Publications by authors named "Richard Eastell"

265 Publications

Effect of selenium supplementation on musculoskeletal health in older women: a randomised, double-blind, placebo-controlled trial.

Lancet Healthy Longev 2021 Apr;2(4):e212-e221

Mellanby Centre for Musculoskeletal Research, University of Sheffield, Northern General Hospital, Sheffield, UK.

Background: Observational and preclinical studies show associations between selenium status, bone health, and physical function. Most adults in Europe have serum selenium below the optimum range. We hypothesised that selenium supplementation could reduce pro-resorptive actions of reactive oxygen species on osteoclasts and improve physical function.

Methods: We completed a 6-month randomised, double-blind, placebo-controlled trial. We recruited postmenopausal women older than 55 years with osteopenia or osteoporosis at the Northern General Hospital, Sheffield, UK. Participants were randomly assigned 1:1:1 to receive selenite 200 μg, 50 μg, or placebo orally once per day. Medication was supplied to the site blinded and numbered by a block randomisation sequence with a block size of 18, and participants were allocated medication in numerical order. All participants and study team were masked to treatment allocation. The primary endpoint was urine N-terminal cross-linking telopeptide of type I collagen (NTx, expressed as ratio to creatinine) at 26 weeks. Analysis included all randomly assigned participants who completed follow-up. Groups were compared with analysis of covariance with Hochberg testing. Secondary endpoints were other biochemical markers of bone turnover, bone mineral density, short physical performance battery, and grip strength. Mechanistic endpoints were glutathione peroxidase, highly sensitive C-reactive protein, and interleukin-6. This trial is registered with EU clinical trials, EudraCT 2016-002964-15, and ClinicalTrials.gov, NCT02832648, and is complete.

Findings: 120 participants were recruited between Jan 23, 2017, and April 11, 2018, and randomly assigned to selenite 200 μg, 50 μg, or placebo (n=40 per group). 115 (96%) of 120 participants completed follow-up and were included in the primary analysis (200 μg [n=39], 50 μg [n=39], placebo [n=37]). Median follow-up was 25·0 weeks (IQR 24·7-26·0). In the 200 μg group, mean serum selenium increased from 78·8 (95% CI 73·5-84·2) to 105·7 μg/L (99·5-111·9). Urine NTx to creatinine ratio (nmol bone collagen equivalent:mmol creatinine) did not differ significantly between treatment groups at 26 weeks: 40·5 (95% CI 34·9-47·0) for placebo, 43·4 (37·4-50·5) for 50 μg, and 42·2 (37·5-47·6) for 200 μg. None of the secondary or mechanistic endpoint measurements differed between treatment groups at 26 weeks. Seven (6%) of 120 participants were withdrawn from treatment at week 13 due to abnormal thyroid-stimulating hormone concentrations (one in the 200 μg group, three in the 50 μg group, and three in the placebo group) and abnormal blood glucose (one in the 50 μg group). There were three serious adverse events: a non-ST elevation myocardial infarction at week 18 (in the 50 μg group), a diagnosis of bowel cancer after routine population screening at week 2 (in the placebo group), and a pulmonary embolus due to metastatic bowel cancer at week 4 (in the 200 μg group). All severe adverse events were judged by the principal investigator as unrelated to trial medication.

Interpretation: Selenium supplementation at these doses does not affect musculoskeletal health in postmenopausal women.

Funding: UK National Institute for Health Research Efficacy and Mechanism Evaluation programme.
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http://dx.doi.org/10.1016/S2666-7568(21)00051-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8020713PMC
April 2021

The Effects of Type 1 Diabetes and Diabetic Peripheral Neuropathy on the Musculoskeletal System: A Case-Control Study.

J Bone Miner Res 2021 Apr 6. Epub 2021 Apr 6.

Academic Unit of Bone Metabolism, University of Sheffield, Sheffield, UK.

Fracture risk is increased in type 1 diabetes (T1D). Diabetic neuropathy might contribute to this increased risk directly through effects on bone turnover and indirectly through effects on balance, muscle strength, and gait. We compared patients with T1D with (T1DN+, n = 20) and without (T1DN-, n = 20) distal symmetric sensorimotor polyneuropathy and controls (n = 20). We assessed areal bone mineral density (aBMD) and appendicular muscle mass by dual-energy X-ray absorptiometry, microarchitecture by high-resolution peripheral quantitative tomography at the standard ultra-distal site and at an exploratory 14% bone length site at the tibia and radius, bone turnover markers, and muscle strength, gait, and balance by Short Physical Performance Battery (SPPB). At the standard ultra-distal site, tibial cortical porosity was 56% higher in T1DN+ compared with T1DN- (p = .009) and correlated positively with the severity of neuropathy (Toronto Clinical Neuropathy Score; r = 0.347, p = .028) and negatively with nerve conduction amplitude and velocity (r = -0.386, p = .015 and r = -0.358, p = .025, respectively). Similar negative correlations were also observed at the radius (r = -0.484, p = .006 and r = -0.446, p = .012, respectively). At the exploratory 14% offset site (less distal), we found higher trabecular volumetric BMD (tibia 25%, p = .024; radius 46%, p = .017), trabecular bone volume (tibia 25%, p = .023; radius 46%, p = .017), and trabecular number (tibia 22%, p = .014; radius 30%, p = .010) in T1DN- compared with controls. Both CTX and PINP were lower in participants with TD1 compared with controls. No difference was found in aBMD and appendicular muscle mass. T1DN+ had worse performance in the SPPB compared with T1DN- and control. In summary, neuropathy was associated with cortical porosity and worse performance in physical tests. Our findings suggest that bone structure does not fully explain the rate of fractures in T1D. We conclude that the increase in the risk of fractures in T1D is multifactorial with both skeletal and non-skeletal contributions. © 2021 The Authors. Journal of Bone and Mineral Research published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4271DOI Listing
April 2021

In Reply to "Risks of Hip and Nonvertebral Fractures in Patients With CKD".

Am J Kidney Dis 2021 04 10;77(4):546-547. Epub 2021 Feb 10.

Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.

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http://dx.doi.org/10.1053/j.ajkd.2020.11.010DOI Listing
April 2021

Randomised Controlled Trial of Nutritional Supplement on Bone Turnover Markers in Indian Premenopausal Women.

Nutrients 2021 Jan 26;13(2). Epub 2021 Jan 26.

Academic Unit of Bone Metabolism, University of Sheffield, Sheffield S10 2NR, UK.

Young Indian women may be at risk of poor bone health due to malnutrition. The aim of this study was to examine the effects on bone metabolism of a nutritional supplement in women aged 25 to 44. The nutritional supplement was a protein-rich beverage powder fortified with multi-micronutrients including calcium (600 mg), vitamin D (400 IU), and vitamin K (55 mcg) per daily serving, while a placebo supplement was low-protein non-fortified isocaloric beverage powder. This 6-month randomised, controlled trial showed favorable changes in bone turnover markers (decreased) and calcium homeostasis; such changes in older adults have been associated with slowing of bone loss and reduced fracture risk. For example, serum CTX decreased by about 30% and PINP by about 20% as a result of the increase in calcium intake. There were also changes in the ratio of carboxylated to undercarboxylated osteocalcin and such changes have been linked to a slowing of bone loss in older subjects. For example, the ratio increased by about 60% after 3 months as a result in the improvement in vitamin K status. Finally, there were improvements in the status of B vitamins, and such changes have been associated with reductions in homocysteine, but it is uncertain whether this would affect fracture risk. The product was generally well tolerated. This study shows the nutritional supplement holds promise for improved bone health among young Indian women.
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http://dx.doi.org/10.3390/nu13020364DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7912479PMC
January 2021

Efficacy of Zoledronic Acid in Maintaining Areal and Volumetric Bone Density After Combined Denosumab and Teriparatide Administration: DATA-HD Study Extension.

J Bone Miner Res 2021 Jan 28. Epub 2021 Jan 28.

Department of Medicine, Endocrine Unit, Massachusetts General Hospital, Harvard University, Boston, MA, USA.

Combined teriparatide and denosumab rapidly and substantially increases bone mineral density (BMD) at all anatomic sites. Discontinuation of denosumab however, results in high-turnover bone loss and increased fracture risk. The optimal way to prevent this bone loss remains undefined. This study is a preplanned extension of the DATA-HD study, where postmenopausal women with osteoporosis were randomized to receive 9 months of either 20 μg or 40 μg of teriparatide daily overlapping with denosumab (60 mg administered at months 3 and 9). At the completion of this 15-month study, women were invited to enroll in the DATA-HD Extension where they received a single dose of zoledronic acid (5 mg) 24 to 35 weeks after the last denosumab dose. Areal BMD and bone turnover markers were measured at month 27 and 42 (12 and 27 months after zoledronic acid, respectively) and spine and hip volumetric bone density by quantitative CT was measured at month 42. Fifty-three women enrolled in the DATA-HD Extension. At the femoral neck and total hip, the mean 5.6% and 5.1% gains in BMD achieved from month 0 to 15 were maintained both 12 and 27 months after zoledronic acid administration. At the spine, the mean 13.6% gain in BMD achieved from month 0 to 15 was maintained for the first 12 months but modestly decreased thereafter, resulting in a 3.0% reduction (95% CI, -4.0% to -2.0%, p < .0001) 27 months after zoledronic acid. The pattern of BMD changes between months 15 and 42 were qualitatively similar in the 20-μg and 40-μg groups. A single dose of zoledronic acid effectively maintains the large and rapid total hip and femoral neck BMD increases achieved with combination teriparatide/denosumab therapy for at least 27 months following the transition. Spine BMD was also largely, though not fully, maintained during this period. These data suggest that the DATA-HD Extension regimen may be an effective strategy in the long-term management of patients at high risk of fragility fracture. © 2021 American Society for Bone and Mineral Research (ASBMR).
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http://dx.doi.org/10.1002/jbmr.4259DOI Listing
January 2021

Off-treatment bone mineral density changes in postmenopausal women receiving anastrozole for 5 years: 7-year results from the IBIS-II prevention trial.

Br J Cancer 2021 Apr 22;124(8):1373-1378. Epub 2021 Jan 22.

Department of Oncology and Metabolism, University of Sheffield, Western Bank, Sheffield, S10 2TN, UK.

Background: Anastrozole has been associated with substantial accelerated bone mineral density (BMD) loss during active treatment.

Methods: One thousand four hundred and ten women were included in a BMD substudy and stratified into three strata according to their baseline T-score at spine or femoral neck. The primary objective of this analysis was to investigate whether DXA BMD at the spine and hip changed two years after treatment cessation (between years 5 and 7) in those who did not receive risedronate.

Results: Five- and seven-year BMD data were available for a total of 528 women who did not receive risedronate. In women with normal BMD at baseline, an increase in BMD at the lumbar spine after anastrozole withdrawal was observed 1.25% (95% CI 0.73 to 1.77) (P = 0.0004), which was larger than in those on placebo (0.14% (-0.29 to 0.56))). At the hip, BMD remained unchanged between years 5 and 7 for those previously on anastrozole but continued to a decrease in those who had been randomised to placebo (-1.35% (-1.70 to -0.98)).

Conclusions: These are the first results reporting BMD changes after stopping anastrozole in a breast cancer prevention setting. Our results show that the negative effects of anastrozole on BMD in the preventive setting are partially reversible.
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http://dx.doi.org/10.1038/s41416-020-01228-2DOI Listing
April 2021

Analytical considerations and plans to standardize or harmonize assays for the reference bone turnover markers PINP and β-CTX in blood.

Clin Chim Acta 2021 Apr 28;515:16-20. Epub 2020 Dec 28.

PathWest Laboratory Medicine, Fiona Stanley Hospital, Murdoch, WA, Australia. Electronic address:

Procollagen type I N-propeptide (PINP) and the C-terminal telopeptide of type I collagen (β-CTX) in blood have been designated as reference bone turnover markers in osteoporosis by the International Osteoporosis Foundation (IOF) and International Federation of Clinical Chemistry and Laboratory Medicine (IFCC). The IFCC Committee on Bone Metabolism (C-BM) has examined current commercial assays and performed a multicentre study to examine the agreement between assays for PINP and β-CTX in serum and plasma. The results of these studies will inform our work towards the harmonization of PINP assays and the standardization of β-CTX assays in blood, with the development of common calibrators and reference measurement procedures in collaboration with the reagent manufacturing industry. Successful achievement of these goals will help develop universally acceptable practice guidelines for the management of osteoporosis with the inclusion of common reference intervals and treatment targets for PINP and β-CTX.
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http://dx.doi.org/10.1016/j.cca.2020.12.023DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8033406PMC
April 2021

Clinical and biochemical characteristics of adults with hypophosphatasia attending a metabolic bone clinic.

Bone 2021 Mar 7;144:115795. Epub 2020 Dec 7.

Academic Unit of Bone Metabolism, University of Sheffield, Sheffield, UK; Mellanby Centre for Musculoskeletal Research, University of Sheffield, Sheffield, UK. Electronic address:

Objectives: This study sought to identify the clinical and biochemical characteristics that would help distinguish hypophosphatasia (HPP) from other metabolic bone diseases in adult patients attending a metabolic bone clinic by comparing patients who have genetically confirmed HPP with a group of patients with low bone mineral density (BMD) in the osteoporotic or osteopenic range.

Methods: Data were collected from February 2016 to October 2018 for 41 patients (n = 20 in the HPP group, n = 21 in the low-BMD group) attending the metabolic bone clinic at Sheffield, United Kingdom (UK) or who were recruited via the Rare UK Diseases Study (RUDY) platform during the same period. A study questionnaire was administered to all patients, and assessments were conducted for laboratory values, physical functions, BMD, and spine imaging.

Results: Patients with HPP were characterized as being younger, more likely to have metatarsal or femoral shaft fractures, and less likely to have vertebral fractures compared with patients in the low-BMD group. The HPP group had lower total and bone-specific alkaline phosphatase, higher pyridoxal 5'-phosphate (PLP), and lower, albeit sufficient, 25-hydroxyvitamin D. Low-BMD group had lower C-terminal telopeptide and tartrate-resistant acid phosphatase 5b (61.9% were on bisphosphonates at enrollment). Dual X-ray absorptiometry (DXA) analysis found that the HPP group had higher total hip and lumbar BMD T- and Z-scores compared with the low-BMD group. There were no differences found between the two groups with physical functional assessments. Results of receiver operating characteristic analysis indicated strong diagnostic accuracy of these biomarkers for HPP. Thresholds of total alkaline phosphatase (ALP) activity of 43 IU/L or less and PLP level of 120 nmol/L or more were determined to be potentially clinically useful for distinguishing HPP from other metabolic bone diseases.

Conclusion: This study supported the use of ALP and PLP measurements as predictive of HPP diagnosis along with certain demographic and clinical characteristics (younger age, metatarsal or femoral fractures without low mean BMD T- and Z-scores on a DXA scan) that can aid in recognizing adults who should be further evaluated for HPP. The critical values identified need to be applied to an independent sample to be tested for diagnostic accuracy.
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http://dx.doi.org/10.1016/j.bone.2020.115795DOI Listing
March 2021

Atypical Femur Fracture Risk versus Fragility Fracture Prevention with Bisphosphonates. Reply.

N Engl J Med 2020 11;383(22):2189-2190

Kaiser Permanente Southern California, Pasadena, CA.

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http://dx.doi.org/10.1056/NEJMc2029828DOI Listing
November 2020

Normocalcaemic hyperparathyroidism and primary hyperparathyroidism: least significant change for adjusted serum calcium.

Eur J Endocrinol 2021 Jan;184(1):K7-K10

Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.

Introduction: The least significant change (LSC) is a term used in individuals in order to evaluate whether one measurement has changed significantly from the previous one. It is widely used when assessing bone mineral density (BMD) scans. To the best of our knowledge, there no such estimate available in the literature for patients with disorders of calcium metabolism. Our aim was to provide an estimate of the least significant change for albumin-adjusted calcium in patients with normocalcaemic hyperparathyroidism (NPHPT) and primary hyperparathyroidism (PHPT).

Methods: We used the within-subject standard deviatio calculated in a population of NPHPT and PHPT patients and multiplied it by 2.77.

Results: The LSC for NPHPT and PHPT were found to be 0.25 and 0.24 mmol/L, respectively (1.00 and 0.96 mg/dL). In clinical practice, the value of 0.25 mmol/L could be used.

Discussion: The least significant change given, could be used in two ways in these patients. First, it gives a range to which values are expected. This can provide some reassurance for the patient and the physician in cases of intermittent hypercalcaemia. Moreover, it can be a marker of whether an individual has an actual significant change of his calcium after parathyroid surgery.
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http://dx.doi.org/10.1530/EJE-20-0634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7707804PMC
January 2021

Fracture risk and management of discontinuation of denosumab therapy: a systematic review and position statement by ECTS.

J Clin Endocrinol Metab 2020 10 26. Epub 2020 Oct 26.

Medical Department of Endocrinology, Aarhus University Hospital, Aarhus, Denmark.

Context: Denosumab discontinuation is characterized by an increase in bone turnover overriding pre-treatment status, a rapid bone loss in the majority and multiple vertebral fractures (VFx) in some patients.

Methods: A working group of the European Calcified Tissue Society (ECTS) performed an updated systematic review of existing literature on changes of bone turnover, bone mineral density (BMD), and fracture risk after denosumab discontinuation and provided advice on management based on expert opinion.

Results: Important risk factors for multiple VFx following denosumab cessation are prevalent VFx, longer duration off therapy, greater gain in hip BMD during therapy, and greater loss of hip BMD after therapy according to a retrospective analysis of the FREEDOM Extension Study. Case series indicate that prior bisphosphonate therapy mitigates the biochemical rebound phenomenon after denosumab discontinuation, but it is uncertain whether this attenuation prevents BMD loss and fractures. Current evidence indicates partial efficacy of subsequent antiresorptive treatment with results seemingly dependent on duration of denosumab treatment.

Conclusions: A careful assessment of indications to start denosumab treatment is advised, especially for younger patients. A case for long-term treatment with denosumab can be made for patients at high fracture risk already on denosumab treatment given the favorable efficacy and safety profile. In case of denosumab discontinuation, alternative antiresorptive treatment should be initiated 6 months after the final denosumab injection. Assessment of bone turnover markers may help define the optimal regimen, pending results of ongoing RCTs. Patients having sustained VFx should be offered prompt treatment to reduce high bone turnover.
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http://dx.doi.org/10.1210/clinem/dgaa756DOI Listing
October 2020

Vascular calcification relationship to vascular biomarkers and bone metabolism in advanced chronic kidney disease.

Bone 2021 Feb 20;143:115699. Epub 2020 Oct 20.

Sheffield Kidney Institute, Sheffield Teaching Hospitals NHS Foundation Trust, United Kingdom.

Background: Vascular calcification (VC) and renal osteodystrophy are important complications of advanced chronic kidney disease (CKD). High resolution peripheral quantitative computed tomography (HRpQCT) is able to assess bone microstructure in renal osteodystrophy and lower leg arterial calcification (LLAC) is usually seen as an incidental finding. LLAC can be a useful quantitative assessment of VC in CKD but the relationship between LLAC and vascular biomarkers and bone is unknown. We aimed to assess the relationship between LLAC and biomarkers, bone turnover and microstructure.

Methods: In this cross-sectional study, fasting blood samples were taken from 69 CKD stages 4-5D patients and 68 healthy controls. HRpQCT of distal tibia and radius were performed. 43 CKD patients had trans-iliac bone biopsy after tetracycline labelling.

Results: LLAC was more severe in CKD than controls (median [IQR] 1.043 [0.05-16.52] vs 0 [0-0.55] mgHA, p < 0.001). CKD patients with diabetes (28%) had significantly higher LLAC compared to non-diabetic CKD (median [IQR] 24.07 [3.42-61.30] vs 0.23 [0-3.78] mgHA, p < 0.001). LLAC mass in CKD correlated with serum phosphate (rho = 0.29, p < 0.05), calcium x phosphate product (rho = 0.31, p < 0.05), intact parathyroid hormone (rho = 0.38, p < 0.01), intact fibroblast growth factor-23 (iFGF23) (rho = 0.40, p = 0.001), total alkaline phosphatase (rho = 0.41, p < 0.001), bone alkaline phosphatase (rho = 0.29, p < 0.05), osteocalcin (rho = 0.32, p < 0.05), osteoprotegerin (rho = 0.40, p = 0.001) and dephosphorylated-uncarboxylated matrix Gla protein (rho = 0.31, p < 0.05). LLAC in CKD also correlated with worse distal tibia cortical bone mineral density, thickness and porosity. No association was found between LLAC and bone turnover, mineralization or volume on biopsy in CKD. In multivariate analysis, only age, diabetes, iPTH and iFGF23 were independently associated with LLAC in CKD.

Conclusions: High levels of PTH and FGF23, along with older age and the presence of diabetes may all play independent roles in the development of LLAC in advanced CKD.
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http://dx.doi.org/10.1016/j.bone.2020.115699DOI Listing
February 2021

The role of static bone histomorphometry in diagnosing renal osteodystrophy.

Bone 2021 Jan 14;142:115689. Epub 2020 Oct 14.

Department of Oncology and Metabolism, Mellanby Centre for Bone Research, University of Sheffield, United Kingdom.

Background: Bone biopsy is the gold standard test to diagnose renal osteodystrophy (ROD). There is a preference to perform bone biopsy during renal transplantation but tetracycline bone labelling is usually not possible. We aimed to test if histomorphometry static parameters can identify low and high bone turnover as assessed by dynamic measurement using double tetracycline labelling.

Methods: 43 CKD stages 4-5D had trans-iliac bone biopsy using a 4 mm Jamshidi trephine and needle after tetracycline labelling. Quantitative histomorphometry was performed using the Bioquant Osteo histomorphometry system. Normal bone turnover was defined as bone formation rate/bone surface (BFR/BS) of 18-38 μm/μm/year. Static parameters of bone turnover included osteoblast surface/bone surface (Ob.S/BS, %), osteoclast surface/bone surface (Oc.S/BS, %) and erosion surface/bone surface (ES/BS, %). Receiver operating characteristics (ROC) analysis was used to evaluate diagnostic accuracy of these static parameters for low and high bone turnover (based on BFR/BS).

Results: Median (IQR) for BFR/BS in this study was 32.12 (17.76-48.25) μm/μm/year. 26% of patients had low, 34% had normal and 40% had high bone turnover. The area under the ROC curve (AUC) for Ob.S/BS, Oc.S/BS and ES/BS were non-significant indicating poor accuracy for identifying low bone turnover. The AUC for Ob.S/BS was 0.697 (95% CI 0.538 to 0.827) indicating fair accuracy for identifying high bone turnover. Oc.S/BS and ES/BS had non-significant AUCs for high bone turnover.

Conclusions: Static histomorphometry parameters for bone turnover are unable to replace dynamic parameter in diagnosing ROD. Tetracycline bone labelling is still required.
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http://dx.doi.org/10.1016/j.bone.2020.115689DOI Listing
January 2021

Bone mineral density as a surrogate biomarker for fracture risk reduction - Authors' reply.

Lancet Diabetes Endocrinol 2020 11;8(11):876

Academic Unit of Bone Metabolism, University of Sheffield, Sheffield, UK.

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http://dx.doi.org/10.1016/S2213-8587(20)30340-5DOI Listing
November 2020

Treatment-Related Changes in Bone Turnover and Fracture Risk Reduction in Clinical Trials of Antiresorptive Drugs: Proportion of Treatment Effect Explained.

J Bone Miner Res 2021 Feb 2;36(2):236-243. Epub 2020 Oct 2.

Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.

Few analyses of antiresorptive (AR) treatment trials relate short-term changes in bone turnover markers (BTMs) to subsequent fracture reduction seeking to estimate the proportion of treatment effect explained (PTE) by BTMs. Pooling such information would be useful to assess new ARs or novel dosing regimens. In the Foundation for the National Institutes of Health (FNIH) Bone Quality project, we analyzed individual-level data from up to 62,000 participants enrolled in 12 bisphosphonate (BP) and four selective estrogen receptor modulator (SERM) placebo-controlled fracture endpoint trials. Using BTM results for two bone formation markers (bone-specific alkaline phosphatase [bone ALP] and pro-collagen I N-propeptide [PINP]) and one bone resorption marker (C-terminal telopeptide of type I collagen [CTX]) and incident fracture outcome data, we estimated the PTE using two different models. Separate analyses were performed for incident morphometric vertebral, nonvertebral, and hip fractures over 1 to 5 years of follow-up. For vertebral fracture, the results showed that changes in all three BTMs at 6 months explained a large proportion of the treatment effect of ARs (57 to >100%), but not for and non-vertebral or hip fracture. We conclude that short-term AR treatment-related changes in bone ALP, PINP, and CTX account for a large proportion of the treatment effect for vertebral fracture. Change in BTMs is a useful surrogate marker to study the anti-fracture efficacy of new AR compounds or novel dosing regiments with approved AR drugs. © 2020 The Authors. Journal of Bone and Mineral Research published by American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.4178DOI Listing
February 2021

Reference interval for albumin-adjusted calcium based on a large UK population.

Clin Endocrinol (Oxf) 2021 Jan 22;94(1):34-39. Epub 2020 Sep 22.

Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.

Context: Primary hyperparathyroidism is a common condition and results in hypercalcaemia, especially in older women. Thus, it is critical to obtain a robust estimate for the upper limit of the reference interval for albumin-adjusted serum calcium in the general population. The current reference interval in use in the UK (Pathology Harmony range, 2.20 to 2.60 mmol/L) was based on a consensus.

Objectives: To establish a reference interval for albumin-adjusted serum calcium in men and women.

Design: Cross-sectional study of men and women who did not have chronic kidney disease or vitamin D deficiency; outliers were identified statistically and then rejected and then a 99% reference interval was calculated.

Patients: 502 524 men and women aged 40 to 69 years from the UK Biobank Study.

Measurements: Serum total calcium, albumin, 25-hydroxyvitamin D, estimated glomerular function (eGFR).

Results: We developed an equation for albumin-adjusted serum calcium and applied it to 178 377 men and women who did not have chronic kidney disease or vitamin D deficiency. We identified 2962 (1.7%) as outliers, and when excluded, we report a 99% reference interval of 2.19 to 2.56 mmol/L (8.76 to 10.24 mg/dL). We found that for older (55-69 years) and younger women (40-55 years) the upper limits were 2.59 mmol/L and 2.57 mmol/L and that for all men, the upper limit was 2.55 mmol/L.

Conclusions: We have established an upper limit of the reference range for older women that would identify all high outliers (2.60 mmol/L and above). The upper limit for young women and for men is lower, at 2.57 and 2.55 mmol/L respectively. The current reference interval in use has to be updated and improved based on these findings. These upper limits may prove helpful for identifying hypercalcaemic disorders like primary hyperparathyroidism in clinical practice.
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http://dx.doi.org/10.1111/cen.14326DOI Listing
January 2021

Urinary calcium indices in primary hyperparathyroidism (PHPT) and familial hypocalciuric hypercalcaemia (FHH): which test performs best?

Postgrad Med J 2020 Sep 5. Epub 2020 Sep 5.

The University of Sheffield, Sheffield, UK.

Aim: Primary hyperparathyroidism (PHPT) is much more common than familial hypocalciuric hypercalcaemia (FHH), but there is considerable overlap in biochemical features. Urine calcium indices help with the differential diagnosis, but their reliability in making this distinction is not clear. The aim of this study was to compare urinary calcium values in patients with PHPT and FHH.

Methods: This was a case-control study of patients with PHPT who had successful surgery and genetically proven FHH between 2011 and 2016. Due to low FHH numbers, patients from neighbouring hospitals and outside study period (2017-2019) were allowed to improve power. Data on demographics and urinary calcium were obtained from electronic records and compared between the two groups.

Results: During the study period, 250 patients underwent successful PHPT surgery, while in the FHH arm, 19 genetically proven cases were included. The median (IQR) 24-hour urine calcium excretion (UCE) in the PHPT group was 8.3 (5.6-11.2) mmol/24 hours compared with 3.2 (2.1-6.1) mmol/24 hour in the FHH group (p<0.001). Median (IQR) calcium to creatinine clearance ratio (CCCR) in the PHPT and FHH groups was 0.020 (0.013-0.026) and 0.01 (0.002-0.02), respectively (p=0.001). The sensitivity of urinary tests for PHPT was 96% for UCE (cut-off ≥2.5 mmol/24 hour) and 47% for CCCR (cut-off >0.02). The specificity of the urinary tests for FHH was 29.4% for UCE (cut-off <2.5 mmol/24 hour) and 93% for CCCR (cut-off <0.02).

Conclusions: 24-hour UCE is more sensitive in diagnosing PHPT; however, it is less specific in ruling out FHH as compared with CCCR, when the cut-offs suggested by the International guidelines from the fourth international workshop are used. A significant proportion of patients with PHPT would have also required genetic studies if the guidelines were followed.
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http://dx.doi.org/10.1136/postgradmedj-2020-137718DOI Listing
September 2020

Atypical Femur Fracture Risk versus Fragility Fracture Prevention with Bisphosphonates.

N Engl J Med 2020 08;383(8):743-753

From the Departments of Epidemiology and Biostatistics (D.M.B., E.V.) and Orthopedic Surgery (E.J.G.), University of California, San Francisco, San Francisco, the Department of Research and Evaluation, Kaiser Permanente Southern California, Pasadena (D.M.B., B.H.L., D.S.R., A.L.A.), and the Department of Orthopedics, Kaiser Permanente Southern California, Downey (R.M.D.) - all in California; and the Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom (R.E.).

Background: Bisphosphonates are effective in reducing hip and osteoporotic fractures. However, concerns about atypical femur fractures have contributed to substantially decreased bisphosphonate use, and the incidence of hip fractures may be increasing. Important uncertainties remain regarding the association between atypical femur fractures and bisphosphonates and other risk factors.

Methods: We studied women 50 years of age or older who were receiving bisphosphonates and who were enrolled in the Kaiser Permanente Southern California health care system; women were followed from January 1, 2007, to November 30, 2017. The primary outcome was atypical femur fracture. Data on risk factors, including bisphosphonate use, were obtained from electronic health records. Fractures were radiographically adjudicated. Multivariable Cox models were used. The risk-benefit profile was modeled for 1 to 10 years of bisphosphonate use to compare associated atypical fractures with other fractures prevented.

Results: Among 196,129 women, 277 atypical femur fractures occurred. After multivariable adjustment, the risk of atypical fracture increased with longer duration of bisphosphonate use: the hazard ratio as compared with less than 3 months increased from 8.86 (95% confidence interval [CI], 2.79 to 28.20) for 3 years to less than 5 years to 43.51 (95% CI, 13.70 to 138.15) for 8 years or more. Other risk factors included race (hazard ratio for Asians vs. Whites, 4.84; 95% CI, 3.57 to 6.56), height, weight, and glucocorticoid use. Bisphosphonate discontinuation was associated with a rapid decrease in the risk of atypical fracture. Decreases in the risk of osteoporotic and hip fractures during 1 to 10 years of bisphosphonate use far outweighed the increased risk of atypical fracture among Whites but less so among Asians. After 3 years, 149 hip fractures were prevented and 2 bisphosphonate-associated atypical fractures occurred in Whites, as compared with 91 and 8, respectively, in Asians.

Conclusions: The risk of atypical femur fracture increased with longer duration of bisphosphonate use and rapidly decreased after bisphosphonate discontinuation. Asians had a higher risk than Whites. The absolute risk of atypical femur fracture remained very low as compared with reductions in the risk of hip and other fractures with bisphosphonate treatment. (Funded by Kaiser Permanente and others.).
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http://dx.doi.org/10.1056/NEJMoa1916525DOI Listing
August 2020

Establishing race-, gender- and age-specific reference intervals for pyridoxal 5'-phosphate in the NHANES population to better identify adult hypophosphatasia.

Bone 2020 12 11;141:115577. Epub 2020 Aug 11.

Department of Oncology and Metabolism, University of Sheffield, UK.

Introduction: Bisphosphonate treatment in adults with hypophosphatasia (HPP) may increase fracture risk. PLP is a useful marker in biochemically differentiating HPP from osteoporosis in adults. In order to identify elevated PLP, robust reference intervals are needed which are calculated in a large, representative sample population.

Methods: Complete data from 9069 individuals (ages 20-80, 50.6% female) from two years of the NHANES Survey (2007-2008 and 2009-2010) were investigated. Differences in PLP in the presence of four factors; inflammation (CRP ≥5.0 mg/L), low ALP (<36 IU/L), chronic kidney disease (eGFR <60 mL/min/1.73), and daily vitamin B6 supplementation, were investigated. Race, gender and age differences in PLP were then investigated; 95% reference intervals were calculated that reflected these differences.

Results: Inflammation and chronic kidney disease were associated with lower PLP (p < .0001 and p = .0005 respectively), while low ALP and vitamin B6 supplementation were associated with higher PLP (both p < .0001). Individuals were excluded based on the presence of these factors; a reference interval population (n = 4463) was established. There were significant differences in PLP depending on race and gender (p < .0001) Increasing age was correlated with decreasing PLP (spearman's rho -0.204, p < .0001). Race- and gender-specific 95% reference intervals were calculated. In male patients, these were also calculated according to age groups: young and older adults (ages 20-49 years and ≥50 years respectively).

Conclusions: In order to identify adult hypophosphatasia based on elevated PLP, considerations must be made depending on the race, gender and age of the individual. Factors associated with significant differences in PLP must also be considered when assessing biochemical measurements.
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http://dx.doi.org/10.1016/j.bone.2020.115577DOI Listing
December 2020

Bone Turnover Markers Do Not Predict Fracture Risk in Type 2 Diabetes.

J Bone Miner Res 2020 12 29;35(12):2363-2371. Epub 2020 Sep 29.

Department Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, CA, USA.

Type 2 diabetes (T2D) is characterized by increased fracture risk despite higher BMD and reduced bone turnover. BMD underestimates fracture risk in T2D, but the predictive role of bone turnover markers (BTMs) on fracture risk in T2D has not been explored. Thus, we sought to determine whether BTMs predict incident fractures in subjects with T2D. For this case-cohort study, we used data from the Health, Aging, and Body Composition (Health ABC) Study of well-functioning older adults, aged 70 to 79 years at baseline (April 1997-June 1998). The case-cohort sample consisted of (i) the cases, composed of all 223 participants who experienced incident fractures of the hip, clinical spine, or distal forearm within the first 9 years of study follow-up; and (ii) the subcohort of 508 randomly sampled participants from three strata at baseline (T2D, prediabetes, and normoglycemia) from the entire Health ABC cohort. A total of 690 subjects (223 cases, of whom 41 were in the subcohort) were included in analyses. BTMs (C-terminal telopeptide of type I collagen [CTX], osteocalcin [OC], and procollagen type 1 N-terminal propeptide [P1NP]) were measured in archived baseline serum. Cox regression with robust variance estimation was used to estimate the adjusted hazard ratio (HR) for fracture per 20% increase in BTMs. In nondiabetes (prediabetes plus normoglycemia), fracture risk was increased with higher CTX (HR 1.10; 95% confidence interval [CI], 1.01 to 1.20 for each 20% increase in CTX). Risk was not increased in T2D (HR 0.92; 95% CI, 0.81 to 1.04; p for interaction .045). Similarly, both OC and P1NP were associated with higher risk of fracture in nondiabetes, but not in T2D, with p for interaction of .078 and .109, respectively. In conclusion, BTMs did not predict incident fracture risk in T2D but were modestly associated with fracture risk in nondiabetes. © 2020 American Society for Bone and Mineral Research.
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http://dx.doi.org/10.1002/jbmr.4140DOI Listing
December 2020

Treatment-related changes in bone mineral density as a surrogate biomarker for fracture risk reduction: meta-regression analyses of individual patient data from multiple randomised controlled trials.

Lancet Diabetes Endocrinol 2020 08;8(8):672-682

Center for Advanced Orthopedic Studies, Department of Orthopedic Surgery, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, MA, USA.

Background: The validation of bone mineral density (BMD) as a surrogate outcome for fracture would allow the size of future randomised controlled osteoporosis registration trials to be reduced. We aimed to determine the association between treatment-related changes in BMD, assessed by dual-energy x-ray absorptiometry, and fracture outcomes, including the proportion of treatment effect explained by BMD changes.

Methods: We did a pooled analysis of individual patient data from multiple randomised placebo-controlled clinical trials. We included data from multicentre, randomised, placebo-controlled, double-blind trials of osteoporosis medications that included women and men at increased osteoporotic fracture risk. Using individual patient data for each trial we calculated mean 24-month BMD percent change together with fracture reductions and did a meta-regression of the association between treatment-related differences in BMD changes (percentage difference, active minus placebo) and fracture risk reduction. We also used individual patient data to determine the proportion of anti-fracture treatment effect explained by BMD changes and the BMD change needed in future trials to ensure fracture reduction efficacy.

Findings: Individual patient data from 91 779 participants of 23 randomised, placebo-controlled trials were included. The trials had 1-9 years of follow-up and included 12 trials of bisphosphonate, one of odanacatib, two of hormone therapy (one of conjugated equine oestrogen and one of conjugated equine oestrogen plus medroxyprogesterone acetate), three of PTH receptor agonists, one of denosumab, and four of selective oestrogen receptor modulator trials. The meta-regression revealed significant associations between treatment-related changes in hip, femoral neck, and spine BMD and reductions in vertebral (r 0·73, p<0·0001; 0·59, p=0·0005; 0·61, p=0·0003), hip (0·41, p=0·014; 0·41, p=0·0074; 0·34, p=0·023) and non-vertebral fractures (0·53, p=0·0021; 0·65, p<0·0001; 0·51, p=0·0019). Minimum 24-month percentage changes in total hip BMD providing almost certain fracture reductions in future trials ranged from 1·42% to 3·18%, depending on fracture site. Hip BMD changes explained substantial proportions (44-67%) of treatment-related fracture risk reduction.

Interpretation: Treatment-related BMD changes are strongly associated with fracture reductions across randomised trials of osteoporosis therapies with differing mechanisms of action. These analyses support BMD as a surrogate outcome for fracture outcomes in future randomised trials of new osteoporosis therapies and provide an important demonstration of the value of public access to individual patient data from multiple trials.

Funding: Foundation for National Institutes of Health.
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http://dx.doi.org/10.1016/S2213-8587(20)30159-5DOI Listing
August 2020

Dietary Selenium Intakes and Musculoskeletal Function in Very Old Adults: Analysis of the Newcastle 85+ Study.

Nutrients 2020 Jul 12;12(7). Epub 2020 Jul 12.

The MRC-Versus Arthritis Centre for Integrated Research into Musculoskeletal Ageing (CIMA), Newcastle upon Tyne NE2 4HH, UK.

: Selenium is a trace element essential for health. Severe selenium deficiencies are associated with poor musculoskeletal (MSK) function. However, the effects of moderate deficiency on MSK function, especially in older adults, is unclear. : To determine the associations between selenium intake and MSK function in very old adults. : Selenium intake at baseline and, hand-grip strength (HGS) and timed-up-and-go (TUG) at four phases over 5 years, were available in 791 participants in the Newcastle 85+ Study, a community-based, longitudinal cohort of ≥85 year old individuals. We investigated relationships between selenium intake and HGS and TUG in cross-sectional analyses at baseline using multivariate analyses and, prospectively using linear mixed models to explore HGS and TUG changes over 5 years in association with baseline selenium intake. : At baseline, 53% of participants had selenium intakes that were classified as low. These individuals had 2.80 kg lower HGS and were 2.30 s slower performing the TUG, cross-sectionally. In multivariate, baseline analyses, selenium intake had no significant impact on HGS or TUG. Selenium intake had no significant effect on MSK function, prospectively. : Low selenium intake is common among very old adults and, in cross-sectional analyses, is associated with poorer MSK function.
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http://dx.doi.org/10.3390/nu12072068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7400825PMC
July 2020

Risks of Hip and Nonvertebral Fractures in Patients With CKD G3a-G5D: A Systematic Review and Meta-analysis.

Am J Kidney Dis 2020 10 9;76(4):521-532. Epub 2020 Jul 9.

Department of Oncology and Metabolism, University of Sheffield, Sheffield, United Kingdom.

Rationale & Objective: Disordered mineral metabolism complicates chronic kidney disease (CKD), but the effect of reduced kidney function on fracture risk has not been fully established. We conducted a systematic review and meta-analysis of the risks for hip and nonvertebral fractures in people with CKD. We also investigated the effects of age, sex, and CKD stage.

Study Design: Systematic review and meta-analysis.

Study Population: Adults with CKD glomerular filtration rate (GFR) categories 3a-5D (G3a-G5D) compared with adults without CKD G3a-G5D.

Selection Criteria For Studies: Observational studies.

Data Extraction: Data extraction was conducted by 1 reviewer and checked by a second reviewer.

Analytical Approach: MEDLINE, EMBASE, and Cochrane databases were searched in March 2018 and an update was conducted in November 2019. We used random-effects models to calculate pooled risk estimates and 95% CIs.

Results: 17 studies met the inclusion criteria. We included 13 studies in the hip fracture systematic review and 10 studies in the meta-analysis. Studies reported data from 250,440,035 participants; 5,798,566 with CKD G3a-G5D and 363,410 with hip fractures. 4 studies were included in the nonvertebral fracture analysis, reporting data from 1,396,976 participants; 464,978 with CKD G3a-G5D and 115,284 fractures. Studies reported data from participants aged 18 to older than 90 years. We found a significant increase in fracture risk both for hip (relative risk [RR], 2.36; 95% CI, 1.64-3.39) and nonvertebral fractures (RR, 1.47; 95% CI, 1.15-1.88). For hip fractures, younger patients (<65 years) had higher relative risk (RR, 7.66; 95% CI, 2.76-21.26) than older patients (>65 years; RR, 2.11; 95% CI, 1.41-3.16). Greater GFR loss was associated with higher relative risk for fractures.

Limitations: We could not assess the effects of bone mineral density, biochemical abnormalities, renal osteodystrophy, frailty, falls, or medications on risk for fractures.

Conclusions: Risks for hip and nonvertebral fractures are increased in CKD G3a-G5D. The relative risk of hip fracture is greater in the younger than the older population and increases progressively with loss of GFR. We suggest that fracture prevention should be a consideration in CKD at any age.
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http://dx.doi.org/10.1053/j.ajkd.2020.02.450DOI Listing
October 2020

The risk of hip and non-vertebral fractures in type 1 and type 2 diabetes: A systematic review and meta-analysis update.

Bone 2020 08 29;137:115457. Epub 2020 May 29.

Academic Unit of Bone Metabolism, The Mellanby Centre for Bone Research, University of Sheffield, UK. Electronic address:

Background: Diabetes is associated with increased fracture risk but we do not know what affects this risk. We investigated the risk of hip and non-vertebral fractures in diabetes and whether this risk was affected by age, gender, body mass index, diabetes type and duration, insulin use and diabetic complications.

Methods: We selected a previously published review to be updated. MEDLINE, Embase and Cochrane databases were searched up to March 2020. We included observational studies with age and gender-adjusted risk of fractures in adults with diabetes compared to adults without diabetes. We extracted data from published reports that we summarised using random effects model.

Findings: From the 3140 records identified, 49 were included, 42 in the hip fracture analysis, reporting data from 17,571,738 participants with 319,652 fractures and 17 in the non-vertebral fracture review, reporting data from 2,978,487 participants with 181,228 fractures. We found an increase in the risk of fracture in diabetes both for hip (RR 4.93, 3.06-7.95, in type 1 diabetes and RR1.33, 1.19-1.49, in type 2 diabetes) and for non-vertebral fractures (RR 1.92, 0.92-3.99, in type 1 and RR 1.19, 1,11-1.28 in type 2). At the hip, the risk was higher in the younger population in both type 1 and type 2 diabetes. In those with type 2 diabetes, longer diabetes duration and insulin use was associated with an increased risk. We did not investigate the effect of bone density, falls, anti-diabetic drugs and hypoglycemia.

Conclusion: Diabetes is associated with an increase in both hip and non-vertebral fracture risk.
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http://dx.doi.org/10.1016/j.bone.2020.115457DOI Listing
August 2020

Response to Letter to the Editor: "Normocalcemic Hyperparathyroidism: Study of its Prevalence and Natural History".

J Clin Endocrinol Metab 2020 07;105(7)

Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.

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http://dx.doi.org/10.1210/clinem/dgaa278DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7271762PMC
July 2020

The prevalence and natural history of normocalcaemic hypoparathyroidism in a United Kingdom referral population.

Clin Endocrinol (Oxf) 2020 08 1;93(2):119-126. Epub 2020 Jun 1.

Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.

Context: Normocalcaemic hypoparathyroidism (NHYPO) is characterized by low levels of parathyroid hormone (PTH) with normal levels of calcium. There is little in the current literature on this disease, with only two studies published on its prevalence, while its natural history remains relatively unknown.

Objectives: To identify the prevalence of NHYPO in a UK referral population and to study the natural history of the disorder.

Design: Retrospective study. Five-year follow-up.

Patients: 6280 patients referred for a BMD measurement in a Metabolic Bone referral centre.

Measurements: Prevalence of NHYPO and variability of calcium.

Results: Based on laboratory results on the index day, 22 patients with NHYPO were identified. Four patients were excluded due to non-PTH-induced hypocalcaemia and unconfirmed data. The final prevalence was 0.29%. Only 67% had persistent normocalcaemia, and the rest had intermittent hypocalcaemia. Two of these patients also had persistently low PTH on two occasions. Most of the patients had one PTH measurement available. No patient developed permanent hypoparathyroidism.

Conclusions: The prevalence calculated from this UK referral population is lower when compared to results from previous studies. NHYPO patients often have episodes of hypocalcaemia with some cases having no apparent reason for calcium levels below the reference range.
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http://dx.doi.org/10.1111/cen.14209DOI Listing
August 2020

The challenge of long-term adherence: The role of bone turnover markers in monitoring bisphosphonate treatment of osteoporosis.

Bone 2020 07 28;136:115336. Epub 2020 Mar 28.

Academic Unit of Bone Metabolism, University of Sheffield, Sheffield, UK.

Oral Bisphosphonates (BPs) are the mainstay of osteoporotic treatment, however long-term adherence remains a challenge, primarily owing to the chronic character of the disease and the regimen complexity. Poor compliance has been shown to have a clear link to fracture risk. The role of bone turnover markers (BTMs) as a tool to ascertain adherence and response to therapy is supported by their rapid response to treatment; a decrease in values is witnessed within days or weeks of commencing treatment. A greater reduction of serum CTX and NTX is evidenced with alendronate and ibandronate compared to risedronate. A change in bone formation BTMs appears to be related to vertebral fracture risk reduction, whereas no significant relationship is evident for hip and non-vertebral fractures. The utility of BTMs as an adjunct for monitoring withdrawal of treatment with oral BP has also been suggested. Finally, studies evaluating BTMs as an intervention, failed to demonstrate any effect on adherence. This review explores the challenge of long-term adherence with bisphosphonates and provides an analytic framework with respect to the role of BTMs in monitoring bisphosphonate treatment, adherence and the offset of treatment effect.
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http://dx.doi.org/10.1016/j.bone.2020.115336DOI Listing
July 2020

Maternal pregnancy vitamin D supplementation increases offspring bone formation in response to mechanical loading: Findings from a MAVIDOS Trial sub-study.

J Musculoskelet Neuronal Interact 2020 03;20(1):4-11

Academic Unit of Child Health, Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.

The Maternal Vitamin D Osteoporosis (MAVIDOS) trial reported higher total body bone mineral content in winter-born infants of mothers receiving vitamin D supplementation [1000 IU/day cholecalciferol] compared with placebo from 14 weeks gestation until delivery. This sub-study aimed to determine whether antenatal vitamin D supplementation altered postnatal bone formation in response to mechanical stimulation. Thirty-one children born to MAVIDOS participants randomised to either placebo (n=19) or cholecalciferol (n=12) were recruited at age 4-5 years. Children received whole body vibration (WBV) for 10 minutes on 5 consecutive days. Fasting blood samples for bone homeostasis, 25 hydroxyvitamin D (25OHD), parathyroid hormone (PTH), and bone turnover markers (Pro-collagen Type 1 N-terminal propeptide, P1NP; Cross-linked C-telopeptide of Type I Collagen, CTX) were collected pre-WBV and on day 8 (D8). Mean changes (D) in P1NP (ng/ml) between baseline and D8 in the vitamin-D intervention and placebo groups were 40.6 and -92.6 respectively and mean changes (Δ) in CTX (ng/ml) were 0.034 (intervention) and -0.084 (placebo) respectively. Between-group DP1NP difference was 133.2ng/ml [95% CI 0.4, 266.0; p=0.049] and ΔCTX 0.05ng/ml (95% CI -0.159, 0.26ng/mL; p=0.62). Antenatal vitamin-D supplementation resulted in increased P1NP in response to WBV, suggesting early life vitamin D supplementation increases the anabolic response of bone to mechanical loading in children.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7104581PMC
March 2020

Normocalcemic Hyperparathyroidism: Study of its Prevalence and Natural History.

J Clin Endocrinol Metab 2020 04;105(4)

Department of Oncology and Metabolism, University of Sheffield, Sheffield, UK.

Context: Normocalcemic hyperparathyroidism (NPHPT) is characterized by persistently normal calcium levels and elevated parathyroid hormone (PTH) values, after excluding other causes of secondary hyperparathyroidism. The prevalence of the disease varies greatly and the data on the natural history of this disease are sparse and inconclusive.

Objectives: The objectives of this study are to describe the prevalence of NPHPT and its natural history in a referral population and to compare the variability of serum calcium with a group of patients with primary hyperparathyroidism (PHPT).

Design: A retrospective study was conducted over 5 years.

Setting: The setting for this study was a metabolic bone referral center.

Patients: A total of 6280 patients were referred for a bone mineral density measurement (BMD).

Main Outcome Measures: The prevalence and natural history of NPHPT and variability of calcium were the main outcome measures.

Results: We identified NPHPT patients using data from the day of the BMD measurement. We excluded patients with low estimated glomerular filtration rate (eGFR) or vitamin D, or with no measurements available. Based on the evaluation of their medical files, we identified 11 patients with NPHPT (prevalence 0.18%). Only 4 patients had consistent normocalcemia throughout their follow-up, with only 2 also having consistently high PTH. None had consistently normal eGFR or vitamin D.Intermittent hypercalcemia was present in 7 of the 11 NPHPT patients. The mean adjusted calcium was found to be significantly lower in the NPHPT group compared with the PHPT group but higher than the control group. PTH was similar for NPHPT and PHPT. These 2 groups had similar variability in serum calcium.

Conclusions: NPHPT patients often have episodes of hypercalcemia. We believe that NPHPT is a mild form of PHPT.
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http://dx.doi.org/10.1210/clinem/dgaa084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7069345PMC
April 2020

Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Guideline Update.

J Clin Endocrinol Metab 2020 03;105(3)

The University of Sheffield, Sheffield, United Kingdom.

Objective: The objective is to provide an update of the 2019 Pharmacological Management of Osteoporosis in Postmenopausal Women: An Endocrine Society Clinical Practice Guideline for the pharmacological management of osteoporosis in postmenopausal women using romosozumab.

Conclusions: We reviewed findings from the meta-analysis and primary clinical trials assessing the efficacy of romosozumab, a monoclonal antibody targeting sclerostin, for the prevention of fractures and concluded that this agent can be considered a treatment option for postmenopausal women at very high risk for osteoporotic fracture. The romosozumab label has a boxed warning, recommending careful consideration by the treating clinician as to cardiovascular risk profile in the individual woman who might receive this agent, since clinical trial data from an active comparator study show an imbalance in serious cardiovascular adverse events between romosozumab and alendronate.
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http://dx.doi.org/10.1210/clinem/dgaa048DOI Listing
March 2020