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.

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.

Effect of the Ginger Derivative, 6-Shogaol, on Ferritin Levels in Patients With Low to Intermediate-1-Risk Myelodysplastic Syndrome-A Small, Investigative Study.

BACKGROUND: Myelodysplastic syndrome (MDS) is a heterogeneous group of clonal stem cell disorders characterized by dysplastic and ineffective hematopoiesis and peripheral cytopenias. Elevated serum ferritin (SF) is often observed in nontransfused, lower risk MDS. It has been reported that ineffective erythropoiesis enhances iron absorption in MDS through downregulation of hepcidin and its prohormones such that SF rises. AIM: To determine the effect of 6-shogaol, a dehydration derivative of ginger, known to have hepatoprotective and chemotherapeutic activity, on 6 early-stage, transfusion-independent patients with MDS, 3 of whom had raised levels of SF. METHOD: Six patients with MDS with low or intermediate-1 subtypes, as defined by the International Prognostic Scoring System (IPSS), were recruited into the study and were administered 1 gel capsule daily containing 20 mg ginger extract standardized for 20% 6-shogaol. Blood and urine samples were collected and various markers monitored at regular intervals. RESULTS: 6-shogaol caused a decrease in SF levels in 3 of 6 patients with early MDS (50%) whose SF levels were elevated at the start of the study. Our findings suggest upregulation of hepcidin and its prohormones, possibly through an improvement in liver function. DISCUSSION: In light of the encouraging results in this small, investigative study, we are planning a larger study to confirm the beneficial effect of 6-shogaol in patients with raised ferritin levels due to ineffective erythropoiesis.

B-Cell Disorders and Curcumin.

Clinical studies with patients with early hematological malignancies (ie, monoclonal gammopathy of undetermined significance, smoldering multiple myeloma, or stage 0/1 chronic lymphocytic leukemia) suggest that early intervention with curcumin, derived from the spice turmeric, may lead to prolonged survival and delay in progressive disease in some of these patients.

Addition of Rice Bran Arabinoxylan to Curcumin Therapy May Be of Benefit to Patients With Early-Stage B-Cell Lymphoid Malignancies (Monoclonal Gammopathy of Undetermined Significance, Smoldering Multiple Myeloma, or Stage 0/1 Chronic Lymphocytic Leukemia): A Preliminary Clinical Study.

Hypothesis Prior studies on patients with early B-cell lymphoid malignancies suggest that early intervention with curcumin may lead to delay in progressive disease and prolonged survival. These patients are characterized by increased susceptibility to infections. Rice bran arabinoxylan (Ribraxx) has been shown to have immunostimulatory, anti-inflammatory, and proapoptotic effects. We postulated that addition of Ribraxx to curcumin therapy may be of benefit. Study design Monoclonal gammopathy of undetermined significance (MGUS)/smoldering multiple myeloma (SMM) or stage 0/1 chronic lymphocytic leukemia (CLL) patients who had been on oral curcumin therapy for a period of 6 months or more were administered both curcumin (as Curcuforte) and Ribraxx. Methods Ten MGUS/SMM patients and 10 patients with stage 0/1 CLL were administered 6 g of curcumin and 2 g Ribraxx daily. Blood samples were collected at baseline and at 2-month intervals for a period of 6 months, and various markers were monitored. MGUS/SMM patients included full blood count (FBC); paraprotein; free light chains/ratio; C-reactive protein (CRP)and erythrocyte sedimentation rate (ESR); B2 microglobulin and immunological markers. Markers monitored for stage 0/1 CLL were FBC, CRP and ESR, and immunological markers. Results Of 10 MGUS/SMM patients,5 (50%) were neutropenic at baseline, and the Curcuforte/Ribraxx combination therapy showed an increased neutrophil count, varying between 10% and 90% among 8 of the 10 (80%) MGUS/SMM patients. An additional benefit of the combination therapy was the potent effect in reducing the raised ESR in 4 (44%) of the MGUS/SMM patients. Conclusion Addition of Ribraxx to curcumin therapy may be of benefit to patients with early-stage B-cell lymphoid malignancies.

Stabilisation of Laryngeal AL Amyloidosis with Long Term Curcumin Therapy.

Multiple myeloma (MM), smoldering myeloma (SMM), and monoclonal gammopathy of undetermined significance (MGUS) represent a spectrum of plasma cell dyscrasias (PCDs). Immunoglobulin light chain amyloidosis (AL) falls within the spectrum of these diseases and has a mortality rate of more than 80% within 2 years of diagnosis. Curcumin, derived from turmeric, has been shown to have a clinical benefit in some patients with PCDs. In addition to a clinical benefit in these patients, curcumin has been found to have a strong affinity for fibrillar amyloid proteins. We thus administered curcumin to a patient with laryngeal amyloidosis and smoldering myeloma and found that the patient has shown a lack of progression of his disease for a period of five years. This is in keeping with our previous findings of clinical benefits of curcumin in patients with plasma cell dyscrasias. We recommend further evaluation of curcumin in patients with primary AL amyloidosis.

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.

Vertebroplasty for painful acute osteoporotic vertebral fractures: recent Medical Journal of Australia editorial is not relevant to the patient group that we treat with vertebroplasty.

We use vertebroplasty for patients with the most severe pain caused by osteoporotic vertebral fractures less than 6 weeks old, and have observed dramatic pain relief in this acute setting. A recent editorial in the Journal, written by the authors of two recent vertebroplasty trials, suggested that vertebroplasty is not an effective therapy for acute osteoporotic vertebral fractures. The trials described in the editorial sampled a very different patient cohort to the one that we treat with vertebroplasty. Our clinical experience and most of the published literature relating to the benefits of vertebroplasty are in striking contrast to the opinions presented in that editorial.

The potential role of curcumin in patients with monoclonal gammopathy of undefined significance--its effect on paraproteinemia and the urinary N-telopeptide of type I collagen bone turnover marker.

PURPOSE: To determine the effect of curcumin on plasma cells and osteoclasts in patients with MGUS. EXPERIMENTAL DESIGN: Twenty-six patients with MGUS were recruited into the study and administered 4 grams/day oral curcumin. Blood and urine samples were collected at specified visits after initiating therapy. Full blood count, B2 microglobulin, serum paraprotein, and immunoglobulin electrophoresis (IEPG and EPG) were determined for all patients at each visit. Serum calcium, 25 hydroxyvitamin D3, and bone-specific alkaline phosphatase were determined at baseline only. Urine, as a morning second-void sample, was collected at each visit for urinary N-telopeptide of type I collagen. RESULTS: Our results show that oral curcumin is able to decrease paraprotein load in a select group (i.e., those having a paraprotein level of >20 g/L) of patients with MGUS. Fifty percent (5 of 10) of these patients had a 12% to 30% reduction in their paraprotein levels, while on curcumin therapy. In addition, 27% of patients on curcumin had a >25% decrease in urinary N-telopeptide of type I collagen. CONCLUSION: Due to the possible progression of MGUS to multiple myeloma, the potential role of curcumin as a therapeutic intervention for MGUS patients warrants further investigation.

Recurrent and injurious falls in the year following hip fracture: a prospective study of incidence and risk factors from the Sarcopenia and Hip Fracture study.

BACKGROUND: The incidence and etiology of falls in patients following hip fracture remains poorly understood. METHODS: We prospectively investigated the incidence of, and risk factors for, recurrent and injurious falls in community-dwelling persons admitted for surgical repair of minimal-trauma hip fracture. Fall surveillance methods included phone calls, medical records, and fall calendars. Potential predictors of falls included health status, quality of life, nutritional status, body composition, muscle strength, range of motion, gait velocity, balance, walking endurance, disability, cognition, depression, fear of falling, self-efficacy, social support, physical activity level, and vision. RESULTS: 193 participants enrolled in the study (81 +/- 8 years, 72% women, gait velocity 0.3 +/- 0.2 m/s). We identified 227 falls in the year after hip fracture for the 178 participants with fall surveillance data. Fifty-six percent of participants fell at least once, 28% had recurrent falls, 30% were injured, 12% sustained a new fracture, and 5% sustained a new hip fracture. Age-adjusted risk factors for recurrent and injurious falls included lower strength, balance, range of motion, physical activity level, quality of life, depth perception, vitamin D, and nutritional status, and greater polypharmacy, comorbidity, and disability. Multivariate analyses identified older age, congestive heart failure, poorer quality of life, and nutritional status as independent risk factors for recurrent and injurious falls. CONCLUSIONS: Recurrent and injurious falls are common after hip fracture and are associated with multiple risk factors, many of which are treatable. Interventions should therefore be tailored to alleviating or reversing any nutritional, physiological, and psychosocial risk factors of individual patients.

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.

Clinical outcomes after acute osteoporotic vertebral fractures: a 2-year non-randomised trial comparing percutaneous vertebroplasty with conservative therapy.

OBJECTIVE: To assess the safety and efficacy of percutaneous vertebroplasty for the treatment of acute osteoporotic vertebral fractures. DESIGN: A prospective, non-randomised, "intention-to-treat" 2-year study. PATIENTS AND SETTING: 126 consecutive patients (39 men and 87 women, aged 51-95 years) with acute osteoporotic vertebral fractures presenting to St George Hospital from November 2000 to December 2002. They comprised 88 patients treated by percutaneous vertebroplasty and 38 by conservative therapy. MAIN OUTCOME MEASURES: Primary outcomes--changes in patients' pain score and level of function recorded at 24 hours, 6 weeks, 6-12 months and 24 months after therapy. Secondary outcomes--occurrence of new clinical or radiological vertebral fractures and survival at 2 years. RESULTS: Three minor complications (fractured pedicle and psoas muscle haemorrhage) occurred in the vertebroplasty group during the first year of the study. Outcomes in vertebroplasty-treated patients (60% reduction in visual analogue pain scores from 20 to 8; P < 0.001), a rapid return to normal function (29% improvement in physical functioning from 14 to 18; P < 0.001) and lower rates of hospitalisation (43% reduction in the mean number of hospital bed-days occupied) were better than those treated conservatively (P < 0.001 for the comparison of all variables at 24 hours). Lower pain scores persisted in the vertebroplasty-treated group at 6 weeks (P < 0.001), but no differences between the two groups were evident at 12 and 24 months. In the vertebroplasty-treated group compared with the control group, the rates of new vertebral fractures (clinically and by radiographic assessment) (hazard ratio, 1.13; 95% CI, 0.52-2.46; P = 0.76) and death (hazard ratio, 1.07; 95% CI, 0.42-2.76; P = 0.89) showed no significant difference. CONCLUSION: The analgesic benefit of percutaneous vertebroplasty and the low complication rates suggest that it is a useful therapy for acute painful osteoporotic vertebral fractures.

Osteoporosis and spinal fractures in men with prostate cancer: risk factors and effects of androgen deprivation therapy.

PURPOSE: We determined the risk factors for osteoporosis and spinal fractures in men with prostate cancer receiving androgen deprivation therapy. MATERIALS AND METHODS: We performed a retrospective analysis of 87 consecutive men with prostate cancer receiving androgen deprivation therapy referred for evaluation of osteoporosis. Data were comprised of lateral thoracolumbar radiographs, bone densitometry, serum biochemistry and a detailed assessment of osteoporotic risk factors. Multivariate regression analysis was used to determine the major risk factors for osteoporosis and spinal fractures. RESULTS: There were 38 (44%) men who were 74.5 years old with radiographic evidence of spinal fractures. They had an initial mean prostate specific antigen of 52.8 ng/ml and had received androgen deprivation therapy for a mean of 39.6 months (95% confidence interval 28.7 to 50.4). Mean spinal (quantitative computerized tomography t-score -4.2) and femoral neck bone mineral densities (dual energy x-ray absorptiometry t-score -2.1) were significantly lower than in men without spinal fractures (p < 0.001 for all measurements). In the regression analysis the duration of androgen deprivation therapy (p = 0.002), serum 25-hydroxyvitamin D levels (p = 0.003) and a history of alcohol excess (defined as more than 4 standard drinks daily, p = 0.04) were the main determinants of spinal fractures. CONCLUSIONS: Prolonged androgen deprivation therapy, low serum 25-hydroxyvitamin D levels and a history of alcohol excess are important risk factors for osteoporosis and spinal fractures in men with prostate cancer.

Percutaneous vertebroplasty for acute vertebral body fracture and deformity in multiple myeloma: a short report.

We describe seven patients with multiple myeloma who were treated for acute vertebral body fractures with percutaneous vertebroplasty to a total of 14 vertebrae. Six of the seven patients had at least a 50% decrease in their pain scores at 24 h following vertebroplasty. There were no procedure-related complications. These encouraging results prompt us to suggest further large-scale evaluation of this procedure in myeloma patients.

Osteoporosis in men with prostate carcinoma receiving androgen-deprivation therapy: recommendations for diagnosis and therapies.

BACKGROUND: Androgen-deprivation therapy (ADT) is prescribed with increasing frequency for men with prostate carcinoma. There is growing concern about the effects of such therapy on the skeleton. In the current review, the authors addressed the current research, diagnostic methods, and treatment recommendations for bone loss and osteoporosis in men with prostate carcinoma who received ADT. METHODS: Data were obtained from electronic literature searches (for the years 1986 through 2002) and from abstracts and meeting proceedings. All randomized and nonrandomized clinical trials, retrospective studies, and cross-sectional studies of osteoporosis in men with prostate carcinoma who received ADT with or without other therapies were reviewed. RESULTS: The findings confirmed that ADT resulted in significant bone loss in men with prostate carcinoma. Bone mineral density (BMD) of the hip, as measured by dual-energy X-ray absorptiometry (DXA), is considered the preferred site of assessment in older men. Spinal BMD is equally important, although careful interpretation of spinal DXA values is required, because of coexisting facet joint disease and extravertebral calcification. Osteoporosis is diagnosed when BMD is > 2.5 standard deviations below a reference mean. Men with prostate carcinoma who were treated with ADT had average BMD measurements below those of eugonadal men. Rates of bone loss ranged from 2% to 8% in the lumbar spine and from 1.8% to 6.5% in the femoral neck during the initial 12 months of continuous ADT. Retrospective data indicated an increased risk of fracture in men with prostate carcinoma who were treated with ADT. CONCLUSIONS: For men with prostate carcinoma who are at high risk for osteoporosis and fractures, clinical management should be dictated by the results of radiographic and DXA skeletal assessment.

Management of acute osteoporotic vertebral fractures: a nonrandomized trial comparing percutaneous vertebroplasty with conservative therapy.

PURPOSE: We sought to determine whether percutaneous vertebroplasty--which involves the injection of cement to stabilize a fractured vertebral body--may be an effective treatment for vertebral fracture. METHODS: We enrolled 79 consecutive osteoporotic patients (24 men and 55 women; ages 51 to 93 years) presenting with acute vertebral fractures. Clinical characteristics and bone densitometry were measured at baseline. Pain scores (on a 0 to 25 scale) and levels of function (on a 0 to 20 scale) were recorded on presentation, at 24 hours, at 6 weeks, and 6 to 12 months after therapy. RESULTS: Fifty-five patients (70%) were treated by percutaneous vertebroplasty and 24 (30%) were treated by conservative therapy alone. They were followed for a mean of 215 days (range, 57 to 399 days). The baseline clinical characteristics, bone densitometry, and fracture data were similar in the two groups. Twenty-four hours after vertebroplasty, there was a 53% reduction in pain scores (from 19 to 9; P = 0.0001) and a 29% improvement in physical functioning (from 14 to 18; P = 0.0001), whereas pain scores and physical functioning remained unchanged at 24 hours in the patients treated conservatively (both P = 0.0001 compared with the changes after percutaneous vertebroplasty). Thirteen patients (24%) treated by percutaneous vertebroplasty were able to cease all analgesia after 24 hours (P = 0.0001 compared with none of the 24 patients treated conservatively). Clinical outcomes at 6 weeks and 6 to 12 months were similar in both groups. CONCLUSION: When compared with conservative therapy, percutaneous vertebroplasty results in prompt pain relief and rapid rehabilitation. In experienced hands, it is a safe and effective procedure for treating acute osteoporotic vertebral compression fractures.