Changes in RANKL and TRAcP 5b after discontinuation of denosumab suggest RANKL mediated formation of osteoclasts results in the increased bone resorption.

In patients discontinuing long-term denosumab, RANKL levels are high 6 months after the last denosumab injection. Nine and 12 months after the last denosumab injection RANKL levels are lower, but TRAcP 5b levels are higher, suggesting that accumulated RANKL increases the number of active osteoclasts. PURPOSE: The rapid increase in bone turnover occurring when discontinuing long-term treatment with denosumab (DMAB), an antibody that neutralizes receptor activator of nuclear factor kappa-B ligand (RANKL) is not fully understood. We aimed to investigate the mechanisms underlying the rebound activation of bone resorption by measuring tartrate-resistant acid phosphatase 5b (TRAcP 5b), RANKL, osteoprotegerin (OPG), C-terminal collagen crosslinks (CTX), and procollagen type I N-propeptide (P1NP) in patients discontinuing long-term DMAB. METHODS: Sixty-one patients with BMD T-score > - 2.5 at the spine and hip discontinuing long-term DMAB were randomized to treatment with zoledronate (ZOL) 6 months (6 M group, n = 20), 9 months (9 M group, n = 20) or 12 months after the last DMAB injection or when bone turnover was high (12 M group, n = 21). Bone turnover markers were measured immediately before initiation of ZOL treatment. RESULTS: We found higher CTX and PINP in the 9 M and 12 M groups compared to the 6 M group (p < 0.001). In the 6 M group, TRAcP 5b was lower and RANKL higher than in the other two groups (p < 0.001). TRAcP 5b correlated negatively with RANKL (R = - 0.54), and time since the last DMAB injection correlated positively with CTX (R = 0.56), PINP (R = 0.72), TRAcP 5b (R = 0.51) and negatively with RANKL (R = - 0.70) (p < 0.001 for all). We found no difference in OPG between groups. CONCLUSION: Following discontinuation of long-term DMAB, we find high levels of RANKL, which most likely result in an increase in the number of active osteoclasts (illustrated by TRAcP5b) causing an increased bone turnover.

Discontinuation of denosumab in men with prostate cancer.

In patients with non-metastatic prostate cancer, treated with radiation therapy and androgen deprivation therapy for 3 years and DMAB on average for 5 years, BMD was in the normal or osteopenic range. Discontinuation of DMAB led to a bone loss of 2-5%. In men with osteopenia, the bone loss was prevented by zoledronate. PURPOSE: Patients with prostate cancer receiving androgen deprivation therapy (ADT) are treated with denosumab (DMAB) to prevent fractures and preserve bone mass. We wanted to investigate the change in BMD in men with non-metastatic prostate cancer discontinuing DMAB. METHODS: We conducted a retrospective cohort study based on medical records from patients referred to the Department of Endocrinology from the Department of Urology, Aarhus University Hospital between June 1, 2018, and June 1, 2021. We retrieved information on biochemistry and DXA performed 0-6 months after the last DMAB injection and a second DXA performed approximately 12 months after the first. In case of a BMD T-score ≤ - 1 at the lumbar spine or total hip at the first DXA, the patients were treated with zoledronate. The primary endpoint was change in lumbar spine BMD. RESULTS: We included 50 patients with non-metastatic prostate cancer. The mean DMAB treatment duration was 5 ± 0.1 years. Among the patients treated with zoledronate (n = 9), BMD was maintained at the spine and femoral neck after a mean of 16 months. We found a significant decrease in BMD; - 4.9 ± 4.2%, - 1.9 ± 3.5%, and - 2.4 ± 3.6% at the spine, total hip, and femoral neck between the first and second DXA in the patients not treated with zoledronate (n = 24) (p ≤ 0.01 for all). One patient who did not receive ZOL sustained multiple fragility vertebral fractures after DMAB discontinuation. CONCLUSION: In men with non-metastatic prostate cancer, discontinuation of DMAB after stopping ADT led to an average bone loss of 2-5%. Zoledronate prevented bone loss in men with osteopenia.

The Effect of Effervescent and Buffered Alendronate Compared to Conventional Alendronate on Markers of Bone Turnover: A Randomized Non-inferiority Trial.

Buffered and effervescent alendronate (ALN-EFF) increases gastric pH and is reported to decrease the risk of gastrointestinal side effects compared to conventional formulations of alendronate (ALN). The clinical effectiveness of ALN-EFF, however, has not been investigated. This study aims to investigate if ALN-EFF is non-inferior to ALN in suppressing bone turnover markers (BTM). We conducted a 16-week prospective, randomized, open-label study comprising 64 postmenopausal women with BMD T-score < -1 naïve to osteoporosis treatment. Participants were randomized 1:1 to ALN or ALN-EFF. We collected blood samples at 0, 4, 8, and 16 weeks. Non-inferiority margin was determined as 12% (80% of efficacy retained), and an SD of 15% on change in CTx. CTx decreased by 58.2% ± 24.1% in the ALN group and by 46.9% ± 23.3% (CI - 38.42:- 55.35) in the ALN-EFF group (p = 0.08). The non-inferiority limit was 46.6%. With ALN-EFF the CI crosses the non-inferiority limit thus the test for non-inferiority was indeterminate. PINP decreased by 45.7 ± 22.6% in the ALN group and by 35.1 ± 20.7% in the ALN-EFF group (p = 0.07). Changes over time in the BTMs were not significantly different between the groups, p > 0.10 for both CTx and PINP. There was no difference in frequency of AEs or compliance between the two groups, but rate of discontinuation was lower with ALN-EFF. In conclusion, suppression of BTMs was not significantly different between the groups but formal non-inferiority could not be established.

Denosumab Discontinuation.

PURPOSE OF REVIEW: To review the pathophysiology, the clinical consequences as well as way of mitigating the effects of denosumab discontinuation. RECENT FINDINGS: Treatment with denosumab (DMAB) is reversible and upon discontinuation there is a rapid increase in bone turnover and a subsequent bone loss. During this phase of high bone turnover, an increased risk of fractures has been reported. Therefore, treatment with DMAB could be considered life-long. However, side-effects may prompt the need for discontinuation and moreover, treatment with DMAB may have increased BMD to levels where continuing treatment does not provide further fracture risk reduction. Patients stopping DMAB should be offered subsequent antiresorptive treatment with an intense monitoring regimen during the initial year as most of the bone loss occurs within these initial 12 months. In this review, we evaluated the literature published over the past 1 to 3 years investigating DMAB withdrawal with focus on bone turnover markers, bone mineral density, and fracture risk and the transition to other anti-osteoporosis therapies. Furthermore, we summarized the current recommendations of international guidelines. In this review, we evaluated the literature published over the past 1 to 3 years investigating denosumab (DMAB) discontinuation and the transition to other anti-osteoporosis therapies. Additionally, we summarized the current recommendations of international guidelines.

Determinants of hypercalciuria and renal calcifications in chronic hypoparathyroidism: A cross-sectional study.

OBJECTIVE: Hypercalciuria, impaired kidney function and renal calcifications are common in chronic hypoparathyroidism (HypoPT). We aimed to study associations between indices of known importance to the kidney in HypoPT by hypothesizing adverse effects of hypercalciuria on renal outcomes. DESIGN: We used cross-sectional design. PATIENTS: We identified all patients followed for chronic HypoPT at our department and who had been examined by a 24-h urine collection for measurement of renal calcium excretion (24 h U-Ca). MEASUREMENTS: By chart review, we identified additional biochemistry measured in close connection with the collection of urine, as well as demographic, treatments and anthropometrics. RESULTS: The 166 included patients (79.5% females) had a high prevalence of hypercalciuria (65.7%). In multiple adjusted analyses, hypercalciuria was in an independent manner inversely associated with (residual) levels of plasma PTH and positively associated with levels of 1,25-dihydroxyvitamin D and ionized calcium as well as 24 h U-phosphate, gender, and etiology (surgical vs. non-surgical). Overall, this model explained 54% (p < .001) of the variation in the presence of hypercalciuria. Chronic kidney disease stage three or above was present in 18.3% of the patients, and 42.6% of the 54 patients examined by renal imaging had renal calcifications. However, neither renal function nor renal calcifications were associated with 24 h U-Ca. CONCLUSIONS: Hypercalciuria, impaired renal function and renal calcifications are common in hypoparathyroidism. Hypercalciuria is to a large extent explained by indices of known physiological importance to 24 h U-Ca. However, in the present study, a high renal calcium excretion did not explain renal impairment or kidney calcifications.

T-score differences and nonprogression in lumbar vertebrae as predictors of vertebral fractures.

PURPOSE: In case of a vertebral fracture, the area of the vertebrae decreases with a concomitant increase in BMD, as assessed by a DXA scanning. Furthermore, a vertebral fracture may disrupt the normal increase in vertebral body area from L1 to L4 (nonprogression). We aimed to examine associations between T-score difference and nonprogression of vertebral area and vertebral fractures. METHODS: We identified 100 patients with 1 or more fractures in L1-L4 and 106 patients without fractures. All patients had undergone a DXA scan and a lumbar spine X-ray. In fracture patients, we recorded T-score difference between the fractured vertebra and the adjacent vertebra, and whether the fractured vertebra was smaller than the one above (nonprogression). In nonfracture patients, the greatest positive T-score difference was recorded, and nonprogression was present if vertebral area did not increase successively from L1 to L4. RESULTS: With a T-score difference ≥1 SD odds ratio for fracture was 1.30 (0.74-2.29). Sensitivity and specificity were 0.40 and 0.66, respectively. With T-score difference ≥1.5 SD, odds ratio for fracture was 2.26 (1.08-4.73). Sensitivity and specificity were 0.24 and 0.88, respectively. Nonprogression was very common in the no-fracture group (38%), while only 23% of X-ray verified fractures had nonprogression. CONCLUSION: A randomly found T-score difference ≥1.5 SD between adjacent vertebrae on a DXA scan is associated with a small increased risk of compression fracture. Nonprogression is very common in patients without fractures.

Long-Term High-Dose Resveratrol Supplementation Reduces Bone Mass and Fracture Strength in Rats.

Resveratrol (RSV) is a natural polyphenolic compound. A recent study suggests a positive effect on BMD in men; however, the underlying changes in microstructure and strength remain unknown. We aimed to investigate the effects of RSV on the skeleton in hindlimb-immobilized and non-immobilized rats. Seventy-two female Wistar rats were divided into six groups. Two baseline (BSL) groups underwent short-term diet intervention for 4 weeks before sacrifice [phytoestrogen-deficient diet (PD) (BSL + PD) or RSV diet (600 mg/kg body weight/day) (BSL + RSV)]. Four groups were injected in the right hindlimb with botulinum toxin (BTX) (immobilized) or saline (non-immobilized), and fed either PD diet or RSV diet 4 weeks pre-injection and 6 weeks post-injection before sacrifice (BTX + PD, BTX + RSV, PD, and RSV, respectively). DXA, µCT, dynamic histomorphometry, and mechanical tests were performed. Short-term RSV treatment did not affect bone parameters, whereas long-term RSV exposure had a consistent negative impact on non-immobilized rats (RSV vs. PD); whole femoral aBMD (p = 0.01) and distal femoral metaphyseal Tb.N (p = 0.01), Tb.Sp (p = 0.02), and BV/TV (p = 0.07). At the femoral mid-diaphysis, RSV increased periosteal resorption (p = 0.01) and increased endosteal formation (p = 0.02), while mineralization was unaffected. In addition, RSV reduced femoral mid-diaphyseal three-point bending strength (p = 0.03) and stiffness (p = 0.04). BTX-induced immobilization resulted in significant bone loss and reduced bone strength; however, RSV supplementation was unable to prevent this. In conclusion, long-term high-dose RSV reduced bone mass and fracture strength and did not prevent immobilization-induced bone loss in rats.

The dental perspective on osteogenesis imperfecta in a Danish adult population.

BACKGROUND: To report on dental characteristics and treatment load in Danish adult patients with osteogenesis imperfecta (OI). METHODS: Oral examination of 73 patients with OI was performed and OI type I, III, and IV were represented by 75.3%, 8.2%, and 16.4%, respectively. Patients were diagnosed as having dentinogenesis imperfecta (DI) if they had clinical and radiological signs of DI. In the data analysis, mild OI (type I) was compared to moderate-severe OI (type III and IV). RESULTS: Discoloration of teeth was prevalent in patients with moderate-severe compared to mild OI (83.3% vs. 5.5%, p < 0.001). Cervical constriction and pulpal obliteration were frequent findings in patients with moderate-severe OI (61.1% and 88.9%, respectively), whereas pulp stones and taurodontism were diagnosed in patients with mild OI only (29.1% and 9.1%, respectively). DI was found in 24.7% of OI patients and considerably more frequent in patients with moderate-severe (94.4%) compared to mild OI (1.8%) (p < 0.001). The number of teeth with artificial crowns was significantly higher in patients with moderate-severe OI than in patients with mild OI (median 1.5, range 0-23 vs. median 0, range 0-14) (p < 0.001). The number of teeth with fillings in patients with mild OI was significantly higher than in patients with moderate-severe OI (mean 9.7, SD 5.1, median 9.0, range 1-21 vs. mean 5.0, SD 4.4, median 4.0, range 0-16) (p < 0.001). CONCLUSIONS: One fourth of patients with OI had DI, and the vast majority of them had moderate-severe OI. Whereas discoloration of teeth, cervical constriction and pulp obliteration were frequent findings in patients with moderate-severe OI, pulp stones and taurodontism were found in patients with mild OI only. In patients with moderate-severe OI, the dental treatment load was dominated by prosthetic treatment, whereas restorative treatment with fillings was more prevalent in patients with mild OI.

Health-Related Quality of Life in Adults with Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a systemic connective tissue disorder most often caused by mutations in collagen type 1 related genes. Patients with OI suffer from multiple fractures and various degrees of growth deficiency and bone deformity. It is unknown whether the systemic effect of defect collagen type 1 influences the quality of life in patients with OI. We therefore aimed to investigate health-related quality of life (HRQoL) in a well-characterized cohort of adult patients with OI. We included 85 adult patients with mild to severe OI (types I, III, and IV) and obtained information about skeletal- and non-skeletal phenotypes and patient demographics. We investigated physical and mental HRQoL using a validated questionnaire, SF-36, and compared the data to values obtained in a population without OI. Patients with mild, moderate, and severe OI all had lower mean scores on domains describing physical HRQoL and a lower mean physical component score compared to the general population, p < 0.001. Patients with severe OI had lower mean scores on physical HRQoL, p < 0.05. The scores on domains reflecting mental HRQoL were more inhomogenously affected, but did not differ significantly from the general population. OI has an impact on physical and some aspects of mental HRQoL. The scores on physical health were correlated to severity of the OI disease. The mental component score in the OI patients was unaffected and comparable with the general population.

Resveratrol Increases Osteoblast Differentiation In Vitro Independently of Inflammation.

Low-grade inflammation negatively affects bone. Resveratrol is a natural compound proven to possess both anti-inflammatory and bone protective properties. However, it is uncertain if the bone effects are mediated though anti-inflammatory effects. Firstly, we investigated if resveratrol affects proliferation and differentiation of human bone marrow-derived mesenchymal stem cells. Secondly, we investigated if inflammation negatively affects proliferation and differentiation, and if resveratrol counteracts this through anti-inflammatory effects. Mesenchymal stem cells were obtained from bone marrow aspiration in 13 healthy individuals and cultured towards the osteoblast cell lineage. The cells were stimulated with resveratrol, lipopolysaccharide (LPS), LPS + resveratrol, or vehicle (control) for 21 days. Compared to control, resveratrol decreased cell number by 35 % (p < 0.05) and induced differentiation (a 3-fold increase in alkaline phosphatase (p < 0.002), while P1NP and OPG showed similar trends). LPS induced inflammation with a 44-fold increase in interleukin-6 (p < 0.05) and an extremely prominent increase in interleukin-8 production (p < 0.05) relative to control. In addition, LPS increased cell count (p < 0.05) and decreased differentiation (a reduction in P1NP production (p < 0.02)). Co-stimulation with LPS + resveratrol did not reduce interleukin-6 or interleukin-8, but nonetheless, cell count was reduced (p < 0.05) and alkaline phosphatase, P1NP, and OPG increased (p < 0.05 for all). Thus, resveratrol stimulates osteoblast differentiation independently of inflammation.

Hypercalcemia in metastatic GIST caused by systemic elevated calcitriol: a case report and review of the literature.

BACKGROUND: Hypercalcemia is the most common oncologic metabolic emergency but very rarely observed in patients with gastrointestinal stromal tumour, which is a rare mesenchymal malignancy of the gastrointestinal tract. We describe a case of hypercalcemia caused by elevated levels of activated vitamin D in a patient with gastrointestinal tumour. Prior to this case report, only one paper has reported an association between hypercalcemia, gastrointestinal stromal tumours and elevated levels of vitamin D. CASE PRESENTATION: An otherwise healthy 70-year-old Caucasian woman, previously treated for duodenal gastrointestinal stromal tumour, was diagnosed with liver metastasis, and relapse of gastrointestinal stromal tumour was confirmed by biopsy. At presentation, the patient suffered from severe symptoms of hypercalcemia. The most common causes of hypercalcemia, hyperparathyrodism, parathyroid hormone-related peptide secretion from tumour cells, and metastatic bone disease, were all dismissed as the etiology. Analysis of vitamin D subtypes revealed normal levels of both 25-OH Vitamin D2 and 25-OH Vitamin D3, whereas the level of activated vitamin D, 1,25 OH Vitamin D3, also referred to as calcitriol, was elevated. CONCLUSION: The fact that plasma calcitriol decreased after initiation of oncological treatment and the finding that hypercalcemia did not recur during treatment support the conclusion that elevated calcitriol was a consequence of the gastrointestinal stromal tumour. We suggest that gastrointestinal stromal tumours should be added to the list of causes of humoral hypercalcemia in malignancy, and propose that gastrointestinal stromal tumour tissue may have high activity of the specific enzyme 1α-hydroxylase, which can lead to increased levels of calcitriol and secondarily hypercalcemia.

Bone turnover decreases and bone structure improves during treatment with weekly high-dose methylprednisolone for 12 weeks in Graves' orbitopathy.

PURPOSE: Weekly treatment with the intravenous glucocorticoid methylprednisolone for 12 weeks is mainstay in the treatment of Graves' orbitopathy but may decrease bone mass and impair bone structure. We therefore investigated bone turnover, -mass and -structure during the treatment cause in these patients. METHODS: We included 32 patients with Graves' orbitopathy scheduled for treatment with methylprednisolone. Bone turnover and thyroid function was measured at baseline and after 3, 9, 12, and 24 weeks, bone mineral density (BMD) was measured using dual x-ray absorptiometry at baseline and after 12 and 24 weeks, and bone structure was measured using high-resolution peripheral quantitative computed tomography at baseline and after 12 weeks. RESULTS: Bone turnover and tri-iodothyronine decreased throughout the study. Cortical volumetric BMD at both the radius and tibia increased significantly by 0.98 ± 0.38% (p = 0.01) and 1.35 ± 0.50% (p = 0.01), respectively and cortical porosity at both the radius and tibia decreased significantly by -7.67 ± 3.13% (p = 0.04) and -3.30 ± 2.17% (p = 0.04), respectively. Bone mineral density was stable during the first 12 weeks but increased significantly by 2.26 ± 3.61% at the femoral neck (p < 0.01) and by 2.24 ± 4.24% at the total hip towards week 24 (p = 0.02). Stratified analyses suggested that remission of hyperthyroidism was the most important determinant of changes in bone turnover, bone mass and structure. CONCLUSION: During a 12-week course of high-dose intravenous methylprednisolone bone turnover and cortical porosity decreased and during 24 weeks follow up bone mineral density increased. In terms of bone, methylprednisolone therefore is a safe treatment for Graves' orbitopathy.

Osteoarthritis in osteogenesis imperfecta: A nationwide register-based cohort study.

BACKGROUND: Osteogenesis Imperfecta (OI) is a genetic disease characterized by skeletal fragility. Collagen type 1 is found in many tissues and collagen abnormalities may result in organ specific symptomatology. Musculoskeletal pain is a known issue for patients with OI, osteoarthritis (OA) can be a likely cause. Only few studies have investigated the relationship between OI and OA but demonstrated a greater propensity in OI patients to develop rapidly progressing OA. Therefore, we wanted to investigate if OA is more frequent in patients with OI compared to the general population. OBJECTIVE: To evaluate the risk of osteoarthritis in patients with OI. DESIGN: A Danish nationwide, population-based and register-based longitudinal open cohort study. PARTICIPANTS: From 1977 to 2019, all patients registered with an OI diagnosis and a reference population matched on age and sex 5:1. MEASUREMENTS: Sub-hazard ratios for any, hip, and knee osteoarthritis comparing the OI cohort to the reference population. RESULTS: We identified 907 patients with OI (493 women) and included 4535 patients in the reference population (2465 women). The Sub Hazard Ratio was 2.20 [95% CI 1.73-2.79] for any osteoarthritis with 11.4% of the OI population and 5.4% of the reference population being registered. We found lower incidences of upper extremity joint OA compared to lower joint OA, but upper extremity joint OA was significantly more frequent in the OI population 2.1% vs 0.6%, SHR 3.19 [95% CI 1.78-5.70]. CONCLUSION: Patients with OI have a higher risk of OA than the reference population. MINIABSTRACT: Osteogenesis Imperfecta (OI) is a hereditary connective tissue disorder with skeletal fragility and extraskeletal manifestations. Osteoarthritis is a frequent joint disease and the incidence increases with age. In a population-register-based study, the risk of osteoarthritis was higher in patients with OI at an earlier age compared to a reference population.

Bone Density and Structure in Overweight Men With and Without Diabetes.

Objective: Metabolic syndrome (MetS), type 1 diabetes (T1D), and type 2 diabetes, are associated with an increased risk of fractures; however, the impact of obesity on bone deficits in diabetes is unknown. We aimed to compare markers of bone structure, bone density, and bone turnover in non-diabetic overweight men with MetS and overweight men with T1D or T2D. Methods and Research Design: In this cross-sectional study we included participants from two previously described study cohorts consisting of participants with diabetes and participants with MetS. Participants underwent dual-energy X-ray absorptiometry measuring areal bone mineral density (aBMD) at the hip and lumbar spine, High Resolution peripheral Quantitative (HRpQCT) scan of the tibia and radius and measurement of circulating bone turnover markers. We compared groups with unpaired t test and performed multiple linear regression with adjustment for age, body mass index, and smoking. Results: We included 33 participants with T1D, 25 participants with T2D, and 34 participants with MetS. Bone turnover markers levels were comparable between T1D and MetS. aBMD at the hip was lower in T1D compared to MetS, also after adjustment. P1NP and Osteocalcin levels were lower among individuals with T2D compared to MetS, whereas aBMD were similar between the groups after multiple adjustments. We observed no difference in volumetric BMD at the tibia or radius between MetS and T1D and T2D, respectively. Participants with T2D had a higher trabecular number and lower trabecular separation compared to individuals with MetS at the tibia, which remained signficant after multiple adjustments. Conclusion: In conclusion, we observed no clinically important differences in bone density or structure between men with T2D, T1D, or MetS. However, men with T2D displayed lower bone turnover compared to MetS highlighting that T2D per se and not obesity, is associated with low bone turnover.

Treatment With Zoledronate Subsequent to Denosumab in Osteoporosis: A 2-Year Randomized Study.

Increased bone turnover and rapid bone loss follow discontinuation of denosumab. We investigated the long-term efficacy of zoledronate (ZOL) in maintaining bone mineral density (BMD) after discontinuation of denosumab. In this randomized, open-label, interventional study, we included 61 postmenopausal women and men older than 50 years discontinuing denosumab after 4.6 ± 1.6 years. We administered ZOL 6 months (6 M) or 9 months (9 M) after the last denosumab or when bone turnover had increased (observation group [OBS]). ZOL was readministrated if p-cross-linked C-terminal telopeptide (p-CTX) increased ≥1.26 µg/L or BMD decreased ≥5%. The results after 12 months have previously been published; here we report the outcome after 24 months (ClinicalTrials NCT03087851). Fifty-eight patients completed the study. From 12 to 24 months after the initial ZOL, lumbar spine (LS) BMD was maintained: 0.9 ± 0.9%, 0.4 ± 0.8%, and 0.3 ± 0.7% in the 6 M, 9 M, and OBS groups, respectively (p > .05, no between-group differences). Similarly, total hip (TH) and femoral neck (FN) BMD did not change in any group during year 2. From baseline to 24 months after ZOL, LS BMD decreased by 4.0 ± 0.8%, 4.1 ± 0.8%, and 4.3 ± 1.5% in the 6 M, 9 M, and OBS groups, respectively (p < .001, no between-group differences). Significant bone loss (LS, TH, or FN) was found in all groups 24 months after ZOL: 6 M group: n = 12 (60%), 9 M group: n = 7 (37%), and OBS group: n = 10 (53%). P-CTX did not change significantly during the second year (p > .05, no between-group differences). No patient fulfilled the CTX or fracture criteria for retreatment during year 2; however, 9 patients were retreated at M24 due to BMD loss ≥5%. Two patients sustained a non-vertebral fracture during year 2. Treatment with ZOL subsequent to long-term denosumab did not fully prevent increased bone turnover and bone loss during the first year; however, CTX remained with the reference range and BMD was maintained during the second year. © 2021 American Society for Bone and Mineral Research (ASBMR).

Vitamin K2 (menaquinone-7) increases plasma adiponectin but does not affect insulin sensitivity in postmenopausal women: a randomized controlled trial.

BACKGROUND/OBJECTIVES: Vitamin K is a co-factor in the carboxylation of the bone matrix protein osteocalcin (OC), and thus decreases the concentration of undercarboxylated osteocalcin (ucOC). Animal and in vitro studies suggest that ucOC increases insulin sensitivity. However, epidemiological studies find positive associations between vitamin K intake and insulin sensitivity. We aimed to investigate the effect of vitamin K2 in the form of menaquinone-7 (MK-7) on serum ucOC, bone mass, and insulin sensitivity in postmenopausal women. SUBJECTS/METHODS: This was a randomized placebo-controlled trial. One hundred forty-eight postmenopausal women received MK-7 375 µg daily or placebo, as an add-on to calcium (800 mg) and vitamin D (38 µg) for 12 months. We measured serum ucOC, insulin sensitivity by HOMA-IR, and plasma adiponectin and leptin at baseline and after 12 months. RESULTS: S-ucOC decreased in the MK-7 group (-70.3 (-75.6; -63.8) %) compared to the placebo group (-7.2 (-15.9; 2.0) %) after 12 months (p < 0.01). P-adiponectin increased in the MK-7 group (6.1 ± 20.1%) (mean ± SD) compared to the placebo group (-0.7 ± 15.5%) after 12 months (p = 0.03). HOMA-IR and p-leptin did not change in the two groups. CONCLUSION: Treatment with MK-7 for 12 months decreased p-ucOC, increased p-adiponectin, but did not change insulin sensitivity suggesting that ucOC does not affect insulin sensitivity in healthy postmenopausal women.

Association of Potent and Very Potent Topical Corticosteroids and the Risk of Osteoporosis and Major Osteoporotic Fractures.

Importance: Systemic and inhaled corticosteroids negatively affect bone remodeling and cause osteoporosis and bone fracture when given continuously or in high doses. However, risk of osteoporosis and major osteoporotic fracture (MOF) after application of topical corticosteroids (TCSs) is largely unexplored. Objective: To examine the association between cumulative exposure to potent and very potent TCSs and risk of osteoporosis and MOF. Design, Setting, and Participants: This nationwide retrospective cohort study included 723 251 Danish adults treated with potent or very potent TCSs from January 1, 2003, to December 31, 2017. Data were obtained from Danish nationwide registries. Filled prescription data were converted in equipotent doses to mometasone furoate (1 mg/g). Data were analyzed from June 1 to August 31, 2019. Exposures: Patients were considered exposed when they had filled prescriptions of cumulative amounts corresponding to the equivalent of at least 500 g of mometasone, using filled prescriptions of 200 to 499 g as the reference group. Main Outcomes and Measures: The co-primary outcomes were a diagnosis of osteoporosis or MOF. Hazard ratios (HRs) adjusted for age, sex, socioeconomic status, medication use, and comorbidity were calculated with 95% CIs using Cox proportional hazards regression models. Results: A total of 723 251 adults treated with the equivalent of at least 200 g of mometasone were included in the analysis (52.8% women; mean [SD] age, 52.8 [19.2] years). Dose-response associations were found between increased use of potent or very potent TCSs and the risk of osteoporosis and MOF. For example, HRs of MOF were 1.01 (95% CI, 0.99-1.03) for exposure to 500 to 999 g, 1.05 (95% CI, 1.02-1.08) for exposure to 1000 to 1999 g, 1.10 (95% CI, 1.07-1.13) for exposure to 2000 to 9999 g, and 1.27 (95% CI, 1.19-1.35) for exposure to at least 10 000 g. A 3% relative risk increase of osteoporosis and MOF was observed per doubling of the cumulative TCS dose (HR, 1.03 [95% CI, 1.02-1.04] for both). The overall population-attributable risk was 4.3% (95% CI, 2.7%-5.8%) for osteoporosis and 2.7% (95% CI, 1.7%-3.8%) for MOF. The lowest exposure needed for 1 additional patient to be harmed (454 person-years) was observed for MOF with exposure of at least 10 000 g. Conclusions and Relevance: These findings demonstrate that use of high cumulative amounts of potent or very potent TCSs was associated with an increased risk of osteoporosis and MOF.

Treatment with Zoledronate Subsequent to Denosumab in Osteoporosis: a Randomized Trial.

Discontinuing denosumab is associated with bone loss and possibly increased fracture risk. We investigated if treatment with zoledronate (ZOL) could prevent bone loss and if the timing of the ZOL infusion influenced the outcome. We report on a 2-year randomized, open label, interventional study including 61 patients with osteopenia, discontinuing denosumab after 4.6 ± 1.6 years. We administrated ZOL 6 months (6M group, n = 20) or 9 months (9M group, n = 20) after the last denosumab injection or when bone turnover had increased (OBS group, n = 21). We monitored the patients with DXA and bone turnover markers. Our primary endpoints were change in lumbar spine BMD (LSBMD) 6 months after ZOL and the proportion of patients who failed to maintain BMD. The study is ongoing (clinicaltrials.gov; NCT03087851). We included 61 participants and 59 patients completed follow-up 12 months after ZOL. Six months after ZOL, LSBMD had decreased significantly by (mean ± SE) 2.1% ± 0.9%, 4.3% ± 1.1%, and 3.0% ± 1.1% in the 6M, 9M, and OBS groups, respectively, and by 4.8% ± 0.7%, 4.1% ± 1.1%, and 4.7% ± 1.2% 12 months after ZOL in the 6M, 9M, and OBS groups, respectively (p < .02, no between-group differences). BMD loss above the least significant change was seen in all groups; at the spine: 6M, n = 6 (30%); 9M, n = 9 (45%); and OBS, n = 9 (47%); and at the total hip: 6M, n = 1 (5%); 9M, n = 5 (25%); and OBS, n = 2 (11%). In the 6M group p-crosslinked C-terminal telopeptide (p-CTX) decreased initially, but increased rapidly thereafter, and 6 months after ZOL, p-CTX was 0.60 ± 0.08 g/L. p-CTX increased rapidly in the 9M and OBS groups, was suppressed by ZOL but increased again thereafter; p-CTX was 0.47 ± 0.05 µg/L and 0.47 ± 0.05 µg/L in the 9M and OBS groups 6 months after ZOL, respectively. Incident vertebral fractures were seen in two women in the 9M group. Treatment with ZOL irrespective of the timing did not fully prevent loss of BMD in patients discontinuing denosumab. © 2020 American Society for Bone and Mineral Research.

The risk of osteoporosis in patients with asthma.

It is well-known that use of continuous systemic corticosteroids (SG) affects bone metabolism, bone mineral density (BMD), and ultimately increases the risk of osteoporosis. In patients with asthma, on the other hand, the effects of long-term high-dose inhaled corticosteroids (ICS) on BMD and risk of osteoporotic fractures is controversial. The reasons for this inconsistency could be explained by the fact that only few long-term studies investigating the effect of ICS in patients with asthma exist. The studies are characterized by different study designs and duration of ICS exposure, small study populations, and differences between the used ICS. The aim of this article is to unravel which factors, if any, that contribute to an increased risk of osteoporosis in patients with asthma and to summarize the evidence regarding adverse effects of ICS on bone metabolism, BMD and osteoporotic fractures in patients with asthma.

Bone resorption is unchanged by liraglutide in type 2 diabetes patients: A randomised controlled trial.

BACKGROUND: Liraglutide, a glucagon-like peptide-1 receptor agonist, has well known beneficial effects on glucose metabolism, and animal studies indicate that liraglutide also affects bone turnover by decreasing bone resorption. The primary objective of the study was to investigate the effect of liraglutide on bone turnover in patients with T2D. METHODS: The study was a randomized, double-blinded, clinical trial. Sixty participants with T2D were randomized to treatment with liraglutide 1.8 mg daily or placebo for 26 weeks. The primary endpoint was change in p-collagen I cross-linked C-terminal telopeptide (p-CTX). RESULTS: P-CTX increased in patients treated with liraglutide by 0.07 (0.03; 0.10) µg/L (p < 0.001) and in patients treated with placebo by 0.03 (0.00; 0.06) µg/L (p = 0.04), however, changes were not different between the groups (p = 0.16). Weight decreased in patients treated with liraglutide from baseline to week four (p < 0.001) and remained stable thereafter. P-procollagen type 1 N-terminal propeptide (P1NP) decreased in patients treated with liraglutide from baseline to week four (p < 0.01), increased between weeks 4 and 13 (p = 0.03), and remained elevated thereafter. Weight and p-P1NP did not change in patients treated with placebo. Hip bone mineral density (BMD) decreased in placebo treated patients from baseline to end of study, whereas no changes were seen in patients treated with liraglutide (p = 0.01 difference between groups). CONCLUSION: Liraglutide treatment for 26 weeks did not affect bone resorption and preserved hip BMD despite weight loss in patients with T2D, suggesting that liraglutide has some antiresorptive effect.