Treatment Of Metabolic Bone Disorders Research Articles

Ethanolic Extract of Rubus coreanus Fruits Inhibits Bone Marrow-Derived Osteoclast Differentiation and Lipopolysaccharide-Induced Bone Loss

The inhibition of osteoclast differentiation/bone resorption is a well-known therapeutic strategy for controlling pathological and postmenopausal bone loss. Natural products that specifically inhibit osteoclastogenesis could therefore be developed as antiresorptive drugs for the treatment of metabolic bone disorders characterized by excessive osteoclastic bone resorption. We therefore examined the effects of Rubus coreanus extract (eeRc) on receptor activator of nuclear factor kappa-B ligand (RANKL)-induced differentiation of bone marrow macrophages (BMMs) into osteoclasts and pit formation in vitro. Additionally, the in vivo effects of the eeRc were observed in mice with lipopolysaccharide (LPS)-induced bone erosion. In this study, we found that the ethanolic extract of Rubus coreanus fruits considerably suppressed the RANKL-induced differentiation of primary BMMs into osteoclasts and bone-resorbing activity of mature osteoclasts. Oral administration of eeRc attenuated LPS-induced bone loss in vivo, as demonstrated by the reversal of LPS-induced reduction in bone volume per tissue volume, bone mineral density, and trabecular number to some extent in eeRc-treated mice. In addition, eeRc slightly decreased the serum levels of C-terminal telopeptide fragments of type I collagen, the collagen-breakdown product generated by osteoclasts. Collectively, our results indicate that eeRc has the potential to inhibit bone loss by blocking osteoclast differentiation and could therefore be a promising natural product for the prevention and/or treatment of inflammatory bone loss.

Update on recent progress in vitamin D research. Treatment of metabolic bone disorders by vitamin D.

Vitamin D is indispensable for bone health and calcium metabolism, and decreased action of vitamin D causes various abnormalities in bone metabolism. Severe vitamin D deficiency causes osteomalacia/rickets. Even milder vitamin D insufficiency could still be harmful for bone health via secondary hyperparathyroidism and bone loss, and could also lead to increased risk of falling. Osteomalacia/rickets associated with impaired vitamin D action should be treated by either native or active vitamin D3, depending on its etiology. As for osteoporosis, vitamin D repletion is important to adequate therapeutic effects of anti-resorptives. As a monotherapy, eldecalcitol, active vitamin D3 analogue, has been shown to increase bone mineral density and to decrease the incidence of vertebral fractures with significantly greater efficacy compared to active vitamin D3.

Growth hormone and bone diseases.

Recombinant human GH is now widely used for the treatment of short stature in diseases other than growth hormone deficiency. GH treatment increases bone mineral density in growth hormone deficiency, but a study using conventional method for the calculation of volumetric bone mineral density suggested that this effect was mainly due to the increase in bone size. A more accurate method for the evaluation of volumetric bone mineral density is needed. The effect of GH on mineral metabolism is another point of interest. GH administration induced dramatic changes in serum levels of mineral regulating hormones such as PTH and active vitamin D metabolites. These changes may provide us with new methods for the treatment of metabolic bone disorders.

Identification of adenine nucleotide-containing metabolites of bisphosphonate drugs using ion-pair liquid chromatography–electrospray mass spectrometry

Bisphosphonates are synthetic pyrophosphate analogues, which are used as therapeutic drugs for the treatment of metabolic bone disorders. Some of these bisphosphonates can be metabolised in cells into non-hydrolysable nucleotide analogues. In this paper, we describe an ion-pairing high-performance liquid chromatography method that is compatible with negative ion electrospray mass spectrometry for the separation of these metabolites. Tandem mass spectrometry and collision-induced dissociation (CID) were used for identification of the metabolites. The CID mass spectra of bisphosphonate–adenine nucleotide adducts are very informative, because major fragment ions are formed by cleavage of the bisphosphonate moiety from the conjugate. The method was used for detection of the nucleotide metabolites of clodronate, tiludronate and etidronate in extracts from mammalian cells after treatment with bisphosphonates.

Human pharmacokinetics of tiludronate

Tiludronate is a bisphosphonate evaluated extensively as an osteoregulator in the treatment of metabolic bone disorders. It is highly polar and has a low and variable oral absorption similar to its related compounds. An absolute bioavailability of approximately 6% has been reported with large inter- and intra-subject variability. The extent of absorption is increased at doses above 400 mg and may be reduced by a factor of 5 when tiludronate is administered with, or within 2 h after, food or dairy products. Approximately 90% of tiludronate is bound to serum albumin, and the binding is linear in the concentration range 1-10 mg/L. Preliminary in vitro studies using human hepatocytes failed to show any evidence of biotransformation of tiludronate. The elimination half-life in patients with normal renal function is approximately 40-60 h, but is significantly increased in subjects with severe renal impairment. The renal clearance (0.7 L/h) is independent of dose and suggests that glomerular filtration is the mechanism responsible for elimination. Approximately 50% of the absorbed dose is bound to bone and the rate of release of the drug from this site is limited by bone turnover. In vitro experiments indicate that tiludronate is not an enzyme inducer or inhibitor. Drug interaction studies with the nonsteroidal agents acetylsalicylic acid, indomethacin, and diclofenac indicate that only with indomethacin was there any change in the pharmacokinetic parameters, and that these changes were minimal and unlikely to be of clinical significance. Tiludronate does not influence the pharmacokinetics of digoxin at steady state. Tiludronate appears to exhibit similar pharmacokinetic behavior to other bisphosphonates with the exception that its absolute bioavailability is significantly higher than that previously reported for clodronate and pamidronate. The impact of its pharmacokinetic properties on clinical outcome has yet to be determined.

Gallium nitrate increases type I collagen and fibronectin mRNA and collagen protein levels in bone and fibroblast cells

Gallium is a Group IIIa transitional element with therapeutic efficacy in the treatment of metabolic bone disorders. Previously described antiresorptive effects of gallium on osteoclasts are not sufficient to account for the full range of effects of gallium on bone structure and metabolism. We have recently shown that gallium nitrate inhibits osteocalcin gene expression and the synthesis of osteocalcin protein, an osteoblast-specific bone matrix protein that is thought to serve as a signal to trigger osteoclastic resorption. Here we present evidence for an additional mechanism by which gallium may function to augment bone mass by altering matrix protein synthesis by osteoblastic and fibroblastic cells. Rat calvarial explants exposed to gallium nitrate for 48 h showed increased incorporation of 3H-proline into hydroxyproline and collagenase digestible protein. In addition, gallium treatment increased steady-state mRNA levels for fibronectin and type I procollagen chains in primary rat calvarial osteoblast-enriched cultures, the ROS 17/2.8 osteoblastic osteosarcoma line, and nontransformed human dermal fibroblasts. These findings suggest that the exposure of mesenchymally-derived cells to gallium results in an altered pattern of matrix protein synthesis that would favor increased bone formation.