Category Archives: Drugs

Simvastatin Intensifies Bone Formation and Decreases Resorption in Ovariectomized Rats

Abstract

Effects of simvastatin on the development of osteopenia caused by ovariectomy in rats.

Simvastatin is a competitive inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-determining enzyme for cholesterol synthesis which is used in the treatment of hypercholesterolemias, particularly in type IIa and IIb hyperlipoproteinemias, frequently in postmenopausal women. Inhibition of cholesterol synthesis by simvastatin may cause disorders of bone remodelling. The aim of the present study was to investigate the effects of simvastatin (3 mg and 6 mg/kg/day per os) administered for 4 weeks on the development of ovariectomy-induced osteopenia in 3-month-old female Wistar rats. The experiments were carried out on six groups of animals: I (C)–sham operated rats, II (S-3)–sham operated rats + simvastatin 3 mg/kg/day p.o., III (S-6)–sham operated rats + simvastatin 6 mg/kg/day p.o., IV (OVX)–ovariectomized rats, V (OVX + S-3)–ovariectomized rats + simvastatin 3 mg/kg/day p.o., VI (OVX + S-6)–ovariectomized rats + simvastatin 6 mg/kg/day p.o. In all the groups, we examined body weight gain, and macrometrical, histomorphometrical and mechanical parameters. Bilateral ovariectomy induced osteopenic skeletal changes in mature female rats. In cortical bone, ovariectomy intensified resorption processes at the marrow cavity, as indicated by a decrease in endosteal transverse growth and an increase in transverse cross-section surface area of the marrow cavity in the tibia. Intensification of resorption processes was observed in cancellous bone (a statistically significant decrease in the width of trabeculae in the epiphysis and metaphysis of the femur). Structural changes in the long bones resulting from bilateral ovariectomy were manifested by deterioration of mechanical properties of the shaft and neck of the femur. The force needed to fracture the neck and shaft of the femur was significantly smaller than that in sham operated rats. Simvastatin (3 and 6 mg/kg/day p.o.) slightly influenced bone remodelling in sham operated rats. Simvastatin (3 and 6 mg/kg p.o. daily) administered to ovariectomized rats intensified bone formation processes and decreased bone resorption processes induced by bilateral ovariectomy, showing stronger activity at 6 mg/kg.

Pytlik M, Janiec W, Misiarz-Myrta M, Gubała I
Pol J Pharmacol
PMID: 12856828 | Free Full Text

Video: Dr. Hofflich “Osteoporosis Update 2013” – Stein Institute for Research on Aging

Here is a nice talk by Dr. Heather Hofflich from May 15, 2013. She’s an Associate Professor of Medicine at UCSD. She gives an overview of osteoporosis and discusses the causes and therapies used to treat it. She also takes a look at recent controversies in treatment plans and vitamin usage.

One thing that bothers me about her talk is that she claims Teriparatide is the only thing in the world that builds bone by increasing osteoblast activity. I’ve posted many studies that found increases in osteoblasts from a variety of things. She also didn’t mention any other potentially helpful dietary supplements besides Calcium and Vitamin D. Like most MDs, she is probably unaware of anything that is not FDA approved.

Statins and Fish Oil Improve Lipid in Bones

Abstract

Statins and dietary fish oils improve lipid composition in bone marrow and joints.

There have been numerous efforts to alter the lipid content of cardiovascular tissues. Although equally important, only limited information is available about musculoskeletal tissues. I characterized joint and bone marrow lipids in patients having joint replacement surgery and explored the effects of fish oils and statins on lipid composition in bone marrow and joint fluid. Joint drainage catheters were used to collect marrow lipids from 84 patients having 128 hip and knee replacements for osteoarthritis, osteonecrosis, and femoral neck fractures (osteoporosis). Statins reduced the amount of lipid by 22% in patients with osteoporosis, 26% in patients with osteoarthritis, and 41% in patients with osteonecrosis compared with pretreatment lipid levels in the same patients. Taking fish oils reduced the amount of lipid in bone marrow by 20%. Lipid profiles of disturbed marrow and joint fluid from patients who took statins or dietary fish oil showed an increase in the proportion of unsaturated fatty acids and longer-chain fatty acids relative to pretreatment profiles. The ability to change the amount and character of bone and joint lipids may have major importance for strengthening bone, reducing the severity or preventing osteonecrosis, and enhancing joint lubrication.

Pritchett JW
Clin. Orthop. Relat. Res. Mar 2007
PMID: 17496750

Tocotrienol + Lovastatin Increases Bone Formation in Rats

Abstract

Effects of tocotrienol and lovastatin combination on osteoblast and osteoclast activity in estrogen-deficient osteoporosis.

Statins are HMGCoA reductase inhibitors and had been demonstrated to stimulate bone formation in rodents after high oral doses. Observational studies on patients treated with oral statins were varied. Delta-tocotrienol had been found to stimulate the cleavage of HMGCoA reductase and inhibit its activity. Tocotrienols were found to have both catabolic and anabolic effects on bone in different animal models of osteoporosis. The current study aimed to ascertain the effects of delta-tocotrienol and lovastatin combination on biochemical and static bone histomorphometric parameters in a postmenopausal rat model at clinically tolerable doses. 48 Sprague Dawley female rats were randomly divided into 6 groups: (1) baseline control group; (2) sham-operated control group; (3) ovariectomised control group; (4) ovariectomised and 11 mg/kg lovastatin; (5) ovariectomised and 60 mg/kg delta-tocotrienol; (6) ovariectomised and 60 mg/kg delta-tocotrienol + 11 mg/kg lovastatin. These treatments were given daily via oral gavage for 8 weeks. Delta-tocotrienol plus lovastatin treatment significantly increased bone formation and reduced bone resorption compared to the other groups. Therefore, the combined treatment may have synergistic or additive effects and have the potential to be used as an antiosteoporotic agent in patients who are at risk of both osteoporosis and hypercholesterolemia, especially in postmenopausal women.

Abdul-Majeed S, Mohamed N, Soelaiman IN
Evid Based Complement Alternat Med 2012
PMID: 22927884 | Free Full Text

Resveratrol + Enalapril Improves Microcirculation and Prevents Microfractures in Rats

Abstract

[Comparative evaluation of the osteoprotective effects of resveratrol and resveratrol/enalapril combination in the treatment of experimental osteoporosis].

The osteoprotective effect of resveratrol and a combination of resveratrol with enalapril has been investigated in white Wistar female rats with experimental osteoporosis. It is established that, in rats after ovariectomy, the endothelial dysfunction of microcirculation vessels of the osteal tissue is developed, resulting in the occurrence of osteoporosis. Resveratrol and the combination of resveratrol with enalapril prevented depression of the microcirculation level in the osteal tissue, thus preventing the thinning of osteal trabecules and preventing their microfractures.

Faĭtel’son AV, Koklina NIu, Gudyrev OS, Dubrovin GM…
Eksp Klin Farmakol 2012
PMID: 22834128

Hydrolyzed Collagen as Effective as Raloxifene in Mice

Abstract

Hydrolyzed collagen improves bone status and prevents bone loss in ovariectomized C3H/HeN mice.

This study evaluates the effect of hydrolyzed collagen (HC) on bone health of ovariectomized mice (OVX) at different ages. Twenty-six weeks after the OVX procedure, HC ingestion was still able to improve significantly bone mineral density (BMD) and some femur biomechanical parameters. Moreover, HC ingestion for 1 month before surgery prevented BMD decrease.
HC can play an important role in preserving BMD before osteoporosis appears. The aim of this study was to evaluate the effect of HC on bone health of ovariectomized mice at different ages.
Female C3H mice were either OVX at 3 or 6 months and fed for 6 months (first experiment) or 3 months (second experiment) with diet including 0, 10, or 25 g/kg of HC. In the second experiment, one group received HC 1 month before surgery, and two groups received the supplementation immediately after surgery, one fed ad libitum and the other by gavage. Mice treated with raloxifene were used as a positive control. BMD, femur intrinsic and extrinsic biomechanical properties, and type I collagen C-terminal telopeptide were measured after 12 and 26 weeks. Food intake and spontaneous physical activity were also recorded.
The OVX procedure increased body weight, while food intake decreased, thus suggesting that resting metabolism was decreased. Ingestion of 25 g/kg of HC for 3 or 6 months reduced bone loss significantly in, respectively, 3- and 6-month-old OVX mice. The lowest HC concentration was less efficient. HC ingestion for 3 months is as efficient as raloxifene to protect 3-month-old OVX mice from bone loss. Our results also demonstrated that HC ingestion before surgery prevented the BMD decreases.
This study confirms that dietary collagen reduces bone loss in OVX mice by increasing the diameter of the cortical areas of femurs and can have a preventive effect.

Guillerminet F, Fabien-Soulé V, Even PC, Tomé D…
Osteoporos Int Jul 2012
PMID: 21927918

Low Dose Aspirin May Increase Bone Resorption in Diabetic Mice

Abstract

Low dose aspirin therapy decreases blood glucose levels but does not prevent type i diabetes-induced bone loss.

Diabetes is strongly associated with increased fracture risk. During T1-diabetes onset, levels of blood glucose and pro-inflammatory cytokines (including TNFα) are increased. At the same time, levels of osteoblast markers are rapidly decreased and stay decreased 40 days later at which point bone loss is clearly evident. Inflammation is known to suppress bone formation and induce bone loss. Previous co-culture studies indicate that diabetic bone is inflamed and diabetic bone marrow is capable of enhancing osteoblast death in vitro. Here we investigate a commonly used non-steroidal anti-inflammatory drug, aspirin, to prevent T1-diabetic bone loss in vivo.
We induced diabetes in 16-week-old male C57BL/6 mice and administered aspirin in the drinking water.
Our results demonstrate that aspirin therapy reduced diabetic mouse non-fasting blood glucose levels to less than 400 mg/dl, but did not prevent trabecular and cortical bone loss. In control mice, aspirin treatment increased bone formation markers but did not affect markers of bone resorption or bone density/volume. In diabetic mice, bone formation markers and bone density/volume are decreased and unaltered by aspirin treatment. Bone resorption markers, however, are increased and 2-way ANOVA analysis demonstrates an interaction between aspirin treatment and diabetes (p<0.007). Aspirin treatment did not prevent the previously reported diabetes-induced marrow adiposity.
Taken together, our results suggest that low dose aspirin therapy does not negatively impact bone density in control and diabetic mice, but could potentially increase bone resorption in T1-diabetic mice.

Coe LM, Denison JD, McCabe LR
Cell. Physiol. Biochem. 2011
PMID: 22178944 | Free Full Text

Review: NSAIDs May Inhibit Bone Healing

Abstract

Do nonsteroidal anti-inflammatory drugs affect bone healing? A critical analysis.

Nonsteroidal anti-inflammatory drugs (NSAIDs) play an essential part in our approach to control pain in the posttraumatic setting. Over the last decades, several studies suggested that NSAIDs interfere with bone healing while others contradict these findings. Although their analgesic potency is well proven, clinicians remain puzzled over the potential safety issues. We have systematically reviewed the available literature, analyzing and presenting the available in vitro animal and clinical studies on this field. Our comprehensive review reveals the great diversity of the presented data in all groups of studies. Animal and in vitro studies present so conflicting data that even studies with identical parameters have opposing results. Basic science research defining the exact mechanism with which NSAIDs could interfere with bone cells and also the conduction of well-randomized prospective clinical trials are warranted. In the absence of robust clinical or scientific evidence, clinicians should treat NSAIDs as a risk factor for bone healing impairment, and their administration should be avoided in high-risk patients.

Pountos I, Georgouli T, Calori GM, Giannoudis PV
ScientificWorldJournal 2012
PMID: 22272177 | Free Full Text

Review: NSAIDs on Fracture Healing

Abstract

The effect of nonsteroidal anti-inflammatory drug administration on acute phase fracture-healing: a review.

The analgesic efficacy of nonsteroidal anti-inflammatory drugs (NSAIDs) is well established, and these agents often form an integral part of posttraumatic pain management. However, potentially deleterious effects of resulting prostaglandin suppression on fracture-healing have been suggested.
A systematic literature review involving searches of electronic databases and online sources was performed to identify articles exploring the influence of NSAIDs on fracture-healing.
A structured search approach identified 316 papers as potentially relevant to the topic, and these were manually reviewed. The majority described small-scale studies that were retrospective or observational in nature, with limited control of potentially confounding variables, or presented little key information that was not also present in other studies.
Although increasing evidence from animal studies suggests that cyclooxygenase-2 (COX-2) inhibition suppresses early fracture-healing, in vivo studies involving human subjects have not provided convincing evidence to substantiate this concern. We found no robust evidence to attest to a significant and appreciable patient detriment resulting from the short-term use of NSAIDs following a fracture. The balance of evidence in the available literature appears to suggest that a short-duration NSAID regimen is a safe and effective supplement to other modes of post-fracture pain control, without a significantly increased risk of sequelae related to disrupted healing.

Kurmis AP, Kurmis TP, O’Brien JX, Dalén T
J Bone Joint Surg Am May 2012
PMID: 22552671

Indomethacin Impares Fracture Healing in Mice

Abstract

Anti-inflammatory treatment increases angiogenesis during early fracture healing.

Both inflammation and angiogenesis are crucial for normal fracture healing. The goal of this work was to determine how anti-inflammatory treatment affects angiogenesis during early stages of fracture repair.
Tibia fractures were created in adult mice and animals were treated with indomethacin (2 mg/kg/day), a non-steroidal anti-inflammatory drug, or PBS once a day beginning from 1 day before fracture and continuing to 6 days after fracture. Animals were killed at 7, 14, and 28 days after injury for histomorphometric analysis of fracture healing. A second group of animals were killed at 3 and 7 days after injury to measure tissue levels of VEGF and interleukin-1 beta (IL-1β). A third group of animals were killed at 3 and 7 days after injury for stereology analysis of macrophage and neutrophil infiltration and tissue vascularization.
Indomethacin significantly decreased bone and cartilage formation at 7 days after fracture compared to controls. Indomethacin decreased the tissue levels of IL-1β at 3 days after fracture but did not affect the recruitment of macrophages or neutrophils to injured limbs. Indomethacin-treated fractures had similar length density and surface density of vasculature as the controls at 3 days after injury. At 7 days after fracture, vasculature in indomethacin-treated fractures exhibited higher length density and surface density than that in controls. By 28 days after injury, indomethacin-treated fractures still exhibited defects in fracture repair.
Anti-inflammatory treatments using indomethacin impair bone and cartilage formation and increase tissue vascularization in the callus during early fracture healing.

Lu C, Xing Z, Wang X, Mao J…
Arch Orthop Trauma Surg Aug 2012
PMID: 22622792