Early vertebroplasty within 3 weeks of fracture for acute painful vertebral osteoporotic fractures: subgroup analysis of the VAPOUR trial and review of the literature.

BACKGROUND: VAPOUR found vertebroplasty (V) more effective than placebo (P) in patients with severe pain and fracture duration less than 6 weeks. Exploratory analysis suggested that benefits were concentrated in the subgroup of patients with fractures ≤ 3-week duration. This difference may account for the three negative blinded trials that included few patients within this fracture time frame. PURPOSE: To assess the safety and efficacy of early vertebroplasty for acute painful vertebral osteoporotic fractures within 3 weeks of fracture onset in the VAPOUR study. METHODS: Spearman's rank log coefficients were calculated to reassess the relationship of pain reduction from vertebroplasty and fracture duration in the VAPOUR trial. We more fully report baseline and outcome data in patients with fractures ≤ 3-week duration. RESULTS: There were 46V and 47P patients with fractures ≤ 3-week duration. Baseline characteristics were similar. In total, 86 patients (41V, 45P) completed the 14-day questionnaire. The proportion of patients with reduction in pain from severe (NRS ≥ 7/10 was an inclusion requirement) to mild (NRS < 4) at 14 days was 21 (51%) V-group and 9 (20%) in the P-group (between-group difference 31 percentage points, 95% CI 12-50; p = 0.002). Early vertebroplasty provided greater reductions in mean NRS pain and Roland-Morris Disability. CONCLUSION: Analysis of this patient subgroup from the VAPOUR trial, in the context of other randomised trial evidence, suggests clinically significant benefits from early vertebroplasty if performed within 3 weeks of fracture. These slides can be retrieved from Electronic Supplementary Material.

Safety and efficacy of vertebroplasty for acute painful osteoporotic fractures (VAPOUR): a multicentre, randomised, double-blind, placebo-controlled trial.

BACKGROUND: We hypothesised that vertebroplasty provides effective analgesia for patients with poorly controlled pain and osteoporotic spinal fractures of less than 6 weeks' duration. The effectiveness of vertebroplasty, using an adequate vertebral fill technique, in fractures of less than 6 weeks' duration has not been specifically assessed by previously published masked trials. METHODS: This was a multicentre, randomised, double-blind, placebo-controlled trial of vertebroplasty in four hospitals in Sydney, Australia. We recruited patients with one or two osteoporotic vertebral fractures of less than 6 weeks' duration and Numeric Rated Scale (NRS) back pain greater than or equal to 7 out of 10. We used an automated telephone randomisation service provided by the National Health and Medical Research Council to assign patients (1:1; stratified according to age, degree of vertebral compression, trauma, corticosteroid use, and hospital) to either vertebroplasty or placebo, immediately before the procedure. Patients received conscious sedation. Vertebroplasty was done with the adequate vertebral fill technique and the placebo procedure with simulated vertebroplasty. Follow-up was for 6 months. Outcome assessors and patients were masked to treatment allocation. The primary outcome was the proportion of patients with NRS pain below 4 out of 10 at 14 days post-intervention in the intention-to-treat population. This study is registered with ClinicalTrials.gov, number NCT01482793. FINDINGS: Between Nov 4, 2011, and Dec 5, 2014, 120 patients were enrolled. 61 patients were randomly assigned to vertebroplasty and 59 to placebo. 24 (44%) patients in the vertebroplasty group and 12 (21%) in the control group had an NRS pain score below 4 out of 10 at 14 days (between-group difference 23 percentage points, 95% CI 6-39; p=0·011). Three patients in each group died from causes judged unrelated to the procedure. There were two serious adverse events in each group, related to the procedure (vertebroplasty group) and the fracture (control group). INTERPRETATION: Vertebroplasty is superior to placebo intervention for pain reduction in patients with acute osteoporotic spinal fractures of less than 6 weeks' in duration. These findings will allow patients with acute painful fractures to have an additional means of pain management that is known to be effective. FUNDING: Education grant from CareFusion Corporation.

Is there a practical role for bone biopsy in chronic kidney disease?

Bone biopsy is currently the only means to accurately assess renal osteodystrophy and responses to therapeutic interventions. With sedation, the technique is relatively painless, and complications are uncommon. Bone biopsy should be considered when the aetiology of symptoms or biochemical abnormalities is in question, and results may lead to changes in therapy. Although it remains prudent to use antiresorptive drugs cautiously in patients with chronic kidney disease (CKD) stages 3a-4 and low bone mineral density, bone biopsy may not be warranted before commencing therapy in these patients. Histomorphometric indices adopted for bone biopsy assessment are turnover (T), mineralisation (M) and volume (V). Often, only measurements of trabecular bone are reported; however, marked cortical changes are common in CKD and may be critical to bone structure and integrity. MicroCT of bone biopsies can rapidly assess static parameters and provides information on the cortical and trabecular compartments that may influence management. Limitations of bone biopsy include the time required for pre-biopsy tetracycline labelling and sample processing, and a paucity of facilities to process and report samples. Patients with CKD may not respond predictably to treatments, and because the biopsy sample is illustrative of activity at only one skeletal site and one point in time, assessment of real-time laboratory trends is always required. Optimally, we need a non-invasive 'virtual bone biopsy' that provides information for initiating and monitoring therapy. However, bone biopsy is the current standard by which the accuracy of investigational imaging techniques, hormonal values and biochemical turnover markers are judged.

Endoscopic transsphenoidal pituitary surgery: a single surgeon experience and the learning curve.

Endoscopic transsphenoidal surgery for pituitary adenomas has been introduced as an alternative to transsphenoidal microsurgery. This is the first Australian study to evaluate a single surgeon's experience by comparing our results with other series and attempting to identify a learning curve. Retrospective analysis was carried out on 79 consecutively treated patients by fully endoscopic transsphenoidal surgery by a single neurosurgeon over a period spanning from July 1998 to September 2010 at St George Public and Private hospitals. The mean age at time of surgery was 56.7 years (SD ± 16.3, range 26-85) and the mean follow-up period was 38.2 months (SD ± 33, range 1-136). Gross total resection (GTR) was noted in 63% of patients, endocrinological cure was achieved in 53% and visual field improvements were noted in 86% of patients. Intra-operative CSF leaks occurred in 19% of procedures, while the rates of post-operative CSF rhinorrhea was 3% and post-operative diabetes insipidus was 13%. There was one post-operative death (1%). Compared to microsurgery, intra-operative CSF leaks and meningitis seem less frequent with an endoscopic approach. With increasing experience, we found a non-statistically significant trend towards higher rates of GTR, and improved visual fields. Endocrinological cure rates were clearly better with experience (p < 0.01). There may be a learning curve that can be overcome in 30-40 cases. Endoscopic transsphenoidal surgery provides similar tumour and patient outcomes when compared to transsphenoidal microsurgery. In this single surgeon's experience, there was a trend to indicate improved performance with more case experience.

Early Vertebroplasty for Severely Painful Acute Osteoporotic Compression Fractures: A Critical Review of the Literature.

Vertebroplasty has emerged over the last 30 years as a common treatment for painful osteoporotic vertebral fractures. Patient selection and the time at which vertebroplasty is offered to the patient varies between centres and regions. Vertebroplasty has been studied in comparison to placebo intervention in five blinded trials. One such trial showed more benefit from vertebroplasty than placebo when the procedure was mostly performed within 3 weeks of fracture onset. Others showed no additional benefit from vertebroplasty compared to placebo when it was performed later in the natural history of the fracture. In this review, we examine data from blinded and open label randomised studies of vertebroplasty for evidence relating specifically to the use of early vertebroplasty for patients with severely painful acute osteoporotic fractures.

Two Cases of External Auditory Canal Osteonecrosis in Patients on Antiresorptive Therapy for Osteoporosis.

Bisphosphonates and denosumab have demonstrated overwhelmingly favorable skeletal benefit/risk profile in managing postmenopausal osteoporosis. External auditory canal osteonecrosis is a rare skeletal complication of antiresorptives previously described in 11 patients with bisphosphonate exposure and 1 bisphosphonate-naïve patient on denosumab. We present 2 patients who developed external auditory canal osteonecrosis while taking antiresorptives for postmenopausal osteoporosis; a 79-year-old asymptomatic bisphosphonate-naïve woman with 2-year exposure to denosumab, and a 64-year-old woman with otalgia after 5 years of risedronate and 5 years of denosumab treatment. Neither patient had previous exposure to glucocorticoids or local radiotherapy. Otoscopy performed by an ear/nose/throat (ENT) surgeon revealed exposed areas of bone in external auditory canal in both patients. Computed tomography of temporal bones found no evidence of bone erosion. Bone turnover markers were suppressed. Both patients ceased denosumab and were managed conservatively, with stable external auditory canal findings after 12 months. Although external auditory canal osteonecrosis is a rare skeletal complication of antiresorptive use, development of localizing symptoms in the ear should alert physicians to this rare clinical entity and prompt ENT surgical referral for early diagnosis and initiation of management.

Increased Bone Formation and Accelerated Bone Mass Accrual in a Man Presenting with Diffuse Osteosclerosis/High Bone Mass Phenotype and Adenocarcinoma of Unknown Primary.

A 71-year-old man was referred for evaluation of incidental generalized osteosclerosis. He was found to have a high bone mass (HBM) with an elevated lumbar spine bone mineral density (BMD) Z-score of +5.3. Over an 18-month period, his lumbar spine BMD measured by dual energy X-ray absorptiometry (DXA) had increased by +64% from 1.09 to 1.79 g/cm2 and femoral neck by +21% from 0.83 to 1.01 g/cm2. Biochemical markers of bone turnover were markedly increased (serum propeptide of type 1 collagen and urine telopeptides greater than 10-times normal). The high bone formation and increased skeletal calcium acquisition resulted in profound hypocalcemia (low serum calcium 1.88 mmol/L) and hypocalciuria (low urinary calcium <0.2 mmol/day). Positron emission tomography (PET) with 2-deoxy-2-[fluorine-18] fluoro-D-glucose (FDG) confirmed diffuse osteosclerosis without focal areas of abnormal FDG uptake in the skeleton or elsewhere to suggest either an underlying primary malignancy or metastatic disease. Bone biopsy showed markedly sclerotic woven and lamellar bone. The marrow space was devoid of typical bone cells and adipocytes and instead was filled by fibromyxoid stroma, infiltrated by small clusters of tumor cells. Bone histomorphometry and micro-computed tomography demonstrated an elevated trabecular bone volume and trabecular plate thickness. The bone disorder in this case is unique and raises the possibility of a new yet undefined novel anabolic paracrine factor (or factors) secreted by an adenocarcinoma of unknown primary that resulted in dramatic increases in BMD, HBM, and radiological osteosclerosis. The differential diagnosis and potential mechanisms responsible for the HBM are discussed. © 2023 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, and curcumin: a randomized, double-blind placebo-controlled cross-over 4g study and an open-label 8g extension study.

Monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) represent useful models for studying multiple myeloma precursor disease, and for developing early intervention strategies. Administering a 4g dose of curcumin, we performed a randomised, double-blind placebo-controlled cross-over study, followed by an open-label extension study using an 8g dose to assess the effect of curcumin on FLC response and bone turnover in patients with MGUS and SMM. 36 patients (19 MGUS and 17 SMM) were randomised into two groups: one received 4g curcumin and the other 4g placebo, crossing over at 3 months. At completion of the 4g arm, all patients were given the option of entering an open-label, 8g dose extension study. Blood and urine samples were collected at specified intervals for specific marker analyses. Group values are expressed as mean ± 1 SD. Data from different time intervals within groups were compared using Student's paired t-test. 25 patients completed the 4g cross-over study and 18 the 8g extension study. Curcumin therapy decreased the free light-chain ratio (rFLC), reduced the difference between clonal and nonclonal light-chain (dFLC) and involved free light-chain (iFLC). uDPYD, a marker of bone resorption, decreased in the curcumin arm and increased on the placebo arm. Serum creatinine levels tended to diminish on curcumin therapy. These findings suggest that curcumin might have the potential to slow the disease process in patients with MGUS and SMM.

Ramadan Fasting and Maternal and Fetal Outcomes in Pregnant Women with Diabetes Mellitus: Literature Review.

There is an emerging Muslim and diabetic population in the United States and other Western countries and majority of pregnant women and patients with diabetes mellitus choose to fast during Ramadan. Fasting during Ramadan in pregnant women with diabetes may represent a 'perfect storm' of metabolic disturbances including hyperglycemia, hypoglycemia and ketosis. Recent continuous and flash glucose monitoring data suggests increased glycemic variability (fasting hypo- and post-Iftar hyperglycemia) in non-pregnant patients with diabetes during Ramadan. Only five small-scale studies, predominantly focused on women with gestational diabetes mellitus in Muslim-majority nations have explored maternal glycemic outcomes during Ramadan which is associated with lower mean blood glucose levels and higher frequency of fasting hypoglycemia. Data is limited however on important clinical outcomes such as symptomatic and serious hypoglycemia requiring hospitalization. Results have been conflicting regarding maternal Ramadan fasting and association with fetal outcomes in women without diabetes. Only one recently published study reported on perinatal outcomes in pregnant women with gestational diabetes which found no effect of Ramadan exposure on mean birthweight or macrosomia frequency but lower neonatal hypoglycemia prevalence, however a significant limitation was lack of documentation of maternal fasting status. At this stage, due to paucity of data, the current medical recommendation is against Ramadan fasting for pregnant Muslim women with diabetes. Large-scale population-based studies are warranted regarding maternal and fetal outcomes in pregnant fasting women with diabetes and such studies should characterize maternal fasting status and have meaningful and consistent clinical outcomes. High-quality data derived from these studies can assist clinicians in providing more evidence-based advice to safely navigate both mother and fetus through a potentially challenging pregnancy.

A patient with an ectopic sphenoid bone TSH secretory adenoma: Case report and review of the literature.

Ectopic thyroid-stimulating hormone (TSH)oma located outside the sella turcica is exceedingly rare and can be associated with significant diagnostic delay. The clinical presentation depends on the anatomical location and size of the ectopic tumor and the degree of thyrotoxicosis. A 71-year-old woman presented with goiter and thyrotoxicosis. Initial investigations revealed elevated free thyroxine (fT4) and tri-iodothyronine (fT3) with inappropriately high-normal TSH. Assay interference was unlikely, pituitary magnetic resonance imaging (MRI) scan was reported as "normal," and germline sequencing was negative for thyroid hormone receptor ß pathogenic variants. One year later, total thyroidectomy for enlarging symptomatic goiter and suspicious nodule revealed multifocal microscopic papillary thyroid carcinoma. Six years later, she presented to an ear, nose, and throat surgeon with nasal congestion, and a sphenoid bone mass was discovered on nasoendoscopy and imaging. Ectopic TSHoma was confirmed on surgical resection, and a review of the initial pituitary MRI scan revealed the mass which had initially been missed. This is the first reported case of an ectopic TSHoma located in the sphenoid bone. Ectopic TSHoma should be considered in patients with inappropriate TSH secretion when more common differentials are excluded including thyroid hormone resistance or pituitary TSHoma.

Atypical femoral fracture in a bisphosphonate-naïve patient on denosumab for osteoporosis.

A post-menopausal Caucasian woman sustained an atypical femoral fracture (AFF) after 5-years continuous denosumab for osteoporosis without prior bisphosphonate exposure. This is only the fifth case reported of AFF in a bisphosphonate-naïve patient receiving denosumab for osteoporosis. Although rare, physicians should consider AFF in patients taking denosumab even without prior bisphosphonate exposure. INTRODUCTION: Denosumab has demonstrated overwhelmingly favourable skeletal benefit/risk profile in managing post-menopausal osteoporosis with up to 10-year exposure in the extension of the pivotal FREEDOM randomised placebo-controlled trial. Four previous cases of atypical femoral fracture have been reported in bisphosphonate-naïve patients receiving denosumab for osteoporosis. METHODS: We present an 85-year-old Caucasian post-menopausal woman without prior fragility fracture who sustained unilateral atypical femoral fracture after 5-years continuous subcutaneous denosumab for osteoporosis. She had no prior bisphosphonate or glucocorticoid exposure and had known chronic kidney disease. RESULTS: X-ray scan demonstrated complete, non-comminuted left proximal femoral shaft fracture meeting radiographic criteria for an atypical femoral fracture. Computed tomography (CT) scan lower limbs revealed unusual side-by-side appearance of proximal and distal fragments of left proximal femur. DXA BMD was artefactually elevated at lumbar spine (1.504 g/cm2, T-score + 2.5) and low-normal at right femoral neck (0.856 g/cm2, T-score -1.0). Serum biochemistry showed renal impairment at baseline (eGFR 30 mL/min/1.73m2). Low-normal serum C telopeptide of type 1 collagen (CTX) (230 ng/L) indicated therapeutic suppression of bone resorption. CONCLUSION: The patient underwent intramedullary nailing of the femur and denosumab was ceased. This is only the fifth case reported of atypical femoral fracture in a bisphosphonate-naïve patient receiving denosumab for osteoporosis. Although rare, physicians should maintain a high index of suspicion for atypical femoral fracture in a patient taking denosumab even without prior bisphosphonate exposure.

Cochrane vertebroplasty review misrepresented evidence for vertebroplasty with early intervention in severely affected patients.

The Cochrane vertebroplasty review of April 2018 was replaced with an updated version in November 2018 to address complaints of errors in analysis. The updated version continues to misrepresent the evidence supporting early intervention with vertebroplasty for patients with uncontrolled, severe pain and fracture duration <6 weeks. The VAPOUR trial is the only blinded trial of vertebroplasty restricted to this patient group. It showed the benefit of vertebroplasty over placebo, particularly when the intervention occurred within 3 weeks of fracture. The Cochrane vertebroplasty review has ignored the positive outcomes in the VAPOUR trial. Open randomised trials of fractures <6-week duration support the positive findings of the VAPOUR trial. This is not described in the Cochrane review. The VAPOUR trial is clinically heterogeneous from other blinded trials. Cochrane protocol stipulates that clinically heterogeneous trials be described separately, as independent evidence, and not combined in analysis with dissimilar trials. Failure to observe this represents a serious protocol breach in the Cochrane review.

Use of Curcumin in Multiple Myeloma patients intolerant of steroid therapy.

Curcumin, when used in a combination regimen in multiple myeloma patients, has comparable progression-free survival without the adverse effects of steroid-based combination therapies that is curcumin may be a viable alternative to corticosteroids in combination with an immunomodulatory drug or proteasome inhibitor.

Vitamin D, PTH and calcium levels in pregnant women and their neonates.

OBJECTIVES: To determine the prevalence of vitamin D deficiency in pregnant women and their neonates and to examine factors associated with vitamin D deficiency. DESIGN AND PATIENTS: Population-based study of pregnant women and their neonates from South-eastern Sydney, Australia. MEASUREMENTS: Serum 25 hydroxy-vitamin D (25-OHD), PTH, calcium, albumin, phosphate and alkaline phosphatase were measured in women at 23-32 weeks gestation and on cord blood at delivery. Maternal skin phototype was recorded using the Fitzpatrick scale. RESULTS: Vitamin D deficiency (defined as 25-OHD

Estimation of thigh muscle cross-sectional area by dual-energy X-ray absorptiometry in frail elderly patients.

BACKGROUND: Thigh muscle mass and cross-sectional area (CSA) are useful indexes of sarcopenia and the response to treatment in older patients. Current criterion methods are computed tomography (CT) and magnetic resonance imaging. OBJECTIVE: The objective was to compare thigh muscle mass estimated by dual-energy X-ray absorptiometry (DXA), a less expensive and more accessible method, with thigh muscle CSA determined by CT in a group of elderly patients recovering from hip fracture. DESIGN: Midthigh muscle CSA (in cm(2)) was assessed from a 1-mm CT slice and midthigh muscle mass (g) from a 1.3-cm DXA slice in 30 patients (24 women) aged 81 +/- 8 y during 12 mo of follow-up. Fat-to-lean soft tissue ratios were calculated with each technique to permit direct comparison of a variable in the same units. RESULTS: Baseline midthigh muscle CSA was highly correlated with midthigh muscle mass (r = 0.86, P < 0.001) such that DXA predicted CT-determined CSA with an SEE of 10 cm(2) (an error of approximately 12% of the mean CSA value). CT- and DXA-determined ratios of midthigh fat to lean mass were similarly related (intraclass correlation coefficient = 0.87, P < 0.001). When data were expressed as the changes from baseline to follow-up, CT and DXA changes were weakly correlated (intraclass correlation coefficient = 0.51, P = 0.019). CONCLUSIONS: Assessment of sarcopenia by DXA midthigh slice is a potential low-radiation, accessible alternative to CT scanning of older patients. The errors inherent in this technique indicate, however, that it should be applied to groups of patients rather than to individuals or to evaluate the response to interventions.

Histomorphometric analysis of fracture healing cascade in acute osteoporotic vertebral body fractures.

BACKGROUND: While fracture healing has been well characterised in long bones, there is scant data relating to this process in acute vertebral body fractures. AIM: To characterise the histological process of fracture healing in acute osteoporotic vertebral body fractures using qualitative and quantitative bone histomorphometry. SUBJECTS AND METHODS: Transpedicular bone biopsy was performed in patients undergoing percutaneous vertebroplasty. Undecalcified biopsy specimens were prepared from cores of cancellous bone harvested from vertebral bodies with MRI evidence of bone marrow oedema. These were analysed by light microscopy using grid analysis and defined using bone histomorphometry criteria. Normative data obtained from 5 age-matched volunteers without evidence of metabolic bone disease or osteoporosis was used for comparison. RESULTS: Adequate biopsy specimens were obtained in 72 of 90 patients (15 men and 57 women), mean age 75.6 years. All biopsies confirmed severe osteoporosis with reduced cancellous bone volume (mean of 13.5%; P<0.001 compared to controls). The timing of biopsies varied from 1 to 24 weeks (median of 6 weeks) after the fracture event. There were 4 stages of fracture callus healing observed: Stage I in 17 (24%) patients, Stage II in 16 (22%), Stage III in 22 (30%) and Stage IV in 17 (24%). An overlap between the various stages was evident with 55 (76%) patients demonstrating at least 2 or more of the stages of fracture healing in the same biopsy specimen. The time interval since fracture event was the most important predictor of the stage of the fracture callus (R=0.32; P<0.001). CONCLUSION: Our data demonstrates a mixed fracture callus with overlapping of the various stages of fracture healing. This suggests that individual vertebra may be susceptible to multiple fractures over the course of the healing process.