Tag Archives: positive

Tetracyclines Prevent Bone Loss Induced by Inflammation

Abstract

Tetracyclines convert the osteoclastic-differentiation pathway of progenitor cells to produce dendritic cell-like cells.

Tetracyclines, such as doxycycline and minocycline, are used to suppress the growth of bacteria in patients with inflammatory diseases. Tetracyclines have been shown to prevent bone loss, but the mechanism involved is unknown. Osteoclasts and dendritic cells (DCs) are derived from common progenitors, such as bone marrow-derived macrophages (BMMs). In this article, we show that tetracyclines convert the differentiation pathway, resulting in DC-like cells not osteoclasts. Doxycycline and minocycline inhibited the receptor activator of NF-κB ligand (RANKL)-induced osteoclastogenesis of BMMs, but they had no effects on cell growth and phagocytic activity. They influenced neither the proliferation nor the differentiation of bone-forming osteoblasts. Surprisingly, doxycycline and minocycline induced the expression of DC markers, CD11c and CD86, in BMMs in the presence of RANKL. STAT5 is involved in DC differentiation induced by GM-CSF. Midostaurin, a STAT5-signaling inhibitor, and an anti-GM-CSF-neutralizing Ab suppressed the differentiation induced by GM-CSF but not by tetracyclines. In vivo, the injection of tetracyclines into RANKL-injected mice and RANKL-transgenic mice suppressed RANKL-induced osteoclastogenesis and promoted the concomitant appearance of CD11c(+) cells. These results suggested that tetracyclines prevent bone loss induced by local inflammation, including rheumatoid arthritis and periodontitis, through osteoclast-DC-like cell conversion.

Kinugawa S, Koide M, Kobayashi Y, Mizoguchi T…
J. Immunol. Feb 2012
PMID: 22250082 | Free Full Text

Minocycline Inhhibits Osteoclastogenesis in Mouse Cells

Abstract

Inhibitory effect of minocycline on osteoclastogenesis in mouse bone marrow cells.

To study the effects of minocycline hydrochloride (MINO) on the formation of tartrate-resistant acid phosphatase (TRAP) staining-positive multinucleated osteoclast-like cells in mouse bone marrow cells (BMCs) treated with 1α,25(OH)(2)D(3) or soluble receptor activator of nuclear factor-κB ligand (s-RANKL).
Mouse BMCs were cultured in alpha-modified minimum essential medium containing foetal calf serum (10%) and tetracyclines (2.5, 5 and 10μM), such as MINO, tetracycline hydrochloride (TC), oxytetracycline hydrochloride (OXT) or doxycycline (DOXY) in the presence of 1α,25(OH)(2)D(3) (10nM) or s-RANKL (20ng/ml) for 7 days, and the number of TRAP staining-positive osteoclast-like cells was counted. In RNA isolated from BMCs treated with 1α,25(OH)(2)D(3) or s-RANKL in the presence or absence of MINO, the expressions of osteoclast differentiation relating to mRNA were analysed by reverse transcription-polymerase chain reaction. Cell viability was examined in mouse BMCs and rabbit osteoclasts treated with MINO (0.25-20μM and 2-50μM, respectively) for 24h.
MINO, TC, OXT or DOXY inhibited 1α,25(OH)(2)D(3)-induced osteoclast-like cell formation in mouse BMCs dose dependently. MINO suppressed 1α,25(OH)(2)D(3)-induced up-regulation of mRNA expressions of TRAP, cathepsin K, carbonic anhydrase II, and calcitonin receptor, but not RANKL. MINO inhibited s-RANKL-induced osteoclast-like cell formation and up-regulation of mRNA expressions for nuclear factor of activated T-cells c1 (NFATc1), a key regulator of osteoclast differentiation; however, MINO had no effects on the viability of mouse BMCs and rabbit osteoclasts.
MINO inhibits RANKL-induced osteoclastogenesis via down-regulation of NFATc1 mRNA expression in osteoclast precursor cells.

Nagasawa T, Arai M, Togari A
Arch. Oral Biol. Sep 2011
PMID: 21377143

Minocycline Stimulates Bone Formation in Ovariectomized Rats

Abstract

Effect of minocycline on osteoporosis.

The effect of oral minocycline on osteopenia in ovariectomized (OVX) old rats was examined in this study. Rats were divided into 4 groups: sham-operated, OVX followed by treatment with vehicle, minocycline, or 17 beta-estradiol. The treatment was initiated one day after OVX and proceeded for 8 wks. OVX reduced bone mineral density (BMD) in the whole femur and in the femoral regions that are enriched in trabecular bone. Treatment with minocycline or estrogen prevented a decrease in BMD. Femoral trabecular bone area, trabecular number, and trabecular thickness were reduced, and trabecular separation was increased by OVX. Treatment with minocycline or estrogen abolished the detrimental effects induced by OVX. OVX also reduced indices that reflect the interconnectivity of trabecular bone, and the loss of trabecular connectivity was prevented by treatment with minocycline or estrogen. Based on the levels of urinary pyridinoline, we showed that the effect of estrogen, but not minocycline, was primarily through its inhibitory effect on bone resorption. Analysis of bone turnover activity suggests that OVX increased parameters associated with bone resorption (eroded surface) and formation (osteoid surface, mineralizing surface, mineral apposition rate, and bone formation rate). Treatment with minocycline reduced bone resorption modestly and stimulated bone formation substantially. In contrast, treatment with estrogen drastically reduced parameters associated with both bone resorption and formation. We have concluded that oral minocycline can effectively prevent the decrease in BMD and trabecular bone through its dual effects on bone resorption and formation.

Williams S, Wakisaka A, Zeng QQ, Barnes J…
Adv. Dent. Res. Nov 1998
PMID: 9972125

Palash Prevents Bone Loss and Stimulates Formation in Ovariectomized Rats

Abstract

Total extract and standardized fraction from the stem bark of Butea monosperma have osteoprotective action: evidence for the nonestrogenic osteogenic effect of the standardized fraction.

The aim of this study was to determine the skeletal effects of Butea total extract (BTE) and its acetone soluble fraction (ASF) from Butea monosperma, which is rich in methoxyisoflavones, in ovariectomized (OVx) rats, a model for postmenopausal bone loss.
BTE (1.0 g kg d) and ASF (100 mg kg d) were given orally for 12 weeks to adult OVx rats. The sham-operated and ovariectomy + vehicle groups served as controls. Bone mineral density, osteoid formation (mineral apposition rate and bone formation rate), bone microarchitecture, and bone turnover/resorption markers were studied. Phytoestrogens in rats given BTE and ASF were analyzed by high-performance liquid chromatography. One-way analysis of variance was used to test significance of effects.
OVx rats treated with either BTE or ASF exhibited increased bone mineral density in trabecular bones and improved trabecular microarchitecture compared with the ovariectomy + vehicle group. ASF treatment was more efficient than BTE treatment in maintaining trabecular microarchitecture. Serum osteocalcin and urinary type 1 collagen levels in OVx rats treated with either BTE or ASF were significantly lower than those of the ovariectomy + vehicle group. ASF treatment led to increased mineral apposition rate and bone formation rate compared with ovariectomy + vehicle, whereas BTE had no such effect. In the uterotropic assay, BTE was mildly estrogenic in adult OVx rats. In immature rats, BTE exhibited both estrogenicity and antiestrogenicity. ASF had neither uterine estrogenicity nor antiestrogenicity. Analysis of phytoestrogens revealed significant enrichment of cladrin, isoformononetin, and medicarpin in ASF over BTE.
Derived from B monosperma, ASF at a 10-fold lower dose than that of BTE was effective in preventing OVx-induced bone loss and stimulated new-bone formation.

Pandey R, Gautam AK, Bhargavan B, Trivedi R…
Menopause
PMID: 20395887

Palash Reduces Bone Loss in Ovariectomized Rats

Abstract

Greater Skeletal Gains in Ovary Intact Rats at Maturity Are Achieved by Supplementing a Standardized Extract of Butea monosperma Stem Bark that Confers Better Bone Conserving Effect following Ovariectomy and Concurrent Treatment Withdrawal.

With a longitudinally designed study, we tested whether an acetone soluble fraction (ASF) from the stem bark of Butea monosperma resulted in maximizing bone gain in rats during growth and maturation and thus protected against osteopenia following ovariectomy (OVx) with concomitant treatment withdrawal. Female rats at weaning were given ASF (100 mg/kg/d) or vehicle for 12 weeks, and baseline skeletal parameters (micro-CT) and total plasma antioxidant status (TAS) were measured. At this stage, one group was OVx and the other group was sham operated. Vehicle group (untreated) after OVx was given E2 or continued with vehicle (OVx control). ASF group after OVx was given vehicle (ASF withdrawn, ASFW). After another 12 weeks, all groups were killed and various skeletal parameters were determined. ASF resulted in substantially better skeletal parameters and higher plasma TAS over control at maturity. Rats treated with ASF before OVx had reduced rates of bone loss compared to OVx control. Twelve weeks after OVx, the ASFW group exhibited better trabecular microarchitectural preservation, bone turnover profiles, increased cortical deposition, and biomechanical strength over the OVx control, and the effects were comparable to OVx + E2 group. ASF supplementation during skeletal growth could maximize bone accrual and could confer increased resistance to post-OVx osteopenia despite treatment withdrawal.

Srivastava K, Khan K, Tyagi AM, Khan MP…
Evid Based Complement Alternat Med 2013
PMID: 23710224 | Free Full Text

O-methoxy substitutions of free phenolic hydroxyl groups of the most abundant soy isoflavones (genistein and daidzein) enhance the lipophilicity, metabolic stability, and uterine safety, thus improving pharmacokinetic/metabolic stability profiles of genistein and daidzein and, consequently, enhance the pharmacodynamic effect (in vivo potency) [12, 13]. In our phytopharmacological evaluation program, aimed at discovering effective alternative strategy for reducing the risk of developing postmenopausal osteopenia, we showed that a standardized fraction (an acetone soluble fraction, ASF) made from the stem bark of Butea monosperma contained four methoxyisoflavones: cajanin (7-methoxy genistein), medicarpin (a methoxypterocarpan with cyclized genistein ring structure), isoformononetin (7-methoxy daidzein), and cladrin (3′4,-dimethoxy daidzein) at percent concentration of 0.061, 0.019, 0.007, and 0.003, respectively [14]. Each one of these, when administered to female rats for four weeks after weaning resulted in increased BMD, bone strength, and bone formation rate with varying efficacy. In vitro, all four compounds stimulated osteoblast function more potently than genistein and daidzein by different modes of action [15–17]. These observations prompted us to hypothesize that the presence of these methoxyisoflavones in the ASF could synergistically augment peak bone mass accrual in female rats at maturity that will confer a superior bone conserving ability after surgical menopause (due to ovariectomy, OVx) even as the treatment is withdrawn.

Minocycline Increases Bone Density in Ovariectomized Rats

Abstract

Treatment of osteoporosis with MMP inhibitors.

In the current study, we examined the effects of minocycline on the osteopenia of ovariectomized (OVX) aged rats using the marrow ablation model. This injury induces rapid bone formation followed by bone resorption in the marrow cavity. Old female rats were randomly divided into five groups: sham, OVX, OVX + minocycline (5-15 mg/day, orally), OVX + 17 beta-estradiol (25 micrograms/day, subcutaneously), and OVX + both agents. Rats were OVX, treated with minocycline and/or estrogen, followed by marrow ablation. Bone samples were collected 16 days post-marrow ablation. X-ray radiography of bones operated on showed that treatment of OVX old rats with minocycline increased bone mass in diaphyseal region. Diaphyseal bone mineral density (BMD) was measured by DEXA scan. Diaphyseal BMD of OVX rats was increased 17-25% by treatment with 5-15 mg of minocycline or 17 beta-estradiol. The effects of minocycline and estrogen treatments on the expression of osteoblast and osteoclast markers were also examined. Northern and dot blot analysis of RNA samples showed that treatment of OVX aged rats with minocycline increased the expression of type I collagen (COL I) (49%) and decreased that of interleukin-6 (IL-6) (31%). In contrast, estrogen treatment decreased the expression of interleukin-6 (IL-6) (39%), carbonic anhydrase II (CA II) (36%), and osteopontin (OP) (37%). Neither minocycline nor 17 beta-estradiol had an effect on the expression of osteocalcin (OC) and alkaline phosphatase (AP). To elucidate the mechanism by which minocycline prevented the loss of bone in OVX aged rats, we examined the colony-formation potential of bone marrow stromal cells in ex vivo cultures. Minocycline stimulated the colony-forming efficiency of marrow stromal cells derived from old animals. We have therefore concluded that the modest increase in BMD noted in OVX aged rats, in response to minocycline treatment, may be due to a change in bone remodeling that favors bone formation; and the anabolic effect of minocycline is likely due to its effect on the expression of COL I and/or the metabolism of osteoprogenitor cells.

Williams S, Barnes J, Wakisaka A, Ogasa H…
Ann. N. Y. Acad. Sci. Jun 1999
PMID: 10415730

Virtual Reality Training Improves Balance in Older Adults

Abstract

Effects of balance training using a virtual-reality system in older fallers.

Poor balance is considered a challenging risk factor for falls in older adults. Therefore, innovative interventions for balance improvement in this population are greatly needed. The aim of this study was to evaluate the effect of a new virtual-reality system (the Balance Rehabilitation Unit [BRU]) on balance, falls, and fear of falling in a population of community-dwelling older subjects with a known history of falls. In this study, 60 community-dwelling older subjects were recruited after being diagnosed with poor balance at the Falls and Fractures Clinic, Nepean Hospital (Penrith, NSW, Australia). Subjects were randomly assigned to either the BRU-training or control groups. Both groups received the usual falls prevention care. The BRU-training group attended balance training (two sessions/week for 6 weeks) using an established protocol. Change in balance parameters was assessed in the BRU-training group at the end of their 6-week training program. Both groups were assessed 9 months after their initial assessment (month 0). Adherence to the BRU-training program was 97%. Balance parameters were significantly improved in the BRU-training group (P < 0.01). This effect was also associated with a significant reduction in falls and lower levels of fear of falling (P < 0.01). Some components of balance that were improved by BRU training showed a decline after 9 months post-training. In conclusion, BRU training is an effective and well-accepted intervention to improve balance, increase confidence, and prevent falls in the elderly.

Duque G, Boersma D, Loza-Diaz G, Hassan S…
Clin Interv Aging 2013
PMID: 23467506 | Free Full Text

Teriparatide Stimulates Bone Formation and Resorption, and Decreases Fracture Risk

Abstract

Effect of parathyroid hormone (1-34) on fractures and bone mineral density in postmenopausal women with osteoporosis.

Once-daily injections of parathyroid hormone or its amino-terminal fragments increase bone formation and bone mass without causing hypercalcemia, but their effects on fractures are unknown.
We randomly assigned 1637 postmenopausal women with prior vertebral fractures to receive 20 or 40 microg of parathyroid hormone (1-34) or placebo, administered subcutaneously by the women daily. We obtained vertebral radiographs at base line and at the end of the study (median duration of observation, 21 months) and performed serial measurements of bone mass by dual-energy x-ray absorptiometry.
New vertebral fractures occurred in 14 percent of the women in the placebo group and in 5 percent and 4 percent, respectively, of the women in the 20-microg and 40-microg parathyroid hormone groups; the respective relative risks of fracture in the 20-microg and 40-microg groups, as compared with the placebo group, were 0.35 and 0.31 (95 percent confidence intervals, 0.22 to 0.55 and 0.19 to 0.50). New nonvertebral fragility fractures occurred in 6 percent of the women in the placebo group and in 3 percent of those in each parathyroid hormone group (relative risk, 0.47 and 0.46, respectively [95 percent confidence intervals, 0.25 to 0.88 and 0.25 to 0.861). As compared with placebo, the 20-microg and 40-microg doses of parathyroid hormone increased bone mineral density by 9 and 13 more percentage points in the lumbar spine and by 3 and 6 more percentage points in the femoral neck; the 40-microg dose decreased bone mineral density at the shaft of the radius by 2 more percentage points. Both doses increased total-body bone mineral by 2 to 4 more percentage points than did placebo. Parathyroid hormone had only minor side effects (occasional nausea and headache).
Treatment of postmenopausal osteoporosis with parathyroid hormone (1-34) decreases the risk of vertebral and nonvertebral fractures; increases vertebral, femoral, and total-body bone mineral density; and is well tolerated. The 40-microg dose increased bone mineral density more than the 20-microg dose but had similar effects on the risk of fracture and was more likely to have side effects.

Neer RM, Arnaud CD, Zanchetta JR, Prince R…
N. Engl. J. Med. May 2001
PMID: 11346808 | Free Full Text

Parathyroid hormone stimulates bone formation and resorption and can increase or decrease bone mass, depending on the mode of administration. Continuous infusions and daily subcutaneous injections of parathyroid hormone stimulate bone formation similarly but have different effects on bone resorption and bone mass.1,2 Continuous infusions, which result in a persistent elevation of the serum parathyroid hormone concentration, lead to greater bone resorption than do daily injections, which cause only transient increases in the serum parathyroid hormone concentration.3

Orange Improves Bone in Orchidectomized Rats

Abstract

Feeding orange pulp improved bone quality in a rat model of male osteoporosis.

Oxidative stress and inflammation have been linked to bone loss. We evaluated the effects of feeding orange pulp (OP), a source of vitamin C and flavonoids, on bone quality in a rat model of male osteoporosis. One-year-old retired breeder rats (n = 43) were orchidectomized (ORX) or sham-operated (SHAM). Three days postsurgery, ORX rats were randomly assigned to treatments: ORX or ORX with 2.5% OP, 5% OP, or 10% OP. Diets were isonitrogenous, isocaloric, modified AIN-93M diets with equal fiber content. All ORX rats were fed for 4 months to the mean food intake of the SHAM group. At the end of the study blood, urine and bone samples were collected. Plasma antioxidant capacity and urinary deoxypyridinoline (DPD) were determined. Bone density, structure, and strength were assessed using dual energy X-ray absorptiometry, microcomputed tomography, and finite element analyses. ORX decreased (P < .05) antioxidant status, while OP as low as 2.5% maintained the antioxidant capacity of ORX rats comparable to that of the SHAM group. Cortical thickness at the tibial midshaft was significantly decreased by ORX and increased by OP, and urinary DPD was significantly increased by ORX and decreased by OP. In fourth lumbar trabecular cores, ORX rats had significantly reduced bone volume fraction, connectivity density, and trabecular number and increased trabecular separation. OP significantly increased bone volume fraction and trabecular number and decreased trabecular separation in ORX rats. Improvements due to OP in microarchitectural properties of vertebral bones and in cortical thickness of long bones were subtle but significant. The consistently negative impacts of ORX on bone density, structure, and strength parameters confirm the previously reported importance of testosterone for bone.

Morrow R, Deyhim F, Patil BS, Stoecker BJ
J Med Food Apr 2009
PMID: 19459729

Grapefruit Improves Bone Quality in Orchidectomized Rats Again

Abstract

Grapefruit juice modulates bone quality in rats.

Hypogonadism and oxidative stress increase the risk for developing osteoporosis. The objective of this research was to evaluate the efficacy of drinking grapefruit juice on bone quality in orchidectomized (ORX) and non-ORX rats. Fifty-six 90-day-old male Sprague-Dawley rats were equally divided into four groups–non-ORX rats (sham), sham + grapefruit juice, ORX, and ORX + grapefruit juice–and treated for 60 days. Thereafter, all rats were sacrificed to determine the plasma antioxidant status, insulin-like growth factor I (IGF-I), and indices of bone turnover, bone quality, and calcium and magnesium concentrations in the bone, urine, and feces. Orchidectomy decreased (P < .05) antioxidant status, bone quality, and bone mineral contents and increased (P < .05) indices of bone turnover, urinary deoxypridinoline, calcium, and magnesium, and fecal calcium excretions. In contrast to the ORX group, ORX rats that drank grapefruit juice had an increase (P < .05) in antioxidant status, bone density, and bone mineral contents, delayed femoral fracture, and slowed down (P < .05) bone turnover rate and tended to have a decrease (P = .08) in urinary deoxypridinoline. In sham-treated animals, drinking grapefruit juice increased (P < .05) bone density and tended to increase the femoral strength. The concentration of IGF-I in the plasma was not affected across treatments. In conclusion, drinking grapefruit juice positively affected bone quality by enhancing bone mineral deposition in ORX rats and by improving bone density in non-ORX rats via an undefined mechanism.

Deyhim F, Mandadi K, Faraji B, Patil BS
J Med Food Mar 2008
PMID: 18361744