Clinical Reviews in Bone and Mineral Metabolism (Clin Rev Bone Miner Metabol)

Publications in this journal

• Article: Safety of Anti-Diabetic Therapies on Bone.

  Beata Lecka-Czernik
  [show abstract] [hide abstract]
  ABSTRACT: Osteoporosis and diabetic disease have reached epidemic proportion and create significant public health concerns. The prevalence of these diseases is alarming, and indicates that in the US, 50% of elderly individuals are osteoporotic and almost 20% of population has either diabetic or prediabetic conditions (Centers for Disease Control and Prevention; http://www.cdc.gov). Osteoporosis and diabetes share many features including genetic predispositions and molecular mechanisms. The linkage between these two chronic diseases, which stems from overlapping molecular controls involved in bone homeostasis and energy metabolism, creates a possibility that certain anti-diabetic therapies may affect bone. This concurs with recent findings indicating that bone status is closely linked to regulation of energy metabolism and insulin sensitivity. Indeed, bone and energy homeostasis are under the control of the same regulatory factors, including insulin, peroxisome proliferator activated receptor gamma (PPARγ), gastrointestinal hormones such as glucose inhibitory protein (GIP) and glucagon inhibitory peptide (GLP), and bone derived hormone osteocalcin. These factors and related mechanisms control glucose homeostasis and fatty acids metabolism in fat tissue, pancreas and intestine, which are pharmacological targets for anti-diabetic therapies. The same factors contribute to the bone quality by their effect on bone cell differentiation and bone remodeling process. This implies that bone should be considered as a vital target for therapies which modulate energy metabolism. This review is summarizing available data on the skeletal effects of clinically approved anti-diabetic therapies.
  Clinical Reviews in Bone and Mineral Metabolism 03/2013; 11(1):49-58.
• Article: The role of vitamin D in the metabolic homeostasis of diabetic bone.

  Kathryn M Thrailkill, John L Fowlkes
  [show abstract] [hide abstract]
  ABSTRACT: Most studies across a variety of geographic locations suggest that vitamin D insufficiency is more common in individuals with type 1 diabetes (T1D) compared to the general population. In type 2 diabetes (T2D), while obesity is commonplace and lower vitamin D levels are present in obese adolescents and adults, the association between vitamin D insufficiency and T2D is less clear. Studies suggest that the relationship between T2D and vitamin D may be concurrently influenced by ethnicity, geography, BMI and age. None-the-less, diabetic osteopathy is a significant co-morbidity of both forms of diabetes, and is characterized by micro-architectural changes that decrease bone quality leading to an increased risk for bone fracture in both disorders. The question remains, however, to what degree vitamin D homeostasis contributes to or exacerbates skeletal pathology in diabetes. Proposed mechanisms for vitamin D deficiency in diabetes include: 1) genetic predisposition (T1D); 2) increased BMI (T2D); 3) concurrent albuminuria (T1D or T2D); or 4) exaggerated renal excretion of vitamin D metabolites or vitamin D binding protein (T1D, T2D, animal models). The specific effects of vitamin D treatment on diabetic osteoporosis have been examined in rodents, and demonstrate skeletal improvements even in the face of untreated diabetes. However, human clinical trial data examining whether vitamin D status can be directly related to or is predictive of bone quality and fracture risk in those with diabetes is still needed. Herein, we provide a review of the literature linking vitamin D, diabetes and skeletal health.
  Clinical Reviews in Bone and Mineral Metabolism 03/2013; 11(1):28-37.
• Article: Mechanosensing in Bone

  Jenneke Klein-Nulend
  Clinical Reviews in Bone and Mineral Metabolism 05/2012; 8(4):161-162.
• Article: Urological Aspects of Management

  Joe Miller, Marshall L. Stoller
  [show abstract] [hide abstract]
  ABSTRACT: Renal colic describes the acute, severe, and paroxysmal pain caused by the obstruction, distension, and resultant increase in intraluminal pressure of the urinary tract. The treatment of renal colic is aimed at relief of symptoms, facilitating urinary drainage to preserve renal function and treat infection and ultimately removal or passage of the obstructing stone. The medical management of renal colic is directed at mitigating, through pharmacologic intervention, one or more of the complex processes contributing to the clinical sequelae of obstruction including pain, nausea, vomiting, and irritative voiding symptoms. Numerous medications and combinations of medications have been employed with varying degrees of clinical success. Urgent interventions are typically directed at bypassing ureteral obstruction in order to palliate the patient until such time as definitive treatment may be accomplished or facilitate drainage to further the treatment of urinary tract infection. Timing and mode of urgent intervention are dependent on clinical factors, clinician expertise, and preference and the availability of specialized equipment. Definitive management of ureteral stones is typically performed in an elective fashion and seeks to balance the risks of intervention with the clinical benefits of the various treatment modalities. Treatment approaches vary according to clinical indications, patient preference, clinician expertise, and the availability of facilities and equipment. This section covers current supporting evidence and rationale, indications and techniques for the medical management, urgent intervention, and definitive management of acute renal colic caused by ureteral stones. KeywordsUreteral calculi–Medical expulsive therapy–Ureteroscopy–Shock wave lithotripsy
  Clinical Reviews in Bone and Mineral Metabolism 05/2012; 10(1):19-37.
• Article: Specific Bone and Mineral Disorders in Patients with Chronic Kidney Disease

  Benjamin Morrow, Wajeh Qunibi
  [show abstract] [hide abstract]
  ABSTRACT: Bone lesions, collectively known as renal osteodystrophy (ROD), are a common complication of chronic kidney disease (CKD). Besides osteitis fibrosa and mixed lesions, other bone and mineral disorders such as adynamic bone disease, osteomalacia, osteoporosis, dialysis-related amyloidosis, and calcific uremic arteriolopathy are increasingly recognized in patients with CKD. Although bone lesions usually begin early in the course of CKD and are progressive, symptoms and signs such as bone pain and fractures may not occur until the patient is already on maintenance dialysis. More importantly, these disorders are associated with increased risk of cardiovascular disease and mortality in patients with CKD. The term ROD does not reflect the full spectrum of bone pathology or clinical manifestations of bone and mineral disorders in patients with CKD. Accordingly, the National Kidney Foundation and, more recently the Kidney Disease: Improving Global Outcomes, now consider ROD to represent only one measure of the skeletal component of the broader syndrome of chronic kidney disease-mineral and bone disorders in which abnormalities in bone and mineral metabolism or extraskeletal calcification are observed. In this review, we will discuss, in detail, the epidemiology, pathogenesis, histopathology, clinical manifestation, diagnosis, and treatment of these disorders. KeywordsAdynamic bone disease–Renal osteodystrophy–CKD–PTH–Cardiovascular calcification–Phosphorus–Bone biopsy–Bone turnover–Osteoporosis–Osteomalacia–Aluminum toxicity–Amyloidosis–Beta-2 microglobulin–Calciphylaxis
  Clinical Reviews in Bone and Mineral Metabolism 05/2012;
• Article: Bone Assessment in Children: Clinical Relevance and Interpretation

  Graeme Jones
  [show abstract] [hide abstract]
  ABSTRACT: The assessment of bone in children is more difficult than in adults mainly due to the effect of growth and/or puberty. Despite this, there is an increasing body of evidence showing that measurement of different components of bone is of clinical relevance. Fracture incidence peaks during the early teenage years, and dual energy X-ray absorptiometry (DXA) has been shown to predict fractures in children, especially those of the upper limb, in four prospective studies. Case control and cross-sectional studies have also shown similar associations for peripheral quantitative computed tomography (pQCT), heel ultrasound, metacarpal index, and skeletal age deviation. In some cases, these latter results are additive to DXA suggesting a multifaceted approach to bone assessment in children will lead to greater information. Size or age adjusted Z scores are mandatory for the interpretation of DXA in children. However, other modalities such as heel ultrasound are less affected by growth. Lastly, children have very high bone turnover in comparison to adults but markers of bone turnover also have clinical utility for linear growth, assessment of the impact of vitamin D deficiency and assessment of short term influences on bone such as diet. KeywordsDXA-Children-Fracture-Bone mass-Ultrasound
  Clinical Reviews in Bone and Mineral Metabolism 05/2012; 8(3):135-139.
• Article: Integrin Regulation of the IGF-I Receptor in Bone, and the Response to Load

  Roger K. Long, Bernard P. Halloran, Daniel D. Bikle
  [show abstract] [hide abstract]
  ABSTRACT: Bone loss during skeletal unloading, whether due to neurotrauma resulting in paralysis or prolonged immobilization due to a variety of medical illnesses, accelerates bone loss. In this review the evidence that skeletal unloading leads to bone loss at least in part due to disrupted IGF signaling, resulting in reduced osteoblast proliferation and differentiation, will be examined. The mechanism underlying this disruption in IGF signaling appears to involve integrins, the expression of which is reduced during skeletal unloading. Integrins play an important, albeit not well defined, role in facilitating signaling not only by IGF but also by other growth factors. However, the interaction between selected integrins such as αVβ3 and β1 and the IGF receptor are of especial importance with respect to the ability of bone to respond to mechanical load. Disruption of this interaction blocks IGF signaling and results in bone loss.
  Clinical Reviews in Bone and Mineral Metabolism 05/2012; 5(4):222-233.
• Source

  Available from: aub.edu.lb

  Article: Vitamin D Deficiency in the Middle East and its Health Consequences for Children and Adults

  Ghada El-Hajj Fuleihan
  [show abstract] [hide abstract]
  ABSTRACT: Despite its abundant sunshine the Middle East, a region spanning latitudes from 12°N to 42°N allowing vitamin D synthesis year round, registers some of the lowest levels of vitamin D and the highest rates of hypovitaminosis D worldwide. This major public health problem affects individuals across all life stages including pregnant women, neonates, infants, children and adolescents, adults, and the elderly. Furthermore, while rickets is almost eradicated from developed countries, it is still reported in several countries in the Middle East. These observations can be explained by limited sun exposure due to cultural practices, dark skin color, and very hot climate in several countries in the gulf area, along with prolonged breast feeding without vitamin D supplementation, decreased calcium content of diets and outdoor activity, obesity, and lack of government regulation for vitamin D fortification of food, in several if not in all countries. The lack of population based studies renders estimates for the prevalence and incidence of rickets in the Middle East difficult, but several series from the region illustrate its dire consequences on growth and development. Furthermore, it is reported that 20–80% of apparently healthy individuals from several countries in this region have suboptimal vitamin D levels, depending on the cut-off used for defining hypovitaminosis D, the country, season, age group, and gender studied. Suboptimal levels have been associated with compromised skeletal health across age groups, and with poor muscular function and increased fall risk and osteoporotic fractures in the elderly. Studies detailing associations between low vitamin D levels and musculoskeletal health in the Middle East, and the impact of various treatment regimens are reviewed. Current recommendations for vitamin D derived from data in western subjects may not be sufficient for subjects from the Middle East, therefore suggestions for vitamin D replacement doses based on evidence available to-date are provided. Hypovitaminosis D is a major public health problem across all life stages in the Middle East with deleterious immediate and latent manifestations. Long term strategies to address this often silent disease should include public education, national health policies for screening and prevention through food fortification, and treatment through vitamin D supplementation.
  Clinical Reviews in Bone and Mineral Metabolism 05/2012; 7(1):77-93.
• Article: Epidemiology and Natural History of Nephrolithiasis

  Alan G. Wasserstein
  [show abstract] [hide abstract]
  ABSTRACT: The epidemiology and natural history of nephrolithiasis comprise its incidence and prevalence; role of age, gender, and race; risk factors, comorbidities, and course. As such, epidemiology verges into clinical features, pathogenesis, treatment, and prognosis. Although it is well known that associations derived from epidemiological studies do not prove causal relationships, lessons from epidemiology and natural history have been readily applied to pathogenesis and treatment. Conversely, knowledge derived from experiment and interventional trials has furnished models for understanding epidemiological data. Hence, it is not easy to divide epidemiology from other aspects of nephrolithiasis. While my primary emphasis in this review will be on epidemiological studies, I will consider other kinds of studies that help us to understand the epidemiology and natural history of nephrolithiasis. KeywordsKidney stones–Epidemiology of kidney stones–Risk factors for kidney stones–Natural history of kidney stones–Diet and kidney stones–Hypercalciuria–Hyperoxaluria–Hypocitraturia–Hyperuricosuria
  Clinical Reviews in Bone and Mineral Metabolism 04/2012; 9(3):165-180.
• Article: T-Scores and Z-Scores

  John J. Carey, Miriam F. Delaney
  [show abstract] [hide abstract]
  ABSTRACT: Bone mineral density (BMD) can be measured by a variety of techniques at several skeletal sites. Once measured, the manufacturers’ software uses the BMD to calculate a T-score and/or Z-score. Both T-scores and Z-scores are derived by comparison to a reference population on a standard deviation scale. The recommended reference group for the T-score is a young gender-matched population at peak bone mass, while the Z-score should be derived from an age-matched reference population. T-scores and Z-scores are widely quoted in scientific publications on osteoporosis and BMD studies, and are the values used for DXA diagnostic criteria and current clinical guidelines for the management of osteoporosis. Errors in BMD measurement, differences in reference populations, and variations in calculation methods used, can all affect the actual T-score and Z-score value. Attempts to standardize these values have made considerable progress, but inconsistencies remain within and across BMD technologies. This can be a source of confusion for clinicians interpreting BMD results. A clear understanding of T-scores and Z-scores is essential for correct interpretation of BMD studies in clinical practice. KeywordsDXA-Bone mineral density- T-score- Z-score
  Clinical Reviews in Bone and Mineral Metabolism 04/2012; 8(3):113-121.
• Article: Fracture Risk Assessment in Clinical Practice: T-scores, FRAX, and Beyond

  E. Michael Lewiecki
  [show abstract] [hide abstract]
  ABSTRACT: Assessment of fracture risk is a key component in the evaluation of skeletal health and a critical step in determining whether to initiate pharmacological therapy to reduce fracture risk. The identification of high risk patients allows clinicians to direct limited healthcare resources to those who are most likely to benefit. Bone mineral density (BMD) and clinical risk factors (CRFs) for fracture predict fracture risk better than BMD or CRFs alone. Dual-energy X-ray absorptiometry (DXA) is a technology for the measurement of BMD to diagnose osteoporosis, assess fracture risk, and monitor the BMD response to therapy. Validated CRFs and femoral neck BMD by DXA, when available, provide the input for the World Health Organization fracture risk assessment tool (FRAX) to estimate the 10-year probability of fracture in untreated patients. Economic models have included FRAX in calculations to estimate when pharmacological intervention is likely to be cost-effective in reducing fracture risk. Cost-effectiveness is one of many factors to consider in making treatment decisions. This is a review of the benefits and limitations of BMD testing, CRFs, and FRAX in the management of patients in clinical practice. KeywordsOsteoporosis-Treatment-Prevention-Bone mineral density-BMD-T-score-Clinical risk factors-FRAX
  Clinical Reviews in Bone and Mineral Metabolism 04/2012; 8(3):101-112.
• Article: Biomechanics

  David B. Burr
  [show abstract] [hide abstract]
  ABSTRACT: Therapeutic agents used to treat osteoporosis reduce the incidence of vertebral and nonvertebral fractures in osteoporotic women. The antiremodeling agents, such as the bisphosphonates, prevent bone loss by suppressing the remodeling rate, perhaps increasing bone volume slightly, and increasing mineralization of the tissue. The anabolic agents, of which rhPTH(1–34) is the only one approved, accomplish this in a manner that is almost completely the opposite in terms of biological process. rhPTH(1–34) causes net bone gain by stimulating both modeling and remodeling, by increasing bone volume significantly through direct bone apposition to trabecular and endocortical surfaces, and by reducing the mean degree of tissue mineralization (a natural consequence of enhanced remodeling). Each of these treatments maintains or increases bone strength and is similarly effective at preventing fractures. However, because of their different mode of action, each has different consequences for bone matrix quality (defined here by microdamage accumulation and by the properties of mineral and collagen) and the mechanical properties of the tissue. Although bone's composite nature makes it a relatively tough material—more like fiberglass than glass—the accumulation of damage will nevertheless reduce its residual mechanical properties until the damage is repaired through remodeling. Agents that suppress remodeling are associated with both microdamage accumulation and increased mineralization. The biological importance of damage and mineralization to bone's mechanical properties is still a source of debate.
  Clinical Reviews in Bone and Mineral Metabolism 04/2012; 4(3):155-166.
• Article: Osteoporosis

  Sheryl Follin Vondracek, Judy T. Chen, Gyorgy Csako
  [show abstract] [hide abstract]
  ABSTRACT: Osteoporosis is the most common metabolic bone disease (>70 million cases worldwide) and an increasing cause of morbidity and mortality throughout the world. Over the past 10 yr, the understanding of bone physiology and remodeling and the pathophysiology of osteoporosis expanded dramatically. Paralleling these discoveries has been the development of new drugs for the management of osteoporosis with demonstrated efficacy in improving bone mineral density (BMD) and reducing fracture risk. Despite the availability of several Food and Drug Administration-approved agents with demonstrated efficacy and safety, osteoporosis remains a significant clinical problem. Many patients cannot take or tolerate currently available the rapies, and some patients do not adequately respond to treatment. Additionally, no existing therapy can completely eliminate fracture risk. Therefore, research continues to seek more effective and better-tolerated agents. In addition to agents that target unique aspects of bone resorption and bone formation, there are also drugs nearing approaval that that target multiple areas of the bone remodeling cycle and utilize unique dosage forms potentially maximizing efficacy, safety, and adherence. This article reviews bone remodeling, the pathophysiology of osteoporosis, and drug development in osteoporosis. Select agents with novel mechanisms of action or innovative dosing that are in or nearing human clinical trials are discussed, including cathepsin K inhibitors, nitrosylated nonsteroidal anti-inflammatory drugs (NO-NSAIDs), receptor activator of nuclear factor (NF)-KB ligand (RANKL) inhibitor (AMG 162), recombinant complex of insulin-like growth factor-I and insulin-like growth factor binding protein-3 (SomatoKine®), αvβ3-integrin receptor antagonists, and prote in tyrosine kinase Src inhibitors.
  Clinical Reviews in Bone and Mineral Metabolism 04/2012; 2(4):293-313.
• Article: The pagetic lesion

  Pierre J. Meunier
  Clinical Reviews in Bone and Mineral Metabolism 04/2012; 1(2):103-107.
• Article: Stress Response by Bone Cells and Implications on Microgravity Environment

  Rommel G. Bacabac, Jack J. W. A. Van Loon
  [show abstract] [hide abstract]
  ABSTRACT: Osteocytes are commonly referred to as the professional mechanosensors in bone tissue. Despite recent advances in the study of how bone tissue adapts to mechanical loading, much remains not understood concerning the cellular mechanisms involved. We have shown that bone cell monolayers in vitro release signaling molecules in response to dynamic stress loading in a rate-dependent manner. Fluid shear stress induces high release of nitric oxide (NO) at high rates, whereas vibration stress promotes high NO release but low prostaglandin E2 (PGE2) release at high rates, indicating the specificity for signaling molecule of the type of stress. Also, we show evidence that bone cells require a stress threshold in order to respond to loading. These observations collectively provide basis for hypothesizing a model defining tissue-mimetic mechanosensitivity as a function of the rate of stress above a threshold. Finally, at the cellular level, we show that shape and stiffness, evidently due to underlying cytoskeletal structure, contribute to mechanosensing. This leads to the notion that the mechanical properties of cells are a prerequisite to their tissue-level emergent mechanosensing behavior. Therefore, a condition of disturbed mechanics due to extreme unloading, as in an environment under microgravity, may lead to impaired mechanosensing. KeywordsOsteocytes–Shear stress–Mechanosensing–Cell mechanics–Microrheology–Cell traction–Microgravity–Cytoskeleton–Biopolymers–Networks
  Clinical Reviews in Bone and Mineral Metabolism 04/2012; 8(4):179-188.
• Article: Mechanisms of Osteocyte Mechanotransduction

  Astrid D. Bakker, Jenneke Klein-Nulend
  [show abstract] [hide abstract]
  ABSTRACT: Healthy bones combine a proper resistance against fracture with a minimum use of material. This property is likely brought about by osteocytes in response to mechanical cues, but it is still unknown how whole bone loads are translated into a signal that can be sensed by the osteocytes. The goal of this chapter is to critically analyze our current knowledge on how bone transduction takes place from the level of mechanical loads placed upon the bone as an organ to activation of a cell. KeywordsAdaptation–Osteocytes–Mechanotransduction–Fluid flow–Fluid shear stress–Strain
  Clinical Reviews in Bone and Mineral Metabolism 04/2012; 8(4):163-169.
• Article: Gap Junctions and Biophysical Regulation of Bone Cells

  Shane A. J. Lloyd, Henry J. Donahue
  [show abstract] [hide abstract]
  ABSTRACT: Communication between osteoblasts, osteoclasts, and osteocytes is integral to their ability to build and maintain the skeletal system and respond to physical signals. Various physiological mechanisms, including nerve communication, hormones, and cytokines, play an important role in this process. More recently, the important role of direct, cell–cell communication via gap junctions has been established. In this review, we demonstrate the integral role of gap junctional intercellular communication (GJIC) in skeletal physiology and bone cell mechanosensing. KeywordsGap junctions–Connexins–Mechanosensing–Mechanotransduction–Cell-to-cell communication–Intercellular communication–Osteocytes
  Clinical Reviews in Bone and Mineral Metabolism 04/2012; 8(4):189-200.
• Article: Bisphosphonates in Osteogenesis Imperfecta

  Moira S. Cheung, Francis H. Glorieux
  [show abstract] [hide abstract]
  ABSTRACT: Osteogenesis Imperfecta (OI) is a rare heritable condition characterized by bone fragility and reduced bone mass. Most affected individuals carry a mutation that compromises the synthesis and/or the structural organization of type I collagen. Histologically there is a picture of osteoporosis with increased remodeling rate. On that basis, bisphosphonate treatment was introduced, and definite benefits, in terms of pain control, fracture incidence and degree of ambulation, became rapidly evident. Cyclical intravenous pamidronate is now the standard of care for moderate/severe OI in combination with appropriate orthopedic corrections and rehabilitation programs. While it is amply demonstrated that the use of bisphosphonates in OI is effective and safe for the short term (4–5years), their long term effects are still under investigation.
  Clinical Reviews in Bone and Mineral Metabolism 04/2012; 5(3):159-164.
• Article: Osteogenesis imperfecta

  Nick Bishop
  [show abstract] [hide abstract]
  ABSTRACT: Osteogenesis imperfecta is the most common inherited form of bone disease resulting in osteoporosis in childhood. Progress in the field has been swift over the last decade with the introduction of new forms of medical therapy, such as bisphosphonates, and the appreciation of the need for a multidisciplinary approach to the condition. Progress is also being made in the genetic models for the condition, which should enhance our understanding of the pathophysiology and potential for alternative routes to effective treatment.
  Clinical Reviews in Bone and Mineral Metabolism 04/2012; 2(1):19-35.
• Article: Inhibiting Cysteine Cathepsins in the Bone: New Functions and Off-Target Effects

  Izabela Podgorski
  Clinical Reviews in Bone and Mineral Metabolism 04/2012; 9(2):81-82.