Emerging concepts in the epidemiology, pathophysiology, and clinical care of osteoporosis across the menopausal transition.

Bone loss in women accelerates during perimenopause, and continues into old age. To-date, there has been little progress made in stratifying for fracture risk in premenopausal and early postmenopausal women. Epidemiologic data suggests that changes in serum FSH could predict decrements in bone mass during peri- and postmenopause. In bone, FSH stimulates osteoclast formation by releasing osteoclastogenic cytokines. Here, we address the evidence for bone loss across the menopausal transition, discuss strategies for detection and treatment of early postmenopausal osteoporosis, and describe the role FSH plays in physiology and likely in pathophysiology of early postmenopausal bone loss.

Corrigendum to "The Alliance of Mesenchymal Stem Cells, Bone, and Diabetes".

[This corrects the article DOI: 10.1155/2014/690783.].

Metabolic Bone Disease in the Post-transplant Population: Preventative and Therapeutic Measures.

Post-transplant bone disease contributes significantly to patients' morbidity and mortality after transplantation and has an impact on their quality of life. This article discusses the major contributors to mechanisms causing bone loss, highlighting the role of preexisting disease in both kidney and liver failure and contributions from glucocorticoids and calcineurin inhibitors. Suggested monitoring and investigations are reviewed as well as treatment as far as the current literature supports, emphasizing the difference between kidney and liver recipients.

Questioning the association between bisphosphonates and atypical femoral fractures.

Bisphosphonates are the first-line treatment for osteoporosis. Structurally, they are stable analogues of pyrophosphate and therefore exhibit a high affinity for bone mineral. They reduce bone loss by attenuating the ability of the osteoclast to resorb bone, decreasing activation frequency, and the rate of remodeling. Large prospective randomized placebo-control trials provide unequivocal evidence for a reduction in the incidence of fractures. Impressively, 40 years since their first use in patients, the safety profile of bisphosphonates has been equally reassuring. Questions have arisen lately as to whether bisphosphonates could cause atypical fractures, a rare type of atraumatic or minimal trauma femur fracture occurring below the great trochanter. This question has prompted calls for a broader examination of the long-term effects of bisphosphonate use. An attempt by the Food and Drug Administration to garner consensus and provide definitive views was not successful. This has led to continued anxiety among treating physicians and patients alike, resulting in an overall reduction in prescriptions for bisphosphonates and for osteoporosis therapies in general. Here, we provide an overview of the current data on atypical fractures and bisphosphonate use.

Secondary osteoporosis: pathophysiology & diagnosis.

Osteoporosis is a skeletal disease characterized by decreased bone mass and microarchitectural changes in bone tissue that increase the susceptibility to fracture. Secondary osteoporosis is loosely defined as low bone mineral density or increased risk of fragility fracture caused by any factor other than aging or postmenopausal status. The purpose of this review is to discuss the current understanding of the pathophysiology and contribution to fracture risk of many of the more common causes of secondary osteoporosis, as well as diagnostic considerations, outlined by organ system. While not comprehensive, included are a wide array of diseases, conditions, and medications that have been associated with bone loss and susceptibility to fractures. The hope is to highlight the importance to the general clinician of screening for and treating the osteoporosis in these patients, so to limit the resultant increased morbidity associated with fractures.

The alliance of mesenchymal stem cells, bone, and diabetes.

Bone fragility has emerged as a new complication of diabetes. Several mechanisms in diabetes may influence bone homeostasis by impairing the action between osteoblasts, osteoclasts, and osteocytes and/or changing the structural properties of the bone tissue. Some of these mechanisms can potentially alter the fate of mesenchymal stem cells, the initial precursor of the osteoblast. In this review, we describe the main factors that impair bone health in diabetic patients and their clinical impact.

The effect of dipeptidyl peptidase-IV inhibition on bone in a mouse model of type 2 diabetes.

BACKGROUND: Individuals with type 2 diabetes (T2D) are at greater risk of bone fractures than those without diabetes. Certain oral diabetic medications may further increase the risk of fracture. Dipeptidyl peptidase-IV (DPP-IV) inhibitors are incretin-based therapies that are being increasingly used for the management of T2D. It has been hypothesized that these agents may reduce fracture risk in those with T2D. In this study, we used a mouse model of T2D to examine the effects of the DPP-IV inhibitor, MK-0626, on bone. METHODS: Male wild type (WT) and diabetic muscle-lysine-arginine (MKR) mice were treated with MK-0626, pioglitazone, alendronate or vehicle. The effects of treatment with MK-0626 on bone microarchitecture and turnover were compared with treatment with pioglitazone, alendronate and vehicle. Osteoblast differentiation was determined by alkaline phosphatase staining of bone marrow cells from WT and MKR mice after treatment with pioglitazone, MK-0626 or phosphate buffered saline. RESULTS: We found that MK-0626 had neutral effects on cortical and trabecular bone in diabetic mice. Pioglitazone had detrimental effects on the trabecular bone of WT but not of diabetic mice. Alendronate caused improvements in cortical and trabecular bone architecture in diabetic and WT mice. MK-0626 did not alter osteoblast differentiation, but pioglitazone impaired osteoblast differentiation in vitro. CONCLUSIONS: Overall, the DPP-IV inhibitor, MK-0626, had no adverse effects on bone in an animal model of T2D or directly on osteoblasts in culture. These findings are reassuring as DPP-IV inhibitors are being widely used to treat patients with T2D who are already at an increased risk of fractures.

Quality of life in sarcopenia and frailty.

The reduced muscle mass and impaired muscle performance that define sarcopenia in older individuals are associated with increased risk of physical limitation and a variety of chronic diseases. They may also contribute to clinical frailty. A gradual erosion of quality of life (QoL) has been evidenced in these individuals, although much of this research has been done using generic QoL instruments, particularly the SF-36, which may not be ideal in older populations with significant comorbidities. This review and report of an expert meeting presents the current definitions of these geriatric syndromes (sarcopenia and frailty). It then briefly summarizes QoL concepts and specificities in older populations and examines the relevant domains of QoL and what is known concerning QoL decline with these conditions. It calls for a clearer definition of the construct of disability, argues that a disease-specific QoL instrument for sarcopenia/frailty would be an asset for future research, and discusses whether there are available and validated components that could be used to this end and whether the psychometric properties of these instruments are sufficiently tested. It calls also for an approach using utility weighting to provide some cost estimates and suggests that a time trade-off study could be appropriate.

Transplantation osteoporosis.

Transplantation provides a valuable, often life-saving, treatment for end-stage failure of many organs, including the heart, kidneys, liver, pancreas and lungs. It is also an important therapeutic option in diseases of the bone marrow and the immune system. Despite the undoubted benefits for transplant patients, it is associated with an increased risk of many complications. The potential causes include: poor general health of the patient, heavy burden of the surgery itself and the need for the long-term use of immunosuppression. In addition, the patients are also on numerous other medications, e.g. anti-coagulants, diuretics. Osteoporosis and high risk of fractures have emerged as frequent and devastating complications of the transplantation process. This article provides a review of the current literature on osteoporosis after transplantation, and the treatment options for this serious illness.

Type 2 diabetic mice demonstrate slender long bones with increased fragility secondary to increased osteoclastogenesis.

Type 2 diabetics often demonstrate normal or increased bone mineral density, yet are at increased risk for bone fracture. Furthermore, the anti-diabetic oral thiazolidinediones (PPARgamma agonists) have recently been shown to increase bone fractures. To investigate the etiology of possible structural and/or material quality defects, we have utilized a well-described mouse model of Type 2 diabetes (MKR). MKR mice exhibit muscle hypoplasia from birth with reduced mass by the pre-diabetic age of 3 weeks. A compensatory hyperplasia ensues during early (5 weeks) development; by 6-8 weeks muscle is normal in structure and function. Adult whole-bone mechanical properties were determined by 4-point bending to test susceptibility to fracture. Micro-computed tomography and cortical bone histomorphometry were utilized to assess static and dynamic indices of structure, bone formation and resorption. Osteoclastogenesis assays were performed from bone marrow-derived non-adherent cells. The 8-week and 16-week, but not 3-week, male MKR had slender (i.e., narrow relative to length) femurs that were 20% weaker (p<0.05) relative to WT control femurs. Tissue-level mineral density was not affected. Impaired periosteal expansion during early diabetes resulted from 250% more, and 40% less of the cortical bone surface undergoing resorption and formation, respectively (p<0.05). Greater resorption persisted in adult MKR on both periosteal and endosteal surfaces. Differences were not limited to cortical bone as the distal femur metaphysis of 16 week MKR contained less trabecular bone and trabecular separation was greater than in WT by 60% (p<0.05). At all ages, MKR marrow-derived cultures demonstrated the ability for enhanced osteoclast differentiation in response to M-CSF and RANK-L. Taken together, the MKR mouse model suggests that skeletal fragility in Type 2 diabetes may arise from reduced transverse bone accrual and increased osteoclastogenesis during growth that is accelerated by the diabetic/hyperinsulinemic milieu. Further, these results emphasize the importance of evaluating diabetic bone based on morphology in addition to bone mass.

Diabetes and fragility fractures - a burgeoning epidemic?

Diabetes and osteoporosis are both diseases of epidemic proportions whose incidence is increasing worldwide. The etiology of osteoporosis is multifactorial and may differ for type 1(T1DM) as compared to type 2 (T2DM). Fragility fractures are common to both types of diabetes with hip fractures occurring more frequently in the elderly T2DM population. The use of oral PPAR gamma agonists in the treatment of T2DM has also added to the risk of fracture. This perspective discusses the etiologies and issues relating to the association of diabetes with osteoporosis and fractures and suggests some theories to clarify the underlying pathophysiology. Unfortunately at this time treatment for osteoporosis and fractures remains empirical.

Once-monthly oral ibandronate compared with weekly oral alendronate in postmenopausal osteoporosis: results from the head-to-head MOTION study.

OBJECTIVE: Oral ibandronate 150 mg is the first bisphosphonate approved for once-monthly treatment of postmenopausal osteoporosis. To investigate whether once-monthly ibandronate 150 mg increases lumbar spine and total hip bone mineral density (BMD) to the same degree as weekly alendronate 70 mg. RESEARCH DESIGN AND METHODS: This was a 12-month, randomised, multinational, multicentre, double-blind, double-dummy, parallel-group, non-inferiority trial, conducted in 65 centres in North America, Latin America, Europe and South Africa. The study included postmenopausal women, mean lumbar spine (L2-L4) BMD T-score < -2.5 and > or = -5.0. Patients received either ibandronate 150 mg once monthly or alendronate 70 mg once weekly. MAIN OUTCOME MEASURES: Co-primary efficacy endpoints were 12-month change (%) from baseline in mean lumbar spine and total hip BMD. Changes (%) from baseline in trochanter and femoral neck BMD were also evaluated. Adverse events were monitored throughout. Once-monthly ibandronate was considered non-inferior to weekly alendronate if the lower boundary of the one-sided 97.5% confidence interval (CI) (or two-sided 95% CI) was > or = -1.41% for lumbar spine and > or = -0.87% for total hip. RESULTS: Mean relative 12-month changes were 5.1% and 5.8% (95% CI for difference, -1.13, -0.23) in lumbar spine and 2.9% and 3.0% (95% CI for difference, -0.38, 0.18) in total hip BMD with once-monthly ibandronate and weekly alendronate, respectively; meeting the non-inferiority criteria at both sites. Gains in trochanter and femoral neck BMD were similar with both treatments. Both regimens were well tolerated. TRIAL REGISTRATION: The MOTION study is registered with the International Federation of Pharmaceutical Manufacturers and Associations trial portal, under the ID number MM17385. CONCLUSIONS: Once-monthly ibandronate was shown to be clinically comparable to weekly alendronate at increasing BMD after 12 months in both the lumbar spine and total hip.

Is cortical bone hip? What determines cortical bone properties?

Increased bone turnover may produce a disturbance in bone structure which may result in fracture. In cortical bone, both reduction in turnover and increase in hip bone mineral density (BMD) may be necessary to decrease hip fracture risk and may require relatively greater proportionate changes than for trabecular bone. It should also be noted that increased porosity produces disproportionate reduction in bone strength, and studies have shown that increased cortical porosity and decreased cortical thickness are associated with hip fracture. Continued studies for determining the causes of bone strength and deterioration show distinct promise. Osteocyte viability has been observed to be an indicator of bone strength, with viability as the result of maintaining physiological levels of loading and osteocyte apoptosis as the result of a decrease in loading. Osteocyte apoptosis and decrease are major factors in the bone loss and fracture associated with aging. Both the osteocyte and periosteal cell layer are assuming greater importance in the process of maintaining skeletal integrity as our knowledge of these cells expand, as well being a target for pharmacological agents to reduce fracture especially in cortical bone. The bisphosphonate alendronate has been seen to have a positive effect on cortical bone by allowing customary periosteal growth, while reducing the rate of endocortical bone remodeling and slowing bone loss from the endocortical surface. Risedronate treatment effects were attributed to decrease in bone resorption and thus a decrease in fracture risk. Ibandronate has been seen to increase BMD as the spine and femur as well as a reduced incidence of new vertebral fractures and non vertebral on subset post hoc analysis. And treatment with the anabolic agent PTH(1-34) documented modeling and remodelling of quiescent and active bone surfaces. Receptor activator of nuclear factor kappa B ligand (RANKL) plays a key role in bone destruction, and the human monoclonal antibody denosumab binds to RANKL, inhibiting its action and thus improving BMD significantly.

The problem of low levels of vitamin D and osteoporosis: use of combination therapy with alendronic acid and colecalciferol (vitamin D3).

Osteoporosis and fragility fractures are common in the elderly population and represent a large public health burden. Non-pharmacological recommendations for the management of osteoporosis include modification of lifestyle behaviours, increased weight-bearing exercise and consumption - through dietary or supplement sources - of adequate amounts of calcium and vitamin D. Although current guidelines include recommendations on calcium and vitamin D intake, patients frequently do not take sufficient amounts, even when supplements are provided free of charge. Vitamin D is essential for mineral metabolism, and low levels are associated with impaired skeletal metabolism and neuromuscular function. Nutritional sources of vitamin D are limited, and supplementation is usually necessary. A high prevalence of low vitamin D levels has been reported in a number of populations worldwide, including women being treated for osteoporosis and those with fragility fractures. At present, bisphosphonates are the most commonly prescribed pharmacological treatments for osteoporosis, and alendronic acid is the most frequently prescribed bisphosphonate. A nitrogen-containing bisphosphonate, alendronic acid has demonstrated anti-fracture efficacy at vertebral and non-vertebral skeletal sites, including the hip, in addition to long-term safety and efficacy. Weekly administration of alendronic acid takes advantage of the pharmacokinetics of the drug and osteoclast biology to optimise treatment, and may improve patient adherence. Combining alendronic acid 70mg and colecalciferol (vitamin D(3)) 2800 IU in a single, once-weekly tablet has the advantage of combining the proven efficacy of an established bisphosphonate, alendronic acid, with the amount of vitamin D currently recommended for osteoporosis management.

Oral ibandronate in the management of postmenopausal osteoporosis: review of upper gastrointestinal safety.

Oral daily bisphosphonates carry a potential for gastrointestinal (GI) adverse events, which has been partly addressed by introducing once-weekly regimens. Nevertheless, the need to follow inconvenient dosing instructions every week could still hinder long-term compliance and therapeutic outcome. In addition, survey data indicates that many patients would prefer a once-monthly rather than once-weekly bisphosphonate dosing regimen. Ibandronate is a potent, nitrogen-containing bisphosphonate specifically developed for less frequent administration. In a pivotal study in postmenopausal osteoporosis, oral ibandronate, administered daily or with a between-dose interval of >2 months, demonstrated robust antifracture efficacy and an overall incidence of upper GI adverse events similar to placebo, even in patients at increased risk of such events. This and other clinical studies conducted in postmenopausal women demonstrate that oral ibandronate has an excellent upper GI safety profile.