Bone Strength/Bone Mass Discrepancy in Glucocorticoid-Treated Adult Mice.

Glucocorticoids increase bone fragility in patients in a manner that is underestimated by bone mass measurement. This study aimed to determine if the adult mouse could model this bone strength/bone mass discrepancy. Forty-two 13-week-old BALB/cJ mice were randomized into vehicle and glucocorticoid groups, implanted with vehicle or 6-methylprednisolone pellets, and necropsied after 60 and 120 days.

Sequential Treatment of Estrogen Deficient, Osteopenic Rats with Alendronate, Parathyroid Hormone (1-34), or Raloxifene Alters Cortical Bone Mineral and Matrix Composition.

Anti-resorptive and anabolic treatments can be used sequentially to treat osteoporosis, but their effects on bone composition are incompletely understood. Osteocytes may influence bone tissue composition with sequential therapies because bisphosphonates diffuse into the canalicular network and anabolic treatments increase osteocyte lacunar size. Cortical bone composition of osteopenic, ovariectomized (OVX) rats was compared to that of Sham-operated rats and OVX rats given monotherapy or sequential regimens of single approved anti-osteoporosis medications.

Diet-induced Generalized Periodontitis in Lewis Rats.

Periodontitis is an important public health concern worldwide. Because rodents from the genus are resistant to spontaneous periodontitis, experimental periodontitis must be initiated by mechanical procedures and interventions. Due to their exacerbated Th1 response and imbalanced Th17 regulatory T-cell responses, Lewis rats are highly susceptible to inducible inflammatory and autoimmune diseases.

Zoledronate treatment duration is linked to bisphosphonate-related osteonecrosis of the jaw prevalence in rice rats with generalized periodontitis.

Objectives: To determine the extent that zoledronate (ZOL) dose and duration is associated with bisphosphonate-related osteonecrosis of the jaw (BRONJ) prevalence in rice rats with generalized periodontitis (PD), characterize structural and tissue-level features of BRONJ-like lesions in this model, and examine the specific anti-resorptive role of ZOL in BRONJ.

Materials And Methods: Rice rats (n = 228) consumed high sucrose-casein diet to enhance generalized PD. Groups of rats received 0, 8, 20, 50 or 125 µg/kg IV ZOL/4 weeks encompassing osteoporosis and oncology ZOL doses.

Prevalence of glucocorticoid induced osteonecrosis in the mouse is not affected by treatments that maintain bone vascularity.

Objective: Determine if LLP2A-Ale or PTH (1-34) affects the prevalence of glucocorticoid-induced osteonecrosis (ON) in a mouse model.

Methods: Eight-week-old young adult male BALB/cJ mice were weight-randomized into Control (Con), glucocorticoid (GC)-only, or concurrent treatments with GC and LLP2A-Ale (250 μg/kg or 500 μg/kg, IV, Days 1, 14, 28) or parathyroid hormone hPTH (1-34) (40 μg/kg, 5×/week). Mice were necropsied after 45 days for qualitative evaluation of prevalent ON and quantitative evaluation of vascularity in the distal femoral epiphysis (DFE); and quantitative evaluation of bone mass, microarchitecture, and strength in the distal femoral metaphysis and lumbar vertebral body.

Effect of osteoporosis treatment agents on the cortical bone osteocyte microenvironment in adult estrogen-deficient, osteopenic rats.

Though osteoporosis is a significant cause of disability worldwide, treatment with pharmacologic agents decreases risk of fragility fracture. Though these treatments act through the bone remodeling system to improve bone mass, it is unclear if they alter the response of bone to mechanical loading at the level of the osteocyte. This pre-clinical study determined the relationship between microstructural bone tissue properties and osteocyte lacunar size and density to strain around osteocytes with standard osteoporosis treatment or sequential therapies.

Odanacatib increases mineralized callus during fracture healing in a rabbit ulnar osteotomy model.

The effects of the cathepsin K inhibitor odanacatib (ODN) on fracture healing were monitored for ~6 and 15 weeks post-fracture in two separate studies using the unilateral transverse mid-ulnar osteotomy model in skeletally mature female rabbits. Rabbits were pre-treated for 3-4 weeks with vehicle (Veh), ODN (2 mg/kg, po, daily), or alendronate (ALN) (0.3 mg/kg, sc, twice-weekly) prior to osteotomy.

Breeding, husbandry, veterinary care, and hematology of marsh rice rats (Oryzomys palustris), a small animal model for periodontitis.

Rice rats (Oryzomys palustris) are a recognized animal model for studying periodontal disease and the photoperiodic regulation of reproduction. Here we share information regarding the breeding, husbandry, veterinary care, and hematologic findings about this animal species to facilitate its use in studies at other research institutions. Rice rats initially were quarantined and monitored for excluded pathogens by using microbiologic, parasitologic, and serologic methods with adult female Mus musculus and Rattus norvegicus sentinel animals.

Effect of sequential treatments with alendronate, parathyroid hormone (1-34) and raloxifene on cortical bone mass and strength in ovariectomized rats.

Unlabelled: Anti-resorptive and anabolic agents are often prescribed for the treatment of osteoporosis continuously or sequentially for many years. However their impact on cortical bone quality and bone strength is not clear.

Methods: Six-month old female rats were either sham operated or ovariectomized (OVX).

Cathepsin K inhibitors increase distal femoral bone mineral density in rapidly growing rabbits.

Background: Selective and reversible inhibitors of human Cathepsin K (CatK), including odanacatib (ODN), have been developed as potential therapeutics for the treatment of osteoporosis. Inhibitors of human CatK show significantly less potency for the rodent enzymes compared with that for the human or rabbit enzymes; thus the Schenk model in growing rabbit was developed as a screening assay for the in vivo activity of CatK inhibitors in blocking bone resorption.

Methods: In this study, the efficacy of the selective inhibitors L-833905, L-006235, L-873724, and L-1037536 (ODN) of human CatK in the rapidly growing rabbit 'Schenk' model (age seven weeks) was compared to vehicle, using the bisphosphonate, alendronate (ALN), as a positive control, to assess inhibition of bone resorption.

Oncologic doses of zoledronic acid induce osteonecrosis of the jaw-like lesions in rice rats (Oryzomys palustris) with periodontitis.

Though osteonecrosis of the jaw (ONJ) is temporally-associated with the use of nitrogen-containing bisphosphonates (N-BPs), a cause-and-effect relationship has not yet been established. We hypothesize that ONJ is a two-stage process in which: (1) risk factors initiate pathologic processes in the oral cavity that lead to a supranormal rate of hard tissue necrosis; and (2) powerful antiresorptives reduce the rate of removal of necrotic bone sufficiently to allow its net accumulation in the jaw. To test this hypothesis, we used the rice rat model of periodontitis.

Odanacatib treatment increases hip bone mass and cortical thickness by preserving endocortical bone formation and stimulating periosteal bone formation in the ovariectomized adult rhesus monkey.

Odanacatib (ODN) is a selective and reversible inhibitor of cathepsin K (CatK). Previously, ODN was shown to increase bone mineral density (BMD) and maintained normal bone strength at the spine in ovariectomized (OVX) rhesus monkeys. Here, we further characterize the effects of ODN on BMD, bone strength, and dynamic histomorphometric analyses of the hip from the same monkeys.

Odanacatib reduces bone turnover and increases bone mass in the lumbar spine of skeletally mature ovariectomized rhesus monkeys.

Odanacatib (ODN) is a selective and reversible inhibitor of cathepsin K (CatK) currently being developed as a once-weekly treatment for osteoporosis. In this study, we evaluated the effects of ODN on bone turnover, bone mineral density (BMD), and bone strength in the lumbar spine of estrogen-deficient, skeletally mature rhesus monkeys. Ovariectomized (OVX) monkeys were treated in prevention mode for 21 months with either vehicle, ODN 6 mg/kg, or ODN 30 mg/kg (p.

Cathepsin K inhibitors prevent bone loss in estrogen-deficient rabbits.

Two cathepsin K inhibitors (CatKIs) were compared with alendronate (ALN) for their effects on bone resorption and formation in ovariectomized (OVX) rabbits. The OVX model was validated by demonstrating significant loss (9.8% to 12.

Skeletal microstructural abnormalities in postmenopausal women with chronic obstructive pulmonary disease.

Chronic obstructive pulmonary disease (COPD) is associated with osteoporosis and fragility fractures. The objectives of this study were to assess static and dynamic indices of cancellous and cortical bone structure in postmenopausal women with COPD. Twenty women with COPD who had not received chronic oral glucocorticoids underwent bone biopsies after double tetracycline labeling.

Discovery of the selective androgen receptor modulator MK-0773 using a rational development strategy based on differential transcriptional requirements for androgenic anabolism versus reproductive physiology.

Selective androgen receptor modulators (SARMs) are androgen receptor (AR) ligands that induce anabolism while having reduced effects in reproductive tissues. In various experimental contexts SARMs fully activate, partially activate, or even antagonize the AR, but how these complex activities translate into tissue selectivity is not known. Here, we probed receptor function using >1000 synthetic AR ligands.

Identification of anabolic selective androgen receptor modulators with reduced activities in reproductive tissues and sebaceous glands.

Androgen replacement therapy is a promising strategy for the treatment of frailty; however, androgens pose risks for unwanted effects including virilization and hypertrophy of reproductive organs. Selective Androgen Receptor Modulators (SARMs) retain the anabolic properties of androgens in bone and muscle while having reduced effects in other tissues. We describe two structurally similar 4-aza-steroidal androgen receptor (AR) ligands, Cl-4AS-1, a full agonist, and TFM-4AS-1, which is a SARM.

Design, synthesis, and biological evaluation of 16-substituted 4-azasteroids as tissue-selective androgen receptor modulators (SARMs).

A novel series of 16-substituted-4-azasteroids has been identified as potential tissue-selective androgen receptor modulators. These ligands display potent hAR binding and agonist activity, low virilizing potential, and good pharmacokinetic profiles in dogs. On the basis of its in vitro profile, 21 was evaluated in the OVX and ORX rat models and exhibited an osteoanabolic, tissue-selective profile.

Identification of a nonbasic, nitrile-containing cathepsin K inhibitor (MK-1256) that is efficacious in a monkey model of osteoporosis.

Herein, we report on the identification of nonbasic, potent, and highly selective, nitrile-containing cathepsin K (Cat K) inhibitors that are built on our previously identified cyclohexanecarboxamide core structure. Subsequent to our initial investigations, we have found that incorporation of five-membered heterocycles as P2-P3 linkers allowed for the introduction of a methyl sulfone P3-substitutent that was not tolerated in inhibitors containing a six-membered aromatic P2-P3 linker. The combination of a five-membered N-methylpyrazole linker and a methyl sulfone in P3 yielded subnanomolar Cat K inhibitors that were minimally shifted (<10-fold) in our functional bone resorption assay.

Agonist-like SERM effects on ERalpha-mediated repression of MMP1 promoter activity predict in vivo effects on bone and uterus.

Estradiol receptors (ER), ERalpha and ERbeta, are ligand-dependent transcription factors that regulate gene expression. Human and murine genetics suggest that ERalpha is the key target for estradiol action on bone, uterus and breast. To date, the molecular mode of action of estradiol and selective estradiol receptor modulators (SERMs) on bone is not fully understood.

The discovery of odanacatib (MK-0822), a selective inhibitor of cathepsin K.

Odanacatib is a potent, selective, and neutral cathepsin K inhibitor which was developed to address the metabolic liabilities of the Cat K inhibitor L-873724. Substituting P1 and modifying the P2 side chain led to a metabolically robust inhibitor with a long half-life in preclinical species. Odanacatib was more selective in whole cell assays than the published Cat K inhibitors balicatib and relacatib.

Identification of a potent and selective non-basic cathepsin K inhibitor.

Based on our previous study with trifluoroethylamine as a P2-P3 amide isostere of cathepsin K inhibitor, further optimization led to identification of compound 22 (L-873724) as a potent and selective non-basic cathepsin K inhibitor. This compound showed excellent pharmacokinetics and efficacy in an ovariectomized (OVX) rhesus monkey model. The volumes of distribution close to unity were consistent with this compound not being lysosomotropic, which is a characteristic of basic cathepsin K inhibitors.

Design and synthesis of tri-ring P3 benzamide-containing aminonitriles as potent, selective, orally effective inhibitors of cathepsin K.

We have prepared a series of achiral aminoacetonitriles, bearing tri-ring benzamide moieties and an aminocyclohexanecarboxylate residue at P2. This combination of binding elements resulted in sub-250 pM, reversible, selective, and orally bioavailable cathepsin K inhibitors. Lead compounds displayed single digit nanomolar inhibition in vitro (of rabbit osteoclast-mediated degradation of bovine bone).

Estrogenic control of thermoregulation in ERalphaKO and ERbetaKO mice.

Objective: Estrogen is the most effective treatment for preventing the vasomotor symptoms in women. The ability of estrogen to control tail skin temperature (TST) in rats is used as an animal model for the studies of estrogens on menopausal hot flushes. Today, we know that estrogen can mediate its actions via the interaction with two different estrogen receptors: ERalpha and ERbeta.