Zoledronic Acid (ZOL) Markedly Improves Bone Mineral Density (BMD) for Patients (Pts) with Monoclonal Gammopathy of Undetermined Significance (MGUS) and Bone Loss.

Abstract MGUS occurs in 5% of individuals over 70 yrs of age and these pts have been found to have increased rates of bone resorption. Osteoporosis associated with MGUS have higher bone resorption compared to sex and aged-matched pts with osteoporosis but without evidence of MGUS. Not only do pts with MGUS have a higher prevalence of osteopenia/osteoporosis than the normal population but they also have an increased risk of fractures (fx). ZOL has been shown to increase BMD in the treatment of gonadotropin agonist-induced osteoporosis in men with prostate cancer without metastatic bone disease when administered every 3 mos at 4 mg. The rationale for the use of ZOL for pts with osteopenia/osteoporosis in the setting of MGUS is based on these studies coupled with the knowledge that pts with this disorder have a higher prevalence of bone loss and fx risk. To date, no agents have been formally studied in the treatment of osteopenia/osteoporosis associated with MGUS. A schedule of 4 mg every 6 mos has been shown to be safe and effective in increasing BMD for other cancer pts without metastatic bone disease but with significant bone loss. This open-label study was designed to evaluate the efficacy and safety of this dose and schedule of ZOL for MGUS pts with significant loss of bone. Pts had to have osteopenia/osteoporosis (T-score worse than -1) as verified by a DEXA scan and a diagnosis of MGUS. Pts with prior use of oral bisphosphonates (BIS) or fluorides for more than three mos within the last two yrs or prior use of intravenous (IV) BIS within the last two yrs were excluded. ZOL at 4 mg was administered IV at 0, 6, and 12 mos. To assess the efficacy of ZOL therapy, DEXA scans and skeletal surveys were conducted at screening and one mo after the final ZOL infusion (13 mos). Fifty-four pts were enrolled on this trial with an average age of 68 (range, 50 to 91 yrs). The starting L-spine T-scores ranged from −3.97 to −1.10 (mean = −2.16). After one year of ZOL therapy, T-scores improved by a mean of +0.55 (range, −0.40 to +3.90; P = 0.0042). This corresponded to a mean increase in BMD of +25.5% (range, −19.0% to +134%). Similar evaluation in the hip showed baseline T-scores of −3.50 to −1.00 (mean = −1.88). The mean change in T-score was +0.27 (range, −0.60 to +2.00; P = 0.0046) corresponding to a mean increase of +14.4% (range, −54.5% to +163%). One pt developed chronic lymphocytic leukemia while on study whereas no other pt showed progression to myeloma or a related B-cell disorder. No pt developed osteonecrosis of the jaw or a significant adverse renal event. During the study, no pt developed a new fx. This trial suggests that ZOL administered at 4 mg every 6 mos significantly improves BMD in MGUS pts with bone loss (osteopenia/osteoporosis); and, thus, suggests that this is a safe and effective treatment to prevent the development of new fxs in this high risk population.

Download Full-text

The role of bisphosphonates in breast and prostate cancers.

Endocrine Related Cancer ◽

10.1677/erc.0.0110207 ◽

2004 ◽

Vol 11 (2) ◽

pp. 207-224 ◽

Cited By ~ 97

Author(s):

Janet E Brown ◽

Helen Neville-Webbe ◽

Robert E Coleman

Keyword(s):

Breast Cancer ◽

Zoledronic Acid ◽

Bone Loss ◽

Bone Mineral ◽

Bone Disease ◽

Bone Pain ◽

Metastatic Bone Disease ◽

Mineral Density ◽

Intravenous Pamidronate ◽

Oral Clodronate

Bisphosphonate drugs are a group of pyrophosphate analogues which bind avidly to hydroxyapatite bone mineral surfaces and their major action is to inhibit osteoclast activity and thus bone resorption. In oncology, their role in metastatic bone disease is well established, but there is increasing interest in their potential role in preventing and treating cancer-induced bone loss and their possible anti-tumour effects. Metastatic bone disease is associated with a variety of skeletal complications, including pathologic fractures, bone pain, impaired mobility, spinal cord compression and hypercalcaemia. Intravenous bisphosphonates, particularly zoledronic acid, in conjunction with rehydration, are now established as the treatment of choice for hypercalcaemia. For treatment of bone pain, it has also been shown that bisphosphonates can be an effective supplementary approach to radiotherapy. In breast cancer and myeloma, bisphosphonates have now become part of standard therapy to treat and prevent skeletal-related events (SRE) and, until recently, treatment was largely with intravenous pamidronate or oral clodronate. However, large, randomised, multicentre trials using intravenous administration of the highly potent bisphosphonate zoledronic acid every 3-4 weeks have recently demonstrated a reduction of 20% in the risk of developing an SRE compared with pamidronate for patients with breast cancer. Moreover, these trials have demonstrated, for the first time, that a bisphosphonate significantly reduces the occurrence of skeletal events in hormone-refractory prostate cancer and in non-small cell lung cancer and a range of other solid tumours. Investigations into the potential of the relatively low potency bisphosphonate, clodronate, for the prevention of bone metastases in breast cancer have produced conflicting data. Further large, randomised studies with clodronate and zoledronic acid are planned and until the results are available it is not possible to identify a definite adjuvant role for bisphosphonates. Evidence is accumulating in vitro that bisphosphonates are also able to directly affect tumour cells, in addition to their effects on osteoclasts, with zoledronic acid being particularly potent. Over recent decades there has been a significant improvement in cure rates and survival times in certain cancers and the use of chemotherapy and hormone therapy has expanded greatly, leading to increasing numbers of long-term survivors who have received these treatments. Management of treatment-induced bone loss is therefore assuming a greater importance and bisphosphonates represent an attractive treatment option in such patients. Several placebo-controlled trials using oral clodronate, oral risedronate, intravenous pamidronate and intravenous zoledronic acid have all now demonstrated benefits in reducing the loss in bone mineral density.

Download Full-text

Osteoporosis in Sickle Cell/β-Thalassemia Is Primarily Caused by an Imbalance at the RANKL/OPG Pathway.

Blood ◽

10.1182/blood.v106.11.3173.3173 ◽

2005 ◽

Vol 106 (11) ◽

pp. 3173-3173

Author(s):

Ersi Voskaridou ◽

Ioannis Papassotiriou ◽

Evangelos Premetis ◽

John Meletis ◽

Dimitris Loukopoulos ◽

...

Keyword(s):

Bone Marrow ◽

Renal Function ◽

Bone Resorption ◽

Bone Loss ◽

Sickle Cell ◽

Type I ◽

Mineral Density ◽

T Score ◽

Tracp 5B ◽

Marrow Expansion

Abstract Bone involvement is the commonest clinical manifestation of sickle cell disease (SCD) including chronic disorders, such as osteopenia/osteoporosis. The aim of the present study is to evaluate the bone mineral density (BMD) of patients with SCD/β-thalassemia (S/β-th) in parallel with markers of bone turnover in an attempt to better understand the pathophysiology of bone loss in these patients. We studied 52 patients with S/β-th (23M/29F; median age 40 y). The BMD of the lumbar spine (L) and femoral neck (F) was evaluated by DEXA. Bone remodeling was assessed using the following serum indices: (a) bone resorption markers [C-telopeptide of type-I collagen (CTX), tartrate-resistant acid phosphatase isoform-5b (TRACP-5b)], (b) bone formation markers [bone-alkaline phosphatase (bALP), osteocalcin (OC), and C-terminal propeptide of collagen type-I (CICP)], and (c) osteoclast stimulating factors [soluble receptor activator of nuclear factor κB ligand (sRANKL), and osteoprotegerin (OPG)]. Moreover, all patients had a thorough evaluation of their renal function (creatinine clearance, and cystatin-C serum levels), bone marrow expansion (soluble transferin receptors, sTfR), serum erythropoietin (Epo) and parathyroid hormone (PTH) levels. The same biochemical parameters were also determined in 25 age- and gender-matched controls. According to WHO criteria, 17 patients (32.6%; 8M/9F, median age 45 y) had osteopenia or osteoporosis (median L/T-score: −2.26; L/BMD: 0.9 g/cm2; F/T-score: −1.86; F/BMD: 0.68 g/cm2). In contrast, 30 patients (57.6%; 12M/18F, median age 40 y) had osteosclerosis (median L/T-score: +3.15; L/BMD: 1550.5 g/m2; F/T-score: +0.52; F/BMD: 1113.5 g/cm2). Renal function, Epo, Hb and sTfR levels and the number of crises/year were similar between both groups. All patients displayed increased levels of OPG, bALP, and CICP compared with controls (p<0.02). CTX levels in the osteosclerotic patients were significantly lower than those of both controls (p<0.0001) and osteopenic/osteoporotic patients (p<0.003); this finding implies a diminished bone resorption. Moreover, bALP and PTH in the osteopenia/osteoposis group were higher than those of the osteosclerosis group (p<0.01, and <0.03, respectively). BMD of the osteopenic/osteoporotic patients showed a strong correlation with OPG and CTX levels (p=0.01, and 0.008, respectively). This result, in combination with the significant correlations observed between OPG and sRANKL, TRACP-5b, and bALP in these patients suggests that osteopenia/osteoporosis in S/β-th results mainly from an imbalance at the RANKL/OPG axis. Conversely, considering the absence of correlation between BMD and sTfR in the same patient group, the potential contribution of bone marrow expansion in the development of osteopenia appears much weaker. No correlation between BMD and bone indices observed in osteosclerotic group. In conclusion, this study suggests that the development of bone loss in S/β-th patients is mainly due to an imbalance in RANKL/OPG pathway. Novel agents that target this system, as well as bisphosphonates, maybe useful in the management of this common SCD complication.

Download Full-text

The Ability of Exercise to Mitigate Caloric Restriction-Induced Bone Loss in Older Adults: A Structured Review of RCTs and Narrative Review of Exercise-Induced Changes in Bone Biomarkers

Nutrients ◽

10.3390/nu13041250 ◽

2021 ◽

Vol 13 (4) ◽

pp. 1250

Author(s):

Sarah J. Wherry ◽

Ryan M. Miller ◽

Sarah H. Jeong ◽

Kristen M. Beavers

Keyword(s):

Older Adults ◽

Bone Loss ◽

Caloric Restriction ◽

Controlled Trial ◽

Areal Bone Mineral Density ◽

Bone Biomarkers ◽

Mineral Density ◽

Increased Risk ◽

Exercise Induced ◽

Induced Changes

Despite the adverse metabolic and functional consequences of obesity, caloric restriction- (CR) induced weight loss is often contra-indicated in older adults with obesity due to the accompanying loss of areal bone mineral density (aBMD) and subsequent increased risk of fracture. Several studies show a positive effect of exercise on aBMD among weight-stable older adults; however, data on the ability of exercise to mitigate bone loss secondary to CR are surprisingly equivocal. The purpose of this review is to provide a focused update of the randomized controlled trial literature assessing the efficacy of exercise as a countermeasure to CR-induced bone loss among older adults. Secondarily, we present data demonstrating the occurrence of exercise-induced changes in bone biomarkers, offering insight into why exercise is not more effective than observed in mitigating CR-induced bone loss.

Download Full-text

Importance of calcium, vitamin D and vitamin K for osteoporosis prevention and treatment

Proceedings of The Nutrition Society ◽

10.1017/s0029665108007003 ◽

2008 ◽

Vol 67 (2) ◽

pp. 163-176 ◽

Cited By ~ 66

Author(s):

Susan A. Lanham-New

Keyword(s):

Vitamin D ◽

Bone Loss ◽

Vitamin K ◽

Hypovitaminosis D ◽

Osteoporosis Prevention ◽

Mineral Density ◽

Increased Risk ◽

Post Menopause ◽

Exogenous Factors ◽

The Uk

Throughout the life cycle the skeleton requires optimum development and maintenance of its integrity to prevent fracture. Bones break because the loads placed on them exceed the ability of the bone to absorb the energy involved. It is now estimated that one in three women and one in twelve men aged >55 years will suffer from osteoporosis in their lifetime and at a cost in the UK of >£1·7×109 per year. The pathogenesis of osteoporosis is multifactorial. Both the development of peak bone mass and the rate of bone loss are determined by key endogenous and exogenous factors. Ca supplements appear to be effective in reducing bone loss in women late post menopause (>5 years post menopause), particularly in those with low habitual Ca intake (<400 mg/d). In women early post menopause (<5 years post menopause) who are not vitamin D deficient, Ca supplementation has little effect on bone mineral density. However, supplementation with vitamin D and Ca has been shown to reduce fracture rates in the institutionalised elderly, but there remains controversy as to whether supplementation is effective in reducing fracture in free-living populations. Re-defining vitamin D requirements in the UK is needed since there is evidence of extensive hypovitaminosis D in the UK. Low vitamin D status is associated with an increased risk of falling and a variety of other health outcomes and is an area that requires urgent attention. The role of other micronutrients on bone remains to be fully defined, although there are promising data in the literature for a clear link between vitamin K nutrition and skeletal integrity, including fracture reduction.

Download Full-text

TSH suppressive therapy and bone

Endocrine Connections ◽

10.1530/ec-20-0167 ◽

2020 ◽

Vol 9 (7) ◽

pp. R158-R172 ◽

Cited By ~ 1

Author(s):

Alessandro Brancatella ◽

Claudio Marcocci

Keyword(s):

Bone Loss ◽

Postmenopausal Women ◽

Bone Cells ◽

Trabecular Bone Score ◽

Experimental Studies ◽

Bone Architecture ◽

Tsh Receptor ◽

Suppressive Therapy ◽

Mineral Density ◽

Increased Risk

Thyroid hormones stimulate bone turnover in adults by increasing osteoclastic bone resorption. TSH suppressive therapy is usually applied in patients with differentiated thyroid cancer (DTC) to improve the disease outcome. Over the last decades several authors have closely monitored the potential harm suffered by the skeletal system. Several studies and meta-analyses have shown that chronic TSH suppressive therapy is safe in premenopausal women and men. Conversely, in postmenopausal women TSH suppressive therapy is associated with a decrease of bone mineral density, deterioration of bone architecture (quantitative CT, QCT; trabecular bone score, TBS), and, possibly, an increased risk of fractures. The TSH receptor is expressed in bone cells and the results of experimental studies in TSH receptor knockout mice and humans on whether low TSH levels, as opposed to solely high thyroid hormone levels, might contribute to bone loss in endogenous or exogenous thyrotoxicosis remain controversial. Recent guidelines on the use of TSH suppressive therapy in patients with DTC give value not only to its benefit on the outcome of the disease, but also to the risks associated with exogenous thyrotoxicosis, namely menopause, osteopenia or osteoporosis, age >60 years, and history of atrial fibrillation. Bone health (BMD and/or preferably TBS) should be evaluated in postmenopausal women under chronic TSH suppressive therapy or in those patients planning to be treated for several years. Antiresorptive therapy could also be considered in selected cases (increased risk of fracture or significant decline of BMD/TBS during therapy) to prevent bone loss.

Download Full-text

Gender Differences In Bone Mineral Density In Subjects With COPD: Males At Increased Risk Of Bone Loss

10.1164/ajrccm-conference.2012.185.1_meetingabstracts.a3987 ◽

2012 ◽

Author(s):

Joshua D. Jaramillo ◽

Carla Wilson ◽

Barry J. Make ◽

Marilyn G. Foreman ◽

MeiLan K. Han ◽

...

Keyword(s):

Bone Mineral Density ◽

Gender Differences ◽

Bone Loss ◽

Bone Mineral ◽

Mineral Density ◽

Increased Risk

Download Full-text

Zoledronic Acid Prevents Cancer Treatment–Induced Bone Loss in Premenopausal Women Receiving Adjuvant Endocrine Therapy for Hormone-Responsive Breast Cancer: A Report From the Austrian Breast and Colorectal Cancer Study Group

Journal of Clinical Oncology ◽

10.1200/jco.2005.02.7102 ◽

2007 ◽

Vol 25 (7) ◽

pp. 820-828 ◽

Cited By ~ 223

Author(s):

Michael F.X. Gnant ◽

Brigitte Mlineritsch ◽

Gero Luschin-Ebengreuth ◽

Stephan Grampp ◽

Helmut Kaessmann ◽

...

Keyword(s):

Breast Cancer ◽

Zoledronic Acid ◽

Bone Loss ◽

Endocrine Therapy ◽

Premenopausal Women ◽

Adjuvant Endocrine Therapy ◽

Phase Iii ◽

Endocrine Treatment ◽

Mineral Density ◽

T Score

Purpose Adjuvant therapy for breast cancer can be associated with decreased bone mineral density (BMD) that may lead to skeletal morbidity. This study examined whether zoledronic acid can prevent bone loss associated with adjuvant endocrine therapy in premenopausal patients. Patients and Methods This study is a randomized, open-label, phase III, four-arm trial comparing tamoxifen (20 mg/d orally) and goserelin (3.6 mg every 28 days subcutaneously) ± zoledronic acid (4 mg intravenously every 6 months) versus anastrozole (1 mg/d orally) and goserelin ± zoledronic acid for 3 years in premenopausal women with hormone-responsive breast cancer. In a BMD subprotocol at three trial centers, patients underwent serial BMD measurements at 0, 6, 12, 24, and 36 months. Results Four hundred one patients were included in the BMD subprotocol. Endocrine treatment without zoledronic acid led to significant (P < .001) overall bone loss after 3 years of treatment (BMD, −14.4% after 36 months; mean T score reduction, −1.4). Overall bone loss was significantly more severe in patients receiving anastrozole/goserelin (BMD, −17.3%; mean T score reduction, −2.6) compared with patients receiving tamoxifen/goserelin (BMD, −11.6%; mean T score reduction, −1.1). In contrast, BMD remained stable in zoledronic acid–treated patients (P < .0001 compared with endocrine therapy alone). No interactions with age or other risk factors were noted. Conclusion Endocrine therapy caused significant bone loss that increased with treatment duration in premenopausal women with breast cancer. Zoledronic acid 4 mg every 6 months effectively inhibited bone loss. Regular BMD measurements and initiation of concomitant bisphosphonate therapy on evidence of bone loss should be considered for patients undergoing endocrine therapy.

Download Full-text

Porcupine inhibitors impair trabecular and cortical bone mass and strength in mice

Journal of Endocrinology ◽

10.1530/joe-18-0153 ◽

2018 ◽

Vol 238 (1) ◽

pp. 13-23 ◽

Cited By ~ 12

Author(s):

Thomas Funck-Brentano ◽

Karin H Nilsson ◽

Robert Brommage ◽

Petra Henning ◽

Ulf H Lerner ◽

...

Keyword(s):

Bone Resorption ◽

Bone Loss ◽

Bone Formation ◽

Bone Mass ◽

Trabecular Bone ◽

Cortical Bone ◽

Bone Strength ◽

Bending Test ◽

Bone Homeostasis ◽

Mineral Density

WNT signaling is involved in the tumorigenesis of various cancers and regulates bone homeostasis. Palmitoleoylation of WNTs by Porcupine is required for WNT activity. Porcupine inhibitors are under development for cancer therapy. As the possible side effects of Porcupine inhibitors on bone health are unknown, we determined their effects on bone mass and strength. Twelve-week-old C57BL/6N female mice were treated by the Porcupine inhibitors LGK974 (low dose = 3 mg/kg/day; high dose = 6 mg/kg/day) or Wnt-C59 (10 mg/kg/day) or vehicle for 3 weeks. Bone parameters were assessed by serum biomarkers, dual-energy X-ray absorptiometry, µCT and histomorphometry. Bone strength was measured by the 3-point bending test. The Porcupine inhibitors were well tolerated demonstrated by normal body weight. Both doses of LGK974 and Wnt-C59 reduced total body bone mineral density compared with vehicle treatment (P < 0.001). Cortical thickness of the femur shaft (P < 0.001) and trabecular bone volume fraction in the vertebral body (P < 0.001) were reduced by treatment with LGK974 or Wnt-C59. Porcupine inhibition reduced bone strength in the tibia (P < 0.05). The cortical bone loss was the result of impaired periosteal bone formation and increased endocortical bone resorption and the trabecular bone loss was caused by reduced trabecular bone formation and increased bone resorption. Porcupine inhibitors exert deleterious effects on bone mass and strength caused by a combination of reduced bone formation and increased bone resorption. We suggest that cancer targeted therapies using Porcupine inhibitors may increase the risk of fractures.

Download Full-text

Evaluation of Bone Mineral Density in Subjects with Primary Hyperparathyroidism by Dual Energy X-Ray Absorptiometry

Bangladesh Journal of Nuclear Medicine ◽

10.3329/bjnm.v20i2.37399 ◽

2018 ◽

Vol 20 (2) ◽

pp. 129

Author(s):

Rezwana Haque ◽

Raihan Hussain ◽

Shamim MF Begum

Keyword(s):

Bone Loss ◽

Femoral Neck ◽

Primary Hyperparathyroidism ◽

Dual Energy ◽

Mineral Density ◽

X Ray ◽

T Score ◽

Group A ◽

Group B ◽

Bone Condition

Objective: Bone loss is a major complication of primary hyperparathyroidism (PHPT), and the extent of bone loss is an important factor for parathyroidectomy. Studies focused on this issue of bone loss in subjects with PHPT are quite rare in our country. This study will help the physicians to take proper action by giving an exact reflection of bone condition in subjects with PHPT. The purpose of this study was to evaluate the bone condition by measuring Bone Mineral Density (BMD), in subjects with PHPT using Dual Energy X-ray Absorptiometry (DEXA) and compare these findings with individuals without PHPT.Patients and Methods: It was an analytic cross sectional study (group comparison) carried out at National Institute of Nuclear Medicine and Allied Sciences (NINMAS) BSMMU campus, Dhaka from July 2015-December 2016. Subjects of PHPT diagnosed by biochemical evaluation (increased serum calcium and parathyroid hormone concentrations), between age ranges 15-45 years were selected as group-A. Individuals without biochemical evidence of PHPT or other major illness causing bone loss were selected as comparison group or as group-B. The subjects underwent BMD test by DEXA at lumbar spines from L1-L4 vertebra and the left femoral neck using Norland XR-46 densitometer. BMD was classified according to WHO criteria. Data presented on categorical form were analyzed using chi-squared test. While the data presented on continuous scale were analyzed using student’s t-test. In each analysis, level of significance was 5% and P value <0.05 was considered significant. Data were processed and analyzed with the help of computer software SPSS, version 20.Results: Total number of 90 subjects were selected for this study, 45 subjects with PHPT were in group-A and equal number of subjects without PHPT were in group-B. The findings derived from data analysis showed, a significantly more male participants in group-A. The mean age of group-A and group-B was 37.24 ± 8.03 years and 38.20 ± 5.74 years respectively. Mean BMI of group-A was 25.10 ± 4.35 kg/m2 in compare to 29.43 ± 5.17 kg/m2 in group-B. Higher BMI was noted in both groups. PHPT subjects with high BMI had low BMD. BMD expressed in absolute value (gm/cm2) and T score. BMD was significantly low in group-A (with PHPT) than in group-B (without PHPT), (p<0.0001). In group-A, prevalence of low BMD was 62.2% (osteopenia 37.8% and osteoporosis 24.4%) at lumbar spine and 84.5% (osteopenia 35.6% and osteoporosis 48.9%) at femoral neck. PHPT subjects had significant difference in both T score and BMD between lumbar spine and femoral neck.Conclusion: Primary hyperparathyroidism (PHPT) is shown to be associated with significantly reduced BMD especially at femoral neck. Thus, an increased fracture risk should consider if it is left untreated.Bangladesh J. Nuclear Med. 20(2): 129-135, July 2017

Download Full-text