were identified as carriers of the same variant, which segregated with development of endocrine tumors. Hypercalcemia due to primary hyperparathyroidism occurred in all 13 of the available carriers of the genetic variant, and 4 patients also had functioning or nonfunctioning pituitary adenomas, whereas 1 patient had a metastatic neuroendocrine tumor (carcinoid). Loss-of-heterozygosity was detected in two of five parathyroid adenomas, supporting that CDKN1B acts as a tumor suppressor gene. Thirty cases representing 16 different CDKN1B variants have previously been reported, and these cases presented primarily with primary hyperparathyroidism and functioning and nonfunctioning pituitary tumors. CONCLUSION: Hypercalcemia due to primary hyperparathyroidism and pituitary tumors are common in MEN4. Gastrointestinal neuroendocrine tumors appear to be less prevalent in MEN4 than in MEN1.

Absence of an osteopetrosis phenotype in IKBKG (NEMO) mutation-positive women: A case-control study.

BACKGROUND: NF-κB essential modulator (NEMO), encoded by IKBKG, is necessary for activation of the ubiquitous transcription factor nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Animal studies suggest NEMO is required for NF-κB mediated bone homeostasis, but this has not been thoroughly studied in humans. IKBKG loss-of-function mutation causes incontinentia pigmenti (IP), a rare X-linked disease featuring linear hypopigmentation, alopecia, hypodontia, and immunodeficiency. Single case reports describe osteopetrosis (OPT) in boys carrying hypomorphic IKBKG mutations. METHOD: We studied the bone phenotype in women with IP with evaluation of radiographs of the spine and non-dominant arm and leg; lumbar spine and femoral neck aBMD using DXA; µ-CT and histomorphometry of trans-iliac crest biopsy specimens; bone turnover markers; and cellular phenotype in bone marrow skeletal (stromal) stem cells (BM-MSCs) in a cross-sectional, age-, sex-, and BMI-matched case-control study. X-chromosome inactivation was measured in blood leucocytes and BM-MSCs using a PCR method with methylation of HpaII sites. NF-κB activity was quantitated in BM-MSCs using a luciferase NF-κB reporter assay. RESULTS: Seven Caucasian women with IP (age: 24-67 years and BMI: 20.0-35.2 kg/m2) and IKBKG mutation (del exon 4-10 (n = 4); c.460C>T (n = 3)) were compared to matched controls. The IKBKG mutation carriers had extremely skewed X-inactivation (>90:10%) in blood, but not in BM-MSCs. NF-κB activity was lower in BM-MSCs from IKBKG mutation carriers (n = 5) compared to controls (3094 ±â€¯679 vs. 5422 ±â€¯1038/µg protein, p < 0.01). However, no differences were identified on skeletal radiographics, aBMD, µ-architecture of the iliac crest, or bone turnover markers. The IKBKG mutation carriers had a 1.7-fold greater extent of eroded surfaces relative to osteoid surfaces (p < 0.01), and a 2.0-fold greater proportion of arrested reversal surface relative to active reversal surface (p < 0.01). CONCLUSION: Unlike mutation-positive males, the IKBKG mutation-positive women did not manifest OPT.

Non-parathyroid hypercalcemia associated with paraffin oil injection in 12 younger male bodybuilders: a case series.

INTRODUCTION: Injection of paraffin oil to augment muscles size is a troubling phenomenon known to cause a foreign body reaction with formation of granulomas. In a few case reports, long-term side effects have been reported in terms of hypercalcemia and renal failure. METHODS: We identified a case series of 12 male bodybuilders presenting with non-parathyroid hypercalcemia who previously had injected paraffin oil to increase muscles size. RESULTS: At admission, all patients had moderate-to-severe hypercalcemia with suppressed PTH levels and impaired renal function. Calcitriol levels were within the normal range or slightly elevated. Follow-up measurements showed marked hypercalciuria with nearly normal levels of bone turnover markers. A correlation was found between levels of peptidyl dipeptidase and calcitriol (R = 0.812, P = 0.050). Treatment with antiresorptive agents seemed less effective than glucocorticoids, which resulted in a significantly lowering of ionized calcium levels and improved renal function, although no patients were cured by this treatment. Immunosuppression with azathioprine or mycophenolate may have a glucocorticoid-saving effect. One patient had surgery with removal of affected muscle tissue, without any apparent effect on plasma calcium levels. CONCLUSION: The hypercalcemia and associated hypercalciuria seems to be due to an intestinal hyperabsorption of calcium. It remains to be elucidated, whether an increased calcitriol synthesis within granulomas is the only (main) mechanism by which intestinal calcium absorption is increased. Glucocorticoids seem most appropriate as the first choice for treatment. Bodybuilders should be warned against use of intramuscular oil injections (and other substances), as this may have severe adverse health consequences.

Determinants of bone mineral density in patients on haemodialysis or peritoneal dialysis--a cross-sectional, longitudinal study.

INTRODUCTION: The aim of the study was to identify biomarkers of alteration in bone mineral density (BMD) in patients on haemodialysis (HD) and peritoneal dialysis (PD). MATERIALS AND METHODS: In a cross-sectional, longitudinal study dual-energy X-ray absorptiometry scans were performed in 146 HD-patients and 28 PD-patients. Follow-up after 14 months (mean) was conducted in 73 patients. As potential biomarkers we investigated parathyroid hormone (PTH), 25-hydroxy vitamin-D, ionised calcium, albumin, phosphate, and total alkaline phosphatases (t-ALP). RESULTS: Both groups of dialysis patients had lower BMD in the femoral neck (BMD(neck)) (P < 0.001) and forearm (BMD(forearm)) (P < 0.001) compared to healthy controls, but comparable BMD in the lumbar spine (BMD(spine)). BMD did not differ between dialysis types, but patients ever-treated with glucocorticoids had significantly lower BMD, while patients with polycystic kidney disease had higher BMD. BMD correlated with body weight, actual age, age at initiation of dialysis, duration of dialysis and levels of PTH and t-ALP. However, t-ALP only remained associated with low BMD(spine) after adjusting for other factors (P = 0.001). In the follow-up study all patients had decreased BMD in all three locations, but only for the lumbar spine there was a significant association between BMD and the bone markers t-ALP (P = 0.009) and PTH (P = 0.013). CONCLUSIONS: Both HD and PD patients have low BMD, and increased concentrations of t-ALP is associated BMD(spine) after adjustment, while PTH and t-ALP is associated with decrease in BMD(spine) over time. This substantiates the use of these biomarkers in both types of dialysis patients.

Resources allocation and health care needs in diabetes care in Danish GP clinics.

BACKGROUND: In several countries, morbidity burdens have prompted authorities to change the system for allocating resources among patients from a demographic-based to a morbidity-based casemix system. In Danish general practice clinics, there is no morbidity-based casemix adjustment system. AIM: The aim of this paper was to assess what proportions of the variation in fee-for-service (FFS) expenditures are explained by type 2 diabetes mellitus (T2DM) patients' co-morbidity burden and illness characteristics. METHODS AND DATA: We use patient morbidity characteristics such as diagnostic markers and co-morbidity casemix adjustments based on resource utilisation bands and FFS expenditures for a sample of 6706 T2DM patients in 59 general practices for the year 2010. We applied a fixed-effect approach. RESULTS: Average annual FFS expenditures were approximately 398 euro per T2DM patient. Expenditures increased progressively with the patients' degree of co-morbidity and were higher for patients who suffered from diagnostic markers. A total of 17-25% of the expenditure variation was explained by age, gender and patients' morbidity patterns. CONCLUSION: T2DM patient morbidity characteristics are significant patient related FFS expenditure drivers in diabetes care. To address the specific health care needs of T2DM patients in GP clinics, our study indicates that it may be advisable to introduce a morbidity based casemix adjustment system.

Teriparatide (biosynthetic human parathyroid hormone 1-34): a new paradigm in the treatment of osteoporosis.

The ideal treatment of osteoporosis should preferably prevent fractures through normalization of bone mass and bone micro-architecture. Biosynthetic human parathyroid hormone 1-34 (teriparatide) was recently approved in the EU and the USA as the first anabolic treatment of osteoporosis. The effects of teriparatide are mediated by the G-protein-dependent, parathyroid hormone receptor-1 in the cell membrane. The binding of the ligand to the receptor activates adenylate cyclase and a number of phospholipases (A, C, and D) and increases intracellular levels of cAMP and calcium. Intermittent teriparatide increases the number of osteoblasts and bone formation by activation of pre-existing osteoblasts, increased differentiation of lining cells, and reduced osteoblast apoptosis. Anabolic effects of teriparatide on bone have been demonstrated in several species. It increases bone mass, structural integrity, bone diameter, and bone strength. Clinical efficacy was demonstrated in a randomized study comprising 1637 post-menopausal women with osteoporosis showing a 65% and 35% reduction of the relative risk of vertebral and appendicular fractures, respectively, during 18 months of treatment. Moreover, bone mineral density in the lumbar spine and hip increased by 9.7% and 2.6%, respectively. Similar effects on bone mineral density have been reported in men with osteoporosis and in glucocorticoid-induced osteoporosis, however, fracture data are limited in these groups. Direct comparison with alendronate revealed that teriparatide has a more pronounced effect on bone mineral density. Teriparatide should be used in combination with calcium plus vitamin D, and may be combined with hormonal replacement therapy. In contrast, alendronate attenuates the effect of teriparatide. The efficacy of other combinations remains uncertain. After termination of teriparatide, bone mineral density of the lumbar spine is reduced by approximately 2-3% after 2 1/2 years. This decrease is prevented by treatment with bisphosphonates. The most frequent adverse effects with teriparatide are nausea, headache, dizziness, and leg cramps, however, only the latter two differed significantly between the groups receiving teriparatide 20 microg/day and placebo. In the pivotal clinical study, reduced dosage or termination of therapy due to hypercalcaemia was necessary in 3% and 0.2%, respectively. In a rat toxicology study, in which teriparatide was administered in high dosages for an extended period of time, osteosarcoma was seen in a significant number of animals. However, none of the approximately 2800 patients in clinical trials has developed osteosarcoma. Teriparatide constitutes a break-through in the treatment of severe osteoporosis, although a number of issues about the optimal use of teriparatide remains unsettled. The published data provide proof of concept on anabolic therapy which changes several paradigms of bone physiology. Other parathyroid hormone analogues are being investigated in clinical trials and the development of non-peptide, small molecules targeted at the parathyroid hormone receptor may be envisaged.