Tag Archives: review

Review: New Treatments

Abstract

New developments in the treatment of osteoporosis.

The last 25 years have seen the development of a plethora of new, effective agents for the treatment of osteoporosis. These agents reduce the risk of spine fractures by up to 70%, hip fractures by 40-50% and non-vertebral fractures by up to 50-80%. Amino-bisphosphonates, taken orally or intravenously, remain the dominant treatment modalities for osteoporosis. These so-called anti-resorptive or anti-catabolic agents stabilize the skeleton and reduce fracture risk in osteoporotic as well as osteopenic individuals. A monoclonal antibody against receptor activator of nuclear factor κB ligand, Denosumab, constitutes a new anti-resorptive agent recently approved worldwide. In younger postmenopausal women, low-dose estrogen or estrogen/progestin still has a place for short-term (up to 5 years) preservation of bone mass, especially in women with menopausal symptoms. Likewise, selective estrogen receptor modulators should be considered in younger postmenopausal women, especially those at increased risk of breast cancer. Anabolic (bone forming) regimens, of which parathyroid hormone is the only agent currently available, aid in the build up of new bone, increase bone mass and improve bone architecture. In cancellous bone, 30-60% increases of bone mass have been documented, but cortical bone thickness also increases. These improvements lead to profound reduction in fracture rates in both the axial and appendicular skeleton. Owing to cost and the need for parenteral administration, in most countries these agents are reserved for severe osteoporosis with multiple fractures.

Eriksen EF, Halse J, Moen MH
Acta Obstet Gynecol Scand Jun 2013
PMID: 22646526

Review: Incretins May Stimulate Osteoblasts and Suppress Osteoclasts

Abstract

[Incretin and bone].

Gastrointestinal hormones including gastric inhibitory polypeptide (GIP) and glucagon-like peptide (GLP) -1 are incretin, which are secreted immediately after meal ingestion and stimulate insulin secretion from pancreatic beta-cells. Characterization of extra-pancreatic GIP and GLP-1 receptors has revealed that these hormones regulate bone turnover. GIP intermittently stimulates osteoblasts and GLP-1 suppresses osteoclasts through a calcitonin-dependent pathway to increase the bone volume.

Yamada Y
Clin Calcium Sep 2009
PMID: 19721203

Review: Incretins and Bone

Abstract

Incretins and bone: evolving concepts in nutrient-dependent regulation of bone turnover.

Postprandial variation of bone turnover markers and the closed relationship between bone remodeling and nutrient supply has been extensively studied in the past few years, but the underlying pathophysiologic mechanisms remain largely unknown. Recent studies have shown that the acute regulation of bone turnover induced by feeding is probably mediated by gastrointestinal (GI) peptides. The greater response of bone remodeling during oral versus intravenous glucose administration and the inhibition of this response after administration of octreotide, that inhibits the release of GI peptides, further support the existence of a gutbone axis. Glucose-dependent insulinotropic peptide and glucagon-like peptides-1 and -2 are released from K and L cells of the gastrointestinal tract, respectively, and are considered the main mediators of the postprandial response of bone turnover. In this review we outline the most recent evidence that demonstrates the role of incretins in nutrient-dependent regulation of bone metabolism. Further elucidation of the underlying mechanisms can be exploited therapeutically in the future.

Yavropoulou MP, Yovos JG
Hormones (Athens)
PMID: 23933690 | Free Full Text

Review: Vitamin K2 (MK-4) Monotherapy Modestly Increases Bone Density and Reduces Fractures in Eight Studies

Abstract

Vitamin k2 therapy for postmenopausal osteoporosis.

Vitamin K may play an important role in the prevention of fractures in postmenopausal women with osteoporosis. Menatetrenone is the brand name of a synthetic vitamin K2 that is chemically identical to menaquinone-4. The present review study aimed to clarify the effect of menatetrenone on the skeleton in postmenopausal women with osteoporosis, by reviewing the results of randomized controlled trials (RCTs) in the literature. RCTs that investigated the effect of menatetrenone on bone mineral density (BMD), measured by dual-energy X-ray absorptiometry and fracture incidence in postmenopausal women with osteoporosis, were identified by a PubMed search for literature published in English. Eight studies met the criteria for RCTs. Small RCTs showed that menatetrenone monotherapy decreased serum undercarboxylated osteocalcin (ucOC) concentrations, modestly increased lumbar spine BMD, and reduced the incidence of fractures (mainly vertebral fracture), and that combined alendronate and menatetrenone therapy enhanced the decrease in serum ucOC concentrations and further increased femoral neck BMD. This review of the literature revealed positive evidence for the effects of menatetrenone monotherapy on fracture incidence in postmenopausal women with osteoporosis. Further studies are required to clarify the efficacy of menatetrenone in combination with bisphosphonates against fractures in postmenopausal women with osteoporosis.

Iwamoto J
Nutrients 2014
PMID: 24841104 | Free Full Text

One interesting passage from the full text talks about the unpublished dose range study from Japan:

Orimo, H., et al. “Clinical evaluation of soft capsule menatetrenone (Ea-0167) in the treatment of osteoporosis: late phase II dose study.” J New Remedies Clinics 41 (1992): 1249-79.

A dose-finding study of menatetrenone in Japan [7] administered daily doses of 15, 45, 90, and 135 mg and revealed that 45 mg was the minimum effective dose for improving bone mass parameters evaluated by microdensitometry and/or single photon absorptiometry in postmenopausal women with osteoporosis. This optimal dose (45 mg/day) for the treatment of osteoporosis is about 150–180 times greater than the recommended daily dietary intake of vitamin K (250–300 μg) [8]. No toxic effects of menatetrenone (45 mg/day) have been reported [7]. High-dose vitamin K is needed to prevent fractures in postmenopausal women with osteoporosis [9]. However, the effect of menatetrenone on the skeleton remains a matter of controversy [10–17], and the role of menatetrenone in the treatment of osteoporosis therefore needs to be clarified.

Review: Exercise Only Beneficial with Calcium > 1000mg per Day

Abstract

Evidence for an interaction between calcium intake and physical activity on changes in bone mineral density.

Results of trials on the effects of physical activity on bone mineral density (BMD) are conflicting. The current hypothesis was that calcium intake modifies the bone response to physical activity. Published trials on physical activity and bone density were reviewed, and the results of 17 trials are summarized. Physical activity has beneficial effects on BMD at high calcium intakes, with no effect at mean calcium intakes less than a mean of 1000 mg/day. The modifying effect of calcium intake on BMD among exercise groups is more pronounced in the lumbar spine than in the radius. This analysis may explain conflicting results of trials on physical activity and calcium effects on bone. Controlled trials designed to test adequately this hypothesis are needed.

Specker BL
J. Bone Miner. Res. Oct 1996
PMID: 8889855

Review: Dyslipidemia and Disabetes Associated with Fractures

Abstract

[Bone diseases caused by impaired glucose and lipid metabolism].

The number of patients with lifestyle-related diseases is rapidly increasing in Japan. Metabolic syndrome caused by abdominal fat accumulation induces diabetes mellitus, dyslipidemia, and hypertension, resulting in an increase in cardiovascular diseases. On the other hand, recent studies have shown that the lifestyle-related diseases are risk factors of osteoporotic fractures. Although it remains still unclear how metabolic disorders affect bone tissue, oxidative stress and/or glycation stress might directly have negative impacts on bone tissue and increase the risk of fractures. In this review, we describe the association of diabetes mellitus and dyslipidemia with the fracture risk through oxidative stress and glycation stress.

Kanazawa I, Sugimoto T
Clin Calcium Nov 2013
PMID: 24162600

Review: Strontium Increases Bone Formation and Reduces Resorption, but may Increase Risk of Venous Thromboembolism

Abstract

Strontium ranelate: a review of its use in the treatment of postmenopausal osteoporosis.

This is a review of the pharmacology of strontium ranelate (Protelos, Protos, Protaxos, Bivalos, Osseor), and its efficacy and tolerability in the treatment of patients with postmenopausal osteoporosis. Strontium ranelate is a divalent strontium salt of ranelic acid that is capable of increasing bone formation and reducing bone resorption, thereby uncoupling and rebalancing bone turnover in favour of bone formation. The drug is effective in reducing the risk of fractures, including both vertebral and nonvertebral fractures, in patients with postmenopausal osteoporosis, according to data from two large, double-blind, placebo-controlled, multicentre trials of 5 years’ duration, and reduced the risk of hip fracture in high-risk patients in a post hoc analysis of one trial. Moreover, data from patients who continued to receive the drug during the 3-year extension phases of these trials indicate that strontium ranelate continues to provide protection against new vertebral fractures and nonvertebral fractures for up to 8 years of therapy. It also improves bone mineral density at numerous sites and both increases markers of bone formation and decreases markers of bone resorption. Strontium ranelate is administered orally as a suspension and is generally well tolerated. The nature of adverse events was generally similar regardless of treatment duration in clinical trials, with the most commonly reported being nausea and diarrhoea over 5 years of treatment, and memory loss and diarrhoea during longer-term treatment. Although an increased risk of venous thromboembolism was associated with strontium ranelate relative to placebo over 5 years of treatment in a pooled analysis of clinical trials, postmarketing data have not confirmed this finding. Overall, the clinical data available suggest that strontium ranelate is an effective and generally well tolerated option for the first-line treatment of postmenopausal osteoporosis.

Deeks ED, Dhillon S
Drugs Apr 2010
PMID: 20394457

Review: PGE2 is Complicated

The prostaglandin E(2) system: a toolbox for skeletal repair?

Gelse K, Beyer C
Arthritis Rheum. Apr 2011
PMID: 21190302 | Free Full Text

Prostaglandin E2 (PGE2), the most widely produced member of the prostaglandin group, originates from arachidonic acid that is released from the cell membrane by phospholipase A2, followed by enzymatic conversion by cyclooxygenase (COX) and PGE synthase 1 (PGES-1). PGE2 not only triggers pain and inflammation but also promotes matrix degradation and tissue damage by stimulating the expression of matrix-degrading enzymes (2). Inflammatory cytokines such as interleukin-1 or tumor necrosis factor ’ strongly increase PGE2 levels, but PGE2 secretion may also increase in response to other stimuli including growth factors, hypoxia, and a number of hormones.

Apart from the well-defined role of PGE2 in tissue inflammation, there is increasing evidence that it is involved in the maintenance and repair of the skeletal system. At first glance, the effects of PGE2 on tissue homeostasis of bone and cartilage seem confusing, because they conflict with the long-known destructive potential of the prostaglandins. Nevertheless, both catabolic and anabolic effects have already been described for PGE2 in these tissues. In terms of catabolism, PGE2 can promote osteoclastic bone resorption (3,4) and enhance breakdown of the extracellular matrix by increasing the expression of matrix metalloproteinase 3 (MMP-3) or MMP-13 (2,5). Regarding its anabolic aspects, PGE2 may stimulate chondrogenesis, chondrocyte proliferation (6), cartilage matrix synthesis (7), as well as osteoblast activity (8). To shed light on the apparent ambivalent role of PGE2, a multidimensional view is necessary that addresses the developmental stage, type of tissue, disease status, concentration of PGE2, and specific receptor status of the different cell types.

 

Review: Vitamin K Reviewed by European Vitamin K Experts

Abstract

Beyond deficiency: potential benefits of increased intakes of vitamin K for bone and vascular health.

Vitamin K is well known for its role in the synthesis of a number of blood coagulation factors. During recent years vitamin K-dependent proteins were discovered to be of vital importance for bone and vascular health. Recommendations for dietary vitamin K intake have been made on the basis of the hepatic requirements for the synthesis of blood coagulation factors. Accumulating evidence suggests that the requirements for other functions than blood coagulation may be higher. This paper is the result of a closed workshop (Paris, November 2002) in which a number of European vitamin K experts reviewed the available data and formulated their standpoint with respect to recommended dietary vitamin K intake and the use of vitamin K-containing supplements.

Vermeer C, Shearer MJ, Zittermann A, Bolton-Smith C…
Eur J Nutr Dec 2004
PMID: 15309455 | Free Full Text

Accumulating evidence suggests that in many aspects arterial calcification mimics bone formation, which prompts interest in the effects of vitamin K on the vasculature. Previous population-based studies reported a significant reduction in aortic calcification with high vitamin K1 [62] and vitamin K2 intake [63], and a significant inverse correlation was found between vitamin K2 intake, and the incidence of both ischaemic heart disease and cardiovascular mortality [63]. Based on these findings the effect of treatment on arterial characteristics was monitored in the Maastricht osteostudy. These unpublished findings clearly demonstrated that supplementation with vitamin K1 can protect against vascular hardening and loss of arterial elasticity. High dose MK-4 also seems to have cholesterol lowering properties as shown in studies in rabbits [64] and humans [65].

[…]

Extremely high doses (45–90mg/day) of MK-4 have been used for the treatment of postmenopausal osteoporosis in Japan for several years [66, 67]. After the positive outcomes of the first clinical trials, the treatment is now used on a large scale; thus far, no adverse side-effects have been reported. A number of independent groups have claimed that this medication results in complete prevention of further bone loss in postmenopausal women, and in some women even a significant gain in BMD [68, 69]. The treatment was also reported to be successful in other groups at risk for bone loss such as haemodialysis patients and those treated with corticosteroids.

[…]

In considering the potential efficacy of pharmacological doses of MK-4 it should be noted that there is evidence for a secondary function of this analogue over and above its role in glutamate carboxylation. The available evidence (mainly from cell culture experiments) suggests that MK-4 (but not K1) may also be associated with production of interleukin-6, regulate the synthesis of PGE2 [83], or inhibit the mevalonate pathway in a comparable way to bisphosphonates [84], but at present only preliminary data exist.

[…]

Any risks associated with relatively high consumption of either K1 or K2 appear minimal, with intakes up to 1 mg/d K1 and 45 mg/d MK-4 often having been used without observed adverse events. Two possible exceptions exist. Firstly a potential problem relates to interference with oral anticoagulants. However, a systematic dose-response study among subjects on oral anticoagulant treatment demonstrated that the stability of anticoagulation was not significantly affected by vitamin K supplements at doses below 100 μg/day [14]. Secondly, preliminary studies have suggested that high vitamin K1 supplementation (i. e. above 1 mg/day) can contribute to periodontal disease via a bacterial mechanism on gingival tissue (S. Hodges, unpublished data).

 

 

Review: Glucosamine Might Increase Osteoblasts and Suppress Resorption

Abstract

Biological activities of glucosamine and its related substances.

Glucosamine (GlcN) has been widely used to treat osteoarthritis (OA) in humans. We revealed that among GlcN-derivatives (GlcN and N-acetyl-d-glucosamine) and uronic acids (d-glucuronic acid and d-galacturonic acid), only GlcN induces the production of hyaluronic acid (HA) by synovial cells and chondrocytes, and the production level is much higher (>10-fold) in synovial cells compared with chondrocytes. Moreover, GlcN increases the expression of HA-synthesizing enzymes (HAS) in synovial cells and chondrocytes. These observations indicate that GlcN likely exhibits the chondroprotective action on OA by modulating the expression of HAS and inducing the production of HA (a major component of glycosaminoglycans contained in the synovial fluid) especially by synovial cells. The pathological change of subchondral bone is implicated in the initiation and progression of cartilage damage in OA. Thus, we further determined the effect of GlcN on the bone metabolism (osteoblastic cell differentiation). The results indicated that GlcN increases the mineralization of mature osteoblasts and the expression of middle and late stage markers (osteopontin and osteocalcin, respectively) during osteoblastic differentiation, and reduces the expression of receptor activator of NF-κB ligand (RANKL), a differentiation and activation factor for osteoclasts. These observations likely suggest that GlcN has a potential to induce the osteoblastic cell differentiation and suppress the osteoclastic cell differentiation, thereby increasing bone matrix deposition and decreasing bone resorption to modulate bone metabolism in OA.

Nagaoka I, Igarashi M, Sakamoto K
Adv. Food Nutr. Res. 2012
PMID: 22361198