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Increases in bone mineral density (BMD) with osteoporosis treatment are associated with reduced fracture risk. Increasing BMD is therefore a goal of osteoporosis therapy. Here, we compare the probability of achieving a T-score of > −2.5 over 3 years at the total hip (TH) or lumbar spine (LS) in women with osteoporosis, ≥55 years of age, after the following treatment sequences: 1 year romosozumab followed by 2 years denosumab (FRAME and FRAME extension trials), 1 year romosozumab followed by 2 years alendronate, or alendronate-only for 3 years (ARCH trial). Probabilities of attaining the BMD target within 1 year of treatment were also determined. At both skeletal sites, in women with a baseline Tscore ≥ −2.7, there was >50% probability of achieving the BMD target with any 3-year regimen. The probability of achieving the target BMD in those with a baseline TH Tscore equal to −3.0 was 61% with romosozumab/denosumab, 38% with romosozumab/alendronate, and 9% with alendronate. In those with a baseline LS Tscore equal to −3.0, the probability of achieving a T-score > −2.5 was 93% with romosozumab/denosumab, 81% with romosozumab/alendronate, and 55% with alendronate. With 1 year of treatment, in patients with a baseline TH T-score equal to −2.7, the probability of reaching the target Tscore with romosozumab was 71% to 78% and 38% with alendronate. For patients with an initial LS T-score equal to −3.0, the probability of achieving the target T-score over 1 year was 85% to 86% with romosozumab and 25% for alendronate. Our findings suggest baseline BMD and the probability of achieving BMD T-score goals are factors to consider when selecting initial treatment for patients with osteoporosis. As baseline T-score falls below −2.7 (TH) and −3.0 (LS), alendronate has <50% likelihood of achieving a BMD goal above osteoporosis range, whereas these probabilities remain relatively high for regimens beginning with romosozumab.

Increases in bone mineral density (BMD) with osteoporosis treatment are associated with reduced fracture risk. Increasing BMD is therefore a goal of osteoporosis therapy. Here, we compare the probability of achieving a T-score of > −2.5 over 3 years at the total hip (TH) or lumbar spine (LS) in women with osteoporosis, ≥55 years of age, after the following treatment sequences: 1 year romosozumab followed by 2 years denosumab (FRAME and FRAME extension trials), 1 year romosozumab followed by 2 years alendronate, or alendronate-only for 3 years (ARCH trial). Probabilities of attaining the BMD target within 1 year of treatment were also determined. At both skeletal sites, in women with a baseline Tscore ≥ −2.7, there was >50% probability of achieving the BMD target with any 3-year regimen. The probability of achieving the target BMD in those with a baseline TH Tscore equal to −3.0 was 61% with romosozumab/denosumab, 38% with romosozumab/alendronate, and 9% with alendronate. In those with a baseline LS Tscore equal to −3.0, the probability of achieving a T-score > −2.5 was 93% with romosozumab/denosumab, 81% with romosozumab/alendronate, and 55% with alendronate. With 1 year of treatment, in patients with a baseline TH T-score equal to −2.7, the probability of reaching the target Tscore with romosozumab was 71% to 78% and 38% with alendronate. For patients with an initial LS T-score equal to −3.0, the probability of achieving the target T-score over 1 year was 85% to 86% with romosozumab and 25% for alendronate. Our findings suggest baseline BMD and the probability of achieving BMD T-score goals are factors to consider when selecting initial treatment for patients with osteoporosis. As baseline T-score falls below −2.7 (TH) and −3.0 (LS), alendronate has <50% likelihood of achieving a BMD goal above osteoporosis range, whereas these probabilities remain relatively high for regimens beginning with romosozumab.

Background: Hypophosphatasia (HPP) is an inborn disease caused by pathogenic variants in ALPL. Low levels of alkaline phosphatase (ALP) are a biochemical hallmark of the disease. Scarce knowledge about the prevalence of HPP in Scandinavia exists, and the variable clinical presentations make diagnostics challenging. The aim of this study was to investigate the prevalence of ALPL variants as well as the clinical and biochemical features among adults with endocrinological diagnoses and persistent hypophosphatasaemia. Methods: A biochemical database containing ALP measurements of 26,121 individuals was reviewed to identify adults above 18 years of age with persistently low levels of ALP beneath range (≤ 35 ± 2.7 U/L). ALPL genetic testing, biochemical evaluations and assessment of clinical features by a systematic questionnaire among included patients, were performed. Results: Among 24 participants, thirteen subjects (54.2%) revealed a disease-causing variant in ALPL and reported mild clinical features of HPP, of which musculoskeletal pain was the most frequently reported (n = 9). The variant c. 571G > A; p.(Glu191Lys) was identified in six subjects, and an unreported missense variant (c.1019A > C; p.(His340Pro)) as well as a deletion of exon 2 were detected by genetic screening. Biochemical analyses showed no significant differences in ALP (p = 0.059), the bone specific alkaline phosphatase (BALP) (p = 0.056) and pyridoxal-5′-phosphate (PLP) (p = 0.085) between patients with an ALPL variant and negative genetic screening. Patients with a variant in ALPL had significantly higher PLP levels than healthy controls (p = 0.002). We observed normal ALP activity in some patients classified as mild HPP, and slightly increased levels of PLP in two subjects with normal genetic screening and four healthy controls. Among 51 patients with persistent hypophosphatasaemia, fifteen subjects (29.4%) received antiresorptive treatment. Two patients with unrecognized HPP were treat

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are gut hormones secreted postprandially. In healthy humans, both hormones decrease bone resorption accompanied by a rapid reduction in parathyroid hormone (PTH). The aim of this study was to investigate whether the changes in bone turnover after meal intake and after GIP- and GLP-2 injections, respectively, are mediated via a reduction in PTH secretion. This was tested in female patients with hypoparathyroidism given a standardized liquid mixed-meal test (n = 7) followed by a peptide injection-test (n = 4) using a randomized crossover design. We observed that the meal- and GIP-, but not the GLP-2-induced changes in bone turnover markers, were preserved in the patients with hypoparathyroidism. To understand the underlying mechanisms, we examined the expression of the GIP receptor (GIPR) and the GLP-2 receptor (GLP-2R) in human osteoblasts and osteoclasts as well as in parathyroid tissue. The GIPR was expressed in both human osteoclasts and osteoblasts, whereas the GLP-2R was absent or only weakly expressed in osteoclasts. Furthermore, both GIPR and GLP-2R were expressed in parathyroid tissue. Our findings suggest that the GIP-induced effect on bone turnover may be mediated directly via GIPR expressed in osteoblasts and osteoclasts and that this may occur independent of PTH. In contrast, the effect of GLP-2 on bone turnover seems to depend on changes in PTH and may be mediated through GLP-2R in the parathyroid gland.

Background: Hypophosphatasia (HPP) is an inborn disease caused by pathogenic variants in ALPL. Low levels of alkaline phosphatase (ALP) are a biochemical hallmark of the disease. Scarce knowledge about the prevalence of HPP in Scandinavia exists, and the variable clinical presentations make diagnostics challenging. The aim of this study was to investigate the prevalence of ALPL variants as well as the clinical and biochemical features among adults with endocrinological diagnoses and persistent hypophosphatasaemia. Methods: A biochemical database containing ALP measurements of 26,121 individuals was reviewed to identify adults above 18 years of age with persistently low levels of ALP beneath range (≤ 35 ± 2.7 U/L). ALPL genetic testing, biochemical evaluations and assessment of clinical features by a systematic questionnaire among included patients, were performed. Results: Among 24 participants, thirteen subjects (54.2%) revealed a disease-causing variant in ALPL and reported mild clinical features of HPP, of which musculoskeletal pain was the most frequently reported (n = 9). The variant c. 571G > A; p.(Glu191Lys) was identified in six subjects, and an unreported missense variant (c.1019A > C; p.(His340Pro)) as well as a deletion of exon 2 were detected by genetic screening. Biochemical analyses showed no significant differences in ALP (p = 0.059), the bone specific alkaline phosphatase (BALP) (p = 0.056) and pyridoxal-5′-phosphate (PLP) (p = 0.085) between patients with an ALPL variant and negative genetic screening. Patients with a variant in ALPL had significantly higher PLP levels than healthy controls (p = 0.002). We observed normal ALP activity in some patients classified as mild HPP, and slightly increased levels of PLP in two subjects with normal genetic screening and four healthy controls. Among 51 patients with persistent hypophosphatasaemia, fifteen subjects (29.4%) received antiresorptive treatment. Two patients with unrecognized HPP were treat

Glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-2 (GLP-2) are gut hormones secreted postprandially. In healthy humans, both hormones decrease bone resorption accompanied by a rapid reduction in parathyroid hormone (PTH). The aim of this study was to investigate whether the changes in bone turnover after meal intake and after GIP- and GLP-2 injections, respectively, are mediated via a reduction in PTH secretion. This was tested in female patients with hypoparathyroidism given a standardized liquid mixed-meal test (n = 7) followed by a peptide injection-test (n = 4) using a randomized crossover design. We observed that the meal- and GIP-, but not the GLP-2-induced changes in bone turnover markers, were preserved in the patients with hypoparathyroidism. To understand the underlying mechanisms, we examined the expression of the GIP receptor (GIPR) and the GLP-2 receptor (GLP-2R) in human osteoblasts and osteoclasts as well as in parathyroid tissue. The GIPR was expressed in both human osteoclasts and osteoblasts, whereas the GLP-2R was absent or only weakly expressed in osteoclasts. Furthermore, both GIPR and GLP-2R were expressed in parathyroid tissue. Our findings suggest that the GIP-induced effect on bone turnover may be mediated directly via GIPR expressed in osteoblasts and osteoclasts and that this may occur independent of PTH. In contrast, the effect of GLP-2 on bone turnover seems to depend on changes in PTH and may be mediated through GLP-2R in the parathyroid gland.

Phytoestrogens (PE) are widely used as a dietary supplement. PE affect oestrogen receptors. PE have been investigated regarding menopausal hot flushes, bone mineral density and prostate hyperplasia/cancer. It seems consistent, that PE increase bone mineral density, whereas the effect on hot flushes is controversial. Due to the effect on oestrogen receptors, concerns exist on the risk of cancer and venous thromboembolism related to the intake of PE. To date, no studies with PE have been large enough to clarify their safety. Widespread use of PE should therefore be discouraged.

BACKGROUND & AIMS: Cirrhosis and chronic pancreatitis (CP) are accompanied by inflammation and malnutrition. Both conditions can have negative effects on bone metabolism and promote fractures. We evaluated the risk of fractures among patients with CP or cirrhosis and determined the effect of fat malabsorption on fracture risk among patients with CP.METHODS: We performed a retrospective cohort study using the Danish National Patient Register to identify patients diagnosed with CP or cirrhosis. We analyzed data collected from January 1, 1995, to December 31, 2010, on 20,769 patients (35.5% women with cirrhosis and 11,972 patients (33.5% women) with CP. Each patient was compared with 10 age- and sex-matched controls. We also assessed the risk of fractures among patients with CP who received pancreatic enzyme substitution (PES) for fat malabsorption.RESULTS: During the study period, bone fractures occurred in 3954 patients with cirrhosis and 2594 patients with CP. The adjusted hazard ratio (HR) for any fracture was 2.4 in patients with cirrhosis (95% confidence interval [CI], 2.2-2.5) and 1.7 in patients with CP (95% CI, 1.6-1.8). The relative risk of low-trauma fractures was highest among individuals younger than 50 years old. Alcohol as an etiology was associated with an increased risk of fracture compared with patients with nonalcoholic cirrhosis (HR, 2.4 vs 1.5; P < .0001) and CP (HR, 2.0 vs 1.5; P < .0001). Patients with CP receiving PES for fat malabsorption had a lower risk of fractures than other CP patients (HR, 0.8; 95% CI, 0.7-0.9). However, increasing the duration of treatment with PES was associated with an increased risk of fracture.CONCLUSIONS: Patients, especially younger patients, with cirrhosis or CP have an increased risk of fractures of all types.

BACKGROUND & AIMS: We aimed to assess the risk of death, cancer, and comorbidities among patients with alcoholic and nonalcoholic chronic pancreatitis (CP).METHODS: We performed a nationwide retrospective cohort study, collecting data from Danish registries from 1995 through 2010. We evaluated the prevalences and incidences of death, cancers, and comorbidities among subjects with CP (cases) compared with age- and sex-matched individuals (controls). In total, 11,972 cases (71,814 person-years) and 119,720 controls (917,436 person-years) were included in the analysis. Hazard ratios (HR) were estimated by Cox proportional hazards regression.RESULTS: Forty-six percent of the cases died during the follow-up period, compared with 13.0% of controls (mean age, 63.7 vs 72.1 y; P < .0001), corresponding to a HR of 5.0 for CP (95% confidence interval [CI], 4.8-5.2). Cancer was a frequent cause of death among cases (10.2%) and controls (3.3%). Cancer (particularly pancreatic cancer) was a frequent cause of death among cases; the HR was 6.9 (95% CI, 7.5-11.8). Alcoholic CP did not produce a higher risk for cancer or death than nonalcoholic CP. Cerebrovascular disease (HR, 1.3; 95% CI, 1.2-1.4), chronic pulmonary disease (HR, 1.9; 95% CI, 1.8-2.1), ulcer disease (HR, 3.6; 95% CI, 3.3-3.9), diabetes (HR, 5.2; 95% CI, 5.0-5.6), and chronic renal disease (HR, 1.7; 95% CI, 1.5-1.9) occurred more frequently among patients with CP, but myocardial infarction did not (HR, 0.9; 95% CI, 0.8-1.0).CONCLUSIONS: Based on a Danish nationwide cohort study, individuals with CP are at higher risk for death from cancer (particularly pancreatic cancer) and have a higher incidence of comorbidities than people without CP.

BACKGROUND & AIMS: Cirrhosis and chronic pancreatitis (CP) are accompanied by inflammation and malnutrition. Both conditions can have negative effects on bone metabolism and promote fractures. We evaluated the risk of fractures among patients with CP or cirrhosis and determined the effect of fat malabsorption on fracture risk among patients with CP.METHODS: We performed a retrospective cohort study using the Danish National Patient Register to identify patients diagnosed with CP or cirrhosis. We analyzed data collected from January 1, 1995, to December 31, 2010, on 20,769 patients (35.5% women with cirrhosis and 11,972 patients (33.5% women) with CP. Each patient was compared with 10 age- and sex-matched controls. We also assessed the risk of fractures among patients with CP who received pancreatic enzyme substitution (PES) for fat malabsorption.RESULTS: During the study period, bone fractures occurred in 3954 patients with cirrhosis and 2594 patients with CP. The adjusted hazard ratio (HR) for any fracture was 2.4 in patients with cirrhosis (95% confidence interval [CI], 2.2-2.5) and 1.7 in patients with CP (95% CI, 1.6-1.8). The relative risk of low-trauma fractures was highest among individuals younger than 50 years old. Alcohol as an etiology was associated with an increased risk of fracture compared with patients with nonalcoholic cirrhosis (HR, 2.4 vs 1.5; P < .0001) and CP (HR, 2.0 vs 1.5; P < .0001). Patients with CP receiving PES for fat malabsorption had a lower risk of fractures than other CP patients (HR, 0.8; 95% CI, 0.7-0.9). However, increasing the duration of treatment with PES was associated with an increased risk of fracture.CONCLUSIONS: Patients, especially younger patients, with cirrhosis or CP have an increased risk of fractures of all types.

BACKGROUND & AIMS: We aimed to assess the risk of death, cancer, and comorbidities among patients with alcoholic and nonalcoholic chronic pancreatitis (CP).METHODS: We performed a nationwide retrospective cohort study, collecting data from Danish registries from 1995 through 2010. We evaluated the prevalences and incidences of death, cancers, and comorbidities among subjects with CP (cases) compared with age- and sex-matched individuals (controls). In total, 11,972 cases (71,814 person-years) and 119,720 controls (917,436 person-years) were included in the analysis. Hazard ratios (HR) were estimated by Cox proportional hazards regression.RESULTS: Forty-six percent of the cases died during the follow-up period, compared with 13.0% of controls (mean age, 63.7 vs 72.1 y; P < .0001), corresponding to a HR of 5.0 for CP (95% confidence interval [CI], 4.8-5.2). Cancer was a frequent cause of death among cases (10.2%) and controls (3.3%). Cancer (particularly pancreatic cancer) was a frequent cause of death among cases; the HR was 6.9 (95% CI, 7.5-11.8). Alcoholic CP did not produce a higher risk for cancer or death than nonalcoholic CP. Cerebrovascular disease (HR, 1.3; 95% CI, 1.2-1.4), chronic pulmonary disease (HR, 1.9; 95% CI, 1.8-2.1), ulcer disease (HR, 3.6; 95% CI, 3.3-3.9), diabetes (HR, 5.2; 95% CI, 5.0-5.6), and chronic renal disease (HR, 1.7; 95% CI, 1.5-1.9) occurred more frequently among patients with CP, but myocardial infarction did not (HR, 0.9; 95% CI, 0.8-1.0).CONCLUSIONS: Based on a Danish nationwide cohort study, individuals with CP are at higher risk for death from cancer (particularly pancreatic cancer) and have a higher incidence of comorbidities than people without CP.

Patients with chronic pancreatitis (CP) often develop fat malabsorption and are susceptible to hypovitaminosis D.

Patients with chronic pancreatitis (CP) often develop fat malabsorption and are susceptible to hypovitaminosis D.

Patients with chronic pancreatitis (CP) often develop fat malabsorption and are susceptible to hypovitaminosis D.

Patients with primary hyperparathyroidism (PHPT) have continuously elevated parathyroid hormone (PTH) and consequently increased bone turnover with negative effects on cortical (Ct) bone with preservation of trabecular (Tb) bone. High-resolution peripheral quantitative computed tomography (HR-pQCT) is a new technique for in vivo assessment of geometry, volumetric density, and microarchitecture at the radius and tibia. In this study we aimed to evaluate bone status in women with PHPT compared with controls using HR-pQCT. The distal radius and tibia of 54 women--27 patients with PHPT (median age 60, range 44-75 years) and 27 randomly recruited age-matched healthy controls (median age 60, range 44-76 years)--were imaged using HR-pQCT along with areal bone mineral density (aBMD) by dual-energy X-ray absorptiomentry (DXA) of the ultradistal forearm, femoral neck, and spine (L1-L4). Groups were comparable regarding age, height, and weight. In the radius, patients had reduced Ct area (Ct.Ar) (p =¿.008), Ct thickness (Ct.th) (p =¿.01) along with reduced total (p =¿.002), Ct (p =¿.02), and Tb (p =¿.02) volumetric density and reduced Tb number (Tb.N) (p =¿.04) and increased Tb spacing (Tb.sp) (p = .05). Ct porosity did not differ. In the tibia, no differences in HR-pQCT parameters were found. Moreover, patients had lower ultradistal forearm (p =¿.005), spine (p =¿.04), and femoral neck (p = 0.04) aBMD compared with controls. In conclusion, a negative bone effect of continuously elevated PTH with alteration of HR-pQCT assessed geometry, volumetric density, and both trabecular and cortical microarchitecture in radius but not tibia was found along with reduced aBMD by DXA at all sites in female patients with PHPT. © 2010 American Society for Bone and Mineral Research.

Patients with primary hyperparathyroidism (PHPT) have continuously elevated parathyroid hormone (PTH) and consequently increased bone turnover with negative effects on cortical (Ct) bone with preservation of trabecular (Tb) bone. High-resolution peripheral quantitative computed tomography (HR-pQCT) is a new technique for in vivo assessment of geometry, volumetric density, and microarchitecture at the radius and tibia. In this study we aimed to evaluate bone status in women with PHPT compared with controls using HR-pQCT. The distal radius and tibia of 54 women--27 patients with PHPT (median age 60, range 44-75 years) and 27 randomly recruited age-matched healthy controls (median age 60, range 44-76 years)--were imaged using HR-pQCT along with areal bone mineral density (aBMD) by dual-energy X-ray absorptiomentry (DXA) of the ultradistal forearm, femoral neck, and spine (L1-L4). Groups were comparable regarding age, height, and weight. In the radius, patients had reduced Ct area (Ct.Ar) (p =¿.008), Ct thickness (Ct.th) (p =¿.01) along with reduced total (p =¿.002), Ct (p =¿.02), and Tb (p =¿.02) volumetric density and reduced Tb number (Tb.N) (p =¿.04) and increased Tb spacing (Tb.sp) (p = .05). Ct porosity did not differ. In the tibia, no differences in HR-pQCT parameters were found. Moreover, patients had lower ultradistal forearm (p =¿.005), spine (p =¿.04), and femoral neck (p = 0.04) aBMD compared with controls. In conclusion, a negative bone effect of continuously elevated PTH with alteration of HR-pQCT assessed geometry, volumetric density, and both trabecular and cortical microarchitecture in radius but not tibia was found along with reduced aBMD by DXA at all sites in female patients with PHPT. © 2010 American Society for Bone and Mineral Research.

Udgivelsesdato: 2008-Aug, There is a great need for understanding the impact from dietary OHCs (organohalogen compounds) on bone mineral composition - and thereby osteoporosis - in especially arctic wildlife such as polar bears (Ursus maritimus) as well as humans. For that purpose, we measured BMD (bone mineral density) by DXA scanning (g/cm(-2)) in 15 age and weight normalized sledge dog (Canis familiaris) bitches and their 26 pups divided into a control group (n=26) given 50-200 g/day clean pork (Suis scrofa) fat and a treated group (n=15) given 50-200 g/day OHC polluted minke whale (Balaenoptera acutorostrata) blubber as main lipid sources. The results showed that BMD increased significantly with age (linear regression: p<0.0001, r(2)=0.83, n=41) while no sex difference was found in the F-generation (two-way ANOVA: all p>0.3). No differences in BMD(femur) or BMD(vertebrae) between exposed and control individuals in the bitch generation were found (linear mixed effect model: both p>0.38). Likewise, no difference between exposed and control subadults and juveniles in the F-generation was found (two-way ANOVA: all p>0.33). Correlation analyses between BMD(femur), BMD(vertebrae) and groups of OHCs, respectively, did not show any statistically significant relationships nor a clear or decreasing trend (Pearson's: p: 0.07-0.78; r: -0.2-0.59; n: 10-18). As the groups were similar regarding genetics, age and sex are the only factors that can explain this observation. Either the pollutants did not have an impact on BMD using the present time frame and OHC concentrations (threshold levels not reached), or the difference in food composition (mainly vitamins and n3 fatty acids) conceal the potential OHC impact on BMD. Such information is important when evaluating the positive and negative health consequences from eating polluted marine species.

Udgivelsesdato: 2008-Aug, There is a great need for understanding the impact from dietary OHCs (organohalogen compounds) on bone mineral composition - and thereby osteoporosis - in especially arctic wildlife such as polar bears (Ursus maritimus) as well as humans. For that purpose, we measured BMD (bone mineral density) by DXA scanning (g/cm(-2)) in 15 age and weight normalized sledge dog (Canis familiaris) bitches and their 26 pups divided into a control group (n=26) given 50-200 g/day clean pork (Suis scrofa) fat and a treated group (n=15) given 50-200 g/day OHC polluted minke whale (Balaenoptera acutorostrata) blubber as main lipid sources. The results showed that BMD increased significantly with age (linear regression: p<0.0001, r(2)=0.83, n=41) while no sex difference was found in the F-generation (two-way ANOVA: all p>0.3). No differences in BMD(femur) or BMD(vertebrae) between exposed and control individuals in the bitch generation were found (linear mixed effect model: both p>0.38). Likewise, no difference between exposed and control subadults and juveniles in the F-generation was found (two-way ANOVA: all p>0.33). Correlation analyses between BMD(femur), BMD(vertebrae) and groups of OHCs, respectively, did not show any statistically significant relationships nor a clear or decreasing trend (Pearson's: p: 0.07-0.78; r: -0.2-0.59; n: 10-18). As the groups were similar regarding genetics, age and sex are the only factors that can explain this observation. Either the pollutants did not have an impact on BMD using the present time frame and OHC concentrations (threshold levels not reached), or the difference in food composition (mainly vitamins and n3 fatty acids) conceal the potential OHC impact on BMD. Such information is important when evaluating the positive and negative health consequences from eating polluted marine species.